Angiogenic mechanisms of endothelialization of cardiovascular implants: a review of recent investigative strategies

Both cardiovascular implants and therapeutic interventions on native arteri es fail due to biologic responses occurring at the blood/prosthesis/arteria l wall and tissue/prosthesis/arterial wall interfaces, resulting in the fai lure modes of thrombosis and myointimal hyperplasia. Systemic pharmacologic approaches including use of anti-coagulant and anti-platelet agents have s ignificant untoward side effects and have not resulted in a dramatic impact on failure modes in many applications, including small diameter vascular g rafts. Local delivery of therapeutic agents via surface attachment with def ined release kinetics may alter thrombogenicity and/or myointimal hyperplas ia. Therapeutic agents may include a spectrum of biologic agents from pepti des to endothelial cells. Efficient attachment and release of these agents in biologically active form is dependent upon improved methods of surface m odification. The intended action of the biologic agent may similarly be imp acted by the surface and bulk characteristics of the underlying biomaterial . It is often assumed, without concrete data, that surface re-endothelializat ion may have a beneficial impact on both thrombogenicity acid myointimal hy perplasia. New clinical data on endothelial cell seeding has been supportiv e. Spontaneous re-endothelialization may be stimulated via an induced direc ted angiogenesis resulting in trans-interstitial capillarization and surfac e endothelialization. Recent advances in therapeutic angiogenesis have sugg ested the power of angiogenic factors to induce neovascularization of ische mic tissue beds. These concepts have been used to surface modify prosthetic devices with either VEGF or FGF and both in vitro and animal data suggest a potent stimulation of surface re-endothelialization. Neither of these gro wth factors is likely to be ideal. VEGF is relatively endothelial cell spec ific but is a relatively weak endothelial cell mitogen. FGF-I and FGF-2 are more potent mitogens but are less cell specific. Recent work has led to th e generation of mutant growth Factors via site-induced mutagenesis and resu lts of several such FGF mutants on endothelial cell and smooth muscle cell proliferative response have been studied. The use of 'designer growth facto rs' on cardiovascular implants and on manipulated native vessels may have a significant positive impact on re-endothelialization and thereby on the fa ilure modes of thrombosis and myointimal hyperplasia.