title: Biohybrid cardiac ECM-based hydrogels improve long term cardiac function post myocardial infarction.
abstract: Injectable scaffolds for cardiac tissue regeneration are a promising therapeutic approach for progressive heart failure following myocardial infarction (MI). Their major advantage lies in their delivery modality that is considered minimally invasive due to their direct injection into the myocardium. Biomaterials comprising such scaffolds should mimic the cardiac tissue in terms of composition, structure, mechanical support, and most importantly, bioactivity. Nonetheless, natural biomaterial-based gels may suffer from limited mechanical strength, which often fail to provide the long-term support required by the heart for contraction and relaxation. Here we present newly-developed injectable scaffolds, which are based on solubilized decellularized porcine cardiac extracellular matrix (pcECM) cross-linked with genipin alone or engineered with different amounts of chitosan to better control the gel's mechanical properties while still leveraging the ECM biological activity. We demonstrate that these new biohybrid materials are naturally remodeled by mesenchymal stem cells, while supporting high viabilities and affecting cell morphology and organization. They exhibit neither in vitro nor in vivo immunogenicity. Most importantly, their application in treating acute and long term chronic MI in rat models clearly demonstrates the significant therapeutic potential of these gels in the long-term (12weeks post MI). The pcECM-based gels enable not only preservation, but also improvement in cardiac function eight weeks post treatment, as measured using echocardiography as well as hemodynamics. Infiltration of progenitor cells into the gels highlights the possible biological remodeling properties of the ECM-based platform.
  
  
  
  This work describes the development of new injectable scaffolds for cardiac tissue regeneration that are based on solubilized porcine cardiac extracellular matrix (ECM), combined with natural biomaterials: genipin, and chitosan. The design of such scaffolds aims at leveraging the natural bioactivity and unique structure of cardiac ECM, while overcoming its limited mechanical strength, which may fail to provide the long-term support required for heart contraction and relaxation. Here, we present a biocompatible gel-platform with custom-tailored mechanical properties that significantly improve cardiac function when injected into rat hearts following acute and chronic myocardial infarction. We clearly demonstrate the substantial therapeutic potential of these scaffolds, which not only preserved heart functions but also alleviated MI damage, even after the formation of a mature scar tissue.
authors.affiliation: Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Efraim
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Hadar
authors.initials: H
authors.lastname: Sarig
authors.affiliation: Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Cohen Anavy
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Udi
authors.initials: U
authors.lastname: Sarig
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Elio
authors.initials: E
authors.lastname: de Berardinis
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Su-Yin
authors.initials: SY
authors.lastname: Chaw
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Muthukumar
authors.initials: M
authors.lastname: Krishnamoorthi
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kalifa
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Hanumakumar
authors.initials: H
authors.lastname: Bogireddi
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore.
authors.forename: Thang Vu
authors.initials: TV
authors.lastname: Duc
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kofidis
authors.affiliation: Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Baruch
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Freddy Y C
authors.initials: FYC
authors.lastname: Boey
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore.
authors.forename: Subbu S
authors.initials: SS
authors.lastname: Venkatraman
authors.affiliation: Faculty of Biotechnology & Food Engineering, Technion - Israel Institute of Technology, Haifa 32000, Israel. Electronic address: machlufm@tx.technion.ac.il.
authors.forename: Marcelle
authors.initials: M
authors.lastname: Machluf
mesh_terms: D000818:Animals; D002460:Cell Line; D048271:Chitosan / Q000737:chemistry; D005109:Extracellular Matrix / Q000737:chemistry*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D039823:Iridoids / Q000737:chemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D020100:Hydrogels; D039823:Iridoids; D048271:Chitosan; C007834:genipin
keywords: Biohybrid material; Cardiac tissue engineering; Extracellular matrix; Injectable scaffold