UCSF

Myocardial infarction (MI) is the leading cause of heart failure (HF) and despite advances in the management of MI, subsequent pathologic remodeling of ischemic myocardium with fibrotic scar tissue and aneurysmal degeneration leads to HF and death. Early attempts at stem cell delivery and biological therapeutics to promote positive remodeling following MI have been promising but inconsistent and often involve systemic inhibition of signaling factors, which can have unintended side effects. A compelling approach to combat pathological cellular processes that often arise due to myocardial injury includes engineering materials to mimic biological and physical traits of native ECM architecture to provide biophysical cues that may yield more healthy cell phenotypes. This dissertation describes the therapeutic applications of biophysical cues in cardiovascular diseases (CVDs), specifically myocardial infarction and heart failure. First, Chapter 1 provides a comprehensive discussion regarding how nano- and microscale biophysical cues affect the phenotypes and behaviors of key cardiovascular cells– cardiomyocytes, fibroblasts, and endothelial cells– and how these resulting effects may be leveraged for therapeutic success in CVDs. Chapter 2 then details the development of a biodegradable polymeric microstructure technology made of hyaluronic acid. In this study, we investigated how hyaluronic acid microrods affect fibroblast phenotype and if they can improve cardiac outcomes in rodent models of ischemia-reperfusion (I/R) MI injury. We demonstrated that treatment with hyaluronic acid microrods decreases fibrotic phenotype in fibroblasts as well as exhibits enhanced cardiac function and decreased fibrosis after 6 weeks post-MI. Further, treatment with hyaluronic acid microrods outperformed treatment with equivalent mass of soluble hyaluronic acid material control, indicating the importance of the material geometry. Beyond physical regulation of cellular behaviors by topographical cues, the incorporation of biochemical factors may further enhance the efficacy of these therapeutic strategies. As such, Chapter 3 comprises studies that probed the effects of several pro-angiogenic stimuli (i.e., Qk, RoY, and HepIII peptides) on endothelial cells and the feasibility of conjugating them onto hyaluronic acid microrods to create dual-pronged strategy that tackled both rampant fibrosis and lack of vascularization that occur post-MI. Chapter 4 follows a similar approach but investigates the therapeutic effects of a decorin-loaded hyaluronic acid microrod strategy in rodent models of I/R MI injury. Here, we demonstrate distinguishable improvement in cardiac function and ventricular remodeling and decreased fibrosis and cardiomyocyte hypertrophy in animals treated with decorin-loaded hyaluronic acid microrods. Together, this body of work aims to contribute important knowledge to help develop rationally designed, engineered biomaterials that may be used to successfully treat CVDs.