GROWTH FACTOR MEDIATION OF HEALING OF VASCULAR GRAFTS

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The chemical and biomechanical parameters of implanted blood- contacting biomaterials initiate and/or modulate the resultant inflammatory, regenerative, and thrombotic reactions. These tissue reactions ultimately determine the clinical success of implanted vascular prostheses. Bioresorbable lactide/glycolide copolymeric prostheses which are phagocytized by macrophages lead to extensive myofibroblast and endothelial cell regeneration. The current protocol attempts to clarify the extent of the regenerative capacities of the components of the arterial wall and to analyze the mechanisms by which the prosthetic composition and biomechanical characteristics affect the tissue responses. Specific aims include (1) the effects of compositional and biomechanical characteristics of bioresorbable prostheses on the rate and extent of regeneration of myofibroblasts, endothelial cells, collagen and elastin, the duratin and extent of cellular proliferative activity, and functionality of these regenerated tissues; (2) the role and identification of specific growth factors as mediators of vascular healing following prosthetic implantation; (3) macrophage-biomaterial interactions inducing release of specific macrophage derived growth factors as mediators of vascular healing; and (4) the efficacy of exogenous growth factors in optimization of vascular healing. This proposal will utilize bioresorble and non-resorbable prostheses woven to defined reproducible parameters from well characterized yarns. Prostheses will be implanted into rabbit and canine models and explants will later be analzyed by histologic, immunocytochemical, and ultrastructural techniques, autoradiography, collagen assays, and functional analyses of compliance, strength, and prostacyclin production rates. Northern blot analyses of explanted tissues will identify mRNA for specific growth factors. The content of growth factors within explanted tissues subjected to elutriation techniques will be determined by bioassays and by biochemical and immunochemical growth factor analyses with results expressed as a function of time following implantation. These results will be temporally related to the histologic analyses and to corrobation tissue culture studies of macrophage-biomaterial interactions. These concurrent analyses will document the differential activation of resident macrophages by biomaterials resulting in their production of growth factor(s) as documented by bioassays and specific growth factor identification will utilize biochemical and immunochemical techniques. A related study will examine the modulation of vascular healing in response to the application of a specific growth factor, HBGF-1, applied to biomaterials. The clarification of these issues should lead to a new generation of small caliber vascular prostheses with greater clinical efficacy as well as an ability to selectively stimulate or inhibit aspects of vascular healing by appropriate use of growth factors and their antagonists.