The goal of this research is to improve the biocompatibility of medical implants. It is well established that biomaterials with different surface properties trigger various degrees of adverse reactions, such as inflammation and fibrosis. Insufficient or excessive inflammatory and fibrotic responses have been shown to lead to failure of many types of medical implants. Given the projected percentage increase of older age groups in future population demographics, coupled with continuing development of new implantable devices, it is absolutely clear that improving the biocompatibility of implants will become increasingly important in the years ahead. Unfortunately, the mechanisms involved in biomaterial-mediated tissue responses and the role(s) of material surface properties in affecting the extent of tissue responses to material implants remain largely unknown. Obviously, such knowledge, beginning with the initial protein/cell/surface interactions, is required for the rational design of materials not only to generate the desired tissue response, but also to serve as """"""""smart"""""""" material in promoting wound healing processes when needed. As detailed in this proposal, recent research offers hope for significant progress towards these important goals. Specifically, conformational changes of fibrogen (Fg) upon initial surface adsorption have been strongly linked to the overall biological response to implants. Adsorbed Fg exposes normally occult epitopes, including y 190-202 (hereafter, 'PI') and y377-395 (hereafter, T2'). Most importantly, the degree of P1/P2 exposure correlates closely with the subsequent inflammatory responses to biomaterial implants. Because early studies have shown that inflammatory responses affect greatly the subsequent fibrotic reactions, it is reasonably hypothesized that Fg P1/P2 epitopes are critically involved in directing the inflammatory and fibrotic reactions to implants. The proposed study involves initial in vitro screening of molecularly tailored surfaces, having controlled systematic variations in surface chemical compositions and morphologies, to elicit a range of P1/P2 exposures. The surface chemistries explored will include hydrophobic and hydrophilic, as well as cationic and anionic charged substrates. Surfaces exposing different extents of P1/P2 epitopes, as well as surfaces conjugated with known amounts of P1/P2, will then be used to trigger phagocyte responses (both adhesion and activation) in vivo. The effects of P1/P2 exposure on subsequent fibrotic reactions (capsule formation, collagen deposition and cytokine productions) to biomaterial implants will also be determined. Results obtained will provide in depth, molecular level, information on the sequence of events: material surface chemistry and morphology r Fg P1/P2 epitope exposure r regulating phagocyte responses r controlling ultimate fibrotic tissue formation. The information obtained from these studies will provide valuable new insights into surface properties in dictating biomaterial-mediated tissue responses and to the complex mechanisms of foreign body reactions. This knowledge will provide a starting point for the future design of surface tailored implantable materials having desired tissue reactivity and, as needed, wound healing response.
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