Biomaterial-mediated fibrotic responses

描述（由申请人提供）：生物材料介导的炎症和纤维化反应是许多医疗植入物失败的原因。为了设计生物材料来引起所需的组织反应，提高我们目前对生物材料介导的纤维化反应发病机制的理解是很重要的。由于吞噬细胞产物已被证明对纤维化过程（即成纤维细胞增殖和胶原蛋白产生）有很强的影响，我们假设，通过减少炎症反应的程度，可以减轻对医疗植入物的纤维化反应的程度。根据我们之前的研究，我们假设生物材料介导的纤维化反应是由以下连续过程组成的。首先，在植入后不久，炎症细胞（主要是吞噬细胞）通过转运被招募到植入部位。其次，移植物相关细胞释放的趋化因子吸引了许多向移植物迁移的吞噬细胞。第三，吞噬细胞Mac-1整合素和新暴露的P1/P2表位吸附在纤维蛋白原上，促进了植入物上的吞噬细胞粘附。第四，Mac-1整合素：P1/P2表位结合触发吞噬细胞活化，随后释放促纤维化产物，包括细胞因子和组织因子。第五，附着的吞噬细胞对组织因子的局部收集导致植入物表面充分形成纤维蛋白凝块。最后，这种植体结合的纤维蛋白凝块为成纤维细胞的整合、增殖、胶原蛋白的产生和纤维化组织的形成提供了优越的环境。本研究的目的是首先利用特异性抗体和敲除小鼠确定导致生物材料介导的纤维化反应的关键步骤。随后的研究将评估各种拮抗剂和抑制剂对改变这些关键细胞反应和最终纤维化组织形成的潜在影响。利用系统生物学工具，我们希望在研究个体关键细胞反应和整个异物反应方面取得新的突破。将特别强调不同参数（生物材料、蛋白质和细胞）之间的潜在作用和相互作用，以及促进异体反应的重要细胞反应。从这项工作中获得的全面和系统的信息将有助于开发新的药理学和工程策略，以合理设计具有理想组织相容性和安全性的生物材料。生物材料介导的纤维化反应是导致植入失败的主要原因之一。本研究的目的是利用细胞/分子生物学/组织学技术和数学建模来识别和研究这些不需要的免疫反应的关键反应。这些信息对于设计和开发更好、更安全的医疗设备至关重要。

DESCRIPTION (provided by applicant): Biomaterial-mediated inflammatory and fibrotic responses are responsible for the failure of many medical implants. To engineer biomaterials to evoke desired tissue responses, it is important to improve our current understanding of the pathogenesis of biomaterial-mediated fibrotic reactions. Since phagocyte products have been shown to have a strong influence fibrotic processes (i.e. fibroblast proliferation and collagen production), we have hypothesized that, by reducing the extent of inflammatory responses, the degree of fibrotic reactions to medical implants could lessen. Based on the information gained from our previous investigation, we have assumed that biomaterial-mediated fibrotic reactions are comprised of following continuous processes. First, shortly after implantation, inflammatory cells (mostly phagocytes) are recruited to the implantation site by transmigration. Second, the release of chemokines by implant-associated cells attract many phagocytes which migrate toward the implant. Third, phagocyte adhesion on implants is promoted by phagocyte Mac-1 integrin and newly exposed P1/P2 epitopes on adsorbed fibrinogen. Fourth, Mac-1 integrin: P1/P2 epitope engagement triggers phagocyte activation and later release of pro-fibrotic products, including cytokines and tissue factor. Fifth, the localized collection of tissue factor by adherent phagocytes leads to full formation of a fibrin clot on implant surfaces. Finally, this implant-bound fibrin clot provides a superior environment for fibroblast integration, proliferation, collagen production, and fibrotic tissue formation. The goal of this investigation is to first identify the critical steps in leading to biomaterial-mediated fibrotic reactions using specific antibodies and knock-out mice. Subsequent studies will be carried out to assess the potential influence of various antagonists and inhibitors on modifying those critical cellular responses and final fibrtotic tissue formation. Using system biology tools, we hope to break new ground in studying individual critical cellular responses and then whole foreign body reactions. Special emphasis will be paid to the potential roles and interactions between different parameters (biomaterials, proteins, and cells) and those vital cellular responses in promoting foreign body reactions. The comprehensive and systematic information gained from this work would help to develop novel pharmacological and engineering strategies for rational design of biomaterials with desired tissue compatibility and safety. Biomaterial-mediated fibrotic responses are one of the leading causes of implant failure. The goal of this research is to identify and study the critical responses of these unwanted immune reactions using both cell/molecular biology/histology techniques and mathematical modeling. This information is of utmost importance for the design and development of better and safer medical devices.