BIOCOMPATIBILITY: SURFACE INITIATED BIOCHEMISTRY

描述（由申请人提供）：本研究的目的是改善医用植入物的生物相容性。众所周知，具有不同表面特性的生物材料会引发不同程度的不良反应，如炎症和纤维化。炎症和纤维化反应不足或过度已被证明会导致许多类型的医疗植入物失效。鉴于未来人口统计学中老年组的预计百分比增加，加上新植入式器械的持续开发，很明显，提高植入物的生物相容性在未来几年将变得越来越重要。不幸的是，生物材料介导的组织反应所涉及的机制以及材料表面性质在影响组织对材料植入物反应程度方面的作用仍然很大程度上未知。显然，从最初的蛋白质/细胞/表面相互作用开始，这些知识对于材料的合理设计是必需的，不仅要产生所需的组织反应，而且要在需要时作为促进伤口愈合过程的“智能”材料。如本提案所详述，最近的研究为实现这些重要目标取得重大进展带来了希望。具体而言，初始表面吸附后纤维原（Fg）的构象变化与植入物的整体生物学反应密切相关。吸附的Fg暴露通常隐藏的表位，包括γ 190-202（下文称为“PI”）和γ 377 -395（下文称为“T2”）。最重要的是，P1/P2暴露的程度与随后对生物材料植入物的炎症反应密切相关。由于早期的研究表明，炎症反应极大地影响了随后的纤维化反应，因此可以合理地假设，Fg P1/P2表位在将炎症和纤维化反应导向植入物中起关键作用。拟议的研究涉及初步的体外筛选的分子定制的表面，控制系统的变化，表面化学成分和形态，引起一系列的P1/P2曝光。探索的表面化学将包括疏水性和亲水性，以及阳离子和阴离子带电基材。暴露不同程度的P1/P2表位的表面，以及与已知量的P1/P2缀合的表面，然后将用于在体内触发吞噬细胞应答（粘附和活化）。还将确定P1/P2暴露对生物材料植入物后续纤维化反应（包膜形成、胶原蛋白沉积和细胞因子产生）的影响。所获得的结果将提供关于事件顺序的深入、分子水平的信息：材料表面化学和形态学r Fg P1/P2表位暴露r调节吞噬细胞反应r控制最终纤维化组织形成。从这些研究中获得的信息将提供有价值的新的见解，表面特性在支配生物材料介导的组织反应和异物反应的复杂机制。这些知识将为未来设计具有所需组织反应性和（根据需要）伤口愈合反应的表面定制可植入材料提供起点。

DESCRIPTION (provided by applicant): 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.