The proposed studies in this application are directed toward obtaining a better understanding of the mechanisms of infection of implanted cardiovascular prostheses. Our hypothesis is that material surface interactions with flowing blood lead to alteration of basic pathophysiologic mechanisms which increase the probability of bacterial interaction and subsequent infection. The approach considers the importance of the material surface, the blood, the blood flow, and the bacteria in the development of cardiovascular prosthesis infections. The studies emphasize the use of clinically iderived human materials, i.e., blood and bacteria, and clinically relevant cardiovascular materials coupled with controlled in vitro systems to systematically and comprehensively elucidate infection mechanisms with cardiovascular prostheses. The overall goals of the project are to: 1) characterize in a comprehensive fashion blood and bacterial surface interactions with cardiovascular materials, 2) determine the similarities and differences in the thrombogenesis mechanisms and infection mechanisms which lead to infections in cardiovascular prostheses with special emphasis on the synergistic effects of material surface thrombosis and bacterial adhesion and colonization, and 3) to develop new design strategies for infection- and thrombosis-resistant cardiovascular materials. The experimental design is an interdisciplinary approach utilizing the engineering and biomedical expertise of six experienced investigators. The experimental design and methodology are soundly based on current activities being carried out in the laboratories of these investigators in the School of Engineering and the School of Medicine at Case Western Reserve University. The proposal is divided into seven interrelated sections. These include in vitro recirculating and rotating disc studies on blood/bacteria/material interactions, imaging and identification of protein adsorption, neutrophil and monocyte adhesion and activation, design, synthesis and characterization of modified substrates, substrate effects on bacterial adhesion, and antimicrobial resistance studies of bacterial adhesion. The interdisciplinary experi- mental design utilizes the same materials, bacteria and experimental conditions in the dynamic and static studies. The collaborative, interdisciplinary and broad-based approach enhances the potential for success in the elucidation of infection mechanisms of cardiovascular prostheses as well as providing new design strategies for infection- and thrombosis-resistant cardiovascular materials.
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