BIOMATERIAL MEDIATED INFLAMMATION AND FIBROSIS

大多数类型的植入生物材料触发炎症和纤维化反应的机制仍然很大程度上是未知的。吞噬反应已被证明影响纤维化反应（即成纤维细胞增殖和胶原蛋白产生）。我们提出的研究旨在阐明炎症和纤维化之间的相互关系，从而制定控制生物材料介导的纤维化反应程度的策略。组织接触生物材料会不同程度地引发纤维化反应。不充分和过度的纤维化反应往往导致医疗植入物的失败。例如，人工韧带经常因为缺乏足够的组织整合而失效，而过度的纤维化反应可能导致植入式传感器失效。由于涉及生物材料介导的组织反应的机制在很大程度上仍然未知，我们仍然不知道如何控制材料植入物周围的纤维化组织形成。在这项资助的前三年，我们阐明了一系列与生物材料介导的炎症反应有关的事件。(1)实施后不久，吞噬细胞通过迁移和趋化过程被招募到腹腔。(2)植入物上的吞噬细胞聚集是由被吸附的纤维蛋白原介导的，吞噬细胞被激活产生许多促纤维化产物，包括细胞因子和组织因子。(4)粘附的吞噬细胞产生组织因子，使纤维蛋白凝块在植入物表面积累，为成纤维细胞迁移、增殖、胶原蛋白的产生提供了基础，通过改变吞噬细胞的募集和活化，我们可以有目的地调节纤维化反应，以适应不同材料装置的目的。为此，利用不同的特异性抗体、拮抗剂、化学物质、药物研究(1)吞噬细胞募集、(2)吞噬细胞粘附、(3)吞噬细胞相互作用的影响，我们将研究(1)吞噬细胞募集、(2)吞噬细胞粘附、(3)吞噬细胞粘附、(3)吞噬细胞活化、(4)吞噬细胞介导凝血对生物材料植入体纤维化组织形成程度的影响。总的来说，这些研究将首次为未来合理设计具有理想组织反应性和可能的伤口愈合反应的植入式医疗器械提供详细和具体的新知识。

Most types of implanted biomaterials trigger both inflammatory and fibrotic responses through mechanisms which are still largely unknown. Phagocytic responses have been demonstrated to influence fibrotic responses (i.e., fibroblast proliferation and collagen production). Our proposed investigations are aimed at elucidating the interrelation(s) between inflammation and fibrosis and consequently developing strategies which control the extent of biomaterial-mediated fibrotic responses. Tissue contact biomaterials trigger, to varying degrees, fibrotic responses. Both insufficient and excessive fibrotic responses an often lead to the failure of medical implants. For example, artificial ligaments often fail because of the lack of adequate tissue integration whereas exuberant fibrotic reactions can lead to the failure of implantable sensors. Because the mechanisms involved in biomaterial-mediated tissue responses remain largely unknown, we still do not know how to control fibrotic tissue formation surrounding material implants. During the first three years of this grant, we elucidated a sequence of events involved in biomaterial- mediated inflammatory responses. (1) Shortly after implementation, phagocytes are recruited to peritoneal cavity via transmigration and chemotactic processes. (2) Phagocyte accumulation on implants is mediated by the adsorbed fibrinogen, phagocytes are activated to produce many pro-fibrotic products, including cytokines and tissue factor. (4) The generation of tissue factor by adherent phagocytes causes the accumulation of fibrin clot on implant surfaces, providing a foundation for fibroblast immigration, proliferation, collagen production, and by changing phagocyte recruitment and activation, we may purposefully modulate fibrotic reactions to suit the purpose of different material devices. For his, using different specific antibodies, antagonists, chemicals, drug investigate the influences of (1) phagocyte recruitment, (2) phagocyte adhesion, (3) phagocyte interactions, we shall investigate the influences of (1) phagocyte recruitment, (2) phagocyte adhesion, (3) phagocyte adhesion, (3) phagocyte activation, and (4) phagocyte- mediated coagulation on the extent of fibrotic tissue formation on biomaterial implants. Overall, these studies will provide, for the first time, detailed and specific new knowledge required for the future rational design of implantable medical devices with desired tissue reactivity and, possibly wound healing responses.