The problem of limited availability of biological replacements for diseased vessels and organs is exacerbated by the failure of most prosthetic implants and organ substitutes due to repeated thrombo-embolic events. The mechanism which underlie the deposition of thrombotic masses on biomaterial surfaces is poorly understood. The objective of the present proposal is to investigate the influence of vascular surfaces on the deposition of platelets and fibrin on selected prosthetic surfaces. A tubular perfusion chamber has been developed for mounting the materials immediately downstream of injured vascular surfaces exposing the composite substrates to blood in an ex vivo perfusion system. Blood from both swine and human subjects will be utilized to investigate the specific mechanisms which are important in determining the deposition of thrombotic material on the biomaterial surface. Evaluation of the surface deposits will be performed by several techniques. In swine, III-In labelled platelets will be injected and the quantity of deposited radioactivity determined. In swine and humans, morphometric analysis of epoxy embedded semi-thin sections will be utilized to quantify platelet and fibrin deposits. The thrombotic deposits will be evaluated for several exposure times, axial positions from the proximal surface and wall shear rates, such that the full physiological range of flow conditions is investigated (wall shear rates from 50-5000 sec-1). Variation of proximal (vascular) and distal (biomaterial) surfaces and the condition of the blood will utilized to explore the mechanisms of platelet and fibrin deposition on the prosthetic surface. Various components of the vessel wall, including, subendothelium and its modifications, collagen, and tissue factor will be utilized as the activating proximal surface. Blood from patients and animal models with various bleeding disorders will be utilized to investigate the importance of von Willebrand factor, platelet glycoproteins Ib and IIb-IIIa, platelet released products and the relative importance of the Factor XI, coagulation and the tissue factor, Factor VII, IX pathways. Antibodies of VWF, and glycoproteins Ib and IIb-IIIa will also be employed and compared to results obtained with the corresponding naturally occurring deficiency. The mechanisms of growth of thrombotic deposits will also be investigated in nonstreamline (recirculation) flow by appropriately modifying the perfusion chambers and a theory for particle deposition will be developed.
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