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

被引：71

作者：

van der Valk, Dewy C. ^{[1
]}

van der Ven, Casper F. T. ^{[2
,3
]}

Blaser, Mark C. ^{[1
]}

Grolman, Joshua M. ^{[4
,5
]}

Wu, Pin-Jou ^{[1
]}

Fenton, Owen S. ^{[3
]}

Lee, Lang H. ^{[1
]}

Tibbitt, Mark W. ^{[3
,6
]}

Andresen, Jason L. ^{[3
]}

Wen, Jennifer R. ^{[1
]}

Ha, Anna H. ^{[1
]}

Buffolo, Fabrizio ^{[1
]}

van Mil, Alain ^{[7
,8
]}

Bouten, Carlijn V. C. ^{[9
,10
]}

Body, Simon C. ^{[11
]}

Mooney, David J. ^{[4
,5
]}

Sluijter, Joost P. G. ^{[7
,8
]}

Aikawa, Masanori ^{[1
,2
,12
]}

Hjortnaes, Jesper ^{[7
,8
]}

Langer, Robert ^{[3
,13
]}

Aikawa, Elena ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Ctr Interdisciplinary Cardiovasc Sci, Dept Med,Div Cardiovasc Med, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womans Hosp, Ctr Excellence Cardiovasc Biol, Dept Med,Div Cardiovasc Med, Boston, MA 02115 USA

[3] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[4] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA

[5] Harvard Univ, John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA

[6] Swiss Fed Inst Technol, Dept Mech & Proc Engn, Macromol Engn Lab, CH-8092 Zurich, Switzerland

[7] Univ Utrecht, Univ Med Ctr Utrecht, Dept Cardiol, Expt Cardiol Lab, NL-3584 CX Utrecht, Netherlands

[8] Univ Med Ctr Utrecht, Regenerat Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands

[9] Eindhoven Univ Technol, Dept Biomed Engn, NL-5600 MB Eindhoven, Netherlands

[10] Eindhoven Univ Technol, Inst Complex Mol Syst, NL-5600 MB Eindhoven, Netherlands

[11] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Perioperat Genom, Boston, MA 02115 USA

[12] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA

[13] MIT, Dept Chem Engn, Cambridge, MA 02142 USA

来源：

NANOMATERIALS | 2018年 / 8卷 / 05期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

aortic valve; calcific aortic valve disease; calcification; mechanobiology; bioprinting; 3D printing; microdissection; nanoindentation; INTERSTITIAL CELL PHENOTYPE; BICUSPID AORTIC VALVES; DYNAMIC NANOINDENTATION; FORCE MICROSCOPY; 3D CULTURE; HYDROGELS; CALCIFICATION; TISSUE; STENOSIS; LEAFLET;

D O I：

10.3390/nano8050296

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页数：21

共 58 条

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