Engineering a 3D-Bioprinted model of human heart valve disease using nanoindentation-based biomechanics

Dewy C. van der Valk, Casper F.T. van der Ven, Mark C. Blaser, Joshua M. Grolman, Pin-Jou Wu, Owen S. Fenton, Lang H. Lee, Mark W. Tibbitt, Jason L. Andresen, Jennifer R. Wen, Anna H. Ha, Fabrizio Buffolo, Alain van Mil, Carlijn V.C. Bouten, Simon C. Body, David J. Mooney, Joost P.G. Sluijter, Masanori Aikawa, Jesper Hjortnaes, Robert LangerElena Aikawa

Research output: Contribution to journalArticleAcademicpeer-review

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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’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’s moduli of the AV layers were 37.1, 15.4, and 26.9 kPa (fibrosa/spongiosa/ ventricularis, respectively). The fibrosa and spongiosa Young’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.

Original languageEnglish
Article number296
Number of pages21
JournalNanomaterials
Volume8
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • 3D printing
  • Aortic valve
  • Bioprinting
  • Calcific aortic valve disease
  • Calcification
  • Mechanobiology
  • Microdissection
  • Nanoindentation

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