UC San Diego

As cardiovascular disease continues to be the leading cause of death in the Western world, new therapies are needed to treat end stage heart failure (HF). Post- myocardial infarction (MI), the extracellular matrix (ECM) is degraded, and thus cellular or acellular scaffold materials have been explored to repair the damaged ECM. Injectable scaffolds offer the advantage of intramyocardial delivery, as well as potential minimally invasive catheter delivery. However, current materials being explored for cardiac repair do not mimic the complexity of native cardiac ECM and may not be compatible with catheter delivery. The objective of this dissertation is to test the hypothesis that a naturally derived myocardial matrix, developed specifically to mimic the native myocardial ECM, can serve as an injectable acellular scaffold for cardiac repair. Herein, a solubilized myocardial matrix material has been developed from the decellularization of porcine ventricular tissue. Characterization indicates a retained biochemical complexity after decellularization. Additionally, the solubilized myocardial matrix is able to self-assemble, forming a nanofibrous and porous structure, similar to native ECM, at 37°C in vitro. Furthermore, it is demonstrated that the myocardial matrix gel can be altered via crosslinking, leading to increased storage modulus, slowed degradation, and decreased cell migration rates. After initial development and characterization, the myocardial matrix was shown to gel and allow for infiltration of vascular cells, upon injection into rat myocardium. Additionally, effects of myocardial matrix injection in a rat ischemia-reperfusion model were evaluated. This work assesses effects on left ventricular (LV) geometry, shows preserved cardiac function, and attempts to understand local effects of the matrix upon injection into the ischemic region. Finally, the myocardial matrix was tested for feasibility of clinical translation, through percutaneous transendocardial delivery in a porcine model. Following successful injection of matrix post-MI, animals were evaluated for up to three-months, without harmful side effects. This work provides the field of injectable materials for cardiac tissue-engineering with a novel injectable scaffold, designed specifically for the heart that is able to be chemically crosslinked, is able to preserve cardiac function, and has potential for clinical translation to treat HF post-MI