title: Anisotropic silk biomaterials containing cardiac extracellular matrix for cardiac tissue engineering.
abstract: Cardiac malformations and disease are the leading causes of death in the United States in live-born infants and adults, respectively. In both of these cases, a decrease in the number of functional cardiomyocytes often results in improper growth of heart tissue, wound healing complications, and poor tissue repair. The field of cardiac tissue engineering seeks to address these concerns by developing cardiac patches created from a variety of biomaterial scaffolds to be used in surgical repair of the heart. These scaffolds should be fully degradable biomaterial systems with tunable properties such that the materials can be altered to meet the needs of both in vitro culture (e.g. disease modeling) and in vivo application (e.g. cardiac patch). Current platforms do not utilize both structural anisotropy and proper cell-matrix contacts to promote functional cardiac phenotypes and thus there is still a need for critically sized scaffolds that mimic both the structural and adhesive properties of native tissue. To address this need, we have developed a silk-based scaffold platform containing cardiac tissue-derived extracellular matrix (cECM). These silk-cECM composite scaffolds have tunable architectures, degradation rates, and mechanical properties. Subcutaneous implantation in rats demonstrated that addition of the cECM to aligned silk scaffold led to 99% endogenous cell infiltration and promoted vascularization of a critically sized scaffold (10 × 5 × 2.5 mm) after 4 weeks in vivo. In vitro, silk-cECM scaffolds maintained the HL-1 atrial cardiomyocytes and human embryonic stem cell-derived cardiomyocytes and promoted a more functional phenotype in both cell types. This class of hybrid silk-cECM anisotropic scaffolds offers new opportunities for developing more physiologically relevant tissues for cardiac repair and disease modeling.
authors.affiliation: Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Stoppel
authors.forename: Dongjian
authors.initials: D
authors.lastname: Hu
authors.forename: Ibrahim J
authors.initials: IJ
authors.lastname: Domian
authors.forename: David L
authors.initials: DL
authors.lastname: Kaplan
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Black
mesh_terms: D000818:Animals; D016880:Anisotropy; D001672:Biocompatible Materials / Q000737:chemistry; D002478:Cells, Cultured; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005109:Extracellular Matrix / Q000737:chemistry*; D008422:Materials Testing; D009206:Myocardium / Q000737:chemistry; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047011:Silk / Q000737:chemistry*; D023822:Tissue Engineering / Q000295:instrumentation* / Q000379:methods; D054457:Tissue Scaffolds
chemical_list: D001672:Biocompatible Materials; D047011:Silk
references.citation: FASEB J. 2000 Apr;14(5):669-79
references.pmid: 10744624
references.citation: Circulation. 2002 Jan 1;105(1):93-8
references.pmid: 11772882
references.citation: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H823-9
references.pmid: 14766671
references.citation: Circ Res. 2005 Dec 9;97(12):1220-31
references.pmid: 16339494
references.citation: Nat Med. 2006 Apr;12(4):452-8
references.pmid: 16582915
references.citation: Cell Transplant. 2006;15(4):351-8
references.pmid: 16898229
references.citation: Eur Heart J. 2007 Mar;28(5):638
references.pmid: 17298971
references.citation: Nat Protoc. 2006;1(6):2753-8
references.pmid: 17406532
references.citation: J Thorac Cardiovasc Surg. 2007 May;133(5):1336-43
references.pmid: 17467453
references.citation: J Biomed Mater Res A. 2008 Sep;86(3):713-24
references.pmid: 18041719
references.citation: Circulation. 2008 Dec 9;118(24):2571-87
references.pmid: 19064692
references.citation: Tissue Eng Part A. 2009 Oct;15(10):3099-108
references.pmid: 19338433
references.citation: Pharmacol Ther. 2009 Aug;123(2):255-78
references.pmid: 19460403
references.citation: Biomaterials. 2009 Oct;30(29):5409-16
references.pmid: 19608268
references.citation: Circulation. 2010 Feb 23;121(7):e46-e215
references.pmid: 20019324
references.citation: Curr Pharm Des. 2010;16(8):915-28
references.pmid: 20041829
references.citation: Biomaterials. 2011 Feb;32(5):1280-90
references.pmid: 21035179
references.citation: Regen Med. 2010 Nov;5(6):919-32
references.pmid: 21082891
references.citation: Circulation. 2011 Feb 1;123(4):364-73
references.pmid: 21242485
references.citation: Pediatr Cardiol. 2011 Mar;32(3):334-41
references.pmid: 21293854
references.citation: Biomacromolecules. 2011 May 9;12(5):1686-96
references.pmid: 21425769
references.citation: Biomaterials. 2011 Aug;32(24):5558-67
references.pmid: 21555151
references.citation: Br Med Bull. 2011;98:161-85
references.pmid: 21652595
references.citation: J Biomed Mater Res B Appl Biomater. 2011 Oct;99(1):89-101
references.pmid: 21695778
references.citation: Nat Protoc. 2011 Sep 22;6(10):1612-31
references.pmid: 21959241
references.citation: J Vis Exp. 2011 Sep 19;(55):null
references.pmid: 21968517
references.citation: Lancet. 2011 Nov 26;378(9806):1847-57
references.pmid: 22088800
references.citation: J Vis Exp. 2010 Dec 20;(46):null
references.pmid: 22158083
references.citation: Lancet. 2012 Mar 10;379(9819):895-904
references.pmid: 22336189
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):E1848-57
references.pmid: 22645348
references.citation: Acta Biomater. 2012 Dec;8(12):4357-64
references.pmid: 22842035
references.citation: Biomaterials. 2012 Dec;33(36):9214-24
references.pmid: 23036961
references.citation: Expert Opin Drug Deliv. 2013 Jan;10(1):59-72
references.pmid: 23140533
references.citation: Circulation. 2013 Jan 1;127(1):e6-e245
references.pmid: 23239837
references.citation: Sci Transl Med. 2013 Feb 20;5(173):173ra25
references.pmid: 23427245
references.citation: Cell Stem Cell. 2013 Jun 6;12(6):689-98
references.pmid: 23746978
references.citation: Nat Methods. 2013 Aug;10(8):781-7
references.pmid: 23793239
references.citation: Biochem Biophys Res Commun. 2013 Sep 20;439(2):161-6
references.pmid: 23994333
references.citation: Acta Biomater. 2014 Jan;10(1):194-204
references.pmid: 24012606
references.citation: Development. 2013 Oct;140(20):4165-76
references.pmid: 24026118
references.citation: FASEB J. 2014 Feb;28(2):644-54
references.pmid: 24174427
references.citation: Tissue Eng Part A. 2014 Jun;20(11-12):1654-67
references.pmid: 24410342
references.citation: Biomacromolecules. 2014 Feb 10;15(2):635-43
references.pmid: 24417502
references.citation: Tissue Eng Part A. 2014 Jul;20(13-14):1877-87
references.pmid: 24433519
references.citation: Stem Cell Res Ther. 2014 Jan 24;5(1):14
references.pmid: 24460869
references.citation: Adv Healthc Mater. 2014 Nov;3(11):1759-64
references.pmid: 24805162
references.citation: Nat Med. 2014 Jun;20(6):616-23
references.pmid: 24813252
references.citation: Methods Mol Biol. 2014;1181:109-20
references.pmid: 25070331
references.citation: Exp Cell Res. 2015 Jan 15;330(2):311-24
references.pmid: 25220424
references.citation: Cell Mol Bioeng. 2014 Sep 1;7(3):432-445
references.pmid: 25295125
references.citation: Adv Funct Mater. 2014 Apr 16;24(15):2188-2196
references.pmid: 25395920
references.citation: Adv Funct Mater. 2014 Aug 6;24(29):4615-4624
references.pmid: 25395921
references.citation: Acta Biomater. 2015 Mar;14:84-95
references.pmid: 25463503
references.citation: Circulation. 2015 Jan 27;131(4):e29-322
references.pmid: 25520374
references.citation: Heart Asia. 2013 Jun 25;5(1):106-11
references.pmid: 27326099
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2979-84
references.pmid: 9501201