@article {1773891,
	title = {Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle},
	journal = {Sci Robot},
	volume = {8},
	number = {76},
	year = {2023},
	month = {2023 Mar 22},
	pages = {eadd9369},
	abstract = {Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.},
	keywords = {Animals, Anti-Inflammatory Agents, Mice, Muscle, Skeletal, Regeneration, Robotics},
	issn = {2470-9476},
	doi = {10.1126/scirobotics.add9369},
	author = {McNamara, S L and Seo, B R and Freedman, B R and Roloson, E B and Alvarez, J T and O{\textquoteright}Neill, C T and Vandenburgh, H H and C.J. Walsh and Mooney, D J}
}
@article {1773866,
	title = {High-Throughput Screening of Thiol-ene Click Chemistries for Bone Adhesive Polymers},
	journal = {ACS Appl Mater Interfaces},
	year = {2023},
	month = {2023 Oct 31},
	abstract = {Metal surgical pins and screws are employed in millions of orthopedic surgical procedures every year worldwide, but their usability is limited in the case of complex, comminuted fractures or in surgeries on smaller bones. Therefore, replacing such implants with a bone adhesive material has long been considered an attractive option. However, synthesizing a biocompatible bone adhesive with a high bond strength that is simple to apply presents many challenges. To rapidly identify candidate polymers for a biocompatible bone adhesive, we employed a high-throughput screening strategy to assess human mesenchymal stromal cell (hMSC) adhesion toward a library of polymers synthesized via thiol-ene click chemistry. We chose thiol-ene click chemistry because multifunctional monomers can be rapidly cured via ultraviolet (UV) light while minimizing residual monomer, and it provides a scalable manufacturing process for candidate polymers identified from a high-throughput screen. This screening methodology identified a copolymer (1-S2-FT01) composed of the monomers 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TATATO) and pentaerythritol tetrakis (3-mercaptopropionate) (PETMP), which supported highest hMSC adhesion across a library of 90 polymers. The identified copolymer (1-S2-FT01) exhibited favorable compressive and tensile properties compared to existing commercial bone adhesives and adhered to bone with adhesion strengths similar to commercially available bone glues such as Histoacryl. Furthermore, this cytocompatible polymer supported osteogenic differentiation of hMSCs and could adhere 3D porous polymer scaffolds to the bone tissue, making this polymer an ideal candidate as an alternative bone adhesive with broad utility in orthopedic surgery.},
	issn = {1944-8252},
	doi = {10.1021/acsami.3c12072},
	author = {Ganabady, Kavya and Contessi Negrini, Nicola and Scherba, Jacob C and Nitschke, Brandon M and Alexander, Morgan R and Vining, Kyle H and Grunlan, Melissa A and Mooney, David J and Celiz, Adam D}
}
@article {1773871,
	title = {Multifunctional magnetic nanoparticles elicit anti-tumor immunity in a mouse melanoma model},
	journal = {Mater Today Bio},
	volume = {23},
	year = {2023},
	month = {2023 Dec},
	pages = {100817},
	abstract = {Immunotherapy has emerged as a promising strategy to eradicate cancer cells. Particularly, the development of cancer vaccines to induce a potent and sustained antigen-specific T cell response has become a center of attention. Herein, we describe a novel immunotherapy based on magnetic nanoparticles (MNP) covalently modified with the OVA254-267 antigen and a CpG oligonucleotide via disulfide bonds. The MNP-CpG-COVA significantly enhances dendritic cell activation and CD8+ T cell antitumoral response against B16-OVA melanoma cells in vitro. Notably, the immune response induced by the covalently modified MNP is more potent and sustained over time than that triggered by the free components, highlighting the advantage of nanoformulations in immunotherapies. What is more, the nanoparticles are stable in the blood after in vivo administration and induce potent levels of systemic tumor-specific effector CD8 + T cells. Overall, our findings highlight the potential of covalently functionalized MNP to induce robust immune responses against mouse melanoma.},
	issn = {2590-0064},
	doi = {10.1016/j.mtbio.2023.100817},
	author = {Lafuente-G{\'o}mez, Nuria and de L{\'a}zaro, Irene and Dhanjani, M{\'o}nica and Garc{\'\i}a-Soriano, David and Sobral, Miguel C and Salas, Gorka and Mooney, David J and Somoza, {\'A}lvaro}
}
@article {1773876,
	title = {SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Aug 07},
	abstract = {Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20\% of hospitalized patients are at risk for thromboembolic events 1 . This prothrombotic state is considered a key factor in the increased risk of stroke, which has been observed clinically during both acute infection and long after symptoms have cleared 2 . Here we developed a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells, pericytes, and smooth muscle cells to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly smooth muscle cells (SMCs), are a specifically susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterized the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, and endothelial cells (ECs). We observed that infected human SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we showed human ECs exposed to the secretome of infected SMCs produce hemostatic factors that can contribute to vascular dysfunction, despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level.},
	doi = {10.1101/2023.08.06.552160},
	author = {Richards, Alexsia and Khalil, Andrew and Max Friesen and Whitfield, Troy W and Tenzin Lungjangwa and Gehrke, Lee and Mooney, David and Jaenisch, Rudolf}
}
@article {1741851,
	title = {Adoptive T cell transfer and host antigen-presenting cell recruitment with cryogel scaffolds promotes long-term protection against solid tumors},
	journal = {Nat Commun},
	volume = {14},
	number = {1},
	year = {2023},
	month = {2023 Jun 15},
	pages = {3546},
	abstract = {Although adoptive T cell therapy provides the T cell pool needed for immediate tumor debulking, the infused T cells generally have a narrow repertoire for antigen recognition and limited ability for long-term protection. Here, we present a hydrogel that locally delivers adoptively transferred T cells to the tumor site while recruiting and activating host antigen-presenting cells with GMCSF or FLT3L and CpG, respectively. T cells alone loaded into these localized cell depots provided significantly better control of subcutaneous B16-F10 tumors than T cells delivered through direct peritumoral injection or intravenous infusion. T cell delivery combined with biomaterial-driven accumulation and activation of host immune cells prolonged the activation of the delivered T cells, minimized host T cell exhaustion, and enabled long-term tumor control. These findings highlight how this integrated approach provide both immediate tumor debulking and long-term protection against solid tumors, including against tumor antigen escape.},
	keywords = {Antigen-Presenting Cells, Cryogels, Humans, Immunotherapy, Adoptive, Neoplasms, T-Lymphocytes},
	issn = {2041-1723},
	doi = {10.1038/s41467-023-39330-7},
	author = {Adu-Berchie, Kwasi and Brockman, Joshua M and Liu, Yutong and To, Tania W and Zhang, David K Y and Najibi, Alexander J and Binenbaum, Yoav and Stafford, Alexander and Dimitrakakis, Nikolaos and Sobral, Miguel C and Dellacherie, Maxence O and Mooney, David J}
}
@article {1741861,
	title = {Aging and injury affect nuclear shape heterogeneity in tendon},
	journal = {J Orthop Res},
	year = {2023},
	month = {2023 Jun 14},
	abstract = {Tissue level properties are commonly studied using histological stains assessed with qualitative scoring methods. As qualitative evaluation is typically insensitive, quantitative analysis provides additional information about pathological mechanisms, but cannot capture structural heterogeneity across cell subpopulations. However, molecular analyses of cell and nuclear behavior have identified that cell and more recently also nuclear shape are highly associated with cell function and malfunction. This study combined a Visually Aided Morpho-Phenotyping Image Recognition analysis that automatically segments cells based on their shape with an added capacity to further discriminate between cells in certain protein-rich extracellular matrix regions. We used tendon as a model system given the enormous changes in organization and cell and nuclear shape they undergo during aging and injury. Our results uncover that multiple shape modes of nuclei exist during maturity and aging in rat tendon and that distinct subgroups of cell nuclei shapes exist in proteoglycan-rich regions during aging. With injury, several immunomarkers (αSMA, CD31, CD146) were associated with more rounded shape modes. In human tendons, the cell nuclei at sites of injury were found to be more rounded relative to uninjured tissues. To conclude, the tendon tissue changes occurring during aging and injury could be associated with a variation in cell nuclear morphology and the appearance of various region-specific subpopulations. Thus, the methodologies developed allow for a deeper understanding of cell heterogeneity during tendon aging and injury and may be extended to study further clinical applications.},
	issn = {1554-527X},
	doi = {10.1002/jor.25649},
	author = {Tinguely, Yann and Shi, Vivian and Klatte-Schulz, Franka and Duda, Georg N and Freedman, Benjamin R and Mooney, David J}
}
@article {1741856,
	title = {Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix},
	journal = {Nat Biomed Eng},
	year = {2023},
	month = {2023 Jun 26},
	abstract = {The efficacy of adoptive T-cell therapies largely depends on the generation of T-cell populations that provide rapid effector function and long-term protective immunity. Yet it is becoming clearer that the phenotypes and functions of T cells are inherently linked to their localization in tissues. Here we show that functionally distinct T-cell populations can be generated from T cells that received the same stimulation by altering the viscoelasticity of their surrounding extracellular matrix (ECM). By using a model ECM based on a norbornene-modified collagen type I whose viscoelasticity can be adjusted independently from its bulk stiffness by varying the degree of covalent crosslinking via a bioorthogonal click reaction with tetrazine moieties, we show that ECM viscoelasticity regulates T-cell phenotype and function via the activator-protein-1 signalling pathway, a critical regulator of T-cell activation and fate. Our observations are consistent with the tissue-dependent gene-expression profiles of T cells isolated from mechanically distinct tissues from patients with cancer or fibrosis, and suggest that matrix viscoelasticity could be leveraged when generating T-cell products for therapeutic applications.},
	issn = {2157-846X},
	doi = {10.1038/s41551-023-01052-y},
	author = {Adu-Berchie, Kwasi and Liu, Yutong and Zhang, David K Y and Freedman, Benjamin R and Brockman, Joshua M and Vining, Kyle H and Nerger, Bryan A and Garmilla, Andrea and Mooney, David J}
}
@article {1701216,
	title = {Breakthrough treatments for accelerated wound healing},
	journal = {Sci Adv},
	volume = {9},
	number = {20},
	year = {2023},
	month = {2023 May 19},
	pages = {eade7007},
	abstract = {Skin injuries across the body continue to disrupt everyday life for millions of patients and result in prolonged hospital stays, infection, and death. Advances in wound healing devices have improved clinical practice but have mainly focused on treating macroscale healing versus underlying microscale pathophysiology. Consensus is lacking on optimal treatment strategies using a spectrum of wound healing products, which has motivated the design of new therapies. We summarize advances in the development of novel drug, biologic products, and biomaterial therapies for wound healing for marketed therapies and those in clinical trials. We also share perspectives for successful and accelerated translation of novel integrated therapies for wound healing.},
	keywords = {Biocompatible Materials, Humans, Wound Healing},
	issn = {2375-2548},
	doi = {10.1126/sciadv.ade7007},
	author = {Freedman, Benjamin R and Hwang, Charles and Simon Talbot and Hibler, Brian and Matoori, Simon and Mooney, David J}
}
@article {1701226,
	title = {Hydrogel viscoelasticity modulates migration and fusion of mesenchymal stem cell spheroids},
	journal = {Bioeng Transl Med},
	volume = {8},
	number = {3},
	year = {2023},
	month = {2023 May},
	pages = {e10464},
	abstract = {Multicellular spheroids made of stem cells can act as building blocks that fuse to capture complex aspects of native in vivo environments, but the effect of hydrogel viscoelasticity on cell migration from spheroids and their fusion remains largely unknown. Here, we investigated the effect of viscoelasticity on migration and fusion behavior of mesenchymal stem cell (MSC) spheroids using hydrogels with a similar elasticity but different stress relaxation profiles. Fast relaxing (FR) matrices were found to be significantly more permissive to cell migration and consequent fusion of MSC spheroids. Mechanistically, inhibition of ROCK and Rac1 pathways prevented cell migration. Moreover, the combination of biophysical and biochemical cues provided by fast relaxing hydrogels and platelet-derived growth factor (PDGF) supplementation, respectively, resulted in a synergistic enhancement of migration and fusion. Overall, these findings emphasize the important role of matrix viscoelasticity in tissue engineering and regenerative medicine strategies based on spheroids.},
	issn = {2380-6761},
	doi = {10.1002/btm2.10464},
	author = {Wu, David T and Diba, Mani and Yang, Stephanie and Freedman, Benjamin R and Elosegui-Artola, Alberto and Mooney, David J}
}
@article {1701231,
	title = {Microporogen-Structured Collagen Matrices for Embedded Bioprinting of Tumor Models for Immuno-Oncology},
	journal = {Adv Mater},
	volume = {35},
	number = {33},
	year = {2023},
	month = {2023 Aug},
	pages = {e2210748},
	abstract = {Embedded bioprinting enables the rapid design and fabrication of complex tissues that recapitulate in vivo microenvironments. However, few biological matrices enable good print fidelity, while simultaneously facilitate cell viability, proliferation, and migration. Here, a new microporogen-structured ({\textmu}POROS) matrix for embedded bioprinting is introduced, in which matrix rheology, printing behavior, and porosity are tailored by adding sacrificial microparticles composed of a gelatin-chitosan complex to a prepolymer collagen solution. To demonstrate its utility, a 3D tumor model is created via embedded printing of a murine melanoma cell ink within the {\textmu}POROS collagen matrix at 4 {\textdegree}C. The collagen matrix is subsequently crosslinked around the microparticles upon warming to 21~{\textdegree}C, followed by their melting and removal at 37~{\textdegree}C. This process results in a {\textmu}POROS matrix with a fibrillar collagen type-I network akin to that observed in vivo. Printed tumor cells remain viable and proliferate, while antigen-specific cytotoxic T cells incorporated in the matrix migrate to the tumor site, where they induce cell death. The integration of the {\textmu}POROS matrix with embedded bioprinting opens new avenues for creating complex tissue microenvironments in vitro that may find widespread use in drug discovery, disease modeling, and tissue engineering for therapeutic use.},
	keywords = {Animals, Bioprinting, Collagen, Gelatin, Hydrogels, Mice, Neoplasms, Printing, Three-Dimensional, Tissue Engineering, Tissue Scaffolds, Tumor Microenvironment},
	issn = {1521-4095},
	doi = {10.1002/adma.202210748},
	author = {Reynolds, Daniel S and de L{\'a}zaro, Irene and Blache, Manon L and Liu, Yutong and Jeffreys, Nicholas C and Doolittle, Ramsey M and Grandidier, Est{\'e}e and Olszewski, Jason and Dacus, Mason T and Mooney, David J and Lewis, Jennifer A.}
}
@article {1701221,
	title = {T cell development and function},
	journal = {Rejuvenation Res},
	year = {2023},
	month = {2023 May 08},
	abstract = {T cells play critical roles in the immune system, including in responses to cancer, autoimmunity and tissue regeneration. T cells arise from common lymphoid progenitors (CLPs) which differentiate from hematopoietic stem cells (HSCs) in the bone marrow. CLPs then traffic to the thymus, where they undergo thymopoiesis via a number of selection steps, resulting in mature single positive na{\"\i}ve CD4 helper or CD8 cytotoxic T cells. Na{\"\i}ve T cells home to secondary lymphoid organs like lymph nodes and are primed by antigen presenting cells (APCs), which scavenge for both foreign and self-antigens. Effector T cell function is multi-faceted, including direct target cell lysis and secretion of cytokines which regulate the functions of other immune cells (refer to Graphical Abstract). This review will discuss T cell development and function, from the development of lymphoid progenitors in the bone marrow to principles that govern T cell effector function and dysfunction, specifically within the context of cancer.},
	issn = {1557-8577},
	doi = {10.1089/rej.2023.0015},
	author = {Adu-Berchie, Kwasi and Obuseh, Favour O and Mooney, David J}
}
@article {1690151,
	title = {Conductive Hydrogel Scaffolds for the 3D Localization and Orientation of Fibroblasts},
	journal = {Macromol Biosci},
	year = {2023},
	month = {2023 Apr 05},
	pages = {e2300044},
	abstract = {Dermal wounds and their healing are a collection of complex, multistep processes which are poorly recapitulated by existing 2D in vitro platforms. Biomaterial scaffolds that support the 3D growth of cell cultures can better resemble the native dermal environment, while bioelectronics has been used as a tool to modulate cell proliferation, differentiation, and migration. A porous conductive hydrogel scaffold which mimics the properties of dermis, while promoting the viability and growth of fibroblasts is described. As these scaffolds are also electrically conductive, the application of exogenous electrical stimulation directs the migration of cells across and/or through the material. The mechanical properties of the scaffold, as well as the amplitude and/or duration of the electrical pulses, are independently tunable and further influence the resulting fibroblast networks. This biomaterial platform may enable better recapitulation of wound healing and can be utilized to develop and screen therapeutic interventions.},
	issn = {1616-5195},
	doi = {10.1002/mabi.202300044},
	author = {Tringides, Christina M and Mooney, David J}
}
@article {1690146,
	title = {Enhancing CAR-T cell functionality in a patient-specific manner},
	journal = {Nat Commun},
	volume = {14},
	number = {1},
	year = {2023},
	month = {2023 Jan 31},
	pages = {506},
	abstract = {Patient responses to autologous CD19 chimeric antigen receptor (CAR) T-cell therapies are limited by insufficient and inconsistent cellular functionality. Here, we show that controlling the precise level of stimulation during T-cell activation to accommodate individual differences in the donor cells will dictate the functional attributes of CAR-T cell products. The functionality of CAR-T cell products, consisting of a diverse set of blood samples derived from healthy donors, acute lymphoblastic leukemia (ALL), and chronic lymphocytic lymphoma (CLL) patient samples, representing a range of patient health status, is tested upon culturing on artificial antigen-presenting cell scaffolds to deliver T-cell stimulatory ligands (anti-CD3/anti-CD28) at highly defined densities. A clear relationship is observed between the dose of stimulation, the phenotype of the T-cell blood sample prior to T-cell activation, and the functionality of the~resulting CAR-T cell products. We present a model, based on this dataset, that predicts the precise stimulation needed to manufacture a desired CAR-T cell product, given the input T-cell attributes in the initial blood sample. These findings demonstrate a simple approach to enhance CAR-T functionality by personalizing the level of stimulation during T-cell activation to enable flexible manufacturing of more consistent and potent CAR-T cells.},
	keywords = {Antigen-Presenting Cells, Antigens, CD19, Humans, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, T-Lymphocytes},
	issn = {2041-1723},
	doi = {10.1038/s41467-023-36126-7},
	author = {Zhang, David K Y and Adu-Berchie, Kwasi and Iyer, Siddharth and Liu, Yutong and Cieri, Nicoletta and Brockman, Joshua M and Neuberg, Donna and Wu, Catherine J and Mooney, David J}
}
@article {1690141,
	title = {Immune-responsive biodegradable scaffolds for enhancing neutrophil regeneration},
	journal = {Bioeng Transl Med},
	volume = {8},
	number = {1},
	year = {2023},
	month = {2023 Jan},
	pages = {e10309},
	abstract = {Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.},
	issn = {2380-6761},
	doi = {10.1002/btm2.10309},
	author = {Kerr, Matthew D and McBride, David A and Johnson, Wade T and Chumber, Arun K and Najibi, Alexander J and Seo, Bo Ri and Stafford, Alexander G and Scadden, David T and Mooney, David J and Shah, Nisarg J}
}
@article {1662835,
	title = {Active tissue adhesive activates mechanosensors and prevents muscle atrophy},
	journal = {Nat Mater},
	volume = {22},
	number = {2},
	year = {2023},
	month = {2023 Feb},
	pages = {249-259},
	abstract = {While mechanical stimulation is known to regulate a wide range of biological processes at the cellular and tissue levels, its medical use for tissue regeneration and rehabilitation has been limited by the availability of suitable devices. Here we present a mechanically active gel-elastomer-nitinol tissue adhesive (MAGENTA) that generates and delivers muscle-contraction-mimicking stimulation to a target tissue with programmed strength and frequency. MAGENTA consists of a shape memory alloy spring that enables actuation up to 40\% strain, and an adhesive that efficiently transmits the actuation to the underlying tissue. MAGENTA activates mechanosensing pathways involving yes-associated protein and myocardin-related transcription factor A, and increases the rate of muscle protein synthesis. Disuse muscles treated with MAGENTA exhibit greater size and weight, and generate higher forces compared to untreated muscles, demonstrating the prevention of atrophy. MAGENTA thus has promising applications in the treatment of muscle atrophy and regenerative medicine.},
	keywords = {Humans, Muscle Contraction, Muscle, Skeletal, Muscular Atrophy, Rosaniline Dyes, Tissue Adhesives},
	issn = {1476-4660},
	doi = {10.1038/s41563-022-01396-x},
	author = {Nam, Sungmin and Seo, Bo Ri and Najibi, Alexander J and McNamara, Stephanie L and Mooney, David J}
}
@article {1662834,
	title = {Controlled Delivery of Corticosteroids Using Tunable Tough Adhesives},
	journal = {Adv Healthc Mater},
	volume = {12},
	number = {3},
	year = {2023},
	month = {2023 Jan},
	pages = {e2201000},
	abstract = {Hydrogel-based drug delivery systems typically aim to release drugs locally to tissue in an extended manner. Tissue adhesive alginate-polyacrylamide tough hydrogels are recently demonstrated to serve as an extended-release system for the corticosteroid triamcinolone acetonide. Here, the stimuli-responsive controlled release of triamcinolone acetonide from the alginate-polyacrylamide tough hydrogel drug delivery systems (TADDS) and evolving new approaches to combine alginate-polyacrylamide tough hydrogel with drug-loaded nano and microparticles, generating composite TADDS is described. Stimulation with ultrasound pulses or temperature changes is demonstrated to control the release of triamcinolone acetonide from the TADDS. The incorporation of laponite nanoparticles or PLGA microparticles into the tough hydrogel is shown to further enhance the versatility to control and modulate the release of triamcinolone acetonide. A first technical exploration of a TADDS shelf-life concept is performed using lyophilization, where lyophilized TADDS are physically stable and the bioactive integrity of released triamcinolone acetonide is demonstrated. Given the tunability of properties, the TADDS are a suggested technology platform for controlled drug delivery.},
	keywords = {Adhesives, Adrenal Cortex Hormones, Alginates, Hydrogels, Triamcinolone Acetonide},
	issn = {2192-2659},
	doi = {10.1002/adhm.202201000},
	author = {Koh, Esther and Freedman, Benjamin R and Ramazani, Farshad and Gross, Johannes and Graham, Adam and Kuttler, Andreas and Weber, Eckhard and Mooney, David J}
}
@article {1662833,
	title = {Cytokine conjugation to enhance T cell therapy},
	journal = {Proc Natl Acad Sci U S A},
	volume = {120},
	number = {1},
	year = {2023},
	month = {2023 Jan 03},
	pages = {e2213222120},
	abstract = {Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.},
	keywords = {Cell- and Tissue-Based Therapy, Cytokines, Humans, Immunotherapy, Adoptive, Neoplasms, Receptors, Antigen, T-Cell, T-Lymphocytes},
	issn = {1091-6490},
	doi = {10.1073/pnas.2213222120},
	author = {Liu, Yutong and Adu-Berchie, Kwasi and Brockman, Joshua M and Pezone, Matthew and Zhang, David K Y and Zhou, Jingyi and Pyrdol, Jason W and Wang, Hua and Wucherpfennig, Kai W and Mooney, David J}
}
@article {1662830,
	title = {Matrix viscoelasticity controls spatiotemporal tissue organization},
	journal = {Nat Mater},
	volume = {22},
	number = {1},
	year = {2023},
	month = {2023 Jan},
	pages = {117-127},
	abstract = {Biomolecular and physical cues of the extracellular matrix environment regulate collective cell dynamics and tissue patterning. Nonetheless, how the viscoelastic properties of the matrix regulate collective cell spatial and temporal organization is not fully understood. Here we show that the passive viscoelastic properties of the matrix encapsulating a spheroidal tissue of breast epithelial cells guide tissue proliferation in space and in time. Matrix viscoelasticity prompts symmetry breaking of the spheroid, leading to the formation of invading finger-like protrusions, YAP nuclear translocation and epithelial-to-mesenchymal transition both in vitro and in vivo in a Arp2/3-complex-dependent manner. Computational modelling of these observations allows us to establish a phase diagram relating morphological stability with matrix viscoelasticity, tissue viscosity, cell motility and cell division rate, which is experimentally validated by biochemical assays and in vitro experiments with an intestinal organoid. Altogether, this work highlights the role of stress relaxation mechanisms in tissue growth dynamics, a fundamental process in morphogenesis and oncogenesis.},
	keywords = {Elasticity, Epithelial Cells, Extracellular Matrix, Viscosity},
	issn = {1476-4660},
	doi = {10.1038/s41563-022-01400-4},
	author = {Elosegui-Artola, Alberto and Anupam Gupta and Najibi, Alexander J and Seo, Bo Ri and Garry, Ryan and Tringides, Christina M and de L{\'a}zaro, Irene and Darnell, Max and Gu, Wei and Zhou, Qiao and Weitz, David A and Mahadevan, L and Mooney, David J}
}
@article {1662837,
	title = {Tunable Conductive Hydrogel Scaffolds for Neural Cell Differentiation},
	journal = {Adv Healthc Mater},
	volume = {12},
	number = {7},
	year = {2023},
	month = {2023 Mar},
	pages = {e2202221},
	abstract = {Multielectrode arrays would benefit from intimate engagement with neural cells, but typical arrays do not present a physical environment that mimics that of neural tissues. It is hypothesized that a porous, conductive hydrogel scaffold with appropriate mechanical and conductive properties could support neural cells in 3D, while tunable electrical and mechanical properties could modulate the growth and differentiation of the cellular networks. By incorporating carbon nanomaterials into an alginate hydrogel matrix, and then freeze-drying the formulations, scaffolds which mimic neural tissue properties are formed. Neural progenitor cells (NPCs) incorporated in the scaffolds form neurite networks which span the material in 3D and differentiate into astrocytes and myelinating oligodendrocytes. Viscoelastic and more conductive scaffolds produce more dense neurite networks, with an increased percentage of astrocytes and higher myelination. Application of exogenous electrical stimulation to the scaffolds increases the percentage of astrocytes and the supporting cells localize differently with the surrounding neurons. The tunable biomaterial scaffolds can support neural cocultures for over 12 weeks, and enable a physiologically mimicking in vitro platform to study the formation of neuronal networks. As these materials have sufficient electrical properties to be used as electrodes in implantable arrays, they may allow for the creation of biohybrid neural interfaces and living electrodes.},
	keywords = {Astrocytes, Cell Differentiation, Hydrogels, Nerve Tissue, Neural Stem Cells, Tissue Engineering, Tissue Scaffolds},
	issn = {2192-2659},
	doi = {10.1002/adhm.202202221},
	author = {Tringides, Christina M and Boulingre, Marjolaine and Khalil, Andrew and Tenzin Lungjangwa and Jaenisch, Rudolf and Mooney, David J}
}
@article {1662827,
	title = {Self-Healing Injectable Hydrogels for Tissue Regeneration},
	journal = {Chem Rev},
	volume = {123},
	number = {2},
	year = {2023},
	month = {2023 Jan 25},
	pages = {834-873},
	abstract = {Biomaterials with the ability to self-heal and recover their structural integrity offer many advantages for applications in biomedicine. The past decade has witnessed the rapid emergence of a new class of self-healing biomaterials commonly termed injectable, or printable in the context of 3D printing. These self-healing injectable biomaterials, mostly hydrogels and other soft condensed matter based on reversible chemistry, are able to temporarily fluidize under shear stress and subsequently recover their original mechanical properties. Self-healing injectable hydrogels offer distinct advantages compared to traditional biomaterials. Most notably, they can be administered in a locally targeted and minimally invasive manner through a narrow syringe without the need for invasive surgery. Their moldability allows for a patient-specific intervention and shows great prospects for personalized medicine. Injected hydrogels can facilitate tissue regeneration in multiple ways owing to their viscoelastic and diffusive nature, ranging from simple mechanical support, spatiotemporally controlled delivery of cells or therapeutics, to local recruitment and modulation of host cells to promote tissue regeneration. Consequently, self-healing injectable hydrogels have been at the forefront of many cutting-edge tissue regeneration strategies. This study provides a critical review of the current state of self-healing injectable hydrogels for tissue regeneration. As key challenges toward further maturation of this exciting research field, we identify (i) the trade-off between the self-healing and injectability of hydrogels vs their physical stability, (ii) the lack of consensus on rheological characterization and quantitative benchmarks for self-healing injectable hydrogels, particularly regarding the capillary flow in syringes, and (iii) practical limitations regarding translation toward therapeutically effective formulations for regeneration of specific tissues. Hence, here we (i) review chemical and physical design strategies for self-healing injectable hydrogels, (ii) provide a practical guide for their rheological analysis, and (iii) showcase their applicability for regeneration of various tissues and 3D printing of complex tissues and organoids.},
	keywords = {Biocompatible Materials, Humans, Hydrogels, Tissue Engineering},
	issn = {1520-6890},
	doi = {10.1021/acs.chemrev.2c00179},
	author = {Bertsch, Pascal and Diba, Mani and Mooney, David J and Leeuwenburgh, Sander C G}
}
@article {1662828,
	title = {Advances toward transformative therapies for tendon diseases},
	journal = {Sci Transl Med},
	volume = {14},
	number = {661},
	year = {2022},
	month = {2022 Sep 07},
	pages = {eabl8814},
	abstract = {Approved therapies for tendon diseases have not yet changed the clinical practice of symptomatic pain treatment and physiotherapy. This review article summarizes advances in the development of novel drugs, biologic products, and biomaterial therapies for tendon diseases with perspectives for translation of integrated therapies. Shifting from targeting symptom relief toward disease modification and prevention of disease progression may open new avenues for therapies. Deep evidence-based clinical, cellular, and molecular characterization of the underlying pathology of tendon diseases, as well as therapeutic delivery optimization and establishment of multidiscipline interorganizational collaboration platforms, may accelerate the discovery and translation of transformative therapies for tendon diseases.},
	keywords = {Tendons},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.abl8814},
	author = {Freedman, Benjamin R and Mooney, David J and Weber, Eckhard}
}
@article {1662839,
	title = {Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells},
	journal = {Cell Mol Bioeng},
	volume = {15},
	number = {6},
	year = {2022},
	month = {2022 Dec},
	pages = {535-551},
	abstract = {INTRODUCTION: Tumor and immune cells interact through a variety of cell-surface proteins that can either restrain or promote tumor progression. The impacts of cytotoxic chemotherapy dose and delivery route on this interaction profile remain incompletely understood, and could support the development of more effective combination therapies for cancer treatment.

METHODS AND RESULTS: Here, we found that exposure to the anthracycline doxorubicin altered the expression of numerous immune-interacting markers (MHC-I, PD-L1, PD-L2, CD47, Fas, and calreticulin) on live melanoma, breast cancer, and leukemia cells in a dose-dependent manner in vitro. Notably, an intermediate dose best induced immunogenic cell death and the expression of immune-activating markers without maximizing expression of markers associated with immune suppression. Bone marrow-derived dendritic cells exposed to ovalbumin-expressing melanoma treated with intermediate doxorubicin dose became activated and best presented tumor antigen. In a murine melanoma model, both the doxorubicin dose and delivery location (systemic infusion versus local administration) affected the expression of these markers on live tumor cells. Particularly, local release of doxorubicin from a hydrogel increased calreticulin expression on tumor cells without inducing immune-suppressive markers, in a manner dependent on the loaded dose. Doxorubicin exposure also altered the expression of immune-interacting markers in patient-derived melanoma cells.

CONCLUSIONS: Together, these results illustrate how standard-of-care chemotherapy, when administered in various manners, can lead to distinct expression of immunogenic markers on cancer cells. These findings may inform development of chemo-immunotherapy combinations for cancer treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-022-00742-y.},
	issn = {1865-5025},
	doi = {10.1007/s12195-022-00742-y},
	author = {Najibi, Alexander J and Larkin, Kerry and Feng, Zhaoqianqi and Jeffreys, Nicholas and Dacus, Mason T and Rustagi, Yashika and Hodi, F Stephen and Mooney, David J}
}
@article {1662831,
	title = {A combination microparticle strategy for achieving antigen-specific tolerance},
	journal = {Proc Natl Acad Sci U S A},
	volume = {119},
	number = {52},
	year = {2022},
	month = {2022 Dec 27},
	pages = {e2216976119},
	keywords = {Antigens, Immune Tolerance},
	issn = {1091-6490},
	doi = {10.1073/pnas.2216976119},
	author = {Scott, Evan A and Mooney, David J}
}
@article {1662832,
	title = {Correction: Actuated 3D microgels for single cell mechanobiology},
	journal = {Lab Chip},
	volume = {22},
	number = {18},
	year = {2022},
	month = {2022 Sep 13},
	pages = {3565-3566},
	abstract = {Correction for {\textquoteright}Actuated 3D microgels for single cell mechanobiology{\textquoteright} by Berna {\"O}zkale et al., Lab Chip, 2022, 22, 1962-1970, https://doi.org/10.1039/D2LC00203E.},
	issn = {1473-0189},
	doi = {10.1039/d2lc90078e},
	author = {{\"O}zkale, Berna and Lou, Junzhe and {\"O}zel{\c c}i, Ece and Elosegui-Artola, Alberto and Tringides, Christina M and Mao, Angelo S and Sakar, Mahmut Selman and Mooney, David J}
}
@article {1662838,
	title = {Development of a physiological insulin resistance model in human stem cell-derived adipocytes},
	journal = {Sci Adv},
	volume = {8},
	number = {24},
	year = {2022},
	month = {2022 Jun 17},
	pages = {eabn7298},
	abstract = {Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell-derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell-derived adipocytes.},
	keywords = {Adipocytes, Diabetes Mellitus, Type 2, Glucose, Humans, Insulin, Insulin Resistance, Stem Cells},
	issn = {2375-2548},
	doi = {10.1126/sciadv.abn7298},
	author = {Max Friesen and Khalil, Andrew S and Barrasa, M Inmaculada and Jeppesen, Jacob F and Mooney, David J and Jaenisch, Rudolf}
}
@article {1662829,
	title = {Rapid Ultratough Topological Tissue Adhesives},
	journal = {Adv Mater},
	volume = {34},
	number = {35},
	year = {2022},
	month = {2022 Sep},
	pages = {e2205567},
	abstract = {Tissue adhesives capable of achieving strong and tough adhesion in permeable wet environments are useful in many biomedical applications. However, adhesion generated through covalent bond formation directly with the functional groups of tissues (i.e., COOH and NH2 ~groups in collagen), or using non-covalent interactions can both be limited by weak, unstable, or slow adhesion. Here, it is shown that by combining pH-responsive bridging chitosan polymer chains and a tough hydrogel dissipative matrix one can achieve unprecedented ultratough adhesion to tissues (\&gt;2000~J~m-2 ) in 5-10~min without covalent bond formation. The strong non-covalent adhesion is shown to be stable under physiologically relevant conditions and strongly influenced by chitosan molecular weight, molecular weight of polymers in the matrix, and pH. The adhesion mechanism relies primarily on the topological entanglement between the chitosan chains and the permeable adherends. To further expand the applicability of the adhesives, adhesion time can be decreased by dehydrating the hydrogel matrix to facilitate rapid chitosan interpenetration and entanglement (\&gt;1000~J~m-2 ~in <=1~min). The unprecedented adhesive properties presented in this study open opportunities for new strategies in the development of non-covalent tissue adhesives and numerous bioapplications.},
	keywords = {Adhesives, Chitosan, Hydrogels, Polymers, Tissue Adhesives},
	issn = {1521-4095},
	doi = {10.1002/adma.202205567},
	author = {Cintron-Cruz, Juan A and Freedman, Benjamin R and Lee, Matthew and Johnson, Christopher and Ijaz, Hamza and Mooney, David J}
}
@article {1662836,
	title = {Targeting tumor extracellular matrix activates the tumor-draining lymph nodes},
	journal = {Cancer Immunol Immunother},
	volume = {71},
	number = {12},
	year = {2022},
	month = {2022 Dec},
	pages = {2957-2968},
	abstract = {Disruption of the tumor extracellular matrix (ECM) may alter immune cell infiltration into the tumor and antitumor T cell priming in the tumor-draining lymph nodes (tdLNs). Here, we explore how intratumoral enzyme treatment (ET) of B16 melanoma tumors with ECM-depleting enzyme hyaluronidase alters adaptive and innate immune populations, including T cells, DCs, and macrophages, in the tumors and tdLNs. ET increased CD103+ DC abundance in the tdLNs, as well as antigen presentation of a model tumor antigen ovalbumin (OVA), eliciting local OVA-specific CD8+ T cell responses. Delivered in combination with a distant cryogel-based cancer vaccine, ET increased the systemic antigen-specific CD8+ T cell response. By enhancing activity within the tdLN, ET may broadly support immunotherapies in generating tumor-specific immunity.},
	keywords = {Animals, Antigens, Neoplasm, Cancer Vaccines, Cryogels, Dendritic Cells, Extracellular Matrix, Humans, Hyaluronoglucosaminidase, Lymph Nodes, Melanoma, Experimental, Ovalbumin},
	issn = {1432-0851},
	doi = {10.1007/s00262-022-03212-6},
	author = {Najibi, Alexander J and Shih, Ting-Yu and Zhang, David K Y and Lou, Junzhe and Sobral, Miguel C and Wang, Hua and Dellacherie, Maxence O and Adu-Berchie, Kwasi and Mooney, David J}
}
@article {1662824,
	title = {The future of engineered immune cell therapies},
	journal = {Science},
	volume = {378},
	number = {6622},
	year = {2022},
	month = {2022 Nov 25},
	pages = {853-858},
	abstract = {Immune cells are being engineered to recognize and respond to disease states, acting as a "living drug" when transferred into patients. Therapies based on engineered immune cells are now a clinical reality, with multiple engineered T cell therapies approved for treatment of hematologic malignancies. Ongoing preclinical and clinical studies are testing diverse strategies to modify the fate and function of immune cells for applications in cancer, infectious disease, and beyond. Here, we discuss current progress in treating human disease with immune cell therapeutics, emerging strategies for immune cell engineering, and challenges facing the field, with a particular emphasis on the treatment of cancer, where the most effort has been applied to date.},
	keywords = {Adoptive Transfer, Cell Engineering, Hematologic Neoplasms, Humans, T-Lymphocytes},
	issn = {1095-9203},
	doi = {10.1126/science.abq6990},
	author = {Irvine, Darrell J and Maus, Marcela V and Mooney, David J and Wong, Wilson W}
}
@article {1662826,
	title = {Mechanical checkpoint regulates monocyte differentiation in fibrotic niches},
	journal = {Nat Mater},
	volume = {21},
	number = {8},
	year = {2022},
	month = {2022 Aug},
	pages = {939-950},
	abstract = {Myelofibrosis is a progressive bone marrow malignancy associated with monocytosis, and is believed to promote the pathological remodelling of the extracellular matrix. Here we show that the mechanical properties of myelofibrosis, namely the liquid-to-solid properties (viscoelasticity) of the bone marrow, contribute to aberrant differentiation of monocytes. Human monocytes cultured in stiff, elastic hydrogels show proinflammatory polarization and differentiation towards dendritic cells, as opposed to those cultured in a viscoelastic matrix. This mechanically induced cell differentiation is blocked by inhibiting a myeloid-specific isoform of phosphoinositide 3-kinase, PI3K-γ. We further show that murine bone marrow with myelofibrosis has a significantly increased stiffness and unveil a positive correlation between myelofibrosis grading and viscoelasticity. Treatment with a PI3K-γ inhibitor in vivo reduced frequencies of monocyte and dendritic cell populations in murine bone marrow with myelofibrosis. Moreover, transcriptional changes driven by viscoelasticity are consistent with transcriptional profiles of myeloid cells in other human fibrotic diseases. These results demonstrate that a fibrotic bone marrow niche can physically promote a proinflammatory microenvironment.},
	keywords = {Animals, Bone Marrow, Cell Differentiation, Fibrosis, Humans, Mice, Monocytes, Phosphatidylinositol 3-Kinases, Primary Myelofibrosis},
	issn = {1476-4660},
	doi = {10.1038/s41563-022-01293-3},
	author = {Vining, Kyle H and Marneth, Anna E and Adu-Berchie, Kwasi and Grolman, Joshua M and Tringides, Christina M and Liu, Yutong and Wong, Waihay J and Pozdnyakova, Olga and Severgnini, Mariano and Stafford, Alexander and Duda, Georg N and Hodi, F Stephen and Mullally, Ann and Wucherpfennig, Kai W and Mooney, David J}
}
@article {1662825,
	title = {STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models},
	journal = {Proc Natl Acad Sci U S A},
	volume = {119},
	number = {28},
	year = {2022},
	month = {2022 Jul 12},
	pages = {e2111003119},
	abstract = {Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.},
	keywords = {Animals, Brain Neoplasms, Glioblastoma, Humans, Immunity, Immunotherapy, Killer Cells, Natural, Membrane Proteins, Mice, Tumor Microenvironment},
	issn = {1091-6490},
	doi = {10.1073/pnas.2111003119},
	author = {Berger, Gilles and Knelson, Erik H and Jimenez-Macias, Jorge L and Nowicki, Michal O and Han, Saemi and Panagioti, Eleni and Lizotte, Patrick H and Adu-Berchie, Kwasi and Stafford, Alexander and Dimitrakakis, Nikolaos and Zhou, Lanlan and Chiocca, E Antonio and Mooney, David J and Barbie, David A and Lawler, Sean E}
}
@article {1662823,
	title = {A vaccine targeting resistant tumours by dual T cell plus NK cell attack},
	journal = {Nature},
	volume = {606},
	number = {7916},
	year = {2022},
	month = {2022 Jun},
	pages = {992-998},
	abstract = {Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.},
	keywords = {Histocompatibility Antigens Class I, Humans, Killer Cells, Natural, Myelodysplastic Syndromes, Neoplasms, NK Cell Lectin-Like Receptor Subfamily K, Skin Diseases, Genetic, Vaccines},
	issn = {1476-4687},
	doi = {10.1038/s41586-022-04772-4},
	author = {Badrinath, Soumya and Dellacherie, Maxence O and Li, Aileen and Zheng, Shiwei and Zhang, Xixi and Sobral, Miguel and Pyrdol, Jason W and Smith, Kathryn L and Lu, Yuheng and Haag, Sabrina and Ijaz, Hamza and Connor-Stroud, Fawn and Tsuneyasu Kaisho and Dranoff, Glenn and Yuan, Guo-Cheng and Mooney, David J and Wucherpfennig, Kai W}
}
@article {1638861,
	title = {Materials for Implantable Surface Electrode Arrays: Current Status and Future Directions},
	journal = {Adv Mater},
	volume = {34},
	number = {20},
	year = {2022},
	month = {2022 May},
	pages = {e2107207},
	abstract = {Surface electrode arrays are mainly fabricated from rigid or elastic materials, and precisely manipulated ductile metal films, which offer limited stretchability. However, the living tissues to which they are applied are nonlinear viscoelastic materials, which can undergo significant mechanical deformation in dynamic biological environments. Further, the same arrays and compositions are often repurposed for vastly different tissues rather than optimizing the materials and mechanical properties of the implant for the target application. By first characterizing the desired biological environment, and then designing a technology for a particular organ, surface electrode arrays may be more conformable, and offer better interfaces to tissues while causing less damage. Here, the various materials used in each component of a surface electrode array are first reviewed, and then electrically active implants in three specific biological systems, the nervous system, the muscular system, and skin, are described. Finally, the fabrication of next-generation surface arrays that overcome current limitations is discussed.},
	keywords = {Electrodes, Implanted, Tensile Strength},
	issn = {1521-4095},
	doi = {10.1002/adma.202107207},
	author = {Tringides, Christina M and Mooney, David J}
}
@article {1638860,
	title = {Quantifying face mask comfort},
	journal = {J Occup Environ Hyg},
	volume = {19},
	number = {1},
	year = {2022},
	month = {2022 Jan},
	pages = {23-34},
	abstract = {Face mask usage is one of the most effective ways to limit SARS-CoV-2 transmission, but a mask is only useful if user compliance is high. Through anonymous surveys (n = 679), it was shown that mask discomfort is the primary source of noncompliance in mask wearing. Further, through these surveys, three critical predicting variables that dictate mask comfort were identified: air resistance, water vapor permeability, and face temperature change. To validate these predicting variables in a physiological context, experiments (n = 9) were performed to measure the respiratory rate and change in face temperature while wearing different types of three commonly used masks. Finally, using values of these predicting variables from experiments and the literature, and surveys asking users to rate the comfort of various masks, three machine learning algorithms were trained and tested to generate overall comfort scores for those masks. Although all three models performed with an accuracy of approximately 70\%, the multiple linear regression model provides a simple analytical expression to predict the comfort scores for common face masks provided the input predicting variables. As face mask usage is crucial during the COVID-19 pandemic, the goal of this quantitative framework to predict mask comfort is hoped to improve user experience and prevent discomfort-induced noncompliance.},
	keywords = {COVID-19, Humans, Masks, Pandemics, SARS-CoV-2, Surveys and Questionnaires},
	issn = {1545-9632},
	doi = {10.1080/15459624.2021.2002342},
	author = {Koh, Esther and Ambatipudi, Mythri and Boone, DaLoria L and Luehr, Julia B W and Blaise, Alena and Gonzalez, Jose and Sule, Nishant and Mooney, David J and He, Emily M}
}
@article {1638852,
	title = {Actuated 3D microgels for single cell mechanobiology},
	journal = {Lab Chip},
	volume = {22},
	number = {10},
	year = {2022},
	month = {2022 May 17},
	pages = {1962-1970},
	abstract = {We present a new cell culture technology for large-scale mechanobiology studies capable of generating and applying optically controlled uniform compression on single cells in 3D. Mesenchymal stem cells (MSCs) are individually encapsulated inside an optically triggered nanoactuator-alginate hybrid biomaterial using microfluidics, and the encapsulating network isotropically compresses the cell upon activation by light. The favorable biomolecular properties of alginate allow cell culture in vitro up to a week. The mechanically active microgels are capable of generating up to 15\% compressive strain and forces reaching 400 nN. As a proof of concept, we demonstrate the use of the mechanically active cell culture system in mechanobiology by subjecting singly encapsulated MSCs to optically generated isotropic compression and monitoring changes in intracellular calcium intensity.},
	keywords = {Alginates, Biophysics, Cell Culture Techniques, Mesenchymal Stem Cells, Microgels},
	issn = {1473-0189},
	doi = {10.1039/d2lc00203e},
	author = {{\"O}zkale, Berna and Lou, Junzhe and {\"O}zel{\c c}i, Ece and Elosegui-Artola, Alberto and Tringides, Christina M and Mao, Angelo S and Sakar, Mahmut Selman and Mooney, David J}
}
@article {1638854,
	title = {Aging and matrix viscoelasticity affect multiscale tendon properties and tendon derived cell behavior},
	journal = {Acta Biomater},
	volume = {143},
	year = {2022},
	month = {2022 Apr 15},
	pages = {63-71},
	abstract = {Aging is the largest risk factor for Achilles tendon associated disorders and rupture. Although Achilles tendon macroscale elastic properties are suggested to decline with aging, less is known about the effect of maturity and aging on multiscale viscoelastic properties and their effect on tendon cell behavior. Here, we show dose dependent changes in native multiscale tendon mechanical and structural properties and uncover several nanoindentation properties predicted by tensile mechanics and echogenicity. Alginate hydrogel systems designed to mimic juvenile tendon microscale mechanics revealed that stiffness and viscoelasticity affected Achilles tendon cell aspect ratio and proliferation during aging. This knowledge provides further evidence for the negative impact of maturity and aging on tendon and begins to elucidate how viscoelasticity can control tendon derived cell morphology and expansion. STATEMENT OF SIGNIFICANCE: Aging is the largest risk factor for Achilles tendon associated disorders and rupture. Although Achilles tendon macroscale elastic properties are suggested to decline with aging, less is known about the effect of maturity and aging on multiscale viscoelastic properties and their effect on tendon cell behavior. Here, we show dose dependent changes in native multiscale tendon mechanical and structural properties and uncover several nanoindentation properties predicted by tensile mechanics and echogenicity. Alginate hydrogel systems designed to mimic juvenile tendon microscale mechanics revealed that stiffness and viscoelasticity affected Achilles tendon cell spreading and proliferation during aging. This knowledge provides further evidence for the negative impact of maturity and aging on tendon and begins to elucidate how viscoelasticity can control tendon derived cell morphology and expansion.},
	keywords = {Achilles Tendon, Aging, Alginates, Humans, Hydrogels, Rupture, Viscosity},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2022.03.006},
	author = {Freedman, Benjamin R and Knecht, Raphael S and Tinguely, Yann and Eskibozkurt, G Ege and Wang, Cathy S and Mooney, David J}
}
@article {1638855,
	title = {Antiplatelet therapy for Staphylococcus aureus bacteremia: Will it stick?},
	journal = {PLoS Pathog},
	volume = {18},
	number = {2},
	year = {2022},
	month = {2022 Feb},
	pages = {e1010240},
	abstract = {Staphylococcus aureus bacteremia (SAB) remains a clinically challenging infection despite extensive investigation. Repurposing medications approved for other indications is appealing as clinical safety profiles have already been established. Ticagrelor, a reversible adenosine diphosphate receptor antagonist that prevents platelet aggregation, is indicated for patients suffering from acute coronary syndrome (ACS). However, some clinical data suggest that patients treated with ticagrelor are less likely to have poor outcomes due to S. aureus infection. There are several potential mechanisms by which ticagrelor may affect S. aureus virulence. These include direct antibacterial activity, up-regulation of the innate immune system through boosting platelet-mediated S. aureus killing, and prevention of S. aureus adhesion to host tissues. In this Pearl, we review the clinical data surrounding ticagrelor and infection as well as explore the evidence surrounding these proposed mechanisms of action. While more evidence is needed before antiplatelet medications formally become part of the arsenal against S. aureus infection, these potential mechanisms represent exciting pathways to target in the host/pathogen interface.},
	keywords = {Bacteremia, Blood Platelets, Host-Pathogen Interactions, Humans, Immunity, Innate, Platelet Aggregation Inhibitors, Staphylococcal Infections, Staphylococcus aureus, Ticagrelor},
	issn = {1553-7374},
	doi = {10.1371/journal.ppat.1010240},
	author = {Tatara, Alexander M and Gandhi, Ronak G and Mooney, David J and Nelson, Sandra B}
}
@article {1638858,
	title = {Cryogel vaccines effectively induce immune responses independent of proximity to the draining lymph nodes},
	journal = {Biomaterials},
	volume = {281},
	year = {2022},
	month = {2022 Feb},
	pages = {121329},
	abstract = {The delivery location of traditional vaccines can impact immune responses and resulting efficacy. Cryogel-based cancer vaccines, which are typically injected near the inguinal lymph nodes (iLNs), recruit and activate dendritic cells (DC) in situ, induce DC homing to the iLNs, and have generated potent anti-tumor immunity against several murine cancer models. However, whether cryogel vaccination distance to a draining LN affects the kinetics of DC homing and downstream antigen-specific immunity is unknown, given the heightened importance of the scaffold vaccine site. We hypothesized that vaccination near the iLNs would lead to more rapid DC trafficking to the iLNs, thereby inducing faster and stronger immune responses. Here, mice were injected with cryogel vaccines against ovalbumin either adjacent or distal to the iLNs, and the resultant DC trafficking kinetics, T cell phenotypes, antigen-specific T cell and humoral responses, and prophylactic efficacy in an ovalbumin-expressing tumor model were assessed. Cryogel vaccines induced potent, long-lasting antigen-specific immune responses independent of distance to the iLNs, with no significant differences in DC trafficking kinetics, ovalbumin-specific T cell and antibody responses, or prophylactic efficacy. Moreover, DC trafficking and activation state were not impacted when cryogels were injected near a tumor. These results demonstrate a flexibility in vaccination location for scaffold-based vaccines, independent of draining LN distance.},
	keywords = {Animals, Antigens, Cancer Vaccines, Cryogels, Dendritic Cells, Immunity, Lymph Nodes, Mice, Mice, Inbred C57BL, Neoplasms, Ovalbumin},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2021.121329},
	author = {Najibi, Alexander J and Shih, Ting-Yu and Mooney, David J}
}
@article {1638853,
	title = {Development of a liposomal near-infrared fluorescence lactate assay for human blood},
	journal = {Biomaterials},
	volume = {283},
	year = {2022},
	month = {2022 Apr},
	pages = {121475},
	abstract = {In emergency medicine, blood lactate is a commonly used biomarker of hypoxia (e.g., sepsis, trauma, cardiac arrest) but the median time to obtain the results from a clinical lactate test is 3~h. We recently developed a near-infrared fluorescent blood lactate assay based on a two-step enzymatic cascade in a vesicular reaction compartment. Previously, we reported a response of this assay to lactate-spiked bovine blood after 10~min. To develop a point-of-care test, we optimized this assay in commercial human blood, validated it in fresh capillary blood of healthy volunteers in an institutional review board-approved study, and improved the stability of the formulation. External pH and luminal enzyme concentrations were identified as key parameters of sensor response and kinetics, as they impact transmembrane lactate diffusion and turnover rate. The preparation process was also simplified and the stability was improved to allow storage at 4~{\textdegree}C for at least 5 days. The final formulation exhibited a strong and linear response to lactate-spiked human blood in a clinically relevant range, and accurately quantified a lactate standard at a clinically used cut-off in fresh capillary blood after 2~min. These findings motivate a clinical evaluation of this rapid and easy-to-use lactate assay.},
	keywords = {Animals, Cattle, Fluorescence, Humans, Kinetics, Lactic Acid, Liposomes, Sepsis},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2022.121475},
	author = {Matoori, Simon and Mooney, David J}
}
@article {1638857,
	title = {Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity},
	journal = {Nat Biomed Eng},
	volume = {6},
	number = {10},
	year = {2022},
	month = {2022 Oct},
	pages = {1167-1179},
	abstract = {Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m-2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with {\textquoteright}Janus{\textquoteright} surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.},
	keywords = {Achilles Tendon, Adhesives, Animals, Chemokines, Chitosan, Humans, Hydrogels, Rats, Swine, Tendon Injuries, Triamcinolone Acetonide},
	issn = {2157-846X},
	doi = {10.1038/s41551-021-00810-0},
	author = {Freedman, Benjamin R and Kuttler, Andreas and Beckmann, Nicolau and Nam, Sungmin and Kent, Daniel and Schuleit, Michael and Ramazani, Farshad and Accart, Nathalie and Rock, Anna and Li, Jianyu and Kurz, Markus and Fisch, Andreas and Ullrich, Thomas and Hast, Michael W and Tinguely, Yann and Weber, Eckhard and Mooney, David J}
}
@article {1638850,
	title = {Nanoparticle Properties Influence Transendothelial Migration of Monocytes},
	journal = {Langmuir},
	volume = {38},
	number = {18},
	year = {2022},
	month = {2022 May 10},
	pages = {5603-5616},
	abstract = {Nanoparticle-based delivery of therapeutics to the brain has had limited clinical impact due to challenges crossing the blood-brain barrier (BBB). Certain cells, such as monocytes, possess the ability to migrate across the BBB, making them attractive candidates for cell-based brain delivery strategies. In this work, we explore nanoparticle design parameters that impact both monocyte association and monocyte-mediated BBB transport. We use electrohydrodynamic jetting to prepare nanoparticles of varying sizes, compositions, and elasticity to address their impact on uptake by THP-1 monocytes and permeation across the BBB. An in vitro human BBB model is developed using human cerebral microvascular endothelial cells (hCMEC/D3) for the assessment of migration. We compare monocyte uptake of both polymeric and synthetic protein nanoparticles (SPNPs) of various sizes, as well as their effect on cell migration. SPNPs (human serum albumin/HSA or human transferrin/TF) are shown to promote increased monocyte-mediated transport across the BBB over polymeric nanoparticles. TF SPNPs (200 nm) associate readily, with an average uptake of 138 particles/cell. Nanoparticle loading is shown to influence the migration of THP-1 monocytes. The migration of monocytes loaded with 200 nm TF and 200 nm HSA SPNPs was 2.3-fold and 2.1-fold higher than that of an untreated control. RNA-seq analysis after TF SPNP treatment suggests that the upregulation of several migration genes may be implicated in increased monocyte migration (ex. integrin subunits α M and α L). Integrin β 2 chain combines with either integrin subunit α M chain or integrin subunit α L chain to form macrophage antigen 1 and lymphocyte function-associated antigen 1 integrins. Both products play a pivotal role in the transendothelial migration cascade. Our findings highlight the potential of SPNPs as drug and/or gene delivery platforms for monocyte-mediated BBB transport, especially where conventional polymer nanoparticles are ineffective or otherwise not desirable.},
	keywords = {Endothelial Cells, Humans, Integrins, Monocytes, Nanoparticles, Transendothelial and Transepithelial Migration, Transferrin},
	issn = {1520-5827},
	doi = {10.1021/acs.langmuir.2c00200},
	author = {Habibi, Nahal and Brown, Tyler D and Adu-Berchie, Kwasi and Christau, Stephanie and Raymond, Jeffery E and Mooney, David J and Mitragotri, Samir and Lahann, Joerg}
}
@article {1638856,
	title = {Recent and Future Strategies of Mechanotherapy for Tissue Regenerative Rehabilitation},
	journal = {ACS Biomater Sci Eng},
	volume = {8},
	number = {11},
	year = {2022},
	month = {2022 Nov 14},
	pages = {4639-4642},
	abstract = {Mechanotherapy, the application of various mechanical forces on injured or diseased tissue, is a viable option for tissue regenerative rehabilitation. Recent advances in tissue engineering (i.e., engineered materials and 3D printing) and soft-robotic technologies have enabled systematic and controlled studies to demonstrate the therapeutic impacts of mechanical stimulation on severely injured tissue. Along with innovation in actuation systems, improvements in analysis methods uncovering cellular and molecular landscapes during tissue regeneration under mechanical loading expand our understanding of how mechanical cues are translated into specific biological responses (i.e., stem cell self-renewal and differentiation, immune responses, etc.). Moving forward, the development of diversified actuation systems that are mechanically tissue friendly, easily scalable, and capable of delivering various modes of loading and monitoring functional biomarkers will facilitate systematic and controlled preclinical and clinical studies. Combining these future actuation systems with single-cell resolution analysis of cellular and molecular markers will enable detailed knowledge of underlying biological responses, and optimization of mechanotherapy protocols for specific tissues/injuries. These advancements will enable diverse mechanotherapy therapies in the future.},
	keywords = {Printing, Three-Dimensional, Tissue Engineering},
	issn = {2373-9878},
	doi = {10.1021/acsbiomaterials.1c01477},
	author = {Seo, Bo Ri and Mooney, David J}
}
@article {1638851,
	title = {Viscoelastic Biomaterials for Tissue Regeneration},
	journal = {Tissue Eng Part C Methods},
	volume = {28},
	number = {7},
	year = {2022},
	month = {2022 Jul},
	pages = {289-300},
	abstract = {The extracellular matrix (ECM) mechanical properties regulate key cellular processes in tissue development and regeneration. The majority of scientific investigation has focused on ECM elasticity as the primary mechanical regulator of cell and tissue behavior. However, all living tissues are viscoelastic, exhibiting both solid- and liquid-like mechanical behavior. Despite increasing evidence regarding the role of ECM viscoelasticity in directing cellular behavior, this aspect is still largely overlooked in the design of biomaterials for tissue regeneration. Recently, with the emergence of various bottom-up material design strategies, new approaches can deliver unprecedented control over biomaterial properties at multiple length scales, thus enabling the design of viscoelastic biomaterials that mimic various aspects of the native tissue ECM microenvironment. This review describes key considerations for the design of viscoelastic biomaterials for tissue regeneration. We provide an overview of the role of matrix viscoelasticity in directing cell behavior toward regenerative outcomes, highlight recent strategies utilizing viscoelastic hydrogels for regenerative therapies, and outline remaining challenges, potential solutions, and emerging applications for viscoelastic biomaterials in tissue engineering and regenerative medicine. Impact statement All living tissues are viscoelastic. As we design viscoelastic biomaterials for tissue engineering and regenerative medicine, we must understand the effect of matrix viscoelasticity on in vitro cell behavior and in vivo regenerative outcomes. Engineering the next generation of biomaterials with tunable viscoelasticity to direct cell and tissue behavior will contribute to the development of in vitro tissue models and in vivo regenerative therapies to address unmet clinical needs.},
	keywords = {Biocompatible Materials, Extracellular Matrix, Hydrogels, Regenerative Medicine, Tissue Engineering},
	issn = {1937-3392},
	doi = {10.1089/ten.TEC.2022.0040},
	author = {Wu, David T and Jeffreys, Nicholas and Diba, Mani and Mooney, David J}
}
@article {1617259,
	title = {Biomaterial vaccines capturing pathogen-associated molecular patterns protect against bacterial infections and septic shock},
	journal = {Nat Biomed Eng},
	volume = {6},
	number = {1},
	year = {2022},
	month = {2022 Jan},
	pages = {8-18},
	abstract = {Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.},
	keywords = {Animals, Bacterial Infections, Biocompatible Materials, Escherichia coli, Methicillin-Resistant Staphylococcus aureus, Mice, Pathogen-Associated Molecular Pattern Molecules, Shock, Septic, Swine, Vaccines},
	issn = {2157-846X},
	doi = {10.1038/s41551-021-00756-3},
	author = {Super, Michael and Doherty, Edward J and Cartwright, Mark J and Seiler, Benjamin T and Langellotto, Fernanda and Dimitrakakis, Nikolaos and White, Des A and Stafford, Alexander G and Karkada, Mohan and Graveline, Amanda R and Horgan, Caitlin L and Lightbown, Kayla R and Urena, Frank R and Yeager, Chyenne D and Rifai, Sami A and Dellacherie, Maxence O and Li, Aileen W and Leese-Thompson, Collin and Ijaz, Hamza and Jiang, Amanda R and Chandrasekhar, Vasanth and Scott, Justin M and Lightbown, Shanda L and Ingber, Donald E and Mooney, David J}
}
@article {1638862,
	title = {Author Correction: An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation},
	journal = {Nat Biotechnol},
	volume = {39},
	number = {11},
	year = {2021},
	month = {2021 Nov},
	pages = {1466},
	issn = {1546-1696},
	doi = {10.1038/s41587-021-01081-5},
	author = {Shah, Nisarg J and Mao, Angelo S and Shih, Ting-Yu and Kerr, Matthew D and Sharda, Azeem and Raimondo, Theresa M and Weaver, James C and Vrbanac, Vladimir D and Deruaz, Maud and Tager, Andrew M and Mooney, David J and Scadden, David T}
}
@article {1638859,
	title = {Ultrasound-triggered release reveals optimal timing of CpG-ODN delivery from a cryogel cancer vaccine},
	journal = {Biomaterials},
	volume = {279},
	year = {2021},
	month = {2021 12},
	pages = {121240},
	abstract = {Recently, several injectable scaffold-based cancer vaccines have been developed that can recruit and activate host dendritic cells (DCs) and generate potent antitumor responses. However, the optimal timing of adjuvant delivery, particularly of the commonly used cytosine-phosphodiester-guanine-oligonucleotide (CpG-ODN), for scaffold-based cancer vaccines remains unknown. We hypothesized that optimally timed CpG-ODN delivery will lead to enhanced immune responses, and designed a cryogel vaccine system where CpG-ODN release can be triggered on-demand by ultrasound. CpG-ODN was first condensed with polyethylenimine and then adsorbed to cryogels. Little adsorbed CpG-ODN was released in vitro. Ultrasound stimulation triggered continuous CpG-ODN release, at an enhanced rate even after ultrasound was turned off, with minimal burst release. In vivo, ultrasound stimulation four days post-vaccination induced a significantly higher antigen-specific cytotoxic T-lymphocyte (CTL) response compared to control mice. Furthermore, ultrasound stimulation at this time point generated a significantly higher IgG2a/c antibody titer than all the groups except ultrasound stimulation eight days post-vaccination. This optimal timing of ultrasound-triggered release coincided with peak DC accumulation in the cryogels. By enabling temporal control of vaccine components through release on-demand, this system is a promising platform to study the optimal timing of delivery of immunomodulatory agents for cancer vaccination.},
	keywords = {Adjuvants, Immunologic, Animals, Cancer Vaccines, Cryogels, Immunomodulating Agents, Mice, Mice, Inbred C57BL, Neoplasms, Oligodeoxyribonucleotides, T-Lymphocytes, Cytotoxic},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2021.121240},
	author = {Shih, Ting-Yu and Najibi, Alexander J and Bartlett, Alexandra L and Li, Aileen W and Mooney, David J}
}
@article {1617257,
	title = {Anti-inflammatory nanoparticles significantly improve muscle function in a murine model of advanced muscular dystrophy},
	journal = {Sci Adv},
	volume = {7},
	number = {26},
	year = {2021},
	month = {2021 Jun},
	abstract = {Chronic inflammation contributes to the pathogenesis of all muscular dystrophies. Inflammatory T cells damage muscle, while regulatory T cells (Tregs) promote regeneration. We hypothesized that providing anti-inflammatory cytokines in dystrophic muscle would promote proregenerative immune phenotypes and improve function. Primary T cells from dystrophic (mdx) mice responded appropriately to inflammatory or suppressive cytokines. Subsequently, interleukin-4 (IL-4)- or IL-10-conjugated gold nanoparticles (PA4, PA10) were injected into chronically injured, aged, mdx muscle. PA4 and PA10 increased T cell recruitment, with PA4 doubling CD4+/CD8- T cells versus controls. Further, 50\% of CD4+/CD8- T cells were immunosuppressive Tregs following PA4, versus 20\% in controls. Concomitant with Treg recruitment, muscles exhibited increased fiber area and fourfold increases in contraction force and velocity versus controls. The ability of PA4 to shift immune responses, and improve dystrophic muscle function, suggests that immunomodulatory treatment may benefit many genetically diverse muscular dystrophies, all of which share inflammatory pathology.},
	issn = {2375-2548},
	doi = {10.1126/sciadv.abh3693},
	author = {Raimondo, Theresa M and Mooney, David J}
}
@article {1617255,
	title = {Generation of the Compression-induced Dedifferentiated Adipocytes (CiDAs) Using Hypertonic Medium},
	journal = {Bio Protoc},
	volume = {11},
	number = {4},
	year = {2021},
	month = {2021 Feb 20},
	pages = {e3920},
	abstract = {Current methods to obtain mesenchymal stem cells (MSCs) involve sampling, culturing, and expanding of primary MSCs from adipose, bone marrow, and umbilical cord tissues. However, the drawbacks are the limited numbers of total cells in MSC pools, and their decaying stemness during in vitro expansion. As an alternative resource, recent ceiling culture methods allow the generation of dedifferentiated fat cells (DFATs) from mature adipocytes. Nevertheless, this process of spontaneous dedifferentiation of mature adipocytes is laborious and time-consuming. This paper describes a modified protocol for in vitro dedifferentiation of adipocytes by employing an additional physical stimulation, which takes advantage of augmenting the stemness-related Wnt/β-catenin signaling. Specifically, this protocol utilizes a polyethylene glycol (PEG)-containing hypertonic medium to introduce extracellular physical stimulation to obtain higher efficiency and introduce a simpler procedure for adipocyte dedifferentiation.},
	issn = {2331-8325},
	doi = {10.21769/BioProtoc.3920},
	author = {Li, Yiwei and Mao, Angelo S and Seo, Bo Ri and Zhao, Xing and Gupta, Satish Kumar and Chen, Maorong and Han, Yulong and Shih, Ting-Yu and Mooney, David J and Guo, Ming}
}
@article {1617258,
	title = {A Modular Biomaterial Scaffold-Based Vaccine Elicits Durable Adaptive Immunity to Subunit SARS-CoV-2 Antigens},
	journal = {Adv Healthc Mater},
	volume = {10},
	number = {22},
	year = {2021},
	month = {2021 11},
	pages = {e2101370},
	abstract = {The coronavirus disease 2019 (COVID-19) pandemic demonstrates the importance of generating safe and efficacious vaccines that can be rapidly deployed against emerging pathogens. Subunit vaccines are considered among the safest, but proteins used in these typically lack strong immunogenicity, leading to poor immune responses. Here, a biomaterial COVID-19 vaccine based on a mesoporous silica rods (MSRs) platform is described. MSRs loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF), the toll-like receptor 4 (TLR-4) agonist monophosphoryl lipid A (MPLA), and SARS-CoV-2 viral protein antigens slowly release their cargo and form subcutaneous scaffolds that locally recruit and activate antigen-presenting cells (APCs) for the generation of adaptive immunity. MSR-based vaccines generate robust and durable cellular and humoral responses against SARS-CoV-2 antigens, including the poorly immunogenic receptor binding domain (RBD) of the spike (S) protein. Persistent antibodies over the course of 8 months are found in all vaccine configurations tested and robust in vitro viral neutralization is observed both in a prime-boost and a single-dose regimen. These vaccines can be fully formulated ahead of time or stored lyophilized and reconstituted with an antigen mixture moments before injection, which can facilitate its rapid deployment against emerging SARS-CoV-2 variants or new pathogens. Together, the data show a promising COVID-19 vaccine candidate and a generally adaptable vaccine platform against infectious pathogens.},
	keywords = {Adaptive Immunity, Antibodies, Viral, Biocompatible Materials, COVID-19, COVID-19 Vaccines, Humans, SARS-CoV-2},
	issn = {2192-2659},
	doi = {10.1002/adhm.202101370},
	author = {Langellotto, Fernanda and Dellacherie, Maxence O and Yeager, Chyenne and Ijaz, Hamza and Yu, Jingyou and Cheng, Chi-An and Dimitrakakis, Nikolaos and Seiler, Benjamin T and Gebre, Makda S and Gilboa, Tal and Johnson, Rebecca and Storm, Nadia and Bardales, Sarai and Graveline, Amanda and White, Des and Tringides, Christina M and Cartwright, Mark J and Doherty, Edward J and Honko, Anna and Griffiths, Anthony and Barouch, Dan H and Walt, David R and Mooney, David J}
}
@article {1617256,
	title = {Risk quantification for SARS-CoV-2 infection through airborne transmission in university settings},
	journal = {J Occup Environ Hyg},
	volume = {18},
	number = {12},
	year = {2021},
	month = {2021 12},
	pages = {590-603},
	abstract = {The COVID-19 pandemic has significantly impacted learning as many institutions switched to remote or hybrid instruction. An in-depth assessment of the risk of infection that considers environmental setting and mitigation strategies is needed to make safe and informed decisions regarding reopening university spaces. A quantitative model of infection probability that accounts for space-specific parameters is presented to enable assessment of the risk in reopening university spaces at given densities. The model uses the fraction of the campus population that are viral shedders, room capacity, face covering filtration efficiency, air exchange rate, room volume, and time spent in the space as parameters to calculate infection probabilities in teaching spaces, dining halls, dorms, and shared bathrooms. The model readily calculates infection probabilities in various university spaces, with face covering filtration efficiency and air exchange rate being among the dominant variables. When applied to university spaces, this model demonstrated that, under specific conditions that are feasible to implement, in-person classes could be held in large lecture halls with an infection risk over the semester \&lt;1\%. Meal pick-ups from dining halls and usage of shared bathrooms in residential dormitories among small groups of students could also be accomplished with low risk. The results of applying this model to spaces at Harvard University (Cambridge and Allston campuses) and Stanford University are reported. Finally, a user-friendly web application was developed using this model to calculate infection probability following input of space-specific variables. The successful development of a quantitative model and its implementation through a web application may facilitate accurate assessments of infection risk in university spaces. However, since this model is thus far unvalidated, validation using infection rate and contact tracing data from university campuses will be crucial as such data becomes available at larger scales. In light of the impact of the COVID-19 pandemic on universities, this tool could provide crucial insight to students, faculty, and university officials in making informed decisions.},
	keywords = {COVID-19, Humans, Pandemics, SARS-CoV-2, Students, Universities},
	issn = {1545-9632},
	doi = {10.1080/15459624.2021.1985725},
	author = {Ambatipudi, Mythri and Carrillo Gonzalez, Paola and Tasnim, Kazi and Daigle, Jordan T and Kulyk, Taisa and Jeffreys, Nicholas and Sule, Nishant and Trevino, Rafael and He, Emily M and Mooney, David J and Koh, Esther}
}
@article {1617253,
	title = {Skeletal muscle regeneration with robotic actuation-mediated clearance of neutrophils},
	journal = {Sci Transl Med},
	volume = {13},
	number = {614},
	year = {2021},
	month = {2021 Oct 06},
	pages = {eabe8868},
	abstract = {Mechanical stimulation (mechanotherapy) can promote skeletal muscle repair, but a lack of reproducible protocols and mechanistic understanding of the relation between mechanical cues and tissue regeneration limit progress in this field. To address these gaps, we developed a robotic device equipped with real-time force control and compatible with ultrasound imaging for tissue strain analysis. We investigated the hypothesis that specific mechanical loading improves tissue repair by modulating inflammatory responses that regulate skeletal muscle regeneration. We report that cyclic compressive loading within a specific range of forces substantially improves functional recovery of severely injured muscle in mice. This improvement is attributable in part to rapid clearance of neutrophil populations and neutrophil-mediated factors, which otherwise may impede myogenesis. Insights from this work will help advance therapeutic strategies for tissue regeneration broadly.},
	keywords = {Muscle, Skeletal, Neutrophils, Regeneration, Robotic Surgical Procedures, Robotics},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.abe8868},
	author = {Seo, Bo Ri and Payne, Christopher J and McNamara, Stephanie L and Freedman, Benjamin R and Kwee, Brian J and Nam, Sungmin and de L{\'a}zaro, Irene and Darnell, Max and Alvarez, Jonathan T and Dellacherie, Maxence O and Vandenburgh, Herman H and Conor J Walsh and Mooney, David J}
}
@article {1617254,
	title = {Viscoelastic surface electrode arrays to interface with viscoelastic tissues},
	journal = {Nat Nanotechnol},
	volume = {16},
	number = {9},
	year = {2021},
	month = {2021 09},
	pages = {1019-1029},
	abstract = {Living tissues are non-linearly elastic materials that exhibit viscoelasticity and plasticity. Man-made, implantable bioelectronic arrays mainly rely on rigid or elastic encapsulation materials and stiff films of ductile metals that can be manipulated with microscopic precision to offer reliable electrical properties. In this study, we have engineered a surface microelectrode array that replaces the traditional encapsulation and conductive components with viscoelastic materials. Our array overcomes previous limitations in matching the stiffness and relaxation behaviour of soft biological tissues by using hydrogels as the outer layers. We have introduced a hydrogel-based conductor made from an ionically conductive alginate matrix enhanced with carbon nanomaterials, which provide electrical percolation even at low loading fractions. Our combination of conducting and insulating viscoelastic materials, with top-down manufacturing, allows for the fabrication of electrode arrays compatible with standard electrophysiology platforms. Our arrays intimately conform to the convoluted surface of the heart or brain cortex and offer promising bioengineering applications for recording and stimulation.},
	keywords = {Bioengineering, Electrodes, Hydrogels, Microelectrodes, Nanostructures, Surface Properties, Viscoelastic Substances, Viscosity},
	issn = {1748-3395},
	doi = {10.1038/s41565-021-00926-z},
	author = {Tringides, Christina M and Vachicouras, Nicolas and de L{\'a}zaro, Irene and Wang, Hua and Trouillet, Alix and Seo, Bo Ri and Elosegui-Artola, Alberto and Fallegger, Florian and Shin, Yuyoung and Casiraghi, Cinzia and Kostarelos, Kostas and Lacour, St{\'e}phanie P and Mooney, David J}
}
@article {1617250,
	title = {Advanced bandages for diabetic wound healing},
	journal = {Sci Transl Med},
	volume = {13},
	number = {585},
	year = {2021},
	month = {2021 Mar 17},
	abstract = {Current treatment options for foot ulcers, a serious and prevalent complication of diabetes, remain nonspecific. In this Perspective, we present recent advances in understanding the pathophysiology of diabetic wound healing and the emergence of previously unidentified targets. We discuss wound dressings tailored to the diabetic wound environment currently under development.},
	keywords = {Bandages, Hydrocolloid, Diabetes Mellitus, Diabetic Foot, Humans, Wound Healing},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.abe4839},
	author = {Matoori, Simon and Veves, Aristidis and Mooney, David J}
}
@article {1617252,
	title = {Degradable and Removable Tough Adhesive Hydrogels},
	journal = {Adv Mater},
	volume = {33},
	number = {17},
	year = {2021},
	month = {2021 Apr},
	pages = {e2008553},
	abstract = {The development of tough adhesive hydrogels has enabled unprecedented adhesion to wet and moving tissue surfaces throughout the body, but they are typically composed of nondegradable components. Here, a family of degradable tough adhesive hydrogels containing ≈90\% water by incorporating covalently networked degradable crosslinkers and hydrolyzable ionically crosslinked main-chain polymers is developed. Mechanical toughness, adhesion, and degradation of these new formulations are tested in both accelerated in vitro conditions and up to 16 weeks in vivo. These degradable tough adhesives are engineered with equivalent mechanical and adhesive properties to nondegradable tough adhesives, capable of achieving stretches \&gt;20 times their initial length, fracture energies \&gt;6~kJ~m-2 ,~and~adhesion~energies \&gt;1000~J~m-2 .~All degradable systems show complete degradation within 2 weeks under accelerated aging conditions in vitro and weeks to months in vivo depending on the degradable crosslinker selected. Excellent biocompatibility is observed for all groups after 1, 2, 4, 8, and 16 weeks of implantation, with minimal fibrous encapsulation and no signs of organ toxicity. On-demand removal of the adhesive is achieved with treatment of chemical agents which do not cause damage to underlying skin tissue in mice. The broad versatility of this family of adhesives provides the foundation for numerous in vivo indications.},
	keywords = {Adhesives, Animals, Biocompatible Materials, Hydrogels, Mice, Polymers, Skin},
	issn = {1521-4095},
	doi = {10.1002/adma.202008553},
	author = {Freedman, Benjamin R and Uzun, Oktay and Luna, Nadja M Maldonado and Rock, Anna and Clifford, Charles and Stoler, Emily and {\"O}stlund-Sholars, Gabrielle and Johnson, Christopher and Mooney, David J}
}
@article {1617251,
	title = {Obstacles and opportunities in a forward vision for cancer nanomedicine},
	journal = {Nat Mater},
	volume = {20},
	number = {11},
	year = {2021},
	month = {2021 11},
	pages = {1469-1479},
	abstract = {Cancer nanomedicines were initially envisioned as magic bullets, travelling through the circulation to target tumours while sparing healthy tissues the toxicity of classic chemotherapy. While a limited number of nanomedicine therapies have resulted, the disappointing news is that major obstacles were overlooked in the nanoparticle{\textquoteright}s journey. However, some of these challenges may be turned into opportunities. Here, we discuss biological barriers to cancer nanomedicines and elaborate on two directions that the field is currently exploring to meet its initial expectations. The first strategy entails re-engineering cancer nanomedicines to prevent undesired interactions en route to the tumour. The second aims instead to leverage these obstacles into out-of-the-box diagnostic and therapeutic applications of nanomedicines, for cancer and beyond. Both paths require, among other developments, a deeper understanding of nano-bio interactions. We offer a forward look at how classic cancer nanomedicine may overcome its limitations while contributing to other areas of research.},
	keywords = {Drug Carriers, Drug Delivery Systems, Humans, Nanomedicine, Nanoparticles, Neoplasms},
	issn = {1476-1122},
	doi = {10.1038/s41563-021-01047-7},
	author = {de L{\'a}zaro, Irene and Mooney, David J}
}
@article {1576543,
	title = {Active biomaterials for mechanobiology},
	journal = {Biomaterials},
	volume = {267},
	year = {2021},
	month = {2021 Jan},
	pages = {120497},
	abstract = {Active biomaterials offer novel approaches to study mechanotransduction in mammalian cells. These material systems probe cellular responses by dynamically modulating their resistance to endogenous forces or applying exogenous forces on cells in a temporally controlled manner. Stimuli-responsive molecules, polymers, and nanoparticles embedded inside cytocompatible biopolymer networks transduce external signals such as light, heat, chemicals, and magnetic fields into changes in matrix elasticity (few kPa to tens of kPa) or forces (few pN to several μN) at the cell-material interface. The implementation of active biomaterials in mechanobiology has generated scientific knowledge and therapeutic potential relevant to a variety of conditions including but not limited to cancer metastasis, fibrosis, and tissue regeneration. We discuss the repertoire of cellular responses that can be studied using these platforms including receptor signaling as well as downstream events namely, cytoskeletal organization, nuclear shuttling of mechanosensitive transcriptional regulators, cell migration, and differentiation. We highlight recent advances in active biomaterials and comment on their future impact.},
	keywords = {Animals, Biocompatible Materials, Biophysics, Cell Differentiation, Mechanotransduction, Cellular, Polymers},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2020.120497},
	author = {{\"O}zkale, Berna and Sakar, Mahmut Selman and Mooney, David J}
}
@article {1576536,
	title = {A novel two-component, expandable bioadhesive for exposed defect coverage: Applicability to prenatal procedures},
	journal = {J Pediatr Surg},
	volume = {56},
	number = {1},
	year = {2021},
	month = {2021 Jan},
	pages = {165-169},
	abstract = {BACKGROUND/PURPOSE: We sought to test select properties of a novel, expandable bioadhesive composite that allows for enhanced adhesion control in liquid environments.

METHODS: Rabbit fetuses (n = 23) underwent surgical creation of spina bifida on gestational day 22-25 (term 32-33 days). Defects were immediately covered with a two-component tough adhesive consisting of a hydrogel made of a double network of ionically crosslinked alginate and covalently crosslinked polyacrylamide linked to a bridging chitosan polymer adhesive. Animals were euthanized prior to term for different analyses, including hydraulic pressure testing.

RESULTS: Hydrogels remained adherent in 70\% (16/23) of the recovered fetuses and in all of the last 14 fetuses as the procedure was optimized. Adherent hydrogels showed a median two-fold (IQR: 1.7-2.4) increase in area at euthanasia, with defect coverage confirmed by ultrasound and histology. The median maximum pressure to repair failure was 15 mmHg (IQR: 7.8-55.3), exceeding reported neonatal cerebrospinal fluid pressures.

CONCLUSIONS: This novel bioadhesive composite allows for selective, stable attachment of an alginate-polyacrylamide hydrogel to specific areas of the spina bifida defect in a fetal rabbit model, while the hydrogel expands with the defect over time. It could become a valuable alternative for the prenatal repair of spina bifida and possibly other congenital anomalies.

TYPE OF STUDY: N/A (animal and laboratory study).

LEVEL OF EVIDENCE: N/A (animal and laboratory study).},
	keywords = {Alginates, Animals, Biological Dressings, Disease Models, Animal, Female, Fetal Diseases, Fetoscopy, Fetus, Hydrogels, Pregnancy, Prenatal Care, Rabbits, Spinal Dysraphism},
	issn = {1531-5037},
	doi = {10.1016/j.jpedsurg.2020.09.030},
	author = {Lazow, Stefanie P and Labuz, Daniel F and Freedman, Benjamin R and Rock, Anna and Zurakowski, David and Mooney, David J and Fauza, Dario O}
}
@article {1576531,
	title = {3D encapsulation and inflammatory licensing of mesenchymal stromal cells alter the expression of common reference genes used in real-time RT-qPCR},
	journal = {Biomater Sci},
	volume = {8},
	number = {23},
	year = {2020},
	month = {2020 Dec 07},
	pages = {6741-6753},
	abstract = {Human mesenchymal stromal cells (hMSCs) hold great promise in the treatment of inflammatory and immune diseases, due to their immunomodulatory capacity. Their therapeutic activity is often assessed measuring levels of expression of immunomodulatory genes such as indoleamine 2,3-dioxygenase 1 (IDO1) and real-time RT-qPCR is most predominantly the method of choice due to its high sensitivity and relative simplicity. Currently, multiple strategies are explored to promote hMSC-mediated immunomodulation, overlooking the effects they pose in the expression of genes commonly used as internal calibrators in real-time RT-qPCR analyses. However, variations in their expression could introduce significant errors in the evaluation of the therapeutic potential of hMSCs. This work investigates, for the first time, how some of these strategies - 3D encapsulation, the mechanical properties of the 3D matrix and inflammatory licensing - influence the expression of common reference genes in hMSCs. Both 3D encapsulation and inflammatory licensing alter significantly the expression of β-actin (ACTB) and Ubiquitin C (UBC), respectively. Using them as normalization factors leads to an erroneous assessment of IDO1 mRNA levels, therefore resulting in over or underestimation of the therapeutic potential of hMSCs. In contrast, the range of mechanical properties of the matrix encapsulating the cells did not significantly affect the expression of any of the reference genes studied. Moreover, we identify RPS13 and RPL30 as reference genes of choice under these particular experimental conditions. These results demonstrate the vital importance of validating the expression of reference genes to correctly assess the therapeutic potential of hMSCs by real-time RT-qPCR.},
	keywords = {Gene Expression Profiling, Humans, Immunomodulation, Mesenchymal Stem Cells, Real-Time Polymerase Chain Reaction, RNA, Messenger},
	issn = {2047-4849},
	doi = {10.1039/d0bm01562h},
	author = {Gonzalez-Pujana, Ainhoa and de L{\'a}zaro, Irene and Vining, Kyle H and Santos-Vizcaino, Edorta and Igartua, Manoli and Hernandez, Rosa Maria and Mooney, David J}
}
@article {1576544,
	title = {Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors},
	journal = {Nat Commun},
	volume = {11},
	number = {1},
	year = {2020},
	month = {2020 11 10},
	pages = {5696},
	abstract = {Poorly immunogenic tumors, including triple negative breast cancers (TNBCs), remain resistant to current immunotherapies, due in part to the difficulty of reprogramming the highly immunosuppressive tumor microenvironment (TME). Here we show that peritumorally injected, macroporous alginate gels loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) for concentrating dendritic cells (DCs), CpG oligonucleotides, and a doxorubicin-iRGD conjugate enhance the immunogenic death of tumor cells, increase systemic tumor-specific CD8 + T cells, repolarize tumor-associated macrophages towards an inflammatory M1-like phenotype, and significantly improve antitumor efficacy against poorly immunogenic TNBCs. This system also prevents tumor recurrence after surgical resection and results in 100\% metastasis-free survival upon re-challenge. This chemo-immunotherapy that concentrates DCs to present endogenous tumor antigens generated in situ may broadly serve as a facile platform to modulate the suppressive TME, and enable in situ personalized cancer vaccination.},
	keywords = {Animals, Antigens, Neoplasm, Biocompatible Materials, Biotechnology, Cancer Vaccines, CD8-Positive T-Lymphocytes, Dendritic Cells, Drug Delivery Systems, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Immunologic Factors, Immunotherapy, Macrophages, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Recurrence, Local, Neoplasms, Triple Negative Breast Neoplasms, Tumor Microenvironment},
	issn = {2041-1723},
	doi = {10.1038/s41467-020-19540-z},
	author = {Wang, Hua and Najibi, Alexander J and Sobral, Miguel C and Seo, Bo Ri and Lee, Jun Yong and Wu, David and Li, Aileen Weiwei and Verbeke, Catia S and Mooney, David J}
}
@article {1576538,
	title = {Biomaterials as Local Niches for Immunomodulation},
	journal = {Acc Chem Res},
	volume = {53},
	number = {9},
	year = {2020},
	month = {2020 09 15},
	pages = {1749-1760},
	abstract = {A major function of the immune system is to detect threat from foreign invaders, tissue damage, or cancer and to mount a counter response that resolves the threat, restores homeostasis, and supplies immunological memory to prevent a second assault. Our increasing understanding of the immune system has opened up numerous avenues for modulating immune responses against infections, cancer, and autoimmunity. However, agents used for immunomodulation have been traditionally administered systemically via bolus injection, leading to unintended consequences by disrupting homeostasis at nontarget sites. Consequently, systemic hyperactivation and hypoactivation can result from bolus administration of immune-activators and immunosuppressants, respectively. Macroscale biomaterial scaffolds can instead be placed at the intended target site to provide both localized, controlled release of immunomodulatory agents and control over local immune cell trafficking and function, potentially maximizing therapeutic efficacy and limiting systemic exposure. These scaffolds have found utility in the area of cancer immunotherapy, especially in situ cancer vaccination where controlled release of factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and the local presentation of tumor antigen and danger signals lead to the recruitment of immature dendritic cells and facilitate their activation and antigen presentation. These cells eventually migrate into secondary lymphoid organs where they prime tumor specific T cells for downstream tumor clearance. Scaffolds can also be used in adoptive T cell therapy to generate large numbers of potent antigen specific T cells or chimeric antigen receptor (CAR) T cells in vitro for subsequent delivery to patients. Macroscale biomaterial scaffolds have also found utility beyond cancer immunotherapy and have been developed to promote immune tolerance by regulatory T cell induction and to expedite tissue regeneration. The design of these macroscale biomaterial scaffolds considers their biocompatibility, biodegradability, mode of delivery, porosity, and kinetics of therapeutic cargo release. Consequently, the numerous approaches that have been developed to fabricate biomaterial scaffolds are aimed at tuning these parameters to achieve the desired therapeutic outcome. This Account will discuss the use of biomaterial scaffolds as niches for immunomodulation and will focus on (1) approaches that have been used to fabricate various biomaterial systems being employed as niches for immunomodulation and (2) how these biomaterial systems have been used to modulate immune responses, specifically in area of cancer immunotherapy, where we will discuss the role of macroscale biomaterial scaffolds for in situ vaccination and in vitro T cell expansion. We will also briefly discuss the utility of biomaterial scaffolds beyond cancer, drawing examples from tolerance and tissue regeneration.},
	keywords = {Animals, Biocompatible Materials, Cancer Vaccines, Gels, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Immunologic Factors, Immunotherapy, Nanoparticles, Neoplasms, Polylactic Acid-Polyglycolic Acid Copolymer, Receptors, Chimeric Antigen, Stem Cell Transplantation, T-Lymphocytes},
	issn = {1520-4898},
	doi = {10.1021/acs.accounts.0c00341},
	author = {Adu-Berchie, Kwasi and Mooney, David J}
}
@article {1576534,
	title = {Biomaterials functionalized with MSC secreted extracellular vesicles and soluble factors for tissue regeneration},
	journal = {Adv Funct Mater},
	volume = {30},
	number = {37},
	year = {2020},
	month = {2020 Sep 10},
	abstract = {The therapeutic benefits of mesenchymal stromal cell (MSC) transplantation have been attributed to their secreted factors, including extracellular vesicles (EVs) and soluble factors. The potential of employing the MSC secretome as an alternative acellular approach to cell therapy is being investigated in various tissue injury indications, but EVs administered via bolus injections are rapidly sequestered and cleared. However, biomaterials offer delivery platforms to enhance EV retention rates and healing efficacy. In this review, we highlight the mechanisms underpinning the therapeutic effects of MSC-EVs and soluble factors as effectors of immunomodulation and tissue regeneration, conferred primarily via their nucleic acid and protein contents. We discuss how manipulating the cell culture microenvironment or genetic modification of MSCs can further augment the potency of their secretions. The most recent advances in the development of EV-functionalized biomaterials that mediate enhanced angiogenesis and cell survival, while attenuating inflammation and fibrosis, are presented. Finally, some technical challenges to be considered for the clinical translation of biomaterials carrying MSC-secreted bioactive cargo are discussed.},
	issn = {1616-301X},
	doi = {10.1002/adfm.201909125},
	author = {Brennan, Meadhbh {\'A} and Layrolle, Pierre and Mooney, David J}
}
@article {1576541,
	title = {Cell and tissue engineering in lymph nodes for cancer immunotherapy},
	journal = {Adv Drug Deliv Rev},
	volume = {161-162},
	year = {2020},
	month = {2020},
	pages = {42-62},
	abstract = {In cancer, lymph nodes (LNs) coordinate tumor antigen presentation necessary for effective antitumor immunity, both at the levels of local cellular interactions and tissue-level organization. In this review, we examine how LNs may be engineered to improve the therapeutic outcomes of cancer immunotherapy. At the cellular scale, targeting the LNs impacts the potency of cancer vaccines, immune checkpoint blockade, and adoptive cell transfer. On a tissue level, macro-scale biomaterials mimicking LN features can function as immune niches for cell reprogramming or delivery in vivo, or be utilized in vitro to enable preclinical testing of drugs and vaccines. We additionally review strategies to induce ectopic lymphoid sites reminiscent of LNs that may improve antitumor T cell priming.},
	keywords = {Adoptive Transfer, Animals, Antineoplastic Agents, Immunological, Biocompatible Materials, Cancer Vaccines, Drug Administration Routes, Humans, Hydrogels, Immune Checkpoint Inhibitors, Immunotherapy, Immunotherapy, Adoptive, Lab-On-A-Chip Devices, Lymph Nodes, Nanoparticles, Neoplasms, Tissue Engineering, Tissue Scaffolds},
	issn = {1872-8294},
	doi = {10.1016/j.addr.2020.07.023},
	author = {Najibi, Alexander J and Mooney, David J}
}
@article {1576535,
	title = {Dual alginate crosslinking for local patterning of biophysical and biochemical properties},
	journal = {Acta Biomater},
	volume = {115},
	year = {2020},
	month = {2020 10 01},
	pages = {185-196},
	abstract = {Hydrogels with patterned biophysical and biochemical properties have found increasing attention in the biomaterials community. In this work, we explore alginate-based materials with two orthogonal crosslinking mechanisms: the spontaneous Diels-Alder reaction and the ultraviolet light-initiated thiol-ene reaction. Combining these mechanisms in one material and spatially restricting the location of the latter using photomasks, enables the formation of dual-crosslinked hydrogels with patterns in stiffness, biomolecule presentation and degradation, granting local control over cell behavior. Patterns in stiffness are characterized morphologically by confocal microscopy and mechanically by uniaxial compression and microindentation measurement. Mouse embryonic fibroblasts seeded on stiffness-patterned substrates attach preferably and attain a spread morphology on stiff compared to soft regions. Human mesenchymal stem cells demonstrate preferential adipogenic differentiation on soft surfaces and osteogenic differentiation on stiff surfaces. Patterns in biomolecule presentation reveal favored attachment of mouse pre-osteoblasts on stripe regions, where thiolated cell-adhesive biomolecules have been coupled. Patterns in degradation are visualized by microindentation measurement following collagenase exposure. Patterned tissue infiltration into degradable regions on the surface is discernible in n=5/12 samples, when these materials are implanted subcutaneously into the backs of mice. Taken together, these results demonstrate that our hydrogel system with patterns in biophysical and biochemical properties enables the study of how environmental cues affect multiple cell behaviors in vitro and could be applied to guide endogenous tissue growth in diverse healing scenarios in vivo. STATEMENT OF SIGNIFICANCE: Hydrogels with patterns in biophysical and biochemical properties have been explored in the biomaterials community in order to spatially control or guide cell behavior. In our alginate-based system, we demonstrate the effect of local substrate stiffness and biomolecule presentation on the in vitro cell attachment, morphology, migration and differentiation behavior of two different mouse cell lines and human primary cells. Additionally, the effect of degradation patterns on the in vivo tissue infiltration is analyzed following subcutaneous implantation into a mouse model. The achievement of patterned tissue infiltration following the hydrogel template represents an important step towards guiding endogenous healing responses, thus inviting application in various tissue engineering contexts.},
	keywords = {Alginates, Animals, Fibroblasts, Hydrogels, Mice, Osteogenesis, Tissue Engineering},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2020.07.047},
	author = {Lueckgen, Aline and Garske, Daniela S and Ellinghaus, Agnes and Mooney, David J and Duda, Georg N and Cipitria, Amaia}
}
@article {1576530,
	title = {Effects of extracellular matrix viscoelasticity on cellular behaviour},
	journal = {Nature},
	volume = {584},
	number = {7822},
	year = {2020},
	month = {2020 08},
	pages = {535-546},
	abstract = {Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials-they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell-matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.},
	keywords = {Biocompatible Materials, Cell Culture Techniques, Cell Shape, Elasticity, Extracellular Matrix, Humans, Mechanotransduction, Cellular, Mesenchymal Stem Cells, Models, Biological, Regenerative Medicine, Viscoelastic Substances},
	issn = {1476-4687},
	doi = {10.1038/s41586-020-2612-2},
	author = {Chaudhuri, Ovijit and Cooper-White, Justin and Janmey, Paul A. and Mooney, David J and Shenoy, Vivek B}
}
@article {1576539,
	title = {Engineered tissues and strategies to overcome challenges in drug development},
	journal = {Adv Drug Deliv Rev},
	volume = {158},
	year = {2020},
	month = {2020},
	pages = {116-139},
	abstract = {Current preclinical studies in drug development utilize high-throughput in vitro screens to identify drug leads, followed by both in vitro and in vivo models to predict lead candidates{\textquoteright} pharmacokinetic and pharmacodynamic properties. The goal of these studies is to reduce the number of lead drug candidates down to the most likely to succeed in later human clinical trials. However, only 1 in 10 drug candidates that emerge from preclinical studies will succeed and become an approved therapeutic. Lack of efficacy or undetected toxicity represents roughly 75\% of the causes for these failures, despite these parameters being the primary exclusion criteria in preclinical studies. Recently, advances in both biology and engineering have created new tools for constructing new preclinical models. These models can complement those used in current preclinical studies by helping to create more realistic representations of human tissues in vitro and in vivo. In this review, we describe current preclinical models to identify their value and limitations and then discuss select areas of research where improvements in preclinical models are particularly needed to advance drug development. Following this, we discuss design considerations for constructing preclinical models and then highlight recent advances in these efforts. Taken together, we aim to review the advances as of 2020 surrounding the prospect of biological and engineering tools for adding enhanced biological relevance to preclinical studies to aid in the challenges of failed drug candidates and the burden this poses on the drug development enterprise and thus healthcare.},
	keywords = {Animals, Drug Development, Drug Discovery, Drug Evaluation, Preclinical, Humans, In Vitro Techniques, Models, Animal, Models, Biological, Neoplasms, Neurodegenerative Diseases, Obesity, Tissue Engineering, Vaccines},
	issn = {1872-8294},
	doi = {10.1016/j.addr.2020.09.012},
	author = {Khalil, Andrew S and Jaenisch, Rudolf and Mooney, David J}
}
@article {1576537,
	title = {Extracellular matrix plasticity as a driver of cell spreading},
	journal = {Proc Natl Acad Sci U S A},
	volume = {117},
	number = {42},
	year = {2020},
	month = {2020 10 20},
	pages = {25999-26007},
	abstract = {Mammalian cell morphology has been linked to the viscoelastic properties of the adhesion substrate, which is particularly relevant in biological processes such as wound repair and embryonic development where cell spreading and migration are critical. Plastic deformation, degradation, and relaxation of stress are typically coupled in biomaterial systems used to explore these effects, making it unclear which variable drives cell behavior. Here we present a nondegradable polymer architecture that specifically decouples irreversible creep from stress relaxation and modulus. We demonstrate that network plasticity independently controls mesenchymal stem cell spreading through a biphasic relationship dependent on cell-intrinsic forces, and this relationship can be shifted by inhibiting actomyosin contractility. Kinetic Monte Carlo simulations also show strong correlation with experimental cell spreading data as a function of the extracellular matrix (ECM) plasticity. Furthermore, plasticity regulates many ECM adhesion and remodeling genes. Altogether, these findings confirm a key role for matrix plasticity in stem cell biophysics, and we anticipate this will have ramifications in the design of biomaterials to enhance therapeutic applications of stem cells.},
	keywords = {Alginates, Cell Adhesion, Cell Culture Techniques, Cell Plasticity, Extracellular Matrix, Humans, Hydrogels, Mechanotransduction, Cellular, Mesenchymal Stem Cells, Polymers, Rheology, Stress, Mechanical, Viscoelastic Substances},
	issn = {1091-6490},
	doi = {10.1073/pnas.2008801117},
	author = {Grolman, Joshua M and Weinand, Philipp and Mooney, David J}
}
@article {1576542,
	title = {Metabolic glycan labelling for cancer-targeted therapy},
	journal = {Nat Chem},
	volume = {12},
	number = {12},
	year = {2020},
	month = {2020 12},
	pages = {1102-1114},
	abstract = {Metabolic glycoengineering with unnatural sugars provides a powerful tool to label cell membranes with chemical tags for subsequent targeted conjugation of molecular cargos via efficient chemistries. This technology has been widely explored for cancer labelling and targeting. However, as this metabolic labelling process can occur in both cancerous and normal cells, cancer-selective labelling needs to be achieved to develop cancer-targeted therapies. Unnatural sugars can be either rationally designed to enable preferential labelling of cancer cells, or specifically delivered to cancerous tissues. In this Review Article, we will discuss the progress to date in design and delivery of unnatural sugars for metabolic labelling of tumour cells and subsequent development of tumour-targeted therapy. Metabolic cell labelling for cancer immunotherapy will also be discussed. Finally, we will provide a perspective on future directions of metabolic labelling of cancer and immune cells for the development of potent, clinically translatable cancer therapies.},
	keywords = {Animals, Antineoplastic Agents, Azides, Cell Line, Tumor, Cell Membrane, click chemistry, Drug Carriers, Humans, Immunotherapy, Monosaccharides, Neoplasms, Polysaccharides},
	issn = {1755-4349},
	doi = {10.1038/s41557-020-00587-w},
	author = {Wang, Hua and Mooney, David J}
}
@article {1576533,
	title = {Multifunctional biomimetic hydrogel systems to boost the immunomodulatory potential of mesenchymal stromal cells},
	journal = {Biomaterials},
	volume = {257},
	year = {2020},
	month = {2020 10},
	pages = {120266},
	abstract = {Mesenchymal stromal cells (MSCs) hold great therapeutic potential, in part because of their immunomodulatory properties. However, these properties can be transient and depend on multiple factors. Here, we developed a multifunctional hydrogel system to synergistically enhance the immunomodulatory properties of MSCs, using a combination of sustained inflammatory licensing and three-dimensional (3D) encapsulation in hydrogels with tunable mechanical properties. The immunomodulatory extracellular matrix hydrogels (iECM) consist of an interpenetrating network of click functionalized-alginate and fibrillar collagen, in which interferon γ (IFN-γ) loaded heparin-coated beads are incorporated. The 3D microenvironment significantly enhanced the expression of a wide panel of pivotal immunomodulatory genes in bone marrow-derived primary human MSCs (hMSCs), compared to two-dimensional (2D) tissue culture. Moreover, the inclusion of IFN-γ loaded heparin-coated beads prolonged the expression of key regulatory genes upregulated upon licensing, including indoleamine 2,3-dioxygenase 1 (IDO1) and galectin-9 (GAL9). At a protein level, iECM hydrogels enhanced the secretion of the licensing responsive factor Gal-9 by hMSCs. Its presence in hydrogel conditioned media confirmed the correct release and diffusion of the factors secreted by hMSCs from the system. Furthermore, co-culture of iECM-encapsulated hMSCs and activated human T cells resulted in suppressed proliferation, demonstrating direct regulation on immune cells. These data highlight the potential of iECM hydrogels to enhance the immunomodulatory properties of hMSCs in cell therapies.},
	keywords = {Biomimetics, Culture Media, Conditioned, Humans, Hydrogels, Immunomodulation, Mesenchymal Stem Cells},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2020.120266},
	author = {Gonzalez-Pujana, Ainhoa and Vining, Kyle H and Zhang, David K Y and Santos-Vizcaino, Edorta and Igartua, Manoli and Hernandez, Rosa Maria and Mooney, David J}
}
@article {1576540,
	title = {Regenerating Antithrombotic Surfaces through Nucleic Acid Displacement},
	journal = {ACS Biomater Sci Eng},
	volume = {6},
	number = {4},
	year = {2020},
	month = {2020 04 13},
	pages = {2159-2166},
	abstract = {Blood-contacting devices are commonly coated with antithrombotic agents to prevent clot formation and to extend the lifespan of the device. However, in vivo degradation of these bioactive surface agents ultimately limits device efficacy and longevity. Here, a regenerative antithrombotic catheter surface treatment is developed using oligodeoxynucleotide (ODN) toehold exchange. ODN strands modified to carry antithrombotic payloads can inhibit the thrombin enzyme when bound to a surface and exchange with rapid kinetics over multiple cycles, even while carrying large payloads. The surface-bound ODNs inhibit thrombin activity to significantly reduce fibrinogen cleavage and fibrin formation, and this effect is sustained after ODN exchange of the surface-bound strands with a fresh antithrombotic payload. This study presents a unique strategy for achieving a continuous antithrombotic state for blood-contacting devices using an ODN-based regeneration method.},
	keywords = {Fibrin, Fibrinogen, Fibrinolytic Agents, Nucleic Acids, Regeneration},
	issn = {2373-9878},
	doi = {10.1021/acsbiomaterials.0c00038},
	author = {McNamara, Stephanie L and Brudno, Yevgeny and Miller, Alex B and Ham, Hyun Oki and Aizenberg, Michael and Chaikof, Elliot L and Mooney, David J}
}
@article {1576532,
	title = {Steroid-Peptide Immunoconjugates for Attenuating T Cell Responses in an Experimental Autoimmune Encephalomyelitis Murine Model of Multiple Sclerosis},
	journal = {Bioconjug Chem},
	volume = {31},
	number = {12},
	year = {2020},
	month = {2020 12 16},
	pages = {2779-2788},
	abstract = {Diseases of immunity, including autoimmune diseases such as multiple sclerosis, transplantation graft rejection, allergy, and asthma, are prevalent and increasing in prevalence. They contribute to significant morbidity and mortality; however, few if any curative therapies exist, and those that are available lack either potency or specificity. Dendritic cells (DCs) are sentinels of the immune system that connect the innate and adaptive immune system and are critical regulators of both immunity and tolerance. We posited that the tolerogenic potential of DC could be harnessed to develop more specific and potent therapies for diseases of immunity by delivering autoantigen to a sufficient number of tolerogenic DCs in situ that could then inhibit pathogenic effector T cell responses. Specifically, we hypothesized that the steroid dexamethasone covalently coupled to a peptide antigen could be processed by DCs, induce tolerogenic DCs, and attenuate antigen-specific pathogenic T cell responses. To test this hypothesis, we synthesized a series of dexamethasone-peptide immunoconjugates by standard solid-phase peptide synthesis. The antigenic portion of the immunoconjugate could be presented by DCs, and the immunoconjugate induced a tolerogenic phenotype in DCs that then inhibited antigen-specific T cell proliferation in vitro. When the immunoconjugate was administered prophylactically in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis, disease was attenuated compared to dexamethasone and peptide delivered as uncoupled components. Together, this work demonstrates the utility of immunoconjugates for inducing tolerance while establishing the foundation for future studies exploring methods to enrich and target DCs for tolerogenic therapies.},
	keywords = {Adaptive Immunity, Animals, Dexamethasone, Encephalomyelitis, Autoimmune, Experimental, Immunity, Innate, Immunoconjugates, Mice, Multiple Sclerosis, Peptides, T-Lymphocytes},
	issn = {1520-4812},
	doi = {10.1021/acs.bioconjchem.0c00582},
	author = {Sands, R Warren and Tabansky, Inna and Verbeke, Catia S and Keskin, Derin and Michel, Samuel and Stern, Joel and Mooney, David J}
}
@article {1513167,
	title = {Extracellular matrix mechanics regulate transfection and SOX9-directed differentiation of mesenchymal stem cells},
	journal = {Acta Biomater},
	volume = {110},
	year = {2020},
	month = {2020 07 01},
	pages = {153-163},
	abstract = {Gene delivery within hydrogel matrices can potentially direct mesenchymal stem cells (MSCs) towards a chondrogenic fate to promote regeneration of cartilage. Here, we investigated whether the mechanical properties of the hydrogel containing the gene delivery systems could enhance transfection and chondrogenic programming of primary human bone marrow-derived MSCs. We developed collagen-I-alginate interpenetrating polymer network hydrogels with tunable stiffness and adhesion properties. The hydrogels were activated with nanocomplexed SOX9 polynucleotides to direct chondrogenic differentiation of MSCs. MSCs transfected within the hydrogels showed higher expression of chondrogenic markers compared to MSCs transfected in 2D prior to encapsulation. The nanocomplex uptake and resulting expression of transfected SOX9 were jointly enhanced by increased stiffness and cell-adhesion ligand density in the hydrogels. Further, transfection of SOX9 effectively induced MSCs chondrogenesis and reduced markers of hypertrophy compared to control matrices. These findings highlight the importance of matrix stiffness and adhesion as design parameters in gene-activated matrices for regenerative medicine. STATEMENT OF SIGNIFICANCE: Gene-activated matrices (GAMs) are biodegradable polymer networks integrating gene therapies, and they are promising technologies for supporting tissue regeneration. Despite this interest, there is still limited information on how to rationally design these systems. Here, we provide a systematic study of the effect of matrix stiffness and cell adhesion ligands on gene transfer efficiency. We show that high stiffness and the presence of cell-binding sites promote transfection efficiency and that this result is related to more efficient internalization and trafficking of the gene therapies. GAMs with optimized mechanical properties can induce cartilage formation and result in tissues with better characteristics for articular cartilage tissue engineering as compared to previously described standard methods.},
	keywords = {Cell Differentiation, Chondrogenesis, Extracellular Matrix, Humans, Hydrogels, Mesenchymal Stem Cells, SOX9 Transcription Factor, Transfection},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2020.04.027},
	author = {Ledo, Adriana M and Vining, Kyle H and Alonso, Maria J and Garcia-Fuentes, Marcos and Mooney, David J}
}
@article {1513168,
	title = {Metabolic labeling and targeted modulation of dendritic cells},
	journal = {Nat Mater},
	volume = {19},
	number = {11},
	year = {2020},
	month = {2020 11},
	pages = {1244-1252},
	abstract = {Targeted immunomodulation of dendritic cells (DCs) in vivo will enable manipulation of T-cell priming and amplification of anticancer immune responses, but a general strategy has been lacking. Here we show that DCs concentrated by a biomaterial can be metabolically labelled with azido groups in situ, which allows for their subsequent tracking and targeted modulation over time. Azido-labelled DCs were detected in lymph nodes for weeks, and could covalently capture dibenzocyclooctyne (DBCO)-bearing antigens and adjuvants via efficient Click chemistry for improved antigen-specific CD8+ T-cell responses and antitumour efficacy. We also show that azido labelling of DCs allowed for in vitro and in vivo conjugation of DBCO-modified cytokines, including DBCO-IL-15/IL-15Rα, to improve priming of antigen-specific CD8+ T cells. This DC labelling and targeted modulation technology provides an unprecedented strategy for manipulating DCs and regulating DC-T-cell interactions in vivo.},
	keywords = {Azides, Cancer Vaccines, Cell Line, Tumor, click chemistry, Dendritic Cells, Humans, Immunomodulation, Immunotherapy, Staining and Labeling},
	issn = {1476-1122},
	doi = {10.1038/s41563-020-0680-1},
	author = {Wang, Hua and Sobral, Miguel C and Zhang, David K Y and Cartwright, Adam N and Li, Aileen Weiwei and Dellacherie, Maxence O and Tringides, Christina M and Koshy, Sandeep T and Wucherpfennig, Kai W and Mooney, David J}
}
@article {1503077,
	title = {Activation and expansion of human T cells using artificial antigen-presenting cell scaffolds},
	journal = {Nat Protoc},
	volume = {15},
	number = {3},
	year = {2020},
	month = {2020 03},
	pages = {773-798},
	abstract = {Synthetic antigen-presenting cells (APCs) are used to mediate scalable ex vivo T-cell expansion for adoptive cell therapy. Recently, we developed APC-mimetic scaffolds (APC-ms), which present signals to T cells in a physiological manner to mediate rapid and controlled T-cell expansion. APC-ms are composed of individual high-aspect-ratio silica microrods loaded with soluble mitogenic cues and coated with liposomes of defined compositions, to form supported lipid bilayers. Membrane-bound ligands for stimulation and co-stimulation of T-cell receptors are presented via the fluid, synthetic membranes, while mitogenic cues are released slowly from the microrods. In culture, interacting T cells assemble the individual APC-ms microrods into a biodegradable 3D matrix. Compared to conventional methods, APC-ms facilitates several-fold greater polyclonal T-cell expansion and improved antigen-specific enrichment of rare T-cell subpopulations. Here we provide a detailed protocol for APC-ms synthesis and use for human T-cell activation, and discuss important considerations for material design and T-cell co-culture. This protocol describes the facile assembly of APC-ms in ~4 h and rapid expansion or enrichment of relevant T-cell clones in ,
	keywords = {Antigen-Presenting Cells, Cell Lineage, Cloning, Molecular, Gene Expression Regulation, Humans, T-Lymphocytes},
	issn = {1750-2799},
	doi = {10.1038/s41596-019-0249-0},
	author = {Zhang, David K Y and Cheung, Alexander S and Mooney, David J}
}
@article {1503073,
	title = {Alginate Hydrogels for  Bone Regeneration: The Immune Competence of the Animal Model Matters},
	journal = {Tissue Eng Part A},
	volume = {26},
	number = {15-16},
	year = {2020},
	month = {2020 08},
	pages = {852-862},
	abstract = {Biomaterials with tunable biophysical properties hold great potential for tissue engineering. The adaptive immune system plays an important role in bone regeneration. Our goal is to investigate the regeneration potential of cell-laden alginate hydrogels depending on the immune status of the animal model. Specifically, the regeneration potential of rat mesenchymal stromal cell (MSC)-laden, void-forming alginate hydrogels, with a stiffness optimized for osteogenic differentiation, is studied in 5-mm critical-sized femoral defects, in both T cell-deficient athymic Rowett Nude (RNU) rats and immunocompetent Sprague Dawley rats. Bone volume fraction, bone mineral density, and tissue mineral density are higher for athymic RNU nude rats 6 weeks postsurgery. In addition, these animals show a significantly higher number of total cells and cells with non-lymphocyte morphology at the defect site, while the number of cells with lymphocyte-like morphology is lower. Hydrogel degradation is slower and the remaining alginate fragments are surrounded by a thicker fibrous capsule. Ossification islands originating from alginate residues suggest that encapsulated MSCs differentiate into the osteogenic lineage and initiate the mineralization process. However, this effect is insufficient to fully bridge the bone defect in both animal models. Alginate hydrogels can be used to deliver MSCs and thereby recruit endogenous cells through paracrine signaling, but additional osteogenic stimuli are needed to regenerate critical-sized segmental femoral defects.},
	issn = {1937-335X},
	doi = {10.1089/ten.TEA.2019.0310},
	author = {Garske, Daniela S and Schmidt-Bleek, Katharina and Ellinghaus, Agnes and Dienelt, Anke and Gu, Luo and Mooney, David J and Duda, Georg N and Cipitria, Amaia}
}
@article {1503076,
	title = {A biomaterial-based vaccine eliciting durable tumour-specific responses against acute myeloid leukaemia},
	journal = {Nat Biomed Eng},
	volume = {4},
	number = {1},
	year = {2020},
	month = {2020 01},
	pages = {40-51},
	abstract = {Acute myeloid leukaemia (AML) is a malignancy of haematopoietic origin that has limited therapeutic options. The standard-of-care cytoreductive chemotherapy depletes AML cells to induce remission, but is infrequently curative. An immunosuppressive AML microenvironment in the bone marrow and the paucity of suitable immunotherapy targets limit the induction of effective immune responses. Here, in mouse models of AML, we show that a macroporous-biomaterial vaccine that delivers the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), the Toll-like-receptor-9 agonist cytosine-guanosine oligodeoxynucleotide and one or multiple leukaemia antigens (in the form of a defined peptide antigen, cell lysates or antigens sourced from AML cells recruited in vivo) induces local immune-cell infiltration and activated dendritic cells, evoking a potent anti-AML response. The biomaterial-based vaccine prevented the engraftment of AML cells when administered as a prophylactic and when combined with chemotherapy, and eradicated established AML even in the absence of a defined vaccine antigen. Biomaterial-based AML vaccination can induce potent immune responses, deplete AML cells and prevent disease relapse.},
	keywords = {Animals, Biocompatible Materials, Bone Marrow, Cancer Vaccines, Disease Models, Animal, Drug Development, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Leukemia, Myeloid, Acute, Mice, Inbred C57BL, Toll-Like Receptor 9},
	issn = {2157-846X},
	doi = {10.1038/s41551-019-0503-3},
	author = {Shah, Nisarg J and Najibi, Alexander J and Shih, Ting-Yu and Mao, Angelo S and Sharda, Azeem and Scadden, David T and Mooney, David J}
}
@article {1503075,
	title = {Compression-induced dedifferentiation of adipocytes promotes tumor progression},
	journal = {Sci Adv},
	volume = {6},
	number = {4},
	year = {2020},
	month = {2020 01},
	pages = {eaax5611},
	abstract = {Dysregulated physical stresses are generated during tumorigenesis that affect the surrounding compliant tissues including adipocytes. However, the effect of physical stressors on the behavior of adipocytes and their cross-talk with tumor cells remain elusive. Here, we demonstrate that compression of cells, resulting from various types of physical stresses, can induce dedifferentiation of adipocytes via mechanically activating Wnt/β-catenin signaling. The compression-induced dedifferentiated adipocytes (CiDAs) have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity, but do not form teratomas. We then show that CiDAs notably enhance human mammary adenocarcinoma proliferation both in vitro and in a xenograft model, owing to myofibrogenesis of CiDAs in the tumor-conditioned environment. Collectively, our results highlight unique physical interplay in the tumor ecosystem; tumor-induced physical stresses stimulate de novo generation of CiDAs, which feedback to tumor growth.},
	keywords = {Adipocytes, Animals, Cell Dedifferentiation, Cell Line, Tumor, Cell Transformation, Neoplastic, Disease Models, Animal, Disease Progression, Disease Susceptibility, Gene Expression Profiling, Humans, Mice, Neoplasms, Adipose Tissue, Stress, Mechanical, Xenograft Model Antitumor Assays},
	issn = {2375-2548},
	doi = {10.1126/sciadv.aax5611},
	author = {Li, Yiwei and Mao, Angelo S and Seo, Bo Ri and Zhao, Xing and Gupta, Satish Kumar and Chen, Maorong and Han, Yulong and Shih, Ting-Yu and Mooney, David J and Guo, Ming}
}
@article {1503072,
	title = {Filmed over with CAR-T cells},
	journal = {Nat Biomed Eng},
	volume = {4},
	number = {2},
	year = {2020},
	month = {2020 02},
	pages = {142-143},
	keywords = {Alloys, Humans, Immunotherapy, Adoptive, Neoplasms, T-Lymphocytes},
	issn = {2157-846X},
	doi = {10.1038/s41551-020-0517-x},
	author = {Adu-Berchie, Kwasi and Mooney, David J}
}
@article {1503069,
	title = {A nanoparticle{\textquoteright}s pathway into tumours},
	journal = {Nat Mater},
	volume = {19},
	number = {5},
	year = {2020},
	month = {2020 05},
	pages = {486-487},
	keywords = {Humans, Nanoparticles, Neoplasms},
	issn = {1476-1122},
	doi = {10.1038/s41563-020-0669-9},
	author = {de L{\'a}zaro, Irene and Mooney, David J}
}
@article {1503070,
	title = {Near-Infrared Fluorescence Hydrogen Peroxide Assay for Versatile Metabolite Biosensing in Whole Blood},
	journal = {Small},
	volume = {16},
	number = {20},
	year = {2020},
	month = {2020 05},
	pages = {e2000369},
	abstract = {In emergency medicine, blood lactate levels are commonly measured to assess the severity and response to treatment of hypoperfusion-related diseases (e.g., sepsis, trauma, cardiac arrest). Clinical blood lactate testing is conducted with laboratory analyzers, leading to a delay of 3 h between triage and lactate result. Here, a fluorescence-based blood lactate assay, which can be utilized for bedside testing, based on measuring the hydrogen peroxide generated by the enzymatic oxidation of lactate is described. To establish a hydrogen peroxide assay, near-infrared cyanine derivatives are screened and sulfo-cyanine 7 is identified as a new horseradish peroxidase (HRP) substrate, which loses its fluorescence in presence of HRP and hydrogen peroxide. As hydrogen peroxide is rapidly cleared by erythrocytic catalase and glutathione peroxidase, sulfo-cyanine 7, HRP, and lactate oxidase are encapsulated in a liposomal reaction compartment. In lactate-spiked bovine whole blood, the newly developed lactate assay exhibits a linear response in a clinically relevant range after 10 min. Substituting lactate oxidase with glucose and alcohol oxidase allows for blood glucose, ethanol, and methanol biosensing, respectively. This easy-to-use, rapid, and versatile assay may be useful for the quantification of a variety of enzymatically oxidizable metabolites, drugs, and toxic substances in blood and potentially other biological fluids.},
	issn = {1613-6829},
	doi = {10.1002/smll.202000369},
	author = {Matoori, Simon and Mooney, David J}
}
@article {1503071,
	title = {Soft extracellular matrix enhances inflammatory activation of mesenchymal stromal cells to induce monocyte production and trafficking},
	journal = {Sci Adv},
	volume = {6},
	number = {15},
	year = {2020},
	month = {2020 04},
	pages = {eaaw0158},
	abstract = {Mesenchymal stromal cells (MSCs) modulate immune cells to ameliorate multiple inflammatory pathologies. Biophysical signals that regulate this process are poorly defined. By engineering hydrogels with tunable biophysical parameters relevant to bone marrow where MSCs naturally reside, we show that soft extracellular matrix maximizes the ability of MSCs to produce paracrine factors that have been implicated in monocyte production and chemotaxis upon inflammatory stimulation by tumor necrosis factor-α (TNFα). Soft matrix increases clustering of TNF receptors, thereby enhancing NF-κB activation and downstream gene expression. Actin polymerization and lipid rafts, but not myosin-II contractility, regulate mechanosensitive activation of MSCs by TNFα. We functionally demonstrate that human MSCs primed with TNFα in soft matrix enhance production of human monocytes in marrow of xenografted mice and increase trafficking of monocytes via CCL2. The results suggest the importance of biophysical signaling in tuning inflammatory activation of stromal cells to control the innate immune system.},
	keywords = {Actins, Animals, Biomarkers, Cell Movement, Cells, Cultured, Chemotaxis, Cytokines, Extracellular Matrix, Humans, Inflammation, Inflammation Mediators, Lipid Metabolism, Mesenchymal Stem Cells, Mice, Monocytes, NF-kappa B, Protein Binding, Receptors, Tumor Necrosis Factor, Signal Transduction, Tumor Necrosis Factor-alpha},
	issn = {2375-2548},
	doi = {10.1126/sciadv.aaw0158},
	author = {Wong, Sing Wan and Lenzini, Stephen and Cooper, Madeline H and Mooney, David J and Shin, Jae-Won}
}
@article {1478948,
	title = {Clickable, acid labile immunosuppressive prodrugs for in vivo targeting},
	journal = {Biomater Sci},
	volume = {8},
	number = {1},
	year = {2020},
	month = {2020 Jan 01},
	pages = {266-277},
	abstract = {Allotransplantation offers the potential to restore the anatomy and function of injured tissues and organs, but typically requires life-long, systemic administration of immunosuppressive drugs to prevent rejection, which can result in serious complications. Targeting the immunosuppressive drug to the graft favors local tissue concentration versus systemic drug exposure and end-organ toxicity. This could reduce the overall dose and dosing frequency of immunosuppressive drugs, and improve the safety and efficacy of treatment. Here, we developed dibenzocyclooctyne (DBCO)-modified prodrugs of the immunosuppressive drugs tacrolimus, rapamycin and mycophenolic acid, and demonstrated their targeted conjugation both in vitro and in vivo to azido-modified hydrogels via Click chemistry. Such azido-modified hydrogels placed in transplanted tissues enable sustained local release of drugs, and could be repeatedly refilled with systemically administered acid-labile prodrugs after drug exhaustion. Thus, clickable prodrugs with degradable linkers provide new possibilities for graft targeted immunosuppression in the context of allotransplantation.},
	keywords = {Alginates, Animals, click chemistry, Drug Carriers, Drug Liberation, Half-Life, Hydrocarbons, Cyclic, Hydrogels, Hydrogen-Ion Concentration, Immunosuppressive Agents, Mice, Mice, Inbred BALB C, Mycophenolic Acid, Prodrugs, Sirolimus, Tacrolimus},
	issn = {2047-4849},
	doi = {10.1039/c9bm01487j},
	author = {Wang, Hua and Sobral, Miguel C and Snyder, Tracy and Brudno, Yevgeny and Gorantla, Vijay S and Mooney, David J}
}
@article {1478947,
	title = {Niche-mimicking interactions in peptide-functionalized 3D hydrogels amplify mesenchymal stromal cell paracrine effects},
	journal = {Biomaterials},
	volume = {230},
	year = {2020},
	month = {2020 02},
	pages = {119639},
	abstract = {Cells encounter complex environments in vivo where they interact with the extracellular matrix, neighboring cells, and soluble cues, which together influence their fate and function. However, the interplay of these interactions and their collective impact on the regenerative effects of mesenchymal stromal cells (MSCs) remains insufficiently explored. Here, we show that 3D culture in microporous (~125~μm) hydrogels that passively promote cell-cell interactions sensitizes MSCs to growth factors, particularly to IGF-1. IGF-1 enhances MSC paracrine secretion activity, and application of secreted factors to myoblasts potently stimulates their migration and differentiation. In contrast, the paracrine activity of MSCs encapsulated in nanoporous (~10~nm) hydrogels remain unchanged. Blocking N-cadherin on MSCs abrogates the stimulatory effects of IGF-1 in microporous but not nanoporous hydrogels. The role of N-cadherin in regulating MSC function is further clarified by functionalizing alginates with the HAVDI peptide sequence that is derived from the extracellular domain of N-cadherin and that acts to mimic cell-cell interactions. MSCs encapsulated in nanoporous HAVDI-gels, but not in gels functionalized with a scrambled sequence, show heightened paracrine activity in response to IGF-1. These findings reveal how interactions with the matrix, neighboring cells, and soluble factors impact and maximize the regenerative potential of MSCs.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2019.119639},
	author = {Qazi, Taimoor H and Mooney, David J and Duda, Georg N and Geissler, Sven}
}
@article {1465241,
	title = {Treating ischemia via recruitment of antigen-specific T cells},
	journal = {Sci Adv},
	volume = {5},
	number = {7},
	year = {2019},
	month = {2019 Jul},
	pages = {eaav6313},
	abstract = {Ischemic diseases are a leading cause of mortality and can result in autoamputation of lower limbs. We explored the hypothesis that implantation of an antigen-releasing scaffold, in animals previously vaccinated with the same antigen, can concentrate T2 T cells and enhance vascularization of ischemic tissue. This approach may be clinically relevant, as all persons receiving childhood vaccines recommended by the Centers for Disease Control and Prevention have vaccines that contain aluminum, a T2 adjuvant. To test the hypothesis, mice with hindlimb ischemia, previously vaccinated with ovalbumin (OVA) and aluminum, received OVA-releasing scaffolds. Vaccinated mice receiving OVA-releasing scaffolds locally concentrated antigen-specific T2 T cells in the surrounding ischemic tissue. This resulted in local angiogenesis, increased perfusion in ischemic limbs, and reduced necrosis and enhanced regenerating myofibers in the muscle. These findings support the premise that antigen depots may provide a treatment for ischemic diseases in patients previously vaccinated with aluminum-containing adjuvants.},
	issn = {2375-2548},
	doi = {10.1126/sciadv.aav6313},
	author = {Kwee, Brian J and Seo, Bo Ri and Najibi, Alexander J and Li, Aileen W and Shih, Ting-Yu and White, Des and Mooney, David J}
}
@article {1454913,
	title = {Antibiotic containing agarose hydrogel for wound and burn care},
	journal = {J Burn Care Res},
	year = {2019},
	month = {2019 Jun 27},
	abstract = {Wound infections cause inflammation, tissue damage and delayed healing that can lead to invasive infection and even death. The efficacy of systemic antibiotics is limited due to poor tissue penetration that is especially a problem in burn and blast wounds where the microcirculation is disrupted. Topical administration of antimicrobials is an attractive approach because it prevents infection and avoids systemic toxicity, while hydrogels are an appealing vehicle for topical drug delivery. They are easy to apply to the wound site by being injectable, the drug release properties can be controlled and their many characteristics, such as biodegradation, mechanical strength, and chemical and biological response to stimuli can be tailored. Hydrogels also create a moist wound environment that is beneficial for healing. The purpose of this study was to formulate an agarose hydrogel that contains high concentrations of minocycline or gentamicin and study its characteristics. Subsequently, the minocycline agarose hydrogel was tested in a porcine burn model and its effect as a prophylactic treatment was studied. The results demonstrated that 0.5 \% agarose in water was the optimal concentration in terms of viscosity and pH. Bench testing at room temperature demonstrated that both antibiotics remained stable in the hydrogel for at least 7 days and both antibiotics demonstrated sustained release over the time of the experiment. The porcine burn experiment showed that prophylactic treatment with the agarose minocycline hydrogel decreased the burn depth and reduced the number of bacteria as efficiently as the commonly used silver sulfadiazine cream.},
	issn = {1559-0488},
	doi = {10.1093/jbcr/irz113},
	author = {Grolman, Joshua M and Singh, Mansher and Mooney, David J and Eriksson, Elof and Nuutila, Kristo}
}
@article {1454910,
	title = {Bioinspired mechanically active adhesive dressings to accelerate wound closure},
	journal = {Sci Adv},
	volume = {5},
	number = {7},
	year = {2019},
	month = {2019 Jul},
	pages = {eaaw3963},
	abstract = {Inspired by embryonic wound closure, we present mechanically active dressings to accelerate wound healing. Conventional dressings passively aid healing by maintaining moisture at wound sites. Recent developments have focused on drug and cell delivery to drive a healing process, but these methods are often complicated by drug side effects, sophisticated fabrication, and high cost. Here, we present novel active adhesive dressings consisting of thermoresponsive tough adhesive hydrogels that combine high stretchability, toughness, tissue adhesion, and antimicrobial function. They adhere strongly to the skin and actively contract wounds, in response to exposure to the skin temperature. In vitro and in vivo studies demonstrate their efficacy in accelerating and supporting skin wound healing. Finite element models validate and refine the wound contraction process enabled by these active adhesive dressings. This mechanobiological approach opens new avenues for wound management and may find broad utility in applications ranging from regenerative medicine to soft robotics.},
	issn = {2375-2548},
	doi = {10.1126/sciadv.aaw3963},
	author = {Blacklow, S O and Li, J. and Freedman, B R and Zeidi, M and Chen, C and Mooney, D J}
}
@article {1454912,
	title = {Enzymatically-degradable alginate hydrogels promote cell spreading and in vivo tissue infiltration},
	journal = {Biomaterials},
	volume = {217},
	year = {2019},
	month = {2019 Oct},
	pages = {119294},
	abstract = {Enzymatically-degradable materials recapitulate the dynamic and reciprocal interactions between cells and their native microenvironment by allowing cells to actively shape the degradation process. In order to engineer a synthetic 3D environment enabling cells to orchestrate the degradation of the surrounding material, norbornene-modified alginate was crosslinked with two different peptide crosslinkers susceptible to cleavage by matrix metalloproteinases using UV-initiated thiol-ene chemistry. Resulting hydrogels were characterized for their initial mechanical and rheological properties, and their degradation behavior was measured by tracking changes in wet weight upon enzyme incubation. This process was found to be a function of the crosslinker type and enzyme concentration, indicating that degradation kinetics could be controlled and tuned. When mouse embryonic fibroblasts were encapsulated in 3D, cell number remained constant and viability was high in all materials, while cell spreading and extensive filopodia formation was observed only in the degradable gels, not in non-degradable controls. After implanting hydrogels into the backs of C57/Bl6 mice for 8 weeks, histological stainings of recovered gel remnants and surrounding tissue revealed higher tissue and cell infiltration into degradable materials compared to non-degradable controls. This alginate-based material platform with cell-empowered enzymatic degradation could prove useful in diverse tissue engineering contexts, such as regeneration and drug delivery.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2019.119294},
	author = {Lueckgen, Aline and Garske, Daniela S and Ellinghaus, Agnes and Mooney, David J and Duda, Georg N and Cipitria, Amaia}
}
@article {1454911,
	title = {Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation},
	journal = {Proc Natl Acad Sci U S A},
	volume = {116},
	number = {31},
	year = {2019},
	month = {2019 Jul 30},
	pages = {15392-15397},
	abstract = {Mesenchymal stem cell (MSC) therapies demonstrate particular promise in ameliorating diseases of immune dysregulation but are hampered by short in vivo cell persistence and inconsistencies in phenotype. Here, we demonstrate that biomaterial encapsulation into alginate using a microfluidic device could substantially increase in vivo MSC persistence after intravenous (i.v.) injection. A combination of cell cluster formation and subsequent cross-linking with polylysine led to an increase in injected MSC half-life by more than an order of magnitude. These modifications extended persistence even in the presence of innate and adaptive immunity-mediated clearance. Licensing of encapsulated MSCs with inflammatory cytokine pretransplantation increased expression of immunomodulatory-associated genes, and licensed encapsulates promoted repopulation of recipient blood and bone marrow with allogeneic donor cells after sublethal irradiation by a \~{}2-fold increase. The ability of microgel encapsulation to sustain MSC survival and increase overall immunomodulatory capacity may be applicable for improving MSC therapies in general.},
	issn = {1091-6490},
	doi = {10.1073/pnas.1819415116},
	author = {Mao, Angelo S and {\"O}zkale, Berna and Shah, Nisarg J and Vining, Kyle H and Descombes, Tiphaine and Zhang, Liyuan and Tringides, Christina M and Wong, Sing-Wan and Shin, Jae-Won and Scadden, David T and Weitz, David A and Mooney, David J}
}
@article {1442815,
	title = {Combined delivery of VEGF and IGF-1 promotes functional innervation in mice and improves muscle transplantation in rabbits},
	journal = {Biomaterials},
	volume = {216},
	year = {2019},
	month = {2019 Jun 07},
	pages = {119246},
	abstract = {Microvascular muscle transfer is the gold standard for reanimation following chronic facial nerve paralysis, however, despite the regenerative capacity of peripheral motor axons, poor reinnervation often results in sub-optimal function. We hypothesized that injection of alginate hydrogels releasing growth factors directly into donor tissue would promote reinnervation, muscle regeneration, and function. A murine model of sciatic nerve ligation and neurorrhaphy was first used to assess the ability of gel delivery of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) to promote functional reinnervation. VEGF~+~IGF-1 gel delivery to aged mice resulted in prolonged ability to control toe movement, increased toe spreading, and improved static sciatic index score, indicative of improved sciatic nerve and neuromuscular junction function. Further, a 26\% increase in muscle fiber area, and 2.8 and 3.0-fold increases in muscle contraction force and velocity, respectively, were found compared to blank alginate in the murine model. This strategy was subsequently tested in a rabbit model of craniofacial gracilis muscle transplantation. Electromyography demonstrated a 71\% increase in compound muscle action potential 9 weeks after transplantation following treatment with VEGF~+~IGF-1 alginate, compared to blank alginate in the rabbit model. Improving functional innervation in transplanted muscle via a hydrogel source of growth factors may enhance the therapeutic outcomes of facial palsy treatments and, more broadly, muscle transplantations.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2019.119246},
	author = {Raimondo, Theresa M and Li, Hehuan and Kwee, Brian J and Kinsley, Sarah and Budina, Erica and Anderson, Erin M and Doherty, Edward J and Simon G. Talbot and Mooney, David J}
}
@article {1442816,
	title = {Design molecular topology for wet-dry adhesion},
	journal = {ACS Appl Mater Interfaces},
	year = {2019},
	month = {2019 Jun 13},
	abstract = {Recent innovations highlight the integration of diverse materials with synthetic and biological hydrogels. Examples include brain-machine interfaces, tissue regeneration, and soft ionic devices. Existing methods of strong adhesion mostly focus on the chemistry of bonds and the mechanics of dissipation, but largely overlook the molecular topology of connection. Here, we highlight the significance of molecular topology by designing a specific bond-stitch topology. The bond-stitch topology achieves strong adhesion between preformed hydrogels and various materials, where the hydrogels have no functional groups for chemical coupling, and the adhered materials have functional groups on the surface. The adhesion principle requires a species of polymer chains to form bond with a material through complementary functional groups, and form a network in situ that stitches with the polymer network of a hydrogel. We study the physics and chemistry of this topology, and describe its potential applications in medicine and engineering.},
	issn = {1944-8252},
	doi = {10.1021/acsami.9b07522},
	author = {Yang, Jiawei and Bai, Ruobing and Li, Jianyu and Can Hui Yang and Yao, Xi and Liu, Qihan and Joost J. Vlassak and Mooney, David J and Zhigang Suo}
}
@article {1442817,
	title = {Multi-flow channel bioreactor enables real-time monitoring of cellular dynamics in 3D engineered tissue},
	journal = {Commun Biol},
	volume = {2},
	year = {2019},
	month = {2019},
	pages = {158},
	abstract = {The key to understanding, harnessing, and manipulating natural biological processes for the benefit of tissue engineering lies in providing a controllable dynamic environment for tissue development in vitro while being able to track cell activity in real time. This work presents a multi-channel bioreactor specifically designed to enable on-line imaging of fluorescently labeled cells embedded in replicated 3D engineered constructs subjected to different flow conditions. The images are acquired in 3D using a standard upright confocal microscope and further analyzed and quantified by computer vision. The platform is used to characterize and quantify the pace and directionality of angiogenic processes induced by flow. The presented apparatus bears considerable potential to advance scientific research, from basic research pursuing the effect of flow versus static conditions on 3D scaffolds and cell types, to clinically oriented modeling in drug screening and cytotoxicity assays.},
	issn = {2399-3642},
	doi = {10.1038/s42003-019-0400-z},
	author = {Zohar, Barak and Blinder, Yaron and Epshtein, Mark and Szklanny, Ariel A and Kaplan, Ben and Korin, Netanel and Mooney, David J and Levenberg, Shulamit}
}
@article {1434679,
	title = {Anti-tumor immunity induced by ectopic expression of viral antigens is transient and limited by immune escape},
	journal = {Oncoimmunology},
	volume = {8},
	number = {4},
	year = {2019},
	month = {2019},
	pages = {e1568809},
	abstract = {Immunotherapeutic treatments in head and neck cancer clinical trials include cancer vaccines targeting foreign viral antigens or mutational neoantigens derived from cancer-expressed proteins. Anti-tumor immune responses place cancer cells under selective pressure to lose or downregulate target antigens; therefore, vaccination against virus- or host- "driver" oncogenes are proposed as a strategy to overcome immune escape. Herein, we demonstrate the impact of immunogenic viral antigens on anti-tumor response and immune editing in MOC2-E6E7, a syngeneic murine oral cancer cell line expressing HPV-16 E6 and E7 oncoproteins. Using orthotopic syngeneic models, we observed  tumor growth kinetics of MOC2-E6E7 is delayed in immunocompetent mice compared to parental MOC2 tumors. In contrast, tumor growth remained similar in  mice lacking adaptive immunity. MOC2-E6E7 tumors demonstrated an "inflamed" or immune-activated tumor microenvironment and greater infiltration of CD8 T cells compared to MOC2. By real-time PCR, we detected downregulation of  and  genes in MOC2-E6E7 tumors only in immunocompetent mice, suggesting the loss of ectopic viral antigen expression due to immune editing. We then assessed the efficacy of a biomaterials-based mesoporous silica rod (MSR) cancer vaccine targeting HPV-16 E7 in our model. Vaccination induced robust infiltration of antigen-specific CD8~T cells, which led to tumor growth delay and modestly prolonged survival in MOC2-E6E7 tumors. Increased efficacy was seen in a separate head and neck cancer tumor model, mEER, which obligately expresses E7 antigen. Collectively, our data highlight the need for both immunogenicity and {\textquoteright}driver{\textquoteright} status of target antigens to be considered in cancer vaccine design.},
	issn = {2162-4011},
	doi = {10.1080/2162402X.2019.1568809},
	author = {Dharmaraj, Neeraja and Piotrowski, Stacey L and Huang, Chen and Newton, Jared M and Golfman, Leonard S and Hanoteau, Aurelie and Koshy, Sandeep T and Li, Aileen W and Pulikkathara, Merlyn X and Zhang, Bing and Burks, Jared K and Mooney, David J and Lei, Yu L and Sikora, Andrew G and Young, Simon}
}
@article {1434680,
	title = {Biomaterials to Mimic and Heal Connective Tissues},
	journal = {Adv Mater},
	year = {2019},
	month = {2019 Mar 25},
	pages = {e1806695},
	abstract = {Connective tissue is one of the four major types of animal tissue and plays essential roles throughout the human body. Genetic factors, aging, and trauma all contribute to connective tissue dysfunction and motivate the need for strategies to promote healing and regeneration. The goal here is to link a fundamental understanding of connective tissues and their multiscale properties to better inform the design and translation of novel biomaterials to promote their regeneration. Major clinical problems in adipose tissue, cartilage, dermis, and tendon are discussed that inspire the need to replace native connective tissue with biomaterials. Then, multiscale structure-function relationships in native soft connective tissues that may be used to guide material design are detailed. Several biomaterials strategies to improve healing of these tissues that incorporate biologics and are biologic-free are reviewed. Finally, important guidance documents and standards (ASTM, FDA, and EMA) that are important to consider for translating new biomaterials into clinical practice are highligted.},
	issn = {1521-4095},
	doi = {10.1002/adma.201806695},
	author = {Freedman, Benjamin R and Mooney, David J}
}
@article {1434678,
	title = {An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation},
	journal = {Nat Biotechnol},
	volume = {37},
	number = {3},
	year = {2019},
	month = {2019 03},
	pages = {293-302},
	abstract = {Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for multiple disorders, but deficiency and dysregulation of T cells limit its utility. Here we report a biomaterial-based scaffold that mimics features of T cell lymphopoiesis in the bone marrow. The bone marrow cryogel (BMC) releases bone morphogenetic protein-2 to recruit stromal cells and presents the Notch ligand Delta-like ligand-4 to facilitate T cell lineage specification of mouse and human hematopoietic progenitor cells. BMCs subcutaneously injected in mice at the time of HSCT enhanced T cell progenitor seeding of the thymus, T cell neogenesis and diversification of the T cell receptor repertoire. Peripheral T cell reconstitution increased ~6-fold in mouse HSCT and ~2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4 regulatory T cell generation and improved survival after allogeneic HSCT. In comparison to adoptive transfer of T cell progenitors, BMCs increased donor chimerism, T cell generation and antigen-specific T cell responses to vaccination. BMCs may provide an off-the-shelf approach for enhancing T cell regeneration and mitigating graft-versus-host disease in HSCT.},
	keywords = {Adoptive Transfer, Animals, Bone Marrow, Bone Marrow Transplantation, Chimerism, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Mice, T-Lymphocytes, Regulatory, Tissue Scaffolds, Transplantation, Heterologous, Transplantation, Homologous},
	issn = {1546-1696},
	doi = {10.1038/s41587-019-0017-2},
	author = {Shah, Nisarg J and Mao, Angelo S and Shih, Ting-Yu and Kerr, Matthew D and Sharda, Azeem and Raimondo, Theresa M and Weaver, James C and Vrbanac, Vladimir D and Deruaz, Maud and Tager, Andrew M and Mooney, David J and Scadden, David T}
}
@article {1434677,
	title = {Modular soft robotic microdevices for dexterous biomanipulation},
	journal = {Lab Chip},
	volume = {19},
	number = {5},
	year = {2019},
	month = {2019 Feb 26},
	pages = {778-788},
	abstract = {We present a methodology for building biologically inspired, soft microelectromechanical systems (MEMS) devices. Our strategy combines several advanced techniques including programmable colloidal self-assembly, light-harvesting with plasmonic nanotransducers, and in situ polymerization of compliant hydrogel mechanisms. We synthesize optomechanical microactuators using a template-assisted microfluidic approach in which gold nanorods coated with thermoresponsive poly(N-isopropylmethacrylamide) (pNIPMAM) polymer function as nanoscale building blocks. The resulting microactuators exhibit mechanical properties (4.8 {\textpm} 2.1 kPa stiffness) and performance metrics (relative stroke up to 0.3 and stress up to 10 kPa) that are comparable to that of bioengineered muscular constructs. Near-infrared (NIR) laser illumination provides effective spatiotemporal control over actuation (sub-micron spatial resolution at millisecond temporal resolution). Spatially modulated hydrogel photolithography guided by an experimentally validated finite element-based design methodology allows construction of compliant poly(ethylene glycol) diacrylate (PEGDA) mechanisms around the microactuators. We demonstrate the versatility of our approach by manufacturing a diverse array of microdevices including lever arms, continuum microrobots, and dexterous microgrippers. We present a microscale compression device that is developed for mechanical testing of three-dimensional biological samples such as spheroids under physiological conditions.},
	issn = {1473-0189},
	doi = {10.1039/c8lc01200h},
	author = {{\"O}zkale, Berna and Parreira, Raquel and Bekdemir, Ahmet and Pancaldi, Lucio and {\"O}zel{\c c}i, Ece and Amadio, Claire and Kaynak, Murat and Stellacci, Francesco and Mooney, David J and Sakar, Mahmut Selman}
}
@article {1405459,
	title = {Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels},
	journal = {Biomaterials},
	volume = {188},
	year = {2019},
	month = {2019 Jan},
	pages = {187-197},
	abstract = {Materials that can mimic the fibrillar architecture of native extracellular matrix (ECM) while allowing for independent regulation of viscoelastic properties may serve as ideal, artificial ECM (aECM) to regulate cell functions. Here we describe an interpenetrating network of click-functionalized alginate, crosslinked with a combination of ionic and covalent crosslinking, and fibrillar collagen type I. Varying the mode and magnitude of crosslinking enables tunable stiffness and viscoelasticity, while altering neither the hydrogel{\textquoteright}s microscale architecture nor diffusional transport of molecules with molecular weight relevant to typical nutrients. Further, appropriately timing sequential ionic and covalent crosslinking permits self-assembly of collagen into fibrillar structures within the network. Culture of human mesenchymal stem cells (MSCs) in this mechanically-tunable ECM system revealed that MSC expression of immunomodulatory markers is differentially impacted by the viscoelasticity and stiffness of the matrix. Together, these results describe and validate a novel material system for investigating how viscoelastic mechanical properties of ECM regulate cellular behavior.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2018.10.013},
	author = {Vining, Kyle H and Stafford, Alexander and Mooney, David J}
}
@article {1434681,
	title = {Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir},
	journal = {Nat Biomed Eng},
	volume = {2},
	number = {6},
	year = {2018},
	month = {2018 Jun},
	pages = {416-428},
	abstract = {The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use.},
	issn = {2157-846X},
	doi = {10.1038/s41551-018-0247-5},
	author = {Whyte, William and Ellen T Roche and Varela, Claudia E and Keegan Mendez and Islam, Shahrin and Hugh O{\textquoteright}Neill and Weafer, Fiona and Shirazi, Reyhaneh Neghabat and Weaver, James C and Nikolay V. Vasilyev and McHugh, Peter E and Murphy, Bruce and Duffy, Garry P and Conor J Walsh and Mooney, David J}
}
@article {1405460,
	title = {Functional muscle recovery with nanoparticle-directed M2 macrophage polarization in mice},
	journal = {Proc Natl Acad Sci U S A},
	volume = {115},
	number = {42},
	year = {2018},
	month = {2018 10 16},
	pages = {10648-10653},
	abstract = {Persistence of inflammation, and associated limits in tissue regeneration, are believed to be due in part to the imbalance of M1 over M2 macrophages. Here, we hypothesized that providing a sustained source of an antiinflammatory polarizing cytokine would shift the balance of macrophages at a site of tissue damage to improve functional regeneration. Specifically, IL-4-conjugated gold nanoparticles (PA4) were injected into injured murine skeletal muscle, resulting in improved histology and an \~{}40\% increase in muscle force compared with mice treated with vehicle only. Macrophages were the predominant infiltrating immune cell, and treatment with PA4 resulted in an approximately twofold increase in the percentage of macrophages expressing the M2a phenotype and an approximately twofold decrease in M1 macrophages, compared with mice treated with vehicle only. Intramuscular injection of soluble IL-4 did not shift macrophage polarization or result in functional muscle improvements. Depletion of monocytes/macrophages eliminated the therapeutic effects of PA4, suggesting that improvement in muscle function was the result of M2-shifted macrophage polarization. The ability of PA4 to direct macrophage polarization in vivo may be beneficial in the treatment of many injuries and inflammatory diseases.},
	keywords = {Animals, Cell Differentiation, Cell Proliferation, Female, Gold, Inflammation, Interleukin-4, Ischemia, Macrophages, Metal Nanoparticles, Mice, Mice, Inbred C57BL, Muscle, Skeletal, Phenotype, Recovery of Function},
	issn = {1091-6490},
	doi = {10.1073/pnas.1806908115},
	author = {Raimondo, Theresa M and Mooney, David J}
}
@article {1327619,
	title = {Biomaterial-assisted targeted modulation of immune cells in cancer treatment},
	journal = {Nat Mater},
	volume = {17},
	number = {9},
	year = {2018},
	month = {2018 Sep},
	pages = {761-772},
	abstract = {The past decade has witnessed the accelerating development of immunotherapies for cancer treatment. Immune checkpoint blockade therapies and chimeric antigen receptor (CAR)-T cell therapies have demonstrated clinical efficacy against a variety of cancers. However, issues including life-threatening off-target side effects, long processing times, limited patient responses and high cost still limit the clinical utility of cancer immunotherapies. Biomaterial carriers of these therapies, though, enable one to troubleshoot the delivery issues, amplify immunomodulatory effects, integrate the synergistic effect of different molecules and, more importantly, home and manipulate immune cells in vivo. In this Review, we will analyse thus-far developed immunomaterials for targeted modulation of dendritic cells, T cells, tumour-associated macrophages, myeloid-derived suppressor cells, B cells and natural killer cells, and summarize the promises and challenges of cell-targeted immunomodulation for cancer treatment.},
	issn = {1476-1122},
	doi = {10.1038/s41563-018-0147-9},
	author = {Wang, Hua and Mooney, David J}
}
@article {1327621,
	title = {Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes},
	journal = {FASEB J},
	year = {2018},
	month = {2018 Aug 08},
	pages = {fj201801059},
	abstract = {Diabetic foot ulcers (DFUs) are a major complication of diabetes, and there is a critical need to develop novel cell- and tissue-based therapies to treat these chronic wounds. Induced pluripotent stem cells (iPSCs) offer a replenishing source of allogeneic and autologous cell types that may be beneficial to improve DFU wound-healing outcomes. However, the biologic potential of iPSC-derived cells to treat DFUs has not, to our knowledge, been investigated. Toward that goal, we have performed detailed characterization of iPSC-derived fibroblasts from both diabetic and nondiabetic patients. Significantly, gene array and functional analyses reveal that iPSC-derived fibroblasts from both patients with and those without diabetes are more similar to each other than were the primary cells from which they were derived. iPSC-derived fibroblasts showed improved migratory properties in 2-dimensional culture. iPSC-derived fibroblasts from DFUs displayed a unique biochemical composition and morphology when grown as 3-dimensional (3D), self-assembled extracellular matrix tissues, which were distinct from tissues fabricated using the parental DFU fibroblasts from which they were reprogrammed. In vivo transplantation of 3D tissues with iPSC-derived fibroblasts showed they persisted in the wound and facilitated diabetic wound closure compared with primary DFU fibroblasts. Taken together, our findings support the potential application of these iPSC-derived fibroblasts and 3D tissues to improve wound healing.-Kashpur, O., Smith, A., Gerami-Naini, B., Maione, A. G., Calabrese, R., Tellechea, A., Theocharidis, G., Liang, L., Pastar, I., Tomic-Canic, M., Mooney, D., Veves, A., Garlick, J. A. Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes.},
	issn = {1530-6860},
	doi = {10.1096/fj.201801059},
	author = {Kashpur, Olga and Smith, Avi and Gerami-Naini, Behzad and Maione, Anna G and Calabrese, Rossella and Tellechea, Ana and Theocharidis, Georgios and Liang, Liang and Pastar, Irena and Tomic-Canic, Marjana and Mooney, David and Veves, Aristidis and Garlick, Jonathan A}
}
@article {1327620,
	title = {Hydrolytically-degradable click-crosslinked alginate hydrogels},
	journal = {Biomaterials},
	volume = {181},
	year = {2018},
	month = {2018 Jul 24},
	pages = {189-198},
	abstract = {Degradable biomaterials aim to recapitulate the dynamic microenvironment that cells are naturally exposed to. By oxidizing the alginate polymer backbone, thereby rendering it susceptible to hydrolysis, and crosslinking it via norbornene-tetrazine click chemistry, we can control rheological, mechanical, and degradation properties of resulting hydrogels. Chemical modifications were confirmed by nuclear magnetic resonance (NMR) and the resulting mechanical properties measured by rheology and unconfined compression testing, demonstrating that these are both a function of norbornene coupling and oxidation state. The degradation behavior was verified by tracking mechanical and swelling behavior over time, showing that degradation could be decoupled from initial mechanical properties. The cell compatibility was assessed in 2D and 3D using a mouse pre-osteoblast cell line and testing morphology, proliferation, and viability. Cells attached, spread and proliferated in 2D and retained a round morphology and stable number in 3D, while maintaining high viability in both contexts over 7 days. Finally, oxidized and unoxidized control materials were implanted subcutaneously into the backs of C57/Bl6 mice, and recovered after 8 weeks. Histological staining revealed morphological differences and fibrous tissue infiltration only in oxidized materials. These materials with tunable and decoupled mechanical and degradation behavior could be useful in many tissue engineering applications.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2018.07.031},
	author = {Lueckgen, Aline and Garske, Daniela S and Ellinghaus, Agnes and Desai, Rajiv M and Stafford, Alexander G and Mooney, David J and Duda, Georg N and Cipitria, Amaia}
}
@article {1327618,
	title = {Material microenvironmental properties couple to induce distinct transcriptional programs in mammalian stem cells},
	journal = {Proc Natl Acad Sci U S A},
	volume = {115},
	number = {36},
	year = {2018},
	month = {2018 09 04},
	pages = {E8368-E8377},
	abstract = {Variations in a multitude of material microenvironmental properties have been observed across tissues in vivo, and these have profound effects on cell phenotype. Phenomenological experiments have suggested that certain of these features of the physical microenvironment, such as stiffness, could sensitize cells to other features; meanwhile, mechanistic studies have detailed a number of biophysical mechanisms for this sensing. However, the broad molecular consequences of these potentially complex and nonlinear interactions bridging from biophysical sensing to phenotype have not been systematically characterized, limiting the overall understanding and rational deployment of these biophysical cues. Here, we explore these interactions by employing a 3D cell culture system that allows for the independent control of culture substrate stiffness, stress relaxation, and adhesion ligand density to systematically explore the transcriptional programs affected by distinct combinations of biophysical parameters using RNA-seq. In mouse mesenchymal stem cells and human cortical neuron progenitors, we find dramatic coupling among these substrate properties, and that the relative contribution of each property to changes in gene expression varies with cell type. Motivated by the bioinformatic analysis, the stiffness of hydrogels encapsulating mouse mesenchymal stem cells was found to regulate the secretion of a wide range of cytokines, and to accordingly influence hematopoietic stem cell differentiation in a Transwell coculture model. These results give insights into how biophysical features are integrated by cells across distinct tissues and offer strategies to synthetic biologists and bioengineers for designing responses to a cell{\textquoteright}s biophysical environment.},
	keywords = {Alginates, Animals, Cell Culture Techniques, Cell Differentiation, Glucuronic Acid, Hematopoietic Stem Cells, Hexuronic Acids, Hydrogels, Mesenchymal Stem Cells, Mice, Stem Cell Niche, Transcription, Genetic},
	issn = {1091-6490},
	doi = {10.1073/pnas.1802568115},
	author = {Darnell, Max and O{\textquoteright}Neil, Alison and Mao, Angelo and Gu, Luo and Rubin, Lee L and Mooney, David J}
}
@article {1327622,
	title = {RNA-seq reveals diverse effects of substrate stiffness on mesenchymal stem cells},
	journal = {Biomaterials},
	volume = {181},
	year = {2018},
	month = {2018 Jul 30},
	pages = {182-188},
	abstract = {Substrate stiffness has been recognized as an important regulator of cell fate and function, but an understanding of the full extent of processes affected by stiffness is lacking as its transcriptome-wide effects have not been mapped. This limited understanding has restricted the contexts in which engineers can employ stiffness as an engineering design parameter. To address these limitations, we performed RNA-seq on mesenchymal stem cells (MSCs) cultured in alginate hydrogels over a range of moduli to broadly map the transcriptome-wide changes associated with stiffness sensing. We found a large number of stiffness-sensitive genes, and that many genes respond to stiffness in nonlinear ways. Informed by these differential expression results, we explored a hypothesis related to current MSC clinical activity, and found that stiffness can regulate the expression of MSC immunomodulatory markers in response to cytokine stimulation. Overall, these results reveal previously unknown features of MSC stiffness response and demonstrate the value of coupling -omics approaches with biophysical experiments.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2018.07.039},
	author = {Darnell, Max and Gu, Luo and Mooney, David}
}
@article {1327617,
	title = {Targeting DEC-205DCIR2 dendritic cells promotes immunological tolerance in proteolipid protein-induced experimental autoimmune encephalomyelitis},
	journal = {Mol Med},
	volume = {24},
	number = {1},
	year = {2018},
	month = {2018 May 03},
	pages = {17},
	abstract = {BACKGROUND: Dendritic cells (DC) induce adaptive responses against foreign antigens, and play an essential role in maintaining peripheral tolerance to self-antigens. Therefore they are involved in preventing fatal autoimmunity. Selective delivery of antigens to immature DC via the endocytic DEC-205 receptor on their surface promotes antigen-specific T cell tolerance, both by recessive and dominant mechanisms. We provide evidence that the induction of antigen-specific T cell tolerance is not a unique property of CD11cCD8DEC-205 DCs.

METHODS: We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139-151 of myelin-derived proteolipid protein (PLP), to target CD11c CD8 DCs with a DEC-205-DCIR2 phenotype in vivo, and to substantially improve clinical symptoms in the PLP-induced model of experimental autoimmune encephalomyelitis (EAE).

RESULTS: Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP fusion antibody (Ab) depended on an immature state of targeted DCIR2 DCs. The mechanism of αDCIR2-PLP mAb function included the deletion of IL-17- and IFN-γ-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of αDEC-205 fusion antibodies, which involves extrathymic induction of a Foxp3 Treg cell phenotype in na{\"\i}ve CD4Foxp3 T cells, treatment of animals with DCIR2 fusion antibodies resulted in antigen-specific activation and proliferative expansion of natural Foxp3 Treg cells.

CONCLUSIONS: These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted.},
	issn = {1528-3658},
	doi = {10.1186/s10020-018-0017-6},
	author = {Tabansky, Inna and Keskin, Derin B and Watts, Deepika and Petzold, Cathleen and Funaro, Michael and Sands, Warren and Wright, Paul and Yunis, Edmond J and Najjar, Souhel and Diamond, Betty and Cao, Yonghao and Mooney, David and Kretschmer, Karsten and Stern, Joel N H}
}
@article {1317765,
	title = {CD4 T-cells regulate angiogenesis and myogenesis},
	journal = {Biomaterials},
	volume = {178},
	year = {2018},
	month = {2018 Jun 06},
	pages = {109-121},
	abstract = {Ischemic diseases, such as peripheral artery disease, affect millions of people worldwide. While CD4 T-cells regulate angiogenesis and myogenesis, it is not understood how the phenotype of these adaptive immune cells regulate these regenerative processes. The secreted factors from different types of CD4 T-cells (Th1, Th2, Th17, and Treg) were utilized in a series of in~vitro assays and delivered from an injectable alginate biomaterial into a murine model of ischemia to study their effects on vascular and skeletal muscle regeneration. Conditioned medium from Th2 and Th17  T-cells enhanced angiogenesis in~vitro and in~vivo, in part by directly stimulating endothelial sprouting. Th1 conditioned medium induced vascular regression in~vitro and provided no benefit to angiogenesis in~vivo. Th1, Th2, and Th17 conditioned medium, to varying extents, enhanced muscle precursor cell proliferation and inhibited their differentiation in~vitro, and prolonged early stages of muscle regeneration in~vivo. Treg conditioned medium had a moderate or no effect on these processes in~vitro and no discernible effect in~vivo. These findings suggest that Th2 and Th17 T-cells may enhance angiogenesis and myogenesis in ischemic injuries, which may be useful in the design of immunomodulatory biomaterials to treat these diseases.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2018.06.003},
	author = {Kwee, Brian J and Budina, Erica and Najibi, Alexander J and Mooney, David J}
}
@article {1317770,
	title = {Dental, Oral, and Craniofacial Regenerative Medicine: Transforming Biotechnologies for Innovating Patient Care},
	journal = {J Dent Res},
	volume = {97},
	number = {4},
	year = {2018},
	month = {2018 Apr},
	pages = {361-363},
	issn = {1544-0591},
	doi = {10.1177/0022034518761346},
	author = {Giannobile, W V and Chai, Y and Chen, Y. and Healy, K E and Klein, O and Lane, N and Longaker, M T and Lotz, J C and Mooney, D J and Sfeir, C S and Urata, M and Wagner, W R and Wu, B M and Kohn, D H}
}
@article {1317768,
	title = {Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics},
	journal = {Nanomaterials (Basel)},
	volume = {8},
	number = {5},
	year = {2018},
	month = {2018 May 03},
	abstract = {In calcific aortic valve disease (CAVD), microcalcifications originating from nanoscale calcifying vesicles disrupt the aortic valve (AV) leaflets, which consist of three (biomechanically) distinct layers: the fibrosa, spongiosa, and ventricularis. CAVD has no pharmacotherapy and lacks in vitro models as a result of complex valvular biomechanical features surrounding resident mechanosensitive valvular interstitial cells (VICs). We measured layer-specific mechanical properties of the human AV and engineered a three-dimensional (3D)-bioprinted CAVD model that recapitulates leaflet layer biomechanics for the first time. Human AV leaflet layers were separated by microdissection, and nanoindentation determined layer-specific Young\&rsquo;s moduli. Methacrylated gelatin (GelMA)/methacrylated hyaluronic acid (HAMA) hydrogels were tuned to duplicate layer-specific mechanical characteristics, followed by 3D-printing with encapsulated human VICs. Hydrogels were exposed to osteogenic media (OM) to induce microcalcification, and VIC pathogenesis was assessed by near infrared or immunofluorescence microscopy. Median Young\&rsquo;s moduli of the AV layers were 37.1, 15.4, and 26.9 kPa (fibrosa/spongiosa/ventricularis, respectively). The fibrosa and spongiosa Young\&rsquo;s moduli matched the 3D 5\% GelMa/1\% HAMA UV-crosslinked hydrogels. OM stimulation of VIC-laden bioprinted hydrogels induced microcalcification without apoptosis. We report the first layer-specific measurements of human AV moduli and a novel 3D-bioprinted CAVD model that potentiates microcalcification by mimicking the native AV mechanical environment. This work sheds light on valvular mechanobiology and could facilitate high-throughput drug-screening in CAVD.},
	issn = {2079-4991},
	doi = {10.3390/nano8050296},
	author = {van der Valk, Dewy C and van der Ven, Casper F T and Blaser, Mark C and Grolman, Joshua M and Wu, Pin-Jou and Fenton, Owen S and Lee, Lang H and Tibbitt, Mark W and Andresen, Jason L and Wen, Jennifer R and Ha, Anna H and Buffolo, Fabrizio and van Mil, Alain and Bouten, Carlijn V C and Body, Simon C and Mooney, David J and Sluijter, Joost P G and Aikawa, Masanori and Hjortnaes, Jesper and Langer, Robert and Elena Aikawa}
}
@article {1317769,
	title = {FGF2 Enhances Odontoblast Differentiation by αSMA Progenitors In Vivo},
	journal = {J Dent Res},
	year = {2018},
	month = {2018 Apr 01},
	pages = {22034518769827},
	abstract = {The goal of this study was to examine the effects of early and limited exposure of perivascular cells expressing α (αSMA) to fibroblast growth factor 2 (FGF2) in vivo. We performed in vivo fate mapping by inducible Cre-loxP and experimental pulp injury in molars to induce reparative dentinogenesis. Our results demonstrate that early delivery of exogenous FGF2 to exposed pulp led to proliferative expansion of αSMA-tdTomato cells and their accelerated differentiation into odontoblasts. In vivo lineage-tracing experiments showed that the calcified bridge/reparative dentin in FGF2-treated pulps were lined with an increased number of Dspp odontoblasts and devoid of BSP osteoblasts. The increased number of odontoblasts derived from αSMA-tdTomato cells and the formation of reparative dentin devoid of osteoblasts provide in vivo evidence for the stimulatory effects of FGF signaling on odontoblast differentiation from early progenitors in dental pulp.},
	issn = {1544-0591},
	doi = {10.1177/0022034518769827},
	author = {Vidovic-Zdrilic, I and Vining, K H and Vijaykumar, A and Kalajzic, I and Mooney, D J and Mina, M}
}
@article {1317766,
	title = {Replenishable drug depot to combat post-resection cancer recurrence},
	journal = {Biomaterials},
	year = {2018},
	month = {2018 May 06},
	abstract = {Local drug presentation made possible by drug-eluting depots has demonstrated benefits in a vast array of diseases, including in cancer, microbial infection and in wound healing. However, locally-eluting depots are single-use systems that cannot be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. New strategies to noninvasively refill drug-eluting depots could dramatically enhance their clinical use. In this report we present a refillable hydrogel depot system based on bioorthogonal click chemistry. The click-modified hydrogel depots capture prodrug refills from the blood and subsequently release active drugs locally in a sustained manner. Capture of the systemically-administered refills serves as an efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills achieve sustained release at precancerous tumor sites to improve cancer therapy while eliminating systemic side effects. The ability to target tissues without enhanced permeability could allow the use of refillable depots in cancer and many other medical applications.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2018.05.005},
	author = {Brudno, Yevgeny and Pezone, Matthew J and Snyder, Tracy K and Uzun, Oktay and Moody, Christopher T and Aizenberg, Michael and Mooney, David J}
}
@article {1317767,
	title = {Towards Alternative Approaches for Coupling of a Soft Robotic Sleeve to the Heart},
	journal = {Ann Biomed Eng},
	year = {2018},
	month = {2018 May 15},
	abstract = {Efficient coupling of soft robotic cardiac assist devices to the external surface of the heart is crucial to augment cardiac function and represents a hurdle to translation of this technology. In this work, we compare various fixation strategies for local and global coupling of a direct cardiac compression sleeve to the heart. For basal fixation, we find that a sutured Velcro band adheres the strongest to the epicardium. Next,~we demonstrate that a mesh-based sleeve coupled to the myocardium improves function in an acute porcine heart failure model. Then, we analyze the biological integration of global interface material candidates (medical mesh and silicone) in a healthy and infarcted murine model and show that a mesh interface yields superior mechanical coupling via pull-off force, histology, and microcomputed tomography. These results can inform the design of a therapeutic approach where a mesh-based soft robotic DCC is implanted, allowed to biologically integrate with the epicardium, and actuated for active assistance at a later timepoint. This strategy may result in more efficient coupling of extracardiac sleeves to heart tissue, and lead to increased augmentation of heart function in end-stage heart failure patients.},
	issn = {1573-9686},
	doi = {10.1007/s10439-018-2046-2},
	author = {Markus A. Horvath and Varela, Claudia E and Dolan, Eimear B and Whyte, William and Monahan, David S and Payne, Christopher J and Wamala, Isaac A and Nikolay V. Vasilyev and Frank A Pigula and Mooney, David J and Conor J Walsh and Duffy, Garry P and Ellen T Roche}
}
@article {1312615,
	title = {Matrix stiffness and tumor-associated macrophages modulate epithelial to mesenchymal transition of human adenocarcinoma cells},
	journal = {Biofabrication},
	volume = {10},
	number = {3},
	year = {2018},
	month = {2018 Mar 28},
	pages = {035004},
	abstract = {The tumor microenvironment (TME) is gaining increasing attention in oncology, as it is recognized to be functionally important during tumor development and progression. Tumors are heterogeneous tissues that, in addition to tumor cells, contain tumor-associated cell types such as immune cells, fibroblasts, and endothelial cells. These other cells, together with the specific extracellular matrix (ECM), create a permissive environment for tumor growth. While the influence of tumor-infiltrating cells and mechanical properties of the ECM in tumor invasion and progression have been studied separately, their interaction within the complex TME and the epithelial -to-mesenchymal transition (EMT) is still unclear. In this work, we develop a 3D co-culture model of lung adenocarcinoma cells and macrophages in an interpenetrating network hydrogel, to investigate the influence of the macrophage phenotype and ECM stiffness in the induction of EMT. Rising ECM stiffness increases both tumor cell proliferation and invasiveness. The presence of tumor-associated macrophages and the ECM stiffness jointly contribute to an invasive phenotype, and modulate the expression of key EMT-related markers. Overall, these findings support the utility of in vitro 3D cancer models that allow one to study interactions among key components of the TME.},
	issn = {1758-5090},
	doi = {10.1088/1758-5090/aaafbc},
	author = {Alonso-Nocelo, Marta and Raimondo, Theresa M and Vining, Kyle H and L{\'o}pez-L{\'o}pez, Rafael and de la Fuente, Maria and Mooney, David J}
}
@article {1303722,
	title = {Covalent Conjugation of Peptide Antigen to Mesoporous Silica Rods to Enhance Cellular Responses},
	journal = {Bioconjug Chem},
	year = {2018},
	month = {2018 Jan 10},
	abstract = {Short peptides are the minimal modality of antigen recognized by cellular immunity and are therefore considered a safe and highly specific source of antigen for vaccination. Nevertheless, successful peptide immunotherapy is limited by the short half-life of peptide antigens in vivo as well as their weak immunogenicity. We recently reported a vaccine strategy based on dendritic cell-recruiting Mesoporous Silica Rod (MSR) scaffolds to enhance T-cell responses against subunit antigen. In this study, we investigated the effect of covalently conjugating peptide antigens to MSRs to increase their retention in the scaffolds. Using both stable thioether and reducible disulfide linkages, peptide conjugation greatly increased peptide loading compared to passive adsorption. In vitro, Bone Marrow derived Dendritic Cells (BMDCs) could present Ovalbumin (OVA)-derived peptides conjugated to MSRs and induce antigen-specific T-cell proliferation. Stable conjugation decreased presentation in vitro while reducible conjugation maintained levels of presentation as high as soluble peptide. Compared to soluble peptide, in vitro, expansion of OT-II T-cells was not affected by adsorption or stable conjugation to MSRs but was enhanced with reversible conjugation to MSRs. Both conjugation schemes increased peptide residence time in MSR scaffolds in vivo compared to standard bolus injections or a simple adsorption method. When MSR scaffolds loaded with GM-CSF and CpG-ODN were injected subcutaneously, recruited dendritic cells could present antigen in situ with the stable conjugation increasing presentation capacity. Overall, this simple conjugation approach could serve as a versatile platform to efficiently incorporate peptide antigens in MSR vaccines and potentiate cellular responses.},
	issn = {1520-4812},
	doi = {10.1021/acs.bioconjchem.7b00656},
	author = {Dellacherie, Maxence O and Li, Aileen W and Lu, Beverly Y and Mooney, David J}
}
@article {1303715,
	title = {A facile approach to enhance antigen response for personalized cancer vaccination},
	journal = {Nat Mater},
	year = {2018},
	month = {2018 Mar 05},
	abstract = {Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumours in about 80\% of mice and generated immunological memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumour growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumour models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination.},
	issn = {1476-1122},
	doi = {10.1038/s41563-018-0028-2},
	author = {Li, Aileen Weiwei and Sobral, Miguel C and Badrinath, Soumya and Choi, Youngjin and Graveline, Amanda and Stafford, Alexander G and Weaver, James C and Dellacherie, Maxence O and Shih, Ting-Yu and Ali, Omar A and Kim, Jaeyun and Wucherpfennig, Kai W and Mooney, David J}
}
@article {1303717,
	title = {Injectable, Tough Alginate Cryogels as Cancer Vaccines},
	journal = {Adv Healthc Mater},
	year = {2018},
	month = {2018 Feb 14},
	abstract = {A covalently crosslinked methacrylated (MA)-alginate cryogel vaccine has been previously shown to generate a potent response against murine melanoma, but is not mechanically robust and requires a large 16G needle for delivery. Here, covalent and ionic crosslinking of cryogels are combined with the hypothesis that this will result in a tough MA-alginate cryogel with improved injectability. All tough cryogels can be injected through a smaller, 18G needle without sustaining any damage, while covalently crosslinked-only cryogels break after injection. Cytosine-phosphodiester-guanine (CpG)-delivering tough cryogels effectively activate dendritic cells (DCs). Granulocyte macrophage colony-stimulating factor releasing tough cryogels recruit four times more DCs than blank gels by day 7 in vivo. The tough cryogel vaccine induces strong antigen-specific cytotoxic T-lymphocyte and humoral responses. These vaccines prevent tumor formation in 80\% of mice inoculated with HER2/neu-overexpressing DD breast cancer cells. The MA-alginate tough cryogels provide a promising minimally invasive delivery platform for cancer vaccinations.},
	issn = {2192-2659},
	doi = {10.1002/adhm.201701469},
	author = {Shih, Ting-Yu and Blacklow, Serena O and Li, Aileen W and Freedman, Benjamin R and Bencherif, Sidi and Koshy, Sandeep T and Darnell, Max C and Mooney, David J}
}
@article {1303716,
	title = {A Ligand System for the Flexible Functionalization of Quantum Dots via Click Chemistry},
	journal = {Angew Chem Int Ed Engl},
	volume = {57},
	number = {17},
	year = {2018},
	month = {2018 Apr 16},
	pages = {4652-4656},
	abstract = {We present a novel ligand, 5-norbornene-2-nonanoic acid, which can be directly added during established quantum dot (QD) syntheses in organic solvents to generate "clickable" QDs at a few hundred nmol scale. This ligand has a carboxyl group at one terminus to bind to the surface of QDs and a norbornene group at the opposite end that enables straightforward phase transfer of QDs into aqueous solutions via efficient norbornene/tetrazine click chemistry. Our ligand system removes the traditional ligand-exchange step and can produce water-soluble QDs with a high quantum yield and a small hydrodynamic diameter of approximately 12 nm at an order of magnitude higher scale than previous methods. We demonstrate the effectiveness of our approach by incubating azido-functionalized CdSe/CdS QDs with 4T1 cancer cells that are metabolically labeled with a dibenzocyclooctyne-bearing unnatural sugar. The QDs exhibit high targeting efficiency and minimal nonspecific binding.},
	issn = {1521-3773},
	doi = {10.1002/anie.201801113},
	author = {Chen, Yue and Cordero, Jose M and Wang, Hua and Franke, Daniel and Achorn, Odin B and Freyria, Francesca S and Coropceanu, Igor and Wei, He and Chen, Ou and Mooney, David J and Bawendi, Moungi G}
}
@article {1303721,
	title = {Microfluidic Templated Multicompartment Microgels for 3D Encapsulation and Pairing of Single Cells},
	journal = {Small},
	volume = {14},
	number = {9},
	year = {2018},
	month = {2018 Mar},
	abstract = {Controlled encapsulation and pairing of single cells within a confined 3D matrix can enable the replication of the highly ordered cellular structure of human tissues. Microgels with independently controlled compartments that can encapsulate cells within separately confined hydrogel matrices would provide precise control over the route of pairing single cells. Here, a one-step microfluidic method is presented to generate monodisperse multicompartment microgels that can be used as a 3D matrix to pair single cells in a highly biocompatible manner. A method is presented to induce microgels formation on chip, followed by direct extraction of the microgels from oil phase, thereby avoiding prolonged exposure of the microgels to the oil. It is further demonstrated that by entrapping stem cells with niche cells within separate but adjacent compartments of the microgels, it can create complex stem cell niche microenvironments in a controlled manner, which can serve as a useful tool for the study of cell-cell interactions. This microfluidic technique represents a significant step toward high-throughput single cells encapsulation and pairing for the study of intercellular communications at single cell level, which is of significant importance for cell biology, stem cell therapy, and tissue engineering.},
	issn = {1613-6829},
	doi = {10.1002/smll.201702955},
	author = {Zhang, Liyuan and Chen, Kaiwen and Zhang, Haoyue and Pang, Bo and Choi, Chang-Hyung and Mao, Angelo S and Liao, Hongbing and Utech, Stefanie and Mooney, David J and Wang, Huanan and Weitz, David A}
}
@article {1303719,
	title = {Physical Polyurethane Hydrogels via Charge Shielding through Acids or Salts},
	journal = {Macromol Rapid Commun},
	year = {2018},
	month = {2018 Jan 31},
	abstract = {Physical hydrogels with tunable stress-relaxation and excellent stress recovery are formed from anionic polyurethanes via addition of acids, monovalent salts, or divalent salts. Gel properties can be widely adjusted through pH, salt valence, salt concentration, and monomer composition. We propose and investigate a novel gelation mechanism based on a colloidal system interacting through charge repulsion and chrage shielding, allowing a broad use of the material, from acidic (pH 4-5.5) to pH-neutral hydrogels with Young{\textquoteright}s moduli ranging from 10 to 140 kPa.},
	issn = {1521-3927},
	doi = {10.1002/marc.201700711},
	author = {Leiendecker, Mai-Thi and Licht, Christopher J and Borghs, Jannik and Mooney, David J and Zimmermann, Marc and B{\"o}ker, Alexander}
}
@article {1303720,
	title = {Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells},
	journal = {Nat Biotechnol},
	volume = {36},
	number = {2},
	year = {2018},
	month = {2018 Feb},
	pages = {160-169},
	abstract = {Therapeutic ex vivo T-cell expansion is limited by low rates and T-cell products of limited functionality. Here we describe a system that mimics natural antigen-presenting cells (APCs) and consists of a fluid lipid bilayer supported by mesoporous silica micro-rods. The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28, and interleukin-2, we show that the APC-mimetic scaffolds (APC-ms) promote two- to tenfold greater polyclonal expansion of primary mouse and human T cells compared with commercial expansion beads (Dynabeads). The efficiency of expansion depends on the density of stimulatory cues and the amount of material in the starting culture. Following a single stimulation, APC-ms enables antigen-specific expansion of rare cytotoxic T-cell subpopulations at a greater magnitude than autologous monocyte-derived dendritic cells after 2 weeks. APC-ms support over fivefold greater expansion of restimulated CD19 CAR-T cells than Dynabeads, with similar efficacy in a xenograft lymphoma model.},
	issn = {1546-1696},
	doi = {10.1038/nbt.4047},
	author = {Cheung, Alexander S and Zhang, David K Y and Koshy, Sandeep T and Mooney, David J}
}
@article {1303718,
	title = {Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs},
	journal = {Adv Healthc Mater},
	year = {2018},
	month = {2018 Feb 14},
	abstract = {Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine.},
	issn = {2192-2659},
	doi = {10.1002/adhm.201701393},
	author = {Li, Jianyu and Weber, Eckhard and Guth-Gundel, Sabine and Schuleit, Michael and Kuttler, Andreas and Halleux, Christine and Accart, Nathalie and Doelemeyer, Arno and Basler, Anne and Tigani, Bruno and Wuersch, Kuno and Fornaro, Mara and Kneissel, Michaela and Stafford, Alexander and Freedman, Benjamin R and Mooney, David J}
}
@article {1255141,
	title = {Injectable nanocomposite cryogels for versatile protein drug delivery},
	journal = {Acta Biomater},
	volume = {65},
	year = {2018},
	month = {2018 Jan},
	pages = {36-43},
	abstract = {Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems.

STATEMENT OF SIGNIFICANCE: Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein{\textquoteright}s activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2017.11.024},
	author = {Koshy, Sandeep T and Zhang, David K Y and Grolman, Joshua M and Stafford, Alexander G and Mooney, David J}
}
@article {1276581,
	title = {Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs},
	journal = {Biomaterials},
	volume = {140},
	year = {2017},
	month = {2017 Sep},
	pages = {103-114},
	abstract = {Mesenchymal stromal cells (MSCs) secrete paracrine factors that play crucial roles during tissue regeneration. Whether this paracrine function is influenced by the properties of biomaterials in general, and those used for cell delivery in particular, largely remains unexplored. Here, we investigated if three-dimensional culture in distinct microenvironments - nanoporous hydrogels (mean pore size \~{}5~nm) and macroporous scaffolds (mean pore size \~{}120~μm) - affects the secretion pattern of MSCs, and consequently leads to differential paracrine effects on target progenitor cells such as myoblasts. We report that compared to MSCs encapsulated in hydrogels, scaffold seeded MSCs show an enhanced secretion profile and exert beneficial paracrine effects on various myoblast functions including migration and proliferation. Additionally, we show that the heightened paracrine effects of scaffold seeded cells can in part be attributed to N-cadherin mediated cell-cell interactions during culture. In hydrogels, this physical interaction between cells is prevented by the encapsulating matrix. Functionally blocking N-cadherin negatively affected the secretion profile and paracrine effects of MSCs on myoblasts, with stronger effects observed for scaffold seeded compared to hydrogel encapsulated cells. Together, these findings demonstrate that the therapeutic potency of MSCs can be enhanced by biomaterials that promote cell-cell interactions.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2017.06.019},
	author = {Qazi, Taimoor H and Mooney, David J and Duda, Georg N and Geissler, Sven}
}
@article {1276566,
	title = {Cell volume change through water efflux impacts cell stiffness and stem cell fate},
	journal = {Proc Natl Acad Sci U S A},
	volume = {114},
	number = {41},
	year = {2017},
	month = {2017 Oct 10},
	pages = {E8618-E8627},
	abstract = {Cells alter their mechanical properties in response to their local microenvironment; this plays a role in determining cell function and can even influence stem cell fate. Here, we identify a robust and unified relationship between cell stiffness and cell volume. As a cell spreads on a substrate, its volume decreases, while its stiffness concomitantly increases. We find that both cortical and cytoplasmic cell stiffness scale with volume for numerous perturbations, including varying substrate stiffness, cell spread area, and external osmotic pressure. The reduction of cell volume is a result of water efflux, which leads to a corresponding increase in intracellular molecular crowding. Furthermore, we find that changes in cell volume, and hence stiffness, alter stem-cell differentiation, regardless of the method by which these are induced. These observations reveal a surprising, previously unidentified relationship between cell stiffness and cell volume that strongly influences cell biology.},
	issn = {1091-6490},
	doi = {10.1073/pnas.1705179114},
	author = {Guo, Ming and Pegoraro, Adrian F and Mao, Angelo and Zhou, Enhua H. and Arany, Praveen R and Han, Yulong and Burnette, Dylan T and Jensen, Mikkel H. and Kasza, Karen E. and Moore, Jeffrey R. and MacKintosh, Frederick C and Fredberg, Jeffrey J. and Mooney, David J and Lippincott-Schwartz, Jennifer and Weitz, David A}
}
@article {1276561,
	title = {Evaluation of a bioengineered construct for tissue engineering applications},
	journal = {J Biomed Mater Res B Appl Biomater},
	year = {2017},
	month = {2017 Nov 11},
	abstract = {Effective biomaterial options for tissue repair and regeneration are limited. Current biologic meshes are derived from different tissue sources and are generally sold as decellularized tissues. This work evaluated two collagen based bioengineered constructs and a commercial product in a model of abdominal full thickness defect repair. To prepare the bioengineered construct, collagen type 1 from porcine skin was isolated using an acid solubilization method. After purification, the collagen was formed into collagen sheets that were physically bonded to form a mechanically robust construct that was subsequently laser micropatterned with pores as a means to promote tissue integration (collagen only construct). A second engineered construct consisted of the aforementioned collagen construct embedded in an RGD-functionalized alginate gel that serves as a bioactive interface (collagen-alginate construct). The commercial product is a biologic mesh derived from bovine pericardium (Veritas{\textregistered} ). We observed enhanced vascularization in the midportion of the engineered collagen-alginate construct 2 weeks after implantation. Overall, the performance of the bioengineered constructs was similar to that of the commercial product with comparable integration strength at 8 weeks. Bioengineered constructs derived from monomeric collagen demonstrate promise for a variety of load bearing applications in tissue engineering. {\textcopyright} 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017.},
	issn = {1552-4981},
	doi = {10.1002/jbm.b.34042},
	author = {Ayala, Perla and Dai, Erbin and Hawes, Michael and Liu, Liying and Chaudhuri, Ovijit and Haller, Carolyn A and Mooney, David J and Chaikof, Elliot L}
}
@article {1276576,
	title = {In-situ tissue regeneration through SDF-1α driven cell recruitment and stiffness-mediated bone regeneration in a critical-sized segmental femoral defect},
	journal = {Acta Biomater},
	volume = {60},
	year = {2017},
	month = {2017 Sep 15},
	pages = {50-63},
	abstract = {In-situ tissue regeneration aims to utilize the body{\textquoteright}s endogenous healing capacity through the recruitment of host stem or progenitor cells to an injury site. Stromal cell-derived factor-1α (SDF-1α) is widely discussed as a potent chemoattractant. Here we use a cell-free biomaterial-based approach to (i) deliver SDF-1α for the recruitment of endogenous bone marrow-derived stromal cells (BMSC) into a critical-sized segmental femoral defect in rats and to (ii) induce hydrogel stiffness-mediated osteogenic differentiation in-vivo. Ionically crosslinked alginate hydrogels with a stiffness optimized for osteogenic differentiation were used. Fast-degrading porogens were incorporated to impart a macroporous architecture that facilitates host cell invasion. Endogenous cell recruitment to the defect site was successfully triggered through the controlled release of SDF-1α. A trend for increased bone volume fraction (BV/TV) and a significantly higher bone mineral density (BMD) were observed for gels loaded with SDF-1α, compared to empty gels at two weeks. A trend was also observed, albeit not statistically significant, towards matrix stiffness influencing BV/TV and BMD at two weeks. However, over a six week time-frame, these effects were insufficient for bone bridging of a segmental femoral defect. While mechanical cues combined with ex-vivo cell encapsulation have been shown to have an effect in the regeneration of less demanding in-vivo models, such as cranial defects of nude rats, they are not sufficient for a SDF-1α mediated in-situ regeneration approach in segmental femoral defects of immunocompetent rats, suggesting that additional osteogenic cues may also be required.

STATEMENT OF SIGNIFICANCE: Stromal cell-derived factor-1α (SDF-1α) is a chemoattractant used to recruit host cells for tissue regeneration. The concept that matrix stiffness can direct mesenchymal stromal cell (MSC) differentiation into various lineages was described a decade ago using in-vitro experiments. Recently, alginate hydrogels with an optimized stiffness and ex-vivo encapsulated MSCs were shown to have an effect in the regeneration of skull defects of nude rats. Here, we apply this material system, loaded with SDF-1α and without encapsulated MSCs, to (i) recruit endogenous cells and (ii) induce stiffness-mediated osteogenic differentiation in-vivo, using as model system a load-bearing femoral defect in immunocompetent rats. While a cell-free approach is of great interest from a translational perspective, the current limitations are described.},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2017.07.032},
	author = {Cipitria, Amaia and Boettcher, Kathrin and Schoenhals, Sophia and Garske, Daniela S and Schmidt-Bleek, Katharina and Ellinghaus, Agnes and Dienelt, Anke and Peters, Anja and Mehta, Manav and Madl, Christopher M and Huebsch, Nathaniel and Mooney, David J and Duda, Georg N}
}
@article {1276556,
	title = {Leveraging advances in biology to design biomaterials},
	journal = {Nat Mater},
	volume = {16},
	number = {12},
	year = {2017},
	month = {2017 Nov 24},
	pages = {1178-1185},
	abstract = {Biomaterials have dramatically increased in functionality and complexity, allowing unprecedented control over the cells that interact with them. From these engineering advances arises the prospect of improved biomaterial-based therapies, yet practical constraints favour simplicity. Tools from the biology community are enabling high-resolution and high-throughput bioassays that, if incorporated into a biomaterial design framework, could help achieve unprecedented functionality while minimizing the complexity of designs by identifying the most important material parameters and biological outputs. However, to avoid data explosions and to effectively match the information content of an assay with the goal of the experiment, material screens and bioassays must be arranged in specific ways. By borrowing methods to design experiments and workflows from the bioprocess engineering community, we outline a framework for the incorporation of next-generation bioassays into biomaterials design to effectively optimize function while minimizing complexity. This framework can inspire biomaterials designs that maximize functionality and translatability.},
	issn = {1476-1122},
	doi = {10.1038/nmat4991},
	author = {Darnell, Max and Mooney, David J}
}
@article {1276571,
	title = {Mechanical confinement regulates cartilage matrix formation by chondrocytes},
	journal = {Nat Mater},
	volume = {16},
	number = {12},
	year = {2017},
	month = {2017 Dec},
	pages = {1243-1251},
	abstract = {Cartilage tissue equivalents formed from hydrogels containing chondrocytes could provide a solution for replacing damaged cartilage. Previous approaches have often utilized elastic hydrogels. However, elastic stresses may restrict cartilage matrix formation and alter the chondrocyte phenotype. Here we investigated the use of viscoelastic hydrogels, in which stresses are relaxed over time and which exhibit creep, for three-dimensional (3D) culture of chondrocytes. We found that faster relaxation promoted a striking increase in the volume of interconnected cartilage matrix formed by chondrocytes. In slower relaxing gels, restriction of cell volume expansion by elastic stresses led to increased secretion of IL-1β, which in turn drove strong up-regulation of genes associated with cartilage degradation and cell death. As no cell-adhesion ligands are presented by the hydrogels, these results reveal cell sensing of cell volume confinement as an adhesion-independent mechanism of mechanotransduction in 3D culture, and highlight stress relaxation as a key design parameter for cartilage tissue engineering.},
	issn = {1476-1122},
	doi = {10.1038/nmat4993},
	author = {Lee, Hong-Pyo and Gu, Luo and Mooney, David J and Levenston, Marc E and Chaudhuri, Ovijit}
}
@article {1276586,
	title = {Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation},
	journal = {Nat Commun},
	volume = {8},
	year = {2017},
	month = {2017 May 31},
	pages = {15654},
	abstract = {DNA nanostructures have evoked great interest as potential therapeutics and diagnostics due to ease and robustness of programming their shapes, site-specific functionalizations and responsive behaviours. However, their utility in biological fluids can be compromised through denaturation induced by physiological salt concentrations and degradation mediated by nucleases. Here we demonstrate that DNA nanostructures coated by oligolysines to 0.5:1 N:P (ratio of nitrogen in lysine to phosphorus in DNA), are stable in low salt and up to tenfold more resistant to DNase I digestion than when uncoated. Higher N:P ratios can lead to aggregation, but this can be circumvented by coating instead with an oligolysine-PEG copolymer, enabling up to a 1,000-fold protection against digestion by serum nucleases. Oligolysine-PEG-stabilized DNA nanostructures survive uptake into endosomal compartments and, in a mouse model, exhibit a modest increase in pharmacokinetic bioavailability. Thus, oligolysine-PEG is a one-step, structure-independent approach that provides low-cost and effective protection of DNA nanostructures for in vivo applications.},
	issn = {2041-1723},
	doi = {10.1038/ncomms15654},
	author = {Ponnuswamy, Nandhini and Bastings, Maartje M C and Nathwani, Bhavik and Ryu, Ju Hee and Chou, Leo Y T and Vinther, Mathias and Li, Weiwei Aileen and Anastassacos, Frances M and Mooney, David J and Shih, William M}
}
@article {1276551,
	title = {Synthetic Light-Curable Polymeric Materials Provide a Supportive Niche for Dental Pulp Stem Cells},
	journal = {Adv Mater},
	year = {2017},
	month = {2017 Dec 07},
	abstract = {Dental disease annually affects billions of patients, and while regenerative dentistry aims to heal dental tissue after injury, existing polymeric restorative materials, or fillings, do not directly participate in the healing process in a bioinstructive manner. There is a need for restorative materials that can support native functions of dental pulp stem cells (DPSCs), which are capable of regenerating dentin. A polymer microarray formed from commercially available monomers to rapidly identify materials that support DPSC adhesion is used. Based on these findings, thiol-ene chemistry is employed to achieve rapid light-curing and minimize residual monomer of the lead materials. Several triacrylate bulk polymers support DPSC adhesion, proliferation, and differentiation in vitro, and exhibit stiffness and tensile strength similar to existing dental materials. Conversely, materials composed of a trimethacrylate monomer or bisphenol A glycidyl methacrylate, which is a monomer standard in dental materials, do not support stem cell adhesion and negatively impact matrix and signaling pathways. Furthermore, thiol-ene polymerized triacrylates are used as permanent filling materials at the dentin-pulp interface in direct contact with irreversibly injured pulp tissue. These novel triacrylate-based biomaterials have potential to enable novel regenerative dental therapies in the clinic by both restoring teeth and providing a supportive niche for DPSCs.},
	issn = {1521-4095},
	doi = {10.1002/adma.201704486},
	author = {Vining, Kyle H and Scherba, Jacob C and Bever, Alaina M and Alexander, Morgan R and Celiz, Adam D and Mooney, David J}
}
@article {1255131,
	title = {Mechanical forces direct stem cell behaviour in development and regeneration},
	journal = {Nat Rev Mol Cell Biol},
	volume = {18},
	number = {12},
	year = {2017},
	month = {2017 Dec},
	pages = {728-742},
	abstract = {Stem cells and their local microenvironment, or niche, communicate through mechanical cues to regulate cell fate and cell behaviour and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their self-renewal and differentiation. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and to examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.},
	keywords = {Adult Stem Cells, Animals, Biomechanical Phenomena, Extracellular Matrix, Humans, Organogenesis, Regeneration, Stem Cell Niche},
	issn = {1471-0080},
	doi = {10.1038/nrm.2017.108},
	author = {Vining, Kyle H and Mooney, David J}
}
@article {1192121,
	title = {Hydrogel substrate stress-relaxation regulates the spreading and proliferation of mouse myoblasts},
	journal = {Acta Biomater},
	volume = {62},
	year = {2017},
	month = {2017 Oct 15},
	pages = {82-90},
	abstract = {Mechanical properties of the extracellular microenvironment are known to alter cellular behavior, such as spreading, proliferation or differentiation. Previous studies have primarily focused on studying the effect of matrix stiffness on cells using hydrogel substrates that exhibit purely elastic behavior. However, these studies have neglected a key property exhibited by the extracellular matrix (ECM) and various tissues; viscoelasticity and subsequent stress-relaxation. As muscle exhibits viscoelasticity, stress-relaxation could regulate myoblast behavior such as spreading and proliferation, but this has not been previously studied. In order to test the impact of stress relaxation on myoblasts, we created a set of two-dimensional RGD-modified alginate hydrogel substrates with varying initial elastic moduli and rates of relaxation. The spreading of myoblasts cultured on soft stress-relaxing substrates was found to be greater than cells on purely elastic substrates of the same initial elastic modulus. Additionally, the proliferation of myoblasts was greater on hydrogels that exhibited stress-relaxation, as compared to cells on elastic hydrogels of the same modulus. These findings highlight stress-relaxation as an important mechanical property in the design of a biomaterial system for the culture of myoblasts.

STATEMENT OF SIGNIFICANCE: This article investigates the effect of matrix stress-relaxation on spreading and proliferation of myoblasts by using tunable elastic and stress-relaxing alginate hydrogels substrates with different initial elastic moduli. Many past studies investigating the effect of mechanical properties on cell fate have neglected the viscoelastic behavior of extracellular matrices and various tissues and used hydrogels exhibiting purely elastic behavior. Muscle tissue is viscoelastic and exhibits stress-relaxation. Therefore, stress-relaxation could regulate myoblast behavior if it were to be incorporated into the design of hydrogel substrates. Altogether, we showed that stress-relaxation impacts myoblasts spreading and proliferation. These findings enable a better understanding of myoblast behavior on viscoelastic substrates and could lead to the design of more suitable substrates for myoblast expansion in vitro.},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2017.08.041},
	author = {Bauer, Aline and Gu, Luo and Kwee, Brian and Li, Weiwei Aileen and Dellacherie, Maxence and Celiz, Adam D and Mooney, David J}
}
@article {1192116,
	title = {VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits},
	journal = {J Vasc Res},
	volume = {54},
	number = {5},
	year = {2017},
	month = {2017},
	pages = {288-298},
	abstract = {Biomaterial-based delivery of angiogenic growth factors restores perfusion more effectively than bolus delivery methods in rodent models of peripheral vascular disease, but the same success has not yet been demonstrated in clinically relevant studies of aged or large animals. These studies explore, in clinically relevant models, a therapeutic angiogenesis strategy for the treatment of peripheral vascular disease that overcomes the challenges encountered in previous clinical trials. Alginate hydrogels providing sustained release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF) were injected into ischemic hind limbs in middle-aged and old mice, and also in young rabbits, as a test of the scalability of this local growth factor treatment. Spontaneous perfusion recovery diminished with increasing age, and only the combination of VEGF and IGF delivery from gels significantly rescued perfusion in middle-aged (13 months) and old (20 months) mice. In rabbits, the delivery of VEGF alone or in combination with IGF from alginate hydrogels, at a dose 2 orders of magnitude lower than the typical doses used in past rabbit studies, enhanced perfusion recovery when given immediately after surgery, or as a treatment for chronic ischemia. Capillary density measurements and angiographic analysis demonstrated the benefit of gel delivery. These data together suggest that alginate hydrogels providing local delivery of low doses of VEGF and IGF constitute a safe and effective treatment for hind-limb ischemia in clinically relevant animal models, thereby supporting the potential clinical translation of this concept.},
	keywords = {Age Factors, Alginates, Angiogenesis Inducing Agents, Angiography, Digital Subtraction, Animals, Disease Models, Animal, Drug Carriers, Drug Compounding, Female, Glucuronic Acid, Hexuronic Acids, Hindlimb, Hydrogels, Insulin-Like Growth Factor I, Ischemia, Mice, Inbred C57BL, Muscle, Skeletal, Neovascularization, Physiologic, Rabbits, Recovery of Function, Regional Blood Flow, Time Factors, Vascular Endothelial Growth Factor A},
	issn = {1423-0135},
	doi = {10.1159/000479869},
	author = {Anderson, Erin M and Silva, Eduardo A and Hao, Yibai and Martinick, Kathleen D and Vermillion, Sarah A and Stafford, Alexander G and Doherty, Elisabeth G and Wang, Lin and Doherty, Edward J and Grossman, Paul M and Mooney, David J}
}
@article {1124901,
	title = {Biophysical induction of cell release for minimally manipulative cell enrichment strategies},
	journal = {PLoS One},
	volume = {12},
	number = {6},
	year = {2017},
	month = {2017},
	pages = {e0180568},
	abstract = {The use of autologous cells harvested and subsequently transplanted in an intraoperative environment constitutes a new approach to promote regeneration. Usually cells are isolated by selection methods such as fluorescence- or magnetic- activated cell sorting with residual binding of the antibodies or beads. Thus, cell-based therapies would benefit from the development of new devices for cell isolation that minimally manipulate the target cell population. In the clinic, 5 to 10 percent of fractures do not heal properly and CD31+ cells have been identified as promising candidates to support bone regeneration. The aim of this project was to develop and prototype a simple system to facilitate the enrichment of CD31+ cells from whole blood. After validating the specificity of a commercially available aptamer for CD31, we combined this aptamer with traditional magnetic bead strategies, which led to enrichment of CD31+ cells with a purity of 91{\textpm}10\%. Subsequently, the aptamer was attached to agarose beads ({\O} = 100-165 um) that were incorporated into a column-based system to enable capture and subsequent release of the CD31+ enriched cells. Different parameters were investigated to allow a biophysical-based cell release from beads, and a simple mixing was found sufficient to release initially bound cells from the optimized column without the need for any chemicals that promote disassociation. The system led to a significant enrichment of CD31+ cells (initial population: 63{\textpm}9\%, released: 87{\textpm}3\%) with excellent cell viability (released: 97{\textpm}1\%). The composition of the released CD31+ fraction indicated an enrichment of the monocyte population. The angiogenic and osteogenic potential of the released cell population were confirmed in vitro. These results and the simplicity of this system highlight the potential of such approach to enable cell enrichment strategies in intraoperative settings.},
	keywords = {Biophysical Phenomena, Culture Media, Conditioned, Flow Cytometry, Human Umbilical Vein Endothelial Cells, Humans, Immunomagnetic Separation, Monocytes, Neovascularization, Physiologic, Osteogenesis, Platelet Endothelial Cell Adhesion Molecule-1},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0180568},
	author = {Joly, Pascal and Schaus, Thomas and Sass, Andrea and Dienelt, Anke and Cheung, Alexander S and Duda, Georg N and Mooney, David J}
}
@article {1124896,
	title = {Controlled self-assembly of alginate microgels by rapidly binding molecule pairs},
	journal = {Lab Chip},
	volume = {17},
	number = {14},
	year = {2017},
	month = {2017 Jul 11},
	pages = {2481-2490},
	abstract = {Controlled self-assembly of cell-encapsulating microscale polymeric hydrogels (microgels) could be advantageous in a variety of tissue engineering and regenerative medicine applications. Here, a method of assembly by chemical modification of alginate polymer with binding pair molecules (BPM) was explored. Alginate was modified with several types of BPM, specifically biotin and streptavidin and click chemistry compounds, and fabricated into 25-30 μm microgels using a microfluidic platform. These microgels were demonstrated to self-assemble under physiological conditions. By combining complementary microgels at a high ratio, size-defined assemblages were created, and the effects of BPM type and assembly method on the number of microgels per assemblage and packing density were determined. Furthermore, a magnetic process was developed to separate assemblages from single microgels, and allow formation of multilayer spheroids. Finally, cells were singly encapsulated into alginate microgels and assembled using BPM-modified alginate, suggesting potential applications in regenerative medicine.},
	issn = {1473-0189},
	doi = {10.1039/c7lc00500h},
	author = {Hu, Yuebi and Mao, Angelo S and Desai, Rajiv M and Wang, Huanan and Weitz, David A and Mooney, David J}
}
@article {1124891,
	title = {Timed Delivery of Therapy Enhances Functional Muscle Regeneration},
	journal = {Adv Healthc Mater},
	volume = {6},
	number = {19},
	year = {2017},
	month = {2017 Oct},
	abstract = {Cell transplantation is a promising therapeutic strategy for the treatment of traumatic muscle injury in humans. Previous investigations have typically focused on the identification of potent cell and growth factor treatments and optimization of spatial control over delivery. However, the optimal time point for cell transplantation remains unclear. Here, this study reports how myoblast and morphogen delivery timed to coincide with specific phases of the inflammatory response affects donor cell engraftment and the functional repair of severely injured muscle. Delivery of a biomaterial-based therapy timed with the peak of injury-induced inflammation leads to potent early and long-term regenerative benefits. Diminished inflammation and fibrosis, enhanced angiogenesis, and increased cell engraftment are seen during the acute stage following optimally timed treatment. Over the long term, treatment during peak inflammation leads to enhanced functional regeneration, as indicated by reduced chronic inflammation and fibrosis along with increased tissue perfusion and muscle contractile force. Treatments initiated immediately after injury or after inflammation had largely resolved provided more limited benefits. These results demonstrate the importance of appropriately timing the delivery of biologic therapy in the context of muscle regeneration. Biomaterial-based timed delivery can likely be applied to other tissues and is of potential wide utility in regenerative medicine.},
	issn = {2192-2659},
	doi = {10.1002/adhm.201700202},
	author = {Cezar, Christine A and Arany, Praveen and Vermillion, Sarah A and Seo, Bo Ri and Vandenburgh, Herman H and Mooney, David J}
}
@article {1124881,
	title = {Tough adhesives for diverse wet surfaces},
	journal = {Science},
	volume = {357},
	number = {6349},
	year = {2017},
	month = {2017 07 28},
	pages = {378-381},
	abstract = {Adhesion to wet and dynamic surfaces, including biological tissues, is important in many fields but has proven to be extremely challenging. Existing adhesives are cytotoxic, adhere weakly to tissues, or cannot be used in wet environments. We report a bioinspired design for adhesives consisting of two layers: an adhesive surface and a dissipative matrix. The former adheres to the substrate by electrostatic interactions, covalent bonds, and physical interpenetration. The latter amplifies energy dissipation through hysteresis. The two layers synergistically lead to higher adhesion energies on wet surfaces as compared with those of existing adhesives. Adhesion occurs within minutes, independent of blood exposure and compatible with in vivo dynamic movements. This family of adhesives may be useful in many areas of application, including tissue adhesives, wound dressings, and tissue repair.},
	issn = {1095-9203},
	doi = {10.1126/science.aah6362},
	author = {Li, J. and Celiz, A D and Yang, J and Yang, Q and Wamala, I and Whyte, W and Seo, B R and Vasilyev, N V and J.J. Vlassak and Z. Suo and Mooney, D J}
}
@article {1092261,
	title = {Biomaterials for skeletal muscle tissue engineering},
	journal = {Curr Opin Biotechnol},
	volume = {47},
	year = {2017},
	month = {2017 Oct},
	pages = {16-22},
	abstract = {Although skeletal muscle can naturally regenerate in response to minor injuries, more severe damage and myopathies can cause irreversible loss of muscle mass and function. Cell therapies, while promising, have not yet demonstrated consistent benefit, likely due to poor survival of delivered cells. Biomaterials can improve muscle regeneration by presenting chemical and physical cues to muscle cells that mimic the natural cascade of regeneration. This brief review describes strategies for muscle repair utilizing biomaterials that can provide signals to either transplanted or host muscle cells. These strategies range from approaches that utilize biomaterials alone to those that combine biomaterials with exogenous growth factors, ex vivo cultured cells, and extensive culture time.},
	issn = {1879-0429},
	doi = {10.1016/j.copbio.2017.05.003},
	author = {Kwee, Brian J and Mooney, David J}
}
@article {1092271,
	title = {Emerging Trends in Micro- and Nanoscale Technologies in Medicine: From Basic Discoveries to Translation},
	journal = {ACS Nano},
	volume = {11},
	number = {6},
	year = {2017},
	month = {2017 Jun 27},
	pages = {5195-5214},
	abstract = {We discuss the state of the art and innovative micro- and nanoscale technologies that are finding niches and opening up new opportunities in medicine, particularly in diagnostic and therapeutic applications. We take the design of point-of-care applications and the capture of circulating tumor cells as illustrative examples of the integration of micro- and nanotechnologies into solutions of diagnostic challenges. We describe several novel nanotechnologies that enable imaging cellular structures and molecular events. In therapeutics, we describe the utilization of micro- and nanotechnologies in applications including drug delivery, tissue engineering, and pharmaceutical development/testing. In addition, we discuss relevant challenges that micro- and nanotechnologies face in achieving cost-effective and widespread clinical implementation as well as forecasted applications of micro- and nanotechnologies in medicine.},
	issn = {1936-086X},
	doi = {10.1021/acsnano.7b01493},
	author = {Alvarez, Mario M and Aizenberg, Joanna and Analoui, Mostafa and Andrews, Anne M and Bisker, Gili and Edward S Boyden and Kamm, Roger D and Karp, Jeffrey M and Mooney, David J and Oklu, Rahmi and Peer, Dan and Stolzoff, Michelle and Strano, Michael S and Trujillo-de Santiago, Grissel and Webster, Thomas J and Weiss, Paul S and Khademhosseini, Ali}
}
@article {1092276,
	title = {In Vivo Enrichment of Diabetogenic T Cells},
	journal = {Diabetes},
	volume = {66},
	number = {8},
	year = {2017},
	month = {2017 Aug},
	pages = {2220-2229},
	abstract = {Dysfunctional T cells can mediate autoimmunity, but the inaccessibility of autoimmune tissues and the rarity of autoimmune T cells in the blood hinder their study. We describe a method to enrich and harvest autoimmune T cells in vivo by using a biomaterial scaffold loaded with protein antigens. In model antigen systems, we found that antigen-specific T cells become enriched within scaffolds containing their cognate antigens. When scaffolds containing lysates from an insulin-producing β-cell line were implanted subcutaneously in autoimmune diabetes-prone NOD mice, β-cell-reactive T cells homed to these scaffolds and became enriched. These T cells induced diabetes after adoptive transfer, indicating their pathogenicity. Furthermore, T-cell receptor (TCR) sequencing identified many expanded TCRs within the β-cell scaffolds that were also expanded within the pancreata of NOD mice. These data demonstrate the utility of biomaterial scaffolds loaded with disease-specific antigens to identify and study rare, therapeutically important T cells.},
	keywords = {Adoptive Transfer, Animals, Antigens, Autoimmunity, Cell Line, Cell Movement, Diabetes Mellitus, Type 1, Female, Insulin-Secreting Cells, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Pancreas, Receptors, Antigen, T-Cell, T-Lymphocytes, Tissue Scaffolds},
	issn = {1939-327X},
	doi = {10.2337/db16-0946},
	author = {Thelin, Martin A and Kissler, Stephan and Vigneault, Frederic and Watters, Alexander L and White, Des and Koshy, Sandeep T and Vermillion, Sarah A and Mooney, David J and Serwold, Thomas and Ali, Omar A}
}
@article {1092281,
	title = {Single cell-laden protease-sensitive microniches for long-term culture in 3D},
	journal = {Lab Chip},
	volume = {17},
	number = {4},
	year = {2017},
	month = {2017 Feb 14},
	pages = {727-737},
	abstract = {Single cell-laden three-dimensional (3D) microgels that can serve to mimic stem cell niches in vitro, and are therefore termed microniches, can be efficiently fabricated by droplet-based microfluidics. In this technique an aqueous polymer solution along with a highly diluted cell solution is injected into a microfluidic device to create monodisperse pre-microgel droplets that are then solidified by a polymer crosslinking reaction to obtain monodisperse single cell-laden microniches. However, problems limiting this approach studying the fate of single cells include Poisson encapsulation statistics that result in mostly empty microniches, and cells egressing from the microniches during subsequent cell culture. Here, we present a strategy to bypass Poisson encapsulation statistics in synthetic microniches by selective crosslinking of only cell-laden pre-microgel droplets. Furthermore, we show that we can position cells in the center of the microniches, and that even in protease-sensitive microniches this greatly reduces cell egress. Collectively, we present the development of a versatile protocol that allows for unprecedented efficiency in creation of synthetic protease-sensitive microniches for probing single stem cell fate in 3D.},
	issn = {1473-0189},
	doi = {10.1039/c6lc01444e},
	author = {Lienemann, Philipp S and Rossow, Torsten and Mao, Angelo S and Vallmajo-Martin, Queralt and Ehrbar, Martin and Mooney, David J}
}
@article {979496,
	title = {Multicomponent Injectable Hydrogels for Antigen-Specific Tolerogenic Immune Modulation},
	journal = {Adv Healthc Mater},
	volume = {6},
	number = {6},
	year = {2017},
	month = {2017 Mar},
	abstract = {Biomaterial scaffolds that enrich and modulate immune cells in situ can form the basis for potent immunotherapies to elicit immunity or re{\"e}stablish tolerance. Here, the authors explore the potential of an injectable, porous hydrogel to induce a regulatory T cell (Treg) response by delivering a peptide antigen to dendritic cells in a noninflammatory context. Two methods are described for delivering the BDC peptide from pore-forming alginate gels in the nonobese diabetic mouse model of type 1 diabetes: encapsulation in poly(lactide-co-glycolide) (PLG) microparticles, or direct conjugation to the alginate polymer. While particle-based delivery leads to antigen-specific T cells responses in vivo, PLG particles alter the phenotype of the cells infiltrating the gels. Following gel-based peptide delivery, transient expansion of endogenous antigen-specific T cells is observed in the draining lymph nodes. Antigen-specific T cells accumulate in the gels, and, strikingly, ≈60\% of the antigen-specific CD4(+) T cells in the gels are Tregs. Antigen-specific T cells are also enriched in the pancreatic islets, and administration of peptide-loaded gels does not accelerate diabetes. This work demonstrates that a noninflammatory biomaterial system can generate antigen-specific Tregs in vivo, which may enable the development of new therapies for the treatment of transplant rejection or autoimmune diseases.},
	issn = {2192-2659},
	doi = {10.1002/adhm.201600773},
	author = {Verbeke, Catia S and Gordo, Susana and Schubert, David A and Lewin, Sarah A and Desai, Rajiv M and Dobbins, Jessica and Wucherpfennig, Kai W and Mooney, David J}
}
@article {979491,
	title = {Soft robotic sleeve supports heart function},
	journal = {Sci Transl Med},
	volume = {9},
	number = {373},
	year = {2017},
	month = {2017 Jan 18},
	abstract = {There is much interest in form-fitting, low-modulus, implantable devices or soft robots that can mimic or assist in complex biological functions such as the contraction of heart muscle. We present a soft robotic sleeve that is implanted around the heart and actively compresses and twists to act as a cardiac ventricular assist device. The sleeve does not contact blood, obviating the need for anticoagulation therapy or blood thinners, and reduces complications with current ventricular assist devices, such as clotting and infection. Our approach used a biologically inspired design to orient individual contracting elements or actuators in a layered helical and circumferential fashion, mimicking the orientation of the outer two muscle layers of the mammalian heart. The resulting implantable soft robot mimicked the form and function of the native heart, with a stiffness value of the same order of magnitude as that of the heart tissue. We demonstrated feasibility of this soft sleeve device for supporting heart function in a porcine model of acute heart failure. The soft robotic sleeve can be customized to patient-specific needs and may have the potential to act as a bridge to transplant for patients with heart failure.},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.aaf3925},
	author = {Ellen T Roche and Markus A. Horvath and Wamala, Isaac and Alazmani, Ali and Song, Sang-Eun and Whyte, William and Machaidze, Zurab and Payne, Christopher J and Weaver, James C and Fishbein, Gregory and Kuebler, Joseph and Nikolay V. Vasilyev and Mooney, David J and Frank A Pigula and Conor J Walsh}
}
@article {979481,
	title = {Deterministic encapsulation of single cells in thin tunable microgels for niche modelling and therapeutic delivery},
	journal = {Nat Mater},
	volume = {16},
	number = {2},
	year = {2017},
	month = {2017 Feb},
	pages = {236-243},
	abstract = {Existing techniques to encapsulate cells into microscale hydrogels generally yield high polymer-to-cell ratios and lack control over the hydrogel{\textquoteright}s mechanical properties. Here, we report a microfluidic-based method for encapsulating single cells in an approximately six-micrometre layer of alginate that increases the proportion of cell-containing microgels by a factor of ten, with encapsulation efficiencies over 90\%. We show that in vitro cell viability was maintained over a three-day period, that the microgels are mechanically tractable, and that, for microscale cell assemblages of encapsulated marrow stromal cells cultured in microwells, osteogenic differentiation of encapsulated cells depends on gel stiffness and cell density. We also show that intravenous injection of singly encapsulated marrow stromal cells into mice delays clearance kinetics and sustains donor-derived soluble factors in vivo. The encapsulation of single cells in tunable hydrogels should find use in a variety of tissue engineering and regenerative medicine applications.},
	issn = {1476-1122},
	doi = {10.1038/nmat4781},
	author = {Mao, Angelo S and Shin, Jae-Won and Utech, Stefanie and Wang, Huanan and Uzun, Oktay and Li, Weiwei and Cooper, Madeline and Hu, Yuebi and Zhang, Liyuan and Weitz, David A and Mooney, David J}
}
@article {1129171,
	title = {Designing hydrogels for controlled drug delivery},
	journal = {Nature Reviews Materials},
	volume = {1},
	year = {2016},
	pages = {16071},
	abstract = {Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform on which various physiochemical interactions with the encapsulated drugs occur to control drug release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel{\textendash}drug interactions across the network, mesh and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.},
	url = {https://www.nature.com/articles/natrevmats201671?WT.feed_name=subjects_drug-delivery},
	author = {Li, Jianyu and Mooney, David J}
}
@article {979476,
	title = {Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias},
	journal = {Proc Natl Acad Sci U S A},
	volume = {113},
	number = {43},
	year = {2016},
	month = {2016 Oct 25},
	pages = {12126-12131},
	abstract = {Extracellular matrix stiffness influences biological functions of some tumors. However, it remains unclear how cancer subtypes with different oncogenic mutations respond to matrix stiffness. In addition, the relevance of matrix stiffness to in vivo tumor growth kinetics and drug efficacy remains elusive. Here, we designed 3D hydrogels with physical parameters relevant to hematopoietic tissues and adapted them to a quantitative high-throughput screening format to facilitate mechanistic investigations into the role of matrix stiffness on myeloid leukemias. Matrix stiffness regulates proliferation of some acute myeloid leukemia types, including MLL-AF9(+) MOLM-14 cells, in a biphasic manner by autocrine regulation, whereas it decreases that of chronic myeloid leukemia BCR-ABL(+) K-562 cells. Although Arg-Gly-Asp (RGD) integrin ligand and matrix softening confer resistance to a number of drugs, cells become sensitive to drugs against protein kinase B (PKB or AKT) and rapidly accelerated fibrosarcoma (RAF) proteins regardless of matrix stiffness when MLL-AF9 and BCR-ABL are overexpressed in K-562 and MOLM-14 cells, respectively. By adapting the same hydrogels to a xenograft model of extramedullary leukemias, we confirm the pathological relevance of matrix stiffness in growth kinetics and drug sensitivity against standard chemotherapy in vivo. The results thus demonstrate the importance of incorporating 3D mechanical cues into screening for anticancer drugs.},
	issn = {1091-6490},
	doi = {10.1073/pnas.1611338113},
	author = {Shin, Jae-Won and Mooney, David J}
}
@article {979466,
	title = {Label-free bacterial detection using polydiacetylene liposomes.},
	journal = {Chem Commun (Camb)},
	volume = {52},
	number = {68},
	year = {2016},
	month = {2016 Aug 16},
	pages = {10346-9},
	abstract = {Polydiacetylene (PDA) liposomes were prepared to selectively capture target released from bacteria. Specific interplay between released-surfactin and PDA resulted in a conformal change in the structure of PDA, highlighting the potential of indirect interactions between bacteria and PDA in the construction of new label-free bacterial sensors.},
	issn = {1364-548X},
	doi = {10.1039/c6cc03116a},
	author = {Park, Jimin and Ku, Seul Kathy and Seo, Deokwon and Hur, Kahyun and Jeon, Hojeong and Shvartsman, Dmitry and Seok, Hyun-Kwang and Mooney, David J and Lee, Kangwon}
}
@article {979471,
	title = {One-Step Microfluidic Fabrication of Polyelectrolyte Microcapsules in Aqueous Conditions for Protein Release},
	journal = {Angew Chem Int Ed Engl},
	volume = {55},
	number = {43},
	year = {2016},
	month = {2016 Oct 17},
	pages = {13470-13474},
	abstract = {We report a microfluidic approach for one-step fabrication of polyelectrolyte microcapsules in aqueous conditions. Using two immiscible aqueous polymer solutions, we generate transient water-in-water-in-water double emulsion droplets and use them as templates to fabricate polyelectrolyte microcapsules. The capsule shell is formed by the complexation of oppositely charged polyelectrolytes at the immiscible interface. We find that attractive electrostatic interactions can significantly prolong the release of charged molecules. Moreover, we demonstrate the application of these microcapsules in encapsulation and release of proteins without impairing their biological activities. Our platform should benefit a wide range of applications that require encapsulation and sustained release of molecules in aqueous environments.},
	issn = {1521-3773},
	doi = {10.1002/anie.201606960},
	author = {Zhang, Liyuan and Cai, Li-Heng and Lienemann, Philipp S and Rossow, Torsten and Polenz, Ingmar and Vallmajo-Martin, Queralt and Ehrbar, Martin and Na, Hui and Mooney, David J and Weitz, David A}
}
@article {743931,
	title = {Biomaterials and emerging anticancer therapeutics: engineering the microenvironment},
	journal = {Nat Rev Cancer},
	volume = {16},
	number = {1},
	year = {2016},
	month = {2016 01},
	pages = {56-66},
	abstract = {The microenvironment is increasingly recognized to have key roles in cancer, and biomaterials provide a means to engineer microenvironments both in vitro and in vivo to study and manipulate cancer. In vitro cancer models using 3D matrices recapitulate key elements of the tumour microenvironment and have revealed new aspects of cancer biology. Cancer vaccines based on some of the same biomaterials have, in parallel, allowed for the engineering of durable prophylactic and therapeutic anticancer activity in preclinical studies, and some of these vaccines have moved to clinical trials. The impact of biomaterials engineering on cancer treatment is expected to further increase in importance in the years to come.},
	keywords = {Biocompatible Materials, Humans, Neoplasms, Tissue Engineering, Tumor Microenvironment},
	issn = {1474-1768},
	doi = {10.1038/nrc.2015.3},
	author = {Gu, Luo and Mooney, David J}
}
@article {743891,
	title = {Biologic-free mechanically induced muscle regeneration},
	journal = {Proc Natl Acad Sci U S A},
	volume = {113},
	number = {6},
	year = {2016},
	month = {2016 Feb 09},
	pages = {1534-9},
	abstract = {Severe skeletal muscle injuries are common and can lead to extensive fibrosis, scarring, and loss of function. Clinically, no therapeutic intervention exists that allows for a full functional restoration. As a result, both drug and cellular therapies are being widely investigated for treatment of muscle injury. Because muscle is known to respond to mechanical loading, we investigated instead whether a material system capable of massage-like compressions could promote regeneration. Magnetic actuation of biphasic ferrogel scaffolds implanted at the site of muscle injury resulted in uniform cyclic compressions that led to reduced fibrous capsule formation around the implant, as well as reduced fibrosis and inflammation in the injured muscle. In contrast, no significant effect of ferrogel actuation on muscle vascularization or perfusion was found. Strikingly, ferrogel-driven mechanical compressions led to enhanced muscle regeneration and a \~{}threefold increase in maximum contractile force of the treated muscle at 2 wk compared with no-treatment controls. Although this study focuses on the repair of severely injured skeletal muscle, magnetically stimulated bioagent-free ferrogels may find broad utility in the field of regenerative medicine.},
	keywords = {Animals, Biological Products, Biomechanical Phenomena, Electric Stimulation, Female, Fibrosis, Gels, Hindlimb, Implants, Experimental, Inflammation, Macrophages, Magnetic Phenomena, Mice, Inbred C57BL, Muscle Contraction, Muscle Fibers, Skeletal, Muscle, Skeletal, Oxygen, Perfusion, Regeneration},
	issn = {1091-6490},
	doi = {10.1073/pnas.1517517113},
	author = {Cezar, Christine A and Ellen T Roche and Vandenburgh, Herman H and Duda, Georg N and Conor J Walsh and Mooney, David J}
}
@article {743896,
	title = {Click-Crosslinked Injectable Gelatin Hydrogels},
	journal = {Adv Healthc Mater},
	volume = {5},
	number = {5},
	year = {2016},
	month = {2016 Mar 09},
	pages = {541-7},
	abstract = {Injectable gelatin hydrogels formed with bioorthogonal click chemistry (ClickGel) are cell-responsive ECM mimics for in vitro and in vivo biomaterials applications. Gelatin polymers with pendant norbornene (GelN) or tetrazine (GelT) groups can quickly and spontaneously crosslink upon mixing, allowing for high viability of encapsulated cells, establishment of 3D elongated cell morphologies, and biodegradation when injected in vivo.},
	keywords = {3T3 Cells, Animals, Cell Adhesion, Cell Proliferation, Cell Shape, click chemistry, Cross-Linking Reagents, Female, Gelatin, Hydrogels, Mice, Subcutaneous Tissue},
	issn = {2192-2659},
	doi = {10.1002/adhm.201500757},
	author = {Koshy, Sandeep T and Desai, Rajiv M and Joly, Pascal and Li, Jianyu and Bagrodia, Rishi K and Lewin, Sarah A and Joshi, Neel S and Mooney, David J}
}
@article {743901,
	title = {The effect of surface modification of mesoporous silica micro-rod scaffold on immune cell activation and infiltration},
	journal = {Biomaterials},
	volume = {83},
	year = {2016},
	month = {2016 Mar},
	pages = {249-56},
	abstract = {Biomaterial scaffold based vaccines show significant potential in generating potent antigen-specific immunity. However, the role of the scaffold surface chemistry in initiating and modulating the immune response is not well understood. In this study, a mesoporous silica micro-rod (MSR) scaffold was modified with PEG, PEG-RGD and PEG-RDG groups. PEG modification significantly enhanced BMDC activation marker up-regulation and IL-1β production in vitro, and innate immune cell infiltration in vivo. PEG-RGD MSRs and PEG-RDG MSRs displayed decreased inflammation compared to PEG MSRs, and the effect was not RGD specific. Finally, the Nlrp3 inflammasome was found to be necessary for MSR stimulated IL-1β production in vitro and played a key role in regulating immune cell infiltration in vivo. These findings suggest that simply modulating the surface chemistry of a scaffold can regulate its immune cell infiltration profile and have implications for the design and development of new material based vaccines.},
	keywords = {Animals, Bone Marrow Cells, Carrier Proteins, Cytokines, Dendritic Cells, Female, Inflammasomes, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Porosity, Silicon Dioxide, Surface Properties, Tissue Scaffolds},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2016.01.026},
	author = {Li, Weiwei Aileen and Lu, Beverly Ying and Gu, Luo and Choi, Youngjin and Kim, Jaeyun and Mooney, David J}
}
@article {743906,
	title = {Improving Stem Cell Therapeutics with Mechanobiology},
	journal = {Cell Stem Cell},
	volume = {18},
	number = {1},
	year = {2016},
	month = {2016 Jan 07},
	pages = {16-9},
	abstract = {In recent years, it has become clear that mechanical cues play an integral role in maintaining stem cell functions. Here we discuss how integrating physical approaches and engineering principles in stem cell biology, including culture systems, preclinical models, and functional assessment, may improve clinical application in regenerative medicine.},
	keywords = {Animals, Disease Models, Animal, Disease Progression, Hematopoietic Stem Cells, Humans, Induced Pluripotent Stem Cells, Organogenesis, Regeneration, Regenerative Medicine, Stem Cell Transplantation, Stem Cells, Tissue Engineering},
	issn = {1875-9777},
	doi = {10.1016/j.stem.2015.12.007},
	author = {Shin, Jae-Won and Mooney, David J}
}
@article {743916,
	title = {Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication},
	journal = {Cancer Immunol Res},
	volume = {4},
	number = {2},
	year = {2016},
	month = {2016 Feb},
	pages = {95-100},
	abstract = {We demonstrate that a poly(lactide-co-glycolide) (PLG) cancer vaccine can be used in combination with immune checkpoint antibodies, anti-CTLA-4 or anti-PD-1, to enhance cytotoxic T-cell (CTL) activity and induce the regression of solid B16 tumors in mice. Combination therapy obviated the need for vaccine boosting and significantly skewed intratumoral reactions toward CTL activity, resulting in the regression of B16 tumors up to 50 mm(2) in size and 75\% survival rates. These data suggest that combining material-based cancer vaccines with checkpoint antibodies has the potential to mediate tumor regression in humans.},
	keywords = {Animals, Antibodies, Monoclonal, Cancer Vaccines, CTLA-4 Antigen, Disease Models, Animal, Female, Immunologic Factors, Immunomodulation, Lymphocytes, Tumor-Infiltrating, Melanoma, Experimental, Mice, Neoplasms, Programmed Cell Death 1 Receptor, T-Lymphocytes, Cytotoxic},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-14-0126},
	author = {Ali, Omar A and Lewin, Sarah A and Dranoff, Glenn and Mooney, David J}
}
@article {743871,
	title = {Adjuvant-Loaded Subcellular Vesicles Derived From Disrupted Cancer Cells for Cancer Vaccination},
	journal = {Small},
	volume = {12},
	number = {17},
	year = {2016},
	month = {2016 05},
	pages = {2321-33},
	abstract = {Targeted subunit vaccines for cancer immunotherapy do not capture tumor antigenic complexity, and approaches employing tumor lysate are often limited by inefficient antigen uptake and presentation, and low immunogenicity. Here, whole cancer cells are processed to generate antigen-rich, membrane-enclosed subcellular particles, termed "reduced cancer cells", that reflect the diversity and breadth of the parent cancer cell antigen repertoire, and can be loaded with disparate adjuvant payloads. These vesicular particles enhance the uptake of the adjuvant payload, and potentiate the activation of primary dendritic cells in vitro. Similarly, reduced cancer cell-associated antigens are more efficiently presented by primary dendritic cells in vitro than their soluble counterparts or lysate control. In mice, vaccination using adjuvant-loaded reduced cancer cells facilitates the induction of antigen-specific cellular and humoral immune responses. Taken together, these observations demonstrate that adjuvant-loaded reduced cancer cells could be utilized in cancer vaccines as an alternative to lysate.},
	issn = {1613-6829},
	doi = {10.1002/smll.201600061},
	author = {Cheung, Alexander S and Koshy, Sandeep T and Stafford, Alexander G and Bastings, Maartje M C and Mooney, David J}
}
@article {743881,
	title = {Advances in Therapeutic Cancer Vaccines},
	journal = {Adv Immunol},
	volume = {130},
	year = {2016},
	month = {2016},
	pages = {191-249},
	abstract = {Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, an ex vivo dendritic cell vaccine for prostate cancer, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines. The clinical success of checkpoint blockade has underscored the role of peripheral tolerance mechanisms in limiting vaccine responses and highlighted the potential for combination therapies. Recent advances in transcriptome sequencing, computational modeling, and material engineering further suggest new opportunities to intensify cancer vaccines. This review will discuss the major approaches to therapeutic cancer vaccination and explore recent advances that inform the design of the next generation of cancer vaccines.},
	keywords = {Animals, Antigens, Neoplasm, Apoptosis, Biomedical Engineering, Cancer Vaccines, Dendritic Cells, Humans, Immunotherapy, Active, Mice, Neoplasms, Oncolytic Viruses, Peripheral Tolerance},
	issn = {1557-8445},
	doi = {10.1016/bs.ai.2015.12.001},
	author = {Wong, Karrie K and Li, Weiwei Aileen and Mooney, David J and Dranoff, Glenn}
}
@article {743861,
	title = {Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair},
	journal = {Wound Repair Regen},
	volume = {24},
	number = {4},
	year = {2016},
	month = {2016 Jul},
	pages = {630-43},
	abstract = {Current chronic wound treatments often fail to promote healing of diabetic foot ulcers (DFU), leading to amputation and increased patient morbidity. A critical mediator of proper wound healing is the production, assembly, and remodeling of the extracellular matrix (ECM) by fibroblasts. However, little is known about how these processes are altered in fibroblasts within the DFU microenvironment. Thus, we investigated the capacity of multiple, primary DFU-derived fibroblast strains to express, produce, and assemble ECM proteins compared to diabetic patient-derived fibroblasts and healthy donor-derived fibroblasts. Gene expression microarray analysis showed differential expression of ECM and ECM-regulatory genes by DFU-derived fibroblasts which translated to functional differences in a 3D in vitro ECM tissue model. DFU-derived fibroblasts produced thin, fibronectin-rich matrices, and responded abnormally when challenged with transforming growth factor-beta, a key regulator of matrix production during healing. These results provide novel evidence that DFU-derived fibroblasts contribute to the defective matrices of DFUs and chronic wound pathogenesis.},
	issn = {1524-475X},
	doi = {10.1111/wrr.12437},
	author = {Maione, Anna G and Smith, Avi and Kashpur, Olga and Yanez, Vanessa and Knight, Elana and Mooney, David J and Veves, Aristidis and Tomic-Canic, Marjana and Garlick, Jonathan A}
}
@article {743886,
	title = {Biomaterials for enhancing anti-cancer immunity},
	journal = {Curr Opin Biotechnol},
	volume = {40},
	year = {2016},
	month = {2016 Aug},
	pages = {1-8},
	abstract = {Cancer immunotherapy is becoming a standard approach to treat many cancers. However, shortcomings of current methods limit therapeutic benefit in many patients. Rationally designed biomaterial strategies to deliver immune modulatory drugs can potentially show improved safety profiles, while providing multifunctional and spatiotemporally controlled signals to immune cells to improve their anti-cancer activity. This brief review describes biomaterials-based strategies that enhance immune cell function at various tissue sites to improve anti-cancer immunity. Continued collaboration between bioengineers, immunologists, industry, and clinicians is required for biomaterial-based immunotherapy strategies to continue moving to the clinic.},
	keywords = {Antigen-Presenting Cells, Biocompatible Materials, Humans, Immunomodulation, Immunotherapy, Neoplasms, Tumor Microenvironment},
	issn = {1879-0429},
	doi = {10.1016/j.copbio.2016.02.001},
	author = {Koshy, Sandeep T and Mooney, David J}
}
@article {743856,
	title = {CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness},
	journal = {Biomaterials},
	volume = {98},
	year = {2016},
	month = {2016 Aug},
	pages = {152-62},
	abstract = {Two-dimensional (2D) cultures often fail to mimic key architectural and physical features of the tumor microenvironment. Advances in biomaterial engineering allow the design of three-dimensional (3D) cultures within hydrogels that mimic important tumor-like features, unraveling cancer cell behaviors that would not have been observed in traditional 2D plastic surfaces. This study determined how 3D cultures impact CD44 alternative splicing in gastric cancer (GC) cells. In 3D cultures, GC cells lost expression of the standard CD44 isoform (CD44s), while gaining CD44 variant 6 (CD44v6) expression. This splicing switch was reversible, accelerated by nutrient shortage and delayed at lower initial cell densities, suggesting an environmental stress-induced response. It was further shown to be dependent on the hydrogel matrix mechanical properties and accompanied by the upregulation of genes involved in epithelial-mesenchymal transition (EMT), metabolism and angiogenesis. The 3D cultures reported here revealed the same CD44 alternative splicing pattern previously observed in human premalignant and malignant gastric lesions. These findings indicate that fundamental features of 3D cultures - such as soluble factors diffusion and mechanical cues - influence CD44 expression in GC cells. Moreover, this study provides a new model system to study CD44 dysfunction, whose role in cancer has been in the spotlight for decades.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2016.04.016},
	author = {Branco da Cunha, Cristiana and Klumpers, Darinka D and Koshy, Sandeep T and Weaver, James C and Chaudhuri, Ovijit and Seruca, Raquel and Carneiro, F{\'a}tima and Granja, Pedro L and Mooney, David J}
}
@article {743851,
	title = {Effects of substrate stiffness and cell-cell contact on mesenchymal stem cell differentiation},
	journal = {Biomaterials},
	volume = {98},
	year = {2016},
	month = {2016 Aug},
	pages = {184-91},
	abstract = {The mechanical properties of the microenvironment and direct contact-mediated cell-cell interactions are two variables known to be important in the determination of stem cell differentiation fate, but little is known about the interplay of these cues. Here, we use a micropatterning approach on polyacrylamide gels of tunable stiffnesses to study how homotypic cell-cell contacts and mechanical stiffness affect different stages of osteogenesis of mesenchymal stem cells (MSCs). Nuclear localization of transcription factors associated with osteogenesis depended on substrate stiffness and was independent of the degree of cell-cell contact. However, expression of alkaline phosphatase, an early protein marker for osteogenesis, increased only in cells with both direct contact with neighboring cells and adhesion to stiffer substrates. Finally, mature osteogenesis, as assessed by calcium deposition, was low in micropatterned cells, even on stiff substrates and in multicellular clusters. These results indicate that substrate stiffness and the presence of neighboring cells regulate osteogenesis in MSCs.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2016.05.004},
	author = {Mao, Angelo S and Shin, Jae-Won and Mooney, David J}
}
@article {743841,
	title = {Generation of Induced Pluripotent Stem Cells from Diabetic Foot Ulcer Fibroblasts Using a Nonintegrative Sendai Virus},
	journal = {Cell Reprogram},
	volume = {18},
	number = {4},
	year = {2016},
	month = {2016 Aug},
	pages = {214-23},
	abstract = {Diabetic foot ulcers (DFUs) are nonhealing chronic wounds that are a serious complication of diabetes. Since induced pluripotent stem cells (iPSCs) may offer a potent source of autologous cells to heal these wounds, we studied if repair-deficient fibroblasts, derived from DFU patients and age- and site-matched control fibroblasts, could be reprogrammed to iPSCs. To establish this, we used Sendai virus to successfully reprogram six primary fibroblast cell lines derived from ulcerated skin of two DFU patients (DFU8, DFU25), nonulcerated foot skin from two diabetic patients (DFF24, DFF9), and healthy foot skin from two nondiabetic patients (NFF12, NFF14). We confirmed reprogramming to a pluripotent state through three independent criteria: immunofluorescent staining for SSEA-4 and TRA-1-81, formation of embryoid bodies with differentiation potential to all three embryonic germ layers in vitro, and formation of teratomas in vivo. All iPSC lines showed normal karyotypes and typical, nonmethylated CpG sites for OCT4 and NANOG. iPSCs derived from DFUs were similar to those derived from site-matched nonulcerated skin from both diabetic and nondiabetic patients. These results have established for the first time that multiple, DFU-derived fibroblast cell lines can be reprogrammed with efficiencies similar to control fibroblasts, thus demonstrating their utility for future regenerative therapy of DFUs.},
	issn = {2152-4998},
	doi = {10.1089/cell.2015.0087},
	author = {Gerami-Naini, Behzad and Smith, Avi and Maione, Anna G and Kashpur, Olga and Carpinito, Gianpaolo and Veves, Aristides and Mooney, David J and Garlick, Jonathan A}
}
@article {743876,
	title = {Morphogenesis of 3D vascular networks is regulated by tensile forces},
	journal = {Proc Natl Acad Sci U S A},
	volume = {113},
	number = {12},
	year = {2016},
	month = {2016 Mar 22},
	pages = {3215-20},
	abstract = {Understanding the forces controlling vascular network properties and morphology can enhance in vitro tissue vascularization and graft integration prospects. This work assessed the effect of uniaxial cell-induced and externally applied tensile forces on the morphology of vascular networks formed within fibroblast and endothelial cell-embedded 3D polymeric constructs. Force intensity correlated with network quality, as verified by inhibition of force and of angiogenesis-related regulators. Tensile forces during vessel formation resulted in parallel vessel orientation under static stretching and diagonal orientation under cyclic stretching, supported by angiogenic factors secreted in response to each stretch protocol. Implantation of scaffolds bearing network orientations matching those of host abdominal muscle tissue improved graft integration and the mechanical properties of the implantation site, a critical factor in repair of defects in this area. This study demonstrates the regulatory role of forces in angiogenesis and their capacities in vessel structure manipulation, which can be exploited to improve scaffolds for tissue repair.},
	keywords = {Blood Vessels, Human Umbilical Vein Endothelial Cells, Humans, Morphogenesis, Neovascularization, Physiologic, Tensile Strength, Tissue Scaffolds},
	issn = {1091-6490},
	doi = {10.1073/pnas.1522273113},
	author = {Rosenfeld, Dekel and Landau, Shira and Shandalov, Yulia and Raindel, Noa and Freiman, Alina and Shor, Erez and Blinder, Yaron and Vandenburgh, Herman H and Mooney, David J and Levenberg, Shulamit}
}
@article {743866,
	title = {One-step generation of cell-laden microgels using double emulsion drops with a sacrificial ultra-thin oil shell},
	journal = {Lab Chip},
	volume = {16},
	number = {9},
	year = {2016},
	month = {2016 Apr 26},
	pages = {1549-55},
	abstract = {Cell-laden microgels with highly uniform sizes have significant potential in tissue engineering and cell therapy due to their capability to provide a physiologically relevant three-dimensional (3D) microenvironment for living cells. In this work, we present a simple and efficient microfluidic approach to produce monodisperse cell-laden microgels through the use of double emulsion drops with an ultra-thin oil shell as the sacrificial template. Specifically, the thin oil shell in double emulsion spontaneously dewets upon polymerization of the innermost precursor drop and subsequent transfer into an aqueous solution, resulting in direct dispersion of microgels in the aqueous phase. Compared to conventional single emulsion-based techniques for cell encapsulation, this one-step approach prevents prolonged exposure of cells to the oil phase, leading to high-throughput cell encapsulation in microgels without compromising the cell viability. Moreover, this approach allows us to culture cells within a 3D microgel which mimics the extracellular matrix, thus enabling long-term cell functionality. This microfluidic technique represents a significant step forward in high-throughput cell microencapsulation technology and offers a potentially viable option to produce cell-laden microgels for widespread applications in tissue engineering and cell therapies.},
	issn = {1473-0189},
	doi = {10.1039/c6lc00261g},
	author = {Choi, Chang-Hyung and Wang, Huanan and Hyomin Lee and Kim, June Hwan and Zhang, Liyuan and Mao, Angelo and Mooney, David J and Weitz, David A}
}
@article {743846,
	title = {Synthetic niche to modulate regenerative potential of MSCs and enhance skeletal muscle regeneration},
	journal = {Biomaterials},
	volume = {99},
	year = {2016},
	month = {2016 Aug},
	pages = {95-108},
	abstract = {Severe injury to the skeletal muscle often results in the formation of scar tissue, leading to a decline in functional performance. Traditionally, tissue engineering strategies for muscle repair have focused on substrates that promote myogenic differentiation of transplanted cells. In the current study, the reported data indicates that mesenchymal stromal cells (MSCs) transplanted via porous alginate cryogels promote muscle regeneration by secreting bioactive factors that profoundly influence the function of muscle progenitor cells. These cellular functions, which include heightened resistance of muscle progenitor cells to apoptosis, migration to site of injury, and prevention of premature differentiation are highly desirable in the healing cascade after acute muscle trauma. Furthermore, stimulation of MSCs with recombinant growth factors IGF-1 and VEGF165 was found to significantly enhance their paracrine effects on muscle progenitor cells. Multifunctional alginate cryogels were then utilized as synthetic niches that facilitate local stimulation of seeded MSCs by providing a sustained release of growth factors. In a clinically relevant injury model, the modulation of MSC paracrine signaling via engineered niches significantly improved muscle function by remodeling scar tissue and promoting the formation of new myofibers, outperforming standalone cell or growth factor delivery.},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2016.05.009},
	author = {Pumberger, Matthias and Qazi, Taimoor H and Ehrentraut, M Christine and Textor, Martin and Kueper, Janina and Stoltenburg-Didinger, Gisela and Winkler, Tobias and von Roth, Philipp and Reinke, Simon and Borselli, Cristina and Perka, Carsten and Mooney, David J and Duda, Georg N and Gei{\ss}ler, Sven}
}
@article {601601,
	title = {Hydrogels with tunable stress relaxation regulate stem cell fate and activity},
	journal = {Nat Mater},
	volume = {15},
	number = {3},
	year = {2016},
	month = {2016 Mar},
	pages = {326-34},
	abstract = {Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel{\textquoteright}s initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.},
	keywords = {Alginates, Biomechanical Phenomena, Cell Culture Techniques, Cell Differentiation, Extracellular Matrix, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Mesenchymal Stromal Cells, Stress, Mechanical},
	issn = {1476-1122},
	doi = {10.1038/nmat4489},
	author = {Chaudhuri, Ovijit and Gu, Luo and Klumpers, Darinka and Darnell, Max and Bencherif, Sidi A and Weaver, James C and Huebsch, Nathaniel and Lee, Hong-Pyo and Lippens, Evi and Duda, Georg N and Mooney, David J}
}
@article {1192146,
	title = {The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture},
	journal = {Nat Immunol},
	volume = {16},
	number = {1},
	year = {2015},
	month = {2015 Jan},
	pages = {75-84},
	abstract = {In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.},
	keywords = {Amides, Animals, Cell Survival, Collagen, Cytoskeleton, Enzyme Inhibitors, Female, Fibroblasts, Lectins, C-Type, Lymph Nodes, Male, Membrane Glycoproteins, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Phosphorylation, Pyridines, Specific Pathogen-Free Organisms},
	issn = {1529-2916},
	doi = {10.1038/ni.3035},
	author = {Astarita, Jillian L and Cremasco, Viviana and Fu, Jianxin and Darnell, Max C and Peck, James R and Nieves-Bonilla, Janice M and Song, Kai and Kondo, Yuji and Woodruff, Matthew C and Gogineni, Alvin and Onder, Lucas and Ludewig, Burkhard and Weimer, Robby M and Carroll, Michael C and Mooney, David J and Xia, Lijun and Turley, Shannon J}
}
@article {1192141,
	title = {A compressible scaffold for minimally invasive delivery of large intact neuronal networks},
	journal = {Adv Healthc Mater},
	volume = {4},
	number = {2},
	year = {2015},
	month = {2015 Jan 28},
	pages = {301-12},
	abstract = {Millimeter to centimeter-sized injectable neural scaffolds based on macroporous cryogels are presented. The polymer-scaffolds are made from alginate and carboxymethyl-cellulose by a novel simple one-pot cryosynthesis. They allow surgical sterility by means of autoclaving, and present native laminin as an attachment motive for neural adhesion and neurite development. They are designed to protect an extended, living neuronal network during compression to a small fraction of the original volume in order to enable minimally invasive delivery. The scaffolds behave as a mechanical meta-material: they are soft at the macroscopic scale, enabling injection through narrow-bore tubing and potentially good cellular scaffold integration in soft target tissues such as the brain. At the same time, the scaffold material has a high local Young modulus, allowing protection of the neuronal network during injection. Based on macroscopic and nanomechanical characterization, the generic geometrical and mechanical design rules are presented, enabling macroporous cellular scaffold injectability.},
	keywords = {Alginates, Carboxymethylcellulose Sodium, Cell Adhesion, Cell Line, Tumor, Cell Survival, Computer Simulation, Cryogels, Drug Delivery Systems, Finite Element Analysis, Glucuronic Acid, Hexuronic Acids, Humans, Injections, Neurons, Stress, Mechanical, Tissue Scaffolds},
	issn = {2192-2659},
	doi = {10.1002/adhm.201400250},
	author = {B{\'e}duer, Am{\'e}lie and Braschler, Thomas and Peric, Oliver and Fantner, Georg E and Mosser, S{\'e}bastien and Fraering, Patrick C and Bench{\'e}rif, Sidi and Mooney, David J and Renaud, Philippe}
}
@article {1192131,
	title = {Effect of African-American Race on Tumor Recurrence After Radical Cystectomy for Urothelial Carcinoma of the Bladder},
	journal = {Clin Genitourin Cancer},
	volume = {13},
	number = {5},
	year = {2015},
	month = {2015 Oct},
	pages = {469-75},
	abstract = {BACKGROUND: African-American race appears to be associated with higher stages of urothelial carcinoma of the bladder (UCB) at presentation and poorer survival. However, the independent effect of African-American race on objective tumor recurrence after radical cystectomy (RC) after controlling for clinical and pathologic variables is unknown.

PATIENTS AND METHODS: The data from consecutive patients with UCB who underwent RC with curative intent at a single institution (University of Alabama, Birmingham) from 2001 to 2012 with or without perioperative chemotherapy or chemoradiation were reviewed. The patient demographics, risk factors, clinical course, pathologic characteristics, and long-term outcomes were collected. Descriptive statistics were performed. Cox regression analysis was performed for key clinical, demographic, and pathologic variables, including race, stratified as African American versus white.

RESULTS: A total of 215 patients, 163 men (76\%) and 52 women (24\%), with a mean age at RC of 65.6 years, were identified and reviewed. A total of 186 patients (87\%) were white and 28 (13\%) were African American. The median follow-up period after RC was 17.6 months. On conventional multivariate analysis, African-American race nearly attained statistical significance (hazard ratio [HR], 2.48; 95\% confidence interval [CI], 0.98-6.29; P = .055). In a stepwise regression model, race was significantly associated with tumor recurrence (HR, 3.11; 95\% CI, 1.2-7.4; P < .011).

CONCLUSION: African-American race appears to be independently associated with a greater risk of tumor recurrence after RC for UCB. The effect of host genetics on tumor biology needs to be characterized at the genomic level to develop precision medicine.},
	keywords = {Adult, African Americans, Aged, Aged, 80 and over, Cystectomy, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Risk Factors, United States, Urinary Bladder Neoplasms},
	issn = {1938-0682},
	doi = {10.1016/j.clgc.2015.02.010},
	author = {Paluri, Ravi K and Morgan, Charity J and Mooney, David J and Mgbemena, Okechukwu and Yang, Eddy S and Wei, Shi and Kouba, Erik and Naik, Gurudatta and El Mouallem, Nemer R and Poston, Tyler and Jones, Benjamin and Nix, Jeffrey and Bolger, Graeme B and Deshazo, Mollie and Sonpavde, Guru}
}
@article {1192136,
	title = {Three-dimensional human tissue models that incorporate diabetic foot ulcer-derived fibroblasts mimic in vivo features of chronic wounds},
	journal = {Tissue Eng Part C Methods},
	volume = {21},
	number = {5},
	year = {2015},
	month = {2015 May},
	pages = {499-508},
	abstract = {Diabetic foot ulcers (DFU) are a major, debilitating complication of diabetes mellitus. Unfortunately, many DFUs are refractory to existing treatments and frequently lead to amputation. The development of more effective therapies has been hampered by the lack of predictive in vitro methods to investigate the mechanisms underlying impaired healing. To address this need for realistic wound-healing models, we established patient-derived fibroblasts from DFUs and site-matched controls and used them to construct three-dimensional (3D) models of chronic wound healing. Incorporation of DFU-derived fibroblasts into these models accurately recapitulated the following key aspects of chronic ulcers: reduced stimulation of angiogenesis, increased keratinocyte proliferation, decreased re-epithelialization, and impaired extracellular matrix deposition. In addition to reflecting clinical attributes of DFUs, the wound-healing potential of DFU fibroblasts demonstrated in this suite of models correlated with in vivo wound closure in mice. Thus, the reported panel of 3D DFU models provides a more biologically relevant platform for elucidating the cell-cell and cell-matrix-related mechanisms responsible for chronic wound pathogenesis and may improve translation of in vitro findings into efficacious clinical applications.},
	keywords = {Animals, Cell Culture Techniques, Cytokines, Diabetic Foot, Extracellular Matrix, Fibroblasts, Humans, In Vitro Techniques, Keratinocytes, Male, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic, Tissue Engineering, Wound Healing},
	issn = {1937-3392},
	doi = {10.1089/ten.TEC.2014.0414},
	author = {Maione, Anna G and Brudno, Yevgeny and Stojadinovic, Olivera and Park, Lara K and Smith, Avi and Tellechea, Ana and Leal, Ermelindo C and Kearney, Cathal J and Veves, Aristidis and Tomic-Canic, Marjana and Mooney, David J and Garlick, Jonathan A}
}
@article {743926,
	title = {Engineered Materials for Cancer Immunotherapy},
	journal = {Nano Today},
	volume = {10},
	number = {4},
	year = {2015},
	month = {2015 Aug 01},
	pages = {511-531},
	abstract = {Immunotherapy is a promising treatment modality for cancer as it can promote specific and durable anti-cancer responses. However, limitations to current approaches remain. Therapeutics administered as soluble injections often require high doses and frequent re-dosing, which can result in systemic toxicities. Soluble bolus-based vaccine formulations typically elicit weak cellular immune responses, limiting their use for cancer. Current methods for ex vivo T cell expansion for adoptive T cell therapies are suboptimal, and achieving high T cell persistence and sustained functionality with limited systemic toxicity following transfer remains challenging. Biomaterials can play important roles in addressing some of these limitations. For example, nanomaterials can be employed as vehicles to deliver immune modulating payloads to specific tissues, cells, and cellular compartments with minimal off-target toxicity, or to co-deliver antigen and danger signal in therapeutic vaccine formulations. Alternatively, micro-to macroscale materials can be employed as devices for controlled molecular and cellular delivery, or as engineered microenvironments for recruiting and programming immune cells in situ. Recent work has demonstrated the potential for combining cancer immunotherapy and biomaterials, and the application of biomaterials to cancer immunotherapy is likely to enable the development of effective next-generation platforms. This review discusses the application of engineered materials for the delivery of immune modulating agents to the tumor microenvironment, therapeutic cancer vaccination, and adoptive T cell therapy.},
	issn = {1748-0132},
	doi = {10.1016/j.nantod.2015.06.007},
	author = {Cheung, Alexander S and Mooney, David J}
}
@article {743921,
	title = {Vasculogenic dynamics in 3D engineered tissue constructs},
	journal = {Sci Rep},
	volume = {5},
	year = {2015},
	month = {2015 Dec 09},
	pages = {17840},
	abstract = {Implantable 3D engineered vascular tissue constructs can be formed by co-culturing endothelial and fibroblast cells on macroporous scaffolds. Here we show that these constructs can be used for studying the dynamics of neovascular formation in-vitro by a combination of live confocal imaging and an array of image processing and analysis tools, revealing multiple distinct stages of morphogenesis. We show that this process involves both vasculogenic and angiogenic elements, including an initial endothelial multicellular cluster formation followed by rapid extensive sprouting, ultimately resulting in a stable interconnected endothelial network morphology. This vascular morphogenesis is time-correlated with the deposition and formation of an extensive extra-cellular matrix environment. We further show that endothelial network junctions are formed by two separate morphogenic mechanisms of anastomosis and cluster thinning.},
	keywords = {Cell Culture Techniques, Endothelial Cells, Extracellular Matrix Proteins, Fibroblasts, Humans, Neovascularization, Physiologic, Tissue Engineering, Tissue Scaffolds, Vascular Endothelial Growth Factor Receptor-2},
	issn = {2045-2322},
	doi = {10.1038/srep17840},
	author = {Blinder, Yaron J and Freiman, Alina and Raindel, Noa and Mooney, David J and Levenberg, Shulamit}
}
@article {601656,
	title = {Alginate and DNA Gels Are Suitable Delivery Systems for Diabetic Wound Healing},
	journal = {Int J Low Extrem Wounds},
	volume = {14},
	number = {2},
	year = {2015},
	month = {2015 Jun},
	pages = {146-53},
	abstract = {Diabetic foot ulcers (DFU) represent a severe health problem and an unmet clinical challenge. In this study, we tested the efficacy of novel biomaterials in improving wound healing in mouse models of diabetes mellitus (DM). The biomaterials are composed of alginate- and deoxyribonucleic acid (DNA)-based gels that allow incorporation of effector cells, such as outgrowth endothelial cells (OEC), and provide sustained release of bioactive factors, such as neuropeptides and growth factors, which have been previously validated in experimental models of DM wound healing or hind limb ischemia. We tested these biomaterials in mice and demonstrate that they are biocompatible and can be injected into the wound margins without major adverse effects. In addition, we show that the combination of OEC and the neuropeptide Substance P has a better healing outcome than the delivery of OEC alone, while subtherapeutic doses of vascular endothelial growth factor (VEGF) are required for the transplanted cells to exert their beneficial effects in wound healing. In summary, alginate and DNA scaffolds could serve as potential delivery systems for the next-generation DFU therapies.},
	keywords = {Alginates, Animals, Bandages, Biocompatible Materials, Diabetes Mellitus, Experimental, Diabetic Foot, Drug Carriers, Drug Delivery Systems, Gels, Glucuronic Acid, Hexuronic Acids, Mice, Mice, Inbred C57BL, Vascular Endothelial Growth Factor A, Wound Healing},
	issn = {1552-6941},
	doi = {10.1177/1534734615580018},
	author = {Tellechea, Ana and Silva, Eduardo A and Min, Jianghong and Leal, Ermelindo C and Auster, Michael E and Pradhan-Nabzdyk, Leena and Shih, William and Mooney, David J and Veves, Aristidis}
}
@article {601686,
	title = {Biomaterials based strategies for skeletal muscle tissue engineering: existing technologies and future trends},
	journal = {Biomaterials},
	volume = {53},
	year = {2015},
	month = {2015},
	pages = {502-21},
	abstract = {Skeletal muscles have a robust capacity to regenerate, but under compromised conditions, such as severe trauma, the loss of muscle functionality is inevitable. Research carried out in the field of skeletal muscle tissue engineering has elucidated multiple intrinsic mechanisms of skeletal muscle repair, and has thus sought to identify various types of cells and bioactive factors which play an important role during regeneration. In order to maximize the potential therapeutic effects of cells and growth factors, several biomaterial based strategies have been developed and successfully implemented in animal muscle injury models. A suitable biomaterial can be utilized as a template to guide tissue reorganization, as a matrix that provides optimum micro-environmental conditions to cells, as a delivery vehicle to carry bioactive factors which can be released in a controlled manner, and as local niches to orchestrate in situ tissue regeneration. A myriad of biomaterials, varying in geometrical structure, physical form, chemical properties, and biofunctionality have been investigated for skeletal muscle tissue engineering applications. In the current review, we present a detailed summary of studies where the use of biomaterials favorably influenced muscle repair. Biomaterials in the form of porous three-dimensional scaffolds, hydrogels, fibrous meshes, and patterned substrates with defined topographies, have each displayed unique benefits, and are discussed herein. Additionally, several biomaterial based approaches aimed specifically at stimulating vascularization, innervation, and inducing contractility in regenerating muscle tissues are also discussed. Finally, we outline promising future trends in the field of muscle regeneration involving a deeper understanding of the endogenous healing cascades and utilization of this knowledge for the development of multifunctional, hybrid, biomaterials which support and enable muscle regeneration under compromised conditions.},
	keywords = {Biocompatible Materials, Humans, Muscle, Skeletal, Tissue Engineering, Tissue Scaffolds},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2015.02.110},
	author = {Qazi, Taimoor H and Mooney, David J and Pumberger, Matthias and Geissler, Sven and Duda, Georg N}
}
@article {601661,
	title = {The collagen I mimetic peptide DGEA enhances an osteogenic phenotype in mesenchymal stem cells when presented from cell-encapsulating hydrogels},
	journal = {J Biomed Mater Res A},
	volume = {103},
	number = {11},
	year = {2015},
	month = {2015 Nov},
	pages = {3516-25},
	abstract = {Interactions between cells and the extracellular matrix (ECM) are known to play critical roles in regulating cell phenotype. The identity of ECM ligands presented to mesenchymal stem cells (MSCs) has previously been shown to direct the cell fate commitment of these cells. To enhance osteogenic differentiation of MSCs, alginate hydrogels were prepared that present the DGEA ligand derived from collagen I. When presented from hydrogel surfaces in 2D, the DGEA ligand did not facilitate cell adhesion, while hydrogels presenting the RGD ligand derived from fibronectin did encourage cell adhesion and spreading. However, the osteogenic differentiation of MSCs encapsulated within alginate hydrogels presenting the DGEA ligand was enhanced when compared with unmodified alginate hydrogels and hydrogels presenting the RGD ligand. MSCs cultured in DGEA-presenting gels exhibited increased levels of osteocalcin production and mineral deposition. These data suggest that the presentation of the collagen I-derived DGEA ligand is a feasible approach for selectively inducing an osteogenic phenotype in encapsulated MSCs.},
	keywords = {Alkaline Phosphatase, Animals, Cell Adhesion, Cell Differentiation, Cells, Cultured, Collagen Type I, Humans, Hydrogels, Mesenchymal Stromal Cells, Mice, Oligopeptides, Osteogenesis, Peptides, Phenotype, Rats},
	issn = {1552-4965},
	doi = {10.1002/jbm.a.35497},
	author = {Mehta, Manav and Madl, Christopher M and Lee, Shimwoo and Duda, Georg N and Mooney, David J}
}
@article {601681,
	title = {The effect of growth-mimicking continuous strain on the early stages of skeletal development in micromass culture},
	journal = {PLoS One},
	volume = {10},
	number = {4},
	year = {2015},
	month = {2015},
	pages = {e0124948},
	abstract = {Embryonic skeletogenesis involves proliferation, condensation and subsequent chondrogenic differentiation of mesenchymal precursor cells, and the strains and stresses inherent to these processes have been hypothesized to influence skeletal development. The aim of this study was to determine the effect of growth-mimicking strain on the process of early skeletal development in vitro. To this end, we applied continuous uniaxial strain to embryonic skeletal precursor cells in micromass culture. Strain was applied at different times of culture to specifically address the effect of mechanical loading on the sequential stages of cellular proliferation, condensation and differentiation. We found that growth-mimicking strain at all three times did not affect proliferation or chondrogenic differentiation under the tested conditions. However, the timing of the applied strain did play a role in the density of mesenchymal condensations. This finding suggests that a mechanically dynamic environment, and specifically strain, can influence skeletal patterning. The growth-mimicking micromass model presented here may be a useful tool for further studies into the role of mechanical loading in early skeletal development.},
	keywords = {Animals, Cell Culture Techniques, Cell Differentiation, Cell Proliferation, Chick Embryo, Chondrocytes, Models, Biological, Skeleton, Stress, Mechanical},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0124948},
	author = {Klumpers, Darinka D and Smit, Theo H and Mooney, David J}
}
@article {601666,
	title = {From Skeletal Development to Tissue Engineering: Lessons from the Micromass Assay},
	journal = {Tissue Eng Part B Rev},
	volume = {21},
	number = {5},
	year = {2015},
	month = {2015 Oct},
	pages = {427-37},
	abstract = {Damage and degeneration of the skeletal elements due to disease, trauma, and aging lead to a significant health and economical burden. To reduce this burden, skeletal tissue engineering strategies aim to regenerate functional bone and cartilage in the adult body. However, challenges still exist. Such challenges involve the identification of the external cues that determine differentiation, how to control chondrocyte hypertrophy, and how to achieve specific tissue patterns and boundaries. To address these issues, it could be insightful to look at skeletal development, a robust morphogenetic process that takes place during embryonic development and is commonly modeled in vitro by the micromass assay. In this review, we investigate what the tissue engineering field can learn from this assay. By comparing embryonic skeletal precursor cells from different anatomic locations and developmental stages in micromass, the external cues that guide lineage commitment can be identified. The signaling pathways regulating chondrocyte hypertrophy, and the cues required for tissue patterning, can be elucidated by combining the micromass assay with genetic, molecular, and engineering tools. The lessons from the micromass assay are limited by two major differences between developmental and regenerative skeletogenesis: cell type and scale. We highlight an important difference between embryonic and adult skeletal progenitor cells, in that adult progenitors are not able to form mesenchymal condensations spontaneously. Also, the mechanisms of tissue patterning need to be adjusted to the larger tissue engineering constructs. In conclusion, mechanistic insights of skeletal tissue generation gained from the micromass model could lead to improved tissue engineering strategies and constructs.},
	keywords = {Animals, Bone Development, Chick Embryo, Humans, Tissue Engineering},
	issn = {1937-3376},
	doi = {10.1089/ten.TEB.2014.0704},
	author = {Klumpers, Darinka D and Mooney, David J and Smit, Theo H}
}
@article {601696,
	title = {Key elements for nourishing the translational research environment},
	journal = {Sci Transl Med},
	volume = {7},
	number = {282},
	year = {2015},
	month = {2015 Apr 08},
	pages = {282cm2},
	abstract = {Translation in an academic environment requires a support system--people, goals, models, partnerships, and infrastructures--that will push promising basic science and technology projects forward into the clinic.},
	keywords = {Animals, Clinical Trials as Topic, Humans, Translational Medical Research},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.aaa2049},
	author = {Volk, Hans-Dieter and Stevens, Molly M and Mooney, David J and Grainger, David W and Duda, Georg N}
}
@article {601651,
	title = {Microfluidic Generation of Monodisperse, Structurally Homogeneous Alginate Microgels for Cell Encapsulation and 3D Cell Culture},
	journal = {Adv Healthc Mater},
	volume = {4},
	number = {11},
	year = {2015},
	month = {2015 Aug 05},
	pages = {1628-33},
	abstract = {Monodisperse alginate microgels (10-50 μm) are created via droplet-based microfluidics by a novel crosslinking procedure. Ionic crosslinking of alginate is induced by release of chelated calcium ions. The process separates droplet formation and gelation reaction enabling excellent control over size and homogeneity under mild reaction conditions. Living mesenchymal stem cells are encapsulated and cultured in the generated 3D microenvironments.},
	keywords = {Alginates, Calcium Carbonate, Cell Culture Techniques, Gels, Glucuronic Acid, Hexuronic Acids, Microfluidic Analytical Techniques, Microspheres, Nanoparticles},
	issn = {2192-2659},
	doi = {10.1002/adhm.201500021},
	author = {Utech, Stefanie and Prodanovic, Radivoje and Mao, Angelo S and Ostafe, Raluca and Mooney, David J and Weitz, David A}
}
@article {601671,
	title = {Modeling and Validation of Multilayer Poly(Lactide-Co-Glycolide) Scaffolds for In Vitro Directed Differentiation of Juxtaposed Cartilage and Bone},
	journal = {Tissue Eng Part A},
	volume = {21},
	number = {15-16},
	year = {2015},
	month = {2015 Aug},
	pages = {2228-40},
	abstract = {Polymeric scaffolds, which release growth factors in a temporally controlled manner, have successfully directed the differentiation of stem cells into monolithic tissues of a single lineage. However, engineering precise boundaries in multilineage functional tissues, such as the juxtaposed cartilaginous and osseous tissue present in articulated joints, often remains a challenge. This work demonstrates a precise materials system for in vitro reconstruction of the three-dimensional architecture of these types of human tissues. Multilayer poly(lactide-co-glycolide) (PLG) scaffolds were used to produce spatiotemporal gradients to direct the differentiation of an initially uniform population of mesenchymal stem cells (MSCs) into juxtaposed cartilage and bone. Specifically, growth factors (chondrogenic transforming growth factor-β3 and osteogenic bone morphogenetic protein-4) and their neutralizing antibodies were incorporated within distinct layers of the PLG scaffolds to create spatially segregated morphogen fields within the scaffold volume. The multilayer PLG scaffold designs were optimized by mathematical modeling, and generation of spatially segregated morphogen gradients was validated by assessing activity of luciferase reporter cell lines responsive to each growth factor. Scaffolds seeded with MSCs demonstrated production of juxtaposed cartilage and bone, as evaluated by biochemical staining and western blotting for tissue-specific matrix proteins. This work demonstrates a significant advance for the engineering of implantable constructs comprising tissues of multiple lineages, with potential applications in orthopedic regenerative medicine.},
	keywords = {Animals, Bone and Bones, Cartilage, Cell Line, Humans, Mesenchymal Stromal Cells, Mice, Mink, Models, Biological, Polyglactin 910, Tissue Scaffolds},
	issn = {1937-335X},
	doi = {10.1089/ten.TEA.2015.0089},
	author = {Huang, George X and Arany, Praveen R and Mooney, David J}
}
@article {601676,
	title = {Soft nanofluidics governing minority ion exclusion in charged hydrogels},
	journal = {Soft Matter},
	volume = {11},
	number = {20},
	year = {2015},
	month = {2015 May 28},
	pages = {4081-90},
	abstract = {We investigate ionic partition of negatively charged molecular probes into also negatively charged, covalently crosslinked alginate hydrogels. The aim is to delimit the domain of validity of the major nanoelectrostatic models, and in particular to assess the influence of hydrogel chain mobility on ionic partition. We find that the widely used Gibbs-Donnan model greatly overestimates exclusion of the co-ion probes used. For low molecular weight probes, a much better fit is obtained by taking into account the electrostatics in the nanometric gel pores by means of the Poisson-Boltzmann framework; the fit is improved slightly when taking into account alginate chain mobility. For high molecular weight probes, we find it essential to take into account local gel deformation due to electrostatic repulsion between the flexible gel strands and the probe. This is achieved by combining Poisson-Boltzmann simulations with heterogeneous pore size distribution given by the Ogston model, or more simply and precisely, by applying a semi-empirical scaling law involving the ratio between Debye length and pore size.},
	keywords = {Alginates, Glucuronic Acid, Hexuronic Acids, Hydrogels, Lab-On-A-Chip Devices, Nanotechnology, Potassium Chloride, Static Electricity},
	issn = {1744-6848},
	doi = {10.1039/c5sm00705d},
	author = {Braschler, Thomas and Wu, Songmei and Wildhaber, Fabien and Bencherif, Sidi A and Mooney, David J}
}
@article {601691,
	title = {Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype},
	journal = {Am J Pathol},
	volume = {185},
	number = {6},
	year = {2015},
	month = {2015 Jun},
	pages = {1638-48},
	abstract = {Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds.},
	keywords = {Animals, Diabetes Mellitus, Experimental, Diabetic Neuropathies, Inflammation, Macrophages, Mice, Rabbits, Receptors, Neurokinin-1, Skin, Substance P, Wound Healing},
	issn = {1525-2191},
	doi = {10.1016/j.ajpath.2015.02.011},
	author = {Leal, Ermelindo C and Carvalho, Eug{\'e}nia and Tellechea, Ana and Kafanas, Antonios and Tecilazich, Francesco and Kearney, Cathal and Kuchibhotla, Sarada and Auster, Michael E and Kokkotou, Efi and Mooney, David J and LoGerfo, Frank W and Pradhan-Nabzdyk, Leena and Veves, Aristidis}
}
@article {601641,
	title = {The Combination of Vascular Endothelial Growth Factor and Stromal Cell-Derived Factor Induces Superior Angiogenic Sprouting by Outgrowth Endothelial Cells},
	journal = {J Vasc Res},
	volume = {52},
	number = {1},
	year = {2015},
	month = {2015},
	pages = {62-9},
	abstract = {Endothelial progenitor cells are being broadly explored for the treatment of ischemic cardiovascular diseases, but their response to molecules commonly used to promote the growth of new blood vessels has not been fully characterized. In this study, angiogenic sprout formation in a 3-dimensional, in vitro model by one type of endothelial progenitor, outgrowth endothelial cells (OECs), was characterized in response to exposure to stromal cell-derived factor (SDF) and vascular endothelial growth factor (VEGF) and then compared to mature endothelial cells. Exposure to SDF alone did not increase angiogenic sprouting in comparison to control media, while a combination of VEGF and SDF demonstrated greater potency than VEGF alone for all cell types. Together, VEGF and SDF reduced the sprout initiation time and maintained sprouting levels over time. In direct competition with mature endothelial cells, OECs preferentially localized to the tip cell position, suggesting an enhanced sprouting potential. Overall, these results reveal the impact of the combination of VEGF and SDF on endothelial cell sprouting, and support the enhanced potential of OECs, as opposed to mature endothelial cells, for treating ischemic diseases.},
	keywords = {Cell Culture Techniques, Cell Division, Chemokine CXCL12, Coculture Techniques, Endothelial Cells, Fetal Blood, Human Umbilical Vein Endothelial Cells, Humans, Microspheres, Microvessels, Neovascularization, Physiologic, Recombinant Proteins, Time-Lapse Imaging, Vascular Endothelial Growth Factor A},
	issn = {1423-0135},
	doi = {10.1159/000382129},
	author = {Anderson, Erin M and Mooney, David J}
}
@article {601631,
	title = {Engineered composite fascia for stem cell therapy in tissue repair applications},
	journal = {Acta Biomater},
	volume = {26},
	year = {2015},
	month = {2015 Oct},
	pages = {1-12},
	abstract = {UNLABELLED: A critical challenge in tissue regeneration is to develop constructs that effectively integrate with the host tissue. Here, we describe a composite, laser micromachined, collagen-alginate construct containing human mesenchymal stem cells (hMSCs) for tissue repair applications. Collagen type I was fashioned into laminated collagen sheets to form a mechanically robust fascia that was subsequently laser micropatterned with pores of defined dimension and spatial distribution as a means to modulate mechanical behavior and promote tissue integration. Significantly, laser micromachined patterned constructs displayed both substantially greater compliance and suture retention strength than non-patterned constructs. hMSCs were loaded in an RGD-functionalized alginate gel modified to degrade in vivo. Over a 7 day observation period in vitro, high cell viability was observed with constant levels of VEGF, PDGF-β and MCP-1 protein expression. In a full thickness abdominal wall defect model, the composite construct prevented hernia recurrence in Wistar rats over an 8-week period with de novo tissue and vascular network formation and the absence of adhesions to underlying abdominal viscera. As compared to acellular constructs, constructs containing hMSCs displayed greater integration strength (cell seeded: 0.92 {\textpm} 0.19 N/mm vs. acellular: 0.59 {\textpm} 0.25 N/mm, p=0.01), increased vascularization (cell seeded: 2.7-2.1/hpf vs. acellular: 1.7-2.1/hpf, p,
	keywords = {Alginates, Animals, Biomimetic Materials, Collagen, Equipment Design, Equipment Failure Analysis, Fascia, Female, Glucuronic Acid, Guided Tissue Regeneration, Hernia, Herniorrhaphy, Hexuronic Acids, Humans, Mesenchymal Stem Cell Transplantation, Rats, Rats, Wistar, Tissue Engineering, Tissue Scaffolds, Treatment Outcome},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2015.08.012},
	author = {Ayala, Perla and Caves, Jeffrey and Dai, Erbin and Siraj, Layla and Liu, Liying and Chaudhuri, Ovijit and Haller, Carolyn A and Mooney, David J and Chaikof, Elliot L}
}
@article {601636,
	title = {Injectable cryogel-based whole-cell cancer vaccines},
	journal = {Nat Commun},
	volume = {6},
	year = {2015},
	month = {2015 Aug 12},
	pages = {7556},
	abstract = {A biomaterial-based vaccination system that uses minimal extracorporeal manipulation could provide in situ enhancement of dendritic cell (DC) numbers, a physical space where DCs interface with transplanted tumour cells, and an immunogenic context. Here we encapsulate GM-CSF, serving as a DC enhancement factor, and CpG ODN, serving as a DC activating factor, into sponge-like macroporous cryogels. These cryogels are injected subcutaneously into mice to localize transplanted tumour cells and deliver immunomodulatory factors in a controlled spatio-temporal manner. These vaccines elicit local infiltrates composed of conventional and plasmacytoid DCs, with the subsequent induction of potent, durable and specific anti-tumour T-cell responses in a melanoma model. These cryogels can be delivered in a minimally invasive manner, bypass the need for genetic modification of transplanted cancer cells and provide sustained release of immunomodulators. Altogether, these findings indicate the potential for cryogels to serve as a platform for cancer cell vaccinations.},
	keywords = {Animals, Cancer Vaccines, Cryogels, Dendritic Cells, Female, Melanoma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, T-Lymphocytes},
	issn = {2041-1723},
	doi = {10.1038/ncomms8556},
	author = {Bencherif, Sidi A and Warren Sands, R and Ali, Omar A and Li, Weiwei A and Lewin, Sarah A and Braschler, Thomas M and Shih, Ting-Yu and Verbeke, Catia S and Bhatta, Deen and Dranoff, Glenn and Mooney, David J}
}
@article {601611,
	title = {Injectable, Pore-Forming Hydrogels for In Vivo Enrichment of Immature Dendritic Cells},
	journal = {Adv Healthc Mater},
	volume = {4},
	number = {17},
	year = {2015},
	month = {2015 Dec 09},
	pages = {2677-87},
	abstract = {Biomaterials-based vaccines have emerged as a powerful method to evoke potent immune responses directly in vivo, without the need for ex vivo cell manipulation, and modulating dendritic cell (DC) responses in a noninflammatory context could enable the development of tolerogenic vaccines to treat autoimmunity. This study describes the development of a noninflammatory, injectable hydrogel system to locally enrich DCs in vivo without inducing their maturation or activation, as a first step toward this goal. Alginate hydrogels that form pores in situ are characterized and used as a physical scaffold for cell infiltration. These gels are also adapted to control the release of granulocyte-macrophage colony stimulating factor (GM-CSF), a potent inducer of DC recruitment and proliferation. In vivo, sustained release of GM-CSF from the pore-forming gels leads to the accumulation of millions of cells in the material. These cells are highly enriched in CD11b(+) CD11c(+) DCs, and further analysis of cell surface marker expression indicates these DCs are immature. This study demonstrates that a polymeric delivery system can mediate the accumulation of a high number and percentage of immature DCs, and may provide the basis for further development of materials-based, therapeutic vaccines.},
	keywords = {Animals, Biomarkers, Cell Proliferation, Dendritic Cells, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Hydrogels, Injections, Mice, Mice, Inbred C57BL, Vaccines},
	issn = {2192-2659},
	doi = {10.1002/adhm.201500618},
	author = {Verbeke, Catia S and Mooney, David J}
}
@article {601616,
	title = {A light-reflecting balloon catheter for atraumatic tissue defect repair},
	journal = {Sci Transl Med},
	volume = {7},
	number = {306},
	year = {2015},
	month = {2015 Sep 23},
	pages = {306ra149},
	abstract = {A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinical translation. We developed a multifunctional, catheter-based technology with no implantable rigid components that functions by unfolding an adhesive-loaded elastic patch and deploying a double-balloon design to stabilize and apply pressure to the patch against the tissue defect site. The device uses a fiber-optic system and reflective metallic coating to uniformly disperse ultraviolet light for adhesive activation. Using this device, we demonstrate closure on the distal side of a defect in porcine abdominal wall, stomach, and heart tissue ex vivo. The catheter was further evaluated as a potential tool for tissue closure in vivo in rat heart and abdomen and as a perventricular tool for closure of a challenging cardiac septal defect in a large animal (porcine) model. Patches attached to the heart and abdominal wall with the device showed similar inflammatory response as sutures, with 100\% small animal survival, indicating safety. In the large animal model, a ventricular septal defect in a beating heart was reduced to ,
	keywords = {Animals, Catheters, Rats, Wound Healing},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.aaa2406},
	author = {Ellen T Roche and Fabozzo, Assunta and Lee, Yuhan and Panagiotis Polygerinos and Friehs, Ingeborg and Schuster, Lucia and Whyte, William and Casar Berazaluce, Alejandra Maria and Bueno, Alejandra and Lang, Nora and Pereira, Maria J. N. and Feins, Eric and Wasserman, Steven and O{\textquoteright}Cearbhaill, Eoin D and Nikolay V. Vasilyev and Mooney, David J and Karp, Jeffrey M and Pedro J. del Nido and Conor J Walsh}
}
@article {601626,
	title = {Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone~formation},
	journal = {Nat Mater},
	volume = {14},
	number = {12},
	year = {2015},
	month = {2015 Dec},
	pages = {1269-77},
	abstract = {The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype. Stem cell behaviour can also be controlled in~vitro by manipulating the elasticity of both porous and non-porous materials, yet translation to therapeutic processes in~vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in~vitro, and cell deployment in~vitro and in~vivo, can be controlled by modifying, respectively, the hydrogel{\textquoteright}s elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel{\textquoteright}s elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direct therapeutic stem cell behaviours in~situ.},
	keywords = {Biocompatible Materials, Bone Development, Elasticity, Extracellular Matrix, Hydrogels, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells},
	issn = {1476-1122},
	doi = {10.1038/nmat4407},
	author = {Huebsch, Nathaniel and Lippens, Evi and Lee, Kangwon and Mehta, Manav and Koshy, Sandeep T and Darnell, Max C and Desai, Rajiv M and Madl, Christopher M and Xu, Maria and Zhao, Xuanhe and Chaudhuri, Ovijit and Verbeke, Catia and Kim, Woo Seob and Alim, Karen and Mammoto, Akiko and Ingber, Donald E and Duda, Georg N and Mooney, David J}
}
@article {601621,
	title = {On-demand drug delivery from local depots},
	journal = {J Control Release},
	volume = {219},
	year = {2015},
	month = {2015 Dec 10},
	pages = {8-17},
	abstract = {Stimuli-responsive polymeric depots capable of on-demand release of therapeutics promise a substantial improvement in the treatment of many local diseases. These systems have the advantage of controlling local dosing so that payload is released at a time and with a dose chosen by a physician or patient, and the dose can be varied as disease progresses or healing occurs. Macroscale drug depot can be induced to release therapeutics through the action of physical stimuli such as ultrasound, electric and magnetic fields and light as well as through the addition of pharmacological stimuli such as nucleic acids and small molecules. In this review, we highlight recent advances in the development of polymeric systems engineered for releasing therapeutic molecules through physical and pharmacological stimulation.},
	keywords = {Delayed-Action Preparations, Drug Delivery Systems, Humans, Pharmaceutical Preparations, Polymers},
	issn = {1873-4995},
	doi = {10.1016/j.jconrel.2015.09.011},
	author = {Brudno, Yevgeny and Mooney, David J}
}
@article {601606,
	title = {Regenerative medicine: Current therapies and future directions},
	journal = {Proc Natl Acad Sci U S A},
	volume = {112},
	number = {47},
	year = {2015},
	month = {2015 Nov 24},
	pages = {14452-9},
	abstract = {Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies.},
	keywords = {Animals, Biocompatible Materials, Embryonic Stem Cells, Hematopoietic Stem Cells, Humans, Immune System, Regenerative Medicine, Tissue Engineering},
	issn = {1091-6490},
	doi = {10.1073/pnas.1508520112},
	author = {Mao, Angelo S and Mooney, David J}
}
@article {601646,
	title = {Switchable Release of Entrapped Nanoparticles from Alginate Hydrogels},
	journal = {Adv Healthc Mater},
	volume = {4},
	number = {11},
	year = {2015},
	month = {2015 Aug 05},
	pages = {1634-1639},
	abstract = {Natural biological processes are intricately controlled by the timing and spatial distribution of various cues. To mimic this precise level of control, the physical sizes of gold nanoparticles are utilized to sterically entrap them in hydrogel materials, where they are subsequently released only in response to ultrasound. These nanoparticles can transport bioactive factors to cells and direct cell behavior on-demand.},
	keywords = {Alginates, Animals, Bone Morphogenetic Protein 2, Cells, Cultured, Drug Carriers, Glucuronic Acid, Gold, Hexuronic Acids, Humans, Hydrogels, Mesenchymal Stromal Cells, Metal Nanoparticles, Mice, Nanoparticles, Polyethylene Glycols, Recombinant Proteins, Sonication},
	issn = {2192-2659},
	doi = {10.1002/adhm.201500254},
	author = {Kearney, Cathal J and Skaat, Hadas and Kennedy, Stephen M and Hu, Jennifer and Darnell, Max and Raimondo, Theresa M and Mooney, David J}
}
@article {380556,
	title = {Versatile click alginate hydrogels crosslinked via tetrazine-norbornene chemistry},
	journal = {Biomaterials},
	volume = {50},
	year = {2015},
	month = {2015 May},
	pages = {30-7},
	abstract = {Alginate hydrogels are well-characterized, biologically inert materials that are used in many biomedical applications for the delivery of drugs, proteins, and cells. Unfortunately, canonical covalently crosslinked alginate hydrogels are formed using chemical strategies that can be biologically harmful due to their lack of chemoselectivity. In this work we introduce tetrazine and norbornene groups to alginate polymer chains and subsequently form covalently crosslinked click alginate hydrogels capable of encapsulating cells without damaging them. The rapid, bioorthogonal, and specific click reaction is irreversible and allows for easy incorporation of cells with high post-encapsulation viability. The swelling and mechanical properties of the click alginate hydrogel can be tuned via the total polymer concentration and the stoichiometric ratio of the complementary click functional groups. The click alginate hydrogel can be modified after gelation to display cell adhesion peptides for 2D cell culture using thiol-ene chemistry. Furthermore, click alginate hydrogels are minimally inflammatory, maintain structural integrity over several months, and reject cell infiltration when injected subcutaneously in mice. Click alginate hydrogels combine the numerous benefits of alginate hydrogels with powerful bioorthogonal click chemistry for use in tissue engineering applications involving the stable encapsulation or delivery of cells or bioactive molecules.},
	keywords = {Alginates, Animals, Cell Adhesion, Cell Proliferation, Cells, Immobilized, click chemistry, Compressive Strength, Cross-Linking Reagents, Elastic Modulus, Female, Glucuronic Acid, Heterocyclic Compounds, 1-Ring, Hexuronic Acids, Hydrogels, Injections, Mice, Mice, Inbred C57BL, NIH 3T3 Cells, Norbornanes, Oligopeptides},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2015.01.048},
	author = {Desai, Rajiv M and Koshy, Sandeep T and Hilderbrand, Scott A and Mooney, David J and Joshi, Neel S}
}
@article {380561,
	title = {Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis},
	journal = {Tissue Eng Part B Rev},
	volume = {21},
	number = {4},
	year = {2015},
	month = {2015 Aug},
	pages = {354-64},
	abstract = {Delayed healing or nonhealing of bone is an important clinical concern. Although bone, one of the two tissues with scar-free healing capacity, heals in most cases, healing is delayed in more than 10\% of clinical cases. Treatment of such delayed healing condition is often painful, risky, time consuming, and expensive. Tissue healing is a multistage regenerative process involving complex and well-orchestrated steps, which are initiated in response to injury. At best, these steps lead to scar-free tissue formation. At the onset of healing, during the inflammatory phase, stationary and attracted macrophages and other immune cells at the fracture site release cytokines in response to injury. This initial reaction to injury is followed by the recruitment, proliferation, and differentiation of mesenchymal stromal cells, synthesis of extracellular matrix proteins, angiogenesis, and finally tissue remodeling. Failure to heal is often associated with poor revascularization. Since blood vessels mediate the transport of circulating cells, oxygen, nutrients, and waste products, they appear essential for successful healing. The strategy of endogenous regeneration in a tissue such as bone is interesting to analyze since it may represent a blueprint of successful tissue formation. This review highlights the interdependency of the time cascades of inflammation, angiogenesis, and tissue regeneration. A better understanding of these inter-relations is mandatory to early identify patients at risk as well as to overcome critical clinical conditions that limit healing. Instead of purely tolerating the inflammatory phase, modulations of inflammation (immunomodulation) might represent a valid therapeutic strategy to enhance angiogenesis and foster later phases of tissue regeneration.},
	keywords = {Bone and Bones, Bone Regeneration, Humans, Inflammation, Leukocytes, Neovascularization, Physiologic},
	issn = {1937-3376},
	doi = {10.1089/ten.TEB.2014.0677},
	author = {Schmidt-Bleek, Katharina and Kwee, Brian J and Mooney, David J and Duda, Georg N}
}
@article {373611,
	title = {In vivo targeting through click chemistry},
	journal = {ChemMedChem},
	volume = {10},
	number = {4},
	year = {2015},
	month = {2015 Apr},
	pages = {617-20},
	abstract = {Targeting small molecules to diseased tissues as therapy or diagnosis is a significant challenge in drug delivery. Drug-eluting devices implanted during invasive surgery allow the controlled presentation of drugs at the disease site, but cannot be modified once the surgery is complete. We demonstrate that bioorthogonal click chemistry can be used to target circulating small molecules to hydrogels resident intramuscularly in diseased tissues. We also demonstrate that small molecules can be repeatedly targeted to the diseased area over the course of at least one month. Finally, two bioorthogonal reactions were used to segregate two small molecules injected as a mixture to two separate locations in a mouse disease model. These results demonstrate that click chemistry can be used for pharmacological drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.},
	keywords = {Alginates, Alkynes, Animals, Azides, Benzene Derivatives, click chemistry, Cyclooctanes, Drug Delivery Systems, Fluorescent Dyes, Glucuronic Acid, Heterocyclic Compounds, 1-Ring, Hexuronic Acids, Hydrogels, Mice, Muscles},
	issn = {1860-7187},
	doi = {10.1002/cmdc.201402527},
	author = {Brudno, Yevgeny and Desai, Rajiv M and Kwee, Brian J and Joshi, Neel S and Aizenberg, Michael and Mooney, David J}
}
@article {373616,
	title = {Local delivery of VEGF and SDF enhances endothelial progenitor cell recruitment and resultant recovery from ischemia},
	journal = {Tissue Eng Part A},
	volume = {21},
	number = {7-8},
	year = {2015},
	month = {2015 Apr},
	pages = {1217-27},
	abstract = {Biomaterials may improve outcomes of endothelial progenitor-based therapies for the treatment of ischemic cardiovascular disease, due to their ability to direct cell behavior. We hypothesized that local, sustained delivery of exogenous vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF) from alginate hydrogels could increase recruitment of systemically infused endothelial progenitors to ischemic tissue, and subsequent neovascularization. VEGF and SDF were found to enhance in vitro adhesion and migration of outgrowth endothelial cells (OECs) and circulating angiogenic cells (CACs), two populations of endothelial progenitors, by twofold to sixfold, and nearly doubled recruitment to both ischemic and nonischemic muscle tissue in vivo. Local delivery of VEGF and SDF to ischemic hind-limbs in combination with systemic CAC delivery significantly improved functional perfusion recovery over OEC delivery, or either treatment alone. Compared with OECs, CACs were more responsive to VEGF and SDF treatment, promoted in vitro endothelial sprout formation in a paracrine manner more potently, and demonstrated greater influence on infiltrating inflammatory cells in vivo. These studies demonstrate that accumulation of infused endothelial progenitors can be enriched using biomaterial-based delivery of VEGF and SDF, and emphasize the therapeutic benefit of using CACs for the treatment of ischemia.},
	keywords = {Alginates, Animals, Blood Vessels, Cell Adhesion, Cell Movement, Chemokine CXCL12, Drug Delivery Systems, Endothelial Progenitor Cells, Glucuronic Acid, Hexuronic Acids, Hindlimb, Humans, Hydrogels, Inflammation, Ischemia, Mice, Inbred C57BL, Neovascularization, Physiologic, Reperfusion, Vascular Endothelial Growth Factor A},
	issn = {1937-335X},
	doi = {10.1089/ten.TEA.2014.0508},
	author = {Anderson, Erin M and Kwee, Brian J and Lewin, Sarah A and Raimondo, Theresa and Mehta, Manav and Mooney, David J}
}
@article {373606,
	title = {Substrate stress relaxation regulates cell spreading},
	journal = {Nat Commun},
	volume = {6},
	year = {2015},
	month = {2015 Feb 19},
	pages = {6364},
	abstract = {Studies of cellular mechanotransduction have converged upon the idea that cells sense extracellular matrix (ECM) elasticity by gauging resistance to the traction forces they exert on the ECM. However, these studies typically utilize purely elastic materials as substrates, whereas physiological ECMs are viscoelastic, and exhibit stress relaxation, so that cellular traction forces exerted by cells remodel the ECM. Here we investigate the influence of ECM stress relaxation on cell behaviour through computational modelling and cellular experiments. Surprisingly, both our computational model and experiments find that spreading for cells cultured on soft substrates that exhibit stress relaxation is greater than cells spreading on elastic substrates of the same modulus, but similar to that of cells spreading on stiffer elastic substrates. These findings challenge the current view of how cells sense and respond to the ECM.},
	keywords = {3T3 Cells, Alginates, Animals, Cell Adhesion, Cell Culture Techniques, Cell Line, Tumor, Cell Shape, Extracellular Matrix, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Mechanotransduction, Cellular, Mice, Models, Biological, Stress, Mechanical, Viscoelastic Substances},
	issn = {2041-1723},
	doi = {10.1038/ncomms7365},
	author = {Chaudhuri, Ovijit and Gu, Luo and Darnell, Max and Klumpers, Darinka and Bencherif, Sidi A and Weaver, James C and Huebsch, Nathaniel and Mooney, David J}
}
@article {365901,
	title = {Biomaterial-based delivery for skeletal muscle repair},
	journal = {Adv Drug Deliv Rev},
	volume = {84},
	year = {2015},
	month = {2015 Apr},
	pages = {188-97},
	abstract = {Skeletal muscle possesses a remarkable capacity for regeneration in response to minor damage, but severe injury resulting in a volumetric muscle loss can lead to extensive and irreversible fibrosis, scarring, and loss of muscle function. In early clinical trials, the intramuscular injection of cultured myoblasts was proven to be a safe but ineffective cell therapy, likely due to rapid death, poor migration, and immune rejection of the injected cells. In recent years, appropriate therapeutic cell types and culturing techniques have improved progenitor cell engraftment upon transplantation. Importantly, the identification of several key biophysical and biochemical cues that synergistically regulate satellite cell fate has paved the way for the development of cell-instructive biomaterials that serve as delivery vehicles for cells to promote in vivo regeneration. Material carriers designed to spatially and temporally mimic the satellite cell niche may be of particular importance for the complete regeneration of severely damaged skeletal muscle.},
	keywords = {Biocompatible Materials, Humans, Muscle, Skeletal, Regeneration, Stem Cell Transplantation},
	issn = {1872-8294},
	doi = {10.1016/j.addr.2014.09.008},
	author = {Cezar, Christine A and Mooney, David J}
}
@article {365906,
	title = {Manipulating the intersection of angiogenesis and inflammation},
	journal = {Ann Biomed Eng},
	volume = {43},
	number = {3},
	year = {2015},
	month = {2015 Mar},
	pages = {628-40},
	abstract = {There exists a critical need to develop strategies that promote blood vessel formation (neovascularization) in virtually all tissue engineering and regenerative medicine efforts. While research typically focuses on understanding and exploiting the role of angiogenic factors and vascular cells on new blood vessel formation, the activity of the immune system is being increasingly recognized to impact vascular formation and adaptation. This review will provide both an overview of the intersection of angiogenesis and the immune system, and how biomaterials may be designed to promote favorable interactions between these two systems to promote effective vascularization.},
	keywords = {Animals, Biocompatible Materials, Humans, Inflammation, Neovascularization, Physiologic, Tissue Engineering},
	issn = {1573-9686},
	doi = {10.1007/s10439-014-1145-y},
	author = {Kwee, Brian J and Mooney, David J}
}
@article {365916,
	title = {Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy},
	journal = {Nat Biotechnol},
	volume = {33},
	number = {1},
	year = {2015},
	month = {2015 Jan},
	pages = {64-72},
	abstract = {Implanting materials in the body to program host immune cells is a promising alternative to transplantation of cells manipulated ex vivo to direct an immune response, but doing so requires a surgical procedure. Here we demonstrate that high-aspect-ratio, mesoporous silica rods (MSRs) injected with a needle spontaneously assemble in vivo to form macroporous structures that provide a 3D cellular microenvironment for host immune cells. In mice, substantial numbers of dendritic cells are recruited to the pores between the scaffold rods. The recruitment of dendritic cells and their subsequent homing to lymph nodes can be modulated by sustained release of inflammatory signals and adjuvants from the scaffold. Moreover, injection of an MSR-based vaccine formulation enhances systemic helper T cells TH1 and TH2 serum antibody and cytotoxic T-cell levels compared to bolus controls. These findings suggest that injectable MSRs may serve as a multifunctional vaccine platform to modulate host immune cell function and provoke adaptive immune responses.},
	keywords = {Animals, Immune System, Mice, Tissue Scaffolds, Vaccines},
	issn = {1546-1696},
	doi = {10.1038/nbt.3071},
	author = {Kim, Jaeyun and Li, Weiwei Aileen and Choi, Youngjin and Lewin, Sarah A and Verbeke, Catia S and Dranoff, Glenn and Mooney, David J}
}
@article {1192166,
	title = {13. From tissue engineering to therapeutic cancer vaccines: Original research article: Bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery, 2000},
	journal = {J Control Release},
	volume = {190},
	year = {2014},
	month = {2014 Sep 28},
	pages = {54-6},
	keywords = {Animals, Cancer Vaccines, Drug Delivery Systems, History, 20th Century, Polymers, Tissue Engineering},
	issn = {1873-4995},
	author = {Ali, Omar A and Mooney, David J}
}
@article {1192176,
	title = {Cell-friendly inverse opal-like hydrogels for a spatially separated co-culture system},
	journal = {Macromol Rapid Commun},
	volume = {35},
	number = {18},
	year = {2014},
	month = {2014 Sep},
	pages = {1578-86},
	abstract = {Three-dimensional macroporous scaffolds have extensively been studied for cell-based tissue engineering but their use is mostly limited to mechanical support for cell adhesion and growth on the surface of macropores. Here, a templated fabrication method is described to prepare cell-friendly inverse opal-like hydrogels (IOHs) allowing both cell encapsulation within the hydrogel matrix and cell seeding on the surface of macropores. Ionically crosslinked alginate microbeads and photocrosslinkable biocompatible polymers are used as a sacrificial template and as a matrix, respectively. The alginate microbeads are easily removed by a chelating agent, with minimal toxicity for the encapsulated cells during template removal. The outer surface of macropores in IOHs can also provide a space for cell adherence. The cells encapsulated or attached in IOHs are able to remain viable and to proliferate over time. The elastic modulus and cell-adhesion properties of IOHs can be easily controlled and tuned. Finally, it is demonstrated that IOH can be used to co-culture two distinct cell populations in different spatial positions. This cell-friendly IOH system provides a 3D scaffold for organizing different cell types in a controllable microenvironment to investigate biological processes such as stem cell niches or tumor microenvironments.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cell Adhesion, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Green Fluorescent Proteins, Human Umbilical Vein Endothelial Cells, Humans, Hydrogel, Luminescent Proteins, Mesenchymal Stromal Cells, Mice, Microscopy, Fluorescence, Microspheres, Polymers, Porosity, Reproducibility of Results, Tissue Engineering, Tissue Scaffolds},
	issn = {1521-3927},
	doi = {10.1002/marc.201400278},
	author = {Kim, Jaeyun and Bencherif, Sidi A and Li, Weiwei Aileen and Mooney, David J}
}
@article {1192161,
	title = {Influence of the stiffness of three-dimensional alginate/collagen-I interpenetrating networks on fibroblast biology},
	journal = {Biomaterials},
	volume = {35},
	number = {32},
	year = {2014},
	month = {2014 Oct},
	pages = {8927-36},
	abstract = {Wound dressing biomaterials are increasingly being designed to incorporate bioactive molecules to promote healing, but the impact of matrix mechanical properties on the biology of resident cells orchestrating skin repair and regeneration remains to be fully understood. This study investigated whether tuning the stiffness of a model wound dressing biomaterial could control the behavior of dermal fibroblasts. Fully interpenetrating networks (IPNs) of collagen-I and alginate were fabricated to enable gel stiffness to be tuned independently of gel architecture, polymer concentration or adhesion ligand density. Three-dimensional cultures of dermal fibroblasts encapsulated within matrices of different stiffness were shown to promote dramatically different cell morphologies, and enhanced stiffness resulted in upregulation of key-mediators of inflammation such as IL-10 and COX-2. These findings suggest that simply modulating the matrix mechanical properties of a given wound dressing biomaterial deposited at the wound site could regulate the progression of wound healing.},
	keywords = {Alginates, Biocompatible Materials, Biological Dressings, Cell Adhesion, Cells, Cultured, Collagen Type I, Cyclooxygenase 2, Fibroblasts, Glucuronic Acid, Hexuronic Acids, Humans, Interleukin-10, Microscopy, Electron, Scanning, Polymers, Regeneration, Tissue Scaffolds, Up-Regulation, Wound Healing},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2014.06.047},
	author = {Branco da Cunha, Cristiana and Klumpers, Darinka D and Li, Weiwei A and Koshy, Sandeep T and Weaver, James C and Chaudhuri, Ovijit and Granja, Pedro L and Mooney, David J}
}
@article {1192181,
	title = {Injectable MMP-sensitive alginate hydrogels as hMSC delivery systems},
	journal = {Biomacromolecules},
	volume = {15},
	number = {1},
	year = {2014},
	month = {2014 Jan 13},
	pages = {380-90},
	abstract = {Hydrogels with the potential to provide minimally invasive cell delivery represent a powerful tool for tissue-regeneration therapies. In this context, entrapped cells should be able to escape the matrix becoming more available to actively participate in the healing process. Here, we analyzed the performance of proteolytically degradable alginate hydrogels as vehicles for human mesenchymal stem cells (hMSC) transplantation. Alginate was modified with the matrix metalloproteinase (MMP)-sensitive peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG), which did not promote dendritic cell maturation in vitro, neither free nor conjugated to alginate chains, indicating low immunogenicity. hMSC were entrapped within MMP-sensitive and MMP-insensitive alginate hydrogels, both containing cell-adhesion RGD peptides. Softer (2 wt \% alginate) and stiffer (4 wt \% alginate) matrices were tested. When embedded in a Matrigel layer, hMSC-laden MMP-sensitive alginate hydrogels promoted more extensive outward cell migration and invasion into the tissue mimic. In vivo, after 4 weeks of subcutaneous implantation in a xenograft mouse model, hMSC-laden MMP-sensitive alginate hydrogels showed higher degradation and host tissue invasion than their MMP-insensitive equivalents. In both cases, softer matrices degraded faster than stiffer ones. The transplanted hMSC were able to produce their own collagenous extracellular matrix, and were located not only inside the hydrogels, but also outside, integrated in the host tissue. In summary, injectable MMP-sensitive alginate hydrogels can act as localized depots of cells and confer protection to transplanted cells while facilitating tissue regeneration.},
	keywords = {Alginates, Animals, Cells, Cultured, Drug Delivery Systems, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Injections, Male, Matrix Metalloproteinases, Mesenchymal Stromal Cells, Mice, Mice, SCID},
	issn = {1526-4602},
	doi = {10.1021/bm4016495},
	author = {Fonseca, Keila B and Gomes, David B and Lee, Kangwon and Santos, Susana G and Sousa, Aureliana and Silva, Eduardo A and Mooney, David J and Granja, Pedro L and Barrias, Cristina C}
}
@article {1192156,
	title = {Multi-lineage MSC differentiation via engineered morphogen fields},
	journal = {J Dent Res},
	volume = {93},
	number = {12},
	year = {2014},
	month = {2014 Dec},
	pages = {1250-7},
	abstract = {Tissue loss due to oral diseases requires the healing and regeneration of tissues of multiple lineages. While stem cells are native to oral tissues, a current major limitation to regeneration is the ability to direct their lineage-specific differentiation. This work utilizes polymeric scaffold systems with spatiotemporally controlled morphogen cues to develop precise morphogen fields to direct mesenchymal stem cell differentiation. First, a simple three-layer scaffold design was developed that presented two spatially segregated, lineage-specific cues (Dentinogenic TGF-β1 and Osteogenic BMP4). However, this system resulted in diffuse morphogen fields, as assessed by the in vitro imaging of cell-signaling pathways triggered by the morphogens. Mathematical modeling was then exploited, in combination with incorporation of specific inhibitors (neutralizing antibodies or a small molecule kinase inhibitor) into each morphogen in an opposing spatial pattern as the respective morphogen, to design a five-layer scaffold that was predicted to yield distinct, spatially segregated zones of morphogen signaling. To validate this system, undifferentiated MSCs were uniformly seeded in these scaffold systems, and distinct mineralized tissue differentiation were noted within these morphogen zones. Finally, to demonstrate temporal control over morphogen signaling, latent TGF-β1 was incorporated into one region of a concentric scaffold design, and laser treatment was used to activate the morphogen on-demand and to induce dentin differentiation solely within that specific spatial zone. This study demonstrates a significant advance in scaffold design to generate precise morphogen fields that can be used to develop in situ models to explore tissue differentiation and may ultimately be useful in engineering multi-lineage tissues in clinical dentistry.},
	keywords = {Animals, Bone Morphogenetic Protein 4, Cell Culture Techniques, Cell Differentiation, Cell Lineage, Dentinogenesis, Diffusion, Humans, Intercellular Signaling Peptides and Proteins, Lactic Acid, Lasers, Semiconductor, Mesenchymal Stromal Cells, Mice, Models, Biological, Osteogenesis, Paracrine Communication, Polyglycolic Acid, Prosthesis Design, Tissue Engineering, Tissue Scaffolds, Transforming Growth Factor beta1},
	issn = {1544-0591},
	doi = {10.1177/0022034514542272},
	author = {Arany, P R and Huang, G X and Gadish, O and Feliz, J and Weaver, J C and Kim, J. and Yuen, W W and Mooney, D J}
}
@article {1192151,
	title = {Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer},
	journal = {BJU Int},
	volume = {114},
	number = {6b},
	year = {2014},
	month = {2014 Dec},
	pages = {E25-E31},
	abstract = {OBJECTIVE: To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS: Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons.

RESULTS: An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall{\textquoteright}s τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review.

CONCLUSIONS: Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.},
	keywords = {Antineoplastic Combined Chemotherapy Protocols, Disease Progression, Disease-Free Survival, Drug Discovery, Gossypol, Humans, Indoles, Male, Prednisone, Prostatic Neoplasms, Castration-Resistant, Pyrroles, Radiography, Retrospective Studies, Survival Rate, Taxoids, Time Factors},
	issn = {1464-410X},
	doi = {10.1111/bju.12589},
	author = {Sonpavde, Guru and Pond, Gregory R and Armstrong, Andrew J and Galsky, Matthew D and Leopold, Lance and Wood, Brian A and Wang, Shaw-Ling and Paolini, Jolanda and Chen, Isan and Chow-Maneval, Edna and Mooney, David J and Lechuga, Mariajose and Smith, Matthew R and Michaelson, M Dror}
}
@article {1192171,
	title = {The Young Innovators of Cellular and Molecular Bioengineering},
	journal = {Cell Mol Bioeng},
	volume = {7},
	number = {3},
	year = {2014},
	month = {2014 Sep 01},
	pages = {291-292},
	issn = {1865-5025},
	doi = {10.1007/s12195-014-0352-9},
	author = {Reinhart-King, Cynthia A and Mooney, David J and Schaffer, David V}
}
@article {380551,
	title = {Rapid and extensive collapse from electrically responsive macroporous hydrogels.},
	journal = {Adv Healthc Mater},
	volume = {3},
	number = {4},
	year = {2014},
	month = {2014 Apr},
	pages = {500-7},
	abstract = {Electrically responsive hydrogels are created with interconnected macropores, which greatly enhance their ability to rapidly undergo volumetric collapse when subjected to moderate electric fields. When optimized, these electrogels are easily integrated into arrays capable of rapid configurational and chromatic optical modulations, and when loaded with drugs, are able to coordinate the delivery profile of multiple drugs.},
	keywords = {Biocompatible Materials, Electrochemistry, Hydrogels, Particle Size, Polymers, Porosity, Water},
	issn = {2192-2659},
	doi = {10.1002/adhm.201300260},
	author = {Kennedy, Stephen and Bencherif, Sidi and Norton, Daniel and Weinstock, Laura and Mehta, Manav and Mooney, David}
}
@article {380546,
	title = {Photoactivation of endogenous latent transforming growth factor-β1 directs dental stem cell differentiation for regeneration.},
	journal = {Sci Transl Med},
	volume = {6},
	number = {238},
	year = {2014},
	month = {2014 May 28},
	pages = {238ra69},
	abstract = {Rapid advancements in the field of stem cell biology have led to many current efforts to exploit stem cells as therapeutic agents in regenerative medicine. However, current ex vivo cell manipulations common to most regenerative approaches create a variety of technical and regulatory hurdles to their clinical translation, and even simpler approaches that use exogenous factors to differentiate tissue-resident stem cells carry significant off-target side effects. We show that non-ionizing, low-power laser (LPL) treatment can instead be used as a minimally invasive tool to activate an endogenous latent growth factor complex, transforming growth factor-β1 (TGF-β1), that subsequently differentiates host stem cells to promote tissue regeneration. LPL treatment induced reactive oxygen species (ROS) in a dose-dependent manner, which, in turn, activated latent TGF-β1 (LTGF-β1) via a specific methionine residue (at position 253 on LAP). Laser-activated TGF-β1 was capable of differentiating human dental stem cells in vitro. Further, an in vivo pulp capping model in rat teeth demonstrated significant increase in dentin regeneration after LPL treatment. These in vivo effects were abrogated in TGF-β receptor II (TGF-βRII) conditional knockout (DSPP(Cre)TGF-βRII(fl/fl)) mice or when wild-type mice were given a TGF-βRI inhibitor. These findings indicate a pivotal role for TGF-β in mediating LPL-induced dental tissue regeneration. More broadly, this work outlines a mechanistic basis for harnessing resident stem cells with a light-activated endogenous cue for clinical regenerative applications.},
	keywords = {Animals, Cell Differentiation, Dentin, Mice, Regenerative Medicine, Stem Cells, Tooth, Transforming Growth Factor beta1},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.3008234},
	author = {Arany, Praveen R and Cho, Andrew and Hunt, Tristan D and Sidhu, Gursimran and Shin, Kyungsup and Hahm, Eason and Huang, George X and Weaver, James and Chen, Aaron Chih-Hao and Padwa, Bonnie L and Hamblin, Michael R and Barcellos-Hoff, Mary Helen and Kulkarni, Ashok B and Mooney, David J}
}
@article {373621,
	title = {Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts},
	journal = {Epigenetics},
	volume = {9},
	number = {10},
	year = {2014},
	month = {2014 Oct},
	pages = {1339-49},
	abstract = {Diabetic foot ulcers (DFUs) are a serious complication of diabetes. Previous exposure to hyperglycemic conditions accelerates a decline in cellular function through metabolic memory despite normalization of glycemic control. Persistent, hyperglycemia-induced epigenetic patterns are considered a central mechanism that activates metabolic memory; however, this has not been investigated in patient-derived fibroblasts from DFUs. We generated a cohort of patient-derived lines from DFU fibroblasts (DFUF), and site- and age-matched diabetic foot fibroblasts (DFF) and non-diabetic foot fibroblasts (NFF) to investigate global and genome-wide DNA methylation patterns using liquid chromatography/mass spectrometry and the Illumina Infinium HumanMethylation450K array. DFFs and DFUFs demonstrated significantly lower global DNA methylation compared to NFFs (p = 0.03). Hierarchical clustering of differentially methylated probes (DMPs, p = 0.05) showed that DFFs and DFUFs cluster together and separately from NFFs. Twenty-five percent of the same probes were identified as DMPs when individually comparing DFF and DFUF to NFF. Functional annotation identified enrichment of DMPs associated with genes critical to wound repair, including angiogenesis (p = 0.07) and extracellular matrix assembly (p = 0.035). Identification of sustained DNA methylation patterns in patient-derived fibroblasts after prolonged passage in normoglycemic conditions demonstrates persistent metabolic memory. These findings suggest that epigenetic-related metabolic memory may also underlie differences in wound healing phenotypes and can potentially identify therapeutic targets.},
	keywords = {Adult, Aged, Cell Line, Computational Biology, Diabetic Foot, DNA Methylation, Epigenesis, Genetic, Female, Fibroblasts, Humans, Male, Middle Aged},
	issn = {1559-2308},
	doi = {10.4161/15592294.2014.967584},
	author = {Park, Lara K and Maione, Anna G and Smith, Avi and Gerami-Naini, Behzad and Iyer, Lakshmanan K and Mooney, David J and Veves, Aristidis and Garlick, Jonathan A}
}
@article {365911,
	title = {Changing the mindset in life sciences toward translation: a consensus},
	journal = {Sci Transl Med},
	volume = {6},
	number = {264},
	year = {2014},
	month = {2014 Nov 26},
	pages = {264cm12},
	abstract = {Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.},
	keywords = {Biological Science Disciplines, Consensus, Humans, International Cooperation, Research Support as Topic, Translational Medical Research},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.aaa0599},
	author = {Duda, Georg N and Grainger, David W and Frisk, Megan L and Bruckner-Tuderman, Leena and Carr, Andrew and Dirnagl, Ulrich and Einh{\"a}upl, Karl Max and Gottschalk, Stephen and Gruskin, Elliott and Huber, Christoph and June, Carl H and Mooney, David J and Rietschel, Ernst Th and Sch{\"u}tte, Georg and Seeger, Werner and Stevens, Molly M and Urban, Robert and Veldman, Alex and Wess, G{\"u}nther and Volk, Hans-Dieter}
}
@article {365896,
	title = {Refilling drug delivery depots through the blood},
	journal = {Proc Natl Acad Sci U S A},
	volume = {111},
	number = {35},
	year = {2014},
	month = {2014 Sep 02},
	pages = {12722-7},
	abstract = {Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.},
	keywords = {Alginates, Animals, Antibiotics, Antineoplastic, Breast Neoplasms, Disease Models, Animal, Doxorubicin, Drug Delivery Systems, Glucuronic Acid, Hexuronic Acids, Humans, Hydrazones, Hydrogels, Injections, Intralesional, Injections, Intravenous, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasm Transplantation, Oligodeoxyribonucleotides, Tumor Cells, Cultured, Xenograft Model Antitumor Assays},
	issn = {1091-6490},
	doi = {10.1073/pnas.1413027111},
	author = {Brudno, Yevgeny and Silva, Eduardo A and Kearney, Cathal J and Lewin, Sarah A and Miller, Alex and Martinick, Kathleen D and Aizenberg, Michael and Mooney, David J}
}
@article {216691,
	title = {A bioinspired soft actuated material},
	journal = {Adv Mater},
	volume = {26},
	number = {8},
	year = {2014},
	month = {2014 Feb 26},
	pages = {1200-6},
	abstract = {A class of soft actuated materials that can achieve lifelike motion is presented. By embedding pneumatic actuators in a soft material inspired by a biological muscle fibril architecture, and developing a simple finite element simulation of the same, tunable biomimetic motion can be achieved with fully soft structures, exemplified here by an active left ventricle simulator.},
	keywords = {Biomimetic Materials, Computer Simulation, Elasticity, Finite Element Analysis, Hardness, Heart, Heart Ventricles, Humans, Linear Models, Materials Testing, Models, Cardiovascular, Motion, Muscle, Skeletal, Muscle, Smooth, Myocardium, Myofibrils, Nonlinear Dynamics, Stomach},
	issn = {1521-4095},
	doi = {10.1002/adma.201304018},
	author = {Ellen T Roche and Wohlfarth, Robert and Overvelde, Johannes TB and Nikolay V. Vasilyev and Frank A Pigula and Mooney, David J and Bertoldi, Katia and Conor J Walsh}
}
@article {216671,
	title = {Endothelial cells expressing low levels of CD143 (ACE) exhibit enhanced sprouting and potency in relieving tissue ischemia},
	journal = {Angiogenesis},
	volume = {17},
	number = {3},
	year = {2014},
	month = {2014 Jul},
	pages = {617-30},
	abstract = {The sprouting of endothelial cells from pre-existing blood vessels represents a critical event in the angiogenesis cascade. However, only a fraction of cultured or transplanted endothelial cells form new vessels. Moreover, it is unclear whether this results from a stochastic process or instead relates to certain endothelial cells having a greater angiogenic potential. This study investigated whether there exists a sub-population of cultured endothelial cells with enhanced angiogenic potency in vitro and in vivo. First, endothelial cells that participated in sprouting, and non-sprouting cells, were separately isolated from a 3D fibrin gel sprouting assay. Interestingly, the sprouting cells, when placed back into the same assay, displayed a sevenfold increase in the number of sprouts, as compared to control cells. Angiotensin-converting enzyme (CD143) was significantly down regulated on sprouting cells, as compared to regular endothelial cells. A subset of endothelial cells with low CD143 expression was then prospectively isolated from an endothelial cell culture. Finally, these cells were found to have greater potency in alleviating local ischemia, and restoring regional blood perfusion when transplanted into ischemic hindlimbs, as compared to unsorted endothelial cells. In summary, this study indicates that low expression of CD143 can be used as a biomarker to identify an endothelial cell sub-population that is more capable to drive neovascularization.},
	keywords = {Animals, Endothelial Cells, Female, Fibrin, Flow Cytometry, Genotype, Hindlimb, Humans, Ischemia, Mice, SCID, Neovascularization, Physiologic, Peptidyl-Dipeptidase A},
	issn = {1573-7209},
	doi = {10.1007/s10456-014-9414-9},
	author = {Silva, Eduardo A and Eseonu, Chikezie and Mooney, David J}
}
@article {216686,
	title = {Injectable, porous, and cell-responsive gelatin cryogels},
	journal = {Biomaterials},
	volume = {35},
	number = {8},
	year = {2014},
	month = {2014 Mar},
	pages = {2477-87},
	abstract = {The performance of biomaterials-based therapies can be hindered by complications associated with surgical implant, motivating the development of materials systems that allow minimally invasive introduction into the host. In this study, we created cell-adhesive and degradable gelatin scaffolds that could be injected through a conventional needle while maintaining a predefined geometry and architecture. These scaffolds supported attachment, proliferation, and survival of cells in~vitro and could be degraded by recombinant matrix metalloproteinase-2 and -9. Prefabricated gelatin cryogels rapidly resumed their original shape when injected subcutaneously into mice and elicited only a minor host response following injection. Controlled release of granulocyte-macrophage colony-stimulating factor from gelatin cryogels resulted in complete infiltration of the scaffold by immune cells and promoted matrix metalloproteinase production leading to cell-mediated degradation of the cryogel matrix. These findings suggest that gelatin cryogels could serve as a cell-responsive platform for biomaterial-based therapy.},
	keywords = {Animals, Biocompatible Materials, Cell Proliferation, Cell Survival, Cryogels, Female, Gelatin, Granulocyte-Macrophage Colony-Stimulating Factor, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Mice, Mice, Inbred C57BL, Microscopy, Electron, Scanning, Porosity, Tissue Scaffolds},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2013.11.044},
	author = {Koshy, Sandeep T and Ferrante, Thomas C and Lewin, Sarah A and Mooney, David J}
}
@article {216676,
	title = {Presentation of BMP-2 mimicking peptides in 3D hydrogels directs cell fate commitment in osteoblasts and mesenchymal stem cells},
	journal = {Biomacromolecules},
	volume = {15},
	number = {2},
	year = {2014},
	month = {2014 Feb 10},
	pages = {445-55},
	abstract = {Many strategies for controlling the fate of transplanted stem cells rely on the concurrent delivery of soluble growth factors that have the potential to produce undesirable secondary effects in surrounding tissue. Such off target effects could be eliminated by locally presenting growth factor peptide mimics from biomaterial scaffolds to control stem cell fate. Peptide mimics of bone morphogenetic protein 2 (BMP-2) were synthesized by solid phase Fmoc-peptide synthesis and covalently bound to alginate hydrogels via either carbodiimide or sulfhydryl-based coupling strategies. Successful peptide conjugation was confirmed by (1)H NMR spectroscopy and quantified by fluorescently labeling the peptides. Peptides derived from the knuckle epitope of BMP-2, presented from both 2D surfaces and 3D alginate hydrogels, were shown to increase alkaline phosphatase activity in clonally derived murine osteoblasts. Furthermore, when presented in 3D hydrogels, these peptides were shown to initiate Smad signaling, upregulate osteopontin production, and increase mineral deposition with clonally derived murine mesenchymal stem cells. These data suggest that these peptide-conjugated hydrogels may be effective alternatives to local BMP-2 release in directly and spatially eliciting osteogenesis from transplanted or host osteoprogenitors in the future.},
	keywords = {Biomimetic Materials, Bone Morphogenetic Protein 2, Cells, Cultured, Humans, Hydrogels, Magnetic Resonance Spectroscopy, Mesenchymal Stromal Cells, Molecular Structure, Osteoblasts, Osteogenesis, Peptides, Recombinant Proteins},
	issn = {1526-4602},
	doi = {10.1021/bm401726u},
	author = {Madl, Christopher M and Mehta, Manav and Duda, Georg N and Heilshorn, Sarah C and Mooney, David J}
}
@article {216636,
	title = {Biphasic ferrogels for triggered drug and cell delivery},
	journal = {Adv Healthc Mater},
	volume = {3},
	number = {11},
	year = {2014},
	month = {2014 Nov},
	pages = {1869-76},
	abstract = {Ferrogels are an attractive material for many biomedical applications due to their ability to deliver a wide variety of therapeutic drugs on-demand. However, typical ferrogels have yet to be optimized for use in cell-based therapies, as they possess limited ability to harbor and release viable cells. Previously, an active porous scaffold that exhibits large deformations and enhanced biological agent release under moderate magnetic fields has been demonstrated. Unfortunately, at small device sizes optimal for implantation (e.g., 2 mm thickness), these monophasic ferrogels no longer achieve significant deformation due to a reduced body force. A new biphasic ferrogel, containing an iron oxide gradient, capable of large deformations and triggered release even at small gel dimensions, is presented in this study. Biphasic ferrogels demonstrate increased porosity, enhanced mechanical properties, and potentially increased biocompatibility due to their reduced iron oxide content. With their ability to deliver drugs and cells on-demand, it is expected that these ferrogels will have wide utility in the fields of tissue engineering and regenerative medicine.},
	keywords = {Animals, Drug Carriers, Drug Delivery Systems, Female, Ferric Compounds, Hydrogels, Magnetics, Mice, Mice, Inbred C57BL, Porosity, Regenerative Medicine, Tissue Engineering},
	issn = {2192-2659},
	doi = {10.1002/adhm.201400095},
	author = {Cezar, Christine A and Kennedy, Stephen M and Mehta, Manav and Weaver, James C and Gu, Luo and Vandenburgh, Herman and Mooney, David J}
}
@article {216651,
	title = {Bone regeneration via novel macroporous CPC scaffolds in critical-sized cranial defects in rats},
	journal = {Dent Mater},
	volume = {30},
	number = {7},
	year = {2014},
	month = {2014 Jul},
	pages = {e199-207},
	abstract = {OBJECTIVES: Calcium phosphate cement (CPC) is promising for dental and craniofacial applications due to its ability to be injected or filled into complex-shaped bone defects and molded for esthetics, and its resorbability and replacement by new bone. The objective of this study was to investigate bone regeneration via novel macroporous CPC containing absorbable fibers, hydrogel microbeads and growth factors in critical-sized cranial defects in rats.

METHODS: Mannitol porogen and alginate hydrogel microbeads were incorporated into CPC. Absorbable fibers were used to provide mechanical reinforcement to CPC scaffolds. Six CPC groups were tested in rats: (1) control CPC without macropores and microbeads; (2) macroporous CPC+large fiber; (3) macroporous CPC+large fiber+nanofiber; (4) same as (3), but with rhBMP2 in CPC matrix; (5) same as (3), but with rhBMP2 in CPC matrix+rhTGF-β1 in microbeads; (6) same as (3), but with rhBMP2 in CPC matrix+VEGF in microbeads. Rats were sacrificed at 4 and 24 weeks for histological and micro-CT analyses.

RESULTS: The macroporous CPC scaffolds containing porogen, absorbable fibers and hydrogel microbeads had mechanical properties similar to cancellous bone. At 4 weeks, the new bone area fraction (mean{\textpm}sd; n=5) in CPC control group was the lowest at (14.8{\textpm}3.3)\%, and that of group 6 (rhBMP2+VEGF) was (31.0{\textpm}13.8)\% (p,
	keywords = {Animals, Bone Regeneration, Calcium Phosphates, Dental Cements, Materials Testing, Porosity, Rats, Skull, Tissue Scaffolds},
	issn = {1879-0097},
	doi = {10.1016/j.dental.2014.03.008},
	author = {Lee, Kangwon and Weir, Michael D and Lippens, Evi and Mehta, Manav and Wang, Ping and Duda, Georg N and Kim, Woo S and Mooney, David J and Xu, Hockin H K}
}
@article {216631,
	title = {Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart},
	journal = {Biomaterials},
	volume = {35},
	number = {25},
	year = {2014},
	month = {2014 Aug},
	pages = {6850-6858},
	abstract = {Cell delivery to the infarcted heart has emerged as a promising therapy, but is limited by very low acute retention and engraftment of cells. The objective of this study was to compare a panel of biomaterials to evaluate if acute retention can be improved with a biomaterial carrier. Cells were quantified post-implantation in a rat myocardial infarct model in five groups (n = 7-8); saline injection (current clinical standard), two injectable hydrogels (alginate, chitosan/β-glycerophosphate (chitosan/{\ss}-GP)) and two epicardial patches (alginate, collagen). Human mesenchymal stem cells (hMSCs) were delivered to the infarct border zone with each biomaterial. At 24 h, retained cells were quantified by fluorescence. All biomaterials produced superior fluorescence to saline control, with approximately 8- and 14-fold increases with alginate and chitosan/β-GP injectables, and 47 and 59-fold increases achieved with collagen and alginate patches, respectively. Immunohistochemical analysis qualitatively confirmed these findings. All four biomaterials retained 50-60\% of cells that were present immediately following transplantation, compared to 10\% for the saline control. In conclusion, all four biomaterials were demonstrated to more efficiently deliver and retain cells when compared to a saline control. Biomaterial-based delivery approaches show promise for future development of efficient in vivo delivery techniques.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cell Survival, Cells, Cultured, Cells, Immobilized, Chitosan, Collagen, Female, Glucuronic Acid, Glycerophosphates, Hexuronic Acids, Humans, Hydrogels, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells, Myocardial Infarction, Rats, Rats, Sprague-Dawley, Tissue Engineering},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2014.04.114},
	author = {Ellen T Roche and Hastings, Conn L and Lewin, Sarah A and Shvartsman, Dmitry and Brudno, Yevgeny and Nikolay V. Vasilyev and O{\textquoteright}Brien, Fergal J and Conor J Walsh and Duffy, Garry P and Mooney, David J}
}
@article {216641,
	title = {Effect of pore structure of macroporous poly(lactide-co-glycolide) scaffolds on the in vivo enrichment of dendritic cells},
	journal = {ACS Appl Mater Interfaces},
	volume = {6},
	number = {11},
	year = {2014},
	month = {2014 Jun 11},
	pages = {8505-12},
	abstract = {The in vivo enrichment of dendritic cells (DCs) in implanted macroporous scaffolds is an emerging strategy to modulate the adaptive immune system. The pore architecture is potentially one of the key factors in controlling enrichment of DCs. However, there have been few studies examining the effects of scaffold pore structure on in vivo DC enrichment. Here we present the effects of surface porosity, pore size, and pore volume of macroporous poly(lactide-co-glycolide) (PLG) scaffolds encapsulating granulocyte macrophage colony-stimulating factor (GM-CSF), an inflammatory chemoattractant, on the in vivo enrichment of DCs. Although in vitro cell seeding studies using PLG scaffolds without GM-CSF showed higher cell infiltration in scaffolds with higher surface porosity, in vivo results revealed higher DC enrichment in GM-CSF loaded PLG scaffolds with lower surface porosity despite a similar level of GM-CSF released. The diminished compressive modulus of high surface porosity scaffolds compared to low surface porosity scaffolds lead to the significant shrinkage of these scaffolds in vivo, suggesting that the mechanical strength of scaffolds was critical to maintain a porous structure in vivo for accumulating DCs. The pore volume was also found to be important in total number of recruited cells and DCs in vivo. Varying the pore size significantly impacted the total number of cells, but similar numbers of DCs were found as long as the pore size was above 10-32 μm. Collectively, these results suggested that one can modulate in vivo enrichment of DCs by altering the pore architecture and mechanical properties of PLG scaffolds.},
	keywords = {Animals, Dendritic Cells, Female, Lactic Acid, Mice, Mice, Inbred C57BL, Microscopy, Electron, Scanning, Polyglycolic Acid, Porosity, Tissue Scaffolds},
	issn = {1944-8252},
	doi = {10.1021/am501376n},
	author = {Kim, Jaeyun and Li, Weiwei Aileen and Sands, Warren and Mooney, David J}
}
@article {216626,
	title = {Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium},
	journal = {Nat Mater},
	volume = {13},
	number = {10},
	year = {2014},
	month = {2014 Oct},
	pages = {970-8},
	abstract = {In vitro models of normal mammary epithelium have correlated increased extracellular matrix (ECM) stiffness with malignant phenotypes. However, the role of increased stiffness in this transformation remains unclear because of difficulties in controlling ECM stiffness, composition and architecture independently. Here we demonstrate that interpenetrating networks of reconstituted basement membrane matrix and alginate can be used to modulate ECM stiffness independently of composition and architecture. We find that, in normal mammary epithelial cells, increasing ECM stiffness alone induces malignant phenotypes but that the effect is completely abrogated when accompanied by an increase in basement-membrane ligands. We also find that the combination of stiffness and composition is sensed through β4 integrin, Rac1, and the PI3K pathway, and suggest a mechanism in which an increase in ECM stiffness, without an increase in basement membrane ligands, prevents normal α6β4 integrin clustering into hemidesmosomes.},
	keywords = {Alginates, Basement Membrane, Biocompatible Materials, Biophysical Phenomena, Cell Line, Cell Transformation, Neoplastic, Epithelium, Extracellular Matrix, Female, Glucuronic Acid, Hemidesmosomes, Hexuronic Acids, Humans, Integrin alpha6beta4, Ligands, Mammary Glands, Human, Mechanotransduction, Cellular, Models, Biological, Phenotype, Phosphatidylinositol 3-Kinases, rac1 GTP-Binding Protein, Signal Transduction},
	issn = {1476-1122},
	doi = {10.1038/nmat4009},
	author = {Chaudhuri, Ovijit and Koshy, Sandeep T and Branco da Cunha, Cristiana and Shin, Jae-Won and Verbeke, Catia S and Allison, Kimberly H and Mooney, David J}
}
@article {216666,
	title = {Identification of immune factors regulating antitumor immunity using polymeric vaccines with multiple adjuvants},
	journal = {Cancer Res},
	volume = {74},
	number = {6},
	year = {2014},
	month = {2014 Mar 15},
	pages = {1670-81},
	abstract = {The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study, we used polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, to identify dendritic cell (DC) subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of granulocyte macrophage colony-stimulating factor (GM-CSF) and various Toll-like receptor (TLR) agonists affected 70\% to 90\% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (<=40 mm(2)), resulting in 33\% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs, plasmacytoid DCs (pDC), along with local interleukin (IL)-12, and granulocyte colony-stimulating factor (G-CSF) concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Furthermore, vaccine studies in Batf3(-/-) mice revealed that CD8(+) DCs are required to affect tumor protection, as vaccines in these mice were deficient in cytotoxic T lymphocytes priming and IL-12 induction in comparison with wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, pDCs, IL-12, and G-CSF play important roles in priming effective antitumor responses with these vaccines.},
	keywords = {Adjuvants, Immunologic, Animals, Cancer Vaccines, Cell Line, Tumor, Delayed-Action Preparations, Dendritic Cells, Drug Carriers, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-12, Lipid A, Melanoma, Experimental, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Transplantation, Oligodeoxyribonucleotides, Poly I-C, Polyglactin 910, T-Lymphocytes, Cytotoxic, Toll-Like Receptors},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-13-0777},
	author = {Ali, Omar A and Verbeke, Catia and Johnson, Chris and Sands, R Warren and Lewin, Sarah A and White, Des and Doherty, Edward and Dranoff, Glenn and Mooney, David J}
}
@article {216656,
	title = {Linear patterning of mesenchymal condensations is modulated by geometric constraints},
	journal = {J R Soc Interface},
	volume = {11},
	number = {95},
	year = {2014},
	month = {2014 Jun 06},
	pages = {20140215},
	abstract = {The development of the vertebral column starts with the formation of a linear array of mesenchymal condensations, forming the blueprint for the eventual alternating pattern of bone and cartilage. Despite growing insight into the molecular mechanisms of morphogenesis, the impact of the physical aspects of the environment is not well understood. We hypothesized that geometric boundary conditions may play a pivotal role in the linear patterning of condensations, as neighbouring tissues provide physical constraints to the cell population. To study the process of condensation and the patterning thereof under tightly controlled geometric constraints, we developed a novel in vitro model that combines micropatterning with the established micromass assay. The spacing and alignment of condensations changed with the width of the cell adhesive patterns, a phenomenon that could not be explained by cell availability alone. Moreover, the extent of chondrogenic commitment was increased on substrates with tighter geometric constraints. When the in vivo pattern of condensations was investigated in the developing vertebral column of chicken embryos, the measurements closely fit into the quantitative relation between geometric constraints and inter-condensation distance found in vitro. Together, these findings suggest a potential role of geometric constraints in skeletal patterning in a cellular process of self-organization.},
	keywords = {Animals, Body Patterning, Cells, Cultured, Chick Embryo, Chondrogenesis, Mesoderm, Models, Biological},
	issn = {1742-5662},
	doi = {10.1098/rsif.2014.0215},
	author = {Klumpers, Darinka D and Mao, Angelo S and Smit, Theo H and Mooney, David J}
}
@article {216646,
	title = {Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling},
	journal = {Mol Ther},
	volume = {22},
	number = {7},
	year = {2014},
	month = {2014 Jul},
	pages = {1243-1253},
	abstract = {Tissue reinnervation following trauma, disease, or transplantation often presents a significant challenge. Here, we show that the delivery of vascular endothelial growth factor (VEGF) from alginate hydrogels ameliorates loss of skeletal muscle innervation after ischemic injury by promoting both maintenance and regrowth of damaged axons in mice. Nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) mediated VEGF-induced axonal regeneration, and the expression of both is induced by VEGF presentation. Using both in vitro and in vivo modeling approaches, we demonstrate that the activity of NGF and GDNF regulates VEGF-driven angiogenesis, controlling endothelial cell sprouting and blood vessel maturation. Altogether, these studies produce evidence of new mechanisms of VEGF action, further broaden the understanding of the roles of NGF and GDNF in angiogenesis and axonal regeneration, and suggest approaches to improve axonal and ischemic tissue repair therapies.},
	keywords = {Animals, Glial Cell Line-Derived Neurotrophic Factor, Mice, Muscle, Skeletal, Nerve Growth Factor, Nerve Regeneration, Signal Transduction, Vascular Endothelial Growth Factor A, Wound Healing},
	issn = {1525-0024},
	doi = {10.1038/mt.2014.76},
	author = {Shvartsman, Dmitry and Storrie-White, Hannah and Lee, Kangwon and Kearney, Cathal and Brudno, Yevgeny and Ho, Nhi and Cezar, Christine and McCann, Corey and Anderson, Erin and Koullias, John and Tapia, Juan Carlos and Vandenburgh, Herman and Lichtman, Jeff W and Mooney, David J}
}
@article {216621,
	title = {Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy},
	journal = {Proc Natl Acad Sci U S A},
	volume = {111},
	number = {27},
	year = {2014},
	month = {2014 Jul 08},
	pages = {9762-7},
	abstract = {Biological systems are exquisitely sensitive to the location and timing of physiologic cues and drugs. This spatiotemporal sensitivity presents opportunities for developing new therapeutic approaches. Polymer-based delivery systems are used extensively for attaining localized, sustained release of bioactive molecules. However, these devices typically are designed to achieve a constant rate of release. We hypothesized that it would be possible to create digital drug release, which could be accelerated and then switched back off, on demand, by applying ultrasound to disrupt ionically cross-linked hydrogels. We demonstrated that ultrasound does not permanently damage these materials but enables nearly digital release of small molecules, proteins, and condensed oligonucleotides. Parallel in vitro studies demonstrated that the concept of applying temporally short, high-dose "bursts" of drug exposure could be applied to enhance the toxicity of mitoxantrone toward breast cancer cells. We thus used the hydrogel system in vivo to treat xenograft tumors with mitoxantrone, and found that daily ultrasound-stimulated drug release substantially reduced tumor growth compared with sustained drug release alone. This approach of digital drug release likely will be applicable to a broad variety of polymers and bioactive molecules, and is a potentially useful tool for studying how the timing of factor delivery controls cell fate in vivo.},
	keywords = {Animals, Antineoplastic Agents, Cell Line, Tumor, Drug Carriers, Humans, Hydrogels, Mice, Mitoxantrone, Ultrasonics, Xenograft Model Antitumor Assays},
	issn = {1091-6490},
	doi = {10.1073/pnas.1405469111},
	author = {Huebsch, Nathaniel and Kearney, Cathal J and Zhao, Xuanhe and Kim, Jaeyun and Cezar, Christine A and Zhigang Suo and Mooney, David J}
}
@article {1192206,
	title = {In vivo time-gated fluorescence imaging with biodegradable luminescent porous silicon nanoparticles},
	journal = {Nat Commun},
	volume = {4},
	year = {2013},
	month = {2013},
	pages = {2326},
	abstract = {Fluorescence imaging is one of the most versatile and widely used visualization methods in biomedical research. However, tissue autofluorescence is a major obstacle confounding interpretation of in vivo fluorescence images. The unusually long emission lifetime (5-13 μs) of photoluminescent porous silicon nanoparticles can allow the time-gated imaging of tissues in vivo, completely eliminating shorter-lived (50-fold in vitro and by >20-fold in vivo when imaging porous silicon nanoparticles. Time-gated imaging of porous silicon nanoparticles accumulated in a human ovarian cancer xenograft following intravenous injection is demonstrated in a live mouse. The potential for multiplexing of images in the time domain by using separate porous silicon nanoparticles engineered with different excited state lifetimes is discussed.},
	keywords = {Animals, Female, Humans, Luminescent Agents, Mice, Nanoparticles, Neoplasm Transplantation, Optical Imaging, Ovarian Neoplasms, Silicon, Xenograft Model Antitumor Assays},
	issn = {2041-1723},
	doi = {10.1038/ncomms3326},
	author = {Gu, Luo and Hall, David J and Qin, Zhengtao and Anglin, Emily and Joo, Jinmyoung and Mooney, David J and Howell, Stephen B and Sailor, Michael J}
}
@article {1192201,
	title = {NF-κB inhibits osteogenic differentiation of mesenchymal stem cells by promoting β-catenin degradation},
	journal = {Proc Natl Acad Sci U S A},
	volume = {110},
	number = {23},
	year = {2013},
	month = {2013 Jun 04},
	pages = {9469-74},
	abstract = {Mesenchymal stem cell (MSC)-based transplantation is a promising therapeutic approach for bone regeneration and repair. In the realm of therapeutic bone regeneration, the defect or injured tissues are frequently inflamed with an abnormal expression of inflammatory mediators. Growing evidence suggests that proinflammatory cytokines inhibit osteogenic differentiation and bone formation. Thus, for successful MSC-mediated repair, it is important to overcome the inflammation-mediated inhibition of tissue regeneration. In this study, using genetic and chemical approaches, we found that proinflammatory cytokines TNF and IL-17 stimulated IκB kinase (IKK)-NF-κB and impaired osteogenic differentiation of MSCs. In contrast, the inhibition of IKK-NF-κB significantly enhanced MSC-mediated bone formation. Mechanistically, we found that IKK-NF-κB activation promoted β-catenin ubiquitination and degradation through induction of Smurf1 and Smurf2. To translate our basic findings to potential clinic applications, we showed that the IKK small molecule inhibitor, IKKVI, enhanced osteogenic differentiation of MSCs. More importantly, the delivery of IKKVI promoted MSC-mediated craniofacial bone regeneration and repair in vivo. Considering the well established role of NF-κB in inflammation and infection, our results suggest that targeting IKK-NF-κB may have dual benefits in enhancing bone regeneration and repair and inhibiting inflammation, and this concept may also have applicability in many other tissue regeneration situations.},
	keywords = {Animals, Anthraquinones, beta Catenin, Blotting, Western, Cell Differentiation, Chromatin Immunoprecipitation, Humans, I-kappa B Kinase, Interleukin-17, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells, Mice, NF-kappa B, Osteogenesis, Rats, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Ubiquitin-Protein Ligases, Ubiquitination},
	issn = {1091-6490},
	doi = {10.1073/pnas.1300532110},
	author = {Chang, Jia and Liu, Fei and Lee, Min and Wu, Benjamin and Ting, Kang and Zara, Janette N and Soo, Chia and Al Hezaimi, Khalid and Zou, Weiping and Chen, XiaoHong and Mooney, David J and Wang, Cun-Yu}
}
@article {1192196,
	title = {Study on the potential of RGD- and PHSRN-modified alginates as artificial extracellular matrices for engineering bone},
	journal = {J Artif Organs},
	volume = {16},
	number = {3},
	year = {2013},
	month = {2013 Sep},
	pages = {284-93},
	abstract = {Alginate is a polysaccharide that can be crosslinked by divalent cations, such as calcium ions, to form a gel. Chemical modification is typically used to improve its cell adhesive properties for tissue engineering applications. In this study, alginates were modified with peptides containing RGD (arginine-glycine-aspartic acid) or PHSRN (proline-histidine-serine-arginine-asparagine) sequences from fibronectin to study possible additive and synergistic effects on adherent cells. Alginates modified with each peptide were mixed at different ratios to form gels containing various concentrations and spacing between the RGD and PHSRN sequences. When normal human osteoblasts (NHOsts) were cultured on or in the gels, the ratio of RGD to PHSRN was found to influence cell behaviors, especially differentiation. NHOsts cultured on gels composed of RGD- and PHSRN-modified alginates showed enhanced differentiation when the gels contained >33~\% RGD-alginate, suggesting the relative distribution of the peptides and the presentation to cells are important parameters in this regulation. NHOsts cultured in gels containing both RGD- and PHSRN-alginates also demonstrated a similar enhancement tendency of calcium deposition that was dependent on the peptide ratio in the gel. However, calcium deposition was greater when cells were cultured in the gels, as compared to on the gels. These results suggest that modifying this biomaterial to more closely mimic the chemistry of natural cell adhesive proteins, (e.g., fibronectin) may be useful in developing scaffolds for bone tissue engineering and provide three-dimensional cell culture systems which more closely mimic the environment of the human body.},
	keywords = {Alginates, Biocompatible Materials, Cells, Cultured, Extracellular Matrix, Gels, Glucuronic Acid, Hexuronic Acids, Humans, Osteoblasts, Tissue Engineering, Tissue Scaffolds},
	issn = {1619-0904},
	doi = {10.1007/s10047-013-0703-7},
	author = {Nakaoka, Ryusuke and Hirano, Yoshiaki and Mooney, David J and Tsuchiya, Toshie and Matsuoka, Atsuko}
}
@article {1192186,
	title = {TGF-{\ss} regulates enamel mineralization and maturation through KLK4 expression},
	journal = {PLoS One},
	volume = {8},
	number = {11},
	year = {2013},
	month = {2013},
	pages = {e82267},
	abstract = {Transforming growth factor-{\ss} (TGF-{\ss}) signaling plays an important role in regulating crucial biological processes such as cell proliferation, differentiation, apoptosis, and extracellular matrix remodeling. Many of these processes are also an integral part of amelogenesis. In order to delineate a precise role of TGF-{\ss} signaling during amelogenesis, we developed a transgenic mouse line that harbors bovine amelogenin promoter-driven Cre recombinase, and bred this line with TGF-{\ss} receptor II floxed mice to generate ameloblast-specific TGF-{\ss} receptor II conditional knockout (cKO) mice. Histological analysis of the teeth at postnatal day 7 (P7) showed altered enamel matrix composition in the cKO mice as compared to the floxed mice that had enamel similar to the wild-type mice. The {\textmu}CT and SEM analyses revealed decreased mineral content in the cKO enamel concomitant with increased attrition and thinner enamel crystallites. Although the mRNA levels remained unaltered, immunostaining revealed increased amelogenin, ameloblastin, and enamelin localization in the cKO enamel at the maturation stage. Interestingly, KLK4 mRNA levels were significantly reduced in the cKO teeth along with a slight increase in MMP-20 levels, suggesting that normal enamel maturation is regulated by TGF-{\ss} signaling through the expression of KLK4. Thus, our study indicates that TGF-{\ss} signaling plays an important role in ameloblast functions and enamel maturation.},
	keywords = {Animals, Dental Enamel, Kallikreins, Mice, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Transforming Growth Factor beta, X-Ray Microtomography},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0082267},
	author = {Cho, Andrew and Haruyama, Naoto and Hall, Bradford and Danton, Mary Jo S and Zhang, Lu and Arany, Praveen and Mooney, David J and Harichane, Yassine and Goldberg, Michel and Gibson, Carolyn W and Kulkarni, Ashok B}
}
@article {1192191,
	title = {Transit of micro-bubbles through the pulmonary circulation of Thoroughbred horses during exercise},
	journal = {Res Vet Sci},
	volume = {95},
	number = {2},
	year = {2013},
	month = {2013 Oct},
	pages = {644-7},
	abstract = {It has been observed that microbubbles may pass through the pulmonary circulation of dogs and humans during exercise. In humans, this phenomenon has been associated with lower pulmonary artery pressures, enhanced right ventricular function and greater exercise capacity. In the exercising Thoroughbred horse, extraordinarily high cardiac outputs exert significant pulmonary vascular stresses. The aim of this study was to determine, using contrast echocardiography, whether Thoroughbred horses performing strenuous exercise developed pulmonary transit of agitated contrast microbubbles (PTAC). At rest, agitated contrast was observed in the right ventricle, but not in the left ventricle. However, post-exercise microbubbles were observed in the left ventricle, confirming the occurrence of PTAC with exercise but not at rest. Further investigation is warranted to investigate whether this phenomenon may be associated with superior physiology and performance measures as has been implicated in other species.},
	keywords = {Animals, Contrast Media, Horses, Lung, Male, Microbubbles, Physical Conditioning, Animal, Pulmonary Circulation},
	issn = {1532-2661},
	doi = {10.1016/j.rvsc.2013.04.002},
	author = {La Gerche, A and Daffy, J R and Mooney, D J and Forbes, G and Davie, A J}
}
@article {216741,
	title = {Guided bone regeneration using injectable vascular endothelial growth factor delivery gel},
	journal = {J Periodontol},
	volume = {84},
	number = {2},
	year = {2013},
	month = {2013 Feb},
	pages = {230-8},
	abstract = {BACKGROUND: Vascularization underlies the success of guided bone regeneration (GBR) procedures. This study evaluates the regenerative potential of GBR in combination with vascular endothelial growth factor (VEGF) delivery via an injectable hydrogel system.

METHODS: Critical-sized defects were created in rat calvariae, and GBR procedures were performed with a collagen membrane alone (control), or plus bolus delivery of VEGF, or plus application of VEGF-releasing hydrogels (VEGF-Alg). Four and 8 weeks after treatment, defect sites were evaluated with microcomputed tomographic and histomorphometric analyses for blood vessel and bone formation.

RESULTS: At 4 weeks, relative to the control condition, the bolus addition of VEGF did not affect blood vessel density within the defect site, yet the application of VEGF-Alg significantly (P ,
	keywords = {Alginates, Animals, Blood Vessels, Bone Diseases, Bone Regeneration, Collagen, Delayed-Action Preparations, Drug Delivery Systems, Guided Tissue Regeneration, Hydrogels, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Injections, Membranes, Artificial, Neovascularization, Physiologic, Osteogenesis, Rats, Rats, Inbred F344, Recombinant Proteins, Skull, Time Factors, Vascular Endothelial Growth Factor A, X-Ray Microtomography},
	issn = {1943-3670},
	doi = {10.1902/jop.2012.110684},
	author = {Kaigler, Darnell and Silva, Eduardo A and Mooney, David J}
}
@article {216726,
	title = {Materials based tumor immunotherapy vaccines},
	journal = {Curr Opin Immunol},
	volume = {25},
	number = {2},
	year = {2013},
	month = {2013 Apr},
	pages = {238-45},
	abstract = {Immunotherapy is a promising approach for treating cancer. However, there are limitations inherent to current approaches which may be addressed by integrating them with biomaterial-based strategies. Material platforms have been fabricated to interact with immune cells through spatially controlled and temporally controlled delivery of immune modulators and to promote immune cell crosstalk. Particle vaccines have been developed to specifically target and deliver agents to organs, cells and subcellular compartments. These strategies have been shown to generate antigen-specific CTL responses and, in some cases, tumor regression. Therefore, collaboration between immunology and materials engineering is likely to result in the creation of strong vaccines to combat cancer in the future.},
	keywords = {Animals, Cancer Vaccines, Humans, Immunotherapy, Neoplasms},
	issn = {1879-0372},
	doi = {10.1016/j.coi.2012.12.008},
	author = {Li, Weiwei Aileen and Mooney, David J}
}
@article {216721,
	title = {Performance and biocompatibility of extremely tough alginate/polyacrylamide hydrogels},
	journal = {Biomaterials},
	volume = {34},
	number = {33},
	year = {2013},
	month = {2013 Nov},
	pages = {8042-8},
	abstract = {Although hydrogels now see widespread use in a host of applications, low fracture toughness and brittleness have limited their more broad use. As a recently described interpenetrating network (IPN) of alginate and polyacrylamide demonstrated a fracture toughness of ≈ 9000 J/m(2), we sought to explore the biocompatibility and maintenance of mechanical properties of these hydrogels in cell culture and in vivo conditions. These hydrogels can sustain a compressive strain of over 90\% with minimal loss of Young{\textquoteright}s Modulus as well as minimal swelling for up to 50 days of soaking in culture conditions. Mouse mesenchymal stem cells exposed to the IPN gel-conditioned media maintain high viability, and although cells exposed to conditioned media demonstrate slight reductions in proliferation and metabolic activity (WST assay), these effects are abrogated in a dose-dependent manner. Implantation of these IPN hydrogels into subcutaneous tissue of rats for 8 weeks led to mild fibrotic encapsulation and minimal inflammatory response. These results suggest the further exploration of extremely tough alginate/PAAM IPN hydrogels as biomaterials.},
	keywords = {Acrylic Resins, Alginates, Animals, Biocompatible Materials, Cell Proliferation, Cells, Cultured, Chromatography, High Pressure Liquid, Glucuronic Acid, Hexuronic Acids, Hydrogels, Materials Testing, Mice, Prostheses and Implants},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2013.06.061},
	author = {Darnell, Max C and Sun, Jeong-Yun and Mehta, Manav and Johnson, Christopher and Arany, Praveen R and Zhigang Suo and Mooney, David J}
}
@article {216711,
	title = {Ca(2+) released from calcium alginate gels can promote inflammatory responses in vitro and in vivo},
	journal = {Acta Biomater},
	volume = {9},
	number = {12},
	year = {2013},
	month = {2013 Dec},
	pages = {9281-91},
	abstract = {In general, alginate hydrogels are considered to be biologically inert and are commonly used for biomedical purposes that require minimum inflammation. However, Ca(2+), which is commonly used to crosslink alginate, is a critical second messenger in immune cell signaling, and little has been done to understand its effect on immune cell fate when delivered as a component of alginate gels. We found that dendritic cells (DCs) encapsulated in Ca(2+)-crosslinked alginate (calcium alginate) secreted at least fivefold more of the inflammatory cytokine IL-1β when compared to DCs encapsulated in agarose and collagen gels, as well as DCs plated on tissue-culture polystyrene (TCPS). Plating cells on TCPS with the alginate polymer could not reproduce these results, whereas culturing DCs on TCPS with increasing concentrations of Ca(2+) increased IL-1β, MHC class II and CD86 expression in a dose-dependent manner. In agreement with these findings, calcium alginate gels induced greater maturation of encapsulated DCs compared to barium alginate gels. When injected subcutaneously in mice, calcium alginate gels significantly upregulated IL-1β secretion from surrounding tissue relative to barium alginate gels, and similarly, the inflammatory effects of LPS were enhanced when it was delivered from calcium alginate gels rather than barium alginate gels. These results confirm that the Ca(2+) used to crosslink alginate gels can be immunostimulatory and suggest that it is important to take into account Ca(2+){\textquoteright}s bioactive effects on all exposed cells (both immune and non-immune) when using calcium alginate gels for biomedical purposes. This work may strongly impact the way people use alginate gels in the future as well as provide insights into past work utilizing alginate gels.},
	keywords = {Alginates, Animals, Calcium, Cell Differentiation, Cells, Cultured, Cross-Linking Reagents, Dendritic Cells, Endotoxins, Female, Gels, Glucuronic Acid, Hexuronic Acids, Inflammation, Interleukin-1beta, Mice, Mice, Inbred C57BL, Polymers, Solubility},
	issn = {1878-7568},
	doi = {10.1016/j.actbio.2013.08.002},
	author = {Chan, Gail and Mooney, David J}
}
@article {216716,
	title = {Cell mediated contraction in 3D cell-matrix constructs leads to spatially regulated osteogenic differentiation},
	journal = {Integr Biol (Camb)},
	volume = {5},
	number = {9},
	year = {2013},
	month = {2013 Sep},
	pages = {1174-83},
	abstract = {During embryonic development, morphogenetic processes give rise to a variety of shapes and patterns that lead to functional tissues and organs. While the impact of chemical signals on these processes is widely studied, the role of physical cues is less understood. The aim of this study was to test the hypothesis that the interplay of cell mediated contraction and mechanical boundary conditions alone can result in spatially regulated differentiation in simple 3D constructs. An experimental model consisting of a 3D cell-gel construct and a finite element (FE) model were used to study the effect of cellular traction exerted by mesenchymal stem cells (MSCs) on an initially homogeneous matrix under inhomogeneous boundary conditions. A robust shape change is observed due to contraction under time-varying mechanical boundary conditions, which is explained by the finite element model. Furthermore, distinct local differences in osteogenic differentiation are observed, with a spatial pattern independent of osteogenic factors in the culture medium. Regions that are predicted to have experienced relatively high shear stress at any time during contraction correlate with the regions of distinct osteogenesis. Taken together, these results support the underlying hypothesis that cellular contractility and mechanical boundary conditions alone can result in spatially regulated differentiation. These results will have important implications for tissue engineering and regeneration.},
	keywords = {Animals, Bone and Bones, Cell Differentiation, Finite Element Analysis, Mesenchymal Stromal Cells, Mice, Mice, Inbred BALB C, Models, Biological, Osteogenesis},
	issn = {1757-9708},
	doi = {10.1039/c3ib40038g},
	author = {Klumpers, Darinka D and Zhao, Xuanhe and Mooney, David J and Smit, Theo H}
}
@article {216701,
	title = {Driving vascular endothelial cell fate of human multipotent Isl1+ heart progenitors with VEGF modified mRNA},
	journal = {Cell Res},
	volume = {23},
	number = {10},
	year = {2013},
	month = {2013 Oct},
	pages = {1172-86},
	abstract = {Distinct families of multipotent heart progenitors play a central role in the generation of diverse cardiac, smooth muscle and endothelial cell lineages during mammalian cardiogenesis. The identification of precise paracrine signals that drive the cell-fate decision of these multipotent progenitors, and the development of novel approaches to deliver these signals in vivo, are critical steps towards unlocking their regenerative therapeutic potential. Herein, we have identified a family of human cardiac endothelial intermediates located in outflow tract of the early human fetal hearts (OFT-ECs), characterized by coexpression of Isl1 and CD144/vWF. By comparing angiocrine factors expressed by the human OFT-ECs and non-cardiac ECs, vascular endothelial growth factor (VEGF)-A was identified as the most abundantly expressed factor, and clonal assays documented its ability to drive endothelial specification of human embryonic stem cell (ESC)-derived Isl1+ progenitors in a VEGF receptor-dependent manner. Human Isl1-ECs (endothelial cells differentiated from hESC-derived ISL1+ progenitors) resemble OFT-ECs in terms of expression of the cardiac endothelial progenitor- and endocardial cell-specific genes, confirming their organ specificity. To determine whether VEGF-A might serve as an in vivo cell-fate switch for human ESC-derived Isl1-ECs, we established a novel approach using chemically modified mRNA as a platform for transient, yet highly efficient expression of paracrine factors in cardiovascular progenitors. Overexpression of VEGF-A promotes not only the endothelial specification but also engraftment, proliferation and survival (reduced apoptosis) of the human Isl1+ progenitors in vivo. The large-scale derivation of cardiac-specific human Isl1-ECs from human pluripotent stem cells, coupled with the ability to drive endothelial specification, engraftment, and survival following transplantation, suggest a novel strategy for vascular regeneration in the heart.},
	keywords = {Cell Differentiation, Cells, Cultured, Endothelial Cells, Gene Expression Regulation, Developmental, Heart, Humans, LIM-Homeodomain Proteins, Myocardium, RNA, Messenger, Stem Cells, Transcription Factors, Up-Regulation, Vascular Endothelial Growth Factor A},
	issn = {1748-7838},
	doi = {10.1038/cr.2013.112},
	author = {Lui, Kathy O and Zangi, Lior and Silva, Eduardo A and Bu, Lei and Sahara, Makoto and Li, Ronald A and Mooney, David J and Chien, Kenneth R}
}
@article {216706,
	title = {Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors},
	journal = {Biomaterials},
	volume = {34},
	number = {36},
	year = {2013},
	month = {2013 Dec},
	pages = {9201-9},
	abstract = {Therapeutic stimulation of angiogenesis to re-establish blood flow in ischemic tissues offers great promise as a treatment for patients suffering from cardiovascular disease or trauma. Since angiogenesis is a complex, multi-step process, different signals may need to be delivered at appropriate times in order to promote a robust and mature vasculature. The effects of temporally regulated presentation of pro-angiogenic and pro-maturation factors were investigated in vitro and in vivo in this study. Pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) cooperatively promoted endothelial sprouting and pericyte detachment in a three-dimensional in vitro EC-pericyte co-culture model. Pro-maturation factors platelet-derived growth factor B (PDGF) and angiopoietin 1 (Ang1) inhibited the early stages of VEGF- and Ang2-mediated angiogenesis if present simultaneously with VEGF and Ang2, but promoted these behaviors if added subsequently to the pro-angiogenesis factors. VEGF and Ang2 were also found to additively enhance microvessel density in a subcutaneous model of blood vessel formation, while simultaneously administered PDGF/Ang1 inhibited microvessel formation. However, a temporally controlled scaffold that released PDGF and Ang1 at a delay relative to VEGF/Ang2 promoted both vessel maturation and vascular remodeling without inhibiting sprouting angiogenesis. Our results demonstrate the importance of temporal control over signaling in promoting vascular growth, vessel maturation and vascular remodeling. Delivering multiple growth factors in combination and sequence could aid in creating tissue engineered constructs and therapies aimed at promoting healing after acute wounds and in chronic conditions such as diabetic ulcers and peripheral artery disease.},
	keywords = {Angiogenesis Inducing Agents, Angiopoietin-1, Angiopoietin-2, Animals, Antigens, CD31, Endothelium, Vascular, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Microvessels, Neovascularization, Physiologic, Pericytes, Platelet-Derived Growth Factor, Time Factors, Vascular Endothelial Growth Factor A},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2013.08.007},
	author = {Brudno, Yevgeny and Ennett-Shepard, Alessandra B and Chen, Ruth R and Aizenberg, Michael and Mooney, David J}
}
@article {216681,
	title = {Fibroblasts derived from human pluripotent stem cells activate angiogenic responses in vitro and in vivo},
	journal = {PLoS One},
	volume = {8},
	number = {12},
	year = {2013},
	month = {2013},
	pages = {e83755},
	abstract = {Human embryonic and induced pluripotent stem cells (hESC/hiPSC) are promising cell sources for the derivation of large numbers of specific cell types for tissue engineering and cell therapy applications. We have describe a directed differentiation protocol that generates fibroblasts from both hESC and hiPSC (EDK/iPDK) that support the repair and regeneration of epithelial tissue in engineered, 3D skin equivalents. In the current study, we analyzed the secretory profiles of EDK and iPDK cells to investigate the production of factors that activate and promote angiogenesis. Analysis of in vitro secretion profiles from EDK and iPDK cells demonstrated the elevated secretion of pro-angiogenic soluble mediators, including VEGF, HGF, IL-8, PDGF-AA, and Ang-1, that stimulated endothelial cell sprouting in a 3D model of angiogenesis in vitro. Phenotypic analysis of EDK and iPDK cells during the course of differentiation from hESCs and iPSCs revealed that both cell types progressively acquired pericyte lineage markers NG2, PDGFRβ, CD105, and CD73 and demonstrated transient induction of pericyte progenitor markers CD31, CD34, and Flk1/VEGFR2. Furthermore, when co-cultured with endothelial cells in 3D fibrin-based constructs, EDK and iPDK cells promoted self-assembly of vascular networks and vascular basement membrane deposition. Finally, transplantation of EDK cells into mice with hindlimb ischemia significantly reduced tissue necrosis and improved blood perfusion, demonstrating the potential of these cells to stimulate angiogenic responses in vivo. These findings demonstrate that stable populations of pericyte-like angiogenic cells can be generated with high efficiency from hESC and hiPSC using a directed differentiation approach. This provides new cell sources and opportunities for vascular tissue engineering and for the development of novel strategies in regenerative medicine.},
	keywords = {Angiogenesis Inducing Agents, Animals, Biomarkers, Cell Differentiation, Embryonic Stem Cells, Endothelial Cells, Extremities, Fibroblasts, Humans, Induced Pluripotent Stem Cells, Ischemia, Mice, Neovascularization, Physiologic, Pericytes, Pluripotent Stem Cells, Proteome, Stem Cell Transplantation},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0083755},
	author = {Shamis, Yulia and Silva, Eduardo A and Hewitt, Kyle J and Brudno, Yevgeny and Levenberg, Shulamit and Mooney, David J and Garlick, Jonathan A}
}
@article {216696,
	title = {Macroscale delivery systems for molecular and cellular payloads},
	journal = {Nat Mater},
	volume = {12},
	number = {11},
	year = {2013},
	month = {2013 Nov},
	pages = {1004-17},
	abstract = {Macroscale drug delivery (MDD) devices are engineered to exert spatiotemporal control over the presentation of a wide range of bioactive agents, including small molecules, proteins and cells. In contrast to systemically delivered drugs, MDD systems act as a depot of drug localized to the treatment site, which can increase drug effectiveness while reducing side effects and confer protection to labile drugs. In this Review, we highlight the key advantages of MDD systems, describe their mechanisms of spatiotemporal control and provide guidelines for the selection of carrier materials. We also discuss the combination of MDD technologies with classic medical devices to create multifunctional MDD devices that improve integration with host tissue, and the use of MDD technology in tissue-engineering strategies to direct cell behaviour. As our ever-expanding knowledge of human biology and disease provides new therapeutic targets that require precise control over their application, the importance of MDD devices in medicine is expected to increase.},
	keywords = {Animals, Biocompatible Materials, Cells, Drug Delivery Systems, Equipment and Supplies, Humans},
	issn = {1476-1122},
	doi = {10.1038/nmat3758},
	author = {Kearney, Cathal J and Mooney, David J}
}
@article {216661,
	title = {Inflammatory cytokines presented from polymer matrices differentially generate and activate DCs in situ},
	journal = {Adv Funct Mater},
	volume = {23},
	number = {36},
	year = {2013},
	month = {2013 Aug 01},
	pages = {4621-4628},
	abstract = {During infection, inflammatory cytokines mobilize and activate dendritic cells (DCs), which are essential for efficacious T cell priming and immune responses that clear the infection. Here we designed macroporous poly(lactide-co-glycolide) (PLG) matrices to release the inflammatory cytokines GM-CSF, Flt3L and CCL20, in order to mimic infection-induced DC recruitment. We then tested the ability of these infection mimics to function as cancer vaccines via induction of specific, anti-tumor T cell responses. All vaccine systems tested were able to confer specific anti-tumor T cell responses and longterm survival in a therapeutic, B16-F10 melanoma model. However, GM-CSF and Flt3L vaccines resulted in similar survival rates, and outperformed CCL20 loaded scaffolds, even though they had differential effects on DC recruitment and generation. GM-CSF signaling was identified as the most potent chemotactic factor for conventional DCs and significantly enhanced surface expression of MHC(II) and CD86(+), which are utilized for priming T cell immunity. In contrast, Flt3L vaccines led to greater numbers of plasmacytoid DCs (pDCs), correlating with increased levels of T cell priming cytokines that amplify T cell responses. These results demonstrate that 3D polymer matrices modified to present inflammatory cytokines may be utilized to effectively mobilize and activate different DC subsets in vivo for immunotherapy.},
	issn = {1616-301X},
	doi = {10.1002/adfm.201203859},
	author = {Ali, Omar A and Tayalia, Prakriti and Shvartsman, Dmitry and Lewin, Sarah and Mooney, David J}
}
@article {1192226,
	title = {Adipose tissue engineering using injectable, oxidized alginate hydrogels},
	journal = {Tissue Eng Part A},
	volume = {18},
	number = {7-8},
	year = {2012},
	month = {2012 Apr},
	pages = {737-43},
	abstract = {Current treatment modalities for soft tissue augmentation which use autologous grafting and commercially available fillers present a number of challenges and limitations, such as donor site morbidity and volume loss over time. Adipose tissue engineering technology may provide an attractive alternative. This study investigated the feasibility of a degradable alginate hydrogel system with commercially available cryopreserved human adipose stem cells (hADSCs) to engineer adipose tissue. hADSCs were differentiated into adipogenic cells, and encapsulated in alginate hydrogels made susceptible to hydrolysis by partial periodate oxidation of the polymer chains. Cell laden gels were subcutaneously injected into the chest wall of male nude mice, and a cell suspension without alginate served as control. After 10 weeks, specimens were harvested and analyzed morphologically, histologically, and with immunoblotting of tissue extractions. Newly generated tissues were semitransparent and soft in all experimental mice, grossly resembling adipose tissue. Analysis using confocal live imaging, immunohistochemisty and western blot analysis revealed that the newly generated tissue was adipose tissue. This study demonstrates that degradable, injectable alginate hydrogels provide a suitable delivery vehicle for preconditioned cryopreserved hADSCs to engineer adipose tissue.},
	keywords = {Adipose Tissue, Alginates, Animals, Cell Differentiation, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Male, Mice, Mice, Nude, Stem Cells, Tissue Engineering},
	issn = {1937-335X},
	doi = {10.1089/ten.TEA.2011.0250},
	author = {Kim, Woo Seob and Mooney, David J and Arany, Praveen R and Lee, Kangwon and Huebsch, Nathaniel and Kim, Jaeyun}
}
@article {1192216,
	title = {Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes},
	journal = {Eur Heart J},
	volume = {33},
	number = {8},
	year = {2012},
	month = {2012 Apr},
	pages = {998-1006},
	abstract = {AIMS: Endurance training may be associated with arrhythmogenic cardiac remodelling of the right ventricle (RV). We examined whether myocardial dysfunction following intense endurance exercise affects the RV more than the left ventricle (LV) and whether cumulative exposure to endurance competition influences cardiac remodelling (including fibrosis) in well-trained athletes.

METHODS AND RESULTS: Forty athletes were studied at baseline, immediately following an endurance race (3-11 h duration) and 1-week post-race. Evaluation included cardiac troponin (cTnI), B-type natriuretic peptide, and echocardiography [including three-dimensional volumes, ejection fraction (EF), and systolic strain rate]. Delayed gadolinium enhancement (DGE) on cardiac magnetic resonance imaging (CMR) was assessed as a marker of myocardial fibrosis. Relative to baseline, RV volumes increased and all functional measures decreased post-race, whereas LV volumes reduced and function was preserved. B-type natriuretic peptide (13.1 {\textpm} 14.0 vs. 25.4 {\textpm} 21.4 ng/L, P = 0.003) and cTnI (0.01 {\textpm} .03 vs. 0.14 {\textpm} .17 μg/L, P < 0.0001) increased post-race and correlated with reductions in RVEF (r = 0.52, P = 0.001 and r = 0.49, P = 0.002, respectively), but not LVEF. Right ventricular ejection fraction decreased with increasing race duration (r = -0.501, P < 0.0001) and VO(2)max (r = -0.359, P = 0.011). Right ventricular function mostly recovered by 1 week. On CMR, DGE localized to the interventricular septum was identified in 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF (47.1 {\textpm} 5.9 vs. 51.1 {\textpm} 3.7\%, P = 0.042) than those with normal CMR.

CONCLUSION: Intense endurance exercise causes acute dysfunction of the RV, but not the LV. Although short-term recovery appears complete, chronic structural changes and reduced RV function are evident in some of the most practiced athletes, the long-term clinical significance of which warrants further study.},
	keywords = {Adult, Athletes, Biomarkers, Exercise, Female, Fibrosis, Humans, Magnetic Resonance Angiography, Male, Middle Aged, Myocardium, Physical Endurance, Stroke Volume, Troponin I, Ventricular Dysfunction, Right, Ventricular Remodeling},
	issn = {1522-9645},
	doi = {10.1093/eurheartj/ehr397},
	author = {La Gerche, Andr{\'e} and Burns, Andrew T and Mooney, Don J and Inder, Warrick J and Taylor, Andrew J and Bogaert, Jan and Macisaac, Andrew I and Heidb{\"u}chel, Hein and Prior, David L}
}
@article {1192211,
	title = {Stem-cell differentiation: Anchoring cell-fate cues},
	journal = {Nat Mater},
	volume = {11},
	number = {7},
	year = {2012},
	month = {2012 Jun 21},
	pages = {568-9},
	keywords = {Cell Culture Techniques, Cell Differentiation, Extracellular Matrix, Humans, Mesenchymal Stromal Cells},
	issn = {1476-1122},
	doi = {10.1038/nmat3366},
	author = {Chaudhuri, Ovijit and Mooney, David J}
}
@article {1192221,
	title = {Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks},
	journal = {Nat Immunol},
	volume = {13},
	number = {5},
	year = {2012},
	month = {2012 Apr 01},
	pages = {499-510},
	abstract = {Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly elucidated. Here, comparative transcriptomic analyses of mouse LNSC subsets demonstrated the expression of important immune mediators, growth factors and previously unknown structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of crosstalk. Fibroblastic reticular cells (FRCs) showed enrichment for higher expression of genes relevant to cytokine signaling, relative to their expression in skin and thymic fibroblasts. LNSCs from inflamed lymph nodes upregulated expression of genes encoding chemokines and molecules involved in the acute-phase response and the antigen-processing and antigen-presentation machinery. Poorly studied podoplanin (gp38)-negative CD31(-) LNSCs showed similarities to FRCs but lacked expression of interleukin 7 (IL-7) and were identified as myofibroblastic pericytes that expressed integrin α(7). Together our data comprehensively describe the transcriptional characteristics of LNSC subsets.},
	keywords = {Acute-Phase Reaction, Animals, Antigen Presentation, Antigens, CD, Cytokines, Fibroblasts, Gene Expression, Homeostasis, Inflammation, Integrin alpha Chains, Interleukin-7, Lymph Nodes, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Pericytes, Self Tolerance, Stromal Cells, Tissue Array Analysis, Transcriptome},
	issn = {1529-2916},
	doi = {10.1038/ni.2262},
	author = {Malhotra, Deepali and Fletcher, Anne L and Astarita, Jillian and Lukacs-Kornek, Veronika and Tayalia, Prakriti and Gonzalez, Santiago F and Elpek, Kutlu G and Chang, Sook Kyung and Knoblich, Konstantin and Hemler, Martin E and Brenner, Michael B and Carroll, Michael C and Mooney, David J and Turley, Shannon J}
}
@article {216771,
	title = {Alginate: properties and biomedical applications},
	journal = {Prog Polym Sci},
	volume = {37},
	number = {1},
	year = {2012},
	month = {2012 Jan},
	pages = {106-126},
	abstract = {Alginate is a biomaterial that has found numerous applications in biomedical science and engineering due to its favorable properties, including biocompatibility and ease of gelation. Alginate hydrogels have been particularly attractive in wound healing, drug delivery, and tissue engineering applications to date, as these gels retain structural similarity to the extracellular matrices in tissues and can be manipulated to play several critical roles. This review will provide a comprehensive overview of general properties of alginate and its hydrogels, their biomedical applications, and suggest new perspectives for future studies with these polymers.},
	issn = {0079-6700},
	doi = {10.1016/j.progpolymsci.2011.06.003},
	author = {Lee, Kuen Yong and Mooney, David J}
}
@article {216751,
	title = {Biomaterial delivery of morphogens to mimic the natural healing cascade in bone},
	journal = {Adv Drug Deliv Rev},
	volume = {64},
	number = {12},
	year = {2012},
	month = {2012 Sep},
	pages = {1257-76},
	abstract = {Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing.},
	keywords = {Animals, Biocompatible Materials, Bone and Bones, Bone Regeneration, Drug Delivery Systems, Humans, Intercellular Signaling Peptides and Proteins, Tissue Engineering},
	issn = {1872-8294},
	doi = {10.1016/j.addr.2012.05.006},
	author = {Mehta, Manav and Schmidt-Bleek, Katharina and Duda, Georg N and Mooney, David J}
}
@article {216736,
	title = {Highly stretchable and tough hydrogels},
	journal = {Nature},
	volume = {489},
	number = {7414},
	year = {2012},
	month = {2012 Sep 06},
	pages = {133-6},
	abstract = {Hydrogels are used as scaffolds for tissue engineering, vehicles for drug delivery, actuators for optics and fluidics, and model extracellular matrices for biological studies. The scope of hydrogel applications, however, is often severely limited by their mechanical behaviour. Most hydrogels do not exhibit high stretchability; for example, an alginate hydrogel ruptures when stretched to about 1.2 times its original length. Some synthetic elastic hydrogels have achieved stretches in the range 10-20, but these values are markedly reduced in samples containing notches. Most hydrogels are brittle, with fracture energies of about 10 J m(-2) (ref. 8), as compared with \~{}1,000 J m(-2) for cartilage and \~{}10,000 J m(-2) for natural rubbers. Intense efforts are devoted to synthesizing hydrogels with improved mechanical properties; certain synthetic gels have reached fracture energies of 100-1,000 J m(-2) (refs 11, 14, 17). Here we report the synthesis of hydrogels from polymers forming ionically and covalently crosslinked networks. Although such gels contain \~{}90\% water, they can be stretched beyond 20 times their initial length, and have fracture energies of \~{}9,000 J m(-2). Even for samples containing notches, a stretch of 17 is demonstrated. We attribute the gels{\textquoteright} toughness to the synergy of two mechanisms: crack bridging by the network of covalent crosslinks, and hysteresis by unzipping the network of ionic crosslinks. Furthermore, the network of covalent crosslinks preserves the memory of the initial state, so that much of the large deformation is removed on unloading. The unzipped ionic crosslinks cause internal damage, which heals by re-zipping. These gels may serve as model systems to explore mechanisms of deformation and energy dissipation, and expand the scope of hydrogel applications.},
	keywords = {Acrylic Resins, Alginates, Carbohydrate Sequence, Elasticity, Glucuronic Acid, Hexuronic Acids, Hydrogels, Materials Testing, Molecular Sequence Data, Polymers},
	issn = {1476-4687},
	doi = {10.1038/nature11409},
	author = {Sun, Jeong-Yun and Zhao, Xuanhe and Illeperuma, Widusha R K and Chaudhuri, Ovijit and Oh, Kyu Hwan and Mooney, David J and Joost J. Vlassak and Zhigang Suo}
}
@article {216731,
	title = {Injectable preformed scaffolds with shape-memory properties},
	journal = {Proc Natl Acad Sci U S A},
	volume = {109},
	number = {48},
	year = {2012},
	month = {2012 Nov 27},
	pages = {19590-5},
	abstract = {Injectable biomaterials are increasingly being explored to minimize risks and complications associated with surgical implantation. We describe a strategy for delivery via conventional needle-syringe injection of large preformed macroporous scaffolds with well-defined properties. Injectable 3D scaffolds, in the form of elastic sponge-like matrices, were prepared by environmentally friendly cryotropic gelation of a naturally sourced polymer. Cryogels with shape-memory properties may be molded to a variety of shapes and sizes, and may be optionally loaded with therapeutic agents or cells. These scaffolds have the capability to withstand reversible deformations at over 90\% strain level, and a rapid volumetric recovery allows the structurally defined scaffolds to be injected through a small-bore needle with nearly complete geometric restoration once delivered. These gels demonstrated long-term release of biomolecules in vivo. Furthermore, cryogels impregnated with bioluminescent reporter cells provided enhanced survival, higher local retention, and extended engraftment of transplanted cells at the injection site compared with a standard injection technique. These injectable scaffolds show great promise for various biomedical applications, including cell therapies.},
	keywords = {Animals, Biocompatible Materials, Cryogels, Female, Hydrogels, Mice, Mice, Inbred C57BL, Tissue Scaffolds},
	issn = {1091-6490},
	doi = {10.1073/pnas.1211516109},
	author = {Bencherif, Sidi A and Sands, R Warren and Bhatta, Deen and Arany, Praveen and Verbeke, Catia S and Edwards, David A and Mooney, David J}
}
@article {216756,
	title = {Optimizing siRNA efficacy through alteration in the target cell-adhesion substrate interaction},
	journal = {J Biomed Mater Res A},
	volume = {100},
	number = {10},
	year = {2012},
	month = {2012 Oct},
	pages = {2637-43},
	abstract = {The clinical potential of short interfering RNA (siRNA) based therapeutics remains hindered by the challenge of delivering enough siRNA into the cytoplasm to yield a clinically relevant effect. Although much research has focused on optimizing delivery vehicles for this class of molecules, considerably less is known about the microenvironmental influences on the response of target cells to siRNA. The substrate to which cells adhere is one component of the microenvironment that can modulate cellular behavior. Here, we tested the hypothesis that modulating the properties of cellular adhesion substrates can alter siRNA efficacy. Specifically, cationic lipid complexed siRNA particles were applied to U251 cells seeded on alginate hydrogel surfaces with systematic variation in elastic modulus and integrin ligand arginine-glycine-aspartate (RGD) peptide density. These experiments revealed no change in siRNA-mediated eGFP knockdown over the elastic modulus range tested (53-133 kPa). However, an eightfold increase in RGD content of the alginate growth substrate resulted in an increase in siRNA knockdown efficacy from 25 {\textpm} 12\% to 52 {\textpm} 10\%, a more than twofold increase in silencing. Our results identify control of the cell-adhesion substrate interaction as a modulator of siRNA protein silencing efficacy.},
	keywords = {Alginates, Cell Adhesion, Cell Count, Cell Line, Tumor, Cell Shape, Elastic Modulus, Gene Silencing, Glucuronic Acid, Green Fluorescent Proteins, Hexuronic Acids, Humans, Hydrogels, Oligopeptides, RNA, Small Interfering},
	issn = {1552-4965},
	doi = {10.1002/jbm.a.34202},
	author = {Khormaee, Sariah and Ali, Omar A and Chodosh, James and Mooney, David J}
}
@article {216761,
	title = {Statistical platform to discern spatial and temporal coordination of endothelial sprouting},
	journal = {Integr Biol (Camb)},
	volume = {4},
	number = {3},
	year = {2012},
	month = {2012 Mar},
	pages = {292-300},
	abstract = {Many biological processes, including angiogenesis, involve intercellular feedback and temporal coordination, but inference of these relations is often drowned in low sample sizes or noisy population data. To address this issue, a methodology was developed to statistically study spatial lateral inhibition and temporal synchronization in one specific biological process, endothelial sprouting mediated by Notch signaling. Notch plays an essential role in the development of organized vasculature, but the effects of Notch on the temporal characteristics of angiogenesis are not well understood. Results from this study showed that Notch lateral inhibition operates at distances less than 31 μm. Furthermore, combining time lapse microscopy with an intraclass correlation model typically used to analyze family data showed intrinsic temporal synchronization among endothelial sprouts originating from the same microcarrier. Such synchronization was reduced with Notch inhibitors, but was enhanced with the addition of Notch ligands. These results indicate that Notch plays a critical role in the temporal regulation of angiogenesis, as well as spatial control, and this method of analysis will be of significant utility in studies of a variety of other biological processes.},
	keywords = {Endothelial Cells, Human Umbilical Vein Endothelial Cells, Humans, Ligands, Models, Biological, Models, Statistical, Neovascularization, Physiologic, Receptors, Notch, Signal Transduction, Systems Biology},
	issn = {1757-9708},
	doi = {10.1039/c2ib00057a},
	author = {Yuen, William W and Du, Nan R and Shvartsman, Dima and Arany, Praveen R and Lam, Henry and Mooney, David J}
}
@article {216746,
	title = {Surface modification with alginate-derived polymers for stable, protein-repellent, long-circulating gold nanoparticles},
	journal = {ACS Nano},
	volume = {6},
	number = {6},
	year = {2012},
	month = {2012 Jun 26},
	pages = {4796-805},
	abstract = {Poly(ethylene) glycol is commonly used to stabilize gold nanoparticles (GNPs). In this study, we evaluated the ability of cysteine-functionalized alginate-derived polymers to both provide colloidal stability to GNPs and avoid recognition and sequestration by the body{\textquoteright}s defense system. These polymers contain multiple reactive chemical groups (hydroxyl and carboxyl groups) that could allow for ready functionalization with, for example, cell-targeting ligands and therapeutic drugs. We report here that alginate-coupled GNPs demonstrate enhanced stability in comparison with bare citrate-coated GNPs and a similar lack of interaction with proteins in vitro and long in vivo circulation as PEG-coated GNPs.},
	keywords = {Adsorption, Alginates, Animals, Blood Proteins, Coated Materials, Biocompatible, Glucuronic Acid, Gold, Hexuronic Acids, Materials Testing, Mice, Nanoparticles, Particle Size, Polyethylene Glycols, Protein Binding},
	issn = {1936-086X},
	doi = {10.1021/nn205073n},
	author = {Kodiyan, Anu and Silva, Eduardo A and Kim, Jaeyun and Aizenberg, Michael and Mooney, David J}
}
@article {1192251,
	title = {Active scaffolds for on-demand drug and cell delivery},
	journal = {Proc Natl Acad Sci U S A},
	volume = {108},
	number = {1},
	year = {2011},
	month = {2011 Jan 04},
	pages = {67-72},
	abstract = {Porous biomaterials have been widely used as scaffolds in tissue engineering and cell-based therapies. The release of biological agents from conventional porous scaffolds is typically governed by molecular diffusion, material degradation, and cell migration, which do not allow for dynamic external regulation. We present a new active porous scaffold that can be remotely controlled by a magnetic field to deliver various biological agents on demand. The active porous scaffold, in the form of a macroporous ferrogel, gives a large deformation and volume change of over 70\% under a moderate magnetic field. The deformation and volume variation allows a new mechanism to trigger and enhance the release of various drugs including mitoxantrone, plasmid DNA, and a chemokine from the scaffold. The porous scaffold can also act as a depot of various cells, whose release can be controlled by external magnetic fields.},
	keywords = {Biocompatible Materials, Chemokines, Delayed-Action Preparations, DNA, Drug Delivery Systems, Gels, Magnetics, Mitoxantrone, Polymers, Porosity, Tissue Scaffolds},
	issn = {1091-6490},
	doi = {10.1073/pnas.1007862108},
	author = {Zhao, Xuanhe and Kim, Jaeyun and Cezar, Christine A and Huebsch, Nathaniel and Lee, Kangwon and Bouhadir, Kamal and Mooney, David J}
}
@article {1192256,
	title = {An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects},
	journal = {Biomaterials},
	volume = {32},
	number = {1},
	year = {2011},
	month = {2011 Jan},
	pages = {65-74},
	abstract = {The treatment of challenging fractures and large osseous defects presents a formidable problem for orthopaedic surgeons. Tissue engineering/regenerative medicine approaches seek to solve this problem by delivering osteogenic signals within scaffolding biomaterials. In this study, we introduce a hybrid growth factor delivery system that consists of an electrospun nanofiber mesh tube for guiding bone regeneration combined with peptide-modified alginate hydrogel injected inside the tube for sustained growth factor release. We tested the ability of this system to deliver recombinant bone morphogenetic protein-2 (rhBMP-2) for the repair of critically-sized segmental bone defects in a rat model. Longitudinal μ-CT analysis and torsional testing provided quantitative assessment of bone regeneration. Our results indicate that the hybrid delivery system resulted in consistent bony bridging of the challenging bone defects. However, in the absence of rhBMP-2, the use of nanofiber mesh tube and alginate did not result in substantial bone formation. Perforations in the nanofiber mesh accelerated the rhBMP-2 mediated bone repair, and resulted in functional restoration of the regenerated bone. μ-CT based angiography indicated that perforations did not significantly affect the revascularization of defects, suggesting that some other interaction with the tissue surrounding the defect such as improved infiltration of osteoprogenitor cells contributed to the observed differences in repair. Overall, our results indicate that the hybrid alginate/nanofiber mesh system is a promising growth factor delivery strategy for the repair of challenging bone injuries.},
	keywords = {Alginates, Angiography, Animals, Biomechanical Phenomena, Bone Morphogenetic Protein 2, Bone Morphogenetic Proteins, Bone Regeneration, Drug Delivery Systems, Femur, Glucuronic Acid, Hexuronic Acids, Humans, Implants, Experimental, Kinetics, Nanofibers, Rats, Recombinant Proteins, Transforming Growth Factor beta, Wound Healing, X-Ray Microtomography},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2010.08.074},
	author = {Kolambkar, Yash M and Dupont, Kenneth M and Boerckel, Joel D and Huebsch, Nathaniel and Mooney, David J and Hutmacher, Dietmar W and Guldberg, Robert E}
}
@article {1192246,
	title = {Biomaterial-based vaccine induces regression of established intracranial glioma in rats},
	journal = {Pharm Res},
	volume = {28},
	number = {5},
	year = {2011},
	month = {2011 May},
	pages = {1074-80},
	abstract = {PURPOSE: The prognosis for glioma patients is poor, and development of new treatments is critical. Previously, we engineered polymer-based vaccines that control GM-CSF, CpG-oligonucleotide, and tumor-lysate presentation to regulate immune cell trafficking and activation, which promoted potent immune responses against peripheral tumors. Here, we extend the use of this system to glioma.

METHODS: Rats were challenged with an intracranial injection of glioma cells followed (1 week) by administration of the polymeric vaccine (containing GM-CSF, CpG, and tumor-lysate) in the tumor bed. Control rats were treated with blank matrices, matrices with GM-CSF and CpG, or intra-tumoral bolus injections of GM-CSF, CpG, and tumor lysate. Rats were monitored for survival and tested for neurological function.

RESULTS: Survival studies confirmed a benefit of the polymeric vaccine as 90\% of vaccinated rats survived for > 100 days. Control rats exhibited minimal benefit. Motor tests revealed that vaccination protected against the loss of forelimb use produced by glioma growth. Histological analysis quantitatively confirmed a robust and rapid reduction in tumor size. Long-term immunity was confirmed when 67\% of survivors also survived a second glioma challenge.

CONCLUSIONS: These studies extend previous reports regarding this approach to tumor therapy and justify further development for glioma treatment.},
	keywords = {Animals, Brain Neoplasms, Cancer Vaccines, Glioma, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Immunotherapy, Oligodeoxyribonucleotides, Rats, Rats, Sprague-Dawley},
	issn = {1573-904X},
	doi = {10.1007/s11095-010-0361-x},
	author = {Ali, Omar A and Doherty, Ed and Bell, William J and Fradet, Tracie and Hudak, Jebecka and Laliberte, Marie-Therese and Mooney, David J and Emerich, Dwaine F}
}
@article {1192261,
	title = {[Cell-traction mediated configuration of the cell/extracellular-matrix interface plays a key role in stem cell fate]},
	journal = {Med Sci (Paris)},
	volume = {27},
	number = {1},
	year = {2011},
	month = {2011 Jan},
	pages = {19-21},
	keywords = {Animals, Cell Adhesion Molecules, Cell Culture Techniques, Cell Differentiation, Cell Division, Cell Lineage, Extracellular Matrix, Integrins, Mechanotransduction, Cellular, Mesenchymal Stromal Cells, Muscle Development, Oligopeptides, Osteogenesis, Stress, Mechanical, Tissue Engineering},
	issn = {0767-0974},
	doi = {10.1051/medsci/201127119},
	author = {Bencherif, Sidi A and Guillemot, Fabien and Huebsch, Nathaniel and Edwards, David A and Mooney, David J}
}
@article {1192241,
	title = {Disproportionate exercise load and remodeling of the athlete{\textquoteright}s right ventricle},
	journal = {Med Sci Sports Exerc},
	volume = {43},
	number = {6},
	year = {2011},
	month = {2011 Jun},
	pages = {974-81},
	abstract = {PURPOSE: There is evolving evidence that intense exercise may place a disproportionate load on the right ventricle (RV) when compared with the left ventricle (LV) of the heart. Using a novel method of estimating end-systolic wall stress (ES-σ), we compared the RV and LV during exercise and assessed whether this influenced chronic ventricular remodeling in athletes.

METHODS: For this study, 39 endurance athletes (EA) and 14 nonathletes (NA) underwent resting cardiac magnetic resonance (CMR), maximal oxygen uptake (VO2), and exercise echocardiography studies. LV and RV end-systolic wall stress (ES-σ) were calculated using the Laplace relation (ES-σ = Pr/(2h)). Ventricular size and wall thickness were determined by CMR; invasive and Doppler echo estimates were used to measure systemic and pulmonary ventricular pressures, respectively; and stroke volume was quantified by Doppler echocardiography and used to calculate changes in ventricular geometry during exercise.

RESULTS: In EA, compared with NA, resting CMR measures showed greater RV than LV remodeling. The ratios RV ESV/LV ESV (1.40 {\textpm} 0.23 vs 1.26 {\textpm} 0.12, P = 0.007) and RV mass/LV mass (0.29 {\textpm} 0.04 vs 0.25 {\textpm} 0.03, P = 0.012) were greater in EA than in NA. RVES-σ was lower at rest than LVES-σ (143 {\textpm} 44 vs 252 {\textpm} 49 kdyn {\textperiodcentered} cm, P < 0.001) but increased more with strenuous exercise (125\% vs 14\%, P < 0.001), resulting in similar peak exercise ES-σ (321 {\textpm} 106 vs 286 {\textpm} 77 kdyn {\textperiodcentered} cm, P = 0.058). Peak exercise RVES-σ was greater in EA than in NA (340 {\textpm} 107 vs 266 {\textpm} 82 kdyn {\textperiodcentered} cm, P = 0.028), whereas RVES-σ at matched absolute workloads did not differ (P = 0.79).

CONCLUSIONS: Exercise induces a relative increase in RVES-σ which exceeds LVES-σ. In athletes, greater RV enlargement and greater wall thickening may be a product of this disproportionate load excess.},
	keywords = {Adult, Athletes, Case-Control Studies, Exercise, Female, Heart Ventricles, Humans, Magnetic Resonance Imaging, Cine, Male, Oxygen Consumption, Physical Exertion, Stroke Volume, Systole, Ultrasonography, Doppler, Ventricular Function, Left, Ventricular Function, Right, Ventricular Remodeling},
	issn = {1530-0315},
	doi = {10.1249/MSS.0b013e31820607a3},
	author = {La Gerche, Andr{\'e} and Heidb{\"u}chel, Hein and Burns, Andrew T and Mooney, Don J and Taylor, Andrew J and Pfluger, Heinz B and Inder, Warrick J and Macisaac, Andrew I and Prior, David L}
}
@article {1192231,
	title = {The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue},
	journal = {J Control Release},
	volume = {154},
	number = {3},
	year = {2011},
	month = {2011 Sep 25},
	pages = {249-57},
	abstract = {We previously engineered a macroporous, polymer-based vaccine that initially produces GM-CSF gradients to recruit local dendritic cells and subsequently presents CpG oligonucleotides, and tumor lysate to cell infiltrates to induce immune cell activation and immunity against tumor cells in peripheral tumor models. Here, we demonstrate that this system eradicates established intracranial glioma following implantation into brain tissue, whereas implantation in resection cavities obviates vaccine efficacy. Rats bearing seven-day old, intracranial glioma tumors were treated with PLG vaccines implanted into the tumor bed, resulting in retention of contralateral forelimb function (day 17) that is compromised by tumor formation in control animals, and 90\% long-term survival (>100 days). Similar benefits were observed in animals receiving tumor resection plus vaccine implants into the adjacent parenchyma, but direct implantation of PLG vaccines into the resection cavity conferred no benefit. This dissociation of efficacy was likely related to GM-CSF distribution, as implantation of PLG vaccines within brain tissue produced significant GM-CSF gradients for prolonged periods, which was not detected after implantation in resection cavities. These studies demonstrate that PLG vaccine efficacy is correlated to GM-CSF gradient formation, which requires direct implantation into brain tissue, and justify further exploration of this approach for glioma treatment.},
	keywords = {Adjuvants, Immunologic, Animals, Brain, Brain Neoplasms, Cancer Vaccines, Glioma, Granulocyte-Macrophage Colony-Stimulating Factor, Immunotherapy, Male, Oligodeoxyribonucleotides, Polyglactin 910, Porosity, Prostheses and Implants, Rats, Rats, Sprague-Dawley},
	issn = {1873-4995},
	doi = {10.1016/j.jconrel.2011.06.021},
	author = {Ali, Omar A and Doherty, Edward and Bell, William J and Fradet, Tracie and Hudak, Jebecka and Laliberte, Marie-Therese and Mooney, David J and Emerich, Dwaine F}
}
@article {1192236,
	title = {Spatiotemporal delivery of bone morphogenetic protein enhances functional repair of segmental bone defects},
	journal = {Bone},
	volume = {49},
	number = {3},
	year = {2011},
	month = {2011 Sep},
	pages = {485-92},
	abstract = {Osteogenic growth factors that promote endogenous repair mechanisms hold considerable potential for repairing challenging bone defects. The local delivery of one such growth factor, bone morphogenetic protein (BMP), has been successfully translated to clinical practice for spinal fusion and bone fractures. However, improvements are needed in the spatial and temporal control of BMP delivery to avoid the currently used supraphysiologic doses and the concomitant adverse effects. We have recently introduced a hybrid protein delivery system comprised of two parts: a perforated nanofibrous mesh that spatially confines the defect region and a functionalized alginate hydrogel that provides temporal growth factor release kinetics. Using this unique spatiotemporal delivery system, we previously demonstrated BMP-mediated functional restoration of challenging 8mm femoral defects in a rat model. In this study, we compared the efficacy of the hybrid system in repairing segmental bone defects to that of the current clinical standard, collagen sponge, at the same dose of recombinant human BMP-2. In addition, we investigated the specific role of the nanofibrous mesh tube on bone regeneration. Our results indicate that the hybrid delivery system significantly increased bone regeneration and improved biomechanical function compared to collagen sponge delivery. Furthermore, we observed that presence of the nanofiber mesh tube was essential to promote maximal mineralized matrix synthesis, prevent extra-anatomical mineralization, and guide an integrated pattern of bone formation. Together, these results suggest that spatiotemporal strategies for osteogenic protein delivery may enhance clinical outcomes by improving localized protein retention.},
	keywords = {Animals, Biomechanical Phenomena, Bone Morphogenetic Protein 2, Bone Morphogenetic Proteins, Bone Regeneration, Drug Carriers, Drug Delivery Systems, Female, Femur, Humans, Nanofibers, Osteogenesis, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Stress, Mechanical, Transforming Growth Factor beta, X-Ray Microtomography},
	issn = {1873-2763},
	doi = {10.1016/j.bone.2011.05.010},
	author = {Kolambkar, Yash M and Boerckel, Joel D and Dupont, Kenneth M and Bajin, Mehmet and Huebsch, Nathaniel and Mooney, David J and Hutmacher, Dietmar W and Guldberg, Robert E}
}
@article {216821,
	title = {At the edge of translation - materials to program cells for directed differentiation},
	journal = {Oral Dis},
	volume = {17},
	number = {3},
	year = {2011},
	month = {2011 Apr},
	pages = {241-51},
	abstract = {Oral Diseases (2011) 17, 241-251 The rapid advancement in basic biology knowledge, especially in the stem cell field, has created new opportunities to develop biomaterials capable of orchestrating the behavior of transplanted and host cells. Based on our current understanding of cellular differentiation, a conceptual framework for the use of materials to program cells in situ is presented, namely a domino vs a switchboard model, to highlight the use of single vs multiple cues in a controlled manner to modulate biological processes. Further, specific design principles of material systems to present soluble and insoluble cues that are capable of recruiting, programming and deploying host cells for various applications are presented. The evolution of biomaterials from simple inert substances used to fill defects, to the recent development of sophisticated material systems capable of programming cells in situ is providing a platform to translate our understanding of basic biological mechanisms to clinical care.},
	keywords = {Biocompatible Materials, Cell Adhesion, Cell Adhesion Molecules, Cell Differentiation, Cell Physiological Phenomena, Guided Tissue Regeneration, Humans, Intercellular Signaling Peptides and Proteins, Nucleic Acids, Stem Cells, Tissue Engineering},
	issn = {1601-0825},
	doi = {10.1111/j.1601-0825.2010.01735.x},
	author = {Arany, P R and Mooney, D J}
}
@article {216831,
	title = {Growth factor delivery-based tissue engineering: general approaches and a review of recent developments},
	journal = {J R Soc Interface},
	volume = {8},
	number = {55},
	year = {2011},
	month = {2011 Feb 06},
	pages = {153-70},
	abstract = {The identification and production of recombinant morphogens and growth factors that play key roles in tissue regeneration have generated much enthusiasm and numerous clinical trials, but the results of many of these trials have been largely disappointing. Interestingly, the trials that have shown benefit all contain a common denominator, the presence of a material carrier, suggesting strongly that spatio-temporal control over the location and bioactivity of factors after introduction into the body is crucial to achieve tangible therapeutic effect. Sophisticated materials systems that regulate the biological presentation of growth factors represent an attractive new generation of therapeutic agents for the treatment of a wide variety of diseases. This review provides an overview of growth factor delivery in tissue engineering. Certain fundamental issues and design strategies relevant to the material carriers that are being actively pursued to address specific technical objectives are discussed. Recent progress highlights the importance of materials science and engineering in growth factor delivery approaches to regenerative medicine.},
	keywords = {Biocompatible Materials, Drug Delivery Systems, Extracellular Matrix, Guided Tissue Regeneration, Intercellular Signaling Peptides and Proteins, Nanoparticles, Receptor Cross-Talk, Signal Transduction, Tissue Engineering},
	issn = {1742-5662},
	doi = {10.1098/rsif.2010.0223},
	author = {Lee, Kangwon and Silva, Eduardo A and Mooney, David J}
}
@article {216841,
	title = {Immunologically active biomaterials for cancer therapy},
	journal = {Curr Top Microbiol Immunol},
	volume = {344},
	year = {2011},
	month = {2011},
	pages = {279-97},
	abstract = {Our understanding of immunological regulation has progressed tremendously alongside the development of materials science, and at their intersection emerges the possibility to employ immunologically active biomaterials for cancer immunotherapy. Strong and sustained anticancer, immune responses are required to clear large tumor burdens in patients, but current approaches for immunotherapy are formulated as products for delivery in bolus, which may be indiscriminate and/or shortlived. Multifunctional biomaterial particles are now being developed to target and sustain antigen and adjuvant delivery to dendritic cells in vivo, and these have the potential to direct and prolong antigen-specific T cell responses. Three-dimensional immune cell niches are also being developed to regulate the recruitment, activation and deployment of immune cells in situ to promote potent antitumor responses. Recent studies demonstrate that materials with immune targeting and stimulatory capabilities can enhance the magnitude and duration of immune responses to cancer antigens, and preclinical results utilizing material-based immunotherapy in tumor models show a strong therapeutic benefit, justifying translation to and future testing in the clinic.},
	keywords = {Adjuvants, Immunologic, Biocompatible Materials, Dendritic Cells, Humans, Immunotherapy, Neoplasms},
	issn = {0070-217X},
	doi = {10.1007/82_2010_69},
	author = {Ali, Omar A and Mooney, David J}
}
@article {216801,
	title = {Controlled architectural and chemotactic studies of 3D cell migration},
	journal = {Biomaterials},
	volume = {32},
	number = {10},
	year = {2011},
	month = {2011 Apr},
	pages = {2634-41},
	abstract = {Chemotaxis plays a critical role in tissue development and wound repair, and is widely studied using ex vivo model systems in applications such as immunotherapy. However, typical chemotactic models employ 2D systems that are less physiologically relevant or use end-point assays, that reveal little about the stepwise dynamics of the migration process. To overcome these limitations, we developed a new model system using microfabrication techniques, sustained drug delivery approaches, and theoretical modeling of chemotactic agent diffusion. This model system allows us to study the effects of 3D architecture and chemotactic agent gradient on immune cell migration in real time. We find that dendritic cell migration is characterized by a strong interplay between matrix architecture and chemotactic gradients, and migration is also influenced dramatically by the cell activation state. Our results indicate that Lipopolysaccharide-activated dendritic cells studied in a traditional transwell system actually exhibit anomalous migration behavior. Such a 3D ex vivo system lends itself for analyzing cell migratory behavior in response to single or multiple competitive cues and could prove useful in vaccine development.},
	keywords = {Animals, Chemokines, Chemotaxis, Dendritic Cells, Flow Cytometry, Mice, Mice, Inbred C57BL, Microtechnology, Models, Biological, Rats, Signal Transduction, Tissue Scaffolds},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2010.12.019},
	author = {Tayalia, Prakriti and Mazur, Eric and Mooney, David J}
}
@article {216796,
	title = {Integrin organization: linking adhesion ligand nanopatterns with altered cell responses},
	journal = {J Theor Biol},
	volume = {274},
	number = {1},
	year = {2011},
	month = {2011 Apr 07},
	pages = {120-30},
	abstract = {Integrin receptors bind to adhesion ligand (e.g. arginine-glycine-aspartic acid or RGD containing peptides) on extracellular matrix and organize into high-density complexes which mediate many cell behaviors. Biomaterials with RGD nanopatterned into multivalent "islands" (\~{}30-70 nm diameter) have been shown to alter cell responses, although the length scale of pattern features is orders of magnitude smaller than adhesion complexes. In this work, we employ together for the first time an extensive data set on osteoblast responses as a function of ligand nanopatterns, a computational model of integrin binding to ligand nanopatterns, and new measures of integrin organization on the cell surface. We quantify, at multiple length scales, integrin organization generated in silico as a function of RGD nanopattern parameters. We develop a correlative model relating these measures of in silico integrin organization and in vitro MC3T3 preosteoblast cell responses as functions of the same RGD nanopatterns: cell spreading correlates with the number of bound integrins, focal adhesion kinase (FAK) phosphorylation correlates with small, homogeneously distributed clusters of integrins, and osteogenic differentiation correlates with large, heterogeneously distributed integrin clusters. These findings highlight the significance of engineering biomaterials at the nanolevel and suggest new approaches to understanding the mechanisms linking integrin organization to cell responses.},
	keywords = {Animals, Cell Adhesion, Cell Differentiation, Cell Line, Cell Movement, Focal Adhesion Protein-Tyrosine Kinases, Integrins, Ligands, Mice, Models, Biological, Nanostructures, Oligopeptides, Osteoblasts, Osteogenesis, Phosphorylation, Protein Binding},
	issn = {1095-8541},
	doi = {10.1016/j.jtbi.2011.01.007},
	author = {Comisar, W A and Mooney, D J and Linderman, J J}
}
@article {216786,
	title = {Metal-enhanced fluorescence to quantify bacterial adhesion},
	journal = {Adv Mater},
	volume = {23},
	number = {12},
	year = {2011},
	month = {2011 Mar 25},
	pages = {H101-4},
	keywords = {Bacterial Adhesion, Biofilms, Gold, Optical Phenomena, Pseudomonas aeruginosa, Spectrometry, Fluorescence, Surface Properties},
	issn = {1521-4095},
	doi = {10.1002/adma.201004096},
	author = {Lee, Kangwon and Hahn, Lewis D and Yuen, William W and Vlamakis, Hera and Kolter, Roberto and Mooney, David J}
}
@article {216781,
	title = {Relationship of vaccine efficacy to the kinetics of DC and T-cell responses induced by PLG-based cancer vaccines},
	journal = {Biomatter},
	volume = {1},
	number = {1},
	year = {2011},
	month = {2011 Jul-Sep},
	pages = {66-75},
	abstract = {Cancer vaccines are typically formulated for bolus injection and often produce short-lived immunostimulation resulting in poor temporal control over immune cell activation and weak oncolytic activity. One means of overcoming these limitations utilizes immunologically active biomaterial constructs. We previously reported that antigen-laden, macroporous PLG scaffolds induce potent dendritic cell (DC) and cytotoxic T-lymphocyte (CTL) responses via the controlled signaling of inflammatory cytokines, antigen and toll-like receptor agonists. In this study, we describe the kinetics of these responses and illustrate their fundamental relationship to potent tumor rejection when implanted subcutaneously in a mouse B16 model of melanoma. By explanting scaffolds from mice at times ranging from 1-7 d, a seamless relationship was observed between the production of controlled CTL responses, tumor growth and long-term survival in both prophylactic and therapeutic models. Scaffolds must be implanted for > 7 d to augment CTL responses via the prolonged presentation of tumor antigen, and the benefits included a notable regression of established tumors. Host DC infiltration into the porous material persisted for 12 days (peaking at day 5 ~1.4 x 10(6) cells), and a sharp attenuation in DC numbers coincided with peak CD8(+) CTL infiltration at day 12 (~8 x 10(5) cells). Importantly, these PLG systems enhanced DC numbers in the draining lymph node, resulting in increased CD(+) CTL subsets at days 10-16 of vaccination. These results indicate that material systems can finely control innate and adaptive immune cell responses to kill typically untreatable melanoma tumors and provide critical kinetic data for the design of vaccine carriers.},
	keywords = {Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, Neoplasm, Cancer Vaccines, Cell Separation, Cytokines, Dendritic Cells, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Oligodeoxyribonucleotides, Porosity, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Time Factors},
	issn = {2159-2535},
	doi = {10.4161/biom.1.1.16277},
	author = {Ali, Omar A and Doherty, Edward and Mooney, David J and Emerich, Dwaine}
}
@article {216776,
	title = {The role of multifunctional delivery scaffold in the ability of cultured myoblasts to promote muscle regeneration},
	journal = {Biomaterials},
	volume = {32},
	number = {34},
	year = {2011},
	month = {2011 Dec},
	pages = {8905-14},
	abstract = {Many cell types of therapeutic interest, including myoblasts, exhibit reduced engraftment if cultured prior to transplantation. This study investigated whether polymeric scaffolds that direct cultured myoblasts to migrate outwards and repopulate the host damaged tissue, in concert with release of angiogenic factors designed to enhance revascularizaton of the regenerating tissue, would enhance the efficacy of this cell therapy and lead to functional muscle regeneration. This was investigated in the context of a severe injury to skeletal muscle tissue involving both myotoxin-mediated direct damage and induction of regional ischemia. Local and sustained release of VEGF and IGF-1 from macroporous scaffolds used to transplant and disperse cultured myogenic cells significantly enhanced their engraftment, limited fibrosis, and accelerated the regenerative process. This resulted in increased muscle mass and, improved contractile function. These results demonstrate the importance of finely controlling the microenvironment of transplanted cells in the treatment of severe muscle damage.},
	keywords = {Alginates, Animals, Cells, Cultured, Female, Glucuronic Acid, Hexuronic Acids, Humans, Insulin-Like Growth Factor I, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Skeletal, Myoblasts, Regeneration, Tissue Scaffolds, Vascular Endothelial Growth Factor A},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2011.08.019},
	author = {Borselli, Cristina and Cezar, Christine A and Shvartsman, Dymitri and Vandenburgh, Herman H and Mooney, David J}
}
@article {216806,
	title = {Targeted delivery of nanoparticles to ischemic muscle for imaging and therapeutic angiogenesis},
	journal = {Nano Lett},
	volume = {11},
	number = {2},
	year = {2011},
	month = {2011 Feb 09},
	pages = {694-700},
	abstract = {Targeting of nanoparticles to ischemic tissues was studied in a murine ischemic hindlimb model. Intravenously injected fluorescent nanoparticles allowed ischemia-targeted imaging of ischemic muscles due to increased permeability of blood vessels in hypoxic tissues. Targeting efficiency correlated with blood perfusion after induction of ischemia and was enhanced in early stages of ischemia (,
	keywords = {Angiogenesis Inhibitors, Animals, Ischemia, Mice, Muscle, Skeletal, Nanocapsules, Treatment Outcome, Vascular Endothelial Growth Factor A},
	issn = {1530-6992},
	doi = {10.1021/nl103812a},
	author = {Kim, Jaeyun and Cao, Lan and Shvartsman, Dmitry and Silva, Eduardo A and Mooney, David J}
}
@article {216791,
	title = {Viability and functionality of cells delivered from peptide conjugated scaffolds},
	journal = {Biomaterials},
	volume = {32},
	number = {15},
	year = {2011},
	month = {2011 May},
	pages = {3721-8},
	abstract = {Many cell-based therapies aim to transplant functional cells to revascularize damaged tissues and ischemic areas. However, conventional cell therapy is not optimally efficient: massive cell death, damage, and non-localization of cells both spatially and temporally all likely contribute to poor tissue functionality. An alginate cell depot system has been proposed as an alternative means to deliver outgrowth endothelial cells (OECs) in a spatiotemporally controllable manner while protecting them in the early stages of tissue re-integration. Here OECs exiting the alginate scaffold were measured for viability, functionality, and migration speed and characterized for cytokine and surface marker profiles. OECs were highly viable in the alginate and were depleted from the scaffold via migration at a speed of 21 {\textpm} 6 μm/h following release. Prolonged interaction with the alginate scaffold microenvironment did not detrimentally change OECs; they retained high functionality, displayed a similar angiogenic cytokine profile as control OECs, and did not have significantly altered surface markers. These results suggest that alginate-OEC interactions do not adversely affect these cells, validating control of cellular migration as a means to control the cell delivery profile from the material system, and supporting usage of the alginate scaffold as an efficient cell delivery vehicle.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cell Adhesion, Cell Survival, Cells, Cultured, Endothelial Cells, Glucuronic Acid, Hexuronic Acids, Humans, Neovascularization, Physiologic, Oligopeptides, Tissue Engineering, Tissue Scaffolds},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2010.12.048},
	author = {Vacharathit, Voranaddha and Silva, Eduardo A and Mooney, David J}
}
@article {216766,
	title = {In Vivo Modulation of Dendritic Cells by Engineered Materials: Towards New Cancer Vaccines},
	journal = {Nano Today},
	volume = {6},
	number = {5},
	year = {2011},
	month = {2011 Oct},
	pages = {466-477},
	abstract = {Therapeutic cancer vaccines are emerging as novel and potent approaches to treat cancer. These vaccines enhance the body{\textquoteright}s immune response to cancerous cells, and dendritic cells (DCs), an initiator of adaptive immunity, are a key cell type targeted by these strategies. Current DC-based cancer vaccines are based on ex vivo manipulation of the cells following their isolation from the patient, followed by reintroduction to the patient, but this approach has many limitations in practical cancer treatment. However, recent progress in materials science has allowed the design and fabrication of physically and chemically functionalized materials platforms that can specifically target DCs in the body. These materials, through their in vivo modulation of DCs, have tremendous potentials as new cancer therapies. Nanoparticles, which are several orders of magnitude smaller than DCs, can efficiently deliver antigen and danger signals to these cells through passive or active targeting. Three-dimensional biomaterials, with sizes several orders of magnitude larger than DCs, create microenvironments that allow the effective recruitment and programming of these cells, and can be used as local depots of nanoparticles targeting resident DCs. Both material strategies have shown potential in promoting antigen-specific T cell responses of magnitudes relevant to treating cancer.},
	issn = {1748-0132},
	doi = {10.1016/j.nantod.2011.08.005},
	author = {Kim, Jaeyun and Mooney, David J}
}
@article {1192276,
	title = {Can tissue engineering concepts advance tumor biology research?},
	journal = {Trends Biotechnol},
	volume = {28},
	number = {3},
	year = {2010},
	month = {2010 Mar},
	pages = {125-33},
	abstract = {Advances in tissue engineering have traditionally led to the design of scaffold- or matrix-based culture systems that better reflect the biological, physical and biochemical environment of the natural extracellular matrix. Although their clinical applications in regenerative medicine tend to receive most of the attention, it is obvious that other areas of biomedical research could be well served by the powerful tools that have already been developed in tissue engineering. In this article, we review the recent literature to demonstrate how tissue engineering platforms can enhance in vitro and in vivo models of tumorigenesis and thus hold great promise to contribute to future cancer research.},
	keywords = {Animals, Bioreactors, Extracellular Matrix, Humans, Models, Biological, Neoplasms, Tissue Culture Techniques, Tissue Engineering, Tissue Scaffolds},
	issn = {1879-3096},
	doi = {10.1016/j.tibtech.2009.12.001},
	author = {Hutmacher, Dietmar W and Loessner, Daniela and Rizzi, Simone and Kaplan, David L and Mooney, David J and Clements, Judith A}
}
@article {1192291,
	title = {Injectable hydrogels providing sustained delivery of vascular endothelial growth factor are neuroprotective in a rat model of Huntington{\textquoteright}s disease},
	journal = {Neurotox Res},
	volume = {17},
	number = {1},
	year = {2010},
	month = {2010 Jan},
	pages = {66-74},
	abstract = {Vascular endothelial growth factor (VEGF) is a potent peptide with well-documented pro-angiogenic effects. Recently, it has also become clear that exogenous administration of VEGF is neuroprotective in animal models of central nervous system diseases. In the present study, VEGF was incorporated into a sustained release hydrogel delivery system to examine its potential benefits in a rat model of Huntington{\textquoteright}s disease (HD). The VEGF-containing hydrogel was stereotaxically injected into the striatum of adult rats. Three days later, quinolinic acid (QA; 225 nmol) was injected into the ipsilateral striatum to produce neuronal loss and behavioral deficits that mimic those observed in HD. Two weeks after surgery, animals were tested for motor function using the placement and cylinder tests. Control animals received either QA alone or QA plus empty hydrogel implants. Behavioral testing confirmed that the QA lesion resulted in significant deficits in the ability of the control animals to use their contralateral forelimb. In contrast, the performance of those animals receiving VEGF was significantly improved relative to controls with only modest motor impairments observed. Stereological counts of NeuN-positive neurons throughout the striatum demonstrated that VEGF implants significantly protected against the loss of striatal neurons induced by QA. These data are the first to demonstrate that VEGF can be used to protect striatal neurons from excitotoxic damage in a rat model of HD.},
	keywords = {Animals, Behavior, Animal, Corpus Striatum, Disease Models, Animal, Functional Laterality, Huntington Disease, Hydrogels, Male, Neurons, Neuroprotective Agents, Phosphopyruvate Hydratase, Psychomotor Performance, Quinolinic Acid, Rats, Rats, Sprague-Dawley, Time Factors, Vascular Endothelial Growth Factor A},
	issn = {1476-3524},
	doi = {10.1007/s12640-009-9079-0},
	author = {Emerich, Dwaine F and Mooney, David J and Storrie, Hannah and Babu, Rangasamy Suresh and Kordower, Jeffrey H}
}
@article {1192281,
	title = {Label-free biomarker detection from whole blood},
	journal = {Nat Nanotechnol},
	volume = {5},
	number = {2},
	year = {2010},
	month = {2010 Feb},
	pages = {138-42},
	abstract = {Label-free nanosensors can detect disease markers to provide point-of-care diagnosis that is low-cost, rapid, specific and sensitive. However, detecting these biomarkers in physiological fluid samples is difficult because of problems such as biofouling and non-specific binding, and the resulting need to use purified buffers greatly reduces the clinical relevance of these sensors. Here, we overcome this limitation by using distinct components within the sensor to perform purification and detection. A microfluidic purification chip simultaneously captures multiple biomarkers from blood samples and releases them, after washing, into purified buffer for sensing by a silicon nanoribbon detector. This two-stage approach isolates the detector from the complex environment of whole blood, and reduces its minimum required sensitivity by effectively pre-concentrating the biomarkers. We show specific and quantitative detection of two model cancer antigens from a 10 microl sample of whole blood in less than 20 min. This study marks the first use of label-free nanosensors with physiological solutions, positioning this technology for rapid translation to clinical settings.},
	keywords = {Antigen-Antibody Reactions, Antigens, Neoplasm, Biomarkers, Tumor, Biosensing Techniques, Female, Humans, Male, Microfluidic Analytical Techniques, Microfluidics, Nanotechnology, Sensitivity and Specificity},
	issn = {1748-3395},
	doi = {10.1038/nnano.2009.353},
	author = {Stern, Eric and Vacic, Aleksandar and Rajan, Nitin K and Criscione, Jason M and Park, Jason and Ilic, Bojan R and Mooney, David J and Reed, Mark A and Fahmy, Tarek M}
}
@article {1192266,
	title = {Pulmonary transit of agitated contrast is associated with enhanced pulmonary vascular reserve and right ventricular function during exercise},
	journal = {J Appl Physiol (1985)},
	volume = {109},
	number = {5},
	year = {2010},
	month = {2010 Nov},
	pages = {1307-17},
	abstract = {Pulmonary transit of agitated contrast (PTAC) occurs to variable extents during exercise. We tested the hypothesis that the onset of PTAC signifies flow through larger-caliber vessels, resulting in improved pulmonary vascular reserve during exercise. Forty athletes and fifteen nonathletes performed maximal exercise with continuous echocardiographic Doppler measures [cardiac output (CO), pulmonary artery systolic pressure (PASP), and myocardial velocities] and invasive blood pressure (BP). Arterial gases and B-type natriuretic peptide (BNP) were measured at baseline and peak exercise. Pulmonary vascular resistance (PVR) was determined as the regression of PASP/CO and was compared according to athletic and PTAC status. At peak exercise, athletes had greater CO (16.0 {\textpm} 2.9 vs. 12.4 {\textpm} 3.2 l/min, P < 0.001) and higher PASP (60.8 {\textpm} 12.6 vs. 47.0 {\textpm} 6.5 mmHg, P < 0.001), but PVR was similar to nonathletes (P = 0.71). High PTAC (defined by contrast filling of the left ventricle) occurred in a similar proportion of athletes and nonathletes (18/40 vs. 10/15, P = 0.35) and was associated with higher peak-exercise CO (16.1 {\textpm} 3.4 vs. 13.9 {\textpm} 2.9 l/min, P = 0.010), lower PASP (52.3 {\textpm} 9.8 vs. 62.6 {\textpm} 13.7 mmHg, P = 0.003), and 37\% lower PVR (P < 0.0001) relative to low PTAC. Right ventricular (RV) myocardial velocities increased more and BNP increased less in high vs. low PTAC subjects. On multivariate analysis, maximal oxygen consumption (VO(2max)) (P = 0.009) and maximal exercise output (P = 0.049) were greater in high PTAC subjects. An exercise-induced decrease in arterial oxygen saturation (98.0 {\textpm} 0.4 vs. 96.7 {\textpm} 1.4\%, P < 0.0001) was not influenced by PTAC status (P = 0.96). Increased PTAC during exercise is a marker of pulmonary vascular reserve reflected by greater flow, reduced PVR, and enhanced RV function.},
	keywords = {Adaptation, Physiological, Adult, Biomarkers, Blood Pressure, Cardiac Output, Contrast Media, Echocardiography, Doppler, Echocardiography, Doppler, Color, Echocardiography, Doppler, Pulsed, Exercise, Gelatin, Heart Ventricles, Hemodynamics, Humans, Lung, Microbubbles, Myocardial Contraction, Natriuretic Peptide, Brain, Oxygen, Oxygen Consumption, Partial Pressure, Physical Endurance, Predictive Value of Tests, Pulmonary Circulation, Succinates, Vascular Resistance, Ventricular Function, Right},
	issn = {1522-1601},
	doi = {10.1152/japplphysiol.00457.2010},
	author = {La Gerche, Andr{\'e} and Macisaac, Andrew I and Burns, Andrew T and Mooney, Don J and Inder, Warrick J and Voigt, Jens-Uwe and Heidb{\"u}chel, Hein and Prior, David L}
}
@article {1192271,
	title = {Stress-relaxation behavior in gels with ionic and covalent crosslinks},
	journal = {J Appl Phys},
	volume = {107},
	number = {6},
	year = {2010},
	month = {2010 Mar 15},
	pages = {63509},
	abstract = {Long-chained polymers in alginate hydrogels can form networks by either ionic or covalent crosslinks. This paper shows that the type of crosslinks can markedly affect the stress-relaxation behavior of the gels. In gels with only ionic crosslinks, stress relaxes mainly through breaking and subsequent reforming of the ionic crosslinks, and the time scale of the relaxation is independent of the size of the sample. By contrast, in gels with only covalent crosslinks, stress relaxes mainly through migration of water, and the relaxation slows down as the size of the sample increases. Implications of these observations are discussed.},
	issn = {0021-8979},
	doi = {10.1063/1.3343265},
	author = {Zhao, Xuanhe and Huebsch, Nathaniel and Mooney, David J and Zhigang Suo}
}
@article {1192286,
	title = {Sustained release of multiple growth factors from injectable polymeric system as a novel therapeutic approach towards angiogenesis},
	journal = {Pharm Res},
	volume = {27},
	number = {2},
	year = {2010},
	month = {2010 Feb},
	pages = {264-71},
	abstract = {PURPOSE: The aim was to investigate that a bio-degradable alginate and poly lactide-co-glycolide (PLG) system capable of delivering growth factors sequentially would be superior to single growth factor delivery in promoting neovascularization and improving perfusion.

METHODS: Three groups of apoE null mice underwent unilateral hindlimb ischemia surgery and received ischemic limb intramuscular injections of alginate (Blank), alginate containing VEGF(165) (VEGF), or alginate containing VEGF(165) combined with PLG microspheres containing PDGF-BB (VEGF/PDGF). Vascularity in the ischemic hindlimb was assessed by morphologic and immunohistochemical end-points, while changes in blood flow were assessed by Laser Doppler Perfusion Index. Muscle VEGF and PDGF content was assessed at multiple time points.

RESULTS: In the VEGF/PDGF group, local tissue VEGF and PDGF levels peaked at week 2 and 4, respectively, with detectable PDGF levels at week 6. At week 6, mean vessel mean diameter was significantly greater in the VEGF/PDGF group compared to the VEGF or Blank groups with evidence of well-formed smooth muscle-lined arterioles.

CONCLUSIONS: Sequential delivery of VEGF and PDGF using an injectable, biodegradable platform resulted in stable and sustained improvements in perfusion. This sustained, control-released, injectable alginate polymer system is a promising approach for multiple growth factor delivery in clinical application.},
	keywords = {Alginates, Angiogenesis Inhibitors, Animals, Delayed-Action Preparations, Drug Carriers, Drug Delivery Systems, Glucuronic Acid, Hexuronic Acids, Hindlimb, Intercellular Signaling Peptides and Proteins, Ischemia, Male, Mice, Mice, Knockout, Neovascularization, Physiologic, Polyesters, Polymers, Random Allocation},
	issn = {1573-904X},
	doi = {10.1007/s11095-009-0014-0},
	author = {Sun, Qinghua and Silva, Eduardo A and Wang, Aixia and Fritton, James C and Mooney, David J and Schaffler, Mitchell B and Grossman, Paul M and Rajagopalan, Sanjay}
}
@article {216871,
	title = {Patterning alginate hydrogels using light-directed release of caged calcium in a microfluidic device},
	journal = {Biomed Microdevices},
	volume = {12},
	number = {1},
	year = {2010},
	month = {2010 Feb},
	pages = {145-51},
	abstract = {This paper describes a simple reversible hydrogel patterning method for 3D cell culture. Alginate gel is formed in select regions of a microfluidic device through light-triggered release of caged calcium. In the pre-gelled alginate solution, calcium is chelated by DM-nitrophen (DM-n) to prevent cross-linking of alginate. After sufficient UV exposure the caged calcium is released from DM-n causing alginate to cross-link. The effect of using different concentrations of calcium and chelating agents as well as the duration of UV exposure is described. Since the cross-linking is based on calcium concentration, the cross-linked alginate can easily be dissolved by EDTA. We also demonstrate application of this capability to patterned microscale 3D co-culture using endothelial cells and osteoblastic cells in a microchannel.},
	keywords = {Alginates, Animals, Calcium, Cell Culture Techniques, Cell Proliferation, Cells, Cultured, Endothelial Cells, Equipment Design, Equipment Failure Analysis, Flow Injection Analysis, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Light, Mice, Microfluidic Analytical Techniques},
	issn = {1572-8781},
	doi = {10.1007/s10544-009-9369-6},
	author = {Chueh, Bor-han and Zheng, Ying and Torisawa, Yu-suke and Hsiao, Amy Y and Ge, Chunxi and Hsiong, Susan and Huebsch, Nathaniel and Franceschi, Renny and Mooney, David J and Takayama, Shuichi}
}
@article {216866,
	title = {Effects of VEGF temporal and spatial presentation on angiogenesis},
	journal = {Biomaterials},
	volume = {31},
	number = {6},
	year = {2010},
	month = {2010 Feb},
	pages = {1235-41},
	abstract = {Therapeutic angiogenesis relies on the delivery of angiogenic factors capable of reversing tissue ischemia. Polymeric materials that can provide spatial and temporal over vascular endothelial growth factor (VEGF) presentation provide clear benefit, but the influence of VEGF dose, temporal, and spatial presentation on the resultant angiogenic process are largely unknown. The influence of the temporal profile of VEGF concentration, dose, and the impact of VEGF spatial distribution on angiogenesis in in vitro models of angiogenesis and ischemic murine limbs was analyzed in this study. Importantly, a profile consisting of a high VEGF concentration initially, followed by a decreasing concentration over time was found to yield optimal angiogenic sprouting. A total VEGF dose 0.1 microg/g, when delivered with kinetics found to be optimal in vitro, provided a favorable therapeutic dose in murine hindlimb ischemia model, and distributing this VEGF dose in two spatial locations induces a higher level of vascularization and perfusion than a single location. These findings suggest that material systems capable of controlling and regulating the temporal and spatial presentation of VEGF maybe useful to achieve a robust and potent therapeutic angiogenic effect in vivo.},
	keywords = {Animals, Dose-Response Relationship, Drug, Drug Carriers, Female, Hindlimb, Ischemia, Mice, Mice, Knockout, Neovascularization, Physiologic, Treatment Outcome, Vascular Endothelial Growth Factor A},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2009.10.052},
	author = {Silva, Eduardo A and Mooney, David J}
}
@article {216856,
	title = {Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors},
	journal = {Proc Natl Acad Sci U S A},
	volume = {107},
	number = {8},
	year = {2010},
	month = {2010 Feb 23},
	pages = {3287-92},
	abstract = {Regenerative efforts typically focus on the delivery of single factors, but it is likely that multiple factors regulating distinct aspects of the regenerative process (e.g., vascularization and stem cell activation) can be used in parallel to affect regeneration of functional tissues. This possibility was addressed in the context of ischemic muscle injury, which typically leads to necrosis and loss of tissue and function. The role of sustained delivery, via injectable gel, of a combination of VEGF to promote angiogenesis and insulin-like growth factor-1 (IGF1) to directly promote muscle regeneration and the return of muscle function in ischemic rodent hindlimbs was investigated. Sustained VEGF delivery alone led to neoangiogenesis in ischemic limbs, with complete return of tissue perfusion to normal levels by 3 weeks, as well as protection from hypoxia and tissue necrosis, leading to an improvement in muscle contractility. Sustained IGF1 delivery alone was found to enhance muscle fiber regeneration and protected cells from apoptosis. However, the combined delivery of VEGF and IGF1 led to parallel angiogenesis, reinnervation, and myogenesis; as satellite cell activation and proliferation was stimulated, cells were protected from apoptosis, the inflammatory response was muted, and highly functional muscle tissue was formed. In contrast, bolus delivery of factors did not have any benefit in terms of neoangiogenesis and perfusion and had minimal effect on muscle regeneration. These results support the utility of simultaneously targeting distinct aspects of the regenerative process.},
	keywords = {Animals, Cell Proliferation, Female, Insulin-Like Growth Factor I, Ischemia, Mice, Mice, Inbred C57BL, Muscle Development, Muscle, Skeletal, Muscular Diseases, Myoblasts, Neovascularization, Physiologic, Regeneration, Vascular Endothelial Growth Factor A},
	issn = {1091-6490},
	doi = {10.1073/pnas.0903875106},
	author = {Borselli, Cristina and Storrie, Hannah and Benesch-Lee, Frank and Shvartsman, Dmitry and Cezar, Christine and Lichtman, Jeff W and Vandenburgh, Herman H and Mooney, David J}
}
@article {216846,
	title = {Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate},
	journal = {Nat Mater},
	volume = {9},
	number = {6},
	year = {2010},
	month = {2010 Jun},
	pages = {518-26},
	abstract = {Stem cells sense and respond to the mechanical properties of the extracellular matrix. However, both the extent to which extracellular-matrix mechanics affect stem-cell fate in three-dimensional microenvironments and the underlying biophysical mechanisms are unclear. We demonstrate that the commitment of mesenchymal stem-cell populations changes in response to the rigidity of three-dimensional microenvironments, with osteogenesis occurring predominantly at 11-30 kPa. In contrast to previous two-dimensional work, however, cell fate was not correlated with morphology. Instead, matrix stiffness regulated integrin binding as well as reorganization of adhesion ligands on the nanoscale, both of which were traction dependent and correlated with osteogenic commitment of mesenchymal stem-cell populations. These findings suggest that cells interpret changes in the physical properties of adhesion substrates as changes in adhesion-ligand presentation, and that cells themselves can be harnessed as tools to mechanically process materials into structures that feed back to manipulate their fate.},
	keywords = {Alginates, Animals, Biomechanical Phenomena, Biophysics, Cell Culture Techniques, Cell Transplantation, Extracellular Matrix, Humans, Hydrogels, Integrins, Mesenchymal Stromal Cells, Microscopy, Osteogenesis, Stem Cells},
	issn = {1476-1122},
	doi = {10.1038/nmat2732},
	author = {Huebsch, Nathaniel and Arany, Praveen R and Mao, Angelo S and Shvartsman, Dmitry and Ali, Omar A and Bencherif, Sidi A and Rivera-Feliciano, Jos{\'e} and Mooney, David J}
}
@article {216826,
	title = {Modulating Notch signaling to enhance neovascularization and reperfusion in diabetic mice},
	journal = {Biomaterials},
	volume = {31},
	number = {34},
	year = {2010},
	month = {2010 Dec},
	pages = {9048-56},
	abstract = {Diabetes can diminish the responsiveness to angiogenic factors (e.g., VEGF) important for wound healing and the treatment of ischemic diseases, and this study investigated the hypothesis that this effect can be reversed by altering Notch signaling. Aortic endothelial cells (ECs) isolated from diabetic mice demonstrated reduced sprouting capability in vitro, but adding a Notch inhibitor (DAPT) led to cell-density and VEGF-dose dependent enhancement of proliferation, migration and sprouting, in both 2-D and 3-D cultures, as compared to VEGF alone. The in vivo effects of VEGF and DAPT were tested in the ischemic hind limbs of diabetic mice. Combining VEGF and DAPT delivery resulted in increased blood vessel density (\~{}150\%) and improved tissue perfusion (\~{}160\%), as compared to VEGF alone. To examine if DAPT would interfere with vessel maturation, DAPT was also delivered with a combination of VEGF and platelet derived growth factor (PDGF). DAPT and PDGF did not interfere with the effects of the other, and highly functional and mature networks of vessels could be formed with appropriate delivery. In summary, modulating Notch signaling enhances neovascularization and perfusion recovery in diabetic mice suffering from ischemia, suggesting this approach could have utility for human diabetics.},
	keywords = {Animals, Aorta, Cell Movement, Cell Proliferation, Diabetes Mellitus, Experimental, Dipeptides, Endothelial Cells, Hindlimb, Ischemia, Mice, Neovascularization, Physiologic, Receptors, Notch, Reperfusion, Signal Transduction, Vascular Endothelial Growth Factor A},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2010.08.002},
	author = {Cao, Lan and Arany, Praveen R and Kim, Jaeyun and Rivera-Feliciano, Jos{\'e} and Wang, Yuan-Shuo and He, Zhiheng and Rask-Madsen, Christian and King, George L and Mooney, David J}
}
@article {216836,
	title = {Polycation structure mediates expression of lyophilized polycation/pDNA complexes},
	journal = {Macromol Biosci},
	volume = {10},
	number = {10},
	year = {2010},
	month = {2010 Oct 08},
	pages = {1210-5},
	abstract = {Lyophilization of polycation/pDNA complexes provides stable, long-term storage of complexes prior to clinical use but also reduces gene delivery efficiency. We examined whether polycation structure mediates effects of lyophilization on gene expression. Linear and branched PEI of the same molecular weight were used as a model system. Interestingly, pDNA/linear PEI complexes led to much smaller effects on gene expression following lyophilization compared with branched PEI complexes. The effect of polycation structure correlated with changes in dissociation ability of pDNA/PEI complexes. These results will be useful for developing new gene delivery vehicles.},
	keywords = {3T3 Cells, Animals, Cations, DNA, Freeze Drying, Gene Expression, Gene Transfer Techniques, Mice, Polyethyleneimine},
	issn = {1616-5195},
	doi = {10.1002/mabi.201000067},
	author = {Hahn, Lewis D and Kong, Hyunjoon and Mooney, David J}
}
@article {216811,
	title = {Mimicking nature by codelivery of stimulant and inhibitor to create temporally stable and spatially restricted angiogenic zones},
	journal = {Proc Natl Acad Sci U S A},
	volume = {107},
	number = {42},
	year = {2010},
	month = {2010 Oct 19},
	pages = {17933-8},
	abstract = {Nature frequently utilizes opposing factors to create a stable activator gradient to robustly control pattern formation. This study employs a biomimicry approach, by delivery of both angiogenic and antiangiogenic factors from spatially restricted zones of a synthetic polymer to achieve temporally stable and spatially restricted angiogenic zones in vivo. The simultaneous release of the two spatially separated agents leads to a spatially sharp angiogenic region that is sustained over 3 wk. Further, the contradictory action of the two agents leads to a stable level of proangiogenic stimulation in this region, in spite of significant variations in the individual release rates over time. The resulting spatially restrictive and temporally sustained profiles of active signaling allow the creation of a spatially heterogeneous and functional vasculature.},
	keywords = {Angiogenesis Inhibitors, Animals, Cells, Cultured, Endothelium, Vascular, Humans, Mice, Mice, SCID, Vascular Endothelial Growth Factor A},
	issn = {1091-6490},
	doi = {10.1073/pnas.1001192107},
	author = {Yuen, William W and Du, Nan R and Chan, Chun H and Silva, Eduardo A and Mooney, David J}
}
@article {1192311,
	title = {Bioactive cell-hydrogel microcapsules for cell-based drug delivery},
	journal = {J Control Release},
	volume = {135},
	number = {3},
	year = {2009},
	month = {2009 May 05},
	pages = {203-10},
	abstract = {Improvement of long-term drug release and design of mechanically more stable encapsulation devices are still major challenges in the field of cell encapsulation. This may be in part due to the weak in vivo stability of calcium-alginate beads and to the use of inactive biomaterials and inert scaffolds that do not mimic the physiological situation of the normal cell milieu. We hypothesized that designing biomimetic cell-hydrogel capsules might promote the in vivo long-term functionality of the enclosed drug-secreting cells and improve the mechanical stability of the capsules. Biomimetic capsules were fabricated by coupling the adhesion peptide arginine glycine aspartic acid (RGD) to alginate polymer chains and by using an alginate-mixture providing a bimodal molecular weight distribution. The biomimetic capsules provide cell adhesion for the enclosed cells, potentially also leading to mechanical stabilization of the cell-polymer system. Strikingly, the novel cell-hydrogel system significantly prolonged the in vivo long-term functionality and drug release, providing a sustained erythropoietin delivery during 300 days without immunosuppressive protocols. Additionally, controlling the cell-dose within the biomimetic capsules enables a controlled in vitro and in vivo drug delivery. Biomimetic cell-hydrogel capsules provide a unique microenvironment for the in vivo long-term de novo delivery of drugs from immobilized cells.},
	keywords = {Alginates, Animals, Biocompatible Materials, Biomimetics, Capsules, Cell Line, Drug Delivery Systems, Glucuronic Acid, Hydrogel, Mice, Mice, Inbred C3H, Molecular Weight, Myoblasts, Oligopeptides, Temperature, Time Factors, Tissue Scaffolds},
	issn = {1873-4995},
	doi = {10.1016/j.jconrel.2009.01.005},
	author = {Orive, Gorka and De Castro, Mar{\'\i}a and Kong, Hyun-Joon and Hern{\'a}ndez, Rosa M A and Ponce, Sara and Mooney, David J and Pedraz, Jos{\'e} Luis}
}
@article {1192316,
	title = {A biomimetic approach for the creation of two-dimensional microscale surface patterns: creation of isolated immunological synapses},
	journal = {Int J Biomater},
	volume = {2009},
	year = {2009},
	month = {2009},
	pages = {821308},
	abstract = {Current efforts in surface functionalization have not produced a robust technique capable of creating specific two-dimensional microscale geometrical arrays composed of multiple proteins. Such a capability is desirable for engineering substrates in sensing and cell patterning applications where at least two different protein functionalities in a specific configuration are required. Here we introduce a new approach for the creation of arrays of microscale geometries. We demonstrate our approach with a biomimetic structure inspired by the immunological synapse, a cell-cell interfacial structure characterized by two concentric rings of proteins: an outer adhesion protein structure and an inner recognition ligand core. The power of the technique lies in its ability to pattern any protein in any defined geometry as well as to create arrays in parallel.},
	issn = {1687-8795},
	doi = {10.1155/2009/821308},
	author = {Stern, Eric and Mooney, David J and Fahmy, Tarek M}
}
@article {1192306,
	title = {Growth factors, matrices, and forces combine and control stem cells},
	journal = {Science},
	volume = {324},
	number = {5935},
	year = {2009},
	month = {2009 Jun 26},
	pages = {1673-7},
	abstract = {Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.},
	keywords = {Animals, Cell Adhesion, Cell Differentiation, Cell Proliferation, Cell Survival, Extracellular Matrix, Fibrosis, Humans, Intercellular Signaling Peptides and Proteins, Stem Cell Niche, Stem Cell Transplantation, Stem Cells},
	issn = {1095-9203},
	doi = {10.1126/science.1171643},
	author = {Discher, Dennis E and Mooney, David J and Zandstra, Peter W}
}
@article {1192296,
	title = {Shear-reversibly crosslinked alginate hydrogels for tissue engineering},
	journal = {Macromol Biosci},
	volume = {9},
	number = {9},
	year = {2009},
	month = {2009 Sep 09},
	pages = {895-901},
	abstract = {Injectable delivery vehicles in tissue engineering are often required for successful tissue formation in a minimally invasive manner. Shear-reversibly crosslinked hydrogels, which can recover gel structures from shear-induced breakdown, can be useful as an injectable, because gels can flow as a liquid when injected but re-gel once placed in the body. In this study, injectable and shear-reversible alginate hydrogels were prepared by combination crosslinking using cell-crosslinking and ionic crosslinking techniques. The addition of a small quantity of calcium ions decreased the number of cells that were required to form cell-crosslinked hydrogels without changing the shear reversibility of the system. The physical properties and gelation behavior of the gels were dependent on the concentration of both the cells and the calcium ions. We found that gels crosslinked by combination crosslinking methods were effective to engineer cartilage tissues in vivo. Using both ionic and cell-crosslinking methods to control the gelation behavior may allow the design of novel injectable systems that can be used to deliver cells and other therapeutics for minimally invasive therapy, including tissue engineering.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cartilage, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Implants, Experimental, Materials Testing, Mice, Peptides, Rabbits, Regeneration, Shear Strength, Tissue Engineering, Tissue Scaffolds},
	issn = {1616-5195},
	doi = {10.1002/mabi.200800376},
	author = {Park, Honghyun and Kang, Sun-Woong and Kim, Byung-Soo and Mooney, David J and Lee, Kuen Yong}
}
@article {1192301,
	title = {Spatiotemporal control over molecular delivery and cellular encapsulation from electropolymerized micro- and nanopatterned surfaces},
	journal = {Adv Funct Mater},
	volume = {19},
	number = {18},
	year = {2009},
	month = {2009 Jul 13},
	pages = {2888-2895},
	abstract = {Bioactive, patterned micro- and nanoscale surfaces that can be spatially engineered for three-dimensional ligand presentation and sustained release of signaling molecules represent a critical advance for the development of next-generation diagnostic and therapeutic devices. Lithography is ideally suited to patterning such surfaces due to its precise, easily scalable, high-throughput nature; however, to date polymers patterned by these techniques have not demonstrated the capacity for sustained release of bioactive agents. We demonstrate here a class of lithographically-defined, electropolymerized polymers with monodisperse micro- and nanopatterned features capable of sustained release of bioactive drugs and proteins. We show that precise control can be achieved over the loading capacity and release rates of encapsulated agents and illustrate this aspect using a fabricated surface releasing a model antigen (ovalbumin) and a cytokine (interleukin-2) for induction of a specific immune response. We further demonstrate the ability of this technique to enable three-dimensional control over cellular encapsulation. The efficacy of the described approach is buttressed by its simplicity, versatility, and reproducibility, rendering it ideally suited for biomaterials engineering.},
	issn = {1616-301X},
	doi = {10.1002/adfm.200900307},
	author = {Stern, Eric and Jay, Steven M and Demento, Stacey L and Murelli, Ryan P and Reed, Mark A and Malinski, Tadeusz and Spiegel, David A and Mooney, David J and Fahmy, Tarek M}
}
@article {216891,
	title = {Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement},
	journal = {Proc Natl Acad Sci U S A},
	volume = {106},
	number = {2},
	year = {2009},
	month = {2009 Jan 13},
	pages = {399-404},
	abstract = {Three-dimensional culture alters cancer cell signaling; however, the underlying mechanisms and importance of these changes on tumor vascularization remain unclear. A hydrogel system was used to examine the role of the transition from 2D to 3D culture, with and without integrin engagement, on cancer cell angiogenic capability. Three-dimensional culture recreated tumor microenvironmental cues and led to enhanced interleukin 8 (IL-8) secretion that depended on integrin engagement with adhesion peptides coupled to the polymer. In contrast, vascular endothelial growth factor (VEGF) secretion was unaffected by 3D culture with or without substrate adhesion. IL-8 diffused greater distances and was present in higher concentrations in the systemic circulation, relative to VEGF. Implantation of a polymeric IL-8 delivery system into GFP bone marrow-transplanted mice revealed that localized IL-8 up-regulation was critical to both the local and systemic control of tumor vascularization in vivo. In summary, 3D integrin engagement within tumor microenvironments regulates cancer cell angiogenic signaling, and controlled local and systemic blockade of both IL-8 and VEGF signaling may improve antiangiogenic therapies.},
	keywords = {Animals, Bone Marrow Transplantation, Cell Culture Techniques, Diffusion, Humans, Hydrogels, Integrins, Interleukin-8, Mice, Models, Biological, Neoplasms, Neovascularization, Pathologic, Signal Transduction, Vascular Endothelial Growth Factor A},
	issn = {1091-6490},
	doi = {10.1073/pnas.0808932106},
	author = {Fischbach, Claudia and Kong, Hyunjoon and Hsiong, Susan X and Evangelista, Marta B and Yuen, Will and Mooney, David J}
}
@article {216896,
	title = {Cellular strain assessment tool (CSAT): precision-controlled cyclic uniaxial tensile loading},
	journal = {J Biomech},
	volume = {42},
	number = {2},
	year = {2009},
	month = {2009 Jan 19},
	pages = {178-82},
	abstract = {The development of a multi-sample strain device and elastomeric culture wells designed to systematically assess strain effects on cell cultures is presented in this report. This device enables one to precisely conduct experimental analyses in sterile conditions while delivering cyclic uniaxial tensile strain. The input to the computer interface allows one to alter variables of frequency, duration, and amplitude of strain. The influence of strain on the migration of human umbilical vein endothelial cell (HUVEC) cultured on 2D polydimethylsiloxane (PDMS) surfaces was examined to verify the utility of this system.},
	keywords = {Cell Culture Techniques, Cell Movement, Cells, Cultured, Endothelial Cells, Humans, Sensitivity and Specificity, Stress, Mechanical, Stress, Physiological, Surface Properties, Umbilical Veins},
	issn = {0021-9290},
	doi = {10.1016/j.jbiomech.2008.10.038},
	author = {Yung, Yu Ching and Vandenburgh, Herman and Mooney, David J}
}
@article {216911,
	title = {Cyclic arginine-glycine-aspartate peptides enhance three-dimensional stem cell osteogenic differentiation},
	journal = {Tissue Eng Part A},
	volume = {15},
	number = {2},
	year = {2009},
	month = {2009 Feb},
	pages = {263-72},
	abstract = {The role of morphogens in bone regeneration has been widely studied, whereas the effect of matrix cues, particularly on stem cell differentiation, are less well understood. In this work, we investigated the effects of arginine-glycine-aspartate (RGD) ligand conformation (linear vs cyclic RGD) on primary human bone marrow stromal cell (hBMSC) and D1 stem cell osteogenic differentiation in three-dimensional (3D) culture and compared their response with that of committed MC3T3-E1 preosteoblasts to determine whether the stage of cell differentiation altered the response to the adhesion ligands. Linear RGD densities that promoted osteogenic differentiation of committed cells (MC3T3-E1 preosteoblasts) did not induce differentiation of hBMSCs or D1 stem cells, although matrices presenting the cyclic form of this adhesion ligand enhanced osteoprogenitor differentiation in 3D culture. This may be due to enhanced integrin-ligand binding. These studies indicate that biomaterial design parameters optimized for differentiated cell types may not directly translate to stem cell populations, because less-committed cells may require more instruction than differentiated cells. It is likely that design of synthetic extracellular matrices tailored to promote stem cell differentiation may enhance bone regeneration by transplanted cells.},
	keywords = {Animals, Bone Marrow Cells, Cell Differentiation, Cell Proliferation, Humans, Mice, Multipotent Stem Cells, Osteogenesis, Peptides, Cyclic, Stem Cells, Stromal Cells, Tissue Culture Techniques},
	issn = {1937-3341},
	doi = {10.1089/ten.tea.2007.0411},
	author = {Hsiong, Susan X and Boontheekul, Tanyarut and Huebsch, Nathaniel and Mooney, David J}
}
@article {216876,
	title = {Cyclic tensile strain triggers a sequence of autocrine and paracrine signaling to regulate angiogenic sprouting in human vascular cells},
	journal = {Proc Natl Acad Sci U S A},
	volume = {106},
	number = {36},
	year = {2009},
	month = {2009 Sep 08},
	pages = {15279-84},
	abstract = {Mechanical signals regulate blood vessel development in vivo, and have been demonstrated to regulate signal transduction of endothelial cell (EC) and smooth muscle cell (SMC) phenotype in vitro. However, it is unclear how the complex process of angiogenesis, which involves multiple cell types and growth factors that act in a spatiotemporally regulated manner, is triggered by a mechanical input. Here, we describe a mechanism for modulating vascular cells during sequential stages of an in vitro model of early angiogenesis by applying cyclic tensile strain. Cyclic strain of human umbilical vein (HUV)ECs up-regulated the secretion of angiopoietin (Ang)-2 and PDGF-betabeta, and enhanced endothelial migration and sprout formation, whereas effects were eliminated with shRNA knockdown of endogenous Ang-2. Applying strain to colonies of HUVEC, cocultured on the same micropatterned substrate with nonstrained human aortic (HA)SMCs, led to a directed migration of the HASMC toward migrating HUVECs, with diminished recruitment when PDGF receptors were neutralized. These results demonstrate that a singular mechanical cue (cyclic tensile strain) can trigger a cascade of autocrine and paracrine signaling events between ECs and SMCs critical to the angiogenic process.},
	keywords = {Autocrine Communication, Biomechanical Phenomena, Cells, Cultured, Endothelial Cells, Humans, Myocytes, Smooth Muscle, Neovascularization, Physiologic, Paracrine Communication, Stress, Mechanical, Umbilical Veins},
	issn = {1091-6490},
	doi = {10.1073/pnas.0905891106},
	author = {Yung, Yu Ching and Chae, Jeiwook and Buehler, Markus J and Hunter, Craig P and Mooney, David J}
}
@article {216886,
	title = {Infection-mimicking materials to program dendritic cells in situ},
	journal = {Nat Mater},
	volume = {8},
	number = {2},
	year = {2009},
	month = {2009 Feb},
	pages = {151-8},
	abstract = {Cancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We propose that materials mimicking key aspects of bacterial infection may instead be used to directly control immune-cell trafficking and activation in the body. It is demonstrated that polymers can be designed to first release a cytokine to recruit and house host dendritic cells, and subsequently present cancer antigens and danger signals to activate the resident dendritic cells and markedly enhance their homing to lymph nodes. Specific and protective anti-tumour immunity was generated with these materials, as 90\% survival was achieved in animals that otherwise die from cancer within 25 days. These materials show promise as cancer vaccines, and more broadly suggest that polymers may be designed to program and control the trafficking of a variety of cell types in the body.},
	keywords = {Animals, Antibody Specificity, Bacterial Infections, Cancer Vaccines, Cell Line, Tumor, Dendritic Cells, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Lymph Nodes, Male, Mice, Mice, Inbred C57BL, Neoplasms},
	issn = {1476-1122},
	doi = {10.1038/nmat2357},
	author = {Ali, Omar A and Huebsch, Nathaniel and Cao, Lan and Dranoff, Glenn and Mooney, David J}
}
@article {216881,
	title = {Promoting angiogenesis via manipulation of VEGF responsiveness with notch signaling},
	journal = {Biomaterials},
	volume = {30},
	number = {25},
	year = {2009},
	month = {2009 Sep},
	pages = {4085-93},
	abstract = {Promoting angiogenesis via delivery of vascular endothelial growth factor (VEGF) and other angiogenic factors is both a potential therapy for cardiovascular diseases and a critical aspect for tissue regeneration. The recent demonstration that VEGF signaling is modulated by the Notch signaling pathway, however, suggests that inhibiting Notch signaling may enhance regional neovascularization, by altering the responsiveness of local endothelial cells to angiogenic stimuli. We tested this possibility with in vitro assays using human endothelial cells, as well as in a rodent hindlimb ischemia model. Treatment of cultured human endothelial cells with DAPT, a gamma secretase inhibitor, increased cell migration and sprout formation in response to VEGF stimulation with a biphasic dependence on DAPT concentration. Further, delivery of an appropriate combination of DAPT and VEGF from an injectable alginate hydrogel system into ischemic hindlimbs led to a faster recovery of blood flow than VEGF or DAPT alone; perfusion levels reached 80\% of the normal level by week 4 with combined DAPT and VEGF delivery. Direct intramuscular or intraperitoneal injection of DAPT did not result in the same level of improvement, suggesting that appropriate presentation of DAPT (gel delivery) is important for its activity. DAPT delivery from the hydrogels also did not lead to any adverse side effects, in contrast to systemic introduction of DAPT. Altogether, these results suggest a new approach to promote angiogenesis by controlling Notch signaling, and may provide new options to treat patients with diseases that diminish angiogenic responsiveness.},
	keywords = {Alginates, Animals, Cells, Cultured, Dipeptides, Endothelial Cells, Endothelium, Vascular, Hindlimb, Humans, Hydrogels, Ischemia, Mice, Neovascularization, Physiologic, Receptors, Notch, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Vinculin},
	issn = {1878-5905},
	doi = {10.1016/j.biomaterials.2009.04.051},
	author = {Cao, Lan and Arany, Praveen R and Wang, Yuan-Shuo and Mooney, David J}
}
@article {216851,
	title = {In situ regulation of DC subsets and T cells mediates tumor regression in mice},
	journal = {Sci Transl Med},
	volume = {1},
	number = {8},
	year = {2009},
	month = {2009 Nov 25},
	pages = {8ra19},
	abstract = {Vaccines are largely ineffective for patients with established cancer, as advanced disease requires potent and sustained activation of CD8(+) cytotoxic T lymphocytes (CTLs) to kill tumor cells and clear the disease. Recent studies have found that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in the production of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector T cell responses. Here, we addressed the hypothesis that coordinated regulation of a DC network, and plasmacytoid DCs (pDCs) and CD8(+) DCs in particular, could enhance host immunity in mice. We used functionalized biomaterials incorporating various combinations of an inflammatory cytokine, immune danger signal, and tumor lysates to control the activation and localization of host DC populations in situ. The numbers of pDCs and CD8(+) DCs, and the endogenous production of interleukin-12, all correlated strongly with the magnitude of protective antitumor immunity and the generation of potent CD8(+) CTLs. Vaccination by this method maintained local and systemic CTL responses for extended periods while inhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant and established melanoma tumors. The efficacy of this vaccine as a monotherapy against large invasive tumors may be a result of the local activity of pDCs and CD8(+) DCs induced by persistent danger and antigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlates with the evolution of therapeutic antitumor responses and provide a template for future vaccine design.},
	keywords = {Animals, Cancer Vaccines, CpG Islands, Dendritic Cells, Granulocyte-Macrophage Colony-Stimulating Factor, Interferons, Interleukin-12, Mice, Neoplasms, Experimental, T-Lymphocytes, Cytotoxic},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.3000359},
	author = {Ali, Omar A and Emerich, Dwaine and Dranoff, Glenn and Mooney, David J}
}
@article {216861,
	title = {Inspiration and application in the evolution of biomaterials},
	journal = {Nature},
	volume = {462},
	number = {7272},
	year = {2009},
	month = {2009 Nov 26},
	pages = {426-32},
	abstract = {Biomaterials, traditionally defined as materials used in medical devices, have been used since antiquity, but recently their degree of sophistication has increased significantly. Biomaterials made today are routinely information rich and incorporate biologically active components derived from nature. In the future, biomaterials will assume an even greater role in medicine and will find use in a wide variety of non-medical applications through biologically inspired design and incorporation of dynamic behaviour.},
	keywords = {Animals, Biocompatible Materials, Biomedical Engineering, Biomedical Research, Biomimetic Materials, Equipment Design, History, 20th Century, History, 21st Century, History, Ancient, Humans, Prostheses and Implants},
	issn = {1476-4687},
	doi = {10.1038/nature08601},
	author = {Huebsch, Nathaniel and Mooney, David J}
}
@article {216816,
	title = {Controlled growth factor delivery for tissue engineering},
	journal = {Adv Mater},
	volume = {21},
	number = {32-33},
	year = {2009},
	month = {2009 Sep 04},
	pages = {3269-85},
	abstract = {Growth factors play a crucial role in information transfer between cells and their microenvironment in tissue engineering and regeneration. They initiate their action by binding to specific receptors on the surface of target cells and the chemical identity, concentration, duration, and context of these growth factors contain information that dictates cell fate. Hence, the importance of exogenous delivery of these molecules in tissue engineering is unsurprising, considering their importance for tissue regeneration. However, the short half-lives of growth factors, their relatively large size, slow tissue penetration, and their potential toxicity at high systemic levels, suggest that conventional routes of administration are unlikely to be effective. In this review, we provide an overview of the design criteria for growth factor delivery vehicles with respect to the growth factor itself and the microenvironment for delivery. We discuss various methodologies that could be adopted to achieve this localized delivery, and strategies using polymers as delivery vehicles in particular.},
	issn = {1521-4095},
	doi = {10.1002/adma.200900241},
	author = {Tayalia, Prakriti and Mooney, David J}
}
@article {1192326,
	title = {Biochemical and functional abnormalities of left and right ventricular function after ultra-endurance exercise},
	journal = {Heart},
	volume = {94},
	number = {7},
	year = {2008},
	month = {2008 Jul},
	pages = {860-6},
	abstract = {BACKGROUND: There is evidence that ultra-endurance exercise causes myocardial injury. The extent and duration of these changes remains unresolved. Recent reports have speculated that structural adaptations to exercise, particularly of the right ventricle, may predispose to tachyarrhythmias and sudden cardiac death.

OBJECTIVE: To quantify the extent and duration of post-exercise cardiac injury with particular attention to right ventricular (RV) dysfunction.

METHODS: 27 athletes (20 male, 7 female) were tested 1 week before, immediately after and 1 week after an ultra-endurance triathlon. Tests included cardiac troponin I (cTnI), B-type natriuretic peptide (BNP) and comprehensive echocardiographic assessment.

RESULTS: 26 athletes completed the race and testing procedures. Post-race, cTnI was raised in 15 athletes (58\%) and the mean value for the entire cohort increased (0.17 vs 0.49 microg/l, p,
	keywords = {Adult, Biomarkers, Echocardiography, Doppler, Color, Exercise, Female, Humans, Male, Middle Aged, Natriuretic Peptide, Brain, Physical Endurance, Troponin I, Ventricular Dysfunction, Left, Ventricular Dysfunction, Right},
	issn = {1468-201X},
	doi = {10.1136/hrt.2006.101063},
	author = {La Gerche, A and Connelly, K A and Mooney, D J and MacIsaac, A I and Prior, D L}
}
@article {1192321,
	title = {Improved bone healing by angiogenic factor-enriched platelet-rich plasma and its synergistic enhancement by bone morphogenetic protein-2},
	journal = {Int J Oral Maxillofac Implants},
	volume = {23},
	number = {5},
	year = {2008},
	month = {2008 Sep-Oct},
	pages = {818-26},
	abstract = {PURPOSE: The purpose of this study was to modify the method of platelet-rich plasma (PRP) preparation for obtaining optimal angiogenic potential and accelerate bone healing. Also, the potential synergistic effect of a suboptimal concentration of bone morphogenic protein-2 (BMP-2) and modified PRP (mPRP) on bone healing was evaluated in vivo.

MATERIALS AND METHODS: The angiogenic factor-enriched PRP, which included peripheral blood mononuclear cells (mostly lymphocytes and monocytes, excluding polymorphonuclear leukocytes [PMNs], was achieved by lowering concentrations of thrombin and CaCl2, after pre-activation with shear stress using a table-top vortex machine and collagen. In vitro, endothelial cell migration activity in the mPRP group was compared to conventional PRP preparation using a modified Boyden chamber assay. In an animal study, PGA scaffold, PGA scaffold + mPRP, PGA scaffold + mPRP + rhBMP-2, and PGA scaffold + rhBMP-2 were applied to critical-sized calvarial defects in 28 nude rats. At 2 weeks, periosteal blood flow was measured using laser Doppler perfusion imaging, and bone formation was evaluated at 8 weeks by histology, dual energy x-ray absorptiometry, and micro-computed tomography.

RESULTS: mPRP induced faster migration of cord blood-derived outgrowth endothelial-like cells. In vivo, the group with mPRP with a low dose of rhBMP-2 showed significantly increased numbers of blood vessels at 2 weeks and notable synergistic effect on bone healing at 8 weeks as evaluated with histology, bone mineral density and bone mineral content, and muCT.

CONCLUSION: The mPRP used in this study improved vascular perfusion around the defect and resulted in enhanced bone healing. Also, combining mPRP with a suboptimal dosage of rhBMP-2 improved bone formation and enhanced bone density.},
	keywords = {Animals, Bone Morphogenetic Protein 2, Bone Regeneration, Centrifugation, Laser-Doppler Flowmetry, Lymphocytes, Monocytes, Neovascularization, Physiologic, Platelet-Rich Plasma, Rats, Rats, Nude, Recombinant Proteins, Skull, Tissue Scaffolds, Vascular Endothelial Growth Factor A},
	issn = {0882-2786},
	author = {Park, Eun-Jin and Kim, Eun-Seok and Weber, Hans-Peter and Wright, Robert F and Mooney, David J}
}
@article {1192336,
	title = {Quantifying interactions between cell receptors and adhesion ligand-modified polymers in solution},
	journal = {Macromol Biosci},
	volume = {8},
	number = {2},
	year = {2008},
	month = {2008 Feb 11},
	pages = {140-5},
	abstract = {Specific interactions between cells and cell-interactive polymers in solution were investigated by the fluorescence resonance energy transfer (FRET) technique and rheological measurements. The green fluorescence emission was dramatically reduced when rhodamine-stained cells were mixed with a fluorescein-labeled RGD-alginate solution, compared with those mixed with no RGD-containing alginate solution, which indicated an occurrence of FRET and existence of specific interactions between the cells and the polymers in solution. Rheological measurements also confirmed the formation of ordered structures of cell/polymer mixtures, caused by specific cell-polymer interactions. The FRET method was able to provide a useful means of investigating cell-polymer interactions, both in a qualitative and quantitative manner, and this approach to monitoring and controlling specific interactions between cells and polymers could be useful in the design and tailoring of polymeric carriers for cells, as well as for biological drugs, especially for tissue engineering applications.},
	keywords = {Alginates, Animals, Cell Adhesion, Cells, Cultured, Fluorescence Resonance Energy Transfer, Glucuronic Acid, Hexuronic Acids, Mice, Oligopeptides, Polymers, Rheology, Rhodamines, Tissue Engineering},
	issn = {1616-5195},
	doi = {10.1002/mabi.200700169},
	author = {Lee, Kuen Yong and Kong, Hyunjoon and Mooney, David J}
}
@article {1192331,
	title = {Synthetic extracellular matrices for tissue engineering},
	journal = {Pharm Res},
	volume = {25},
	number = {5},
	year = {2008},
	month = {2008 May},
	pages = {1209-11},
	keywords = {Biocompatible Materials, Blood Vessel Prosthesis, Cells, Cultured, Extracellular Matrix, Industry, Tissue Engineering, Tissue Scaffolds},
	issn = {0724-8741},
	doi = {10.1007/s11095-008-9541-3},
	author = {Leach, J Kent and Mooney, David J}
}
@article {216981,
	title = {Differentiation stage alters matrix control of stem cells},
	journal = {J Biomed Mater Res A},
	volume = {85},
	number = {1},
	year = {2008},
	month = {2008 Apr},
	pages = {145-56},
	abstract = {Cues from the material to which a cell is adherent (e.g., adhesion ligand presentation, substrate elastic modulus) clearly influence the phenotype of differentiated cells. However, it is currently unclear if stem cells respond similarly to these cues. This study examined how the overall density and nanoscale organization of a model cell adhesion ligand (arginine-glycine-aspartic acid [RGD] containing peptide) presented from hydrogels of varying stiffness regulated the proliferation of a clonally derived stem cell line (D1 cells) and preosteoblasts (MC3T3-E1). While the growth rate of MC3T3-E1 preosteoblasts was responsive to nanoscale RGD ligand organization and substrate stiffness, the D1 stem cells were less sensitive to these cues in their uncommitted state. However, once the D1 cells were differentiated towards the osteoblast lineage, they became more responsive to these signals. These results demonstrate that the cell response to material cues is dependent on the stage of cell commitment or differentiation, and these findings will likely impact the design of biomaterials for tissue regeneration.},
	keywords = {3T3 Cells, Animals, Cell Adhesion, Cell Differentiation, Cell Proliferation, Clone Cells, Extracellular Matrix, Hydrogels, Mice, Oligopeptides, Osteoblasts, Stem Cells},
	issn = {1552-4965},
	doi = {10.1002/jbm.a.31521},
	author = {Hsiong, Susan X and Carampin, Paolo and Kong, Hyun-Joon and Lee, Kuen-Yong and Mooney, David J}
}
@article {216936,
	title = {AFM imaging of RGD presenting synthetic extracellular matrix using gold nanoparticles},
	journal = {Macromol Biosci},
	volume = {8},
	number = {6},
	year = {2008},
	month = {2008 Jun 11},
	pages = {469-77},
	abstract = {Several high-resolution imaging techniques such as FESEM, TEM and AFM are compared with respect to their application on alginate hydrogels, a widely used polysaccharide biomaterial. A new AFM method applicable to RGD peptides covalently conjugated to alginate hydrogels is described. High-resolution images of RGD adhesion ligand distribution were obtained by labeling biotinylated RGD peptides with streptavidin-labeled gold nanoparticles. This method may broadly provide a useful tool for sECM characterization and design for tissue regeneration strategies.},
	keywords = {Alginates, Biocompatible Materials, Biotin, Extracellular Matrix, Gold, Hydrogels, Metal Nanoparticles, Microscopy, Atomic Force, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Oligopeptides, Streptavidin, Tissue Scaffolds},
	issn = {1616-5195},
	doi = {10.1002/mabi.200700313},
	author = {Hsiong, Susan X and Cooke, Peter H and Kong, Hyun-Joon and Fishman, Marshall L and Ericsson, Maria and Mooney, David J}
}
@article {216941,
	title = {Cell delivery mechanisms for tissue repair},
	journal = {Cell Stem Cell},
	volume = {2},
	number = {3},
	year = {2008},
	month = {2008 Mar 06},
	pages = {205-13},
	abstract = {Many cell populations, derived from both adult tissues and embryonic stem cells, show promise for the treatment of a variety of diseases. Although the major effort in stem cell therapies in the past has been identifying potentially therapeutic cells, it is now clear that developing systems to deliver these cells and promote their efficient engraftment will provide an equally challenging task. More sophisticated pretransplantation manipulations and material carriers may dramatically improve the survival, engraftment, and fate control of transplanted stem cells and their ultimate clinical utility.},
	keywords = {Adult Stem Cells, Animals, Embryonic Stem Cells, Graft Survival, Humans, Stem Cell Transplantation},
	issn = {1875-9777},
	doi = {10.1016/j.stem.2008.02.005},
	author = {Mooney, David J and Vandenburgh, Herman}
}
@article {216951,
	title = {Design of biodegradable hydrogel for the local and sustained delivery of angiogenic plasmid DNA},
	journal = {Pharm Res},
	volume = {25},
	number = {5},
	year = {2008},
	month = {2008 May},
	pages = {1230-8},
	abstract = {PURPOSE: To attain the effective local and sustained delivery of plasmid DNA (pDNA) encoding for a growth factor.

METHODS: We hypothesized that controlling the degradation rate of biomaterials encapsulating pDNA via concurrent physical dissociation of the cross-linked structure and hydrolytic chain breakage of polymers would allow one to significantly broaden the range of pDNA release rate. This hypothesis was examined using ionically cross-linked polysaccharide hydrogels which were previously designed to rapidly degrade via engineering of ionic cross-linking junction and partial oxidation of polysaccharide chains.

RESULTS: The hydrogel degradation rates were varied over the broad range, and pDNA release correlated with the gel degradation rate. Degradable hydrogels were used for the local and sustained delivery of a pDNA encoding for vascular endothelial growth factor (VEGF) in the ischemic hindlimbs of mice, and local pDNA release significantly improved the recovery of blood perfusion as compared with a bolus injection of VEGFencoding pDNA.

CONCLUSION: This strategy to control the hydrogel degradation rate may be useful in regulating the delivery of a broad array of macromolecular drugs, and subsequently improve their therapeutic efficacy.},
	keywords = {Alginates, Algorithms, Animals, Cross-Linking Reagents, Delayed-Action Preparations, DNA, Gene Expression, Mice, Mice, Inbred NOD, Molecular Weight, Neovascularization, Physiologic, Plasmids, Vascular Endothelial Growth Factor A},
	issn = {0724-8741},
	doi = {10.1007/s11095-007-9526-7},
	author = {Kong, Hyunjoon and Kim, Eun Seok and Huang, Yen-Chen and Mooney, David J}
}
@article {216931,
	title = {The effect of sustained delivery of vascular endothelial growth factor on angiogenesis in tissue-engineered intestine},
	journal = {Biomaterials},
	volume = {29},
	number = {19},
	year = {2008},
	month = {2008 Jul},
	pages = {2884-90},
	abstract = {Our group has previously created a functional neointestine that is capable of restoring absorptive function. However, the endogenous level of vascular endothelial growth factor (VEGF) is markedly reduced in the construct compared to native bowel. Therefore, we wanted to locally deliver VEGF in a sustained fashion to upregulate angiogenesis in the neointestine. Rat recombinant VEGF was encapsulated in poly(lactide-co-glycolide) microspheres by a double emulsion method. Release kinetics and bioactivity were determined in vitro. Tissue-engineered intestine was generated by seeding donor neonatal rat intestinal organoid units onto a biodegradable polyglycolic acid scaffold along with VEGF-containing or empty microspheres, and wrapped in the omentum of recipient rats. After 4 weeks, the neointestinal cysts were analyzed for morphometry, VEGF levels, epithelial proliferation, and capillary density. Sustained release of biologically active VEGF was confirmed by in vitro studies. Intestinal constructs with VEGF microspheres were significantly larger than those containing empty microspheres. Tissue VEGF levels were significantly higher in neointestine loaded with encapsulated VEGF compared to those without growth factor. Epithelial cellular proliferation and capillary density were significantly increased in the VEGF-containing neointestinal constructs compared to empty constructs. Tissue-engineered intestine responds to sustained delivery of VEGF by upregulating microvasculature and epithelial proliferation.},
	keywords = {Animals, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Intestines, Neovascularization, Physiologic, Rats, Rats, Inbred Lew, Tissue Engineering, Vascular Endothelial Growth Factor A},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2008.03.026},
	author = {Rocha, Flavio G and Sundback, Cathryn A and Krebs, Nicholas J and Leach, J Kent and Mooney, David J and Ashley, Stanley W and Vacanti, Joseph P and Whang, Edward E}
}
@article {216921,
	title = {Integrin-adhesion ligand bond formation of preosteoblasts and stem cells in three-dimensional RGD presenting matrices},
	journal = {Biomacromolecules},
	volume = {9},
	number = {7},
	year = {2008},
	month = {2008 Jul},
	pages = {1843-51},
	abstract = {Cell-interactive polymers have been widely used as synthetic extracellular matrices to regulate cell function and promote tissue regeneration. However, there is a lack of quantitative understanding of the cell-material interface. In this study, integrin-adhesion ligand bond formation of preosteoblasts and D1 stem cells with RGD presenting alginate matrices were examined using FRET and flow cytometry. Bond number increased with adhesion ligand density but did not change with RGD island spacing for both cell types. Integrin expression varied with cell type and substrate in 2D culture, but the integrin expression profiles of both cell types were similar when cultured in 3D RGD presenting substrates and distinct from 2D culture. In summary, combining a FRET technique to quantify bond formation with flow cytometry to elucidate integrin expression can define specific cell-material interactions for a given material system and may be useful for informing biomaterial design strategies for cell-based therapies.},
	keywords = {3T3 Cells, Alginates, Animals, Bone and Bones, Integrins, Ligands, Mice, Oligopeptides, Osteoblasts, Protein Binding, Stem Cells, Tissue Engineering},
	issn = {1526-4602},
	doi = {10.1021/bm8000606},
	author = {Hsiong, Susan X and Huebsch, Nathaniel and Fischbach, Claudia and Kong, Hyunjoon and Mooney, David J}
}
@article {216926,
	title = {New materials for tissue engineering: towards greater control over the biological response},
	journal = {Trends Biotechnol},
	volume = {26},
	number = {7},
	year = {2008},
	month = {2008 Jul},
	pages = {382-92},
	abstract = {One goal of tissue engineering is to replace lost or compromised tissue function, and an approach to this is to control the interplay between materials (scaffolds), cells and growth factors to create environments that promote the regeneration of functional tissues and organs. An increased understanding of the chemical signals that direct cell differentiation, migration and proliferation, advances in scaffold design and peptide engineering that allow this signaling to be recapitulated and the development of new materials, such as DNA-based and stimuli-sensitive polymers, have recently given engineers enhanced control over the chemical properties of a material and cell fate. Additionally, the immune system, which is often overlooked, has been shown to play a beneficial role in tissue repair, and future endeavors in material design will potentially expand to include immunomodulation.},
	keywords = {Animals, Dendritic Cells, DNA, Electric Conductivity, Extracellular Matrix, Humans, Immunity, Inflammation, Oligopeptides, Polymers, Tissue Engineering},
	issn = {0167-7799},
	doi = {10.1016/j.tibtech.2008.03.011},
	author = {Chan, Gail and Mooney, David J}
}
@article {216906,
	title = {Material-based deployment enhances efficacy of endothelial progenitor cells},
	journal = {Proc Natl Acad Sci U S A},
	volume = {105},
	number = {38},
	year = {2008},
	month = {2008 Sep 23},
	pages = {14347-52},
	abstract = {Cell-based therapies are attractive for revascularizing and regenerating tissues and organs, but clinical trials of endothelial progenitor cell transplantation have not resulted in consistent benefit. We propose a different approach in which a material delivery system is used to create a depot of vascular progenitor cells in vivo that exit over time to repopulate the damaged tissue and participate in regeneration of a vascular network. Microenvironmental conditions sufficient to maintain the viability and outward migration of outgrowth endothelial cells (OECs) have been delineated, and a material incorporating these signals improved engraftment of transplanted cells in ischemic murine hindlimb musculature, and increased blood vessel densities from 260 to 670 vessels per mm(2), compared with direct cell injection. Further, material deployment dramatically improved the efficacy of these cells in salvaging ischemic murine limbs, whereas bolus OEC delivery was ineffective in preventing toe necrosis and foot loss. Finally, material deployment of a combination of OECs with another cell population commonly isolated from peripheral or cord blood, endothelial progenitor cells (EPCs) returned perfusion to normal levels in 40 days, and prevented toe and foot necrosis. Direct injection of an EPC/OEC combination was minimally effective in improving limb perfusion, and untreated limbs underwent autoamputation in 3 days. These results demonstrate that vascular progenitor cell utility is highly dependent on the mode of delivery, and suggest that one can create new vascular beds for a variety of applications with this material-controlled deployment of cells.},
	keywords = {Animals, Cell Movement, Cell Proliferation, Cord Blood Stem Cell Transplantation, Endothelial Cells, Hindlimb, Humans, Ischemia, Mice, Mice, SCID, Neovascularization, Physiologic, Stem Cells, Tissue Scaffolds},
	issn = {1091-6490},
	doi = {10.1073/pnas.0803873105},
	author = {Silva, Eduardo A and Kim, Eun-Suk and Kong, Hyunjoon and Mooney, David J}
}
@article {216901,
	title = {Quantifying the relation between bond number and myoblast proliferation},
	journal = {Faraday Discuss},
	volume = {139},
	year = {2008},
	month = {2008},
	pages = {53-70; discussion 105-28, 419-20},
	abstract = {Many functions of the extracellular matrix can be mimicked by small peptide fragments (e.g., arginine-glycine-aspartic acid (RGD) sequence) of the entire molecule, but the presentation of the peptides is critical to their effects on cells. It is likely that some effects of peptide presentation from biomaterials simply relate to the number of bonds formed between cell receptors and the adhesion ligands, but a lack of tools to quantify bond number limits direct investigation of this assumption. The impact of different ligand presentations (density, affinity, and nanoscale distribution) on the proliferation of C2C12 and human primary myoblasts was first examined in this study. Increasing the ligand density or binding affinity led to a similar enhancement in proliferation of C2C12 cells and human primary myoblasts. The nanoscale distribution of clustered RGD ligands also influenced C2C12 cells and human primary myoblast proliferation, but in an opposing manner. A theological technique and a FRET technique were then utilized to quantify the number of receptor-ligand interactions as a function of peptide presentation. Higher numbers of bonds were formed when the RGD density and affinity were increased, as measured with both techniques, and bond number correlated with cell growth rates. However, the influence of the nanoscale peptide distribution did not appear to be solely a function of bond number. Altogether, these findings provide significant insight to the role of peptide presentation in the regulation of cell proliferation, and the approaches developed in this work may have significant utility in probing how adhesion regulates a variety of other cellular functions and aid in developing design criterion for cell-interactive materials.},
	keywords = {Animals, Cell Adhesion, Cell Proliferation, Fluorescence Resonance Energy Transfer, Humans, Mice, Myoblasts, Oligopeptides, Phenotype, Receptors, Immunologic, Receptors, Peptide},
	issn = {1359-6640},
	author = {Boontheekul, Tanyarut and Kong, Hyun-Joon and Hsiong, Susan X and Huang, Yen-Chen and Mahadevan, L and Vandenburgh, Herman and Mooney, David J}
}
@article {216916,
	title = {Sustained GM-CSF and PEI condensed pDNA presentation increases the level and duration of gene expression in dendritic cells},
	journal = {J Control Release},
	volume = {132},
	number = {3},
	year = {2008},
	month = {2008 Dec 18},
	pages = {273-8},
	abstract = {Current techniques to educate dendritic cells (DCs) ex vivo for immunotherapy are plagued by inefficient protocols and DC modifications are often transient and lost upon transplantation. This study investigated the role of sustained presentation of GM-CSF and PEI condensed pDNA (PEI-DNA) on gene transfer and long-term gene expression. Appropriate GM-CSF signaling during DC transfection promoted PEI-DNA uptake, although high cytokine concentrations induced intercellular DNA degradation, indicating the need for controlled presentation. Poly(lactide-co-glycolide) scaffolds that continuously stimulated DCs with both GM-CSF and PEI-DNA led to a 20-fold increase in gene expression, and high levels of expression persisted for a period of 10 days, in vitro. These results encourage the exploitation of biomaterials and GM-CSF to develop novel delivery vectors for genetically modified DCs or to genetically program host DCs in situ for vaccination and the treatment of autoimmunity.},
	keywords = {Animals, Cell Line, Dendritic Cells, Dose-Response Relationship, Drug, Gene Expression Regulation, Genes, Reporter, Genetic Therapy, Granulocyte-Macrophage Colony-Stimulating Factor, Immunotherapy, Lactic Acid, Luciferases, Mice, Nucleic Acid Conformation, Plasmids, Polyethyleneimine, Polyglycolic Acid, Time Factors, Transfection},
	issn = {1873-4995},
	doi = {10.1016/j.jconrel.2008.07.005},
	author = {Ali, Omar A and Mooney, David J}
}
@article {1192356,
	title = {Angiogenic effects of sequential release of VEGF-A165 and PDGF-BB with alginate hydrogels after myocardial infarction},
	journal = {Cardiovasc Res},
	volume = {75},
	number = {1},
	year = {2007},
	month = {2007 Jul 01},
	pages = {178-85},
	abstract = {OBJECTIVE: This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate hydrogels could induce an angiogenic effect and functional improvement greater than single factors after myocardial infarction.

METHODS: Alginate hydrogels were prepared by combining high and low molecular weight alginate. Growth factor release rates were monitored over time in vitro with 125I-labelled VEGF-A(165) and PDGF-BB included in the gels. One week after myocardial infarction was induced in Fisher rats, gels with VEGF-A(165), PDGF-BB, or both were given intra-myocardially along the border of the myocardial infarction. Vessel density was analysed in hearts and cardiac function was determined by Tissue Doppler Echocardiography. In addition, the angiogenic effect of sequenced delivery was studied in vitro in aortic rings from C57B1/6 mice.

RESULTS: Alginate gels were capable of delivering VEGF-A(165) and PDGF-BB in a sustainable manner, and PDGF-BB was released more slowly than VEGF-A(165). Sequential growth factor administration led to a higher density of alpha-actin positive vessels than single factors, whereas no further increment was found in capillary density. Sequential protein delivery increased the systolic velocity-time integral and displayed a superior effect than single factors. In the aortic ring model, sequential delivery led to a higher angiogenic effect than single factor administration.

CONCLUSIONS: The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model. Sequential growth factor delivery of VEGF-A(165) and PDGF-BB induces mature vessels and improves cardiac function more than each factor singly. This may indicate clinical utility.},
	keywords = {Alginates, Animals, Aorta, Echocardiography, Glucuronic Acid, Heart, Hexuronic Acids, Hydrogels, In Vitro Techniques, Injections, Iodine Radioisotopes, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction, Neovascularization, Physiologic, Platelet-Derived Growth Factor, Proto-Oncogene Proteins c-sis, Radiography, Random Allocation, Rats, Rats, Inbred F344, Vascular Endothelial Growth Factor A, Ventricular Dysfunction, Left},
	issn = {0008-6363},
	doi = {10.1016/j.cardiores.2007.03.028},
	author = {Hao, Xiaojin and Silva, Eduardo A and M{\r a}nsson-Broberg, Agneta and Grinnemo, Karl-Henrik and Siddiqui, Anwar J and Dellgren, G{\"o}ran and W{\"a}rdell, Eva and Brodin, Lars Ake and Mooney, David J and Sylv{\'e}n, Christer}
}
@article {1192351,
	title = {Effect of heart rate on tissue Doppler measures of diastolic function},
	journal = {Echocardiography},
	volume = {24},
	number = {7},
	year = {2007},
	month = {2007 Aug},
	pages = {697-701},
	abstract = {BACKGROUND: Our aim was to study the independent effect of heart rate (HR) on parameters of diastolic function, particularly mitral annular velocities measured by tissue Doppler imaging (TDI), an effect which is not well understood.

METHODS: Sixteen patients with dual chamber pacemakers attending for routine pacemaker review underwent detailed echocardiographic assessment during atrial pacing with intact atrioventricular conduction at baseline and accelerated HRs. Mitral inflow and annular tissue Doppler velocities and systolic strain parameters were compared.

RESULTS: Parameters of systolic function were unaffected by increased HR. When these parameters were compared at baseline (mean 67 bpm) and accelerated HR (mean 80 bpm), the following was observed: a significant decrease in early mitral inflow (E) wave (70.5 +/- 5.5 cm/s vs 63.5 +/- 4.9 cm/s, P < 0.02) and early mitral annular (E{\textquoteright}) velocities (7.0 +/- 0.5 cm/s vs 6.3 +/- 0.6 cm/s, P < 0.003) and a significant increase in mitral inflow A wave (70.3 +/- 4.5 cm/s vs 77.3 +/- 4.4 cm/s, P < 0.05) and late mitral annular (A{\textquoteright}) velocities (9.3 +/- 0.6 cm/s vs 10.8 +/- 0.5, P < 0.00004).

CONCLUSION: Changes in HR have previously unrecognized significant effects on tissue Doppler parameters of diastolic function. Further study is required to determine if tissue Doppler derived annular velocities should be corrected for HR.},
	keywords = {Aged, Aged, 80 and over, Blood Flow Velocity, Coronary Circulation, Echocardiography, Doppler, Female, Heart Rate, Heart Ventricles, Humans, Image Interpretation, Computer-Assisted, Male, Middle Aged, Reproducibility of Results, Sensitivity and Specificity, Stroke Volume, Ventricular Function, Ventricular Function, Left},
	issn = {0742-2822},
	doi = {10.1111/j.1540-8175.2007.00466.x},
	author = {Burns, Andrew T and Connelly, Kim A and La Gerche, Andre and Mooney, Donald J and Chan, Justin and Macisaac, Andrew I and Prior, David L}
}
@article {1192361,
	title = {Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects},
	journal = {J Orthop Res},
	volume = {25},
	number = {7},
	year = {2007},
	month = {2007 Jul},
	pages = {941-50},
	abstract = {An 8-mm rat segmental defect model was used to evaluate quantitatively the ability of longitudinally oriented poly(L-lactide-co-D,L-lactide) scaffolds with or without growth factors to promote bone healing. BMP-2 and TGF-beta3, combined with RGD-alginate hydrogel, were co-delivered to femoral defects within the polymer scaffolds at a dose previously shown to synergistically induce ectopic mineralization. A novel modular composite implant design was used to achieve reproducible stable fixation, provide a window for longitudinal in vivo micro-CT monitoring of 3D bone ingrowth, and allow torsional biomechanical testing of functional integration. Sequential micro-CT analysis showed that bone ingrowth increased significantly between 4 and 16 weeks for the scaffold-treated defects with or without growth factors, but no increase with time was observed in empty defect controls. Treatment with scaffold alone improved defect stability at 16 weeks compared to nontreatment, but did not achieve bone union or restoration of mechanical function. Augmentation of scaffolds with BMP-2 and TGF-beta3 significantly increased bone formation at both 4 and 16 weeks compared to nontreatment, but only produced bone bridging of the defect region in two of six cases. Histological evaluation indicated that bone formed first at the periphery of the scaffolds, followed by more limited mineral deposition within the scaffold interior, suggesting that the cells participating in the initial healing response were primarily derived from periosteum. This study introduces a challenging segmental defect model that facilitates quantitative evaluation of strategies to repair critically sized bone defects. Healing of the defect region was improved by implanting structural polymeric scaffolds infused with growth factors incorporated within RGD-alginate. However, functional integration of the constructs appeared limited by continued presence of slow-degrading scaffolds and suboptimal dose or delivery of osteoinductive signals.},
	keywords = {Animals, Biocompatible Materials, Bone Morphogenetic Protein 2, Bone Morphogenetic Proteins, Bone Regeneration, Compressive Strength, Female, Femur, Lactic Acid, Osteogenesis, Osteotomy, Polyglycolic Acid, Polymers, Rats, Rats, Sprague-Dawley, Tissue Engineering, Tomography, X-Ray Computed, Transforming Growth Factor beta, Transforming Growth Factor beta3},
	issn = {0736-0266},
	doi = {10.1002/jor.20372},
	author = {Oest, Megan E and Dupont, Kenneth M and Kong, Hyun-Joon and Mooney, David J and Guldberg, Robert E}
}
@article {1192341,
	title = {Regenerative medicine in orthopaedic surgery},
	journal = {J Orthop Res},
	volume = {25},
	number = {10},
	year = {2007},
	month = {2007 Oct},
	pages = {1261-8},
	abstract = {Regenerative medicine holds great promise for orthopaedic surgery. As surgeons continue to face challenges regarding the healing of diseased or injured musculoskeletal tissues, regenerative medicine aims to develop novel therapies that will replace, repair, or promote tissue regeneration. This review article will provide an overview of the different research areas involved in regenerative medicine, such as stem cells, bioinductive factors, and scaffolds. The potential use of stem cells for orthopaedic tissue engineering will be addressed by presenting the current progress with skeletal muscle-derived stem cells. As well, the development of a revascularized massive allograft will be described and will serve as a prototypic model of orthopaedic tissue engineering. Lastly, we will describe current approaches used to design cell instructive materials and how they can be used to promote and regulate the formation of bony tissue.},
	keywords = {Genetic Therapy, Humans, Orthopedics, Recovery of Function, Regenerative Medicine, Stem Cells, Tissue Engineering},
	issn = {0736-0266},
	doi = {10.1002/jor.20432},
	author = {Corsi, Karin A and Schwarz, Edward M and Mooney, David J and Huard, Johnny}
}
@article {1192366,
	title = {Tissue engineering: a glue for biomaterials},
	journal = {Nat Mater},
	volume = {6},
	number = {5},
	year = {2007},
	month = {2007 May},
	pages = {327-8},
	keywords = {Animals, Biocompatible Materials, Cartilage, Articular, Humans, Tissue Adhesives, Tissue Engineering, Tissue Expansion},
	issn = {1476-1122},
	doi = {10.1038/nmat1896},
	author = {Mooney, David J and Silva, Eduardo A}
}
@article {1192346,
	title = {Upregulation of bone cell differentiation through immobilization within a synthetic extracellular matrix},
	journal = {Biomaterials},
	volume = {28},
	number = {25},
	year = {2007},
	month = {2007 Sep},
	pages = {3644-55},
	abstract = {There is a need for new therapeutic strategies to treat bone defects caused by trauma, disease or tissue loss. Injectable systems for cell transplantation have the advantage of allowing the use of minimally invasive surgical procedures, and thus for less discomfort to patients. In the present study, it is hypothesized that Arg-Gly-Asp (RGD)-coupled in a binary (low and high molecular weight) injectable alginate composition is able to influence bone cell differentiation in a three-dimensional (3D) structure. Viability, metabolic activity, cytoskeleton organization, ultrastructure and differentiation (alkaline phosphatase (ALP), von Kossa, alizarin red stainings and osteocalcin quantification) of immobilized cells were assessed. Cells within RGD-modified alginate microspheres were able to establish more interactions with the synthetic extracellular matrix as visualized by confocal laser scanning microscope and transmission electron microscopy imaging, and presented a much higher level of differentiation (more intense ALP and mineralization stainings and higher levels of osteocalcin secretion) when compared to cells immobilized within unmodified alginate microspheres. These findings demonstrate that peptides covalently coupled to alginate were efficient in influencing cell behavior within this 3D system, and may provide adequate preparation of osteoblasts for cell transplantation.},
	keywords = {3T3 Cells, Alginates, Alkaline Phosphatase, Animals, Cell Adhesion, Cell Differentiation, Cell Proliferation, Cell Survival, Cytoskeleton, Extracellular Matrix, Glucuronic Acid, Hexuronic Acids, Mice, Microscopy, Confocal, Microscopy, Electron, Transmission, Microspheres, Oligopeptides, Osteoblasts, Osteocalcin},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2007.04.028},
	author = {Evangelista, Marta B and Hsiong, Susan X and Fernandes, Rui and Sampaio, Paula and Kong, Hyun-Joon and Barrias, Cristina C and Salema, Roberto and Barbosa, M{\'a}rio A and Mooney, David J and Granja, Pedro L}
}
@article {217021,
	title = {Fluorescent resonance energy transfer: A tool for probing molecular cell-biomaterial interactions in three dimensions},
	journal = {Biomaterials},
	volume = {28},
	number = {15},
	year = {2007},
	month = {2007 May},
	pages = {2424-37},
	abstract = {The current paradigm in designing biomaterials is to optimize material chemical and physical parameters based on correlations between these parameters and downstream biological responses, whether in vitro or in vivo. Extensive developments in molecular design of biomaterials have facilitated identification of several biophysical and biochemical variables (e.g. adhesion peptide density, substrate elastic modulus) as being critical to cell response. However, these empirical observations do not indicate whether different parameters elicit cell responses by modulating redundant variables of the cell-material interface (e.g. number of cell-material bonds, cell-matrix mechanics). Recently, fluorescence resonance energy transfer (FRET) has been applied to quantitatively analyze parameters of the cell-material interface for both two- and three-dimensional adhesion substrates. Tools based on FRET have been utilized to quantify several parameters of the cell-material interface relevant to cell response, including molecular changes in matrix proteins induced by interactions both with surfaces and cells, the number of bonds between integrins and their adhesion ligands, and changes in the crosslink density of hydrogel synthetic extracellular matrix analogs. As such techniques allow both dynamic and 3-D analyses they will be useful to quantitatively relate downstream cellular responses (e.g. gene expression) to the composition of this interface. Such understanding will allow bioengineers to fully exploit the potential of biomaterials engineered on the molecular scale, by optimizing material chemical and physical properties to a measurable set of interfacial parameters known to elicit a predictable response in a specific cell population. This will facilitate the rational design of complex, multi-functional biomaterials used as model systems for studying diseases or for clinical applications.},
	keywords = {Algorithms, Animals, Biocompatible Materials, Cell Adhesion, Extracellular Matrix, Fibronectins, Fluorescence Resonance Energy Transfer, Fluorescent Antibody Technique, Humans, Integrins},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2007.01.023},
	author = {Huebsch, Nathaniel D and Mooney, David J}
}
@article {217061,
	title = {Hypoxia leads to necrotic hepatocyte death},
	journal = {J Biomed Mater Res A},
	volume = {80},
	number = {3},
	year = {2007},
	month = {2007 Mar 01},
	pages = {520-9},
	abstract = {Hepatocyte transplantation is being investigated as a therapy for liver disease; however, its success has been limited by rapid death of the cells following transplantation. This study was dedicated to elucidating the mode of death responsible for loss of transplanted hepatocytes in order to guide future strategies for promoting their survival. Using a tissue engineering model, it was found that the environment within polymer scaffolds containing transplanted cells was hypoxic after 5 days in vivo, with (90 +/- 3)\% of hepatocytes existing at pO(2) < 10 mmHg. The primary mode of hepatocyte death in response to hypoxic conditions of 0 or 2 vol \% oxygen was then determined in vitro. Several assays for features of apoptosis and necrosis demonstrated that hepatocytes cultured in an anoxic environment died via necrosis, while culture at 2\% oxygen inhibited proliferation. These results suggest it will not be possible to prevent hepatocyte death by interfering with the apoptotic process, and hypoxic conditions in the transplants must instead be addressed. The finding that the environment within cell transplantation scaffolds is hypoxic is likely applicable to many cell-based therapies, and a similar analysis of the primary mode of death for other cell types in response to hypoxia may be valuable in guiding future strategies for their transplantation.},
	keywords = {Animals, Apoptosis, Cell Culture Techniques, Cell Transplantation, Cells, Cultured, Hepatocytes, Hypoxia, Male, Necrosis, Oxygen, Partial Pressure, Rats, Rats, Inbred Lew, Tissue Engineering},
	issn = {1549-3296},
	doi = {10.1002/jbm.a.30930},
	author = {Smith, Molly K and Mooney, David J}
}
@article {217031,
	title = {Modifying the proliferative state of target cells to control DNA expression and identifying cell types transfected in vivo},
	journal = {Mol Ther},
	volume = {15},
	number = {2},
	year = {2007},
	month = {2007 Feb},
	pages = {361-8},
	abstract = {Although the majority of current gene transfer techniques have focused on increasing the ability of the DNA to enter the cell, it is possible that changing the proliferative and migratory state of cells will influence the cells ability to take up and express plasmid DNA. This study was designed to test the hypothesis that growth factors (basic fibroblast growth factor (bFGF) and hepatocyte growth factor/scatter factor (HGF/SF)) used to alter the proliferative and migratory state of cells can alter plasmid DNA uptake and expression. In vitro studies indicate that enhancing cell proliferation with growth factor exposure enhances plasmid DNA uptake and expression. Furthermore, dual localized delivery of bFGF and plasmid DNA in vivo increases the expression, 3-6 times over control, as compared to plasmid delivery alone. Dual delivery of a factor promoting cell proliferation and a plasmid led to a further increase in the expression of the plasmid encoding bone morphogenetic protein-2 in a rat cranial defect by specific cell populations. The results of these studies suggest that increasing the proliferative state of target cell populations can enhance non-viral gene transfer.},
	keywords = {Animals, Bone Morphogenetic Proteins, Cell Movement, Cell Proliferation, Fibroblast Growth Factor 2, Gene Expression, Green Fluorescent Proteins, Hepatocyte Growth Factor, Male, Mice, NIH 3T3 Cells, Plasmids, Rats, Rats, Inbred Lew, Skull Fractures, Transfection},
	issn = {1525-0016},
	doi = {10.1038/sj.mt.6300017},
	author = {Riddle, Kathryn W and Kong, Hyun-Joon and Leach, J Kent and Fischbach, Claudia and Cheung, Charles and Anseth, Kristi S and Mooney, David J}
}
@article {217041,
	title = {Nanoscale cell adhesion ligand presentation regulates nonviral gene delivery and expression},
	journal = {Nano Lett},
	volume = {7},
	number = {1},
	year = {2007},
	month = {2007 Jan},
	pages = {161-6},
	abstract = {It is hypothesized that the nanoscale organization of cell adhesion ligands in a synthetic ECM regulates nonviral gene delivery. This hypothesis was examined with pre-osteoblasts cultured on substrates which present varied density and spacing of synthetic adhesion ligands. The levels of gene transfer and expression were increased with the density of adhesion ligands, but decreased with the spacing of ligands, due to changes in the cell growth rate. This study provides a material-based control point on the nanometer scale for nonviral gene based therapies.},
	keywords = {Cell Adhesion, Cell Division, Gene Expression, Gene Transfer Techniques, Ligands, Nanotechnology, Osteoblasts},
	issn = {1530-6984},
	doi = {10.1021/nl062485g},
	author = {Kong, Hyunjoon and Hsiong, Susan and Mooney, David J}
}
@article {217026,
	title = {Polymers for pro- and anti-angiogenic therapy},
	journal = {Biomaterials},
	volume = {28},
	number = {12},
	year = {2007},
	month = {2007 Apr},
	pages = {2069-76},
	abstract = {Dysregulated growth factor signaling is traditionally targeted via bolus injections of therapeutic molecules, but this approach may not recreate necessary qualitative and quantitative aspects of biologic growth factor delivery systems. Polymeric delivery systems may, instead, mimic certain sequestration and binding characteristics of the extracellular matrix and lead to the provision of therapeutic molecules at therapeutically efficient local concentrations [V], in the form of spatial gradients (d[V]/dx) and temporal gradients (d[V]/dt), and in combination with other morphogenetic cues. Both physicochemical and biological attributes dictate their design, and they may be fabricated from synthetic and natural polymers. General concepts for manipulating growth factor signaling with these systems are discussed in the context of angiogenesis with vascular endothelial growth factor (VEGF), and these strategies may be broadly adapted to a multitude of other morphogens and growth factors.},
	keywords = {Animals, Humans, Neovascularization, Pathologic, Polymers},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2006.12.029},
	author = {Fischbach, Claudia and Mooney, David J}
}
@article {217036,
	title = {Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis},
	journal = {J Thromb Haemost},
	volume = {5},
	number = {3},
	year = {2007},
	month = {2007 Mar},
	pages = {590-8},
	abstract = {Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half-life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 mug) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE(-/-)) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm(-2)). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long-term in vivo therapeutic benefit (localized bioactive VEGF for 1-2 weeks) with minimally invasive delivery.},
	keywords = {Alginates, Angiogenesis Inducing Agents, Animals, Apolipoproteins E, Cells, Cultured, Chemistry, Pharmaceutical, Delayed-Action Preparations, Disease Models, Animal, Drug Carriers, Endothelial Cells, Female, Hindlimb, Humans, Hydrogels, Injections, Ischemia, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Neovascularization, Physiologic, Recombinant Proteins, Regional Blood Flow, Reproducibility of Results, Solubility, Time Factors, Vascular Endothelial Growth Factor A},
	issn = {1538-7933},
	doi = {10.1111/j.1538-7836.2007.02386.x},
	author = {Silva, E A and Mooney, D J}
}
@article {217046,
	title = {Spatio-temporal VEGF and PDGF delivery patterns blood vessel formation and maturation},
	journal = {Pharm Res},
	volume = {24},
	number = {2},
	year = {2007},
	month = {2007 Feb},
	pages = {258-64},
	abstract = {PURPOSE: Biological mechanisms of tissue regeneration are often complex, involving the tightly coordinated spatial and temporal presentation of multiple factors. We investigated whether spatially compartmentalized and sequential delivery of factors can be used to pattern new blood vessel formation.

MATERIALS AND METHODS: A porous bi-layered poly(lactide-co-glycolide) (PLG) scaffold system was used to locally present vascular endothelial growth factor (VEGF) alone in one spatial region, and sequentially deliver VEGF and platelet-derived growth factor (PDGF) in an adjacent region. Scaffolds were implanted in severely ischemic hindlimbs of SCID mice for 2 and 6 weeks, and new vessel formation was quantified within the scaffolds.

RESULTS: In the compartment delivering a high dose of VEGF alone, a high density of small, immature blood vessels was observed at 2 weeks. Sequential delivery of VEGF and PDGF led to a slightly lower blood vessel density, but vessel size and maturity were significantly enhanced. Results were similar at 6 weeks, with continued remodeling of vessels in the VEGF and PDGF layer towards increased size and maturation.

CONCLUSIONS: Spatially localizing and temporally controlling growth factor presentation for angiogenesis can create spatially organized tissues.},
	keywords = {Animals, Blood Vessels, Drug Delivery Systems, Hindlimb, Immunohistochemistry, Ischemia, Mice, Models, Statistical, Neovascularization, Physiologic, Platelet-Derived Growth Factor, Regional Blood Flow, Vascular Endothelial Growth Factor A},
	issn = {0724-8741},
	doi = {10.1007/s11095-006-9173-4},
	author = {Chen, Ruth R and Silva, Eduardo A and Yuen, William W and Mooney, David J}
}
@article {216991,
	title = {Engineering RGD nanopatterned hydrogels to control preosteoblast behavior: a combined computational and experimental approach},
	journal = {Biomaterials},
	volume = {28},
	number = {30},
	year = {2007},
	month = {2007 Oct},
	pages = {4409-17},
	abstract = {The adhesion ligand arginine-glycine-aspartic acid (RGD) has been coupled to various materials to be used as tissue culture matrices or cell transplantation vehicles, and recent studies indicate that nanopatterning RGD into high-density islands alters key cell behaviors. Previous studies have failed, however, to conclusively decouple the effects of RGD bulk density and individual pattern parameters (i.e. RGDs/island and island distribution) on these altered cell responses. Using a nanopatterned RGD-coupled alginate hydrogel matrix, this work combines computational, statistical and experimental approaches to elucidate the effects of RGD patterns on four key cell responses. This study shows that in MC3T3 preosteoblasts focal adhesion kinase (FAK) Y397 phosphorylation, cell spreading, and osteogenic differentiation can be controlled by RGD nanopatterning, with the distribution of islands throughout the hydrogel (i.e. how closely spaced the islands are) being the most significant pattern parameter. More closely spaced islands favor FAK Y397 phosphorylation and cell spreading, while more widely spaced islands favor differentiation. Proliferation, in contrast, is primarily a function of RGD bulk density. Nanopatterning of cell adhesion ligands has tremendous potential as a simple tool to gain significant control over multiple cell behaviors in engineered extracellular matrix (ECM).},
	keywords = {Alginates, Animals, Cell Adhesion, Cell Differentiation, Cell Proliferation, Cells, Cultured, Computational Biology, Extracellular Matrix, Focal Adhesion Protein-Tyrosine Kinases, Hydrogels, Ligands, Mice, Models, Biological, Nanotechnology, Oligopeptides, Osteoblasts, Osteocalcin, Phosphorylation, Tissue Engineering},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2007.06.018},
	author = {Comisar, Wendy A and Kazmers, Nikolas H and Mooney, David J and Linderman, Jennifer J}
}
@article {217016,
	title = {Host immune competence and local ischemia affects the functionality of engineered vasculature},
	journal = {Microcirculation},
	volume = {14},
	number = {2},
	year = {2007},
	month = {2007 Feb},
	pages = {77-88},
	abstract = {OBJECTIVE: Localized and sustained delivery of vascular endothelial growth factor (VEGF) is a promising approach to overcome the limited efficacy of bolus delivery. The authors examined the effects of host immune competence and local ischemia on the functionality of new vessel networks formed with this approach.

METHODS: Vessel structure and perfusion resulting from implantation of porous 85:15 poly(lactide-co-glycolide) scaffolds releasing VEGF165 were measured in both subcutaneous tissue and ischemic hindlimbs of immune competent C57BL/6 and immune deficient SCID mice.

RESULTS: Sustained VEGF delivery resulted in a similar approximately 100\% increase in vessel density within scaffolds in both implant sites, and both animal models. However, the resulting perfusion within scaffolds implanted in subcutaneous tissue increased modestly versus control (18-35\%), while perfusion increased 52-110\% above control when VEGF-releasing scaffolds were placed in ischemic hindlimbs of C57BL/6 or SCID mice. VEGF delivery improved perfusion in the entire ischemic limb (55 +/- 18\% of the normal value by week 6; 138\% increase over control) in SCID mice. Although C57BL/6 mice demonstrated spontaneous recovery from ischemia, VEGF delivery accelerated recovery as compared to control.

CONCLUSIONS: Localized and sustained VEGF delivery can create functional vasculature that amplifies recovery of tissue ischemia. However, increases in local and regional perfusion were highly dependent on the implantation site and the animal model.},
	keywords = {Animals, Biocompatible Materials, Corrosion Casting, Drug Delivery Systems, Hindlimb, Immunocompetence, Ischemia, Laser-Doppler Flowmetry, Male, Mice, Mice, Inbred C57BL, Mice, SCID, Microspheres, Neovascularization, Physiologic, Polyglactin 910, Subcutaneous Tissue, Vascular Endothelial Growth Factor A},
	issn = {1073-9688},
	doi = {10.1080/10739680601131101},
	author = {Chen, Ruth R and Snow, Jonathan K and Palmer, Jack P and Lin, Angela S and Duvall, Craig L and Guldberg, Robert E and Mooney, David J}
}
@article {216986,
	title = {Integrated approach to designing growth factor delivery systems},
	journal = {FASEB J},
	volume = {21},
	number = {14},
	year = {2007},
	month = {2007 Dec},
	pages = {3896-903},
	abstract = {Growth factors have been widely used in strategies to regenerate and repair diseased tissues, but current therapies that go directly from bench to bedside have had limited clinical success. We hypothesize that engineering successful therapies with recombinant proteins will often require specific quantitative information of the spatiotemporal role of the factors and the development of sophisticated delivery approaches that provide appropriate tissue exposures. This hypothesis was tested in the context of therapeutic angiogenesis. An in vitro model of angiogenesis was adapted to quantify the role of the concentration/gradient of vascular endothelial growth factor [VEGF(165)] on microvascular endothelial cells, and a delivery system was then designed, based on a mathematical model, to provide the desired profile in ischemic mice hindlimbs. This system significantly enhanced blood vessel formation, and perfusion and recovery from severe ischemia. This general approach may be broadly applicable to growth factor therapies.},
	keywords = {Animals, Cells, Cultured, Disease Models, Animal, Drug Delivery Systems, Hindlimb, Humans, Ischemia, Mice, Mice, SCID, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A},
	issn = {1530-6860},
	doi = {10.1096/fj.06-7873com},
	author = {Chen, Ruth R and Silva, Eduardo A and Yuen, William W and Brock, Andrea A and Fischbach, Claudia and Lin, Angela S and Guldberg, Robert E and Mooney, David J}
}
@article {217006,
	title = {Mechanical strain regulates endothelial cell patterning in vitro},
	journal = {Tissue Eng},
	volume = {13},
	number = {1},
	year = {2007},
	month = {2007 Jan},
	pages = {207-17},
	abstract = {Blood vessels of the vertebrate circulatory system typically exhibit tissue-specific patterning. However, the cues that guide the development of these patterns remain unclear. We investigated the effect of cyclic uniaxial strain on vascular endothelial cell dynamics and sprout formation in vitro in two-dimensional (2D) and three-dimensional (3D) culture systems under the influence of growth factors. Cells preferentially aligned and moved in the direction perpendicular to the major strain axis in monolayer culture, and mechanical strain also regulated the spatial location of cell proliferation in 2D cell culture. Cells in 3D cell culture could be induced to form sprouts by exposure to appropriate growth factor combinations (vascular endothelial growth factor and hepatocyte growth factor), and the strain direction regulated the directionality of this process. Moreover, cyclic uniaxial strain inhibited branching of the structures formed by endothelial cells and increased their thickness. Taken together, these data support the importance of external mechanical stimulation in the regulation of endothelial cell migration, proliferation, and differentiation into primitive vessels.},
	keywords = {Body Patterning, Cell Culture Techniques, Cell Movement, Cell Proliferation, Cells, Cultured, Endothelial Cells, Endothelium, Vascular, Humans, Stress, Mechanical, Umbilical Veins},
	issn = {1076-3279},
	doi = {10.1089/ten.2006.0058},
	author = {Matsumoto, Takuya and Yung, Yu Ching and Fischbach, Claudia and Kong, Hyunjoon and Nakaoka, Ryusuke and Mooney, David J}
}
@article {217001,
	title = {Microenvironmental regulation of biomacromolecular therapies},
	journal = {Nat Rev Drug Discov},
	volume = {6},
	number = {6},
	year = {2007},
	month = {2007 Jun},
	pages = {455-63},
	abstract = {There is currently great interest in molecular therapies to treat various diseases, and this has prompted extensive efforts to achieve target-specific and controlled delivery of bioactive macromolecules (for example, proteins, antibodies, DNA and small interfering RNA) through the design of smart drug carriers. By contrast, the influence of the microenvironment in which the target cell resides and the effect it might have on the success of biomacromolecular therapies has been under-appreciated. The extracellular matrix (ECM) component of the cellular niche may be particularly important, as many diseases and injury disrupt the normal ECM architecture, the cell adhesion to ECM, and the subsequent cellular activities. This Review will discuss the importance of the ECM and the ECM-cell interactions on the cell response to bioactive macromolecules, and suggest how this information could lead to new criteria for the design of novel drug delivery systems.},
	keywords = {Animals, Cell Adhesion, Drug Delivery Systems, Extracellular Matrix, Growth Substances, Humans, Nucleotides, Plasmids, Proteins},
	issn = {1474-1776},
	doi = {10.1038/nrd2309},
	author = {Kong, Hyunjoon and Mooney, David J}
}
@article {217011,
	title = {Noninvasive probing of the spatial organization of polymer chains in hydrogels using fluorescence resonance energy transfer (FRET)},
	journal = {J Am Chem Soc},
	volume = {129},
	number = {15},
	year = {2007},
	month = {2007 Apr 18},
	pages = {4518-9},
	keywords = {Fluorescence Resonance Energy Transfer, Hydrogels, Hydrogen-Ion Concentration, Polymers, Solutions},
	issn = {0002-7863},
	doi = {10.1021/ja0690058},
	author = {Kong, Hyunjoon and Kim, Chanjoong and Huebsch, Nathaniel and David Weitz and Mooney, David J}
}
@article {216976,
	title = {Quantification of human angiogenesis in immunodeficient mice using a photon counting-based method},
	journal = {Biotechniques},
	volume = {43},
	number = {1},
	year = {2007},
	month = {2007 Jul},
	pages = {73-7},
	abstract = {Testing new antiangiogenic drugs for cancer treatment requires the use of animal models, since stromal cells and extracellular matrices mediate signals to endothelial cells that cannot be fully reproduced in vitro. Most methods used for analysis of antiangiogenic drugs in vivo utilized histologic examination of tissue specimens, which often requires large sample sizes to obtain reliable quantitative data. Furthermore, these assays rely on the analysis of murine vasculature that may not be correlated with the responses of human endothelial cells. Here, we engineered human blood vessels in immunodeficient mice with human endothelial cells expressing luciferase, demonstrated that these cells line functional blood vessels, and quantified angiogenesis over time using a photon counting-based method. In a proof-of-principle experiment with PTK/ZK, a small molecule inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase receptors, a strong correlation was observed between the decrease in bioluminescence (9.12-fold) in treated mice and the actual decrease in microvessel density (9.16-fold) measured after retrieval of the scaffolds and immunohistochemical staining of endothelial cells. The method described here allows for quantitative and noninvasive investigation into the effects of anti-cancer drugs on human angiogenesis in a murine host.},
	keywords = {Animals, Cells, Cultured, Endothelial Cells, Humans, Luminescent Measurements, Mice, Mice, SCID, Neovascularization, Physiologic, Photons, Reproducibility of Results, Whole Body Imaging},
	issn = {0736-6205},
	author = {Dong, Zhihong and Neiva, Kathleen G and Jin, Taocong and Zhang, Zhaocheng and Hall, Daniel E and Mooney, David J and Polverini, Peter J and N{\"o}r, Jacques E}
}
@article {216996,
	title = {Regulating myoblast phenotype through controlled gel stiffness and degradation},
	journal = {Tissue Eng},
	volume = {13},
	number = {7},
	year = {2007},
	month = {2007 Jul},
	pages = {1431-42},
	abstract = {Mechanical stiffness and degradability are important material parameters in tissue engineering. The aim of this study was to address the hypothesis that these variables regulate the function of myoblasts cultured in 2-D and 3-D microenvironments. Development of cell-interactive alginate gels with tunable degradation rates and mechanical stiffness was established by a combination of partial oxidation and bimodal molecular weight distribution. Higher gel mechanical properties (13 to 45 kPa) increased myoblast adhesion, proliferation, and differentiation in a 2-D cell culture model. Primary mouse myoblasts were more highly responsive to this cue than the C2C12 myoblast cell line. Myoblasts were then encapsulated in gels varying in degradation rate to simultaneously investigate the effect of degradation and subsequent reduction of mechanical properties on cells in a 3-D environment. C2C12 cells in more rapidly degrading gels exhibited lower proliferation, as they exited the cell cycle to differentiate, compared to those in nondegradable gels. In contrast, mouse primary myoblasts illustrated significantly higher proliferation in degradable gels than in nondegradable gels, and exhibited minimal differentiation in either type of gel. Altogether, these studies suggest that a critical balance between material degradation rate and mechanical properties may be required to regulate formation of engineered skeletal muscle tissue, and that results obtained with the C2C12 cell line may not be predictive of the response of primary myoblasts to environmental cues. The principles delineated in these studies may be useful to tailor smart biomaterials that can be applied to many other polymeric systems and tissue types.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cell Culture Techniques, Cell Line, Cells, Cultured, Gels, Glucuronic Acid, Hexuronic Acids, Mice, Mice, Inbred C57BL, Myoblasts, Phenotype},
	issn = {1076-3279},
	doi = {10.1089/ten.2006.0356},
	author = {Boontheekul, Tanyarut and Hill, Elliott E and Kong, Hyun-Joon and Mooney, David J}
}
@article {216971,
	title = {Rescue of SCID murine ischemic hindlimbs with pH-modified rhbFGF/poly(DL-lactic-co-glycolic acid) implants},
	journal = {J Control Release},
	volume = {122},
	number = {3},
	year = {2007},
	month = {2007 Oct 08},
	pages = {331-7},
	abstract = {Site-specific controlled release of biologically active angiogenic growth factors such as recombinant human basic fibroblast growth factor (rhbFGF) is a promising approach to improve collateral circulation in patients suffering from ischemic heart disease or peripheral vascular disease. Previously, we demonstrated stabilization of rhbFGF encapsulated in injectable poly(DL-lactic-co-glycolic acid) (PLGA) millicylindrical implants upon co-incorporation of Mg(OH)2 to raise the microclimate pH in the polymer. The purpose of this study was to compare stabilized (S; +Mg(OH)2+other stabilizers), partially stabilized (PS; -Mg(OH)2+other stabilizers), unstabilized (US; no stabilizers), and blank (B) PLGA-encapsulated rhFGF formulations to promote angiogenesis in SCID mice. Following 4 weeks subcutaneous implantation at a 0.1 microg dose in healthy animals, the S group exhibited significantly higher blood vessel density (62+/-17 vessels/mm2) compared with PS, US, and B groups (11+/-2*, 17+/-7*, and 3+/-1** respectively) (* p,
	keywords = {Angiogenesis Inducing Agents, Animals, Disease Models, Animal, Drug Carriers, Fibroblast Growth Factors, Hindlimb, Humans, Hydrogen-Ion Concentration, Ischemia, Lactic Acid, Male, Mice, Mice, SCID, Necrosis, Neovascularization, Physiologic, Polyglycolic Acid, Polymers, Recombinant Proteins, Regional Blood Flow},
	issn = {1873-4995},
	doi = {10.1016/j.jconrel.2007.05.016},
	author = {Zhong, Yanqiang and Zhang, Li and Ding, Amy G and Shenderova, Anna and Zhu, Gaozhong and Pei, Ping and Chen, Ruth R and Mallery, Susan R and Mooney, David J and Schwendeman, Steven P}
}
@article {216966,
	title = {Engineering tumors with 3D scaffolds},
	journal = {Nat Methods},
	volume = {4},
	number = {10},
	year = {2007},
	month = {2007 Oct},
	pages = {855-60},
	abstract = {Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells{\textquoteright} dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.},
	keywords = {Animals, Antineoplastic Agents, Carcinoma, Squamous Cell, Cell Culture Techniques, Cell Line, Tumor, Cell Proliferation, Drug Evaluation, Preclinical, Humans, Male, Mice, Mouth Neoplasms, Neoplasm Invasiveness, Neovascularization, Pathologic, Tissue Engineering},
	issn = {1548-7091},
	doi = {10.1038/nmeth1085},
	author = {Fischbach, Claudia and Chen, Ruth and Matsumoto, Takuya and Schmelzle, Tobias and Brugge, Joan S and Polverini, Peter J and Mooney, David J}
}
@article {216956,
	title = {Polymers to direct cell fate by controlling the microenvironment},
	journal = {Curr Opin Biotechnol},
	volume = {18},
	number = {5},
	year = {2007},
	month = {2007 Oct},
	pages = {448-53},
	abstract = {Enhanced understanding of the signals within the microenvironment that regulate cell fate has led to the development of increasingly sophisticated polymeric biomaterials for tissue engineering and regenerative medicine applications. This advancement is exemplified by biomaterials with precisely controlled scaffold architecture that regulate the spatio-temporal release of growth factors and morphogens, and respond dynamically to microenvironmental cues. Further understanding of the biology, qualitatively and quantitatively, of cells within their microenvironments and at the tissue-material interface will expand the design space of future biomaterials.},
	keywords = {Biocompatible Materials, Cell Culture Techniques, Cell Physiological Phenomena, Cell Transplantation, Polymers, Regenerative Medicine, Tissue Engineering},
	issn = {0958-1669},
	doi = {10.1016/j.copbio.2007.10.004},
	author = {Sands, R Warren and Mooney, David J}
}
@article {216961,
	title = {Spatiotemporal control over growth factor signaling for therapeutic neovascularization},
	journal = {Adv Drug Deliv Rev},
	volume = {59},
	number = {13},
	year = {2007},
	month = {2007 Nov 10},
	pages = {1340-50},
	abstract = {Many of the qualitative roles of growth factors involved in neovascularization have been delineated, but it is unclear yet from an engineering perspective how to use these factors as therapies. We propose that an approach that integrates quantitative spatiotemporal measurements of growth factor signaling using 3-D in vitro and in vivo models, mathematic modeling of factor tissue distribution, and new delivery technologies may provide an opportunity to engineer neovascularization on demand.},
	keywords = {Animals, Drug Delivery Systems, Humans, Intercellular Signaling Peptides and Proteins, Models, Statistical, Neovascularization, Physiologic, Signal Transduction, Tissue Engineering},
	issn = {0169-409X},
	doi = {10.1016/j.addr.2007.08.012},
	author = {Cao, Lan and Mooney, David J}
}
@article {1192371,
	title = {Regulation of chondrocyte differentiation level via co-culture with osteoblasts},
	journal = {Tissue Eng},
	volume = {12},
	number = {9},
	year = {2006},
	month = {2006 Sep},
	pages = {2425-33},
	abstract = {The close apposition of osteoblasts and chondrocytes in bone and their interaction during bone development and regeneration suggest that they may each regulate the other{\textquoteright}s growth and differentiation. In these studies, osteoblasts and chondrocytes were co-cultured in vitro, with both direct and indirect contact. Proliferation of the co-cultured chondrocytes was enhanced using soluble factors produced from the osteoblasts, and the differentiation level of the osteoblasts influenced the differentiation level of the chondrocytes. In addition, the chondrocytes regulated differentiation of the co-cultured osteoblasts using soluble factors and direct contact. These data support the possibility of direct, reciprocal instructive interactions between chondrocytes and osteoblasts in a variety of normal processes and further suggest that it may be necessary to account for this signaling in the regeneration of complex tissues comprising cartilage and mineralized tissue.},
	keywords = {Animals, Bone Regeneration, Calcification, Physiologic, Cell Differentiation, Cell Proliferation, Cells, Cultured, Chondrocytes, Coculture Techniques, Growth Substances, Osteoblasts, Rats, Rats, Inbred Lew, Signal Transduction},
	issn = {1076-3279},
	doi = {10.1089/ten.2006.12.2425},
	author = {Nakaoka, Ryusuke and Hsiong, Susan X and Mooney, David J}
}
@article {1192376,
	title = {Role of matrix metalloproteinases in delayed cortical responses after stroke},
	journal = {Nat Med},
	volume = {12},
	number = {4},
	year = {2006},
	month = {2006 Apr},
	pages = {441-5},
	abstract = {Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.},
	keywords = {Animals, Biomarkers, Brain Infarction, Brain Ischemia, Cerebral Cortex, Disease Models, Animal, Immunohistochemistry, Male, Matrix Metalloproteinase 9, Rats, Rats, Sprague-Dawley, Stroke, Time Factors, Tissue Inhibitor of Metalloproteinases, Up-Regulation},
	issn = {1078-8956},
	doi = {10.1038/nm1387},
	author = {Zhao, Bing-Qiao and Wang, Sophia and Kim, Hahn-Young and Storrie, Hannah and Rosen, Bruce R and Mooney, David J and Wang, Xiaoying and Lo, Eng H}
}
@article {217106,
	title = {Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration},
	journal = {Biomaterials},
	volume = {27},
	number = {17},
	year = {2006},
	month = {2006 Jun},
	pages = {3249-55},
	abstract = {Bioactive glasses are potentially useful as bone defect fillers, and vascular endothelial growth factor (VEGF) has demonstrated benefit in bone regeneration as well. We hypothesized that the specific combination of prolonged localized VEGF presentation from a matrix coated with a bioactive glass may enhance bone regeneration. To test this hypothesis, the capacity of VEGF-releasing polymeric scaffolds with a bioactive glass coating was examined in vitro and in vivo using a rat critical-sized defect model. In the presence of a bioactive glass coating, we did not detect pronounced differences in the differentiation of human mesenchymal stem cells in vitro. However, we observed significantly enhanced mitogenic stimulation of endothelial cells in the presence of the bioactive glass coating, with an additive effect with VEGF release. This trend was maintained in vivo, where coated VEGF-releasing scaffolds demonstrated significant improvements in blood vessel density at 2 weeks versus coated control scaffolds. At 12 weeks, bone mineral density was significantly increased in coated VEGF-releasing scaffolds versus coated controls, while only a slight increase in bone volume fraction was observed. The results of this study suggest that a bioactive glass coating on a polymeric substrate participates in bone healing through indirect processes which enhance angiogenesis and bone maturation and not directly on osteoprogenitor differentiation and bone formation. The mass of bioactive glass used in this study provides a comparable and potentially additive, response to localized VEGF delivery over early time points. These studies demonstrate a materials approach to achieve an angiogenic response formerly limited to the delivery of inductive growth factors.},
	keywords = {Animals, Biocompatible Materials, Blood Vessels, Bone and Bones, Bone Regeneration, Cell Differentiation, Cell Proliferation, Cells, Cultured, Endothelial Cells, Endothelium, Vascular, Extracellular Matrix, Glass, Humans, In Vitro Techniques, Mesoderm, Neovascularization, Pathologic, Polymers, Rats, Stem Cells, Time Factors, Tomography, X-Ray Computed, Vascular Endothelial Growth Factor A},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2006.01.033},
	author = {Leach, J Kent and Kaigler, Darnell and Wang, Zhuo and Krebsbach, Paul H and Mooney, David J}
}
@article {217101,
	title = {Delivery of hepatotrophic factors fails to enhance longer-term survival of subcutaneously transplanted hepatocytes},
	journal = {Tissue Eng},
	volume = {12},
	number = {2},
	year = {2006},
	month = {2006 Feb},
	pages = {235-44},
	abstract = {Tissue engineering approaches have been investigated as a strategy for hepatocyte transplantation; however the death of a majority of transplanted cells critically limits success of these approaches. In a previous study, a transient increase in hepatocyte survival was achieved through delivery of vascular endothelial growth factor (VEGF) from the porous polymer scaffold utilized for cell delivery. To enhance longer-term survival of the hepatocytes, this delivery system was modified to additionally deliver epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in a sustained manner. Hepatocytes were subcutaneously implanted in SCID mice on scaffolds containing EGF and/or HGF, in addition to VEGF, and survival was monitored for two weeks. A short-term enhancement of hepatocyte survival was observed after one week and is attributed to VEGF-enhanced vascularization, which was not altered by EGF or HGF. Surprisingly, long-term hepatocyte engraftment was not improved, as survival declined to the level of control conditions for all growth factor combinations after two weeks. This investigation indicates that the survival of hepatocytes transplanted into heterotopic locations is dependent on multiple signals. The delivery system developed for the current study may be useful in elucidating the specific factors controlling this process, and bring therapeutic transplantation of hepatocytes closer to implementation.},
	keywords = {Animals, Biocompatible Materials, Cell Survival, Delayed-Action Preparations, Dose-Response Relationship, Drug, Drug Combinations, Epidermal Growth Factor, Hepatocyte Growth Factor, Hepatocytes, Humans, Male, Mice, Mice, SCID, Microspheres, Neovascularization, Physiologic, NIH 3T3 Cells, Rats, Rats, Inbred Lew, Recombinant Proteins, Time Factors, Tissue Engineering, Transplantation, Heterologous, Vascular Endothelial Growth Factor A},
	issn = {1076-3279},
	doi = {10.1089/ten.2006.12.235},
	author = {Smith, Molly K and Riddle, Kathryn W and Mooney, David J}
}
@article {217081,
	title = {Designing scaffolds to enhance transplanted myoblast survival and migration},
	journal = {Tissue Eng},
	volume = {12},
	number = {5},
	year = {2006},
	month = {2006 May},
	pages = {1295-304},
	abstract = {Myoblast transplantation is currently limited by poor survival and integration of these cells into host musculature. Transplantation systems that enhance the viability of the cells and induce their outward migration to populate injured muscle may enhance the success of this approach to muscle regeneration. In this study, enriched populations of primary myoblasts were seeded onto delivery vehicles formed from alginate, and the role of vehicle design and local growth factor delivery in cell survival and migration were examined. Only 5 +/- 2.5\% of cells seeded into nanoporous alginate gels survived for 24 h and only 4 +/- 0.5\% migrated out of the gels. Coupling cell adhesion peptides (G4RGDSP) to the alginate prior to gelling slightly increased the viability of cells within the scaffold to 16 +/- 1.4\% and outward migration to 6 +/- 1\%. However, processing peptide-modified alginate gels to yield macroporous scaffolds, in combination with sustained delivery of HGF and FGF2 from the material, dramatically increased the viability of seeded cells over a 5-day time course and increased outward migration to 110 +/- 12\%. This data indicate long-term survival and migration of myoblasts placed within polymeric delivery vehicles can be greatly increased by appropriate scaffold composition, architecture, and growth factor delivery. This system may be particularly useful in the regeneration of muscle tissue and be broadly useful in the regeneration of other tissues as well.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cell Movement, Cell Survival, Fibroblast Growth Factor 2, Gels, Glucuronic Acid, Hepatocyte Growth Factor, Hexuronic Acids, Humans, Mice, Muscle, Skeletal, Myoblasts, Skeletal, Oligopeptides, Regeneration, Tissue Engineering},
	issn = {1076-3279},
	doi = {10.1089/ten.2006.12.1295},
	author = {Hill, Elliott and Boontheekul, Tanyarut and Mooney, David J}
}
@article {217116,
	title = {Multi-scale modeling to predict ligand presentation within RGD nanopatterned hydrogels},
	journal = {Biomaterials},
	volume = {27},
	number = {10},
	year = {2006},
	month = {2006 Apr},
	pages = {2322-9},
	abstract = {The adhesion ligand RGD has been coupled to various materials to be used as tissue culture matrices or cell transplantation vehicles, and recent studies indicate that nanopatterning RGD into high-density islands alters cell adhesion, proliferation, and differentiation. However, elucidating the impact of nanopattern parameters on cellular responses has been stymied by a lack of understanding of the actual ligand presentation within these systems. We have developed a multi-scale predictive modeling approach to characterize the adhesion ligand nanopatterns within an alginate hydrogel matrix. The models predict the distribution of ligand islands, the spacing between ligands within an island and the fraction of ligands accessible for cell binding. These model predictions can be used to select pattern parameter ranges for experiments on the effects of individual parameters on cellular responses. Additionally, our technique could also be applied to other polymer systems presenting peptides or other signaling molecules.},
	keywords = {Hydrogels, Ligands, Models, Biological, Molecular Conformation, Molecular Weight, Nanotechnology, Oligopeptides, Surface Properties},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2005.10.037},
	author = {Comisar, Wendy A and Hsiong, Susan X and Kong, Hyun-Joon and Mooney, David J and Linderman, Jennifer J}
}
@article {217096,
	title = {Regeneration of vascularized bone},
	journal = {Periodontol 2000},
	volume = {41},
	year = {2006},
	month = {2006},
	pages = {109-22},
	keywords = {Absorbable Implants, Animals, Bone and Bones, Bone Morphogenetic Proteins, Bone Regeneration, Endothelial Cells, Humans, Mesenchymal Stem Cell Transplantation, Neovascularization, Physiologic, Tissue Engineering, Transforming Growth Factor beta, Transforming Growth Factor beta1, Vascular Endothelial Growth Factor A},
	issn = {0906-6713},
	doi = {10.1111/j.1600-0757.2006.00158.x},
	author = {Hsiong, Susan X and Mooney, David J}
}
@article {217111,
	title = {Regulating activation of transplanted cells controls tissue regeneration},
	journal = {Proc Natl Acad Sci U S A},
	volume = {103},
	number = {8},
	year = {2006},
	month = {2006 Feb 21},
	pages = {2494-9},
	abstract = {Current approaches to tissue regeneration are limited by the death of most transplanted cells and/or resultant poor integration of transplanted cells with host tissue. We hypothesized that transplanting progenitor cells within synthetic microenvironments that maintain viability, prevent terminal differentiation, and promote outward migration would significantly enhance their repopulation and regeneration of damaged host tissue. This hypothesis was addressed in the context of muscle regeneration by transplanting satellite cells to muscle laceration sites on a delivery vehicle releasing factors that induce cell activation and migration (hepatocyte growth factor and fibroblast growth factor 2) or transplantation on materials lacking factor release. Controls included direct cell injection into muscle, the implantation of blank scaffolds, and scaffolds releasing factors without cells. Injected cells demonstrated a limited repopulation of damaged muscle and led to a slight improvement in muscle regeneration, as expected. Delivery of cells on scaffolds that did not promote migration resulted in no improvement in muscle regeneration. Strikingly, delivery of cells on scaffolds that promoted myoblast activation and migration led to extensive repopulation of host muscle tissue and increased the regeneration of muscle fibers at the wound and the mass of the injured muscle. This previously undescribed strategy for cell transplantation significantly enhances muscle regeneration from transplanted cells and may be broadly applicable to the various tissues and organ systems in which provision and instruction of a cell population competent to participate in regeneration may be clinically useful.},
	keywords = {Animals, Cell Transplantation, Mice, Mice, Inbred C57BL, Muscle Fibers, Skeletal, Muscle, Skeletal, Muscular Diseases, Regeneration},
	issn = {0027-8424},
	doi = {10.1073/pnas.0506004103},
	author = {Hill, Elliott and Boontheekul, Tanyarut and Mooney, David J}
}
@article {217086,
	title = {Sustained delivery of plasmid DNA from polymeric scaffolds for tissue engineering},
	journal = {Adv Drug Deliv Rev},
	volume = {58},
	number = {4},
	year = {2006},
	month = {2006 Jul 07},
	pages = {500-14},
	abstract = {The encapsulation of DNA into polymeric depot systems can be used to spatially and temporally control DNA release, leading to a sustained, local delivery of therapeutic factors for tissue regeneration. Prior to encapsulation, DNA may be condensed with cationic polymers to decrease particle size, protect DNA from degradation, promote interaction with cell membranes, and facilitate endosomal release via the proton sponge effect. DNA has been encapsulated with either natural or synthetic polymers to form micro- and nanospheres, porous scaffolds and hydrogels for sustained DNA release and the polymer physical and chemical properties have been shown to influence transfection efficiency. Polymeric depot systems have been applied for bone, skin, and nerve regeneration as well as therapeutic angiogenesis, indicating the broad applicability of these systems for tissue engineering.},
	keywords = {Animals, Delayed-Action Preparations, Drug Delivery Systems, Gene Transfer Techniques, Humans, Plasmids, Polymers, Regenerative Medicine, Tissue Engineering},
	issn = {0169-409X},
	doi = {10.1016/j.addr.2006.03.004},
	author = {Storrie, Hannah and Mooney, David J}
}
@article {217076,
	title = {Temporally regulated delivery of VEGF in vitro and in vivo},
	journal = {J Biomed Mater Res A},
	volume = {79},
	number = {1},
	year = {2006},
	month = {2006 Oct},
	pages = {176-84},
	abstract = {The exposure duration and tissue distribution will likely dictate the success of vascular endothelial growth factor (VEGF) in therapeutic angiogenesis. We hypothesized that these variables can be regulated via the manner in which the VEGF is incorporated into polymer constructs (formed with a gas foaming technique) used for its delivery. VEGF was incorporated directly into poly(lactide-co-glycolide) (PLG) scaffolds or pre-encapsulated in PLG microspheres used to fabricate scaffolds. Protein release kinetics and tissue distribution were determined using iodinated VEGF. VEGF was positioned predominantly adjacent to scaffold pores when incorporated directly and was released rapidly (40-60\% in 5 days). Pre-encapsulation led to the VEGF being more deeply embedded and resulted in a delayed release. Alterations in polymer composition, scaffold size, and matrix composition generated minor variations in release kinetics. In vivo, the released VEGF generated local protein concentrations above 10 ng/mL at distances up to 2 cm from the implant site for the 21 days of the experiment, with negligible release into the systemic circulation, and significantly enhanced local angiogenesis. These data indicate that VEGF can be administered in a sustained and localized fashion in vivo, and the timing of VEGF delivery can be altered with the mechanism of incorporation into polymer scaffolds used for its delivery.},
	keywords = {Animals, Biocompatible Materials, Drug Delivery Systems, Lactic Acid, Mice, Mice, Inbred C57BL, Mice, SCID, Polyglycolic Acid, Polymers, Vascular Endothelial Growth Factor A},
	issn = {1549-3296},
	doi = {10.1002/jbm.a.30771},
	author = {Ennett, Alessandra B and Kaigler, Darnell and Mooney, David J}
}
@article {217071,
	title = {Transplanted endothelial cells enhance orthotopic bone regeneration},
	journal = {J Dent Res},
	volume = {85},
	number = {7},
	year = {2006},
	month = {2006 Jul},
	pages = {633-7},
	abstract = {The aim of this study was to determine if endothelial cells could enhance bone marrow stromal-cell-mediated bone regeneration in an osseous defect. Using poly-lactide-co-glycolide scaffolds as cell carriers, we transplanted bone marrow stromal cells alone or with endothelial cells into 8.5-mm calvarial defects created in nude rats. Histological analyses of blood vessel and bone formation were performed, and microcomputed tomography (muCT) was used to assess mineralized bone matrix. Though the magnitude of the angiogenic response between groups was the same, muCT analysis revealed earlier mineralization of bone in the co-transplantation condition. Ultimately, there was a significant increase (40\%) in bone formation in the co-transplantation group (33 +/- 2\%), compared with the transplantation of bone marrow stromal cells alone (23 +/- 3\%). Analysis of these data demonstrates that, in an orthotopic site, transplanted endothelial cells can influence the bone-regenerative capacity of bone marrow stromal cells.},
	keywords = {Absorbable Implants, Animals, Bone Marrow Transplantation, Bone Regeneration, Cells, Cultured, Endothelial Cells, Humans, Lactic Acid, Neovascularization, Physiologic, Polyglycolic Acid, Polymers, Rats, Rats, Nude, Skull, Stromal Cells, Tissue Engineering},
	issn = {0022-0345},
	doi = {10.1177/154405910608500710},
	author = {Kaigler, D and Krebsbach, P H and Wang, Z and West, E R and Horger, K and Mooney, D J}
}
@article {217091,
	title = {VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects},
	journal = {J Bone Miner Res},
	volume = {21},
	number = {5},
	year = {2006},
	month = {2006 May},
	pages = {735-44},
	abstract = {UNLABELLED: Bone regeneration is challenging in sites where the blood supply has been compromised by radiation. We examined the potential of a growth factor (VEGF) delivery system to enhance angiogenesis and bone formation in irradiated calvarial defects. VEGF-releasing polymers significantly increased blood vessel density and vascular perfusion in irradiated defects and increased bone formation relative to control conditions.

INTRODUCTION: Radiation therapy causes damage to tissues and inhibits its regenerative capacity. Tissue injury from radiation is in large part caused by a compromised vascular supply and reduced perfusion of tissues. The aim of this study was to determine if delivery of vascular endothelial growth factor (VEGF) from a biodegradable PLGA (copolymer of D,L-lactide and glycolide) scaffold could enhance neovascularization and bone regeneration in irradiated osseous defects.

MATERIALS AND METHODS: An isolated area of the calvarium of Fisher rats was irradiated (12 Gy) 2 weeks preoperatively, and two 3.5-mm osseous defects were created in this area, followed by the placement of PLGA scaffolds or VEGF scaffolds (PLGA scaffolds with incorporated VEGF) into the defects. Laser Doppler perfusion imaging was performed to measure perfusion of these areas at 1, 2, and 6 weeks. Implants were retrieved at 2, 6, and 12 weeks, and histologic and muCT analyses were performed to determine neovascularization and bone regeneration.

RESULTS: Histological analyses revealed statistically significant increases in blood vessel formation (>2-fold) and function (30\%) within the VEGF scaffolds compared with PLGA scaffolds. Additionally, evaluation of bone regeneration through bone histomorphometric and muCT analyses revealed significantly greater bone coverage (26.36 +/- 6.91\% versus 7.05 +/- 2.09\% [SD]) and increased BMD (130.80 +/- 58.05 versus 71.28 +/- 42.94 mg/cm(3)) in VEGF scaffolds compared with PLGA scaffolds.

CONCLUSIONS: Our findings show that VEGF scaffolds have the ability to enhance neovascularization and bone regeneration in irradiated osseous defects, outlining a novel approach for engineering tissues in hypovascular environments.},
	keywords = {Animals, Bone and Bones, Bone Density, Bone Regeneration, Laser-Doppler Flowmetry, Neovascularization, Pathologic, Rats, Rats, Inbred F344, Tomography, X-Ray Computed, Vascular Endothelial Growth Factor A},
	issn = {0884-0431},
	doi = {10.1359/jbmr.060120},
	author = {Kaigler, Darnell and Wang, Zhuo and Horger, Kim and Mooney, David J and Krebsbach, Paul H}
}
@article {217066,
	title = {Alginate hydrogels as biomaterials},
	journal = {Macromol Biosci},
	volume = {6},
	number = {8},
	year = {2006},
	month = {2006 Aug 07},
	pages = {623-33},
	abstract = {[Image: see text] Alginate hydrogels are proving to have a wide applicability as biomaterials. They have been used as scaffolds for tissue engineering, as delivery vehicles for drugs, and as model extracellular matrices for basic biological studies. These applications require tight control of a number of material properties including mechanical stiffness, swelling, degradation, cell attachment, and binding or release of bioactive molecules. Control over these properties can be achieved by chemical or physical modifications of the polysaccharide itself or the gels formed from alginate. The utility of these modified alginate gels as biomaterials has been demonstrated in a number of in vitro and in vivo studies.Micro-CT images of bone-like constructs that result from transplantation of osteoblasts on gels that degrade over a time frame of several months leading to improved bone formation.},
	keywords = {Alginates, Biocompatible Materials, Carbohydrate Conformation, Drug Delivery Systems, Glucuronic Acid, Hexuronic Acids, Hydrogels, Tissue Engineering},
	issn = {1616-5187},
	doi = {10.1002/mabi.200600069},
	author = {Augst, Alexander D and Kong, Hyunjoon and Mooney, David J}
}
@article {217056,
	title = {Cell instructive polymers},
	journal = {Adv Biochem Eng Biotechnol},
	volume = {102},
	year = {2006},
	month = {2006},
	pages = {113-37},
	abstract = {Polymeric materials used in tissue engineering were initially used solely as delivery vehicles for transplanting cells. However, these materials are currently designed to actively regulate the resultant tissue structure and function. This control is achieved through spatial and temporal regulation of various cues (e.g., adhesion ligands, growth factors) provided to interacting cells from the material. These polymeric materials that control cell function and tissue formation are termed cell instructive polymers, and recent trends in their design are outlined in this chapter.},
	keywords = {Animals, Cell Physiological Phenomena, Guided Tissue Regeneration, Humans, Polymers, Tissue Engineering},
	issn = {0724-6145},
	author = {Matsumoto, Takuya and Mooney, David J}
}
@article {217051,
	title = {Quantifying the relation between adhesion ligand-receptor bond formation and cell phenotype},
	journal = {Proc Natl Acad Sci U S A},
	volume = {103},
	number = {49},
	year = {2006},
	month = {2006 Dec 05},
	pages = {18534-9},
	abstract = {One of the fundamental interactions in cell biology is the binding of cell receptors to adhesion ligands, and many aspects of cell behavior are believed to be regulated by the number of these bonds that form. Unfortunately, a lack of methods to quantify bond formation, especially for cells in 3D cultures or tissues, has precluded direct probing of this assumption. We now demonstrate that a FRET technique can be used to quantify the number of bonds formed between cellular receptors and synthetic adhesion oligopeptides coupled to an artificial extracellular matrix. Similar quantitative relations were found between bond number and the proliferation and differentiation of MC3T3-E1 preosteoblasts and C2C12 myoblasts, although the relation was distinct for each cell type. This approach to understanding 3D cell-extracellular matrix interactions will allow one to both predict cell behavior and to use bond number as a fundamental design criteria for synthetic extracellular matrices.},
	keywords = {Animals, Cell Adhesion, Cell Differentiation, Cell Line, Cell Proliferation, Fluorescence Resonance Energy Transfer, Ligands, Mice, Myoblasts, Oligopeptides, Osteoblasts, Phenotype, Receptors, Cell Surface},
	issn = {0027-8424},
	doi = {10.1073/pnas.0605960103},
	author = {Kong, Hyunjoon and Boontheekul, Tanyarut and Mooney, David J}
}
@article {1192381,
	title = {Abnormal septal motion affects early diastolic velocities at the septal and lateral mitral annulus, and impacts on estimation of the pulmonary capillary wedge pressure},
	journal = {J Am Soc Echocardiogr},
	volume = {18},
	number = {5},
	year = {2005},
	month = {2005 May},
	pages = {445-53},
	abstract = {Abnormal motion of the interventricular septum (ASM), seen post cardiac operation, with left bundle branch block or right ventricular pacing, may affect septal mitral annular motion and correlation of the ratio between the velocity of early diastolic mitral inflow and the early diastolic mitral annular velocity (E/Ea) with pulmonary capillary wedge pressure (PCWP). We examined the effect of ASM on the relationship between E/Ea and E/Vp (propagation velocity of mitral inflow) ratios and PCWP in adult patients in the intensive care unit (14 with normal septal motion [NSM], 36 with ASM) undergoing echocardiography and pulmonary artery catheterization. E/Ea correlated well with PCWP during NSM ( r = 0.86 lateral annulus, r = 0.75 septal annulus), but poorly during ASM ( r = 0.36 lateral annulus, r = 0.39 septal annulus). E/Vp correlated poorly with PCWP ( r = 0.05 NSM, r = 0.17 ASM). For patients who are critically ill, E/Vp ratios poorly estimate PCWP. During NSM, E/Ea ratios measured at the lateral or septal annulus correlate well with PCWP. ASM affects E/Ea ratios at both the septal and lateral annulus, making E/Ea ratios unreliable for estimating PCWP in this group.},
	keywords = {Aged, Blood Flow Velocity, Diastole, Echocardiography, Doppler, Female, Heart Septum, Humans, Male, Middle Aged, Mitral Valve, Myocardial Contraction, Pulmonary Wedge Pressure},
	issn = {0894-7317},
	doi = {10.1016/j.echo.2005.01.005},
	author = {D{\textquoteright}Souza, Karen Adele and Mooney, Donald John and Russell, Andrew Edyvane and MacIsaac, Andrew Ian and Aylward, Philip Edmund and Prior, David Lloyd}
}
@article {217171,
	title = {Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution},
	journal = {Biomaterials},
	volume = {26},
	number = {15},
	year = {2005},
	month = {2005 May},
	pages = {2455-65},
	abstract = {Degradability is often a critical property of materials utilized in tissue engineering. Although alginate, a naturally derived polysaccharide, is an attractive material due to its biocompatibility and ability to form hydrogels, its slow and uncontrollable degradation can be an undesirable feature. In this study, we characterized gels formed using a combination of partial oxidation of polymer chains and a bimodal molecular weight distribution of polymer. Specifically, alginates were partially oxidized to a theoretical extent of 1\% with sodium periodate, which created acetal groups susceptible to hydrolysis. The ratio of low MW to high MW alginates used to form gels was also varied, while maintaining the gel forming ability of the polymer. The rate of degradation was found to be controlled by both the oxidation and the ratio of high to low MW alginates, as monitored by the reduction of mechanical properties and corresponding number of crosslinks, dry weight loss, and molecular weight decrease. It was subsequently examined whether these modifications would lead to reduced biocompatibility by culturing C2C12 myoblast on these gels. Myoblasts adhered, proliferated, and differentiated on the modified gels at a comparable rate as those cultured on the unmodified gels. Altogether, this data indicates these hydrogels exhibit tunable degradation rates and provide a powerful material system for tissue engineering.},
	keywords = {Alginates, Animals, Biocompatible Materials, Calcium, Cell Adhesion, Cell Culture Techniques, Cell Differentiation, Cell Line, Compressive Strength, Elasticity, Glucuronic Acid, Hexuronic Acids, Hydrogels, Materials Testing, Mice, Molecular Weight, Myoblasts, Oxidation-Reduction, Porosity, Tensile Strength, Tissue Engineering},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2004.06.044},
	author = {Boontheekul, Tanyarut and Kong, Hyun-Joon and Mooney, David J}
}
@article {217206,
	title = {Effects of a bone-like mineral film on phenotype of adult human mesenchymal stem cells in vitro},
	journal = {Biomaterials},
	volume = {26},
	number = {3},
	year = {2005},
	month = {2005 Jan},
	pages = {303-10},
	abstract = {Multipotent cell types are rapidly becoming key components in a variety of tissue engineering schemes, and mesenchymal stem cells (MSCs) are emerging as an important tool in bone tissue regeneration. Although several soluble signals influencing osteogenic differentiation of MSCs in vitro are well-characterized, relatively little is known about the influence of substrate signals. This study was aimed at elucidating the effects of a bone-like mineral (BLM), which is vital in the process of bone bonding to orthopedic implant materials, on the osteogenic differentiation of human MSCs in vitro. Growth of a BLM film (carbonate apatite, Ca/P = 1.55) on poly(lactide-co-glycolide) (PLG) substrates was achieved via surface hydrolysis and subsequent incubation in a modified simulated body fluid. The BLM film demonstrated significantly increased adsorption of fibronectin, and supported enhanced proliferation of human mesenchymal stem cells (hMSCs) relative to PLG substrates. In the absence of osteogenic supplements hMSCs did not display a high expression of osteogenic markers on BLM or PLG. In the presence of osteogenic supplements hMSCs exhibited greater expression of osteogenic markers on PLG substrates than on BLM substrates, as measured by alkaline phosphatase activity and osteocalcin production. Taken together, these data support the concept that substrate signals significantly influence MSC growth and differentiation, highlighting the importance of carrier material composition in stem cell-based tissue engineering schemes.},
	keywords = {Adult, Apatites, Body Fluids, Bone Density, Bone Substitutes, Calcification, Physiologic, Cell Differentiation, Cells, Cultured, Coated Materials, Biocompatible, Humans, Materials Testing, Membranes, Artificial, Mesenchymal Stromal Cells, Osteoblasts, Osteogenesis, Phenotype, Polyglactin 910, Surface Properties},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2004.02.034},
	author = {Murphy, William L and Hsiong, Susan and Richardson, Thomas P and Simmons, Craig A and Mooney, David J}
}
@article {217126,
	title = {Actively regulating bioengineered tissue and organ formation},
	journal = {Orthod Craniofac Res},
	volume = {8},
	number = {3},
	year = {2005},
	month = {2005 Aug},
	pages = {141-4},
	abstract = {OBJECTIVES: Describe current and future approaches to tissue engineering, specifically in the area of bone regeneration. These approaches will allow one to actively regulate the cellular populations participating in this process.

DESIGN: Many approaches to actively regulate cellular phenotype are under exploration, and these typically exploit known signal transduction pathways via presentation of specific receptor-binding ligands, and may also deliver mechanical information via the physical bridge formed by the receptor-ligand interactions. Cellular gene expression may also be directly modulated utilizing gene therapy approaches to control tissue regeneration.

CONCLUSIONS: Significant progress has been made to date in bone regeneration using inductive molecules and transplanted cells, and FDA approved therapies have resulted. While approaches to date have focused on delivery of single stimuli (e.g. one growth factor), future efforts will likely attempt to more closely mimic developmental processes by the delivery of multiple inputs to the cells in spatially and temporally regulated fashions.},
	keywords = {Biocompatible Materials, Bone Regeneration, Carrier Proteins, Growth Substances, Humans, Regeneration, Tissue Engineering},
	issn = {1601-6335},
	doi = {10.1111/j.1601-6343.2005.00327.x},
	author = {Mooney, D J and Boontheekul, T and Chen, R and Leach, K}
}
@article {217166,
	title = {Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4)},
	journal = {Gene Ther},
	volume = {12},
	number = {5},
	year = {2005},
	month = {2005 Mar},
	pages = {418-26},
	abstract = {Gene therapy approaches to bone tissue engineering have been widely explored. While localized delivery of plasmid DNA encoding for osteogenic factors is attractive for promoting bone regeneration, the low transfection efficiency inherent with plasmid delivery may limit this approach. We hypothesized that this limitation could be overcome by condensing plasmid DNA with nonviral vectors such as poly(ethylenimine) (PEI), and delivering the plasmid DNA in a sustained and localized manner from poly(lactic-co-glycolic acid) (PLGA) scaffolds. To address this possibility, scaffolds delivering plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4) were implanted into a cranial critical-sized defect for time periods up to 15 weeks. The control conditions included no scaffold (defect left empty), blank scaffolds (no delivered DNA), and scaffolds encapsulating plasmid DNA (non-condensed). Histological and microcomputed tomography analysis of the defect sites over time demonstrated that bone regeneration was significant at the defect edges and within the defect site when scaffolds encapsulating condensed DNA were placed in the defect. In contrast, bone formation was mainly confined to the defect edges within scaffolds encapsulating plasmid DNA, and when blank scaffolds were used to fill the defect. Histomorphometric analysis revealed a significant increase in total bone formation (at least 4.5-fold) within scaffolds incorporating condensed DNA, relative to blank scaffolds and scaffolds incorporating uncondensed DNA at each time point. In addition, there was a significant increase both in osteoid and mineralized tissue density within scaffolds incorporating condensed DNA, when compared with blank scaffolds and scaffolds incorporating uncondensed DNA, suggesting that delivery of condensed DNA led to more complete mineralized tissue regeneration within the defect area. This study demonstrated that the scaffold delivery system encapsulating PEI-condensed DNA encoding for BMP-4 was capable of enhancing bone formation and may find applications in other tissue types.},
	keywords = {Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Bone Regeneration, DNA, Genetic Therapy, Lactic Acid, Polyethyleneimine, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew, Skull Fractures, Transfection},
	issn = {0969-7128},
	doi = {10.1038/sj.gt.3302439},
	author = {Huang, Y-C and Simmons, C and Kaigler, D and Rice, K G and Mooney, D J}
}
@article {217131,
	title = {Cellular cross-linking of peptide modified hydrogels},
	journal = {J Biomech Eng},
	volume = {127},
	number = {2},
	year = {2005},
	month = {2005 Apr},
	pages = {220-8},
	abstract = {Peptide modification of hydrogel-forming materials is being widely explored as a means to regulate the phenotype of cells immobilized within the gels. Alternatively, we hypothesized that the adhesive interactions between cells and peptides coupled to the gel-forming materials would also enhance the overall mechanical properties of the gels. To test this hypothesis, alginate polymers were modified with RGDSP-containing peptides and the resultant polymer was used to encapsulate C2C12 myoblasts. The mechanical properties of these gels were then assessed as a function of both peptide and cell density using compression and tensile tests. Overall, it was found that above a critical peptide and cell density, encapsulated myoblasts were able to provide additional mechanical integrity to hydrogels composed of peptide-modified alginate. This occurred presumably by means of cell-peptide cross-linking of the alginate polymers, in addition to the usual Ca++ cross-linking. These results are potentially applicable to other polymer systems and important for a range of tissue engineering applications.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cell Culture Techniques, Cell Line, Cells, Immobilized, Compressive Strength, Cross-Linking Reagents, Elasticity, Hydrogels, Materials Testing, Mice, Myoblasts, Oligopeptides, Stress, Mechanical, Tensile Strength, Tissue Engineering},
	issn = {0148-0731},
	author = {Drury, Jeanie L and Boontheekul, Tanyarut and Boontheeku, Tanyarut and Mooney, David J}
}
@article {217146,
	title = {Combined angiogenic and osteogenic factor delivery enhances bone marrow stromal cell-driven bone regeneration},
	journal = {J Bone Miner Res},
	volume = {20},
	number = {5},
	year = {2005},
	month = {2005 May},
	pages = {848-57},
	abstract = {UNLABELLED: Bone formation is a coordinated process involving various biological factors. We have developed a scaffold system capable of sustained and localized presentation of osteogenic (BMP-4) and angiogenic (VEGF) growth factors and human bone marrow stromal cells to promote bone formation at an ectopic site. Combined delivery of these factors significantly enhanced bone formation compared with other conditions.

INTRODUCTION: Tissue regeneration entails complex interactions between multiple signals and materials platforms. Orchestrating the presentation of these signals may greatly enhance the regeneration of lost tissue mass. Bone formation, for example, is dependent on the signaling of BMPs, molecules initiating vascularization (e.g., vascular endothelial growth factor [VEGF]), and osteogenic precursor cells capable of responding to these cues and forming bone tissue. It was hypothesized that combined and concerted delivery of these factors from biodegradable scaffolds would lead to enhanced bone formation.

MATERIALS AND METHODS: Poly(lactic-co-glycolic acid) scaffolds containing combinations of condensed plasmid DNA encoding for BMP-4, VEGF, and human bone marrow stromal cells (hBMSCs) were implanted into the subcutaneous tissue of SCID mice. Implants (n = 6) were retrieved at 3, 8, and 15 weeks after implantation. Bone and blood vessel formation was determined qualitatively and quantitatively by methods including histology, immmunostaining, and muCT.

RESULTS: Scaffolds delivering VEGF resulted in a prominent increase in blood vessel formation relative to the conditions without VEGF. BMP-4 expression in scaffolds encapsulating condensed DNA was also confirmed at the 15-week time-point, showing the characteristic of long-term delivery in this system. Combined delivery of all three types of factors resulted in a significant increase in the quantity of regenerated bone compared with any factor alone or any two factors combined, as measured with DXA, X-ray, and histomorphometric analysis. Furthermore, bone formed with all three factors had elastic moduli significantly higher than any other condition.

CONCLUSIONS: Concerted delivery of BMP-4, VEGF, and hBMSCs promoted greater bone formation relative to any single factor or combination of two factors. Materials systems that allows multifactorial presentation more closely mimic natural developmental processes, and these results may have important implications for bone regeneration therapeutics.},
	keywords = {Animals, Biocompatible Materials, Biodegradation, Environmental, Bone and Bones, Bone Development, Bone Marrow Cells, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Bone Regeneration, Cells, Cultured, DNA, Glycolates, Humans, Image Processing, Computer-Assisted, Lactic Acid, Mice, Mice, SCID, Neovascularization, Physiologic, Osteogenesis, Plasmids, Polyglycolic Acid, Polymers, Stromal Cells, Tissue Engineering, Tomography, X-Ray Computed, Vascular Endothelial Growth Factor A, von Willebrand Factor},
	issn = {0884-0431},
	doi = {10.1359/JBMR.041226},
	author = {Huang, Yen-Chen and Kaigler, Darnell and Rice, Kevin G and Krebsbach, Paul H and Mooney, David J}
}
@article {217161,
	title = {Endothelial cell modulation of bone marrow stromal cell osteogenic potential},
	journal = {FASEB J},
	volume = {19},
	number = {6},
	year = {2005},
	month = {2005 Apr},
	pages = {665-7},
	abstract = {In the context of bone development and regeneration, the intimate association of the vascular endothelium with osteogenic cells suggests that endothelial cells (ECs) may directly regulate the differentiation of osteoprogenitor cells. To investigate this question, bone marrow stromal cells (BMSCs) were cultured: in the presence of EC-conditioned medium, on EC extracellular matrix, and in EC cocultures with and without cell contact. RNA and protein were isolated from ECs and analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, respectively, for expression of bone morphogenetic protein 2 (BMP-2). In animal studies, BMSCs and ECs were cotransplanted into severe combined immunodeficient mice on biodegradable polymer matrices, and histomorphometric analysis was performed to determine the extent of new bone and blood vessel formation. ECs significantly increased BMSC osteogenic differentiation in vitro only when cultured in direct contact. ECs expressed BMP-2, and experiments employing interfering RNA inhibition confirmed its production as contributing to the increased BMSC osteogenic differentiation. In vivo, cotransplantation of ECs with BMSCs resulted in greater bone formation than did transplantation of BMSCs alone. These data suggest that ECs function not only to form the microvasculature that delivers nutrients to developing bone but also to modulate the differentiation of osteoprogenitor cells in vitro and in vivo.},
	keywords = {Alkaline Phosphatase, Animals, Bone Marrow Cells, Bone Marrow Transplantation, Bone Morphogenetic Protein 2, Bone Morphogenetic Proteins, Cell Count, Cell Differentiation, Cells, Cultured, Coculture Techniques, Culture Media, Conditioned, Endothelial Cells, Enzyme-Linked Immunosorbent Assay, Extracellular Matrix, Gene Expression, Humans, Male, Mice, Mice, SCID, Osteocalcin, Osteogenesis, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, RNA, Small Interfering, Stromal Cells, Transforming Growth Factor beta},
	issn = {1530-6860},
	doi = {10.1096/fj.04-2529fje},
	author = {Kaigler, Darnell and Krebsbach, Paul H and West, Erin R and Horger, Kim and Huang, Yen-Chen and Mooney, David J}
}
@article {217151,
	title = {FRET measurements of cell-traction forces and nano-scale clustering of adhesion ligands varied by substrate stiffness},
	journal = {Proc Natl Acad Sci U S A},
	volume = {102},
	number = {12},
	year = {2005},
	month = {2005 Mar 22},
	pages = {4300-5},
	abstract = {The mechanical properties of cell adhesion substrates regulate cell phenotype, but the mechanism of this relation is currently unclear. It may involve the magnitude of traction force applied by the cell, and/or the ability of the cells to rearrange the cell adhesion molecules presented from the material. In this study, we describe a FRET technique that can be used to evaluate the mechanics of cell-material interactions at the molecular level and simultaneously quantify the cell-based nanoscale rearrangement of the material itself. We found that these events depended on the mechanical rigidity of the adhesion substrate. Furthermore, both the proliferation and differentiation of preosteoblasts (MC3T3-E1) correlated to the magnitude of force that cells generate to cluster the cell adhesion ligands, but not the extent of ligand clustering. Together, these data demonstrate the utility of FRET in analyzing cell-material interactions, and suggest that regulation of phenotype with substrate stiffness is related to alterations in cellular traction forces.},
	keywords = {3T3 Cells, Animals, Apoptosis, Biomechanical Phenomena, Biophysical Phenomena, Biophysics, Cell Adhesion, Cell Differentiation, Cell Proliferation, Fluorescence Resonance Energy Transfer, Ligands, Mice, Nanotechnology},
	issn = {0027-8424},
	doi = {10.1073/pnas.0405873102},
	author = {Kong, Hyunjoon and Polte, Thomas R and Alsberg, Eben and Mooney, David J}
}
@article {217136,
	title = {Long-term in vivo gene expression via delivery of PEI-DNA condensates from porous polymer scaffolds},
	journal = {Hum Gene Ther},
	volume = {16},
	number = {5},
	year = {2005},
	month = {2005 May},
	pages = {609-17},
	abstract = {Nonviral delivery vectors are attractive for gene therapy approaches in tissue engineering, but suffer from low transfection efficiency and short-term gene expression. We hypothesized that the sustained delivery of poly(ethylenimine) (PEI)-condensed DNA from three-dimensional biodegradable scaffolds that encourage cell infiltration could greatly enhance gene expression. To test this hypothesis, a PEI-condensed plasmid encoding beta-galactosidase was incorporated into porous poly(lactide-co-glycolide) (PLG) scaffolds, using a gas foaming process. Four conditions were examined: condensed DNA and uncondensed DNA encapsulated into PLG scaffolds, blank scaffolds, and bolus delivery of condensed DNA in combination with implantation of PLG scaffolds. Implantation of scaffolds incorporating condensed beta-galactosidase plasmid into the subcutaneous tissue of rats resulted in a high level of gene expression for the entire 15-week duration of the experiment, as exemplified by extensive positive staining for beta-galactosidase gene expression observed on the exterior surface and throughout the cross-sections of the explanted scaffolds. No positive staining could be observed for the control conditions either on the exterior surface or in the cross-section at 8- and 15-week time points. In addition, a high percentage (55-60\%) of cells within scaffolds incorporating condensed DNA at 15 weeks demonstrated expression of the DNA, confirming the sustained uptake and expression of the encapsulated plasmid DNA. Quantitative analysis of beta-galactosidase gene expression revealed that expression levels in scaffolds incorporating condensed DNA were one order of magnitude higher than those of other conditions at the 2- week time point and nearly two orders of magnitude higher than those of the control conditions at the 8- and 15-week time points. This study demonstrated that the sustained delivery of PEI-condensed plasmid DNA from PLG scaffolds led to an in vivo long-term and high level of gene expression, and this system may find application in areas such as bone tissue engineering.},
	keywords = {Animals, beta-Galactosidase, DNA, Feasibility Studies, Freeze Drying, Gene Expression, Genetic Therapy, Genetic Vectors, Kinetics, Lactic Acid, Male, Plasmids, Polyethyleneimine, Polyglycolic Acid, Polymers, Porosity, Rats, Rats, Inbred Lew, Tissue Engineering, Transfection},
	issn = {1043-0342},
	doi = {10.1089/hum.2005.16.609},
	author = {Huang, Yen-Chen and Riddle, Kathryn and Rice, Kevin G and Mooney, David J}
}
@article {217141,
	title = {Non-viral gene delivery regulated by stiffness of cell adhesion substrates},
	journal = {Nat Mater},
	volume = {4},
	number = {6},
	year = {2005},
	month = {2005 Jun},
	pages = {460-4},
	abstract = {Non-viral gene vectors are commonly used for gene therapy owing to safety concerns with viral vectors. However, non-viral vectors are plagued by low levels of gene transfection and cellular expression. Current efforts to improve the efficiency of non-viral gene delivery are focused on manipulations of the delivery vector, whereas the influence of the cellular environment in DNA uptake is often ignored. The mechanical properties (for example, rigidity) of the substrate to which a cell adheres have been found to mediate many aspects of cell function including proliferation, migration and differentiation, and this suggests that the mechanics of the adhesion substrate may regulate a cell{\textquoteright}s ability to uptake exogeneous signalling molecules. In this report, we present a critical role for the rigidity of the cell adhesion substrate on the level of gene transfer and expression. The mechanism relates to material control over cell proliferation, and was investigated using a fluorescent resonance energy transfer (FRET) technique. This study provides a new material-based control point for non-viral gene therapy.},
	keywords = {3T3 Cells, Animals, Cell Adhesion, Cell Culture Techniques, Elasticity, Genetic Therapy, Hydrogels, Mice, Pharmaceutical Vehicles, Plasmids, Polyethyleneimine, Transfection},
	issn = {1476-1122},
	doi = {10.1038/nmat1392},
	author = {Kong, Hyunjoon and Liu, Jodi and Riddle, Kathryn and Matsumoto, Takuya and Leach, Kent and Mooney, David J}
}
@article {217121,
	title = {Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb},
	journal = {Pharm Res},
	volume = {22},
	number = {7},
	year = {2005},
	month = {2005 Jul},
	pages = {1110-6},
	abstract = {PURPOSE: We hypothesized that sustained delivery of vascular endothelial growth factor (VEGF) using a polymer [85:15 poly(lactide-co-glycolide) (PLG)] would enhance angiogenesis and improve perfusion of ischemic tissue.

METHODS: C57BL/6J mice (n = 20/group) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation (0-Implant), unloaded scaffold implantation (Empty-PLG), or implantation of scaffolds incorporating 3 microg of VEGF165 (PLG-VEGF). Endpoints included laser Doppler perfusion imaging (LDPI, ischemic/nonischemic limb, \%), local vessel counts, immunohistochemistry for CD31, and alpha-smooth muscle actin. In vitro release kinetics of VEGF from PLG was also measured.

RESULTS: PLG-VEGF resulted in improved lower extremity perfusion vs. controls as measured by LDPI\% at 7, 14, 21, and 28 days (p < 0.05). PLG-VEGF was associated with significantly greater percentage of vessels staining for CD31 and alpha-smooth muscle actin compared to the Empty-PLG or 0-Implant (p < 0.05 for both).

CONCLUSIONS: The PLG-VEGF scaffolds resulted in sustained VEGF delivery, improved tissue perfusion, greater capillary density, and more mature vasculature compared to the controls. The sustained-release PLG polymer vehicle is a promising delivery system for therapeutic neovascularization applications.},
	keywords = {Actins, Animals, Antigens, CD31, Biocompatible Materials, Capillaries, Disease Models, Animal, Drug Carriers, Hindlimb, Humans, Ischemia, Lactic Acid, Laser-Doppler Flowmetry, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal, Neovascularization, Physiologic, Perfusion, Polyglycolic Acid, Polymers, Vascular Endothelial Growth Factor A},
	issn = {0724-8741},
	doi = {10.1007/s11095-005-5644-2},
	author = {Sun, Qinghua and Chen, Ruth R and Shen, Yuechun and Mooney, David J and Rajagopalan, Sanjay and Grossman, P Michael}
}
@article {1192386,
	title = {Controlling Degradation of Hydrogels via the Size of Cross-Linked Junctions},
	journal = {Adv Mater},
	volume = {16},
	number = {21},
	year = {2004},
	month = {2004 Nov 30},
	pages = {1917-1921},
	issn = {1521-4095},
	doi = {10.1002/adma.200400014},
	author = {Kong, Hyunjoon and Alsberg, Eben and Kaigler, Darnell and Lee, Kuen Yong and Mooney, David J}
}
@article {1192391,
	title = {Effect of substrate mechanics on chondrocyte adhesion to modified alginate surfaces},
	journal = {Arch Biochem Biophys},
	volume = {422},
	number = {2},
	year = {2004},
	month = {2004 Feb 15},
	pages = {161-7},
	abstract = {This study characterized the attachment of chondrocytes to RGD-functionalized alginate by examining the effect of substrate stiffness on cell attachment and morphology. Bovine chondrocytes were added to wells coated with 2\% alginate or RGD-alginate. The alginate was crosslinked with divalent cations ranging from 1.25 to 62.5 mmol/g alginate. Attachment to RGD-alginate was 10-20 times higher than attachment to unmodified alginate and was significantly inhibited by antibodies to integrin subunits alpha3l and beta1, cytochalasin-D, and soluble RGD peptide. The equilibrium level and rate of attachment increased with crosslink density and substrate stiffness. Substrate stiffness also regulated chondrocyte morphology, which changed from a rounded shape with nebulous actin on weaker substrates to a predominantly flat morphology with actin stress fibers on stiffer substrates. The dependence of attachment on integrins and substrate stiffness suggests that chondrocyte integrins may play a role in sensing the mechanical properties of the matrices to which they are attached.},
	keywords = {Alginates, Amino Acid Sequence, Animals, Barium, Biocompatible Materials, Calcium, Cattle, Cell Adhesion, Chondrocytes, Cross-Linking Reagents, Cytochalasin D, Dose-Response Relationship, Drug, Kinetics, Microscopy, Electron, Scanning, Oligopeptides, Surface Properties},
	issn = {0003-9861},
	doi = {10.1016/j.abb.2003.11.023},
	author = {Genes, Nicholas G and Rowley, Jonathan A and Mooney, David J and Bonassar, Lawrence J}
}
@article {1192396,
	title = {Influence of flow conditions and matrix coatings on growth and differentiation of three-dimensionally cultured rat hepatocytes},
	journal = {Tissue Eng},
	volume = {10},
	number = {1-2},
	year = {2004},
	month = {2004 Jan-Feb},
	pages = {165-74},
	abstract = {Maintenance of liver-specific function of hepatocytes in culture is still difficult. Improved culture conditions may enhance the cell growth and function of cultured cells. We investigated the effect of three-dimensional culture under flow conditions, and the influence of surface modifications in hepatocyte cultures. Hepatocytes were harvested from Lewis rats. Cells were cultured on three-dimensional polymeric poly-lactic-co-glycolic acid (PLGA) matrices in static culture, or in a pulsatile flow-bioreactor system. Different surface modifications of matrices were investigated: coating with collagen I, collagen IV, laminin, or fibronectin; or uncoated matrix. Hepatocyte numbers, DNA content, and albumin secretion rate were assessed over the observation period. Culture under flow condition significantly enhanced cell numbers. An additional improvement of this effect was observed, when matrix coating was used. Cellular function also showed a significant increase (4- to 5-fold) under flow conditions when compared with static culture. Our data showed that culture under flow conditions improves cell number, and strongly enhances cellular function. Matrix modification by coating with extracellular matrix showed overall an additive stimulatory effect. Our conclusion is that combining three-dimensional culture under flow conditions and using matrix modification significantly improves culture conditions and is therefore attractive for the development of successful culture systems for hepatocytes.},
	keywords = {Animals, Cell Culture Techniques, Coated Materials, Biocompatible, Extracellular Matrix, Hepatocytes, Lactic Acid, Microscopy, Electron, Scanning, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew},
	issn = {1076-3279},
	doi = {10.1089/107632704322791817},
	author = {Fiegel, Henning C and Havers, Joerg and Kneser, Ulrich and Smith, Molly K and Moeller, Tim and Kluth, Dietrich and Mooney, David J and Rogiers, Xavier and Kaufmann, Peter M}
}
@article {217226,
	title = {Bone regeneration via a mineral substrate and induced angiogenesis},
	journal = {J Dent Res},
	volume = {83},
	number = {3},
	year = {2004},
	month = {2004 Mar},
	pages = {204-10},
	abstract = {Angiogenesis and biomineral substrates play major roles in bone development and regeneration. We hypothesized that macroporous scaffolds of biomineralized 85:15 poly(lactide-co-glycolide), which locally release vascular endothelial growth factor-165 (VEGF), would direct simultaneous regeneration of bone and vascular tissue. The presence of a bone-like biomineral substrate significantly increased regeneration of osteoid matrix (32 +/- 7\% of total tissue area; mean +/- SD; p < 0.05) and mineralized tissue (14 +/- 2\%; P < 0.05) within a rat cranium critical defect compared with a non-mineralized polymer scaffold (19 +/- 8\% osteoid and 10 +/- 2\% mineralized tissue). Further, the addition of VEGF to a mineralized substrate significantly increased the generation of mineralized tissue (19 +/- 4\%; P < 0.05) compared with mineralized substrate alone. This appeared to be due to a significant increase in vascularization throughout VEGF-releasing scaffolds (52 +/- 9 vessels/mm(2); P < 0.05) compared with mineralized scaffolds without VEGF (34 +/- 4 vessels/mm(2)). Surprisingly, there was no significant difference in total osteoid between the two samples, suggesting that increased vascularization enhances mineralized tissue generation, but not necessarily osteoid formation. These results indicate that induced angiogenesis can enhance tissue regeneration, supporting the concept of therapeutic angiogenesis in tissue-engineering strategies.},
	keywords = {Analysis of Variance, Animals, Biocompatible Materials, Bone Diseases, Bone Matrix, Bone Regeneration, Drug Carriers, Lactic Acid, Minerals, Neovascularization, Physiologic, Osteogenesis, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew, Skull, Tissue Engineering, Vascular Endothelial Growth Factor A, von Willebrand Factor},
	issn = {0022-0345},
	doi = {10.1177/154405910408300304},
	author = {Murphy, W L and Simmons, C A and Kaigler, D and Mooney, D J}
}
@article {217236,
	title = {Controlled degradation of hydrogels using multi-functional cross-linking molecules},
	journal = {Biomaterials},
	volume = {25},
	number = {13},
	year = {2004},
	month = {2004 Jun},
	pages = {2461-6},
	abstract = {Hydrogels, chemically cross-linked or physically entangled, have found a number of applications as novel delivery vehicles of drugs and cells. However, the narrow ranges of degradation rates and mechanical strength currently available from many hydrogels limits their applications. We have hypothesized that utilization of multi-functional cross-linking molecules to form hydrogels could provide a wider range and tighter control over the degradation rates and mechanical stiffness of gels than bi-functional cross-linking molecules. To address the possibility, we isolated alpha-L-guluronate residues of sodium alginate, and oxidized them to prepare poly(aldehyde guluronate) (PAG). Hydrogels were formed with either poly(acrylamide-co-hydrazide) (PAH) as a multi-functional cross-linking molecule or adipic acid dihydrazide (AAD) as a bi-functional cross-linking molecule. The initial properties and degradation behavior of both PAG gel types were monitored. PAG/PAH hydrogels showed higher mechanical stiffness before degradation and degraded more slowly than PAG/AAD gels, at the same concentration of cross-linking functional groups. The enhanced mechanical stiffness and prolonged degradation behavior could be attributed to the multiple attachment points of PAH in the gel at the same concentration of functional groups. This approach to regulating gel properties with multifunctional cross-linking molecules could be broadly used in hydrogels.},
	keywords = {Acrylic Resins, Hydrazines, Hydrogels, Polysaccharides, Bacterial},
	issn = {0142-9612},
	author = {Lee, Kuen Yong and Bouhadir, Kamal H and Mooney, David J}
}
@article {217221,
	title = {Locally enhanced angiogenesis promotes transplanted cell survival},
	journal = {Tissue Eng},
	volume = {10},
	number = {1-2},
	year = {2004},
	month = {2004 Jan-Feb},
	pages = {63-71},
	abstract = {A developing therapy for complete or partial loss of function in various tissues and organs involves transplanting an appropriate cell population, capable of compensating for the existing deficiencies. Clinical application of this type of strategy is currently limited by the death or dedifferentiation of the transplanted cells after delivery to the recipient. A delay in thorough vascularization of the implant area creates an environment low in oxygen and other nutrients, and likely contributes to the initial death of transplanted cells. We have addressed this problem by sustained delivery of vascular endothelial growth factor (VEGF), an initiator of angiogenesis, from a porous polymer matrix utilized simultaneously for cell delivery. As expected from previous studies, VEGF delivered from these constructs elicited an enhanced angiogenic response over a 2-week period when implanted subcutaneously in SCID mice. Hepatocytes implanted using VEGF-containing matrices demonstrated significantly greater survival after 1 week in vivo as compared with cells implanted on matrices without growth factor. The results of this study therefore indicate that enhancing vascularization in the location of transplanted cells promotes their survival. In addition, this delivery system may be used in future studies to directly promote cell survival and function by also providing growth factors specific to the transplanted cells.},
	keywords = {Angiogenesis Inducing Agents, Animals, Cell Survival, Hepatocytes, Male, Mice, Mice, SCID, Microspheres, Neovascularization, Physiologic, Rats, Vascular Endothelial Growth Factor A},
	issn = {1076-3279},
	doi = {10.1089/107632704322791709},
	author = {Smith, Molly K and Peters, Martin C and Richardson, Thomas P and Garbern, Jessica C and Mooney, David J}
}
@article {217231,
	title = {The tensile properties of alginate hydrogels},
	journal = {Biomaterials},
	volume = {25},
	number = {16},
	year = {2004},
	month = {2004 Jul},
	pages = {3187-99},
	abstract = {Alginate hydrogels are currently being employed and explored for a broad range of medical applications including cell encapsulation, drug delivery, and tissue engineering. In these capacities, knowledge of the mechanical and material properties of the hydrogels and the properties that govern and influence them is necessary to adequately design and effectively use these systems. Although much is known about the mechanical properties of alginate in compression and shear, little is known about the tensile characteristics. Thus, an extensive tensile assessment of alginate hydrogels was completed as a function of alginate type, formulation, gelling conditions, incubation, and strain rate. In general, the initial tensile behavior and properties of alginate hydrogels were highly dependent on the choice of the alginate polymer and how it was processed. Specifically, high guluronic acid containing alginate polymers yielded stronger, more ductile hydrogels than high mannuronic acid containing alginates. The ultimate stress, ultimate strain, and tensile modulus were decreased by increased phosphate concentrations, solution reconstitution with phosphate buffered saline instead of culture media, and peptide modification. Incubation of hydrogels for at least 7 days diminished many of the initial tensile property differences associated with formulation and gelling conditions. Overall, by controlling the specific alginate polymer and processing methods, a wide range of tensile properties are available from these hydrogels.},
	keywords = {Alginates, Biocompatible Materials, Body Fluids, Elasticity, Hardness, Hydrogels, Materials Testing, Molecular Weight, Tensile Strength},
	issn = {0142-9612},
	doi = {10.1016/j.biomaterials.2003.10.002},
	author = {Drury, Jeanie L and Dennis, Robert G and Mooney, David J}
}
@article {217201,
	title = {Bone engineering by controlled delivery of osteoinductive molecules and cells},
	journal = {Expert Opin Biol Ther},
	volume = {4},
	number = {7},
	year = {2004},
	month = {2004 Jul},
	pages = {1015-27},
	abstract = {Bone regeneration can be enhanced or accelerated by the delivery of osteogenic signalling factors or bone forming cells. These factors have commonly provided benefit when retained at the defect site with a delivery vehicle formed from natural or synthetic materials. Growth factors can be directly delivered as recombinant proteins or expressed by genetically modified cells to induce bone formation. Furthermore, bone regeneration has been achieved with the transplantation of various cell types that can participate in bone healing. Carriers utilised for the delivery of osteoinductive material allow for a prolonged presentation at the repair site and the timing of presentation can be readily adjusted to correspond to the extent necessary for bone regeneration. This review examines some of the recent developments in delivery systems used to manage the presentation of these factors at the desired site. Moreover, the authors provide suggestions for continued progress in bone regeneration.},
	keywords = {Animals, Bone and Bones, Cells, Cultured, Drug Carriers, Drug Delivery Systems, Forecasting, Genetic Therapy, Genetic Vectors, Growth Substances, Humans, Injections, Intralesional, Osteoblasts, Osteogenesis, Recombinant Proteins, Regeneration, Stem Cell Transplantation, Tissue Engineering},
	issn = {1744-7682},
	doi = {10.1517/14712598.4.7.1015},
	author = {Leach, J Kent and Mooney, David J}
}
@article {217186,
	title = {Controlling rigidity and degradation of alginate hydrogels via molecular weight distribution},
	journal = {Biomacromolecules},
	volume = {5},
	number = {5},
	year = {2004},
	month = {2004 Sep-Oct},
	pages = {1720-7},
	abstract = {The mechanical rigidity and degradation rate of hydrogels utilized as cell transplantation vehicles have been regarded as critical factors in new tissue formation. However, conventional approaches to accelerate the degradation rate of gels deteriorate their function as a mechanical support in parallel. We hypothesized that adjusting the molecular weight distribution of polymers that are hydrolytically labile but capable of forming gels would allow one to alter the degradation rate of the gels over a broad range, while limiting the range of their elastic moduli (E). We investigated this hypothesis with binary alginate hydrogels formed from both ionically and covalently cross-linked partially oxidized (1\% uronic acid residues), low [molecular weight (MW) approximately 60,000 g/mol] and high MW alginates (MW approximately 120,000 g/mol) in order to examine the utility of this approach with various cross-linking strategies. Increasing the fraction of low MW alginates to 0.50 maintained a value of E similar to that for the high MW alginate gels but led to faster degradation, irrespective of the cross-linking mode. This result was attributed to a faster separation between cross-linked domains upon chain breakages for the low MW alginates, coupled with their faster chain scission than the high MW alginates. The more rapidly degrading oxidized binary hydrogels facilitated the formation of new bone tissues from transplanted bone marrow stromal cells, as compared with the nonoxidized high MW hydrogels. The results of these studies will be useful for controlling the physical properties of a broad array of hydrogel-forming polymers.},
	keywords = {Alginates, Animals, Bone Marrow Cells, Bone Marrow Transplantation, Humans, Hydrogels, Mice, Mice, SCID, Molecular Weight, Rats},
	issn = {1525-7797},
	doi = {10.1021/bm049879r},
	author = {Kong, Hyunjoon and Kaigler, Darnell and Kim, Kibum and Mooney, David J}
}
@article {217196,
	title = {Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells},
	journal = {Bone},
	volume = {35},
	number = {2},
	year = {2004},
	month = {2004 Aug},
	pages = {562-9},
	abstract = {Supraphysiological concentrations of exogenous growth factors are typically required to obtain bone regeneration, and it is unclear why lower levels are not effective. We hypothesized that delivery of bone progenitor cells along with appropriate combinations of growth factors and scaffold characteristics would allow physiological doses of proteins to be used for therapeutic bone regeneration. We tested this hypothesis by measuring bone formation by rat bone marrow stromal cells (BMSCs) transplanted ectopically in SCID mice using alginate hydrogels. The alginate was gamma-irradiated to vary the degradation rate and then covalently modified with RGD-containing peptides to control cell behavior. In the same delivery vehicle, we incorporated bone morphogenetic protein-2 (BMP2) and transforming growth factor-beta3 (TGF-beta3), either individually or in combination. Individual delivery of BMP2 or TGF-beta3 resulted in negligible bone tissue formation up to 22 weeks, regardless of the implant degradation rate. In contrast, when growth factors were delivered together from readily degradable hydrogels, there was significant bone formation by the transplanted BMSCs as early as 6 weeks after implantation. Furthermore, bone formation, which appeared to occur by endochondral ossification, was achieved with the dual growth factor condition at protein concentrations that were more than an order of magnitude less than those reported previously to be necessary for bone formation. These data demonstrate that appropriate combinations of soluble and biomaterial-mediated regulatory signals in cell-based tissue engineering systems can result in both more efficient and more effective tissue regeneration.},
	keywords = {Animals, Bone and Bones, Bone Marrow Transplantation, Bone Morphogenetic Protein 2, Bone Morphogenetic Proteins, Mice, Mice, SCID, Osteogenesis, Rats, Rats, Inbred Lew, Stromal Cells, Transforming Growth Factor beta, Transforming Growth Factor beta3},
	issn = {8756-3282},
	doi = {10.1016/j.bone.2004.02.027},
	author = {Simmons, Craig A and Alsberg, Eben and Hsiong, Susan and Kim, Woo J and Mooney, David J}
}
@article {217191,
	title = {Mechanical stimulation and mitogen-activated protein kinase signaling independently regulate osteogenic differentiation and mineralization by calcifying vascular cells},
	journal = {J Biomech},
	volume = {37},
	number = {10},
	year = {2004},
	month = {2004 Oct},
	pages = {1531-41},
	abstract = {Ectopic calcification of vascular tissue is associated with several cardiovascular pathologies and likely involves active regulation by vascular smooth muscle cells and osteoblast-like vascular cells. This process often occurs in sites with altered mechanical environments, suggesting a role for mechanical stimuli in calcification. In this study, we investigated the effect of mechanical stimulation on the proliferation, osteogenic differentiation, calcification, and mitogen-activated protein kinase (MAPK) signaling in calcifying vascular cells (CVCs), a subpopulation of aortic smooth muscle cells putatively involved in vascular calcification. Application of equibiaxial cyclic strain (7\%, 0.25 Hz) to CVCs had no effect on cell proliferation, but accelerated alkaline phosphatase expression and significantly increased mineralization by 3.1-fold over unstrained cells. Fluid motion in the absence of strain also enhanced mineralization, but to a lesser degree. Because MAPK pathways mediate mechanically regulated osteoblast differentiation, we tested whether similar signaling was involved in mineralization by CVCs. In static cultures, pharmacological inhibition of the extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase pathways significantly attenuated mineral production by as much as -94\%, compared with uninhibited CVCs. Strikingly, although mechanical stimulation activated each of the MAPK pathways, inhibition of these pathways had no effect on the mechanically induced enhancement of alkaline phosphatase activity or mineralization. These novel data indicate that mechanical signals regulate calcification by CVCs, and although MAPK signaling is critical to CVC osteogenic differentiation and mineralization, it is not involved directly in transduction of mechanical signals to regulate these processes under the conditions utilized in this study.},
	keywords = {Alkaline Phosphatase, Animals, Anthracenes, Butadienes, Calcification, Physiologic, Cattle, Cell Differentiation, Cell Line, Cell Proliferation, DNA, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Imidazoles, JNK Mitogen-Activated Protein Kinases, Muscle, Smooth, Vascular, Nitriles, Osteogenesis, p38 Mitogen-Activated Protein Kinases, Pyridines, Signal Transduction, Stress, Mechanical},
	issn = {0021-9290},
	doi = {10.1016/j.jbiomech.2004.01.006},
	author = {Simmons, Craig A and Nikolovski, Janeta and Thornton, Amanda J and Matlis, Sean and Mooney, David J}
}
@article {217211,
	title = {Shape retaining injectable hydrogels for minimally invasive bulking},
	journal = {J Urol},
	volume = {172},
	number = {2},
	year = {2004},
	month = {2004 Aug},
	pages = {763-8},
	abstract = {PURPOSE: Particle migration, poor shape definition and/or rapid resorption limit the success of current urethral bulking agents. We propose that shape defining porous scaffolds that allow cell infiltration and anchoring, and may be delivered in a minimally invasive manner may provide many advantageous features.

MATERIALS AND METHODS: Alginate hydrogels were prepared with varying degrees of covalent cross-linking and different pore characteristics. Dehydrated scaffolds were compressed into smaller, temporary forms, introduced into the dorsal subcutaneous space of CD-1 mice by minimally invasive delivery through a 10 gauge angiocatheter and rehydrated in situ with a saline solution delivered through the same catheter. Ionically cross-linked calcium alginate gel served as a control. Specimens were harvested at 2, 6, 12 and 24 weeks to evaluate implant shape retention and volume, cell infiltration and calcification, and the presence of an inflammatory response.

RESULTS: A total of 90 scaffolds were implanted and 95\% were recovered at the site of injection. All of these scaffolds successfully rehydrated and 80\% recovered and maintained their original 3-dimensional shape for 6 months. Scaffold volume and tissue infiltration varied depending on the degree of alginate cross-linking. Highly cross-linked materials (20\% and 35\%) demonstrated the best volume maintenance with the latter facilitating the most tissue infiltration. The inflammatory response was minimal except with the 80\% cross-linked material. Calcification was not observed in covalently cross-linked scaffolds. In contrast, 98\% of calcium alginate implants were calcified.

CONCLUSIONS: Shape retaining porous hydrogels meet many of the requirements necessary for a successful injectable bulking agent and offer advantages over currently used agents.},
	keywords = {Alginates, Animals, Cross-Linking Reagents, Gels, Hydrogels, Implants, Experimental, Male, Mice, Mice, Inbred ICR, Urethra},
	issn = {0022-5347},
	doi = {10.1097/01.ju.0000130466.84214.f7},
	author = {Thornton, Amanda J and Alsberg, Eben and Hill, Elliot E and Mooney, David J}
}
@article {217216,
	title = {Shape-defining scaffolds for minimally invasive tissue engineering},
	journal = {Transplantation},
	volume = {77},
	number = {12},
	year = {2004},
	month = {2004 Jun 27},
	pages = {1798-803},
	abstract = {BACKGROUND: Minimally invasive surgical procedures are increasingly important in medicine, but biomaterials consistent with this delivery approach that allow one to control the structure of the material after implantation are lacking. Biomaterials with shape-memorizing properties could permit minimally invasive delivery of cell transplantation constructs and enable the formation of new tissues or structures in vivo in desired shapes and sizes.

METHODS: Macroporous alginate hydrogel scaffolds were prepared in a number of predefined geometries, compressed into significantly smaller, different "temporary" forms, and introduced into immunocompromised mice by means of minimally invasive surgical delivery through a small catheter. Scaffolds were rehydrated in situ with a suspension of cells (primary bovine articular chondrocytes) or cell-free medium and delivered through the same catheter. Specimens were harvested at 1 hr to evaluate the efficacy of cell delivery and the recovery of scaffold geometry, and at 8 and 24 weeks to evaluate neotissue formation.

RESULTS: A high percentage (88\%) of scaffolds that were introduced with a catheter and rehydrated with cells had recovered their original shape and size within 1 hr. This delivery procedure resulted in cartilage structures with the geometry of the original scaffold by 2 months and histologically mature appearing tissue at 6 months.

CONCLUSIONS: Shaped hydrogels, formed by covalently cross-linking, can be structurally collapsed into smaller, temporary shapes that permit their minimally invasive delivery in vivo. The rapid recovery of scaffold properties facilitates efficient cell seeding in vivo and permits neotissue formation in desired geometries.},
	keywords = {Alginates, Animals, Biocompatible Materials, Cartilage, Articular, Cattle, Chondrocytes, Glucuronic Acid, Hexuronic Acids, Hydrogels, Mice, Mice, SCID, Minimally Invasive Surgical Procedures, Models, Animal, Tissue Engineering},
	issn = {0041-1337},
	author = {Thornton, Amanda J and Alsberg, Eben and Albertelli, Megan and Mooney, David J}
}
@article {217176,
	title = {Synthetic extracellular matrices for tissue engineering and regeneration},
	journal = {Curr Top Dev Biol},
	volume = {64},
	year = {2004},
	month = {2004},
	pages = {181-205},
	abstract = {The need for replacement tissues or organs requires a tissue supply that cannot be satisfied by the donor supply. The tissue engineering and regeneration field is focused on the development of biological tissue and organ substitutes and may provide functional tissues to restore, maintain, or improve tissue formation. This field is already providing new therapeutic options to bypass the limitations of organ?tissue transplantation and will likely increase in medical importance in the future. This interdisciplinary field accommodates principles of life sciences and engineering and encompasses three major strategies. The first, guided tissue regeneration, relies on synthetic matrices that are conductive to host cells populating a tissue defect site and reforming the lost tissue. The second approach, inductive strategy, involves the delivery of growth factors, typically using drug delivery strategies, which are targeted to specific cell populations in the tissues surrounding the tissue defect. In the third approach, specific cell populations, typically multiplied in culture, are directly delivered to the site at which one desires to create a new tissue or organ. In all of these approaches, the knowledge acquired from developmental studies often serves as a template for the tissue engineering approach for a specific tissue or organ. This article overviews the development of synthetic extracellular matrices (ECMs) for use in tissue engineering that aim to mimic functions of the native ECM of developing and regenerating tissues. In addition to the potential therapeutic uses of these materials, they also provide model systems for basic studies that may shed light on developmental processes.},
	keywords = {Blood Vessels, Cell Transplantation, Extracellular Matrix, Genetic Therapy, Guided Tissue Regeneration, Humans, Neovascularization, Physiologic, Osteogenesis, Tissue Engineering},
	issn = {0070-2153},
	doi = {10.1016/S0070-2153(04)64008-7},
	author = {Silva, Eduardo A and Mooney, David J}
}
@article {217181,
	title = {Tracheal reconstruction using tissue-engineered cartilage},
	journal = {Arch Otolaryngol Head Neck Surg},
	volume = {130},
	number = {10},
	year = {2004},
	month = {2004 Oct},
	pages = {1191-6},
	abstract = {OBJECTIVES: To determine whether rabbit cartilage can be tissue engineered using a polyglycolic acid (PGA) construct composed of PGA mesh, autologous chondrocytes, and alginate covalently linked with the cell adhesion sequence arginine-glycine-aspartic acid (RGD), and to investigate the feasibility of reconstructing tracheal defects using the PGA construct in conjunction with a bioabsorbable intratracheal stent.

METHODS: Nineteen New Zealand White rabbits were used. Nine rabbits underwent subcutaneous implantation of 3 different PGA construct combinations: (1) PGA, autologous chondrocytes, and RGD-modified alginate; (2) PGA, autologous chondrocytes, and unmodified alginate; and (3) PGA and RGD-modified alginate. The remaining 10 animals underwent anterior tracheal reconstruction using fascia lata grafts and the complete PGA construct (PGA, autologous chondrocytes, and RGD-modified alginate). At the time of tracheal reconstruction, a poly-l-lactic acid intratracheal stent was placed in 5 of these latter animals. Rates of tracheal stenosis and mortality were compared with those of historical control animals. Histologic analysis was performed on the PGA constructs.

RESULTS: In the subcutaneous implants, the PGA constructs made with chondrocytes (with and without RGD) demonstrated mature cartilage formation in 7 (78\%) of the 9 animals. No cartilage was seen in PGA constructs made without chondrocytes. Two of the 10 animals that underwent tracheal reconstruction with the complete PGA construct survived to 20 weeks and demonstrated patent airways, 1 with a stent and 1 without a stent (80\% overall mortality). Histologic analysis showed mature cartilage formation at the tracheal reconstruction site. Historical control animals that underwent reconstruction with fascia lata alone demonstrated the lowest overall mortality.

CONCLUSIONS: Cartilage can be tissue engineered in rabbits using PGA mesh embedded with alginate-encapsulated autologous chondrocytes. It is also possible to reconstruct tracheal defects with this method of cartilage engineering, although the mortality rate in this study is high.},
	keywords = {Alginates, Animals, Biocompatible Materials, Chondrocytes, Chondrogenesis, Feasibility Studies, Glucuronic Acid, Hexuronic Acids, Lactic Acid, Polyesters, Polyglycolic Acid, Polymers, Rabbits, Stents, Surgical Mesh, Tissue Engineering, Trachea, Transplantation, Autologous},
	issn = {0886-4470},
	doi = {10.1001/archotol.130.10.1191},
	author = {Grimmer, J Fredrik and Gunnlaugsson, Chad B and Alsberg, Eben and Murphy, Hedwig S and Kong, Hyunjoon and Mooney, David J and Weatherly, Robert A}
}
@article {217156,
	title = {Role of poly(lactide-co-glycolide) particle size on gas-foamed scaffolds},
	journal = {J Biomater Sci Polym Ed},
	volume = {15},
	number = {12},
	year = {2004},
	month = {2004},
	pages = {1561-70},
	abstract = {Macroporous polymeric scaffolds are frequently used in tissue engineering to allow for cell seeding and host cell invasion of the scaffold following implantation. The process of gas foaming/particulate leaching (GF/PL) is one method to form porous three dimensional scaffolds from particulate poly(lactide-co-glycolide) (PLG). The current study was designed to test the hypothesis that the size of the polymer particles used in this process will control the properties of the scaffolds. Scaffolds were prepared from PLG particles of various sizes (less than 75 microm, 75-106 microm, 106-250 microm and 250-425 microm) and subsequently analyzed. Scaffolds formed from large particles (250-425 microm) displayed significantly decreased compressive moduli, as compared to scaffolds fabricated from smaller particles. In addition, these scaffolds have a pore structure that is less interconnected and contains closed pores. Analysis of tissue in-growth, utilizing a novel computer-aided method, demonstrated that scaffolds formed from smaller particle sizes (less than 106 microm) have significantly more tissue penetration than those formed from larger particle sizes (greater than 106 microm). These results indicate that using small PLG particles (less than 106 microm) leads to high elastic moduli, provides a more interconnected pore structure and promotes greater tissue penetration into the scaffolds in vivo.},
	keywords = {Animals, Elasticity, Implants, Experimental, Particle Size, Polyglactin 910, Porosity, Rats},
	issn = {0920-5063},
	author = {Riddle, Kathryn W and Mooney, David J}
}
@article {1192401,
	title = {Elastic biodegradable poly(glycolide-co-caprolactone) scaffold for tissue engineering},
	journal = {J Biomed Mater Res A},
	volume = {66},
	number = {1},
	year = {2003},
	month = {2003 Jul 01},
	pages = {29-37},
	abstract = {Cyclic mechanical strain has been demonstrated to enhance the development and function of engineered smooth muscle (SM) tissues, and it would be necessary for the development of the elastic scaffolds if one wishes to engineer SM tissues under cyclic mechanical loading. This study reports on the development of an elastic scaffold fabricated from a biodegradable polymer. Biodegradable poly(glycolide-co-caprolactone) (PGCL) copolymer was synthesized from glycolide and epsilon-caprolactone in the presence of stannous octoate as catalyst. The copolymer was characterized by (1)H-NMR, gel permeation chromatography and differential scanning calorimetry. Scaffolds for tissue engineering applications were fabricated from PGCL copolymer using the solvent-casting and particle-leaching technique. The PGCL scaffolds produced in this fashion had open pore structures (average pore size = 250 microm) without the usual nonporous skin layer on external surfaces. Mechanical testing revealed that PGCL scaffolds were far more elastic than poly(lactic-co-glycolic acid) (PLGA) scaffolds fabricated using the same method. Tensile mechanical tests indicated that PGCL scaffolds could withstand an extension of 250\% without cracking, which was much higher than withstood by PLGA scaffolds (10-15\%). In addition, PGCL scaffolds achieved recoveries exceeding 96\% at applied extensions of up to 230\%, whereas PLGA scaffolds failed (cracked) at an applied strain of 20\%. Dynamic mechanical tests showed that the permanent deformation of the PGCL scaffolds in a dry condition produced was less than 4\% of the applied strain, when an elongation of 20\% at a frequency of 1 Hz (1 cycle per second) was applied for 6 days. Moreover, PGCL scaffolds in a buffer solution also had permanent deformations less than 5\% of the applied strain when an elongation of 10\% at a frequency of 1 Hz was applied for 2 days. The usefulness of the PGCL scaffolds was demonstrated by engineering SM tissues in vivo. This study shows that the elastic PGCL scaffolds produced in this study could be used to engineer SM-containing tissues (e.g. blood vessels and bladders) in mechanically dynamic environments.},
	keywords = {Absorbable Implants, Animals, Biocompatible Materials, Cells, Cultured, Elasticity, Glycosides, Lactic Acid, Lactones, Male, Materials Testing, Mice, Mice, Nude, Microscopy, Electron, Scanning, Muscle, Smooth, Vascular, Nuclear Magnetic Resonance, Biomolecular, Polyglycolic Acid, Polymers, Rats, Rats, Sprague-Dawley, Stress, Mechanical, Tensile Strength, Tissue Engineering, Transplantation, Heterologous},
	issn = {1549-3296},
	doi = {10.1002/jbm.a.10497},
	author = {Lee, Soo-Hong and Kim, Byung-Soo and Kim, Soo Hyun and Choi, Sung Won and Jeong, Sung In and Kwon, Il Keun and Kang, Sun Woong and Nikolovski, Janeta and Mooney, David J and Han, Yang-Kyoo and Kim, Young Ha}
}
@article {1192406,
	title = {Growth of human blood vessels in severe combined immunodeficient mice. A new in vivo model system of angiogenesis},
	journal = {Methods Mol Med},
	volume = {78},
	year = {2003},
	month = {2003},
	pages = {161-77},
	keywords = {Animals, Biological Assay, Endothelium, Vascular, Humans, Mice, Mice, SCID, Models, Animal, Models, Biological, Neovascularization, Physiologic},
	issn = {1543-1894},
	doi = {10.1385/1-59259-332-1:161},
	author = {Polverini, Peter J and N{\"o}r, Jacques E and Peters, Martin C and Mooney, David J}
}
@article {217291,
	title = {Comparison of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in SCID mice},
	journal = {J Control Release},
	volume = {87},
	number = {1-3},
	year = {2003},
	month = {2003 Feb 21},
	pages = {49-56},
	abstract = {Therapeutic angiogenesis is a promising approach to treat patients with cardiovascular disease, and will likely be critical to engineering large tissues. Many growth factors have been found to play significant roles in angiogenesis, and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are the most extensively investigated angiogenic factors to date. However, the appropriate dose to obtain a desired response and the effectiveness of each factor, relative to the other, in promoting angiogenesis at a specific site in the body remains unclear. We have used alginate hydrogels as localized delivery vehicles for VEGF and bFGF, and compared the ability of these factors to promote new blood vessel formation in the subcutaneous tissue of severe combined immunodeficient (SCID) mice. We have found that the thickness of a granulation tissue layer formed around the gel and the number of blood vessels in the layer increased with the dose of VEGF in the gel, but the density of new blood vessels remained relatively constant. Sustained and localized delivery of bFGF from the gels, while similarly leading to an increase in the density of blood vessels in the granulation tissue, did not lead to as high of a blood vessel density as VEGF. The results of this study support previous studies demonstrating the utility of both VEGF and bFGF in promoting angiogenesis, and suggest VEGF is more appropriate for creating a dense bed of new blood vessels in this model.},
	keywords = {Angiogenesis Inducing Agents, Animals, Delayed-Action Preparations, Dose-Response Relationship, Drug, Fibroblast Growth Factor 2, Humans, Hydrogels, Mice, Mice, SCID, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A},
	issn = {0168-3659},
	author = {Lee, Kuen Yong and Peters, Martin C and Mooney, David J}
}
@article {217281,
	title = {Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway},
	journal = {J Biomech},
	volume = {36},
	number = {8},
	year = {2003},
	month = {2003 Aug},
	pages = {1087-96},
	abstract = {Physical stimuli play critical roles in the development, regeneration, and pathology of many mesenchymal tissues, most notably bone. While mature bone cells, such as osteoblasts and osteocytes, are clearly involved in these processes, the role of their progenitors in mechanically mediated tissue responses is unknown. In this study, we investigated the effect of cyclic substrate deformation on the proliferation and osteogenic differentiation of human mesenchymal stem cells (hMSCs). Application of equibiaxial cyclic strain (3\%, 0.25Hz) to hMSCs cultured in osteogenic media inhibited proliferation and stimulated a 2.3-fold increase in matrix mineralization over unstrained cells. The strain stimulus activated the extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinase pathways, but had no effect on c-Jun N-terminal kinase phosphorylation or activity. Strain-induced mineralization was largely mediated by ERK1/2 signaling, as inhibition of ERK1/2 attenuated calcium deposition by 55\%. Inhibition of the p38 pathway resulted in a more mature osteogenic phenotype, suggesting an inhibitory role for p38 signaling in the modulation of strain-induced osteogenic differentiation. These results demonstrate that mechanical signals regulate hMSC function, suggesting a critical role for physical stimulation of this specific cell population in mesenchymal tissue formation.},
	keywords = {Adult, Calcification, Physiologic, Cell Differentiation, Cells, Cultured, Extracellular Matrix, Humans, Mechanotransduction, Cellular, Mesenchymal Stromal Cells, Mitogen-Activated Protein Kinases, Movement, Osteogenesis, p38 Mitogen-Activated Protein Kinases, Periodicity, Physical Stimulation, Stress, Mechanical, Weight-Bearing},
	issn = {0021-9290},
	author = {Simmons, Craig A and Matlis, Sean and Thornton, Amanda J and Chen, Shaoqiong and Wang, Cun Yu and Mooney, David J}
}
@article {217301,
	title = {Cyclic strain inhibits switching of smooth muscle cells to an osteoblast-like phenotype},
	journal = {FASEB J},
	volume = {17},
	number = {3},
	year = {2003},
	month = {2003 Mar},
	pages = {455-7},
	abstract = {Ectopic calcification is commonly associated with cardiovascular disease, injury, aging, and biomaterial implantation. We hypothesized that the normal mechanical environment of smooth muscle cells (SMCs) inhibits a phenotypic switch to a pattern of gene expression more typical for bone and inducive for calcification. This hypothesis was tested using a 3-D engineered smooth muscle tissue model subjected to cyclic mechanical strain. This simplified model maintained a 3-D tissue architecture while eliminating systemic effects as can be seen with in vivo models. All engineered tissues were found to express bone-associated genes (osteopontin, matrix gla protein, alkaline phosphatase, and the transcription factor CBFA-1). Strikingly, however, expression of these genes was down-regulated in tissues exposed to cyclic strain at all time points ranging from 5 to 150 days. Furthermore, long-term strain played a protective role in regard to calcification, as unstrained tissues exhibited increased calcium deposition with respect to strained tissues. The results of this study suggest that without an appropriate mechanical environment, SMCs in 3-D culture undergo a phenotypic conversion to an osteoblast-like pattern of gene expression. This finding has significant implications for the mechanisms underlying a variety of cardiovascular diseases and indicates the broad utility of engineered tissue models in basic biology studies.},
	keywords = {Animals, Aorta, Calcification, Physiologic, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Models, Biological, Muscle, Smooth, Vascular, Neoplasm Proteins, Osteoblasts, Osteocalcin, Osteopontin, Phenotype, Rats, Sialoglycoproteins, Stress, Mechanical, Tissue Engineering, Transcription Factors},
	issn = {1530-6860},
	doi = {10.1096/fj.02-0459fje},
	author = {Nikolovski, Janeta and Kim, Byung-Soo and Mooney, David J}
}
@article {217271,
	title = {Designing alginate hydrogels to maintain viability of immobilized cells},
	journal = {Biomaterials},
	volume = {24},
	number = {22},
	year = {2003},
	month = {2003 Oct},
	pages = {4023-9},
	abstract = {Hydrogel-forming materials have been widely utilized as an immobilization matrix and transport vehicle for cells. Success in these applications is dependent upon maintaining cell viability through the gel preparation process. We hypothesized that the high viscosity of pre-gelled solutions typically used in these applications may decrease cell viability due to the high shear forces required to mix cells with these solutions. Further, we proposed this harmful effect could be mediated by decreasing the molecular weight (Mw) of the polymer used to form the gel, while maintaining its gel-forming ability. To investigate this hypothesis, alginate was used as model system, as this copolymer consists of cross-linkable guluronic acid (G) blocks and non-cross-linkable blocks. Decreasing the Mw of alginate using irradiation (e.g., irradiating at dose of 2 Mrad) decreased the low shear viscosity of 2\% (w/w) pre-gelled solutions from 1000 to 4 cP, while maintaining high elastic moduli, once cross-linked to form a gel. Importantly, the immobilization of cells with these polymer hydrogels increased cell viability from 40\% to 70\%, as compared to using high Mw polymer chains to form the gels. Furthermore, the solids concentration of gels formed with the low Mw alginate could be raised to further increase the moduli of gels without significantly deteriorating the viability of immobilized cells. This was likely due to the limited increase in the viscosity of these solutions. This material design approach may be useful with a variety of synthetic or naturally occurring block copolymers used to immobilize cells.},
	keywords = {Alginates, Biocompatible Materials, Cell Survival, Dose-Response Relationship, Drug, Glucuronic Acid, Hexuronic Acids, Hydrogel, Molecular Weight, Oligopeptides, Polymers},
	issn = {0142-9612},
	author = {Kong, Hyunjoon and Smith, Molly K and Mooney, David J}
}
@article {217311,
	title = {External mechanical strain regulates membrane targeting of Rho GTPases by controlling microtubule assembly},
	journal = {Am J Physiol Cell Physiol},
	volume = {284},
	number = {3},
	year = {2003},
	month = {2003 Mar},
	pages = {C627-39},
	abstract = {Transmission of externally applied mechanical forces to the interior of a cell requires coordination of biochemical signaling pathways with changes in cytoskeletal assembly and organization. In this study, we addressed one potential mechanism for this signal integration by applying uniform single external mechanical strains to aortic smooth muscle cells (SMCs) via their adhesion substrate. A tensile strain applied to the substrate for 15 min significantly increased microtubule (MT) assembly by 32 +/- 7\%, with no apparent effect on the cells{\textquoteright} focal adhesions as revealed by immunofluorescence and quantitative analysis of Triton X-100-insoluble vinculin levels. A compressive strain decreased MT mass by 24 +/- 9\% but did not influence the level of vinculin in focal adhesions. To understand the decoupling of these two cell responses to mechanical strain, we examined a redistribution of the small GTPases RhoA and Rac. Tensile strain was found to decrease the amount of membrane-associated RhoA and Rac by 70 +/- 9\% and 45 +/- 11\%, respectively, compared with static controls. In contrast, compressive strain increased membrane-associated RhoA and Rac levels by 74 +/- 17\% and 36 +/- 13\%, respectively. Disruption of the MT network by prolonged treatments with low doses of either nocodazole or paclitaxel before the application of strain abolished the redistribution of RhoA and Rac in response to the applied forces. Combined, these results indicate that the effects of externally applied mechanical strain on the distribution and activation of the Rho family GTPases require changes in the state of MT polymerization.},
	keywords = {Animals, Cell Adhesion, Cell Membrane, Cytoskeleton, Focal Adhesions, Lysophospholipids, Mechanotransduction, Cellular, Microtubules, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Nocodazole, Paclitaxel, rac GTP-Binding Proteins, Rats, Rats, Sprague-Dawley, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Stress, Mechanical},
	issn = {0363-6143},
	doi = {10.1152/ajpcell.00137.2002},
	author = {Putnam, Andrew J and Cunningham, James J and Pillemer, Brendan B L and Mooney, David J}
}
@article {217286,
	title = {Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells},
	journal = {Tissue Eng},
	volume = {9},
	number = {1},
	year = {2003},
	month = {2003 Feb},
	pages = {95-103},
	abstract = {One of the fundamental principles that underlies tissue-engineering strategies using cell transplantation is that a newly formed tissue must acquire and maintain sufficient vascularization in order to support its growth. Enhancing angiogenesis through delivery of growth factors is one approach to establishing a vascular network to these tissues. In this study, we tested the potential of bone marrow stromal cells (BMSCs) to modulate the growth and differentiation activities of blood vessel precursors, endothelial cells (ECs), by their secretion of soluble angiogenic factors. The growth and differentiation of cultured ECs were enhanced in response to exposure to BMSC conditioned medium (CM). Enzyme-linked immunosorbent assays demonstrated that both mouse and human BMSCs secreted significant quantities of vascular endothelial growth factor (VEGF) (2.4-3.1 ng/10(6) cells per day). Furthermore, eliminating the activity of BMSC-secreted VEGF with blocking antibodies completely blocked the CM effects on cultured ECs. These data demonstrate that human BMSCs secrete sufficient quantities of VEGF to enhance survival and differentiation of endothelial cells in vitro, and suggest they may be capable of directly orchestrating angiogenesis in vivo.},
	keywords = {Bone Marrow Cells, Cell Differentiation, Cell Survival, Endothelial Growth Factors, Endothelium, Vascular, Humans, Intercellular Signaling Peptides and Proteins, Lymphokines, Neovascularization, Physiologic, Stromal Cells, Tissue Engineering, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {1076-3279},
	doi = {10.1089/107632703762687573},
	author = {Kaigler, Darnell and Krebsbach, Paul H and Polverini, Peter J and Mooney, David J}
}
@article {217276,
	title = {Selective adipose tissue ablation by localized, sustained drug delivery},
	journal = {Plast Reconstr Surg},
	volume = {112},
	number = {1},
	year = {2003},
	month = {2003 Jul},
	pages = {162-70},
	abstract = {The reduction of adipose depots is widely considered to be the optimal approach to limit pathologies associated with obesity. While many current antiobesity strategies are centered on regulating satiety, these approaches typically attempt an overall weight loss and are unable to target distinct adipose depots specifically associated with disease risk. The authors report a novel therapeutic modality utilizing localized and sustained delivery of drugs to provide for the selective ablation of adipose tissue. Using the epididymal fat pad of Sprague-Dawley rats as a model, they injected into the tissue poly(lactide-co-glycolide) microspheres encapsulating tumor necrosis factor-alpha, a well-known regulator of adipose tissue mass. The utility of this approach was investigated in vivo by measuring the fat pad mass relative to the contralateral control within the same animal (n = 4 at each time point) and in vitro by measuring apoptosis in adipose organ cultures. The authors demonstrated control over the localization of tumor necrosis factor-alpha by performing blood analysis. This is the first report of localized drug delivery for adipose tissue ablation, and these results indicate the potential utility of the general tissue ablation approach for treatment of numerous pathologies.},
	keywords = {Adipose Tissue, Administration, Topical, Animals, Apoptosis, Biodegradation, Environmental, Blood Glucose, Delayed-Action Preparations, Drug Delivery Systems, Enzyme-Linked Immunosorbent Assay, Glycolates, Injections, Insulin, Lactic Acid, Male, Microspheres, Obesity, Organ Culture Techniques, Polyglycolic Acid, Rats, Rats, Sprague-Dawley, Tumor Necrosis Factor-alpha},
	issn = {0032-1052},
	doi = {10.1097/01.PRS.0000066346.48969.D7},
	author = {Richardson, Thomas P and Murphy, William L and Mooney, David J}
}
@article {217241,
	title = {The effects of poly(ethyleneimine) (PEI) molecular weight on reinforcement of alginate hydrogels},
	journal = {Cell Transplant},
	volume = {12},
	number = {7},
	year = {2003},
	month = {2003},
	pages = {779-85},
	abstract = {Alginate hydrogels are widely used for cell encapsulation and transplantation, and they are frequently surface reinforced with secondary polymers to enhance their mechanical rigidity and stability. We hypothesized that the molecular weight (MW) of the polymer utilized to reinforce alginate would be an important factor in their stability, particularly when the gel network was homogeneously reinforced with the polymer. This hypothesis was investigated with alginate hydrogels cross-linked with Ca2+, and reinforced throughout the bulk of the gel with poly(ethyleneimine) (PEI) having different MWs. Interactions between the two polymers became significant following gelation, leading to higher elastic moduli (E) than gels with no PEI. The decrease in E of gels incubated in isotonic salt solutions over time, utilized as an indication of gel break down, was ameliorated with an increase in the MW of the PEI. In addition, the dependencies of the moduli and viscoelasticity on the temperature also became smaller with the use of high MW PEI. This is likely due to the limited mobility of high MW PEI, leading to a higher energy for dissociation. The stable interactions between the alginate and PEI prevented alterations of the pore structure in the gels, and slowed the deterioration of gel properties even under continuous agitation in a bioreactor. The results of this study will likely be useful in designing alginate encapsulation strategies for various applications.},
	keywords = {Alginates, Biomechanical Phenomena, Hydrogels, Hydrogen-Ion Concentration, Kinetics, Molecular Weight, Polyethyleneimine},
	issn = {0963-6897},
	author = {Kong, Hyunjoon and Mooney, David J}
}
@article {217246,
	title = {Fabrication and in vitro testing of polymeric delivery system for condensed DNA},
	journal = {J Biomed Mater Res A},
	volume = {67},
	number = {4},
	year = {2003},
	month = {2003 Dec 15},
	pages = {1384-92},
	abstract = {Polyethylenimine (PEI) was combined with plasmid DNA and freeze dried following the addition of sucrose as a lyoprotectant and pore-forming agent. Freeze-dried PEI DNA condensates were dry mixed with granular polylactideglycolic acid (PLGA) then compression molded and sponged to encapsulated PEI DNA. A measurement of the elastic modulus indicated that 91 wt\% sucrose substituted for 95 wt\% sodium chloride as a porogen, resulting in PLGA sponges with a mechanical modulus of 100 kPa. The PEI DNA was retained (80\%) within PLGA sponges prepared with sucrose during the leaching and subsequent 2-week release studies, whereas sodium chloride PLGA sponges caused the premature release (100\%) of PEI DNA within 2 days. In vitro gene transfer studies with PEI DNA PLGA sponges established that adherent and infiltrating fibroblasts expressed reporter gene for 15 days compared with the short, 3-day expression mediated by direct gene of PEI DNA on cells in culture. The results demonstrate an approach to encapsulate condensed DNA in a PLGA sponge for the purpose of retaining DNA within the matrices and creating efficient gene transfer during tissue engineering.},
	keywords = {Animals, DNA, Circular, Elasticity, Fibroblasts, Gene Expression Regulation, Gene Transfer Techniques, Genes, Reporter, Lactic Acid, Materials Testing, Mice, NIH 3T3 Cells, Particle Size, Plasmids, Polyethyleneimine, Polyglycolic Acid, Polymers, Sucrose, Surface Properties},
	issn = {1549-3296},
	doi = {10.1002/jbm.a.20036},
	author = {Huang, Yen-Chen and Connell, Maureen and Park, Youmie and Mooney, David J and Rice, Kevin G}
}
@article {217266,
	title = {Hydrogels for tissue engineering: scaffold design variables and applications},
	journal = {Biomaterials},
	volume = {24},
	number = {24},
	year = {2003},
	month = {2003 Nov},
	pages = {4337-51},
	abstract = {Polymer scaffolds have many different functions in the field of tissue engineering. They are applied as space filling agents, as delivery vehicles for bioactive molecules, and as three-dimensional structures that organize cells and present stimuli to direct the formation of a desired tissue. Much of the success of scaffolds in these roles hinges on finding an appropriate material to address the critical physical, mass transport, and biological design variables inherent to each application. Hydrogels are an appealing scaffold material because they are structurally similar to the extracellular matrix of many tissues, can often be processed under relatively mild conditions, and may be delivered in a minimally invasive manner. Consequently, hydrogels have been utilized as scaffold materials for drug and growth factor delivery, engineering tissue replacements, and a variety of other applications.},
	keywords = {Biocompatible Materials, Biological Factors, Drug Design, Gels, Hydrogels, Tissue Engineering},
	issn = {0142-9612},
	author = {Drury, Jeanie L and Mooney, David J}
}
@article {217261,
	title = {Polymeric growth factor delivery strategies for tissue engineering},
	journal = {Pharm Res},
	volume = {20},
	number = {8},
	year = {2003},
	month = {2003 Aug},
	pages = {1103-12},
	abstract = {PURPOSE: Tissue engineering seeks to replace and regrow damaged or diseased tissues and organs from either cells resident in the surrounding tissue or cells transplanted to the tissue site. The purpose of this review is to present the application of polymeric delivery systems for growth factor delivery in tissue engineering.

METHODS: Growth factors direct the phenotype of both differentiated and stem cells, and methods used to deliver these molecules include the development of systems to deliver the protein itself, genes encoding the factor, or cells secreting the factor.

RESULTS: Results in animal models and clinical trials indicate that these approaches may be successfully used to promote the regeneration of numerous tissue types.

CONCLUSIONS: Controlling the dose, location, and duration of these factors through polymeric delivery strategies will dictate their utility in tissue regeneration.},
	keywords = {Animals, Cell Transplantation, Clinical Trials as Topic, Drug Carriers, Genetic Vectors, Growth Substances, Humans, Polymers, Regeneration, Technology, Pharmaceutical, Tissue Engineering, Wound Healing},
	issn = {0724-8741},
	author = {Chen, Ruth R and Mooney, David J}
}
@article {217251,
	title = {Protein-based signaling systems in tissue engineering},
	journal = {Curr Opin Biotechnol},
	volume = {14},
	number = {5},
	year = {2003},
	month = {2003 Oct},
	pages = {559-65},
	abstract = {Tissue engineering aims to replace damaged tissues or organs using either transplanted cells or host cells recruited to the target site. Protein signaling is crucial to regulate cell phenotype and thus engineered tissue structure and function. Biomaterial vehicles are being designed to incorporate and locally deliver various molecules involved in this signaling, including both growth factors and peptides that mimick whole proteins. Controlling the concentration, local duration and spatial distribution of these factors is key to their utility and efficacy. Recent advances have been made in the development of polymeric delivery systems intended to achieve this control.},
	keywords = {Biocompatible Materials, Bone Regeneration, Enzymes, Immobilized, Extracellular Matrix, Humans, Intercellular Signaling Peptides and Proteins, Neovascularization, Physiologic, Signal Transduction, Tissue Engineering, Vascular Endothelial Growth Factor A, Wound Healing},
	issn = {0958-1669},
	author = {Boontheekul, Tanyarut and Mooney, David J}
}
@article {217256,
	title = {Regulating bone formation via controlled scaffold degradation},
	journal = {J Dent Res},
	volume = {82},
	number = {11},
	year = {2003},
	month = {2003 Nov},
	pages = {903-8},
	abstract = {It is widely assumed that coupling the degradation rate of polymers used as cell transplantation carriers to the growth rate of the developing tissue will improve its quantity or quality. To test this hypothesis, we developed alginate hydrogels with a range of degradation rates by gamma-irradiating high-molecular-weight alginate to yield polymers of various molecular weights and structures. Decreasing the size of the polymer chains increased the degradation rate in vivo, as measured by implant retrieval rates, masses, and elastic moduli. Rapidly and slowly degrading alginates, covalently modified with RGD-containing peptides to control cell behavior, were then used to investigate the effect of biodegradation rate on bone tissue development in vivo. The more rapidly degrading gels led to dramatic increases in the extent and quality of bone formation. These results indicate that biomaterial degradability is a critical design criterion for achieving optimal tissue regeneration with cell transplantation.},
	keywords = {Absorbable Implants, Alginates, Animals, Biodegradation, Environmental, Elasticity, Gamma Rays, Hydrogels, Mice, Molecular Weight, Osteoblasts, Osteogenesis, Polymers, Rats, Tissue Engineering},
	issn = {0022-0345},
	doi = {10.1177/154405910308201111},
	author = {Alsberg, E and Kong, H J and Hirano, Y and M.K. Smith and Albeiruti, A and Mooney, D J}
}
@article {1192416,
	title = {Molecular-scale biomimicry},
	journal = {Nat Biotechnol},
	volume = {20},
	number = {1},
	year = {2002},
	month = {2002 Jan},
	pages = {30-1},
	keywords = {Animals, Biocompatible Materials, Biotechnology, Humans, Nanotechnology, Tissue Engineering},
	issn = {1087-0156},
	doi = {10.1038/nbt0102-30},
	author = {Murphy, William L and Mooney, David J}
}
@article {1192411,
	title = {Tissue compatibility of two biodegradable tubular scaffolds implanted adjacent to skin or buccal mucosa in mice},
	journal = {Tissue Eng},
	volume = {8},
	number = {4},
	year = {2002},
	month = {2002 Aug},
	pages = {649-59},
	abstract = {Radiation therapy for cancer in the head and neck region leads to a marked loss of salivary gland parenchyma, resulting in a severe reduction of salivary secretions. Currently, there is no satisfactory treatment for these patients. To address this problem, we are using both tissue engineering and gene transfer principles to develop an orally implantable, artificial fluid-secreting device. In the present study, we examined the tissue compatibility of two biodegradable substrata potentially useful in fabricating such a device. We implanted in Balb/c mice tubular scaffolds of poly-L-lactic acid (PLLA), poly-glycolic acid coated with PLLA (PGA/PLLA), or nothing (sham-operated controls) either beneath the skin on the back, a site widely used in earlier toxicity and biocompatibility studies, or adjacent to the buccal mucosa, a site quite different functionally and immunologically. At 1, 3, 7, 14, and 28 days postimplantation, implant sites were examined histologically, and systemic responses were assessed by conventional clinical chemistry and hematology analyses. Inflammatory responses in the connective tissue were similar regardless of site or type of polymer implant used. However, inflammatory reactions were shorter and without epithelioid and giant cells in sham-operated controls. Also, biodegradation proceeded more slowly with the PLLA tubules than with the PGA/PLLA tubules. No significant changes in clinical chemistry and hematology were seen due to the implantation of tubular scaffolds. These results indicate that the tissue responses to PLLA and PGA/PLLA scaffolds are generally similar in areas subjacent to skin in the back and oral cavity. However, these studies also identified several potentially significant concerns that must be addressed prior to initiating any clinical applications of this device.},
	keywords = {Animals, Biocompatible Materials, Drug Implants, Female, Inflammation, Lactic Acid, Mice, Mice, Inbred BALB C, Mouth Mucosa, Polyesters, Polyglycolic Acid, Polymers, Prostheses and Implants, Skin},
	issn = {1076-3279},
	doi = {10.1089/107632702760240562},
	author = {Aframian, D J and Redman, R S and Yamano, S and Nikolovski, J and Cukierman, E and Yamada, K. M. and Kriete, M F and Swaim, W D and Mooney, D J and Baum, B J}
}
@article {217346,
	title = {Alginate type and RGD density control myoblast phenotype},
	journal = {J Biomed Mater Res},
	volume = {60},
	number = {2},
	year = {2002},
	month = {2002 May},
	pages = {217-23},
	abstract = {Alginates are being increasingly used for cell encapsulation and tissue engineering applications; however, these materials cannot specifically interact with mammalian cells. We have covalently modified alginates of varying monomeric ratio with RGD-containing cell adhesion ligands using carbodiimide chemistry to initiate cell adhesion to these polymers. We hypothesized that we could control the function of cells adherent to RGD-modified alginate hydrogels by varying alginate polymer type and cell adhesion ligand density, and we have addressed this possibility by studying the proliferation and differentiation of C2C12 skeletal myoblasts adherent to these materials. RGD density on alginates of varying monomeric ratio could be controlled over several orders of magnitude, creating a range of surface densities from 1-100 fmol/cm(2). Myoblast adhesion to these materials was specific to the RGD ligand, because adhesion could be competed away with soluble RGD in a dose-dependent manner. Myoblast proliferation and differentiation could be regulated by varying the alginate monomeric ratio and the density of RGD ligands at the substrate surface, and specific combinations of alginate type and RGD density were required to obtain efficient myoblast differentiation on these materials.},
	keywords = {Alginates, Cell Adhesion, Cell Differentiation, Cell Division, Cell Fusion, Cell Line, Extracellular Matrix, Hexuronic Acids, Humans, Hydrogels, Iodine Radioisotopes, Isotope Labeling, Ligands, Muscle, Skeletal, Oligopeptides, Phenotype},
	issn = {0021-9304},
	author = {Rowley, Jon A and Mooney, David J}
}
@article {217341,
	title = {Bioinspired growth of crystalline carbonate apatite on biodegradable polymer substrata},
	journal = {J Am Chem Soc},
	volume = {124},
	number = {9},
	year = {2002},
	month = {2002 Mar 06},
	pages = {1910-7},
	abstract = {Mineralization in biological systems is a widespread, yet incompletely understood phenomenon involving complex interactions at the biomacromolecule-mineral nucleus interface. This study was aimed at understanding and controlling mineral formation in a poly(alpha-hydroxy ester) model system, to gain insight into biological mineralization processes and to develop biomaterials for orthopaedic tissue regeneration. We specifically hypothesized that providing a high surface density of anionic functional groups would enhance nucleation and growth of bonelike mineral following exposure to simulated body fluids (SBF). Polymer surface functionalization was achieved via hydrolysis of 85:15 poly(lactide-co-glycolide) (PLG) films. This treatment led to an increase in surface carboxylic acid and hydroxyl groups, resulting in a substantial increase in polymer surface energy from 42 to 49 dynes/cm2. Treated polymers exhibited a 3-fold increase in heterogeneous mineral grown and growth of a continuous mineral film on the polymer surface. The mineral grown on PLG surfaces is a carbonate apatite, the major mineral component of vertebrate bone tissue. Mineral crystal size and morphology were dependent on the solution characteristics but unaffected by the degree of surface prehydrolysis. The mechanism of heterogeneous carbonate apatite growth was examined via ion binding assays, which indicated that calcium binding is mediated independently by the presence of soluble phosphate counterions and surface functional groups. These findings indicate that poly(alpha-hydroxy ester) materials can be readily mineralized using a biomimetic process, and that the impetus for mineral nucleation in this system appears more complicated than the simple electrostatic interactions proposed in previous biomineralization theory.},
	keywords = {Apatites, Biocompatible Materials, Biodegradation, Environmental, Calcification, Physiologic, Carbonates, Molecular Mimicry, Polyesters, Polyglactin 910, Spectroscopy, Fourier Transform Infrared, Surface Properties},
	issn = {0002-7863},
	author = {Murphy, William L and Mooney, David J}
}
@article {217321,
	title = {Engineering growing tissues},
	journal = {Proc Natl Acad Sci U S A},
	volume = {99},
	number = {19},
	year = {2002},
	month = {2002 Sep 17},
	pages = {12025-30},
	abstract = {Regenerating or engineering new tissues and organs may one day allow routine replacement of lost or failing tissues and organs. However, these engineered tissues must not only grow to fill a defect and integrate with the host tissue, but often they must also grow in concert with the changing needs of the body over time. We hypothesized that tissues capable of growing with time could be engineered by supplying growth stimulus signals to cells from the biomaterial used for cell transplantation. In this study, chondrocytes and osteoblasts were cotransplanted on hydrogels modified with an RGD-containing peptide sequence to promote cell multiplication. New bone tissue was formed that grew in mass and cellularity by endochondral ossification in a manner similar to normal long-bone growth. Transplanted cells organized into structures that morphologically and functionally resembled growth plates. These engineered tissues could find utility in treating diseases and injuries of the growth plate, testing the effect of experimental drugs on growth-plate function and development, and investigating the biology of long-bone growth. Furthermore, this concept of promoting the growth of engineered tissues could find great utility in engineering numerous tissue types by way of the transplantation of a small number of precursor cells.},
	keywords = {Alginates, Animals, Biocompatible Materials, Bone Development, Cartilage, Cattle, Chondrocytes, Glucuronic Acid, Hexuronic Acids, Hydrogels, Male, Mice, Mice, SCID, Models, Biological, Oligopeptides, Osteoblasts, Rats, Rats, Inbred Lew, Tissue Engineering},
	issn = {0027-8424},
	doi = {10.1073/pnas.192291499},
	author = {Alsberg, Eben and Anderson, Kenneth W and Albeiruti, Amru and Rowley, Jon A and Mooney, David J}
}
@article {217331,
	title = {Engineering vascular networks in porous polymer matrices},
	journal = {J Biomed Mater Res},
	volume = {60},
	number = {4},
	year = {2002},
	month = {2002 Jun 15},
	pages = {668-78},
	abstract = {Enhanced vascularization is critical to the treatment of ischemic tissues and the engineering of new tissues and organs. We have investigated whether sustained and localized delivery of vascular endothelial growth factor (VEGF) combined with transplantation of human microvascular endothelial cells (HMVECs) can be used to engineer new vascular networks. VEGF was incorporated and released in a sustained manner from porous poly(lactic-co-glycolic acid) (PLG) matrices to promote angiogenesis at the transplantation site. VEGF could be incorporated and released in a biologically active form from PLG matrices, with the majority of VEGF release (64\%) occurring within 2 weeks. These matrices promoted a 260\% increase in the density of host SCID mouse-derived capillaries invading the matrices after 7 days of implantation, confirming the activity of the released VEGF. HMVECs were transplanted into SCID mice on PLG matrices, and organized to form immature human-derived vessels within 3 days. Functional vessels were observed within 7 days. Importantly, when HMVECs were transplanted on VEGF-releasing matrices, a 160\% increase in the density of human-derived blood vessels was observed after 14 days. These findings suggest that combining elements of vasculogenesis and angiogenesis provides a viable and novel approach to enhancing local vascularization.},
	keywords = {Animals, Biocompatible Materials, Blood Vessels, Cell Transplantation, Endothelial Growth Factors, Endothelium, Vascular, Humans, Intercellular Signaling Peptides and Proteins, Lymphokines, Male, Mice, Mice, SCID, Neovascularization, Physiologic, Polyglactin 910, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {0021-9304},
	author = {Peters, Martin C and Polverini, Peter J and Mooney, David J}
}
@article {217326,
	title = {Quantification of fibronectin adsorption to silicone-rubber cell culture substrates},
	journal = {Biotechniques},
	volume = {32},
	number = {4},
	year = {2002},
	month = {2002 Apr},
	pages = {876, 878, 880 passim},
	abstract = {As the role of mechanical force in cellular signaling gained recognition, investigators designed a number of devices to deliver controlled regimens of mechanical force to cultured cells. One type of device uses thin silicone-rubber membranes to support monolayer cell adhesion and to transmit mechanical force in the form of biaxial strain. We have observed that cell attachment and spreading are impaired on these membranes compared to polystyrene, even when both are passively coated with identical amounts of extracellular matrix. The purpose of these studies was to quantify the efficiency and stability of passive matrix adsorption onto commercially available elastic culture substrates. A theoretically saturating density (1 microg/cm2) of fibronectin was added to each well, and the initial efficiency of adsorption to the walls and elastic membranes was found to be 31 +/- 2\% of the protein added. Strikingly, when the protein adsorbed specifically to the membranes was quantified after seven days, only 10-26 ng/cm2 fibronectin were present, revealing that most of the adsorption is to the sides of the wells. These results indicate that the adsorption of matrix proteins to silicone-rubber substrates is relatively inefficient and that investigators who use these systems must be aware of this fact and design their experiments accordingly.},
	keywords = {Adsorption, Animals, Cell Adhesion, Cells, Cultured, Extracellular Matrix, Fibronectins, Male, Muscle, Smooth, Vascular, Rats, Rats, Inbred Lew, Silicone Elastomers},
	issn = {0736-6205},
	author = {Cunningham, James J and Nikolovski, Janeta and Linderman, Jennifer J and Mooney, David J}
}
@article {217336,
	title = {Salt fusion: an approach to improve pore interconnectivity within tissue engineering scaffolds},
	journal = {Tissue Eng},
	volume = {8},
	number = {1},
	year = {2002},
	month = {2002 Feb},
	pages = {43-52},
	abstract = {Macroporous scaffolds composed of biodegradable polymers have found extensive use as three-dimensional substrates either for in vitro cell seeding followed by transplantation, or as conductive substrates for direct implantation in vivo. Methods abound for creation of macroporous scaffolds for tissue engineering, and common methods typically employ a solid porogen within a three-dimensional polymer matrix to create a well-defined pore size, pore structure, and total scaffold porosity. This study describes an approach to impart improved pore interconnectivity to polymer scaffolds for tissue engineering by partially fusing the solid porogen together prior to creation of a continuous polymer matrix. Three dimensional, porous scaffolds of the copolymer 85:15 poly(lactide-co-glycolide) were fabricated via either a solvent casting/particulate leaching process, or a gas foaming/particulate leaching process. Prior to creation of a continuous polymer matrix the NaCl crystals, which serve as the solid porogen, are partially fused via treatment in 95\% humidity. Scanning electron micrographs clearly display fused salt crystals and an enhancement in pore interconnectivity in the salt fused scaffolds prepared via both solvent casting and gas foaming, and the extent of pore interconnectivity is enhanced with longer treatment times. Fusion of salt crystal for 24 h increased the radius of curvature of salt crystals, and led to a twofold increase in the compressive modulus of solvent cast scaffolds (total porosity of 97 +/- 1\%). Fusion of NaCl crystals prior to gas foaming resulted in a decrease in scaffold compressive modulus from 277 +/- 60k Pa to 187 +/- 30k Pa (total porosity of 94 +/- 1\%). The resulting highly interconnected scaffolds have implications for facilitated cell migration, abundant cell-cell interaction, and potentially improved neural and vascular growth within tissue engineering scaffolds.},
	keywords = {Biocompatible Materials, Extracellular Matrix, Microscopy, Electron, Scanning, Polymers, Sodium Chloride, Surface Properties, Tissue Engineering},
	issn = {1076-3279},
	doi = {10.1089/107632702753503045},
	author = {Murphy, William L and Dennis, Robert G and Kileny, Joel L and Mooney, David J}
}
@article {217306,
	title = {Evaluation of chain stiffness of partially oxidized polyguluronate},
	journal = {Biomacromolecules},
	volume = {3},
	number = {6},
	year = {2002},
	month = {2002 Nov-Dec},
	pages = {1129-34},
	abstract = {The chain stiffness of macromolecules is considered critical in their design and applications. This study utilizes polyguluronate derived from alginate, a typical polysaccharide widely utilized in many biomedical applications, as a model macromolecule to investigate how the chain stiffness can be tightly regulated by partial oxidation. Alginate has a backbone of inherently rigid alpha-L-guluronate (i.e., polyguluronate) and more flexible beta-D-mannuronate. The chain stiffness of the polyguluronate was specifically studied in this paper, as this component plays a critical role in the formation of alginate hydrogels with divalent cations and is the dominant factor in determining the chain stiffness of alginate. We have utilized size-exclusion chromatography, equipped with refractive index, viscosity, and light-scattering detectors, to determine the intrinsic viscosity and the weight-average molecular weight of each fraction of samples. The chain stiffness of partially oxidized polyguluronate was then evaluated from the exponent of the Mark-Houwink equation and the persistence length. We have found that partial oxidation can be used to tightly regulate the steric hindrance and stiffness of the polyguluronate backbone. This approach to control the chain stiffness of inherently rigid polysaccharides by partial oxidation may find many applications in biomedical utilization of these materials.},
	keywords = {Carbohydrate Conformation, Oxidation-Reduction, Periodic Acid, Polysaccharides, Bacterial},
	issn = {1525-7797},
	author = {Lee, Kuen Yong and Bouhadir, Kamal H and Mooney, David J}
}
@article {217316,
	title = {Externally applied cyclic strain regulates localization of focal contact components in cultured smooth muscle cells},
	journal = {Ann Biomed Eng},
	volume = {30},
	number = {7},
	year = {2002},
	month = {2002 Jul-Aug},
	pages = {927-35},
	abstract = {Mechanical signals are critical regulators of cellular gene expression, yet little is understood of the mechanism whereby cells sense mechanical forces. In this study we have tested the hypothesis that mechanical strain applied to populations of cells via their adhesion substrate rapidly alters the cellular distribution of focal contact proteins. Focal contact-associated components (vinculin, a-actinin, paxillin) were assayed by immunofluorescence microscopy and quantitative western blotting. Application of a single step increase in strain in multiple experiments caused overall a small change in focal contact-associated vinculin. In contrast, cyclic strain induced a large and very reproducible increase in detergent-insoluble vinculin (52\% relative to static) after just 1 min of strain. Insoluble paxillin was transiently enriched with a similar time course, whereas insoluble a-actinin did not change significantly in response to cyclic strain. Rhodamine-labeled chicken vinculin added to permeabilized cells preferentially localized to focal contacts in response to cyclic strain, but not a single step increase in strain. These findings establish that insoluble levels of focal contact components are altered rapidly following application of an appropriate number of mechanical perturbations, and suggest that at least one component of the mechanism does not involve soluble intermediates.},
	keywords = {Actinin, Animals, Aorta, Thoracic, Cell Adhesion, Cell Adhesion Molecules, Cells, Cultured, Cytoskeletal Proteins, Focal Adhesions, Male, Mechanotransduction, Cellular, Muscle, Smooth, Vascular, Paxillin, Periodicity, Phosphoproteins, Rats, Rats, Inbred Lew, Reproducibility of Results, Sensitivity and Specificity, Stress, Mechanical, Vinculin},
	issn = {0090-6964},
	author = {Cunningham, James J and Linderman, Jennifer J and Mooney, David J}
}
@article {217296,
	title = {Tissue engineering strategies for in vivo neovascularisation},
	journal = {Expert Opin Biol Ther},
	volume = {2},
	number = {8},
	year = {2002},
	month = {2002 Dec},
	pages = {805-18},
	abstract = {Neovascularisation is a promising alternative therapeutic approach to re-establish blood flow in ischaemic tissues of patients suffering from coronary artery or peripheral artery disease. Often, these patients are not suitable candidates for current revascularisation procedures such as coronary angioplasty or bypass surgery. Several strategies are presently under investigation to induce vascularisation by stimulating the body{\textquoteright}s natural processes of vasculogenesis, angiogenesis and arteriogenesis. These strategies involve transplantation of various cell types into the ischaemic site and the delivery of recombinant angiogenic agents through direct protein administration or gene transfer. We will examine the basic approaches for these neovacularisation strategies and their therapeutic potential as demonstrated in animal models and human trials to date.},
	keywords = {Animals, Cell Transplantation, Genetic Therapy, Growth Substances, Humans, Neovascularization, Physiologic, Tissue Engineering, Vascular Diseases},
	issn = {1471-2598},
	doi = {10.1517/14712598.2.8.805},
	author = {Ennett, Alessandra B and Mooney, David J}
}
@article {1192426,
	title = {Injection molding of chondrocyte/alginate constructs in the shape of facial implants},
	journal = {J Biomed Mater Res},
	volume = {55},
	number = {4},
	year = {2001},
	month = {2001 Jun 15},
	pages = {503-11},
	abstract = {Over one million patients per year undergo some type of procedure involving cartilage reconstruction. Polymer hydrogels, such as alginate, have been shown to be effective carriers for chondrocytes in subcutaneous cartilage formation. The goal of our current study was to develop a method to create complex structures (nose bridge, chin, etc.) with good dimensional tolerance to form cartilage in specific shapes. Molds of facial implants were prepared using Silastic ERTV. Suspensions of chondrocytes in 2\% alginate were gelled by mixing with CaSO(4) (0.2 g/mL) and injected into the molds. Constructs of various cell concentrations (10, 25, and 50 million/mL) were implanted in the dorsal aspect of nude mice and harvested at times up to 30 weeks. Analysis of implanted constructs indicated progressive cartilage formation with time. Proteoglycan and collagen constructs increased with time to approximately 60\% that of native tissue. Equilibrium modulus likewise increased with time to 15\% that of normal tissue, whereas hydraulic permeability decreased to 20 times that of native tissue. Implants seeded with greater concentrations of cells increased proteoglycan content and collagen content and equilibrium and decreased permeability. Production of shaped cartilage implants by this technique presents several advantages, including good dimensional tolerance, high sample-to-sample reproducibility, and high cell viability. This system may be useful in the large-scale production of precisely shaped cartilage implants.},
	keywords = {Absorbable Implants, Alginates, Animals, Biocompatible Materials, Cartilage, Chondrocytes, Face, Glucuronic Acid, Hexuronic Acids, Humans, Mice, Mice, Nude},
	issn = {0021-9304},
	author = {Chang, S C and Rowley, J A and Tobias, G and Genes, N G and Roy, A K and Mooney, D J and Vacanti, C A and Bonassar, L J}
}
@article {1192436,
	title = {Nonviral DNA delivery from polymeric systems},
	journal = {Methods Mol Med},
	volume = {65},
	year = {2001},
	month = {2001},
	pages = {195-207},
	abstract = {Gene therapy holds great promise for the treatment of disease by delivering genes encoding for therapeutic proteins. Although it was originally devised for the treatment of inherited genetic disorders, such as cystic fibrosis, recent work has expanded the applications of gene therapy to develop strategies for HIV, cancer (1), and wound healing applications (2). The challenge of gene therapy is to develop safe and efficient gene delivery systems (1). Most studies have focused on the use of viral vectors because of their potentially high efficiencies; however, the safety and ease of manufacturing of nonviral vectors may make them the preferred choice in the future.},
	issn = {1543-1894},
	doi = {10.1385/1-59259-139-6:195},
	author = {Shea, L D and Mooney, D J}
}
@article {1192431,
	title = {Promoting angiogenesis in engineered tissues},
	journal = {J Drug Target},
	volume = {9},
	number = {6},
	year = {2001},
	month = {2001},
	pages = {397-406},
	abstract = {There is a tremendous need for organs and tissues to replace those lost due to diseases or trauma. In theory, transplanting cells on biomaterial matrices can create functional tissue. A critical question, however, is how to supply cells embedded within large cell-polymer constructs with sufficient oxygen and nutrients to sustain their survival and proliferation, and allow for the integration of the developing tissue with the surrounding tissue. A rapid and high level of vascularization of transplanted polymer-cell matrices is essential in tissue engineering approaches to meet these challenges. This review summarizes the current approaches and materials under development in our laboratory to promote angiogenesis in engineered tissues.},
	keywords = {Alginates, Angiogenesis Inducing Agents, Bioartificial Organs, DNA, Drug Delivery Systems, Endothelium, Vascular, Extracellular Matrix, Growth Substances, Humans, Neovascularization, Physiologic, Polymers, Tissue Engineering, Tissue Transplantation},
	issn = {1061-186X},
	author = {Bouhadir, K H and Mooney, D J}
}
@article {1192421,
	title = {Using HSV-thymidine kinase for safety in an allogeneic salivary graft cell line},
	journal = {Tissue Eng},
	volume = {7},
	number = {4},
	year = {2001},
	month = {2001 Aug},
	pages = {405-13},
	abstract = {Extreme salivary hypofunction is a result of tissue damage caused by irradiation therapy for cancer in the head and neck region. Unfortunately, there is no currently satisfactory treatment for this condition that affects up to 40,000 people in the United States every year. As a novel approach to managing this problem, we are attempting to develop an orally implantable, fluid-secreting device (an artificial salivary gland). We are using the well-studied HSG salivary cell line as a potential allogeneic graft cell for this device. One drawback of using a cell line is the potential for malignant transformation. If such an untoward response occurred, the device could be removed. However, in the event that any HSG cells escaped, we wished to provide additional patient protection. Accordingly, we have engineered HSG cells with a hybrid adeno-retroviral vector, AdLTR.CMV-tk, to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene as a novel safety factor. Cells were grown on plastic plates or on poly-L-lactic acid disks and then transduced with different multiplicities of infection (MOIs) of the hybrid vector. Thereafter, various concentrations of ganciclovir (GCV) were added, and cell viability was tested. Transduced HSG cells expressed HSV-tk and were sensitive to GCV treatment. Maximal effects were seen at a MOI of 10 with 50 microM of GCV, achieving 95\% cell killing on the poly-L-lactic acid substrate. These results suggest that engineering the expression of a suicide gene in an allogeneic graft cell may provide additional safety for use in an artificial salivary gland device.},
	keywords = {Artificial Organs, Bioprosthesis, Cell Line, Genetic Vectors, Humans, Salivary Glands, Simplexvirus, Thymidine Kinase, Tissue Engineering, Transplantation, Homologous},
	issn = {1076-3279},
	doi = {10.1089/10763270152436463},
	author = {Aframian, D J and Zheng, C and Goldsmith, C M and Nikolovski, J and Cukierman, E and Yamada, K. M. and Mooney, D J and Birkedal-Hansen, H and Baum, B J}
}
@article {217401,
	title = {Control of microtubule assembly by extracellular matrix and externally applied strain},
	journal = {Am J Physiol Cell Physiol},
	volume = {280},
	number = {3},
	year = {2001},
	month = {2001 Mar},
	pages = {C556-64},
	abstract = {A number of studies have suggested that externally applied mechanical forces and alterations in the intrinsic cell-extracellular matrix (ECM) force balance equivalently induce changes in cell phenotype. However, this possibility has never been directly tested. To test this hypothesis, we directly investigated the response of the microtubule (MT) cytoskeleton in smooth muscle cells to both mechanical signals and alterations in the ECM. A tensile force that resulted in a positive 10\% step change in substrate strain increased MT mass by 34 +/- 10\% over static controls, independent of the cell adhesion ligand and tyrosine phosphorylation. Conversely, a compressive force that resulted in a negative 10\% step change in substrate strain decreased MT mass by 40 +/- 6\% over static controls. In parallel, increasing the density of the ECM ligand fibronectin from 50 to 1,000 ng/cm(2) in the absence of any applied force increased the amount of polymeric tubulin in the cell from 59 +/- 11\% to 81 +/- 13\% of the total cellular tubulin. These data are consistent with a model in which MT assembly is, in part, controlled by forces imposed on these structures, and they suggest a novel control point for MT assembly by altering the intrinsic cell-ECM force balance and applying external mechanical forces.},
	keywords = {Animals, Cells, Cultured, Collagen, Cytoskeleton, Extracellular Matrix, Fibronectins, Microtubules, Muscle, Smooth, Vascular, Phosphorylation, Polymers, Pressure, Rats, Stress, Mechanical, Tubulin, Tyrosine},
	issn = {0363-6143},
	author = {Putnam, A J and Schultz, K and Mooney, D J}
}
@article {217381,
	title = {Craniofacial tissue engineering},
	journal = {Crit Rev Oral Biol Med},
	volume = {12},
	number = {1},
	year = {2001},
	month = {2001},
	pages = {64-75},
	abstract = {There is substantial need for the replacement of tissues in the craniofacial complex due to congenital defects, disease, and injury. The field of tissue engineering, through the application of engineering and biological principles, has the potential to create functional replacements for damaged or pathologic tissues. Three main approaches to tissue engineering have been pursued: conduction, induction by bioactive factors, and cell transplantation. These approaches will be reviewed as they have been applied to key tissues in the craniofacial region. While many obstacles must still be overcome prior to the successful clinical restoration of tissues such as skeletal muscle and the salivary glands, significant progress has been achieved in the development of several tissue equivalents, including skin, bone, and cartilage. The combined technologies of gene therapy and drug delivery with cell transplantation will continue to increase treatment options for craniofacial cosmetic and functional restoration.},
	keywords = {Adipose Tissue, Biocompatible Materials, Biomedical Engineering, Bone Substitutes, Cartilage, Cell Movement, Cell Transplantation, Guided Tissue Regeneration, Head, Humans, Muscle, Skeletal, Regeneration, Salivary Glands, Skin, Artificial, Skull},
	issn = {1045-4411},
	author = {Alsberg, E and Hill, E E and Mooney, D J}
}
@article {217386,
	title = {Degradable and injectable poly(aldehyde guluronate) hydrogels for bone tissue engineering},
	journal = {J Biomed Mater Res},
	volume = {56},
	number = {2},
	year = {2001},
	month = {2001 Aug},
	pages = {228-33},
	abstract = {Degradable and injectable hydrogels may be ideal for bone-tissue engineering, especially in the craniofacial region because of the ease of access for injection. Alginate hydrogels potentially could be used as injectable cell delivery vehicles, but they exhibit a limited range of mechanical properties and uncontrollable disintegration time. Therefore we synthesized new hydrogels, composed of poly(aldehyde guluronate) (PAG) and adipic acid dihydrazide, that have a wide range of mechanical stiffness and controllable degradation rate. MC3T3-E1 cells adhered and multiplied on PAG hydrogels in vitro. When primary rat calvarial osteoblasts were mixed with PAG hydrogels and subcutaneously injected into the backs of mice, mineralized bone tissues were formed 9 weeks following implantation. These hydrogels may find wide utility as an injectable delivery system for bone precursor cells as well as for other applications in tissue engineering.},
	keywords = {3T3 Cells, Aldehydes, Alginates, Animals, Animals, Newborn, Biocompatible Materials, Biodegradation, Environmental, Biomedical Engineering, Bone and Bones, Cell Adhesion, Cells, Cultured, Cross-Linking Reagents, Elasticity, Injections, Subcutaneous, Mice, Mice, SCID, Osteoblasts, Polysaccharides, Rats, Skull, Time Factors},
	issn = {0021-9304},
	author = {Lee, K Y and Alsberg, E and Mooney, D J}
}
@article {217371,
	title = {Degradation of partially oxidized alginate and its potential application for tissue engineering},
	journal = {Biotechnol Prog},
	volume = {17},
	number = {5},
	year = {2001},
	month = {2001 Sep-Oct},
	pages = {945-50},
	abstract = {Alginate has been widely used in a variety of biomedical applications including drug delivery and cell transplantation. However, alginate itself has a very slow degradation rate, and its gels degrade in an uncontrollable manner, releasing high molecular weight strands that may have difficulty being cleared from the body. We hypothesized that the periodate oxidation of alginate, which cleaves the carbon-carbon bond of the cis-diol group in the uronate residue and alters the chain conformation, would result in promoting the hydrolysis of alginate in aqueous solutions. Alginate, oxidized to a low extent (approximately 5\%), degraded with a rate depending on the pH and temperature of the solution. This polymer was still capable of being ionically cross-linked with calcium ions to form gels, which degraded within 9 days in PBS solution. Finally, the use of these degradable alginate-derived hydrogels greatly improved cartilage-like tissue formation in vivo, as compared to alginate hydrogels.},
	keywords = {Absorbable Implants, Alginates, Animals, Biocompatible Materials, Biodegradation, Environmental, Calcium, Cattle, Chondrocytes, Gels, Glucuronic Acid, Hexuronic Acids, Hydrogels, Mice, Oxidation-Reduction, Tissue Engineering, Transplantation, Heterologous},
	issn = {8756-7938},
	doi = {10.1021/bp010070p},
	author = {Bouhadir, K H and Lee, K Y and Alsberg, E and Damm, K L and Anderson, K W and Mooney, D J}
}
@article {217391,
	title = {Engineering and characterization of functional human microvessels in immunodeficient mice},
	journal = {Lab Invest},
	volume = {81},
	number = {4},
	year = {2001},
	month = {2001 Apr},
	pages = {453-63},
	abstract = {SUMMARY: Current model systems used to investigate angiogenesis in vivo rely on the interpretation of results obtained with nonhuman endothelial cells. Recent advances in tissue engineering and molecular biology suggest the possibility of engineering human microvessels in vivo. Here we show that human dermal microvascular endothelial cells (HDMEC) transplanted into severe combined immunodeficient (SCID) mice on biodegradable polymer matrices differentiate into functional human microvessels that anastomose with the mouse vasculature. HDMEC were stably transduced with Flag epitope or alkaline phosphatase to confirm the human origin of the microvessels. Endothelial cells appeared dispersed throughout the sponge 1 day after transplantation, became organized into empty tubular structures by Day 5, and differentiated into functional microvessels within 7 to 10 days. Human microvessels in SCID mice expressed the physiological markers of angiogenesis: CD31, CD34, vascular cellular adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Human endothelial cells became invested by perivascular smooth muscle alpha-actin-expressing mouse cells 21 days after implantation. This model was used previously to demonstrate that overexpression of the antiapoptotic protein Bcl-2 in HDMEC enhances neovascularization, and that apoptotic disruption of tumor microvessels is associated with apoptosis of surrounding tumor cells. The proposed SCID mouse model of human angiogenesis is ideally suited for the study of the physiology of microvessel development, pathologic neovascular responses such as tumor angiogenesis, and for the development and investigation of strategies designed to enhance the neovascularization of engineered human tissues and organs.},
	keywords = {Absorbable Implants, Animals, Apoptosis, Biomarkers, Biomedical Engineering, Capillaries, Carcinoma, Squamous Cell, Cell Differentiation, Cell Line, Cell Transplantation, Endothelium, Vascular, Humans, Mice, Mice, SCID, Muscle, Smooth, Neovascularization, Pathologic, Neovascularization, Physiologic, Tumor Cells, Cultured},
	issn = {0023-6837},
	author = {N{\"o}r, J E and Peters, M C and Christensen, J B and Sutorik, M M and Linn, S and Khan, M K and Addison, C L and Mooney, D J and Polverini, P J}
}
@article {217376,
	title = {Hydrogels for combination delivery of antineoplastic agents},
	journal = {Biomaterials},
	volume = {22},
	number = {19},
	year = {2001},
	month = {2001 Oct},
	pages = {2625-33},
	abstract = {The systemic delivery of anticancer agents has been widely investigated during the past decade but localized delivery may offer a safer and more effective delivery approach. We have designed and synthesized a novel hydrogel to locally deliver antineoplastic agents, and demonstrate the different types of release that can be achieved from these hydrogels using three model drugs: methotrexate, doxorubicin, and mitoxantrone. Alginate was chemically modified into low molecular weight oligomers and cross-linked with a biodegradable spacer (adipic dihydrazide) to form biodegradable hydrogels. The model antineoplastic agents were loaded into the hydrogel via three different mechanisms. Methotrexate was incorporated within the pores of the hydrogel and was released by diffusion into the surrounding medium. Doxorubicin was covalently attached to the polymer backbone via a hydrolytically labile linker and was released following the chemical hydrolysis of the linker. Mitoxantrone was ionically complexed to the polymer and was released after the dissociation of this complex. These three release mechanisms could potentially be used to deliver a wide selection of antineoplastic agents, based on their chemical structure. This novel delivery system allows for the release of single or combinations of antineoplastic agents, and may find utility in localized antineoplastic agent delivery.},
	keywords = {Alginates, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Doxorubicin, Drug Carriers, Glucuronic Acid, Hexuronic Acids, Humans, Hydrogels, Kinetics, Methotrexate, Mitoxantrone, Models, Biological, Oxidation-Reduction, Phosphates, Sodium Chloride},
	issn = {0142-9612},
	author = {Bouhadir, K H and Alsberg, E and Mooney, D J}
}
@article {217396,
	title = {Up-Regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth},
	journal = {Cancer Res},
	volume = {61},
	number = {5},
	year = {2001},
	month = {2001 Mar 01},
	pages = {2183-8},
	abstract = {Vascular endothelial growth factor (VEGF) has been shown to be a potent mediator of angiogenesis that functions as a survival factor for endothelial cells by up-regulating Bcl-2 expression. We have recently reported that human dermal microvascular endothelial cells (HDMECs) seeded in biodegradable sponges and implanted into severe combined immunodeficient (SCID) mice organize into functional human microvessels that transport mouse blood cells. In this study, we implanted sponges seeded with OSCC-3 (oral squamous cell carcinoma) or SLK (Kaposi{\textquoteright}s sarcoma) together with endothelial cells into SCID mice to generate human tumors vascularized with human microvessels. This model system was used to examine the role of both endothelial cell Bcl-2 and the proangiogenic chemokine interleukin-8 (IL-8) on tumor growth and intratumoral microvascular density. Coimplantation of HDMECs overexpressing Bcl-2 (HDMEC-Bcl-2) and tumor cells resulted in a 3-fold enhancement of tumor growth when compared with the coimplantation of control HDMECs and tumor cells. This was associated with increased intratumoral microvascular density and enhanced endothelial cell survival. To determine whether the enhanced neovascularization mediated by Bcl-2 overexpression in endothelial cells was influenced by the synthesis of endogenous mediators of angiogenesis, we screened these cells for expression of VEGF, basic fibroblast growth factor (bFGF), and IL-8 by ELISA. HDMEC-Bcl-2 cells and VEGF-treated HDMECs exhibited a 15-fold and 4-fold increase, respectively, in the expression of the proangiogenic chemokine IL-8 in vitro, whereas the expression of VEGF and bFGF remained unchanged. Transfection of antisense Bcl-2 into HDMECs blocked VEGF-mediated induction of IL-8. Conditioned media from HDMEC-Bcl-2 induced proliferation and sprouting of endothelial cells in vitro and neovascularization in rat corneas. Anti-IL-8 antibody added to HDMEC-Bcl-2 conditioned media markedly reduced the potency of these responses. SCID mice bearing VEGF-producing tumor implants that were treated with anti-lL-8 antibody exhibited a 43\% reduction in microvessel density and a 50\% reduction in tumor weight compared with treatment with a nonspecific antibody. These results demonstrate that the up-regulation of Bcl-2 expression in endothelial cells that constitute tumor microvessels enhances intratumoral microvascular survival and density and accelerates tumor growth. Furthermore, endothelial cells that overexpress Bcl-2 have more angiogenic potential than control cells, and IL-8-neutralizing antibodies attenuate their angiogenic activity in vitro and in vivo.},
	keywords = {Animals, Antibodies, Carcinoma, Squamous Cell, Cell Division, Cell Transplantation, Disease Models, Animal, Endothelium, Vascular, Gene Expression Regulation, Genes, bcl-2, Humans, Interleukin-8, Mice, Mice, SCID, Mouth Neoplasms, Neoplasm Transplantation, Neoplasms, Neovascularization, Pathologic, Proto-Oncogene Proteins c-bcl-2, Rats, Sarcoma, Kaposi, Transplantation, Heterologous, Up-Regulation},
	issn = {0008-5472},
	author = {N{\"o}r, J E and Christensen, J and Liu, J. and Peters, M and Mooney, D J and Strieter, R M and Polverini, P J}
}
@article {217351,
	title = {Cell-interactive alginate hydrogels for bone tissue engineering},
	journal = {J Dent Res},
	volume = {80},
	number = {11},
	year = {2001},
	month = {2001 Nov},
	pages = {2025-9},
	abstract = {There is significant interest in the development of injectable carriers for cell transplantation to engineer bony tissues. In this study, we hypothesized that adhesion ligands covalently coupled to hydrogel carriers would allow one to control pre-osteoblast cell attachment, proliferation, and differentiation. Modification of alginate with an RGD-containing peptide promoted osteoblast adhesion and spreading, whereas minimal cell adhesion was observed on unmodified hydrogels. Raising the adhesion ligand density increased osteoblast proliferation, and a minimum ligand density (1.5-15 femtomoles/cm2) was needed to elicit this effect. MC3T3-E1 cells demonstrated increased osteoblast differentiation with the peptide-modified hydrogels, as confirmed by the up-regulation of bone-specific differentiation markers. Further, transplantation of primary rat calvarial osteoblasts revealed statistically significant increases of in vivo bone formation at 16 and 24 weeks with G4RGDY-modified alginate compared with unmodified alginate. These findings demonstrate that biomaterials may be designed to control bone development from transplanted cells.},
	keywords = {3T3 Cells, Alginates, Animals, Cell Adhesion, Cell Differentiation, Cell Division, Cell Transplantation, Hydrogels, Ligands, Mice, Oligopeptides, Osteoblasts, Osteogenesis, Rats, Rats, Sprague-Dawley, Tissue Engineering},
	issn = {0022-0345},
	doi = {10.1177/00220345010800111501},
	author = {Alsberg, E and Anderson, K W and Albeiruti, A and Franceschi, R T and Mooney, D J}
}
@article {217356,
	title = {Hydrogels for tissue engineering},
	journal = {Chem Rev},
	volume = {101},
	number = {7},
	year = {2001},
	month = {2001 Jul},
	pages = {1869-79},
	keywords = {Animals, Biomedical Engineering, Humans, Hydrogels, Polymers},
	issn = {0009-2665},
	author = {Lee, K Y and Mooney, D J}
}
@article {217361,
	title = {Polymeric delivery of proteins and plasmid DNA for tissue engineering and gene therapy},
	journal = {Crit Rev Eukaryot Gene Expr},
	volume = {11},
	number = {1-3},
	year = {2001},
	month = {2001},
	pages = {47-58},
	abstract = {In vivo gene expression can be altered by locally delivered DNA and proteins. The ability to deliver bioactive macromolecules, such as proteins and plasmid DNA, over controllable time frames represents a challenging engineering problem. Considerable success has been achieved with polymeric delivery systems that provide the capability to change cell function either acutely or chronically. This review focuses on controlled delivery of proteins and plasmid DNA from polymers and on the effects of controlled delivery on gene expression, and introduces some cell biological and biochemical parameters to be considered when delivering macromolecules to change cell behavior.},
	keywords = {Animals, Biological Availability, Biopolymers, Delayed-Action Preparations, DNA, Recombinant, Drug Carriers, Drug Compounding, Drug Delivery Systems, Drug Stability, Forecasting, Gene Expression Regulation, Genetic Therapy, Genetic Vectors, Glycolates, Growth Substances, Half-Life, Humans, Lactic Acid, Microspheres, Polyesters, Polyglycolic Acid, Polymers, Proteins, Tissue Engineering},
	issn = {1045-4403},
	author = {Richardson, T P and Murphy, W L and Mooney, D J}
}
@article {217366,
	title = {Polymeric system for dual growth factor delivery},
	journal = {Nat Biotechnol},
	volume = {19},
	number = {11},
	year = {2001},
	month = {2001 Nov},
	pages = {1029-34},
	abstract = {The development of tissues and organs is typically driven by the action of a number of growth factors. However, efforts to regenerate tissues (e.g., bone, blood vessels) typically rely on the delivery of single factors, and this may partially explain the limited clinical utility of many current approaches. One constraint on delivering appropriate combinations of factors is a lack of delivery vehicles that allow for a localized and controlled delivery of more than a single factor. We report a new polymeric system that allows for the tissue-specific delivery of two or more growth factors, with controlled dose and rate of delivery. The utility of this system was investigated in the context of therapeutic angiogenesis. We now demonstrate that dual delivery of vascular endothelial growth factor (VEGF)-165 and platelet-derived growth factor (PDGF)-BB, each with distinct kinetics, from a single, structural polymer scaffold results in the rapid formation of a mature vascular network. This is the first report of a vehicle capable of delivery of multiple angiogenic factors with distinct kinetics, and these results clearly indicate the importance of multiple growth factor action in tissue regeneration and engineering.},
	keywords = {Actins, Animals, Blood Vessels, Delayed-Action Preparations, Drug Delivery Systems, Drug Synergism, Endothelial Growth Factors, Kinetics, Lymphokines, Male, Mice, Mice, Inbred NOD, Microspheres, Neovascularization, Physiologic, Platelet-Derived Growth Factor, Polyglactin 910, Proto-Oncogene Proteins c-sis, Rats, Rats, Inbred Lew, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {1087-0156},
	doi = {10.1038/nbt1101-1029},
	author = {Richardson, T P and Peters, M C and Ennett, A B and Mooney, D J}
}
@article {1192441,
	title = {Comparative study of seeding methods for three-dimensional polymeric scaffolds},
	journal = {J Biomed Mater Res},
	volume = {52},
	number = {3},
	year = {2000},
	month = {2000 Dec 05},
	pages = {576},
	issn = {0021-9304},
	author = {Burg, K J and Holder, W D and Culberson, CR and Beiler, RJ and Greene, K G and Loebsack, A B and Roland, W D and Eiselt, P and Mooney, D J and Halberstadt, C R}
}
@article {1192451,
	title = {Comparative study of seeding methods for three-dimensional polymeric scaffolds},
	journal = {J Biomed Mater Res},
	volume = {51},
	number = {4},
	year = {2000},
	month = {2000 Sep 15},
	pages = {642-9},
	abstract = {Development of tissue-engineered devices may be enhanced by combining cells with porous absorbable polymeric scaffolds before implantation. The cells are seeded throughout the scaffolds and allowed to proliferate in vitro for a predetermined amount of time. The distribution of cells throughout the porous material is one critical component determining success or failure of the tissue-engineered device. This can influence both the successful integration of the device with the host tissue as well as the development of a vascularized network throughout the entire scaffold volume. This research sought to compare different seeding and proliferation methods to select an ideal method for a polyglycolide/aortic endothelial cell system. Two seeding environments, static and dynamic, and three proliferation environments, static, dynamic, and bioreactor, were analyzed, for a total of six possible methods. The six seeding and proliferation combinations were analyzed following a 1-week total culture time. It was determined that for this specific system, dynamic seeding followed by a dynamic proliferation phase is the least promising method and dynamic seeding followed by a bioreactor proliferation phase is the most promising.},
	keywords = {Animals, Biocompatible Materials, Biomedical Engineering, Bioreactors, Cell Count, Cell Division, Cells, Cultured, Endothelium, Vascular, Materials Testing, Microscopy, Electron, Scanning, Polyglycolic Acid, Rats},
	issn = {0021-9304},
	author = {Burg, K J and Holder, W D and Culberson, CR and Beiler, RJ and Greene, K G and Loebsack, A B and Roland, W D and Eiselt, P and Mooney, D J and Halberstadt, C R}
}
@article {1192446,
	title = {Delivering DNA with polymer matrices: applications in tissue engineering and gene therapy},
	journal = {Pharm Sci Technolo Today},
	volume = {3},
	number = {11},
	year = {2000},
	month = {2000 Nov 01},
	pages = {381-384},
	abstract = {DNA delivery from polymers is currently being applied to the multidisciplinary science of gene therapy and tissue engineering. This is motivated by the potential of treating a wide range of diseases and the provision of alternatives to tissue and organ transplantation. The combination of these fields involves the incorporation of genes into polymeric matrices that can be injected or implanted to promote tissue regeneration. This review presents an overview of current and developing polymer systems for gene delivery and tissue engineering.},
	issn = {1461-5347},
	author = {Madsen, S and Mooney, D J}
}
@article {1192461,
	title = {The growth and morphological behavior of salivary epithelial cells on matrix protein-coated biodegradable substrata},
	journal = {Tissue Eng},
	volume = {6},
	number = {3},
	year = {2000},
	month = {2000 Jun},
	pages = {209-16},
	abstract = {The purpose of this study was to examine the growth and morphology of a salivary epithelial cell line (HSG) in vitro on several biodegradable substrata as an important step toward developing an artificial salivary gland. The substrates examined were poly-L-lactic acid (PLLA), polyglycolic acid (PGA), and two co-polymers, 85\% and 50\% PLGA, respectively. The substrates were formed into 20- to 25-mm disks, and the cells were seeded directly onto the polymers or onto polymers coated with specific extracellular matrix proteins. The two copolymer substrates became friable over time in aqueous media and proved not useful for these experiments. The purified matrix proteins examined included fibronectin (FN), laminin (LN), collagen I, collagen IV, and gelatin. In the absence of preadsorbed proteins, HSG cells did not attach to the polymer disks. The cells, in general, behaved similarly on both PLLA and PGA, although optimal results were obtained consistently in PLLA. On FN-coated PLLA disks, HSG cells were able to form a uniform monolayer, which was dependent on time and FN concentration. Coating of disks with LN, collagen I, and gelatin also promoted monolayer growth. This study defines the conditions necessary for establishing a monolayer organization of salivary epithelial cells with rapid proliferation on a biodegradable substrate useful for tissue engineering.},
	keywords = {Artificial Organs, Cell Culture Techniques, Cell Division, Epithelial Cells, Extracellular Matrix Proteins, Humans, Lactic Acid, Polyesters, Polyglycolic Acid, Polymers, Salivary Glands},
	issn = {1076-3279},
	doi = {10.1089/10763270050044380},
	author = {Aframian, D J and Cukierman, E and Nikolovski, J and Mooney, D J and Yamada, K. M. and Baum, B J}
}
@article {1192466,
	title = {The impact of tissue engineering on dentistry},
	journal = {J Am Dent Assoc},
	volume = {131},
	number = {3},
	year = {2000},
	month = {2000 Mar},
	pages = {309-18},
	abstract = {BACKGROUND: Tissue engineering is a novel and highly exciting field of research that aims to repair damaged tissues as well as create replacement (bioartificial) organs.

OVERVIEW: The authors provide a general review of the principles underlying key tissue engineering strategies, as well as the typical components used. Several examples of preclinical and clinical progress are presented. These include passive approaches, such as dental implants, and inductive approaches that activate cells with specific molecular signals.

PRACTICE IMPLICATIONS: Tissue engineering will have a considerable effect on dental practice during the next 25 years. The greatest effects will likely be related to the repair and replacement of mineralized tissues, the promotion of oral wound healing and the use of gene transfer adjunctively.},
	keywords = {Animals, Biomedical Engineering, Cell Transplantation, Ethics, Dental, Forecasting, Humans, Technology, Dental},
	issn = {0002-8177},
	author = {Baum, B J and Mooney, D J}
}
@article {1192456,
	title = {Use of internal bioabsorbable PLGA "finger-type" stents in a rabbit tracheal reconstruction model},
	journal = {Arch Otolaryngol Head Neck Surg},
	volume = {126},
	number = {8},
	year = {2000},
	month = {2000 Aug},
	pages = {985-91},
	abstract = {OBJECTIVES: To design and develop a biodegradable tracheal stent that can be used internally to stabilize and support surgically reconstructed airways.

DESIGN: In vitro mechanical and degradative properties of 80:20 poly(D,L-lactide-co-glycolide) (PLGA) "finger-like" stents were determined. The stents were then tested in vivo in rabbits that underwent anterior patch tracheoplasties with fascia lata grafts. Comparisons were made between a control group and an internal stent group for stridor development, overall group mortality, reconstructed airway lumen size, and histological findings.

SUBJECTS: Twenty-five New Zealand white rabbits.

RESULTS: The average dry modulus for the internal stents was 6800 kPa. All of the internal stents cracked by 4 weeks in buffer solution. Significant mass loss was not noted in vitro until after 5 weeks in buffer solution. By 14 weeks, the stents were nearly 100\% degraded. The attrition rate for the control group was 23\% compared with 17\% for the experimental group. The stridor rate for the control group was also higher at 38\% compared with 17\% for the stented group. The stented rabbits had a significantly smaller average stenosis (23\%) across the entire reconstruction site than the control group (34\%) (P,
	keywords = {Animals, Biocompatible Materials, Biomechanical Phenomena, Disease Models, Animal, Fascia, Lactic Acid, Polyglycolic Acid, Polymers, Rabbits, Respiratory Sounds, Stents, Trachea, Transplants},
	issn = {0886-4470},
	author = {Robey, T C and V{\"a}limaa, T and Murphy, H S and T{\^o}rm{\^a}l{\^a}, P and Mooney, D J and Weatherly, R A}
}
@article {217476,
	title = {Bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery},
	journal = {J Control Release},
	volume = {64},
	number = {1-3},
	year = {2000},
	month = {2000 Feb 14},
	pages = {91-102},
	abstract = {Engineering new tissues utilizing cell transplantation on biodegradable polymer matrices is an attractive approach to treat patients suffering from the loss or dysfunction of a number of tissues and organs. The matrices must maintain structural integrity during the process of tissue formation, and promote the vascularization of the developing tissue. A number of molecules (angiogenic factors) have been identified that promote the formation of new vascular beds from endothelial cells present within tissues, and the localized, controlled delivery of these factors from a matrix may allow an enhanced vascularization of engineered tissues. We have developed a gas foaming polymer processing approach that allows the fabrication of three-dimensional porous matrices from bioabsorbable materials (e.g., copolymers of lactide and glycolide [PLG]) without the use of organic solvents or high temperatures. The effects of several processing parameters (e.g., gas type, polymer composition and molecular weight) on the process were studied. Several gases (CO(2), N(2), He) were utilized in the fabrication process, but only CO(2) resulted in the formation of highly porous, structurally intact matrices. Crystalline polymers (polylactide and polyglycolide) did not form porous matrices, while amorphous copolymers (50:50, 75:25, and 85:15 ratio of lactide:glycolide) foamed to yield matrices with porosity up to 95\%. The mechanical properties of matrices were also regulated by the choice of PLG composition and molecular weight. Angiogenic factors (e.g., vascular endothelial growth factor) were subsequently incorporated into matrices during the fabrication process, and released in a controlled manner. Importantly, the released growth factor retains over 90\% of its bioactivity. In summary, a promising system for the incorporation and delivery of angiogenic factors from three-dimensional, biodegradable polymer matrices has been developed, and the fabrication process allows incorporation under mild conditions.},
	keywords = {Absorption, Biomedical Engineering, Carbon Dioxide, Delayed-Action Preparations, Drug Delivery Systems, Drug Stability, Endothelial Growth Factors, Glycosides, Growth Substances, Helium, Lactic Acid, Lymphokines, Nitrogen, Polymers, Porosity, Time Factors, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {0168-3659},
	author = {Sheridan, M H and Shea, L D and Peters, M C and Mooney, D J}
}
@article {217471,
	title = {Growth of continuous bonelike mineral within porous poly(lactide-co-glycolide) scaffolds in vitro},
	journal = {J Biomed Mater Res},
	volume = {50},
	number = {1},
	year = {2000},
	month = {2000 Apr},
	pages = {50-8},
	abstract = {Strategies to engineer bone have focused on the use of natural or synthetic degradable materials as scaffolds for cell transplantation or as substrates to guide bone regeneration. The basic requirements of the scaffold material are biocompatibility, degradability, mechanical integrity, and osteoconductivity. A major design problem is satisfying each of these requirements with a single scaffold material. This study addresses this problem by describing an approach to combine the biocompatibility and degradability of a polymer scaffold with the osteoconductivity and mechanical reinforcement of a bonelike mineral film. We report the nucleation and growth of a continuous carbonated apatite mineral on the interior pore surfaces of a porous, degradable polymer scaffold via a one step, room temperature incubation process. A 3-dimensional, porous scaffold of the copolymer 85:15 poly(lactide-co-glycolide) was fabricated by a solvent casting, particulate leaching process. Fourier transform IR spectroscopy and scanning electron microscopy (SEM) analysis after different incubation times in a simulated body fluid (SBF) demonstrate the growth of a continuous bonelike apatite layer within the pores of the polymer scaffold. Quantification of phosphate on the scaffold displays the growth and development of the mineral film over time with an incorporation of 0.43 mg of phosphate (equivalent to 0.76 mg of hydroxyapatite) per scaffold after 14 days in SBF. The compressive moduli of polymer scaffolds increased fivefold with formation of a mineral film after a 16-day incubation time as compared to control scaffolds. In summary, this biomimetic treatment provides a simple, one step, room temperature method for surface functionalization and subsequent mineral nucleation and growth on biodegradable polymer scaffolds for tissue engineering.},
	keywords = {Analysis of Variance, Biocompatible Materials, Bone Regeneration, Calcium Phosphates, Gold, Kinetics, Lactic Acid, Metal Ceramic Alloys, Microscopy, Electron, Scanning, Models, Biological, Palladium, Polyglycolic Acid, Polymers, Spectroscopy, Fourier Transform Infrared},
	issn = {0021-9304},
	author = {Murphy, W L and Kohn, D H and Mooney, D J}
}
@article {217431,
	title = {Combining chondrocytes and smooth muscle cells to engineer hybrid soft tissue constructs},
	journal = {Tissue Eng},
	volume = {6},
	number = {4},
	year = {2000},
	month = {2000 Aug},
	pages = {297-305},
	abstract = {Engineering new tissues using cell transplantation may provide a valuable tool for reconstructive surgery applications. Chondrocyte transplantation in particular has been successfully used to engineer new tissue masses due to the low metabolic requirements of these cells. However, the engineered cartilaginous tissue is too rigid for many soft tissue applications. We propose that hybrid tissue engineered from chondrocytes and smooth muscle cells could reflect mechanical properties intermediate between these two cell types. In this study, rat aortic smooth muscle cells and pig auricular chondrocytes were co-cultured on polyglycolic acid fiber-based matrices to address this hypothesis. Mixed cell suspensions were seeded by agitating the polymer matrices and a cell suspension with an orbital shaker. After seeding, cell-polymer constructs were cultured in stirred bioreactors for 8 weeks. The cell density and extracellular matrix (collagen, elastin, and glycosaminoglycan) content of the engineered tissues were determined biochemically. After 8 weeks in culture, the hybrid tissue had a high cell density (5.8 x 108 cells/cm(3)), and elastin (519 microg/g wet tissue sample), collagen (272 microg/g wet tissue sample), and glycosaminoglycan (GAG; 10 microg/g wet tissue sample) content. Mechanical testing indicated the compressive modulus of the hybrid tissues after 8 weeks to be 40.8 +/- 4.1 kPa and the equilibrium compressive modulus to be 8.4 +/- 0.8 kPa. Thus, these hybrid tissues exhibited intermediate stiffness; they were less stiff than native cartilage but stiffer than native smooth muscle tissue. This tissue engineering approach may be useful to engineer tissues for a variety of reconstructive surgery applications.},
	keywords = {Animals, Aorta, Biocompatible Materials, Biomedical Engineering, Bioreactors, Cartilage, Articular, Cell Transplantation, Cells, Cultured, Chondrocytes, Coculture Techniques, Extracellular Matrix Proteins, Hybrid Cells, Muscle, Smooth, Vascular, Polyglycolic Acid, Rats, Stress, Mechanical, Swine},
	issn = {1076-3279},
	doi = {10.1089/107632700418029},
	author = {Brown, A N and Kim, B S and Alsberg, E and Mooney, D J}
}
@article {217446,
	title = {Dynamic seeding and in vitro culture of hepatocytes in a flow perfusion system},
	journal = {Tissue Eng},
	volume = {6},
	number = {1},
	year = {2000},
	month = {2000 Feb},
	pages = {39-44},
	abstract = {Our laboratory has investigated hepatocyte transplantation using biodegradable polymer matrices as an alternative treatment to end-stage liver disease. One of the major limitations has been the insufficient survival of an adequate mass of transplanted cells. This study investigates a novel method of dynamic seeding and culture of hepatocytes in a flow perfusion system. In experiment I, hepatocytes were flow-seeded onto PGA scaffolds and cultured in a flow perfusion system for 24 h. Overall metabolic activity and distribution of cells were assessed by their ability to reduce MTT. DNA quantification was used to determine the number of cells attached. Culture medium was analyzed for albumin content. In Experiment II, hepatocyte/polymer constructs were cultured in a perfusion system for 2 and 7 days. The constructs were examined by SEM and histology. Culture medium was analyzed for albumin. In experiment I, an average of 4.4 X 10(6) cells attached to the scaffolds by DNA quantification. Cells maintained a high metabolic activity and secreted albumin at a rate of 13 pg/cell/day. In experiment II, SEM demonstrated successful attachment of hepatocytes on the scaffolds after 2 and 7 days. Cells appeared healthy on histology and maintained a high rate of albumin secretion through day 7. Hepatocytes can be dynamically seeded onto biodegradable polymers and survive with a high rate of albumin synthesis in the flow perfusion culture system.},
	keywords = {Albumins, Animals, Biocompatible Materials, Biomedical Engineering, Cell Culture Techniques, Cell Survival, Cell Transplantation, Liver, Liver Transplantation, Microscopy, Electron, Scanning, Perfusion, Polyglycolic Acid, Rats},
	issn = {1076-3279},
	doi = {10.1089/107632700320874},
	author = {Kim, S S and Sundback, C A and Kaihara, S and Benvenuto, M S and Kim, B S and Mooney, D J and Vacanti, J P}
}
@article {217441,
	title = {Porous carriers for biomedical applications based on alginate hydrogels},
	journal = {Biomaterials},
	volume = {21},
	number = {19},
	year = {2000},
	month = {2000 Oct},
	pages = {1921-7},
	abstract = {Macroporous scaffolds are typically utilized in tissue engineering applications to allow for the migration of cells throughout the scaffold and integration of the engineered tissue with the surrounding host tissue. A method to form macroporous beads with an interconnected pore structure from alginate has been developed by incorporating gas pockets within alginate beads, stabilizing the gas bubbles with surfactants, and subsequently removing the gas. Macroporous scaffolds could be formed from alginate with different average molecular weights (5-200 kDa) and various surfactants. The gross morphology, amount of interconnected pores, and total void volume was investigated both qualitatively and quantitatively. Importantly, macroporous alginate beads supported cell invasion in vitro and in vivo.},
	keywords = {Alginates, Biocompatible Materials, Biomedical Engineering, Drug Carriers, Drug Design, Gases, Glucuronic Acid, Hexuronic Acids, Hydrogels, Microscopy, Electron, Scanning, Molecular Weight, Surface Properties, Surface-Active Agents},
	issn = {0142-9612},
	author = {Eiselt, P and Yeh, J and Latvala, R K and Shea, L D and Mooney, D J}
}
@article {217451,
	title = {Scaffolds for engineering smooth muscle under cyclic mechanical strain conditions},
	journal = {J Biomech Eng},
	volume = {122},
	number = {3},
	year = {2000},
	month = {2000 Jun},
	pages = {210-5},
	abstract = {Cyclic mechanical strain has been demonstrated to enhance the development and function of engineered smooth muscle (SM) tissues, but appropriate scaffolds for engineering tissues under conditions of cyclic strain are currently lacking. These scaffolds must display elastic behavior, and be capable of inducing an appropriate smooth muscle cell (SMC) phenotype in response to mechanical signals. In this study, we have characterized several scaffold types commonly utilized in tissue engineering applications in order to select scaffolds that exhibit elastic properties under appropriate cyclic strain conditions. The ability of the scaffolds to promote an appropriate SMC phenotype in engineered SM tissues under cyclic strain conditions was subsequently analyzed. Poly(L-lactic acid)-bonded polyglycolide fiber-based scaffolds and type I collagen sponges exhibited partially elastic mechanical properties under cyclic strain conditions, although the synthetic polymer scaffolds demonstrated significant permanent deformation after extended times of cyclic strain application. SM tissues engineered with type I collagen sponges subjected to cyclic strain were found to contain more elastin than control tissues, and the SMCs in these tissues exhibited a contractile phenotype. In contrast, SMCs in control tissues exhibited a structure more consistent with the nondifferentiated, synthetic phenotype. These studies indicate the appropriate choice of a scaffold for engineering tissues in a mechanically dynamic environment is dependent on the time frame of the mechanical stimulation, and elastic scaffolds allow for mechanically directed control of cell phenotype in engineered tissues.},
	keywords = {Animals, Aorta, Biomechanical Phenomena, Collagen, Culture Techniques, Elasticity, Lactic Acid, Male, Materials Testing, Membranes, Artificial, Muscle Development, Muscle, Smooth, Vascular, Periodicity, Phenotype, Polyesters, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew, Stress, Mechanical, Tensile Strength, Time Factors},
	issn = {0148-0731},
	author = {Kim, B S and Mooney, D J}
}
@article {217436,
	title = {Smooth muscle cell adhesion to tissue engineering scaffolds},
	journal = {Biomaterials},
	volume = {21},
	number = {20},
	year = {2000},
	month = {2000 Oct},
	pages = {2025-32},
	abstract = {Synthetic polyesters of lactic and glycolic acid, and the extracellular matrix molecule collagen are among the most widely-utilized scaffolding materials in tissue engineering. However, the mechanism of cell adhesion to these tissue engineering scaffolds has not been extensively studied. In this paper, the mechanism of adhesion of smooth muscle cells to these materials was investigated. Vitronectin was found to be the predominant matrix protein adsorbed from serum-containing medium onto polyglycolic acid, poly(lactic co-glycolic) acid, and collagen two-dimensional films and three-dimensional scaffolds. Fibronectin adsorbed to both materials as well, although to a much lower density. Smooth muscle cell adhesion was mediated through specific integrin receptors interacting with these adsorbed proteins, as evidenced by both immunostaining and blocking studies. The receptors involved in adhesion included the alpha(v)beta5 to vitronectin, the alpha5beta1 to fibronectin and the alpha2beta1 to collagen I. Identification of the specific receptors used to adhere to these polymers clarifies why smooth muscle tissue development differs on these scaffolds, and may allow one to design tissue formation by controlling the surface chemistry of tissue engineering scaffolds.},
	keywords = {Adsorption, Animals, Antibodies, Monoclonal, Biocompatible Materials, Blood Proteins, Cell Adhesion, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Extracellular Matrix Proteins, Fluorescent Antibody Technique, Integrins, Muscle, Smooth, Vascular, Rats},
	issn = {0142-9612},
	author = {Nikolovski, J and Mooney, D J}
}
@article {217426,
	title = {Survival and function of rat hepatocytes cocultured with nonparenchymal cells or sinusoidal endothelial cells on biodegradable polymers under flow conditions},
	journal = {J Pediatr Surg},
	volume = {35},
	number = {9},
	year = {2000},
	month = {2000 Sep},
	pages = {1287-90},
	abstract = {BACKGROUND/PURPOSE: The authors have investigated hepatocyte transplantation using biodegradable polymer scaffolds as a possible treatment of end-stage liver disease. The purpose of this study was to investigate the survival rate and function of hepatocytes alone or cocultured with other cell types on 3-dimensional biodegradable polymers for 7 days under continuous flow conditions in vitro.

METHODS: Hepatocytes (group 1, n = 8), hepatocytes with nonparenchymal cells (group 2, n = 7), or hepatocytes with sinusoidal endothelial cells (group 3, n = 6) were isolated from Lewis rats and seeded onto the polymer scaffolds. The polymer devices subsequently were placed under continuous flow conditions for 7 days. Albumin production from the constructs was measured each day, and urea nitrogen synthesis was examined on day 7. The devices also were examined by histology at day 7.

RESULTS: Histology results showed the presence of numerous viable hepatocytes on polymer devices, with no differences in hepatocyte viability between the 3 groups. Albumin secretion in the culture medium gradually decreased by day 7. There also were no significant differences in albumin production or urea nitrogen synthesis between the 3 groups at day 7.

CONCLUSIONS: Hepatocytes could survive on the 3-dimensional polymer scaffolds under flow conditions for 7 days, and albumin secretion and urea synthesis of hepatocytes were seen at day 7. Nonparenchymal cells and sinusoidal endothelial cells had no measurable effect on hepatocyte function in our continuous flow culture system.},
	keywords = {Animals, Cell Transplantation, Coculture Techniques, Hepatocytes, Male, Polymers, Rats, Rats, Inbred Lew, Survival Analysis},
	issn = {0022-3468},
	doi = {10.1053/jpsu.2000.9298},
	author = {Kaihara, S and Kim, S and Kim, B S and Mooney, D J and Tanaka, K and Vacanti, J P}
}
@article {217456,
	title = {Sustained and controlled release of daunomycin from cross-linked poly(aldehyde guluronate) hydrogels},
	journal = {J Pharm Sci},
	volume = {89},
	number = {7},
	year = {2000},
	month = {2000 Jul},
	pages = {910-9},
	abstract = {We have incorporated daunomycin, an antineoplastic agent, into a biodegradable hydrogel through a labile covalent bond. In brief, sodium alginate was chemically broken down to low molecular weight and followed by oxidation to prepare poly(aldehyde guluronate). Adipic dihydrazide was used to incorporate the drug into the polymer backbone and cross-link the polymer to form hydrogels. Daunomycin can be released from the hydrogel after the hydrolysis of the covalent linkage between the drug and the polymer. A wide range of release profiles of daunomycin (e.g., from 2 days to 6 weeks) has been achieved using these materials, and the biological activity of the released daunomycin was maintained.},
	keywords = {Aldehydes, Antibiotics, Antineoplastic, Biological Availability, Carbohydrate Sequence, Cell Survival, Cross-Linking Reagents, Daunorubicin, Delayed-Action Preparations, Humans, Hydrogel, Hydroxamic Acids, KB Cells, Molecular Sequence Data, Polysaccharides, Solubility, Spectrophotometry, Ultraviolet},
	issn = {0022-3549},
	doi = {10.1002/1520-6017(200007)89:7<910::AID-JPS8>3.0.CO;2-$\#$},
	author = {Bouhadir, K H and Kruger, G M and Lee, K Y and Mooney, D J}
}
@article {217421,
	title = {Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-glycolide) scaffolds for tissue engineering},
	journal = {Biomaterials},
	volume = {21},
	number = {24},
	year = {2000},
	month = {2000 Dec},
	pages = {2521-7},
	abstract = {Strategies to engineer bone tissue have focused on either: (1) the use of scaffolds for osteogenic cell transplantation or as conductive substrates for guided bone regeneration; or (2) release of inductive bioactive factors from these scaffold materials. This study describes an approach to add an inductive component to an osteoconductive scaffold for bone tissue engineering. We report the release of bioactive vascular endothelial growth factor (VEGF) from a mineralized, porous, degradable polymer scaffold. Three dimensional, porous scaffolds of the copolymer 85 : 15 poly(lactide-co-glycolide) were fabricated by including the growth factor into a gas foaming/particulate leaching process. The scaffold was then mineralized via incubation in a simulated body fluid. Growth of a bone-like mineral film on the inner pore surfaces of the porous scaffold is confirmed by mass increase measurements and quantification of phosphate content within scaffolds. Release of 125I-labeled VEGF was tracked over a 15 day period to determine release kinetics from the mineralized scaffolds. Sustained release from the mineralized scaffolds was achieved, and growth of the mineral film had only a minor effect on the release kinetics from the scaffolds. The VEGF released from the mineralized and non-mineralized scaffolds was over 70\% active for up to 12 days following mineralization treatment, and the growth of mineral had little effect on total scaffold porosity.},
	keywords = {Biocompatible Materials, Cells, Cultured, Endothelial Growth Factors, Humans, Lactic Acid, Lymphokines, Polyglycolic Acid, Polymers, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {0142-9612},
	author = {Murphy, W L and Peters, M C and Kohn, D H and Mooney, D J}
}
@article {217461,
	title = {Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway},
	journal = {J Vasc Res},
	volume = {37},
	number = {3},
	year = {2000},
	month = {2000 May-Jun},
	pages = {209-18},
	abstract = {Thrombospondin-1 (TSP1) is a potent natural inhibitor of angiogenesis. Although TSP1 has been reported to induce endothelial cell apoptosis in vitro and to downregulate neovascularization in vivo, the molecular mechanisms that link these two processes have yet to be established. Here we report that TSP1 mediates endothelial cell apoptosis and inhibits angiogenesis in association with increased expression of Bax, decreased expression of Bcl-2, and processing of caspase-3 into smaller proapoptotic forms. The ability of TSP1 to induce both endothelial cell apoptosis in vitro and to suppress angiogenesis in vivo was blocked by the caspase-3 inhibitor z-DEVD-FMK. TSP1 also attenuated VEGF-mediated Bcl-2 expression in endothelial cells in vitro and angiogenesis in vivo. Furthermore, TSP1 induced endothelial cell apoptosis and inhibited neovascularization in sponge implants in SCID mice. We conclude that TSP1 induces endothelial cell apoptosis and inhibits neovascularization by altering the profile of survival gene expression and activating caspase-3.},
	keywords = {3T3 Cells, Animals, Apoptosis, bcl-2-Associated X Protein, Caspase 3, Caspase Inhibitors, Caspases, Cells, Cultured, Cysteine Proteinase Inhibitors, Dose-Response Relationship, Drug, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Activation, Lymphokines, Mice, Mice, SCID, Neovascularization, Physiologic, Oligopeptides, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Rats, Skin, Thrombospondin 1, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {1018-1172},
	doi = {25733},
	author = {N{\"o}r, J E and Mitra, R S and Sutorik, M M and Mooney, D J and Castle, V P and Polverini, P J}
}
@article {217416,
	title = {Biodegradable external tracheal stents and their use in a rabbit tracheal reconstruction model},
	journal = {Laryngoscope},
	volume = {110},
	number = {11},
	year = {2000},
	month = {2000 Nov},
	pages = {1936-42},
	abstract = {OBJECTIVES/HYPOTHESIS: To design and develop an external biodegradable tracheal stent for use in airway reconstructive surgery.

STUDY DESIGN: Experimental model.

METHODS: Biodegradable external tracheal stents were fabricated from polyglycolic acid and poly(D,L-lactide-co-glycolide) (85:15). In vitro studies were performed to analyze the mechanical properties and degradative characteristics of these stents. Then the stents were tested in vivo in an anterior tracheal reconstruction model in New Zealand white rabbits.

RESULTS: The average dry modulus for the external stents was 1,800 kilopascal (kPa). All of the external stents cracked by 4 weeks in buffer solution. Significant mass loss was not appreciated until after 10 weeks in solution, but by 20 weeks the stents were nearly 100\% degraded. In the in vivo portion of the study, the attrition rate for the control group was 23.1\% versus 50\% for the external stent group. The stridor rate was approximately 38\% for both groups Of the rabbits that survived the entire 3 months of the study, the stented group, when measured by a balloon catheter method, had more patent airways than the control group, with an average stenosis of 27.8\% versus 47.2\%, respectively (P < .05). However, more accurate postmortem cast measurements of the internal airways did not confirm this.

CONCLUSIONS: The external biodegradable tracheal stent employed in this study degraded in a predictable fashion and may provide a new method to augment surgical reconstruction of the anterior tracheal wall.},
	keywords = {Absorbable Implants, Animals, Polyglycolic Acid, Rabbits, Stents, Trachea},
	issn = {0023-852X},
	doi = {10.1097/00005537-200011000-00032},
	author = {Robey, T C and Eiselt, P M and Murphy, H S and Mooney, D J and Weatherly, R A}
}
@article {217406,
	title = {Controlled growth factor release from synthetic extracellular matrices},
	journal = {Nature},
	volume = {408},
	number = {6815},
	year = {2000},
	month = {2000 Dec 21-28},
	pages = {998-1000},
	abstract = {Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.},
	keywords = {Alginates, Animals, Biomedical Engineering, Collateral Circulation, Culture Techniques, Diabetes Mellitus, Type 1, Drug Delivery Systems, Drug Implants, Endothelial Growth Factors, Extracellular Matrix, Femoral Artery, Glucuronic Acid, Hexuronic Acids, Hydrogels, Lymphokines, Mice, Mice, Inbred NOD, Mice, SCID, Neovascularization, Physiologic, Physical Stimulation, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Wound Healing},
	issn = {0028-0836},
	doi = {10.1038/35050141},
	author = {Lee, K Y and Peters, M C and Anderson, K W and Mooney, D J}
}
@article {217411,
	title = {Engineered bone development from a pre-osteoblast cell line on three-dimensional scaffolds},
	journal = {Tissue Eng},
	volume = {6},
	number = {6},
	year = {2000},
	month = {2000 Dec},
	pages = {605-17},
	abstract = {Bone regeneration is based on the hypothesis that healthy progenitor cells, either recruited or delivered to an injured site, can ultimately regenerate lost or damaged tissue. Three-dimensional porous polymer scaffolds may enhance bone regeneration by creating and maintaining a space that facilitates progenitor cell migration, proliferation, and differentiation. As an initial step to test this possibility, osteogenic cells were cultured on scaffolds fabricated from biodegradable polymers, and bone development on these scaffolds was evaluated. Porous polymer scaffolds were fabricated from biodegradable polymers of lactide and glycolide. MC3T3-E1 cells were statically seeded onto the polymer scaffolds and cultured in vitro in the presence of ascorbic acid and beta-glycerol phosphate. The cells proliferated during the first 4 weeks in culture and formed a space-filling tissue. Collagen messenger RNA levels remained high in these cells throughout the time in culture, which is consistent with an observed increase in collagen deposition on the polymer scaffold. Mineralization of the deposited collagen was initially observed at 4 weeks and subsequently increased. The onset of mineralization corresponded to increased mRNA levels for two osteoblast-specific genes: osteocalcin and bone sialoprotein. Culture of cell/polymer constructs for 12 weeks led to formation of a three-dimensional tissue with architecture similar to that of native bone. These studies demonstrate that osteoblasts within a three-dimensional engineered tissue follow the classic differentiation pathway described for two-dimensional culture. Polymer scaffolds such as these may ultimately be used clinically to enhance bone regeneration by delivering or recruiting progenitor cells to the wound site.},
	keywords = {3T3 Cells, Animals, Biocompatible Materials, Cell Adhesion, Cell Culture Techniques, Cell Differentiation, Cell Division, Collagen, Extracellular Matrix, Lactic Acid, Mice, Osteoblasts, Osteogenesis, Polyglycolic Acid, Polymers, Stem Cells},
	issn = {1076-3279},
	doi = {10.1089/10763270050199550},
	author = {Shea, L D and Wang, D and Franceschi, R T and Mooney, D J}
}
@article {216946,
	title = {High-resolution elasticity imaging for tissue engineering},
	journal = {IEEE Trans Ultrason Ferroelectr Freq Control},
	volume = {47},
	number = {4},
	year = {2000},
	month = {2000},
	pages = {956-66},
	abstract = {An elasticity microscope provides high resolution images of tissue elasticity. With this instrument, it may be possible to monitor cell growth and tissue development in tissue engineering. To test this hypothesis, elasticity micrographs were obtained in two model systems commonly used for tissue engineering. In the first, strain images of a tissue-engineered smooth muscle sample clearly identified a several hundred micron thick cell layer from its supporting matrix. Because a one-dimensional mechanical model was appropriate for this system, strain images alone were sufficient to image the elastic properties. In contrast, a second system was investigated in which a simple one-dimensional mechanical model was inadequate. Uncultured collagen microspheres embedded in an otherwise homogeneous gel were imaged with the elasticity microscope. Strain images alone did not clearly depict the elastic properties of the hard spherical cell carriers. However, reconstructed elasticity images could differentiate the hard inclusion from the background gel. These results strongly suggest that the elasticity microscope may be a valuable tool for tissue engineering and other applications requiring the elastic properties of soft tissue at high spatial resolution (75 microm or less).},
	issn = {0885-3010},
	doi = {10.1109/58.852079},
	author = {Abraham Cohn, N and Kim, B S and Erkamp, R Q and Mooney, D J and Emelianov, S Y and Skovoroda, A R and O{\textquoteright}Donnell, M}
}
@article {1192481,
	title = {Parameters affecting cellular adhesion to polylactide films},
	journal = {J Biomater Sci Polym Ed},
	volume = {10},
	number = {2},
	year = {1999},
	month = {1999},
	pages = {147-61},
	abstract = {Absorbable biomaterials have been recently incorporated into the field of tissue engineering. Little work has been performed, even with the clinically acceptable absorbables, concerning their tissue promoting capability or lack, thereof. Furthermore, the relative attractions of cells to these implants may be largely disguised by the presence of serum. This research involved the development of an adhesion assay to compare the adhesion behavior of two cell types to two different polylactides in a serum free environment. The results showed that the attachment behavior depends not only on the cell or the polymer but a combination of the two.},
	keywords = {Animals, Cell Adhesion, Cell Count, Cell Culture Techniques, Culture Media, Serum-Free, Endothelium, Vascular, Female, Glucose, Lactic Acid, Muscle, Smooth, Polyesters, Rats, Temperature, Time Factors},
	issn = {0920-5063},
	author = {Burg, K J and Holder, W D and Culberson, CR and Beiler, RJ and Greene, K G and Loebsack, A B and Roland, W D and Mooney, D J and Halberstadt, C R}
}
@article {1192476,
	title = {Pilomatrix carcinoma of the eyelid},
	journal = {Am J Ophthalmol},
	volume = {127},
	number = {4},
	year = {1999},
	month = {1999 Apr},
	pages = {463-4},
	abstract = {PURPOSE: To report a case of a recurring mass with an unusual origin on the eyelid of a 34-year-old man.

METHOD: Case report.

RESULT: Histology demonstrated that the mass was a pilomatrix carcinoma.

CONCLUSION: An atypical mass with unusual symptoms or signs needs definitive treatment and diagnostic confirmation with histology.},
	keywords = {Adult, Eyelid Neoplasms, Hair Diseases, Humans, Male, Pilomatrixoma, Skin Neoplasms},
	issn = {0002-9394},
	author = {Cahill, M T and Moriarty, P M and Mooney, D J and Kennedy, S M}
}
@article {1192471,
	title = {Re-engineering the functions of a terminally differentiated epithelial cell in vivo},
	journal = {Ann N Y Acad Sci},
	volume = {875},
	year = {1999},
	month = {1999 Jun 18},
	pages = {294-300},
	abstract = {Because of their easy access, and important role in oral homeostasis, mammalian salivary glands provide a unique site for addressing key issues and problems in tissue engineering. This manuscript reviews studies by us in three major directions involving re-engineering functions of salivary epithelial cells. Using adenoviral-mediated gene transfer in vivo, we show approaches to i) repair damaged, hypofunctional glands and ii) redesign secretory functions to include endocrine as well as exocrine pathways. The third series of studies show our general approach to develop an artificial salivary gland for clinical situations in which all glandular tissue has been lost.},
	keywords = {Animals, Artificial Organs, Cell Differentiation, Humans, Salivary Glands},
	issn = {0077-8923},
	author = {Baum, B J and S. Wang and Cukierman, E and Delporte, C and Kagami, H and Marmary, Y and Fox, P C and Mooney, D J and Yamada, K. M.}
}
@article {217541,
	title = {Alginate hydrogels as synthetic extracellular matrix materials},
	journal = {Biomaterials},
	volume = {20},
	number = {1},
	year = {1999},
	month = {1999 Jan},
	pages = {45-53},
	abstract = {Alginate hydrogels are used extensively in cell encapsulation, cell transplantation, and tissue engineering applications. Alginates possess many favorable properties required in biomaterials, but are unable to specifically interact with mammalian cells. We have therefore covalently modified alginate polysaccharides with RGD-containing cell adhesion ligands utilizing aqueous carbodiimide chemistry. The chemistry has been optimized and quantified with reaction efficiencies reaching 80\% or greater. The concentration of peptide available for reaction was then varied to create hydrogels with a range of ligand densities. Mouse skeletal myoblasts were cultured on alginate hydrogel surfaces coupled with GRGDY peptides to illustrate achievement of cellular interaction with the otherwise non-adhesive hydrogel substrate. Myoblasts adhere to GRGDY-modified alginate surfaces, proliferate, fuse into multinucleated myofibrils, and express heavy-chain myosin which is a differentiation marker for skeletal muscle. Myoblast adhesion and spreading on these GRGDY-modified hydrogels was inhibited with soluble ligand added to the seeding medium, illustrating the specificity of adhesion to these materials. Alginate may prove to be an ideal material with which to confer specific cellular interactive properties, potentially allowing for the control of long-term gene expression of cells within these matrices.},
	keywords = {Alginates, Amino Acid Sequence, Animals, Biocompatible Materials, Cell Adhesion, Cell Division, Cell Line, Extracellular Matrix, Hydrogels, Indicators and Reagents, Ligands, Mice, Muscle, Skeletal, Oligopeptides},
	issn = {0142-9612},
	author = {Rowley, J A and Madlambayan, G and Mooney, D J}
}
@article {217536,
	title = {Regenerative signals for intestinal epithelial organoid units transplanted on biodegradable polymer scaffolds for tissue engineering of small intestine},
	journal = {Transplantation},
	volume = {67},
	number = {2},
	year = {1999},
	month = {1999 Jan 27},
	pages = {227-33},
	abstract = {BACKGROUND: Our laboratory is investigating the tissue engineering of small intestine using intestinal epithelial organoid units seeded onto highly porous biodegradable polymer tubes. This study investigated methods of stimulation for optimizing neointestinal regeneration.

METHODS: Intestinal epithelial organoid units harvested from neonatal Lewis rats were seeded onto porous biodegradable polymer tubes and implanted into the omentum of adult Lewis rats in the following groups: (1) the control group (group C), implantation alone (n=9); (2) the small bowel resection (SBr) group, after 75\% SBr (n=9); (3) the portacaval shunt (PCS) group, after PCS (n=8); and (4) the partial hepatectomy (PH) group, after 75\% PH (n=8). Neointestinal cyst size was recorded using ultrasonography. Constructs were harvested at 10 weeks and were examined using histology. Morphometric analysis of the neomucosa was obtained using a computer image analysis program (NIH Image, version 1.59).

RESULTS: Cyst development was noted in all animals. Cyst lengths and diameters were significantly larger in the SBr group at 7 and 10 weeks compared with the other three groups (P,
	keywords = {Animals, Animals, Newborn, Biocompatible Materials, Body Weight, Cysts, Hepatectomy, Image Processing, Computer-Assisted, Intestinal Mucosa, Intestine, Small, Male, Neovascularization, Physiologic, Organoids, Polyglycolic Acid, Portacaval Shunt, Surgical, Rats, Rats, Inbred Lew, Regeneration, Signal Transduction, Transplantation, Isogeneic, Ultrasonography},
	issn = {0041-1337},
	author = {Kim, S S and Kaihara, S and Benvenuto, M S and Choi, R S and Kim, B S and Mooney, D J and Taylor, G A and Vacanti, J P}
}
@article {217531,
	title = {Small intestinal submucosa as a small-caliber venous graft: a novel model for hepatocyte transplantation on synthetic biodegradable polymer scaffolds with direct access to the portal venous system},
	journal = {J Pediatr Surg},
	volume = {34},
	number = {1},
	year = {1999},
	month = {1999 Jan},
	pages = {124-8},
	abstract = {BACKGROUND/PURPOSE: Hepatotrophic factors in the portal blood are critically important for the survival of heterotopically transplanted hepatocytes. Currently, no model exists for the implantation of hepatocytes on biodegradable polymer scaffolds with direct access to the portal blood. This study investigates the use of small intestinal submucosa (SIS) as a small-caliber venous conduit that may be used for the implantation of tissue-engineered liver.

METHODS: SIS was prepared from segments of rat jejunum and implanted as a venous conduit between the portal vein and inferior vena cava in 26 heparinized Lewis rats. Venograms were performed periodically, and the grafts were harvested at various time-points and examined by scanning electron microscopy (SEM) and histology. Von Willebrand Factor (vWF) staining was performed to assess endothelialization.

RESULTS: Five rats died of technical complications. Seventeen of 21 rats (81\%) maintained patent grafts at the time of death up to 8 weeks. Venograms demonstrated patent grafts at 3 and 8 weeks. SEM results showed a smooth luminal surface with endothelial-like cells by 3 weeks. Histology demonstrated a confluent luminal endothelial monolayer, absence of thrombus, and neovascularization in the SIS graft. VWF staining results were positive, confirming the growth of endothelial cells on the luminal surface. In preliminary studies, implantation of hepatocytes seeded on biodegradable polymer tubes into the SIS graft demonstrated clusters of viable cells after 2 days.

CONCLUSIONS: Rat SIS can be prepared readily, maintains high patency as a small-caliber venous graft, and may be a useful model for the transplantation of tissue-engineered liver with access to the portal circulation.},
	keywords = {Animals, Blood Vessel Prosthesis, Cell Culture Techniques, Cell Transplantation, Intestinal Mucosa, Jejunum, Liver, Liver Circulation, Liver, Artificial, Male, Portal System, Rats, Rats, Inbred Lew},
	issn = {0022-3468},
	author = {Kim, S S and Kaihara, S and Benvenuto, M S and Kim, B S and Mooney, D J and Vacanti, J P}
}
@article {217526,
	title = {Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression},
	journal = {Am J Pathol},
	volume = {154},
	number = {2},
	year = {1999},
	month = {1999 Feb},
	pages = {375-84},
	abstract = {Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and permeability factor that is potently angiogenic in vivo. We report here studies that suggest that VEGF potentiates angiogenesis in vivo and prolongs the survival of human dermal microvascular endothelial cells (HDMECs) in vitro by inducing expression of the anti-apoptotic protein Bcl-2. Growth-factor-enriched and serum-deficient cultures of HDMECs grown on collagen type I gels with VEGF exhibited a 4-fold and a 1.6-fold reduction, respectively, in the proportion of apoptotic cells. Enhanced HDMEC survival was associated with a dose-dependent increase in Bcl-2 expression and a decrease in the expression of the processed forms of the cysteine protease caspase-3. Cultures of HDMECs transduced with and overexpressing Bcl-2 and deprived of growth factors showed enhanced protection from apoptosis and exhibited a twofold increase in cell number and a fourfold increase in the number of capillary-like sprouts. HDMECs overexpressing Bcl-2 when incorporated into polylactic acid sponges and implanted into SCID mice exhibited a sustained fivefold increase in the number of microvessels and a fourfold decrease in the number of apoptotic cells when examined 7 and 14 days later. These results suggest that the angiogenic activity attributed to VEGF may be due in part to its ability to enhance endothelial cell survival by inducing expression of Bcl-2.},
	keywords = {Animals, Apoptosis, Blotting, Western, Cell Survival, Dose-Response Relationship, Drug, Endothelial Growth Factors, Endothelium, Vascular, Gene Expression, Humans, Interleukin-8, Lymphokines, Mice, Mice, SCID, Neovascularization, Physiologic, Proto-Oncogene Proteins c-bcl-2, Skin, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {0002-9440},
	doi = {10.1016/S0002-9440(10)65284-4},
	author = {N{\"o}r, J E and Christensen, J and Mooney, D J and Polverini, P J}
}
@article {217486,
	title = {Cyclic mechanical strain regulates the development of engineered smooth muscle tissue},
	journal = {Nat Biotechnol},
	volume = {17},
	number = {10},
	year = {1999},
	month = {1999 Oct},
	pages = {979-83},
	abstract = {We show that the appropriate combinations of mechanical stimuli and polymeric scaffolds can enhance the mechanical properties of engineered tissues. The mechanical properties of tissues engineered from cells and polymer scaffolds are significantly lower than the native tissues they replace. We hypothesized that application of mechanical stimuli to engineered tissues would alter their mechanical properties. Smooth muscle tissue was engineered on two different polymeric scaffolds and subjected to cyclic mechanical strain. Short-term application of strain increased proliferation of smooth muscle cells (SMCs) and expression of collagen and elastin, but only when SMCs were adherent to specific scaffolds. Long-term application of cyclic strain upregulated elastin and collagen gene expression and led to increased organization in tissues. This resulted in more than an order of magnitude increase in the mechanical properties of the tissues.},
	keywords = {Animals, Biocompatible Materials, Culture Techniques, Muscle, Smooth, Rats, Stress, Mechanical},
	issn = {1087-0156},
	doi = {10.1038/13671},
	author = {Kim, B S and Nikolovski, J and Bonadio, J and Mooney, D J}
}
@article {217506,
	title = {DNA delivery from polymer matrices for tissue engineering},
	journal = {Nat Biotechnol},
	volume = {17},
	number = {6},
	year = {1999},
	month = {1999 Jun},
	pages = {551-4},
	abstract = {We have proposed engineering tissues by the incorporation and sustained release of plasmids encoding tissue-inductive proteins from polymer matrices. Matrices of poly(lactide-co-glycolide) (PLG) were loaded with plasmid, which was subsequently released over a period ranging from days to a month in vitro. Sustained delivery of plasmid DNA from matrices led to the transfection of large numbers of cells. Furthermore, in vivo delivery of a plasmid encoding platelet-derived growth factor enhanced matrix deposition and blood vessel formation in the developing tissue. This contrasts with direct injection of the plasmid, which did not significantly affect tissue formation. This method of DNA delivery may find utility in tissue engineering and gene therapy applications.},
	keywords = {Animals, Biocompatible Materials, Cell Line, DNA, Gene Transfer Techniques, Humans, Lactic Acid, Plasmids, Platelet-Derived Growth Factor, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew},
	issn = {1087-0156},
	doi = {10.1038/9853},
	author = {Shea, L D and Smiley, E and Bonadio, J and Mooney, D J}
}
@article {217481,
	title = {Effects of anastomosis of tissue-engineered neointestine to native small bowel},
	journal = {J Surg Res},
	volume = {87},
	number = {1},
	year = {1999},
	month = {1999 Nov},
	pages = {6-13},
	abstract = {BACKGROUND: Our laboratory is investigating the tissue engineering of small intestine using intestinal epithelial organoid units seeded onto highly porous biodegradable polymer matrices. This study investigated the effects of anastomosis of tissue-engineered intestine to native small bowel alone or combined with small bowel resection on neointestinal regeneration.

METHODS: Intestinal epithelial organoid units harvested from neonatal Lewis rats were seeded onto biodegradable polymer tubes and implanted into the omentum of adult Lewis rats as follows: (1) implantation alone (n = 9); (2) implantation followed by anastomosis to native small bowel at 3 weeks (n = 11); and (3) implantation after small bowel resection and anastomosis to native small bowel at 3 weeks (n = 8). All constructs were harvested at 10 weeks and examined by histology. Morphometric analysis of the neomucosa was obtained using a computer image analysis program.

RESULTS: Cyst development was noted in all animals. All anastomoses were patent at 10 weeks. Histology revealed the development of a vascularized tissue with a neomucosa lining the lumen of the cyst with invaginations resembling crypt-villus structures. Morphometric analysis demonstrated significantly greater villus number, villus height, crypt number, crypt area, and mucosal surface length in groups 2 and 3 compared with group 1, and significantly greater villus number, villus height, crypt area, and mucosal surface length in group 3 compared with group 2 (P < 0.05, ANOVA, Tukey test).

CONCLUSION: Intestinal epithelial organoid units transplanted on biodegradable polymer tubes can regenerate into complex tissue resembling small intestine. Anastomosis to native small bowel combined with small bowel resection and anastomosis alone contribute significant regenerative stimuli for the morphogenesis and differentiation of tissue-engineered neointestine.},
	keywords = {Anastomosis, Surgical, Animals, Cell Transplantation, Intestinal Mucosa, Intestine, Small, Rats, Rats, Inbred Lew},
	issn = {0022-4804},
	doi = {10.1006/jsre.1999.5743},
	author = {Kim, S S and Kaihara, S and Benvenuto, M S and Choi, R S and Kim, B S and Mooney, D J and Vacanti, J P}
}
@article {217496,
	title = {End-to-end anastomosis between tissue-engineered intestine and native small bowel},
	journal = {Tissue Eng},
	volume = {5},
	number = {4},
	year = {1999},
	month = {1999 Aug},
	pages = {339-46},
	abstract = {The purpose of this study was to demonstrate the feasibility of end-to-end anastomosis between tissue-engineered intestine and native small bowel and to investigate the effect of this anastomosis on their growth. Microporous biodegradable polymer tubes were created from a fiber mesh of polyglycolic acid sprayed with 5\% polylactic acid. Intestinal epithelial organoid units were harvested from neonatal Lewis rats and seeded onto polymers. These constructs were implanted into the omentum of adult Lewis rats. Three weeks after the implantation, the constructs (n = 7) were anastomosed to the native jejunum in an end-to-end fashion. Ten weeks after implantation, the tissue-engineered intestine was harvested. Four of 7 rats survived for 10 weeks and the overall patency rate of the anastomosis was 78\% (11 of 14 anastomosis). The maximal length of the tissue-engineered intestine at week 3 and 10 was 1.80 +/- 0.32 and 1.93 +/- 0.39 cm (mean +/- SD). Histologically, the tissue-engineered intestine was lined with a well-developed neomucosal layer that was continuous with the native intestine. We conclude that anastomosis between tissue-engineered intestine and native small bowel had a moderately high patency rate and had a positive effect on maintenance of the size of the neointestine and development of the neomucosa.},
	keywords = {Anastomosis, Surgical, Animals, Animals, Newborn, Artificial Organs, Biocompatible Materials, Biomedical Engineering, Cell Transplantation, Female, Intestinal Mucosa, Intestine, Small, Lactic Acid, Male, Omentum, Polyesters, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew},
	issn = {1076-3279},
	doi = {10.1089/ten.1999.5.339},
	author = {Kaihara, S and Kim, S and Benvenuto, M and Kim, B S and Mooney, D J and Tanaka, K and Vacanti, J P}
}
@article {217501,
	title = {Engineered smooth muscle tissues: regulating cell phenotype with the scaffold},
	journal = {Exp Cell Res},
	volume = {251},
	number = {2},
	year = {1999},
	month = {1999 Sep 15},
	pages = {318-28},
	abstract = {Culturing cells on three-dimensional, biodegradable scaffolds may create tissues suitable either for reconstructive surgery applications or as novel in vitro model systems. In this study, we have tested the hypothesis that the phenotype of smooth muscle cells (SMCs) in three-dimensional, engineered tissues is regulated by the chemistry of the scaffold material. Specifically, we have directly compared cell growth and patterns of extracellular matrix (ECM) (e.g. , elastin and collagen) gene expression on two types of synthetic polymer scaffolds and type I collagen scaffolds. The growth rates of SMCs on the synthetic polymer scaffolds were significantly higher than on type I collagen sponges. The rate of elastin production by SMCs on polyglycolic acid (PGA) scaffolds was 3.5 +/- 1.1-fold higher than that on type I collagen sponges on Day 11 of culture. In contrast, the collagen production rate on type I collagen sponges was 3.3 +/- 1.1-fold higher than that on PGA scaffolds. This scaffold-dependent switching between elastin and collagen gene expression was confirmed by Northern blot analysis. The finding that the scaffold chemistry regulates the phenotype of SMCs independent of the scaffold physical form was confirmed by culturing SMCs on two-dimensional films of the scaffold materials. It is likely that cells adhere to these scaffolds via different ligands, as the major protein adsorbed from the serum onto synthetic polymers was vitronectin, whereas fibronectin and vitronectin were present at high density on type I collagen sponges. In summary, this study demonstrates that three-dimensional smooth muscle-like tissues can be created by culturing SMCs on three-dimensional scaffolds, and that the phenotype of the SMCs is strongly regulated by the scaffold chemistry. These engineered tissues provide novel, three-dimensional models to study cellular interaction with ECM in vitro.},
	keywords = {Animals, Aorta, Biomedical Engineering, Cell Differentiation, Collagen, Culture Techniques, Lactic Acid, Male, Muscle, Smooth, Vascular, Phenotype, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew},
	issn = {0014-4827},
	doi = {10.1006/excr.1999.4595},
	author = {Kim, B S and Nikolovski, J and Bonadio, J and Smiley, E and Mooney, D J}
}
@article {217511,
	title = {Growing new organs},
	journal = {Sci Am},
	volume = {280},
	number = {4},
	year = {1999},
	month = {1999 Apr},
	pages = {60-5},
	keywords = {Biomedical Engineering, Biotechnology, Bone and Bones, Cartilage, Cell Differentiation, Culture Techniques, Growth Substances, Humans, Neovascularization, Physiologic, Organ Transplantation, Regeneration, Skin Physiological Phenomena},
	issn = {0036-8733},
	author = {Mooney, D J and Mikos, A G}
}
@article {217521,
	title = {Regenerative signals for tissue-engineered small intestine},
	journal = {Transplant Proc},
	volume = {31},
	number = {1-2},
	year = {1999},
	month = {1999 Feb-Mar},
	pages = {657-60},
	keywords = {Animals, Animals, Newborn, Biocompatible Materials, Biomedical Engineering, Hepatectomy, Intestinal Mucosa, Intestine, Small, Male, Polyglycolic Acid, Portacaval Shunt, Surgical, Rats, Rats, Inbred Lew, Regeneration, Short Bowel Syndrome, Surgical Mesh, Transplantation, Isogeneic},
	issn = {0041-1345},
	author = {Kim, S S and Kaihara, S and Benvenuto, M and Choi, R S and Kim, B S and Mooney, D J and Taylor, G A and Vacanti, J P}
}
@article {217466,
	title = {Controlled delivery of inductive proteins, plasmid DNA and cells from tissue engineering matrices},
	journal = {J Periodontal Res},
	volume = {34},
	number = {7},
	year = {1999},
	month = {1999 Oct},
	pages = {413-9},
	abstract = {It has been estimated that half the annual health care budget in the United States is spent on patients suffering from tissue loss and late stage organ failure. Critical limitations inherent in traditional therapies call for novel tissue and organ replacement strategies. This paper discusses development of biomaterials for conductive, inductive and cell-based tissue replacement strategies. Biodegradable polymer scaffolds can be used as space-filling matrices for tissue development and barriers to migration of epithelial cells in tissue conductive approaches. Inductive approaches involve sustained delivery of bioactive factors, such as protein growth factors and DNA, to alter cell function in localized regions. Factors can be released from highly porous polymer scaffolds to allow factor delivery and tissue development to occur in concert. Cell-based approaches involve seeding of cells onto polymeric scaffolds in vitro and subsequent transplantation of the scaffold. New scaffold materials are being developed that address specific tissue engineering design requirements, and in some cases attempt to mimic natural extracellular matrices. These strategies together offer the possibility of predictably forming specific tissue structures, and may provide solutions to problems such as periodontal ligament detachment, alveolar bone resorption and furcation defects.},
	keywords = {Absorbable Implants, Biocompatible Materials, Biotechnology, Cell Movement, Cell Transplantation, DNA, Drug Delivery Systems, Epithelial Cells, Extracellular Matrix, Growth Substances, Guided Tissue Regeneration, Periodontal, Humans, Membranes, Artificial, Periodontal Diseases, Polymers, Regeneration},
	issn = {0022-3484},
	author = {Murphy, W L and Mooney, D J}
}
@article {1192486,
	title = {Cellular ingrowth and thickness changes in poly-L-lactide and polyglycolide matrices implanted subcutaneously in the rat},
	journal = {J Biomed Mater Res},
	volume = {41},
	number = {3},
	year = {1998},
	month = {1998 Sep 05},
	pages = {412-21},
	abstract = {Highly porous matrices of poly-L-lactide (PL) and polyglycolide (PG), 24, 50, or 95 mg/cc in the form of 10 x 10 x 3 mm wafers, were implanted subcutaneously (two per rat) in the flanks of 8-12-week-old female Lewis rats (n = 120). Matrices were harvested, two rats per week, for 15 weeks and examined histologically. At weeks 1 and 2, a thin fibrous capsule was present and matrices showed capillary beds and host-cell infiltration along the implant margins. By week 4, the PL specimens had some arterioles while the PG specimens still had only capillary beds. At week 7, PL had well developed arterioles, venules, and capillaries while PG began to show modest vascular beds of capillaries only. In terms of cellular ingrowth, PL remained unchanged from 7 to 15 weeks. Giant cell formation was observed wherever polymer was present. There was a loss of thickness and cell mass for both matrices over time (PG > PL) despite initial host-cell ingrowth. As both polymers degraded and were absorbed, the ingrown cells mass regressed. There was little remaining PG at 15 weeks, leaving no trace of cells that previously had ingrown and no evidence of scar tissue.},
	keywords = {Animals, Biocompatible Materials, Cell Division, Female, Implants, Experimental, Microscopy, Electron, Scanning, Polyesters, Polyglycolic Acid, Rats, Rats, Inbred Lew},
	issn = {0021-9304},
	author = {Holder, W D and Gruber, H E and Moore, A L and Culberson, CR and Anderson, W and Burg, K J and Mooney, D J}
}
@article {217581,
	title = {Development of technologies aiding large-tissue engineering},
	journal = {Biotechnol Prog},
	volume = {14},
	number = {1},
	year = {1998},
	month = {1998 Jan-Feb},
	pages = {134-40},
	abstract = {There are many clinical situations in which a large tissue mass is required to replace tissue lost to surgical resection (e.g., mastectomy). It is possible that autologous cell transplantation on biodegradable polymer matrices may provide a new therapy to engineer large tissue which can be used to treat these patients. A number of challenges must be met to engineer a large soft tissue mass. These include the design of (1) a structural framework to maintain a space for tissue development, (2) a space-filling matrix which provides for localization of transplanted cells, and (3) a strategy to enhance vascularization of the forming tissue. In this paper we provide an overview of several technologies which are under development to address these issues. Specifically, support matrices to maintain a space for tissue development have been fabricated from polymers of lactide and glycolide. The ability of these structures to resist compressive forces was regulated by the ratio of lactide to glycolide in the polymer. Smooth muscle cell seeding onto polyglycolide fiber-based matrices has been optimized to allow formation of new tissues in vitro and in vivo. Finally, polymer microsphere drug delivery technology is being developed to release vascular endothelial growth factor (VEGF), a potent angiogenic molecule, at the site of tissue formation. This strategy, which combines several different technologies, may ultimately allow for the engineering of large soft tissues.},
	keywords = {Animals, Biocompatible Materials, Biomedical Engineering, Lactic Acid, Microspheres, Muscle, Smooth, Polyesters, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew, Transplantation, Autologous},
	issn = {8756-7938},
	doi = {10.1021/bp970135h},
	author = {Eiselt, P and Kim, B S and Chacko, B and Isenberg, B and Peters, M C and Greene, K G and Roland, W D and Loebsack, A B and Burg, K J and Culberson, C and Halberstadt, C R and Holder, W D and Mooney, D J}
}
@article {217576,
	title = {In vitro and in vivo models for the reconstruction of intercellular signaling},
	journal = {Ann N Y Acad Sci},
	volume = {842},
	year = {1998},
	month = {1998 Apr 15},
	pages = {188-94},
	abstract = {A critical need in both tissue-engineering applications and basic cell culture studies is the development of synthetic extracellular matrices (ECMs) and experimental systems that reconstitute three-dimensional cell-cell interactions and control tissue formation in vitro and in vivo. We have fabricated synthetic ECMs in the form of fiber-based fabrics, highly porous sponges, and hydrogels from biodegradable polymers (e.g., polyglycolic acid) and tested their ability to regulate tissue formation. Both cell seeding onto these synthetic ECMs and subsequent culture conditions can be varied to control initial cell-cell interactions and subsequent cell growth and tissue development. Three-dimensional tissues composed of cells of interest, matrix produced by these cells, and the synthetic ECM (until it degrades) can be created with these systems. For example, smooth muscle cells can be grown on polyglycolic acid fiber-based synthetic ECMs to produce tissues with cell densities in excess of 10(8) cells/mL. These tissues contain extensive elastin and collagen, and the smooth muscle cells within the tissue express the contractile phenotype (e.g., alpha-actin staining). Similar approaches can be used to grow a number of other tissues (e.g., dental pulp) that resemble the native tissue. These engineered tissues may provide novel experimental systems to study the role of three-dimensional intercellular signaling in tissue development and may also find clinical application as replacements to lost or damaged tissues.},
	keywords = {Animals, Biocompatible Materials, Cell Communication, Extracellular Matrix Proteins, Humans, Models, Biological, Signal Transduction},
	issn = {0077-8923},
	author = {Bouhadir, K H and Mooney, D J}
}
@article {217571,
	title = {Development of biocompatible synthetic extracellular matrices for tissue engineering},
	journal = {Trends Biotechnol},
	volume = {16},
	number = {5},
	year = {1998},
	month = {1998 May},
	pages = {224-30},
	abstract = {Tissue engineering may provide an alternative to organ and tissue transplantation, both of which suffer from a limitation of supply. Cell transplantation using biodegradable synthetic extracellular matrices offers the possibility of creating completely natural new tissues and so replacing lost or malfunctioning organs or tissues. Synthetic extracellular matrices fabricated from biocompatible, biodegradable polymers play an important role in the formation of functional new tissue from transplanted cells. They provide a temporary scaffolding to guide new tissue growth and organization, and may provide specific signals intended to retain tissue-specific gene expression.},
	keywords = {Animals, Artificial Organs, Biocompatible Materials, Biomedical Engineering, Cell Transplantation, Extracellular Matrix, Humans, Microscopy, Electron, Scanning, Phenotype, Tissue Transplantation},
	issn = {0167-7799},
	author = {Kim, B S and Mooney, D J}
}
@article {217566,
	title = {Engineering smooth muscle tissue with a predefined structure},
	journal = {J Biomed Mater Res},
	volume = {41},
	number = {2},
	year = {1998},
	month = {1998 Aug},
	pages = {322-32},
	abstract = {Nonwoven meshes of polyglycolic acid (PGA) fibers are attractive synthetic extracellular matrices (ECMs) for tissue engineering and have been used to engineer many types of tissues. However, these synthetic ECMs lack structural stability and often cannot maintain their original structure during tissue development. This makes it difficult to design an engineered tissue with a predefined configuration and dimensions. In this study, we investigated the ability of PGA fiber-based matrices bonded at their fiber crosspoints with a secondary polymer, poly-L-lactic acid (PLLA), to resist cellular contractile forces and maintain their predefined structure during the process of smooth muscle (SM) tissue development in vitro. Physically bonded PGA matrices exhibited a 10- to 35-fold increase in the compressive modulus over unbonded PGA matrices, depending on the mass of PLLA utilized to bond the PGA matrices. In addition, the bonded PGA matrices degraded much more slowly than the unbonded matrices. The PLLA bonding of PGA matrices had no effect on the ability of cells to adhere to the matrices. After 7 weeks in culture, the bonded matrices maintained 101 +/- 4\% of their initial volume and an approximate original shape while the unbonded matrices contracted to 5 +/- 1\% of their initial volume with an extreme change in their shape. At this time the bonded PGA matrices had a high cellularity, with smooth muscle cells (SMCs) and ECM proteins produced by these cells (e.g., elastin) filling the pores between PGA fibers. This study demonstrated that physically bonded PGA fiber-based matrices allow the maintenance of the configuration and dimensions of the original matrices and the development of a new tissue in a predefined three-dimensional structure. This approach may be useful for engineering a variety of tissues of various structures and shapes, and our study demonstrates the importance of matching both the initial mechanical properties and the degradation rate of a matrix to the specific tissue one is engineering.},
	keywords = {Animals, Biocompatible Materials, Biomedical Engineering, Cells, Cultured, Elastin, Extracellular Matrix Proteins, Lactic Acid, Male, Materials Testing, Microscopy, Electron, Scanning, Muscle, Smooth, Polyesters, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew, Surgical Mesh},
	issn = {0021-9304},
	author = {Kim, B S and Mooney, D J}
}
@article {217551,
	title = {Microtubule assembly is regulated by externally applied strain in cultured smooth muscle cells},
	journal = {J Cell Sci},
	volume = {111 ( Pt 22)},
	year = {1998},
	month = {1998 Nov},
	pages = {3379-87},
	abstract = {Mechanical forces clearly regulate the development and phenotype of a variety of tissues and cultured cells. However, it is not clear how mechanical information is transduced intracellularly to alter cellular function. Thermodynamic modeling predicts that mechanical forces influence microtubule assembly, and hence suggest microtubules as one potential cytoskeletal target for mechanical signals. In this study, the assembly of microtubules was analyzed in rat aortic smooth muscle cells cultured on silicon rubber substrates exposed to step increases in applied strain. Cytoskeletal and total cellular protein fractions were extracted from the cells following application of the external strain, and tubulin levels were quantified biochemically via a competitive ELISA and western blotting using bovine brain tubulin as a standard. In the first set of experiments, smooth muscle cells were subjected to a step-increase in strain and the distribution of tubulin between monomeric, polymeric, and total cellular pools was followed with time. Microtubule mass increased rapidly following application of the strain, with a statistically significant increase (P,
	keywords = {Animals, Aorta, Abdominal, Cell Culture Techniques, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Gene Expression, Male, Microtubules, Muscle, Smooth, Vascular, Polymers, Rats, Rats, Inbred Lew, Signal Transduction, Stress, Mechanical, Tubulin},
	issn = {0021-9533},
	author = {Putnam, A J and Cunningham, J J and Dennis, R G and Linderman, J J and Mooney, D J}
}
@article {217556,
	title = {Open pore biodegradable matrices formed with gas foaming},
	journal = {J Biomed Mater Res},
	volume = {42},
	number = {3},
	year = {1998},
	month = {1998 Dec 05},
	pages = {396-402},
	abstract = {Engineering tissues utilizing biodegradable polymer matrices is a promising approach to the treatment of a number of diseases. However, processing techniques utilized to fabricate these matrices typically involve organic solvents and/or high temperatures. Here we describe a process for fabricating matrices without the use of organic solvents and/or elevated temperatures. Disks comprised of polymer [e.g., poly (D,L-lactic-co-glycolic acid)] and NaCl particles were compression molded at room temperature and subsequently allowed to equilibrate with high pressure CO2 gas (800 psi). Creation of a thermodynamic instability led to the nucleation and growth of gas pores in the polymer particles, resulting in the expansion of the polymer particles. The polymer particles fused to form a continuous matrix with entrapped salt particles. The NaCl particles subsequently were leached to yield macropores within the polymer matrix. The overall porosity and level of pore connectivity were regulated by the ratio of polymer/salt particles and the size of salt particles. Both the compressive modulus (159+/-130 kPa versus 289+/-25 kPa) and the tensile modulus (334+/-52 kPa versus 1100+/-236 kPa) of the matrices formed with this approach were significantly greater than those formed with a standard solvent casting/particulate leaching process. The utility of these matrices was demonstrated by engineering smooth muscle tissue in vitro with them. This novel process, a combination of high pressure gas foaming and particulate leaching techniques, allows one to fabricate matrices with a well controlled porosity and pore structure. This process avoids the potential negatives associated with the use of high temperatures and/or organic solvents in biomaterials processing.},
	keywords = {Animals, Biocompatible Materials, Cell Adhesion, Cell Division, Cells, Cultured, Gases, Male, Microscopy, Electron, Scanning, Muscle, Smooth, Vascular, Rats, Rats, Inbred Lew},
	issn = {0021-9304},
	author = {Harris, L D and Kim, B S and Mooney, D J}
}
@article {217546,
	title = {Release from alginate enhances the biological activity of vascular endothelial growth factor},
	journal = {J Biomater Sci Polym Ed},
	volume = {9},
	number = {12},
	year = {1998},
	month = {1998},
	pages = {1267-78},
	abstract = {A primary factor which limits engineering tissues of substantial size is the lack of nutrients readily available to transplanted cells. One potential solution to this nutrient limitation is to encourage the rapid development of a vascular network within three-dimensional tissue engineering matrices. Vascular endothelial growth factor (VEGF) has been identified as a potent stimulator of angiogenesis in vivo. Though effective at stimulating endothelial cells to form blood vessels VEGF degrades rapidly. Spherical alginate beads (3.3+/-0.1 mm diameter) were examined as a means of delivering biologically functional VEGF at a controlled rate over extended times. The alginate beads demonstrated the ability to incorporate VEGF with an efficiency between 30 and 67\%, depending on the processing conditions, and release it at a constant rate (5\%/day) for up to 14 days in vitro. The released VEGF, when assayed for its ability to stimulate endothelial cells in culture, was found not only to be functional but more potent (three to five times) than the same mass of VEGF added directly to the culture medium. The release kinetics of freeze dried VEGF containing alginate beads were also examined and found to be comparable to non-freeze dried samples.},
	keywords = {Alginates, Cell Count, Cell Transplantation, Cells, Cultured, Drug Delivery Systems, Endothelial Growth Factors, Endothelium, Vascular, Humans, Hydrogels, Lymphokines, Microspheres, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors},
	issn = {0920-5063},
	author = {Peters, M C and Isenberg, B C and Rowley, J A and Mooney, D J}
}
@article {217561,
	title = {Role of synthetic extracellular matrix in development of engineered dental pulp},
	journal = {J Biomater Sci Polym Ed},
	volume = {9},
	number = {7},
	year = {1998},
	month = {1998},
	pages = {749-64},
	abstract = {In cases of damaged oral tissues, traditional therapies, such as a root canal, replace the injured tissue with a synthetic material. However, while the materials currently used can offer structural replacement of the lost tissue, they are incapable of completely replacing the function of the original tissue, and often fail over time. This report describes a tissue engineering approach to dental pulp tissue replacement utilizing cultured cells seeded upon synthetic extracellular matrices. Human pulp fibroblasts were obtained and multiplied in culture. These cells were then seeded onto three different synthetic matrices: scaffolds fabricated from polyglycolic acid (PGA) fibers, a type I collagen hydrogel, and alginate in an effort to examine which matrix is most suitable for dental pulp tissue formation. In addition, methods previously developed for seeding and culturing pulp cells on PGA were optimized. Culturing cells on PGA resulted in a very high cell density tissue with significant collagen deposition. No cell proliferation was observed on alginate, and the growth of cells in collagen gels after 45 days was only moderate. These studies indicate dental pulp-like tissues can be engineered, and this may provide the first step to engineering a complete tooth.},
	keywords = {Adult, Alginates, Biocompatible Materials, Cell Count, Cell Culture Techniques, Cells, Cultured, Collagen, Dental Pulp, Extracellular Matrix, Fibroblasts, Glucuronic Acid, Hexuronic Acids, Humans, Polyglycolic Acid},
	issn = {0920-5063},
	author = {Bohl, K S and Shon, J and Rutherford, B and Mooney, D J}
}
@article {217516,
	title = {Optimizing seeding and culture methods to engineer smooth muscle tissue on biodegradable polymer matrices},
	journal = {Biotechnol Bioeng},
	volume = {57},
	number = {1},
	year = {1998},
	month = {1998 Jan 05},
	pages = {46-54},
	abstract = {The engineering of functional smooth muscle (SM) tissue is critical if one hopes to successfully replace the large number of tissues containing an SM component with engineered equivalents. This study reports on the effects of SM cell (SMC) seeding and culture conditions on the cellularity and composition of SM tissues engineered using biodegradable matrices (5 x 5 mm, 2-mm thick) of polyglycolic acid (PGA) fibers. Cells were seeded by injecting a cell suspension into polymer matrices in tissue culture dishes (static seeding), by stirring polymer matrices and a cell suspension in spinner flasks (stirred seeding), or by agitating polymer matrices and a cell suspension in tubes with an orbital shaker (agitated seeding). The density of SMCs adherent to these matrices was a function of cell concentration in the seeding solution, but under all conditions a larger number (approximately 1 order of magnitude) and more uniform distribution of SMCs adherent to the matrices were obtained with dynamic versus static seeding methods. The dynamic seeding methods, as compared to the static method, also ultimately resulted in new tissues that had a higher cellularity, more uniform cell distribution, and greater elastin deposition. The effects of culture conditions were next studied by culturing cell-polymer constructs in a stirred bioreactor versus static culture conditions. The stirred culture of SMC-seeded polymer matrices resulted in tissues with a cell density of 6.4 +/- 0.8 x 10(8) cells/cm3 after 5 weeks, compared to 2.0 +/- 1.1 x 10(8) cells/cm3 with static culture. The elastin and collagen synthesis rates and deposition within the engineered tissues were also increased by culture in the bioreactors. The elastin content after 5-week culture in the stirred bioreactor was 24 +/- 3\%, and both the elastin content and the cellularity of these tissues are comparable to those of native SM tissue. New tissues were also created in vivo when dynamically seeded polymer matrices were implanted in rats for various times. In summary, the system defined by these studies shows promise for engineering a tissue comparable in many respects to native SM. This engineered tissue may find clinical applications and provide a tool to study molecular mechanisms in vascular development.},
	keywords = {Animals, Biocompatible Materials, Biodegradation, Environmental, Biomedical Engineering, Biotechnology, Culture Techniques, Microscopy, Electron, Scanning, Muscle Development, Muscle, Smooth, Vascular, Polymers, Rats, Time Factors},
	issn = {0006-3592},
	author = {Kim, B S and Putnam, A J and Kulik, T J and Mooney, D J}
}
@article {1192501,
	title = {Highly porous polymer matrices as a three-dimensional culture system for hepatocytes: initial results},
	journal = {Transplant Proc},
	volume = {29},
	number = {4},
	year = {1997},
	month = {1997 Jun},
	pages = {2032-4},
	keywords = {Animals, Biocompatible Materials, Cell Culture Techniques, Cell Division, Cell Separation, Collagenases, Kinetics, Lactic Acid, Liver, Male, Membranes, Artificial, Polyesters, Polymers, Rats, Rats, Inbred Lew},
	issn = {0041-1345},
	author = {Kaufmann, P M and Heimrath, S and Kim, B S and Mooney, D J}
}
@article {1192496,
	title = {Highly porous polymer matrices as a three-dimensional culture system for hepatocytes},
	journal = {Cell Transplant},
	volume = {6},
	number = {5},
	year = {1997},
	month = {1997 Sep-Oct},
	pages = {463-8},
	abstract = {Hepatocyte-based therapies (e.g., hepatocyte transplantation and extracorporeal support devices) may provide alternative therapies to treat patients with liver disease, but suitable approaches to localize these cells to a given location while maintaining liver-specific gene expression must be developed. The suitability of highly porous three-dimensional sponges fabricated from poly (L-lactic acid) [PLLA] as an hepatocyte culture system was evaluated in this study. Sponges were fabricated utilizing a particulate leaching technique, and were approximately 95\% porous, with an average pore diameter of 180 microns. Hepatocytes seeded into these sponges adhered and remained viable for 14 days. However, the secretion rate of albumin from these cells, an indication of liver-specific gene expression, was low (approximately 6 pg/cell/day at day 1), and decreased steadily over the 14 days of the experiment. Coating sponges with collagen, and more preferably, immobilizing cells within the PLLA sponges with a collagen gel, led to enhanced cell survival and albumin secretion at all time points. These data suggest that porous PLLA sponges may provide a novel system for long-term culture of hepatocytes, and proper design of the system may allow the liver-specific gene expression of hepatocytes transplanted in these matrices to be enhanced.},
	keywords = {Albumins, Animals, Biodegradation, Environmental, Cell Culture Techniques, Collagen, Extracellular Matrix, Gels, Gene Expression Regulation, Lactic Acid, Liver, Polyesters, Polymers, Rats, Rats, Inbred Lew},
	issn = {0963-6897},
	author = {Kaufmann, P M and Heimrath, S and Kim, B S and Mooney, D J}
}
@article {1192491,
	title = {Long-term engraftment of hepatocytes transplanted on biodegradable polymer sponges},
	journal = {J Biomed Mater Res},
	volume = {37},
	number = {3},
	year = {1997},
	month = {1997 Dec 05},
	pages = {413-20},
	abstract = {Hepatocyte transplantation may provide an alternative to orthotopic liver transplantation to treat liver failure. However, suitable systems to transplant hepatocytes and promote long-term engraftment must be developed. In this study, highly porous, biodegradable sponges were fabricated from poly (L-lactic acid) (PLA), and poly (DL-lacticco-glycolic acid) (PLGA), and utilized to transplant hepatocytes into the mesentery of three groups of Lewis rats. The portal vein was shunted to the inferior vena cava in one group of rats (PCS). The second group of animals received a PCS and a 70\% hepatectomy on the day of sponge-hepatocyte implantation (PCS + HEP), and the control group (CON) received no surgical stimulation. The sponges were vascularized by ingrowth of fibrovascular tissue over the first 7 days in vivo. Approximately 95-99\% of the implanted hepatocytes (determined utilizing computer-assisted image analysis) died in all three experimental groups during this time. The number of engrafted hepatocytes in the CON group further decreased over the next 7 days to 1.3 +/- 1.1\% of the original cell number. However, the number of engrafted hepatocytes in the PCS and PCS + HEP increased over this time to 6 +/- 1\% and 5 +/- 2\%, respectively. The number of engrafted hepatocytes in the PCS group continued to increase over the next 2.5 months to a value of 26 +/- 12\% of the initial cell number, and a large number of engrafted hepatocytes was still present at 6 months. These results indicate that stable new tissues can be engineered by transplanting hepatocytes on biodegradable sponges into heterotopic locations if appropriate stimulation is provided.},
	keywords = {Animals, Biocompatible Materials, Cell Survival, Cell Transplantation, Graft Survival, Hepatectomy, Lactic Acid, Liver, Liver Transplantation, Polyglycolic Acid, Polymers, Porosity, Portacaval Shunt, Surgical, Rats, Rats, Inbred Lew},
	issn = {0021-9304},
	author = {Mooney, D J and Sano, K and Kaufmann, P M and Majahod, K and Schloo, B and Vacanti, J P and Langer, R}
}
@article {1192516,
	title = {Localized delivery of epidermal growth factor improves the survival of transplanted hepatocytes},
	journal = {Biotechnol Bioeng},
	volume = {50},
	number = {4},
	year = {1996},
	month = {1996 May 20},
	pages = {422-9},
	abstract = {Hepatocyte transplantation may provide a new approach for treating a variety of liver diseases if a sufficient number of the transplanted cells survive over an extended time period. In this report, we describe a technique to deliver growth factors to transplanted hepatocytes to improve their engraftment. Epidermal growth factor (EGF) was incorporated (0.11\%) into microspheres (19 +/- 12 mum) fabricated from a copolymer of lactic and glycolic acid using a double emulsion technique. The incorporated EGF was steadily released over 1 month in vitro, and it remained biologically active, as determined by its ability to stimulate DNA synthesis, cell division, and long-term survival of cultured hepatocytes. EGF-containing microspheres were mixed with a suspension of hepatocytes, seeded onto porous sponges, and implanted into the mesentery of two groups of Lewis rats. The first group of animals had their portal vein shunted to the inferior vena cava prior to cell transplantation (portal-caval shunt = PCS), and the second group of animals did not (non-PCS). This surgical procedure improves the survival of transplanted hepatocytes. The engraftment of transplanted hepatocytes in PCS animals was increased two-fold by adding EGF microspheres, as compared to adding control microspheres that contained no growth factors. Devices implanted into non-PCS animals had fewer engrafted hepatocytes than devices implanted into PCS animals, regardless of whether blank or EGF-containing microspheres were added. These results first indicate that it is possible to design systems which can alter the microenvironment of transplanted hepatocytes to improve their engraftment. They also suggest that hepatocyte engraftment is not improved by providing single growth factors unless the correct environment (PCS) is provided for the transplanted cells. (c) 1996 John Wiley \& Sons, Inc.},
	issn = {0006-3592},
	doi = {10.1002/(SICI)1097-0290(19960520)50:4<422::AID-BIT9>3.0.CO;2-N},
	author = {Mooney, D J and Kaufmann, P M and Sano, K and Schwendeman, S P and Majahod, K and Schloo, B and Vacanti, J P and Langer, R}
}
@article {1192511,
	title = {Novel approach to fabricate porous sponges of poly(D,L-lactic-co-glycolic acid) without the use of organic solvents},
	journal = {Biomaterials},
	volume = {17},
	number = {14},
	year = {1996},
	month = {1996 Jul},
	pages = {1417-22},
	abstract = {A novel method was developed to produce highly porous sponges for potential use in tissue engineering, without the use of organic solvents. Highly porous sponges of biodegradable polymers are frequently utilized in tissue engineering both to transplant cells or growth factors, and to serve as a template for tissue regeneration. The processes utilized to fabricate sponges typically use organic solvents, but organic residues remaining in the sponges may be harmful to adherent cells, protein growth factors or nearby tissues. This report describes a technique to fabricate macroporous sponges from synthetic biodegradable polymers using high pressure carbon dioxide processing at room temperature. Solid discs of poly (D,L-lactic-co-glycolic acid) were saturated with CO2 by exposure to high pressure CO2 gas (5.5 MPa) for 72 h at room temperature. The solubility of the gas in the polymer was then rapidly decreased by reducing the CO2 gas pressure to atmospheric levels. This created a thermodynamic instability for the CO2 dissolved in the polymer discs, and resulted in the nucleation and growth of gas cells within the polymer matrix. Polymer sponges with large pores (approximately 100 microns) and porosities of up to 93\% could be fabricated with this technique. The porosity of the sponges could be controlled by the perform production technique, and mixing crystalline and amorphous polymers. Fibre-reinforced foams could also be produced by placing polymer fibres within the polymer matrix before CO2 gas processing.},
	keywords = {Biocompatible Materials, Bioprosthesis, Carbon Dioxide, Lactic Acid, Polyesters, Polyglycolic Acid, Polymers, Porosity, Solvents},
	issn = {0142-9612},
	author = {Mooney, D J and Baldwin, D F and Suh, N P and Vacanti, J P and Langer, R}
}
@article {1192521,
	title = {Stabilized polyglycolic acid fibre-based tubes for tissue engineering},
	journal = {Biomaterials},
	volume = {17},
	number = {2},
	year = {1996},
	month = {1996 Jan},
	pages = {115-24},
	abstract = {Polyglycolic acid (PGA) fibre meshes are attractive candidates to transplant cells, but they are incapable of resisting significant compressional forces. To stabilize PGA meshes, atomized solutions of poly(L-lactic acid) (PLLA) and a 50/50 copolymer of poly(D,L-lactic-co-glycolic acid) (PLGA) dissolved in chloroform were sprayed over meshes formed into hollow tubes. The PLLA and PLGA coated the PGA fibres and physically bonded adjacent fibres. The pattern and extent of bonding was controlled by the concentration of polymer in the atomized solution and the total mass of polymer sprayed on the device. The compression resistance of devices increased with the extent of bonding, and PLLA bonded tubes resisted larger compressive forces than PLGA bonded tubes. Tubes bonded with PLLA degraded more slowly than devices bonded with PLGA. Implantation of PLLA bonded tubes into rats revealed that the devices maintained their structure during fibrovascular tissue ingrowth, resulting in the formation of a tubular structure with a central lumen. The potential of these devices to engineer specific tissues was exhibited by the finding that smooth muscle cells and endothelial cells seeded onto devices in vitro formed a tubular tissue with appropriate cell distribution.},
	keywords = {Animals, Biocompatible Materials, Biomechanical Phenomena, Biotechnology, Cell Adhesion, Cell Communication, Cell Transplantation, Delayed-Action Preparations, Endothelium, Vascular, Lactates, Lactic Acid, Muscle, Smooth, Vascular, Polyesters, Polyglycolic Acid, Polymers, Prostheses and Implants, Rats},
	issn = {0142-9612},
	author = {Mooney, D J and Mazzoni, C L and Breuer, C and McNamara, K and Hern, D and Vacanti, J P and Langer, R}
}
@article {1192506,
	title = {von Hippel-Lindau disease and familial polyposis coli in the same family},
	journal = {Arch Ophthalmol},
	volume = {114},
	number = {10},
	year = {1996},
	month = {1996 Oct},
	pages = {1294},
	keywords = {Adenomatous Polyposis Coli, Adult, Chromosome Aberrations, Chromosome Disorders, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 5, Female, Fundus Oculi, Gene Deletion, Hemangioma, Humans, Male, Mutation, Retinal Diseases, von Hippel-Lindau Disease},
	issn = {0003-9950},
	author = {Kilmartin, D J and Mooney, D J and Acheson, R W and Payne, S J and Maher, E R and Eustace, P}
}
@article {217586,
	title = {Engineering dental pulp-like tissue in vitro},
	journal = {Biotechnol Prog},
	volume = {12},
	number = {6},
	year = {1996},
	month = {1996 Nov-Dec},
	pages = {865-8},
	abstract = {Injury or infection of adult dental pulp often necessitates root canal therapy. This terminates dentin formation and subsequent tooth maturation. In addition, the synthetic materials currently utilized to replace lost tooth structure are not capable of completely replacing the function of the lost tissue, and often fail over time. This report describes a technique to engineer new pulp-like tissues utilizing cultured cells and synthetic extracellular matrices. Fibroblasts were obtained from human adult dental pulps and multiplied in culture. These cells were subsequently seeded onto synthetic matrices fabricated from fibers (approximately 15 microns in diameter) of polyglycolic acid (PGA). The pulp-derived fibroblasts adhered to the fibers, proliferated, and formed a new tissue over 60 days in culture with a cellularity similar to that of native pulp. These tissues may find application in the regeneration of oral tissues and may provide novel systems in which to study the biocompatibility of materials and chemicals used in dentistry.},
	keywords = {Adult, Cell Adhesion, Cell Count, Cell Division, Cells, Cultured, Dental Pulp, Fibroblasts, Humans, Kinetics, Microscopy, Electron, Scanning, Regeneration},
	issn = {8756-7938},
	doi = {10.1021/bp960073f},
	author = {Mooney, D J and Powell, C and Piana, J and Rutherford, B}
}
@article {217596,
	title = {Tissue engineering lamb heart valve leaflets},
	journal = {Biotechnol Bioeng},
	volume = {50},
	number = {5},
	year = {1996},
	month = {1996 Jun 05},
	pages = {562-7},
	abstract = {Tissue engineered lamb heart valve leaflets (N - 3) were constructed by repeatedly seeding a concentrated suspension of autologous myofibroblasts onto a biodegradable synthetic polymeric scaffold composed of fibers made from polyglycolic acid and polylactic acid. Over a 2-week period the cells attached to the polymer fibers, multiplied, and formed a tissue core in the shape of the matrix. The tissue core was seeded with autologous large-vessel endothelial cells that formed a monolayer which coated the outer surface of the leaflet. The tissue engineered leaflets were surgically implanted in place of the right posterior pulmonary valve leaflet of the donor lamb while on cardiopulmonary bypass. Pulmonary valve function was evaluated by two-dimensional echocardiography with color Doppler which demonstrated valve function without evidence of stenosis and with only trivial regurgitation under normal physiologic conditions. Histologically, the tissue engineered heart valve leaflets resembled native valve leaflet tissue.},
	issn = {0006-3592},
	doi = {10.1002/(SICI)1097-0290(19960605)50:5<562::AID-BIT11>3.0.CO;2-L},
	author = {Breuer, C K and Shin{\textquoteright}oka, T and Tanel, R E and Zund, G and Mooney, D J and Ma, P X and Miura, T and Colan, S and Langer, R and Mayer, J E and Vacanti, J P}
}
@article {217591,
	title = {Tissue engineering using synthetic extracellular matrices},
	journal = {Nat Med},
	volume = {2},
	number = {7},
	year = {1996},
	month = {1996 Jul},
	pages = {824-6},
	keywords = {Animals, Biocompatible Materials, Extracellular Matrix, Microscopy, Electron, Scanning, Rats, Rats, Inbred Lew, Tissue Transplantation},
	issn = {1078-8956},
	author = {Putnam, A J and Mooney, D J}
}
@article {1192526,
	title = {Biodegradable sponges for hepatocyte transplantation},
	journal = {J Biomed Mater Res},
	volume = {29},
	number = {8},
	year = {1995},
	month = {1995 Aug},
	pages = {959-65},
	abstract = {Liver cell transplantation may provide a means to replace lost or deficient liver tissue, but devices capable of delivering hepatocytes to a desirable anatomic location and guiding the development of a new tissue from these cells and the host tissue are needed. We have investigated whether sponges fabricated from poly-L-lactic acid (PLA) infiltrated with polyvinyl alcohol (PVA) would meet these requirements. Highly porous sponges (porosity = 90-95\%) were fabricated from PLA using a particulate leaching technique. To enable even and efficient cell seeding, the devices were infiltrated with the hydrophilic polymer polyvinyl alcohol (PVA). This reduced their contact angle with water from 79 to 23 degrees, but did not inhibit the ability of hepatocytes to adhere to the polymer. Porous sponges of PLA infiltrated with PVA readily absorbed aqueous solutions into 98\% of their pore volume, and could be evenly seeded with high densities (5 x 10(7) cells/mL) of hepatocytes. Hepatocyte-seeded devices were implanted into the mesentery of laboratory rats, and 6 +/- 2 x 10(5) of the hepatocytes engrafted per sponge. Fibrovascular tissue invaded through the devices{\textquoteright} pores, leading to a composite tissue consisting of hepatocytes, blood vessels and fibrous tissue, and the polymer sponge.},
	keywords = {Animals, Biocompatible Materials, Cell Transplantation, Fibroblasts, Lactic Acid, Liver Transplantation, Microscopy, Electron, Scanning, Polyglycolic Acid, Polymers, Polyvinyl Alcohol, Rats, Rats, Inbred Lew, Surgical Sponges},
	issn = {0021-9304},
	doi = {10.1002/jbm.820290807},
	author = {Mooney, D J and Park, S and Kaufmann, P M and Sano, K and McNamara, K and Vacanti, J P and Langer, R}
}
@article {1192531,
	title = {Cytoskeletal filament assembly and the control of cell spreading and function by extracellular matrix},
	journal = {J Cell Sci},
	volume = {108 ( Pt 6)},
	year = {1995},
	month = {1995 Jun},
	pages = {2311-20},
	abstract = {This study was undertaken to analyze how cell binding to extracellular matrix produces changes in cell shape. We focused on the initial process of cell spreading that follows cell attachment to matrix and, thus, cell {\textquoteright}shape{\textquoteright} changes are defined here in terms of alterations in projected cell areas, as determined by computerized image analysis. Cell spreading kinetics and changes in microtubule and actin microfilament mass were simultaneously quantitated in hepatocytes plated on different extracellular matrix substrata. The initial rate of cell spreading was highly dependent on the matrix coating density and decreased from 740 microns 2/h to 50 microns 2/h as the coating density was lowered from 1000 to 1 ng/cm2. At approximately 4 to 6 hours after plating, this initial rapid spreading rate slowed and became independent of the matrix density regardless of whether laminin, fibronectin, type I collagen or type IV collagen was used for cell attachment. Analysis of F-actin mass revealed that cell adhesion to extracellular matrix resulted in a 20-fold increase in polymerized actin within 30 minutes after plating, before any significant change in cell shape was observed. This was followed by a phase of actin microfilament disassembly which correlated with the most rapid phase of cell extension and ended at about 6 hours; F-actin mass remained relatively constant during the slow matrix-independent spreading phase. Microtubule mass increased more slowly in spreading cells, peaking at 4 hours, the time at which the transition between rapid and slow spreading rates was observed. However, inhibition of this early rise in microtubule mass using either nocodazole or cycloheximide did not prevent this transition. Use of cytochalasin D revealed that microfilament integrity was absolutely required for hepatocyte spreading whereas interference with microtubule assembly (using nocodazole or taxol) or protein synthesis (using cycloheximide) only partially suppressed cell extension. In contrast, cell spreading could be completely inhibited by combining suboptimal doses of cytochalasin D and nocodazole, suggesting that intact microtubules can stabilize cell form when the microfilament lattice is partially compromised. The physiological relevance of the cytoskeleton and cell shape in hepatocyte physiology was highlighted by the finding that a short exposure (6 hour) of cells to nocodazole resulted in production of smaller cells 42 hours later that exhibited enhanced production of a liver-specific product (albumin). These data demonstrate that spreading and flattening of the entire cell body is not driven directly by net polymerization of either microfilaments or microtubules.(ABSTRACT TRUNCATED AT 400 WORDS)},
	keywords = {Animals, Cell Adhesion, Cell Size, Cells, Cultured, Cytoskeleton, Extracellular Matrix Proteins, Liver, Male, Nocodazole, Paclitaxel, Rats, Rats, Wistar},
	issn = {0021-9533},
	author = {Mooney, D J and Langer, R and Ingber, D. E.}
}
@article {217601,
	title = {Fabricating tubular devices from polymers of lactic and glycolic Acid for tissue engineering},
	journal = {Tissue Eng},
	volume = {1},
	number = {2},
	year = {1995},
	month = {1995 Summer},
	pages = {107-18},
	abstract = {Polymers of lactic and glycolic acid are attractive candidates to fabricate devides to transplant cells and engineer new tissues. These polymers are biocompatible, and exhibit a wide range of erosion times and mechanical properties. This manuscript describes the fabrication and characterization, in vitro and in vivo, of hollow, tubular devices from porous films of various polymers of this family. Porous films of these polymers were formed using a particulate leaching technique, and sealed around Teflon cylinders to form hollow tubular devices. The erosion rate of devices was controlled by the specific polymer utilized for fabrication, and ranged from months to years. Devices fabricated from a 50/50 copolymer of D,L-lactic acid and glycolic acid were completely eroded by 2 months, while devices fabricated from a homopolymer of L-lactic acid showed little mass loss after 1 year. Erosion times for devices fabricated from the other polymers [poly-(D,L-lactic acid) and a 85/15 copolymer] were between these two extremes. Devices were capable of resisting significant compressional forces (150 raN) in vitro, and the compression resistance was controlled by the polymer utilized to fabricate the devices. The ability of the devices to maintain their structure after implantation into the mesentery or omentum of laboratory rats was also dependent of the specific polymer utilized to fabricate the device. These results indicate that it is possible to fabricate tubular devices for tissue engineering applications that exhibit a wide range of erosion rates and mechanical properties.},
	issn = {1076-3279},
	doi = {10.1089/ten.1995.1.107},
	author = {Mooney, D J and Breuer, C and McNamara, K and Vacanti, J P and Langer, R}
}
@article {1192551,
	title = {Design and fabrication of biodegradable polymer devices to engineer tubular tissues},
	journal = {Cell Transplant},
	volume = {3},
	number = {2},
	year = {1994},
	month = {1994 Mar-Apr},
	pages = {203-10},
	abstract = {Engineering new tissues by transplanting cells on polymeric delivery devices is one approach to alleviate the vast shortage of donor tissue. However, it will be necessary to fabricate cell delivery devices that deliver cells to a given location and promote the formation of specific tissue structures from the transplanted cells and the host tissue. This report describes the design and fabrication of a polymeric device for guiding the development of tubular vascularized tissues, which may be useful for engineering a variety of tissues including intestine, blood vessels, tracheas, and ureters. Porous films of poly (D, L-lactic-co-glycolic acid) have been formed and fabricated into tubes capable of resisting compressional forces in vitro and in vivo. These devices promote the ingrowth of fibrovascular tissue following implantation into recipient animals, resulting in a vascularized, tubular tissue. To investigate the utility of these devices as cell delivery devices, enterocytes (intestinal epithelial cells) were seeded onto the devices in vitro. Enterocytes were found to attach to these devices and form an organized epithelial cell layer. These results suggest that these devices may be an appropriate delivery vehicle for transplanting cells and engineering new tubular tissues.},
	keywords = {Animals, Biopolymers, Epithelium, Intestines, Lactic Acid, Microscopy, Electron, Scanning, Neovascularization, Pathologic, Polyglycolic Acid, Polymers, Rats, Rats, Inbred Lew, Stress, Mechanical, Time Factors, Transplantation, Transplantation, Isogeneic},
	issn = {0963-6897},
	author = {Mooney, D J and Organ, G and Vacanti, J P and Langer, R}
}
@article {1192536,
	title = {Extracellular matrix controls tubulin monomer levels in hepatocytes by regulating protein turnover},
	journal = {Mol Biol Cell},
	volume = {5},
	number = {12},
	year = {1994},
	month = {1994 Dec},
	pages = {1281-8},
	abstract = {Cells have evolved an autoregulatory mechanism to dampen variations in the concentration of tubulin monomer that is available to polymerize into microtubules (MTs), a process that is known as tubulin autoregulation. However, thermodynamic analysis of MT polymerization predicts that the concentration of free tubulin monomer must vary if MTs are to remain stable under different mechanical loads that result from changes in cell adhesion to the extracellular matrix (ECM). To determine how these seemingly contradictory regulatory mechanisms coexist in cells, we measured changes in the masses of tubulin monomer and polymer that resulted from altering cell-ECM contacts. Primary rat hepatocytes were cultured in chemically defined medium on bacteriological petri dishes that were precoated with different densities of laminin (LM). Increasing the LM density from low to high (1-1000 ng/cm2), promoted cell spreading (average projected cell area increased from 1200 to 6000 microns2) and resulted in formation of a greatly extended MT network. Nevertheless, the steady-state mass of tubulin polymer was similar at 48 h, regardless of cell shape or ECM density. In contrast, round hepatocytes on low LM contained a threefold higher mass of tubulin monomer when compared with spread cells on high LM. Furthermore, similar results were obtained whether LM, fibronectin, or type I collagen were used for cell attachment. Tubulin autoregulation appeared to function normally in these cells because tubulin mRNA levels and protein synthetic rates were greatly depressed in round cells that contained the highest level of free tubulin monomer. However, the rate of tubulin protein degradation slowed, causing the tubulin half-life to increase from approximately 24 to 55 h as the LM density was lowered from high to low and cell rounding was promoted. These results indicate that the set-point for the tubulin monomer mass in hepatocytes can be regulated by altering the density of ECM contacts and changing cell shape. This finding is consistent with a mechanism of MT regulation in which the ECM stabilizes MTs by both accepting transfer of mechanical loads and altering tubulin degradation in cells that continue to autoregulate tubulin synthesis.},
	keywords = {Animals, Cell Movement, Cells, Cultured, Extracellular Matrix, Homeostasis, Liver, Male, Rats, Rats, Wistar, Tubulin},
	issn = {1059-1524},
	author = {Mooney, D J and Hansen, L K and Langer, R and Vacanti, J P and Ingber, D. E.}
}
@article {1192546,
	title = {Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth},
	journal = {Mol Biol Cell},
	volume = {5},
	number = {9},
	year = {1994},
	month = {1994 Sep},
	pages = {967-75},
	abstract = {This study was undertaken to determine the importance of integrin binding and cell shape changes in the control of cell-cycle progression by extracellular matrix (ECM). Primary rat hepatocytes were cultured on ECM-coated dishes in serum-free medium with saturating amounts of growth factors (epidermal growth factor and insulin). Integrin binding and cell spreading were promoted in parallel by plating cells on dishes coated with fibronectin (FN). Integrin binding was separated from cell shape changes by culturing cells on dishes coated with a synthetic arg-gly-asp (RGD)-peptide that acts as an integrin ligand but does not support hepatocyte extension. Expression of early (junB) and late (ras) growth response genes and DNA synthesis were measured to determine whether these substrata induce G0-synchronized hepatocytes to reenter the growth cycle. Cells plated on FN exhibited transient increases in junB and ras gene expression (within 2 and 8 h after plating, respectively) and synchronous entry into S phase. Induction of junB and ras was observed over a similar time course in cells on RGD-coated dishes, however, these round cells did not enter S phase. The possibility that round cells on RGD were blocked in mid to late G1 was confirmed by the finding that when trypsinized and replated onto FN-coated dishes after 30 h of culture, they required a similar time (12-15 h) to reenter S phase as cells that had been spread and allowed to progress through G1 on FN. We have previously shown that hepatocytes remain viable and maintain high levels of liver-specific functions when cultured on these RGD-coated dishes. Thus, these results suggest that ECM acts at two different points in the cell cycle to regulate hepatocyte growth: first, by activating the G0/G1 transition via integrin binding and second, by promoting the G1/S phase transition and switching off the default differentiation program through mechanisms related to cell spreading.},
	keywords = {Amino Acid Sequence, Animals, Cell Adhesion, Cell Cycle, Cell Size, Culture Media, Serum-Free, Epidermal Growth Factor, Extracellular Matrix, Fibronectins, Insulin, Integrins, Liver, Molecular Sequence Data, Oligopeptides, Protein Binding, Rats},
	issn = {1059-1524},
	author = {Hansen, L K and Mooney, D J and Vacanti, J P and Ingber, D. E.}
}
@article {1192541,
	title = {Transplantation of hepatocytes using porous, biodegradable sponges},
	journal = {Transplant Proc},
	volume = {26},
	number = {6},
	year = {1994},
	month = {1994 Dec},
	pages = {3425-6},
	keywords = {Animals, Biocompatible Materials, Biodegradation, Environmental, Cell Transplantation, Cells, Cultured, Lactates, Lactic Acid, Liver, Polyesters, Polyglycolic Acid, Polymers, Portacaval Shunt, Surgical, Rats, Rats, Inbred Lew, Time Factors, Transplantation, Isogeneic},
	issn = {0041-1345},
	author = {Mooney, D J and Kaufmann, P M and Sano, K and McNamara, K M and Vacanti, J P and Langer, R}
}
@article {1192556,
	title = {Government policies on a collision course. Health cost containment and the antitrust laws},
	journal = {Med Group Manage J},
	volume = {40},
	number = {5},
	year = {1993},
	month = {1993 Sep-Oct},
	pages = {46-8, 50, 52},
	abstract = {The Sherman Act, passed in 1890, was initially enacted to break up the huge "trusts" of that era, writes Donald Mooney, but it has been used more frequently as a weapon in the government{\textquoteright}s war to slow mounting health care costs. In this era of mergers, acquisitions and joint ventures, groups need to be readily aware of the laws regarding antitrust.},
	keywords = {Antitrust Laws, Cost Control, Economic Competition, Group Practice, Health Care Costs, Health Facility Merger, Hospital-Physician Joint Ventures, Managed Care Programs, United States},
	issn = {0899-8949},
	author = {Mooney, D J}
}
@article {217606,
	title = {Enterocyte transplantation using cell-polymer devices to create intestinal epithelial-lined tubes},
	journal = {Transplant Proc},
	volume = {25},
	number = {1 Pt 2},
	year = {1993},
	month = {1993 Feb},
	pages = {998-1001},
	keywords = {Animals, Epithelial Cells, Epithelium, Inflammation, Intestinal Mucosa, Male, Prostheses and Implants, Rats, Rats, Inbred Lew, Silicone Elastomers},
	issn = {0041-1345},
	author = {Organ, G M and Mooney, D J and Hansen, L K and Schloo, B and Vacanti, J P}
}
@article {1192561,
	title = {Preoperative pupil fatigue},
	journal = {J Cataract Refract Surg},
	volume = {18},
	number = {3},
	year = {1992},
	month = {1992 May},
	pages = {306-9},
	abstract = {Pupils are frequently dilated on the day before cataract surgery and for retinal detachment surgery so the fundus can be examined. This may, however, interfere with pupil mydriasis on the day of surgery. This study looked at the effect of pupil dilation with tropicamide 1\% and with cyclopentolate 1\% on pupil mydriasis 24 hours later, using phenylephrine 10\% and cyclopentolate 1\%, in 40 cataract patients. The pupils dilated with cyclopentolate one day previously demonstrated a mean reduction in subsequent mydriasis of 0.73 mm compared with pupils that had been dilated with tropicamide (P less than .0001). The magnitude of this difference was not related to the patient age (P = .12) or to iris color (P = .21). If it is necessary to dilate pupils on the day before surgery, tropicamide 1\% rather than cyclopentolate 1\% should be used, as it is less likely to interfere with the pupil mydriasis produced with cyclopentolate 1\% and phenylephrine 10\% on the day of surgery.},
	keywords = {Aged, Aged, 80 and over, Cataract Extraction, Cyclopentolate, Female, Humans, Male, Middle Aged, Mydriasis, Mydriatics, Phenylephrine, Preoperative Care, Pupil, Tropicamide},
	issn = {0886-3350},
	author = {Power, W J and Hope-Ross, M and Mooney, D J}
}
@article {217611,
	title = {Transplantation of enterocytes utilizing polymer-cell constructs to produce a neointestine},
	journal = {Transplant Proc},
	volume = {24},
	number = {6},
	year = {1992},
	month = {1992 Dec},
	pages = {3009-11},
	keywords = {Animals, Cell Adhesion, Cell Survival, Epithelium, Graft Survival, Intestinal Mucosa, Male, Polyglycolic Acid, Prostheses and Implants, Rats, Rats, Inbred Lew},
	issn = {0041-1345},
	author = {Organ, G M and Mooney, D J and Hansen, L K and Schloo, B and Vacanti, J P}
}
@article {1192566,
	title = {Welding arc maculopathy and fluphenazine},
	journal = {Br J Ophthalmol},
	volume = {75},
	number = {7},
	year = {1991},
	month = {1991 Jul},
	pages = {433-5},
	abstract = {A 45-year-old male patient presented with a bilateral maculopathy following unprotected exposure of less than two minutes{\textquoteright} duration to a manual metal arc welding unit. He had been receiving the drug fluphenazine for the previous 10 years for treatment of depression. We believe that the drug fluphenazine, which had accumulated in his retinal pigment epithelium, may have rendered him particularly susceptible to retinal photic damage.},
	keywords = {Fluphenazine, Fundus Oculi, Humans, Macula Lutea, Male, Middle Aged, Occupational Diseases, Radiation Tolerance, Retinal Diseases, Welding},
	issn = {0007-1161},
	author = {Power, W J and Travers, S P and Mooney, D J}
}
@article {1192571,
	title = {Deciphering bloody imprints through chemical enhancement},
	journal = {J Forensic Sci},
	volume = {35},
	number = {2},
	year = {1990},
	month = {1990 Mar},
	pages = {457-65},
	abstract = {Obliterated bloody impressions are occasionally submitted to the crime laboratory, and potentially to the document examiner, for decipherment. Nondestructive methods often lead to inconclusive results in these circumstances. With this point in mind, the researchers explored a series of chemical reagents with the intent to enhance bloody imprints to a legible degree. The reagents selected for this comparison include rhodamine dye, luminol, and Coomassie Blue stain.},
	keywords = {Blood Stains, Coloring Agents, Forensic Medicine, Gossypium, Humans, Lasers, Luminol, Paper, Rhodamines, Rosaniline Dyes, Staining and Labeling},
	issn = {0022-1198},
	author = {Doherty, P E and Mooney, D J}
}
@article {1192576,
	title = {The pattern ERG in Best{\textquoteright}s disease},
	journal = {Doc Ophthalmol},
	volume = {76},
	number = {3},
	year = {1990},
	month = {1990-1991},
	pages = {279-84},
	abstract = {The aim of this study was to assess inner retinal function in patients with Best{\textquoteright}s disease using the pattern ERG (PERG). Nine patients with Best{\textquoteright}s disease, who had good visual acuity, were studied. Five of the nine had abnormal PERGs. All five had some reduction in central visual acuity. We believe that the abnormal PERGs in these patients represents photoreceptor cell loss which is occurring at an early stage in Best{\textquoteright}s disease.},
	keywords = {Adult, Electroretinography, Female, Humans, Macular Degeneration, Male, Pedigree, Visual Acuity},
	issn = {0012-4486},
	author = {Power, W J and Coleman, K and Curtin, D M and Mooney, D J}
}
@article {1192581,
	title = {Anaphylaxis following oral fluorescein angiography},
	journal = {Am J Ophthalmol},
	volume = {106},
	number = {6},
	year = {1988},
	month = {1988 Dec 15},
	pages = {745-6},
	keywords = {Administration, Oral, Adolescent, Anaphylaxis, Fluorescein, Fluorescein Angiography, Fluoresceins, Humans, Male},
	issn = {0002-9394},
	author = {Kinsella, F P and Mooney, D J}
}
@article {1192586,
	title = {Angioid streaks in beta thalassaemia minor},
	journal = {Br J Ophthalmol},
	volume = {72},
	number = {4},
	year = {1988},
	month = {1988 Apr},
	pages = {303-4},
	abstract = {We report what we believe to be the first recorded case of angioid streaks in a patient with beta thalassaemia minor. The occurrence of angioid streaks in a patient with a relatively normal iron balance and only very mild haemolysis may be explained by the combination of pregnancy with associated multiple transfusions in a myopic patient where an inherent defect in Bruch{\textquoteright}s membrane may exist.},
	keywords = {Adult, Angioid Streaks, Female, Fluorescein Angiography, Humans, Retina, Thalassemia},
	issn = {0007-1161},
	author = {Kinsella, F P and Mooney, D J}
}
@article {1192596,
	title = {The additional pressure-lowering effect in patients with glaucoma of pilocarpine 2 per cent, adrenaline 1 per cent, or guanethidine 3 per cent with adrenaline 0.5 per cent and timolol 0.25 per cent: a double-blind cross-over study},
	journal = {Trans Ophthalmol Soc U K},
	volume = {103 ( Pt 6)},
	year = {1983},
	month = {1983},
	pages = {588-92},
	abstract = {A group of twelve comparable patients with primary open angle glaucoma were treated with Timolol 0.25 per cent drops to which was added pilocarpine 2 per cent, adrenaline 1 per cent or guanethidine 3 per cent plus adrenaline 0.5 per cent in a cross-over study. The initial intraocular pressure (IOP) reduction due to timolol was statistically significant. The mean additional IOP lowering due to pilocarpine 2 per cent was 1.37 mm Hg, that due to adrenaline 1 per cent was 1.79 mm Hg and that due to guanethidine 3 per cent plus adrenaline 0.5 per cent was 5.29 mm Hg.},
	keywords = {Aged, Clinical Trials as Topic, Double-Blind Method, Drug Therapy, Combination, Epinephrine, Female, Glaucoma, Open-Angle, Guanethidine, Humans, Intraocular Pressure, Male, Middle Aged, Pilocarpine, Timolol},
	issn = {0078-5334},
	author = {O{\textquoteright}Connor, M A and Mooney, D J}
}
@article {1192591,
	title = {Retinal function in Stargardt{\textquoteright}s disease and fundus flavimaculatus},
	journal = {Am J Ophthalmol},
	volume = {96},
	number = {1},
	year = {1983},
	month = {1983 Jul},
	pages = {57-65},
	abstract = {Ten patients with Stargardt{\textquoteright}s disease and 14 with fundus flavimaculatus underwent thorough ophthalmic examinations, retinal photography, and, when possible, fluorescein angiography. Retinal function was also assessed by static and kinetic perimetry, the Farnsworth-Munsell 100-hue test, electro-oculography, and electroretinography. Visual acuity and color discrimination were reduced in all patients (mean visual acuity, 20/120; mean error score, 365). On electroretinography all patients had some significant abnormality of cone function and 24 eyes had abnormal rod function (mean Vmax, 298.3). Electrooculographic findings were abnormal in 24 eyes and borderline in ten others. These abnormalities were similar in both groups but more severe in fundus flavimaculatus. Stargardt{\textquoteright}s disease and fundus flavimaculatus did not co-exist in any family studied and the mean duration of disease was similar in both, indicating that Stargardt{\textquoteright}s disease did not progress to fundus flavimaculatus. Both the age of onset and duration significantly affected the severity of fundus flavimaculatus but neither had a significant effect on Stargardt{\textquoteright}s disease.},
	keywords = {Adolescent, Adult, Aging, Diagnosis, Differential, Female, Fundus Oculi, Humans, Macular Degeneration, Male, Psychophysiology, Retina, Retinal Diseases, Syndrome, Time Factors},
	issn = {0002-9394},
	author = {Moloney, J B and Mooney, D J and O{\textquoteright}Connor, M A}
}
@article {1192601,
	title = {Basal skin resistance of premature infants},
	journal = {Percept Mot Skills},
	volume = {33},
	number = {3},
	year = {1971},
	month = {1971 Dec},
	pages = {1138},
	keywords = {Arousal, Galvanic Skin Response, Humans, Infant, Newborn, Infant, Premature},
	issn = {0031-5125},
	doi = {10.2466/pms.1971.33.3f.1138},
	author = {Berkson, G and Mooney, D J}
}
@article {1192606,
	title = {Congenital keratolenticular adhesion},
	journal = {Am J Ophthalmol},
	volume = {70},
	number = {6},
	year = {1970},
	month = {1970 Dec},
	pages = {975-7},
	keywords = {Anterior Chamber, Cataract Extraction, Cornea, Corneal Transplantation, Descemet Membrane, Ectoderm, Humans, Lens, Crystalline, Male, Mesoderm, Microphthalmos, Middle Aged, Tissue Adhesions, Transplantation, Homologous, Visual Acuity},
	issn = {0002-9394},
	author = {Harden, A F and Mooney, D O and Mooney, D J}
}
