Despite a dramatic decline over the past 15 years, cardiovascular disease remains the leading cause of death and disability in the Western world. The adult onset disease processes that compromise cardiac function include, infarction, ischemic heart disease, myocarditis, and a variety of idiopathic cardiomyopathies. The focal loss of muscular tissue, as a result of a congenital defect or a disease process, alters the unique architectural arrangement of the heart and impairs its function. An engineered segment of artificial myocardium (cardiac patch) potentially offers a nearly unlimited source of material for reconstructive surgery. In preliminary experiments from our lab we have successfully constructed small, multilayered cultures of fetal and neonatal cardiac myocytes that exhibit a tissue-like pattern of organization. These multilayered cultures are composed of myocytes that have an elongated, rod-like cell shape, but require further development before they would be suitable for transplantation. This proposal takes advantage of the Pl's experience in cardiac development, in vitro cultivation of cardiac myocytes on various ECM components, in vitro mechanical stimulation of cells in culture, morphological characterization of tissues, proof of concept studies, and established collaborations with bioengineering colleagues.
The Specific Aims of this proposal are: 1) To use specially fabricated collagen substrates and a series of bioreactors to produce histotypic cultures of cardiac cells suitable for transplantation. 2) Characterize and compare the artificial myocardium to the intact heart by morphometric, biochemical and molecular techniques. 3) Transplant the artificial myocardium to in vivo locations that will allow vascularization of the tissue. The transplanted cultures will be compared by morphometric, biochemical, and molecular techniques to the structure and function of the intact heart. Data from these studies will identify the mechanical and chemical parameters necessary to produce the three-dimensional organization of the heart patches. These cultures will provide a potential source of biological material for repairing focal damage to the myocardium.
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