This proposal describes studies intended to provide a theoretical framework relating the interaction of the blood with artificial surfaces to surface chemistry, ultimately to lead to the development of more effective thromboresistant materials. The proposal is in two parts which are collaborative and inseparable: experiments to be performed in the laboratory of Dr. Edwin Salzman at the Beth Israel Hospital, Harvard Medical School, and studies to be performed in the laboratory of Professor Edward Merrill, MIT. I. Nature and mechanism of interaction of platelets with fibrinogen adsorbed on artificial surfaces. Using materials developed and fabricated in Merrill's laboratory with well-characterized surface chemistry, Salzman will examine the hypothesis that the concentration of """"""""native"""""""" (antibody detectable) fibrinogen adsorbed on a surface dictates the interaction of platelets with that surface. Assessment of the concentration and confirmation of adsorbed fibrinogen will be carried out by antibody techniques. A model system employing fibrinogen polymers as analogs of fibrinogen adsorbed on an artificial surface will be used to study the mechanism of surface activation of platelets. II. Development of thromboresistant materials. Novel polymers based on polyethylene oxide or covalently bonded with heparin or both will be developed, fabricated, and physically-chemically characterized by Merrill and tested for their biological properties by Salzman, employing chiefly in vitro assessments of fibrinogen adsorption, platelet retention tests involving bead columns previously described, and measurements of platelet cytoplasmic calcium by a new technique involving the calcium sensitive photoprotein aequorin. In the second and third year of this proposal the most promising materials will be employed in the form of intravenous cannulae in a clinical trial in patients, employing 125I-fibrinogen scanning to define the thrombotic endpoint.
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