@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}
}
