Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics
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 mode...
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MDPI AG
2018
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| Online Access: | http://hdl.handle.net/1721.1/115860 https://orcid.org/0000-0002-5585-9280 https://orcid.org/0000-0002-4917-7187 https://orcid.org/0000-0003-4255-0492 |
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| author | van der Valk, Dewy C. Blaser, Mark C. Grolman, Joshua M. Wu, Pin-Jou Lee, Lang H. Wen, Jennifer R. Ha, Anna H. Buffolo, Fabrizio van Mil, Alain Bouten, Carlijn V. C. Body, Simon C. Mooney, David J. Sluijter, Joost P. G. Aikawa, Masanori Hjortnaes, Jesper Aikawa, Elena van der Valk, Dewy van der Ven, Casper Blaser, Mark Grolman, Joshua Fenton, Owen Lee, Lang Tibbitt, Mark Andresen, Jason Wen, Jennifer Ha, Anna Bouten, Carlijn Body, Simon Mooney, David Sluijter, Joost van der Ven, Casper F.t. Tibbitt, Mark W Langer, Robert S Fenton, Owen Shea |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering van der Valk, Dewy C. Blaser, Mark C. Grolman, Joshua M. Wu, Pin-Jou Lee, Lang H. Wen, Jennifer R. Ha, Anna H. Buffolo, Fabrizio van Mil, Alain Bouten, Carlijn V. C. Body, Simon C. Mooney, David J. Sluijter, Joost P. G. Aikawa, Masanori Hjortnaes, Jesper Aikawa, Elena van der Valk, Dewy van der Ven, Casper Blaser, Mark Grolman, Joshua Fenton, Owen Lee, Lang Tibbitt, Mark Andresen, Jason Wen, Jennifer Ha, Anna Bouten, Carlijn Body, Simon Mooney, David Sluijter, Joost van der Ven, Casper F.t. Tibbitt, Mark W Langer, Robert S Fenton, Owen Shea |
| author_sort | van der Valk, Dewy C. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T17:11:21Z |
| format | Article |
| id | mit-1721.1/115860 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T17:11:21Z |
| publishDate | 2018 |
| publisher | MDPI AG |
| record_format | dspace |
| spelling | mit-1721.1/1158602022-10-03T11:03:22Z Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics van der Valk, Dewy C. Blaser, Mark C. Grolman, Joshua M. Wu, Pin-Jou Lee, Lang H. Wen, Jennifer R. Ha, Anna H. Buffolo, Fabrizio van Mil, Alain Bouten, Carlijn V. C. Body, Simon C. Mooney, David J. Sluijter, Joost P. G. Aikawa, Masanori Hjortnaes, Jesper Aikawa, Elena van der Valk, Dewy van der Ven, Casper Blaser, Mark Grolman, Joshua Fenton, Owen Lee, Lang Tibbitt, Mark Andresen, Jason Wen, Jennifer Ha, Anna Bouten, Carlijn Body, Simon Mooney, David Sluijter, Joost van der Ven, Casper F.t. Tibbitt, Mark W Langer, Robert S Fenton, Owen Shea Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT van der Ven, Casper F.t. Fenton, Owen S. Tibbitt, Mark W Andresen, Jason Langer, Robert S 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. 2018-05-24T18:02:58Z 2018-05-24T18:02:58Z 2018-05 2018-04 2018-05-24T15:16:32Z Article http://purl.org/eprint/type/JournalArticle 2079-4991 http://hdl.handle.net/1721.1/115860 van der Valk, Dewy et al. "Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics." Nanomaterials 8, 5 (May 2018): 296 © 2018 The Authors https://orcid.org/0000-0002-5585-9280 https://orcid.org/0000-0002-4917-7187 https://orcid.org/0000-0003-4255-0492 http://dx.doi.org/10.3390/nano8050296 Nanomaterials Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf MDPI AG Multidisciplinary Digital Publishing Institute |
| spellingShingle | van der Valk, Dewy C. Blaser, Mark C. Grolman, Joshua M. Wu, Pin-Jou Lee, Lang H. Wen, Jennifer R. Ha, Anna H. Buffolo, Fabrizio van Mil, Alain Bouten, Carlijn V. C. Body, Simon C. Mooney, David J. Sluijter, Joost P. G. Aikawa, Masanori Hjortnaes, Jesper Aikawa, Elena van der Valk, Dewy van der Ven, Casper Blaser, Mark Grolman, Joshua Fenton, Owen Lee, Lang Tibbitt, Mark Andresen, Jason Wen, Jennifer Ha, Anna Bouten, Carlijn Body, Simon Mooney, David Sluijter, Joost van der Ven, Casper F.t. Tibbitt, Mark W Langer, Robert S Fenton, Owen Shea Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics |
| title | Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics |
| title_full | Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics |
| title_fullStr | Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics |
| title_full_unstemmed | Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics |
| title_short | Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics |
| title_sort | engineering a 3d bioprinted model of human heart valve disease using nanoindentation based biomechanics |
| url | http://hdl.handle.net/1721.1/115860 https://orcid.org/0000-0002-5585-9280 https://orcid.org/0000-0002-4917-7187 https://orcid.org/0000-0003-4255-0492 |
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