Over 1 million Americans suffer a myocardial infarction (MI) each year and many experience post-MI left ventricular (LV) remodeling, which is manifest as progressive changes in LV structure and function. Post-MI LV remodeling is responsible for nearly 70% of all heart failure (HF) cases. HF severely disables 5 million Americans and kills more than 250,000 each year. The proposed project is based on a highly significant translational research approach that seeks to develop a clinically applicable, minimally invasive treatment strategy focused on the newly formed MI intended to interrupt LV remodeling and prevent the development of symptomatic HF. Infarct expansion (stretching) results from progressive changes in MI material properties and has been identified as the biomechanical phenomena that initiates and sustains adverse LV remodeling. The proposed project will build on and advance our previously completed work, which demonstrated that preventing infarct expansion by surgically placed restraint devices significantly reduces LV remodeling. The overarching goal of this project is to establish that targeted delivery of novel biomaterials that have been engineered to induce a phenotypic shift in responding macrophages from the M1 (proteolytic) phenotype to the M2 (reparative) phenotype, will promote extracellular matrix (ECM) stability, favorably alter infarct material properties, limit infarct expansion and improve LV remodeling. In Specific Aim 1 we will test the hypothesis that targeted delivery of monocyte chemoattractant protein-1 (MCP-1) into the infarct region by a hyaluronic acid (HA) hydrogel carrier shifts responding macrophage polarization in favor of the M2 phenotype, which promotes ECM stability, favorably alters infarct material properties, limits infarct expansion and improves LV remodeling. In Specific Aim 2 we will test the hypothesis that the targeted delivery to the infarct region of PLGA microspheres and MCP-1 in a HA-hydrogel carrier will synergistically potentiate both macrophage polarization in favor of the M2 phenotype and ECM stability further reducing infarct expansion and limiting LV remodeling when compared to PLGA microspheres or MCP-1 delivery alone. The significance of the proposed project is further enhanced by the use of a clinically relevant large animal MI model and the application in Specific Aim 3 of minimally invasive catheter-based epicardial approaches for biomaterial delivery guided by state-of-the-art electroanatomic infarct mapping. Both of which heighten the potential for rapid clinical translation of the proposed work.