Biodegradable Nanofibrous Temperature‐Responsive Gelling Microspheres for Heart Regeneration

Abstract

Myocardial infarction (heart attack) is the number-one killer of heart patients. Existing treatments do not address cardiomyocyte (CM) loss and cannot regenerate the myocardium. Introducing exogenous cardiac cells is required for heart regeneration due to the lack of resident progenitor cells and very limited proliferative potential of adult CMs. Poor retention of transplanted cells is the critical bottleneck of heart regeneration. Here, the invention of a poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(N-Isopropylacrylamide) copolymer and its self-assembly into nanofibrous gelling microspheres (NF-GMS) is reported. The NF-GMS undergo a thermally responsive transition to form not only a 3D hydrogel after injection in vivo, but also exhibit characteristics mimicking the native extracellular matrix (ECM) of nanofibrous proteins and gelling proteoglycans or polysaccharides. By integrating the ECM-mimicking features, injectable form, and the capability of maintaining 3D geometry after injection, the transplantation of hESC-derived CMs carried by NF-GMS leads to a striking tenfold graft size increase over direct CM injection in rats, which is the highest reported engraftment to date. Furthermore, NF-GMS-carried CM transplantation dramatically reduces infarct size, enhances integration of transplanted CMs, stimulates vascularization in the infarct zone, and leads to a substantial recovery of cardiac function. The NF-GMS may also be utilized in a variety of biomedical applications.