Design testing of safe and versatile biomaterial therapies for cardiac repair post-myocardial infarction

Heart failure (HF) post-myocardial infarction (MI) is a leading cause of death in the United States. Injectable biomaterials have been evaluated as potential new therapies for MI and HF. These materials have improved left ventricular (LV) geometry and function in animal models, but there remains a need for improved design of biomaterial therapies to ensure patient safety and facilitate therapeutic versatility. The goals of this dissertation were to investigate the effect of biomaterial injection on electrophysiology to inform the design of safe therapies and to improve biomaterial versatility by designing microparticles with tunable release profiles. There remain concerns that biomaterial injection may create a substrate for arrhythmia. We utilized optical mapping to assess the effects of biomaterial injection and interstitial spread on cardiac electrophysiology. Healthy and infarcted rat hearts were injected with a hydrogel with varying degrees of interstitial spread. The degree of the electrophysiological changes depended on the spreading characteristics of the hydrogel, such that hearts injected with highly spread hydrogels showed no conduction abnormalities. Conversely, injection of a hydrogel exhibiting minimal interstitial spread may create a substrate for arrhythmia by causing LV activation delays and reducing gap junction density at the site of injection. Thus, this work establishes site of delivery and interstitial spread characteristics as important factors in the future design of biomaterial therapies for MI treatment. Biomaterials can protect and sustain release of therapeutic payloads, but most biomaterials have defined degradation kinetics, limiting the payload release to one time frame. We harnessed the tunable degradation and acid-sensitivity of acetalated dextran (AcDex) to design microparticles for injection post-MI. Protein release ranging from days to weeks was shown in low pH environments similar to what is found in an infarcted heart. Furthermore, we utilized the tunable degradation of AcDex to determine how delivery rate impacts the efficacy of hepatocyte growth factor (HGF), a known cardioprotective growth factor. HGF-f delivery was optimal over three days post intramyocardial injection, yielding the largest arterioles, fewest apoptotic cardiomyocytes bordering the infarct and the smallest infarcts. This work will help inform the design of future HGF-based therapies and provides a platform for tunable delivery of therapeutics to the heart post-M