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Understanding the Mechanism and Improving the Design of a Myocardial Matrix Hydrogel for Post-Infarct Repair

  • Author(s): Wassenaar, Jean Wang
  • Advisor(s): Christman, Karen L
  • et al.
Abstract

With improved management of patients with acute myocardial infarctions (MI), the prevalence in heart failure (HF) post-MI is expected to rise. Currently, the only successful treatments for HF are total heart transplantation and left ventricular (LV) assist devices, but their uses are limited by the availability of donor hearts and invasiveness of the procedure. In the last decade, advancements have been made towards developing injectable hydrogels for the purpose of cardiac repair. Injections of hydrogels alone have been shown to attenuate the decline in cardiac function and LV remodeling typically seen after MI in both large and small animals models. One of these hydrogels was previously developed by our lab and derived from decellularized porcine ventricular myocardium. The goal of this thesis was study to the mechanisms by which injections of the myocardial matrix hydrogel improve cardiac repair post-MI and improve upon its cardioreparative effects. To better understand how this myocardial matrix is able to induce the beneficial effects observed post-MI, a whole transcriptome microarray was performed on infarct tissue collected from matrix or saline injected infarcts. We showed through pathway analysis that the effects of the injection were dividable into several tissue level phenotypes. To better understand these in vivo phenomena, we wanted to recapitulate the observations by cell culture in vitro with the myocardial matrix. Several cell behaviors relevant to the infarct milieu were studied, including cardiac progenitor cell migration, cardiomyocyte apoptosis, cardiac fibroblast metallomatrix proteinase (MMP) production, and macrophage polarization. We demonstrated that the form of the matrix that is presented to the cells have a dramatic effect on the cellular response, whether through the 3D hydrogel or as soluble peptides released during degradation. In addition, different fractions of the degradation products also have different bioactivity. Results from these in vitro experiments suggested that the bioactivity of the myocardial matrix and its degradation products seemed to be essential to its cardioreparative effects post-MI; thus, we investigated whether this could be enhanced by prolonging the degradation rate of the hydrogel. Through these studies, we provided the first steps towards elucidating the mechanism of actions of the myocardial matrix, by defining the tissue level changes that it induces in infarcted myocardium and identifying the bioactivity in both the hydrogel form and degradation products.

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