| This thesis is focused on developing and characterizing three-dimensional (3-D) engineered cardiac tissues as a model system for basic research and evaluation of novel therapeutic strategies. Given the importance of understanding and controlling structural and mechanical anisotropy in engineered heart tissue, the effects of structural and mechanical cues on engineered tissues were first examined. In particular, cell and matrix response to boundary conditions was investigated and it was suggested that the cells align parallel to local free boundaries. Extended from this study, the ability of highly aligned engineered tissues to remodel in response to altered boundary constraints was examined. It was demonstrated that engineered tissue constructs with highly aligned cells and collagen fibers readily remodeled in response to a change in loading condition, altering the structural and mechanical anisotropy of the tissues.; Furthermore, novel engineered cardiac tissues that are more physiologically realistic such as tissue cylinders mimicking trabecular muscles, and tissue chambers having a simplified ventricular geometry were developed. Living engineered cardiac tissue chambers that exhibit hallmark characteristics of physiologic cardiac function were demonstrated for the first time in this study. These engineered cardiac tissues can be used to better understand how global chamber function relates to underlying geometric, matrix, and cell properties by allowing explicit and independent control not possible in natural heart tissue. Moreover, the feasibility of utilizing these engineered cardiac tissues as novel in vitro models of heart disease was investigated, and this provides an exciting opportunity to explore mechanisms of repair as well as therapeutic interventions for long term studies not possible in isolated heart muscle. Finally, human mesenchymal stem cells were co-cultured in our 3-D engineered tissue system to evaluate the potential for enhanced contractile function in relation to stem cell-based therapies for myocardial infarction. |
