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Nanomaterials 2018, 8(5), 296; https://doi.org/10.3390/nano8050296

Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics

1
Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2
Center of Excellence in Cardiovascular Biology, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Woman’s Hospital, Harvard Medical School, Boston, MA 02115, USA
3
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
4
Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138, USA
5
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
6
Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zürich, 8092 Zürich, Switzerland
7
Experimental Cardiology Laboratory, Department of Cardiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands
8
Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands
9
Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, the Netherlands
10
Center for Perioperative Genomics, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
11
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
12
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 2 April 2018 / Revised: 18 April 2018 / Accepted: 24 April 2018 / Published: 3 May 2018
(This article belongs to the Special Issue Nano-scale Mechanics of Biological Materials)
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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. View Full-Text
Keywords: aortic valve; calcific aortic valve disease; calcification; mechanobiology; bioprinting; 3D printing; microdissection; nanoindentation aortic valve; calcific aortic valve disease; calcification; mechanobiology; bioprinting; 3D printing; microdissection; nanoindentation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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van der Valk, D.C.; van der Ven, C.F.T.; Blaser, M.C.; Grolman, J.M.; Wu, P.-J.; Fenton, O.S.; Lee, L.H.; Tibbitt, M.W.; Andresen, J.L.; Wen, J.R.; Ha, A.H.; Buffolo, F.; van Mil, A.; Bouten, C.V.C.; Body, S.C.; Mooney, D.J.; Sluijter, J.P.G.; Aikawa, M.; Hjortnaes, J.; Langer, R.; Aikawa, E. Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics. Nanomaterials 2018, 8, 296.

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