The proposed studies are aimed at elucidating the mechanism(s) of foreign body responses and device-centered infection. Despite the widespread use of chronic implants, surprisingly little is known about the pathogenesis of biomaterial-mediated adverse responses. In fact, biomaterial-mediated foreign body reactions and infections may be associated with chronic discomfort, implant failure, and sometimes fatality. It is generally accepted that spontaneously adsorbed host proteins may influence subsequent tissue/cell responses. We earlier found that the spontaneous adsorption of fibrinogen triggers subsequent phagocyte accumulation. The portion of fibrinogen responsible for biomaterial-mediated phagocyte adhesion has recently been identified as a 13 amino acid sequence (gammal9O-202) which is recognized by the phagocyte integrin Mac-1. Because fibrinogen: Mac-1 interactions have been found to influence phagocyte responses, we have hypothesized that adsorbed fibrinogen may be critical to the prolonged survival of adherent bacteria, thereby promoting device-centered infection. In fact, we have very recently found that adsorbed fibrinogen does impair phagocyte bactericidal activity by reducing the release of phagocyte bactericidal products, such as superoxide, and indirectly promoting the survival of implant-associated Staphylococcus epidermidis. However, it is still unclear how adsorbed fibrinogen actually enhances the persistence of implant-associated bacteria and how particular surface properties influence both foreign body reactions and device-centered infection. To find the answer, we shall: (1) Determine which epitope(s) displayed by adsorbed fibrinogen are critical to the survival of adherent bacteria on polyethylene terephthalate (PET), (2) Investigate bactericidal activity of adherent phagocytes on surfaces precoated with different fibrinogen fragments and proteins. Finally, (3) using six commonly used biomaterials and a series of radio frequency glow discharge treated surfaces, we will study the influence of surface characteristics in the exposure of fibrinogen neo-epitopes, and the pathogenesis of foreign body reactions and device-centered infection. It is our hope that a more precise understanding of host:implant interactions and the mechanism of device-centered infection may permit the future rational design of biomaterials with markedly improved safety and tissue compatibility.
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