ABSTRACT Over 3 million people in the United States currently suffer from heart failure caused by a myocardial infarction (MI) and more than 600,000 survivable MIs occur each year, including 200,000 ST-segment Elevated MIs (STEMIs). STEMIs are a severe MI caused by a prolonged period of blocked blood supply that affects a large area of the heart muscle. Re-hospitalization rates remain high for STEMI patients and within 5 years approximately 50% of STEMI patients will die. Despite improvements in door-to-balloon times to reperfuse the infarct, an adverse left ventricular (LV) remodeling process occurs post MI that leads to maladaptive changes to the structure and function of the LV. Matrix metalloproteinases (MMPs) are a class of tissue degrading enzymes that contribute to LV wall thinning, expansion and ultimately LV dysfunction. While systemic administration of MMP inhibitors has shown promising results in preserving LV structure and function, dose-limiting side effects of the drugs have stalled clinical translation. To avoid off-target effects of promising therapeutics such as MMPIs and deliver effective concentrations locally to the infarct, Prohibix LLC and investigators at the University of Pennsylvania have invented a breakthrough injectable hydrogel technology to encapsulate and deliver these molecules through a clinically adopted, epicardial access procedure. This innovative hydrogel system, EPICARGO, was successfully delivered to a target region of the myocardium in pigs without complications and localized the release of a fluorescent dye in Phase I studies. In addition, a novel gel formulation containing the FDA approved MMPI, doxycycline, was developed with ideal bioresponsive release kinetics. This Phase II proposal by Prohibix LLC seeks to further validate the safety and stability of EPICARGO gels in pigs, and demonstrate efficacy of localized doxycycline delivery compared to oral dosing of the drug. Successful completion of the proposed Aims will further validate this platform technology in order to attract life science investors and industry partners to fund development through first-in-man trials.