Congenital and acquired disease of the heart valves and great arteries are leading causes of morbidity and mortality. Current prosthetic or bioprosthetic replacement devices are imperfect and subject patients to one or more ongoing risks including thrombosis, limited durability, increased susceptibility to infection, and need for reoperations due to lack of growth. Tissue engineering is a new discipline which offers the potential to create replacement structures from autologous cells and biodegradable polymers. Since tissue engineered (TE) constructs contain living cells, they may have the potential for growth and self-repair and remodeling. Therefore, they could overcome many limitations of existing devices. Cardiac valve leaflets and large conduit arteries have been made with the TE approach. These TE structures have functioned in the pulmonary circulation of growing lambs for up to four months and have demonstrated (1) structural organization to resemble normal valve and artery, (2) satisfactory physiologic function, (3) lack of thrombus formation, and (4) growth. Despite these results, significant questions remain. There is little understanding of cellular interactions and production of extracellular matrix in TE structures. Optimal sources of cells and optimal cell and tissue culture conditions have not been determined. The TE structures created using polyglycolic acid polymer have poor surgical handling characteristics. The longer term fate of TE structures in the circulation is unknown. The proposed studies will attempt to address several issues: (1) the content, structure, and kinetics of degradation of extracellular matrix in normal and TE valve and artery, (2) the influence of anatomic origin and maturation status of cells used to form TE structures, (3) the suitability of new stronger, more flexible polymers in the formation of TE structures, (4) the impact of imposed stretch and shear stress in vitro on developing TE structures. These studies will provide a better understanding of the biological events occurring in the developing TE structures and will guide progress toward the development of clinically useful TE replacements of cardiovascular structures. Abstract)
