Intravascular infusion of a soluble extracellular matrix hydrogel therapy for acute myocardial infarction
Myocardial infarction (MI) is a leading cause of death in the world. Many patients survive the MI; however, the ischemic damage remains, and there are currently no treatments available to repair the heart. Decellularized extracellular matrix (ECM) has been widely used for tissue engineering applications and is becoming increasingly versatile as it can take many forms, including patches, powders, and hydrogels. Following additional processing, decellularized ECM can form an inducible hydrogel that can be injected, providing opportunities for minimally invasive delivery. We have developed a new ECM hydrogel therapy, the soluble fraction derived from decellularized, digested ECM, for intravascular infusion. This new form of ECM is capable of gelation in vivo and can be delivered via intravascular infusion following an injury to specifically target the injured tissue, promote cell survival, and improve vascularization. In this dissertation, we show proof-of-concept for the feasibility of ECM infusions using models of acute myocardial infarction and intracoronary infusion for delivery. Following infusion, the ECM material was retained specifically in the injured tissue and colocalized with endothelial cells, coating the leaky microvasculature. Functional improvements, specifically reduced left ventricular volumes, were observed after ECM infusion post-MI. A range of biological activity modulation was implicated, as pathways associated with angiogenesis, cell-substrate/junction, reactive oxygen species and nitric oxide metabolism, and interleukin 6 were differentially expressed. The soluble ECM was also delivered intravascularly using a clinically relevant catheter in a large animal model of acute MI, mitigated negative left ventricular remodeling, and showed improved left ventricle wall motion. This study shows proof-of-concept for a new therapy and intravascular delivery strategy for ECM biomaterials with potential implications for a variety of pathologies to target injured tissues and injured vasculature.