This Mentored Clinical Scientist Development Award application focuses on the development of a tissue engineered vascular prosthesis. There are 1.4 million surgical procedures performed annually in this country that require arterial prostheses. Medium to small diameter arteries, (less than six mm) when bypassed with artificial materials suffer high rates of early and late thrombosis. Vein grafts are fragile and are sometimes damaged when transplanted into the arterial system. Internal mammary arteries, which perform better than vein grafts, are useful only in the coronary circulation. To address these issues, the long term goal of this project is to develop a method for culturing autologous arteries from a small biopsy of the patient's own tissue. The patient's own cells would be seeded onto tubular biocompatible polymer scaffolds and grown in vitro to form complete blood vessels, with inner linings of endothelial cells and outer smooth muscle cell walls. While the feasibility of seeding and growing human and other mammalian cells on biocompatible polymers has been demonstrated, even in clinical trials, the cell-polymer system for the growth of blood vessels has only begun to be studied. While the proposed project is an extensive one and its completion may require longer than the five years applicable to this award, the applicant feels it is important to present a comprehensive approach to this challenging but important problem. The first goal of this project will be to culture endothelial and smooth muscle cells on biocompatible, biodegradable polymer scaffolds to form a vascular tissue. This will involve selection of the optimum polymer and processing techniques encourage cell adhesion and replication, optimization of cell seeding onto the polymer substrates, and the development of techniques to culture the cell-polymer constructs under conditions of intra-luminal fluid flow, to mimic in vivo vascular conditions. The second goal of this project will be to determine whether cultured vascular tissues will exhibit adequate biomechanical and physiologic properties for use in the arterial system in vivo. This will involve, specifically, the determination of the physical and mechanical characteristics of the cultured tissues, characterization of the smooth muscle layer for contractile phenotype and isometric response to vasoactive agents, and characterization of the endothelial cell layer by assaying the expression of basic cell functions and adhesion molecules on the cell surface. Provided the vessels display adequate biomechanical and physiologic characteristics, animal implant studies will be performed.
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