Development of small-diameter vascular prostheses which release bioactive agents

The need for small-diameter vascular prostheses has been well documented by clinical experience which has shown poor graft patency rates with prostheses less than 6 mm internal diameter. As a consequence, new biomaterials for small-diameter vascular prostheses and/or new concepts in their design and fabrication were warranted. Experimental studies have indicated that long term patency is enhanced when a stable and mature tissue layer (neointima) is established on the inner surface of a vascular prosthesis. A desirable effect of a vascular prosthesis would be one that regenerates a neointima similar to a normal artery. Many characteristics of the prosthesis, such as chemical composition, method of fabrication, compliance, porosity, and bioresorbability have been investigated for their possible roles in promoting appropriate neointima formation. Recent advances in the fields of cell and molecular biology have shown the importance of growth factors produced by various tissues in stimulating cells proliferation. In particular, endothelial cell proliferation is greatly increased by basic fibroblast growth factor (bFGF) which stimulates both large vessel and capillary endothelial cell proliferation in vitro at 1-10 ng/ml concentration. It may be hypothesized that incorporating this substance into biocompatible materials could enhance endothelial cell development when these materials are used for fabrication of vascular prostheses. We have already developed a spraying, phase inversion process which allows solutions of synthetic polymers to be precipitated over a rotating mandrel to fabricate porous grafts. Using a modification of this method we have fabricated 1.5 mm ID, porous, compliant polyurethane tubes which incorporate and release basic fibroblast growth factor (bFGF). In vitro releasing studies were performed using 10% albumin by weight as carrier and which demonstrated 1-2 ng/cm graft/day rate of release of bFGF. The mitogenic effect of released bFGF was tested by incubating 1 cm long pieces of tubing with human endothelial cells seeded at low density (40 cells/mm ) in vitro and using a culture medium without any growth factor added. The [H] thymidine uptake by the cells was measured. After 3 days the cells incubated with tubing that did not contain bFGF did not proliferate to any extent. Cells incubated with tubing that did contain bFGF continued to proliferate actively. The results of these experiments have shown that a bioactive bFGF can be released from vascular prostheses. Release of factors such as bFGF may enhance the early development of confluent endothelial surfaces in vivo that may increase thromboresistance of vascular prostheses.