Elastic exosome-releasing conductive patches for heart repair

Project summary Myocardial infarction (MI) remains a leading cause of morbidity and mortality in the United States and worldwide. Besides cell-based cardiac therapy, the cell-free biodegradable cardiac patch is an appropriate alternative to treat MI and has been determined to restore heart function along with increased wall thickness and angiogenesis as well as reduced scar area. However, the MI-induced scar tissue is non-conductive due to cardiomyocyte death, which lacks electrical integration with surrounding native tissue and cannot electrically couple with viable cardiomyocytes in the infarcted tissue. The conventional cardiac patches are non-conductive, which cannot address such issues. Thus, our goal in this project is to develop a new conductive cardiac patch with good biosafety and bioactivity to promote heart function restoration. Recently, conductive biomaterials have been utilized to manage heart infarction in vivo, which increased conductive induction and electrical coupling along with increased angiogenesis and reduced scar size without pathologic arrhythmias, compared to the conventional non-conductive patches. Current conductive biomaterials are composites from biodegradable polymers and nondegradable conductive polymers (such as polyaniline and polypyrrole with dopant) or nano- scale additives (such as gold nanorod, carbon nanotube, and graphene oxide), which have several concerns in biodegradation, processability, toxicity, and conductivity stability. To address such concerns, our group has developed a fully degradable, elastic, and conductive polyurethane, which does not require to add the extra dopant. It has good biocompatibility and conductivity stability and supports cardiomyocyte growth in vitro. Additionally, the exosomes secreted from primary cells and stem cells have been evidenced to significantly restore heart function with improved angiogenesis and reduced fibrosis and scar size after being delivered into the infarcted heart. Thus, we hypothesize that a combination of fully biodegradable conductive elastic patch and cardiac stromal cell-derived exosome will show synergistic effects on heart function restoration. Furthermore, to reduce the risks of open-chest surgery for patch implantation and enhance the translation of the developed cardiac patches, a minimally invasive approach is developed to deliver the biohybrid patch on the infarcted heart. To reach the goal, three aims are proposed. Aim 1 is to optimize and comprehensively characterize the biodegradable conductive porous polyurethane patch; Aim 2 is to develop the biohybrid scaffolds of combining elastic conductive cardiac patch and cardiac stromal cell-derived exosome and assess their therapeutic efficacy in rat infarction model; and Aim 3 is to evaluate their efficacy of the biohybrid scaffolds in a clinically relevant pig model. The project is innovative and translational. The unicomponent biodegradable conductive polyurethane without adding extra dopant is novel, combining the conductive cardiac patch with exosome is innovative to offer synergistic effects, and the minimally invasive implantation is promising to reduce the open-chest surgery risks.