Improving Post-MI Cardiac Function via Delivery of Mydgf using an Injectable and Fluorescent Polyester-Based Hydrogel

During or after myocardial infarction (MI), the cumulative loss of functioning cardiomyocytes progresses as an imbrication of necrosis, apoptosis, and autophagy, resulting in left ventricular negative remodeling and progressive heart failure. Increasing the number of cardiomyocytes within the damaged myocardium may improve cardiac function, and stem cell based-therapies represent a possible solution to repair damaged myocardial tissue by promoting cardioprotection, angiogenesis, and reduced fibrosis. Cell transplantation therapies have been clinically hampered by low retention and engraftment of donor cells, and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Recent evidence indicates that most of the positive outcomes of cell therapy are likely due to the release of paracrine factors including cytokines, growth factors, and exosomes from the transplanted cells. While the direct use of paracrine factors is an attractive strategy, the retention in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Injectable hydrogels with biodegradable properties have newly emerged as a powerful strategy for tissue regeneration and drug delivery, offering minimally invasive, localized, cavity-filling and biodegradable scaffolding features to provide structural support for the weakened myocardia wall and platforms for sustained drug release. Fluorescent hydrogel also enables real-time imaging to monitor hydrogel degradation for in vivo hydrogel degradation and heart repair efficacy relationship study. This proposed research aims to develop a novel amino-acid based, injectable, tissue compatible and biodegradable hydrogel platform with photoluminescent properties for minimally invasive and sustained delivery of growth factor Mydgf to augment myocardial regeneration via imaging-based implant optimization. To achieve this goal, we will 1) Optimize serine-containing photoluminescent hydrogels via in vitro evaluation of Mydgf hydrogel encapsulation, cardiac myocyte survival, proliferation, and tubular formation in HUVECs; 2) In vivo assessment of Mydgf -loaded hydrogels in a rat LAD ligation myocardial infarction model; and 3) Study the relationship between in vivo hydrogel degradation behavior and therapeutic regeneration to further optimize hydrogel formulation for enhanced cardiac repair and functional recovery in a rat LAD ligation MI model. (AHA Program: AHA Institutional Research Enhancement Award (AIREA))