BIOMATERIAL MEDIATED INFLAMMATION AND FIBROSIS

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Most types of implanted biomaterials trigger both inflammatory and fibrotic responses through mechanisms which are still largely unknown. Phagocytic responses have been demonstrated to influence fibrotic responses (i.e., fibroblast proliferation and collagen production). Our proposed investigations are aimed at elucidating the interrelation(s) between inflammation and fibrosis and consequently developing strategies which control the extent of biomaterial-mediated fibrotic responses. Tissue contact biomaterials trigger, to varying degrees, fibrotic responses. Both insufficient and excessive fibrotic responses an often lead to the failure of medical implants. For example, artificial ligaments often fail because of the lack of adequate tissue integration whereas exuberant fibrotic reactions can lead to the failure of implantable sensors. Because the mechanisms involved in biomaterial-mediated tissue responses remain largely unknown, we still do not know how to control fibrotic tissue formation surrounding material implants. During the first three years of this grant, we elucidated a sequence of events involved in biomaterial- mediated inflammatory responses. (1) Shortly after implementation, phagocytes are recruited to peritoneal cavity via transmigration and chemotactic processes. (2) Phagocyte accumulation on implants is mediated by the adsorbed fibrinogen, phagocytes are activated to produce many pro-fibrotic products, including cytokines and tissue factor. (4) The generation of tissue factor by adherent phagocytes causes the accumulation of fibrin clot on implant surfaces, providing a foundation for fibroblast immigration, proliferation, collagen production, and by changing phagocyte recruitment and activation, we may purposefully modulate fibrotic reactions to suit the purpose of different material devices. For his, using different specific antibodies, antagonists, chemicals, drug investigate the influences of (1) phagocyte recruitment, (2) phagocyte adhesion, (3) phagocyte interactions, we shall investigate the influences of (1) phagocyte recruitment, (2) phagocyte adhesion, (3) phagocyte adhesion, (3) phagocyte activation, and (4) phagocyte- mediated coagulation on the extent of fibrotic tissue formation on biomaterial implants. Overall, these studies will provide, for the first time, detailed and specific new knowledge required for the future rational design of implantable medical devices with desired tissue reactivity and, possibly wound healing responses.