MCP-1 and attenuation of the foreign body response

描述（由申请人提供）： 将生物材料植入软组织中会导致异物反应（FBR）的发生，从而干扰植入物的功能并最终导致植入物失效。一般而言，由于FBR，在生物材料和支架周围形成大部分无血管和致密的胶原胶囊。FBR的一个标志是植入物表面上异物巨细胞（FBGC）的形成和持续存在，这是一个表明慢性炎症反应的过程。此外，FBGC已被证明会对各种生物材料造成广泛的表面损伤，并导致可能具有毒性作用的微粒的释放。此外，FBGC在促进生物材料包封中的作用已被提出。因此，与自限性的伤口愈合反应不同，FBR可以持续植入期的持续时间。尽管FBGC在植入部位很突出，但对其在体内的形成知之甚少。我们已经发现MCP-1缺失小鼠表现出与生物材料损伤减少相关的FBGC形成受损。在本提案的具体目标1中，我们旨在充分表征MCP-1缺失小鼠中的FBR。在具体目标2中，我们将重点关注单核细胞募集和FBGC形成，并通过选择性时间抑制MCP-1，我们将剖析其对这些过程的贡献。在具体目标3中，我们将利用体外试验来研究受MPC-1缺乏影响的分子和生化线索。最后，在特定目标4中，将采用基因递送方法来限制FBGC形成，增加异物包膜新血管形成，并将FBR向伤口愈合表型转变。预计向伤口愈合样反应的转变应通过防止损伤和延长植入物的寿命来增强生物相容性。总之，本申请提出了一种靶向FBR的新方法，主要通过选择性靶向宿主衍生的分子过程。

DESCRIPTION (provided by applicant): The implantation of biomaterials into soft tissues leads to the development of the foreign body response (FBR) that can interfere with the function of the implant and eventually lead to implant failure. In general, due to the FBR a largely avascular and dense collagenous capsule forms around biomaterials and scaffolds. A hallmark of the FBR is the formation and persistence of foreign body giant cells (FBGC) on the surface of the implant, a process that is indicative of a chronic inflammatory response. In addition, FBGC have been shown to cause extensive surface damage to a variety of biomaterials and cause the release of microparticles that can have toxic effects. Furthermore, a role for FBGC in promoting biomaterial encapsulation has been proposed. Thus, unlike a wound healing response that is self-limiting, the FBR can last for the duration of the implantation period. Despite the prominence of FBGC at implantation sites, little is known about their formation in vivo. We have found that MCP-1-null mice display compromised FBGC formation that is associated with reduced biomaterial damage. In Specific Aim 1 of this proposal we aim to fully characterize the FBR in the MCP-1-null mice. In Specific Aim 2 we will focus on monocyte recruitment and FBGC formation and, by selective temporal inhibition of MCP-1, we will dissect its contribution to these processes. In Specific Aim 3 we will utilize an in vitro assay to investigate the molecular and biochemical cues that are influenced by the lack of MPC-1. Finally, in Specific Aim 4 a gene delivery approach will be employed to limit FBGC formation, increase foreign body capsule neovascularization and shift the FBR towards a wound healing phenotype. It is expected that a shift towards a wound healing-like response should enhance biocompatibility by preventing damage and extending the lifespan of implants. Overall, this application proposes a novel approach to target the FBR, primarily by the selective targeting of host-derived molecular processes.