BIOCOMPATIBILITY: SURFACE INITIATED BIOCHEMISTRY

描述(申请人提供)：本研究的目标是提高医用植入物的生物相容性。众所周知，具有不同表面性质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都会导致许多类型的医用植入物失败。鉴于老年群体在未来人口结构中的预计百分比增加，加上新的可植入设备的持续开发，绝对清楚的是，在未来几年，改善植入物的生物兼容性将变得越来越重要。不幸的是，涉及生物材料介导的组织反应的机制以及材料表面属性在影响组织对材料植入的反应程度中的作用(S)仍然很大程度上是未知的。显然，从最初的蛋白质/细胞/表面相互作用开始，这种知识对于合理设计材料是必要的，不仅要产生所需的组织反应，而且在需要时作为促进伤口愈合过程的“智能”材料。正如本提案所详述的那样，最近的研究为实现这些重要目标提供了取得重大进展的希望。具体地说，纤维蛋白原(FibroGen，FG)在初始表面吸附时的构象变化与植入物的整体生物反应密切相关。吸附的FG暴露出正常的隐蔽表位，包括Y190-202(以下简称PI)和Y377-395(以下简称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对随后的纤维化反应有很大的影响，因此可以合理地假设FGP1/P2表位在引导种植体的炎症和纤维化反应中起关键作用。拟议的研究包括对分子定制表面进行初步的体外筛选，控制了表面化学成分和形态的系统变化，以引发一系列P1/P2暴露。所探讨的表面化学性质包括疏水性和亲水性，以及阳离子和阴离子带电底物。暴露不同程度的P1/P2表位的表面，以及与已知数量的P1/P2结合的表面，将被用来在体内触发吞噬细胞反应(包括黏附和激活)。也将确定P1/P2暴露对生物材料植入物随后的纤维化反应(包膜形成、胶原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序列的深入的、分子水平的信息：材料表面化学和形态r FG P1/P2表位暴露r调节吞噬细胞反应r控制最终的纤维组织形成。从这些研究中获得的信息将为决定生物材料介导的组织反应的表面特性和异物反应的复杂机制提供有价值的新见解。这一知识将为未来设计具有期望的组织反应性和伤口愈合反应的表面定制植入材料提供一个起点。

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.