A Sulfonated Thermoresponsive Injectable Gel for Sequential Release of Therapeutic Proteins to Protect Cardiac Function After a Myocardial Infarction

Abstract

Myocardial infarction causes cardiomyocyte death and persistent inflammatory responses, which generates adverse pathological remodeling. Delivering therapeutic proteins from injectable materials in a controlled release manner may present an effective biomedical approach for treating this disease. A thermoresponsive injectable gel composed of chitosan, conjugated with poly(N-isopropylacrylamide) and sulfonate groups, was developed for spatiotemporal protein delivery to protect cardiac function after a myocardial infarction. The thermoresponsive gel delivered VEGF, IL-10 and PDGF in a sequential and sustained manner in vitro. An acute myocardial infarction mouse model was used to evaluate polymer biocompatibility and to determine therapeutic effects from the delivery system on cardiac function. Immunohistochemistry showed biocompatibility of the hydrogel, while the controlled delivery of the proteins reduced macrophage infiltration and increased vascularization. Echocardiography showed an improvement in ejection fraction and fractional shortening after injecting the thermal gel and proteins. A factorial design of experiments study was implemented to optimize the delivery system for the best combination and doses of proteins for further increasing stable vascularization and reducing inflammation using a subcutaneous injection mouse model. The results showed that VEGF, IL-10, and FGF-2 demonstrated significant contributions towards promoting long-term vascularization, while PDGFs effect was minimal.