BIOCOMPATIBILITY: SURFACE INITIATED BIOCHEMISTRY

描述（由申请人提供）：本研究的目的是提高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。不充分或过度的炎症和纤维化反应已被证明会导致许多类型的医疗植入物失败。考虑到老年人群在未来人口统计数据中预计的百分比增长，再加上新的植入设备的不断发展，很明显，在未来几年里，提高植入物的生物相容性将变得越来越重要。不幸的是，生物材料介导的组织反应的机制以及材料表面特性在影响组织对材料植入的反应程度方面的作用在很大程度上仍然未知。显然，这些知识，从最初的蛋白质/细胞/表面相互作用开始，是合理设计材料所必需的，不仅可以产生所需的组织反应，而且还可以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的重大进展提供了希望。具体来说，纤维原（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暴露了通常隐藏的表位，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Fg P1/P2表位在指导对植入物的炎症和纤维化反应中起关键作用。拟议的研究涉及分子定制表面的初步体外筛选，控制表面化学成分和形态的系统变化，以引出一系列P1/P2暴露。表面化学探索将包括疏水和亲水，以及阳离子和阴离子的底物。暴露不同程度P1/P2表位的表面，以及已知数量P1/P2偶联的表面，将被用来触发体内的吞噬细胞反应（粘附和激活）。P1/P2暴露对生物材料植入后的纤维化反应（囊形成、胶原沉积和细胞因子产生）的影响也将被确定。获得的结果将提供深入的、分子水平的事件序列信息：材料表面化学和形态、Fg P1/P2表位暴露、调节吞噬细胞反应、控制最终纤维化组织形成。从这些研究中获得的信息将为指示生物材料介导的组织反应和异物反应的复杂机制的表面特性提供有价值的新见解。这些知识将为未来设计具有理想组织反应性和伤口愈合反应的表面定制植入式材料提供一个起点。

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.