Cardiovascular disease (CVD) is a significant health burden and is the leading cause of death in the United States. Cardiac pathologies which lead to cardiovascular disease, including myocardial infarction and diabetes, often result in damaged, ischemic and/or fibrotic tissue and would benefit from a therapeutic approach to promote cardiac regeneration. The use of a tissue engineering approach, where the principles of biology and engineering are combined to develop functional tissue substitutes, is a very promising and active field of study. However, cardiac tissue engineering approaches to date have been limited due to 1) insufficient vascularization of engineered tissues (essential for the supply of oxygen, nutrients, and immune cells and waste removal) and 2) impaired regulation of extracellular matrix remodeling and turnover (leading to damaging structural, geometric and functional changes in the heart). Therefore, promoting both vascularization and reparative matrix remodeling is one of the key requirements for successful cardiac regeneration via cardiac tissue engineering approaches.

Our long-term goal is to develop a new cardiac tissue engineering approach to treat cardiovascular diseases, including myocardial infarction and diabetic cardiomyopathy, by applying recent advances in nanobiotechnology to modify the microenvironment of heart muscle and promote cardiac regeneration. The studies in this dissertation contribute to this goal by investigating the interactions between cardiac cells, including endothelial cells and fibroblasts, as well as the use of RAD16-II peptide nanofibers and mechanical strain to promote angiogenesis and reparative matrix remodeling by these cells in vitro. The central hypothesis of this research is that RAD16-II peptide nanofibers can be used as a microenvironment for a cardiac tissue engineering approach which promotes cardiac regeneration via revascularization and reparative matrix remodeling by cardiac fibroblasts.

The results from this dissertation research help identify the role of fibroblasts in temporal regulation of the angiogenic process and in reparative matrix remodeling. Additionally, the effects of diabetes on the matrix remodeling response by fibroblasts and potential compensatory tissue engineering strategies (i.e. mechanical stretch, peptide nanofiber microenvironment) were investigated as well. The culture system of RAD16-II nanofibers was utilized as both a controlled microenvironment for study and as a system which supports matrix metalloproteinasemediated extracellular matrix remodeling by cardiac fibroblasts in vitro. The findings of this research will contribute towards developing an optimal microenvironment to enhance cardiac regeneration after injury and for cardiac tissue engineering applications.