Development of a Bio-Inductive Vascular Graft by Compositing a Fast-Resorbing Elastomer with a Slow-Resorbing Polymer

[摘要] Clinically used prosthetic vascular grafts fail frequently from thrombosis and anastomotic stenosis in small diameter applications. A bio-inductive vascular graft could improve performance by remodeling into an artery-like tissue after implantation, thereby approaching the mechanical and physiological function of healthy arteries. We hypothesized that a bio-inductive vascular graft must remodel rapidly to promote neoartery formation rather than a classical foreign body response. To test this hypothesis, we developed vascular grafts made from microporous foams of a fast-resorbing elastomer composited with a slower-resorbing polymer sheath for mechanical support. Composite grafts performed well (80% patency) as infrarenal abdominal aorta interposition grafts in rats, and within 90 days remodeled into neoarteries which approached native arteries in mechanical compliance and tissue architecture. Following this encouraging proof-of-concept, the objective of this dissertation is to assess the potential of our vascular graft design to translate toward clinical application. To assess translational potential, we first assessed the long-term performance of the microporous foam composite design in rats at 1-year post-implantation. We found that the resultant neoarteries maintained 80% patency, contained the same amount of mature elastin as native arteries, and possessed nerves resembling native perivascular nerves. To improve clinical feasibility of the design, we next sought to improve graft surgical handling and simplify the fabrication process, which we achieved by developing a novel technique to fabricate grafts from electrospun PGS microfibers. We then implanted electrospun microfiber grafts in a mouse model to assess whether they retained the favorable long-term performance observed in microporous PGS foam grafts. Electrospun grafts achieved 100% patency up to 1 year post-implant, but all grafts dilated within that time. Remodeled electrospun grafts retained polymer residues at 1 year, thereby demonstrating slower resorption than the original foam design, likely due to reduced pore size. An elastin-rich neotissue containing contractile smooth muscle cells developed on the luminal surface of the graft within 3 months, but macrophages persisted at 1 year, and calcification occurred in all neoarteries at late term. Taken together, these results suggest that a PGS-based vascular graft can achieve excellent long-term performance, but efforts to improve translational potential must preserve fast in-host remodeling.

[发布机构] the University of Pittsburgh