MCP-1 and attenuation of the foreign body response

生物材料植入软组织导致异物反应的发展 (FBR)这会干扰植入物的功能并最终导致植入物失效。总的来说， 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囊。一 FBR的标志是异物巨细胞（FBGC）在FBR表面的形成和持续存在。 植入，这是一个过程，表明慢性炎症反应。此外，FBGC已被证明 对多种生物材料造成广泛的表面损伤，并导致微粒的释放， 具有毒性作用。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可以持续伤口愈合的持续时间。 植入期。尽管FBGC在植入部位很突出，但对其 体内形成。我们发现MCP-1缺失小鼠显示FBGC形成受损， 与减少生物材料损伤相关。在本提案的具体目标1中，我们旨在充分描述 MCP-1缺失小鼠的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MCP-1的选择性时间抑制，我们将剖析其对这些过程的贡献。 在《特定目标3》中，我们将利用体外试验来研究与人类免疫缺陷相关的分子和生化线索。 因为缺少MPC-1。最后，在具体目标4中，将采用基因递送方法， 限制FBGC形成，增加异物包膜新血管形成，并将FBR向伤口转移 愈合表型预期向伤口愈合样反应的转变应增强 通过防止损坏和延长植入物的寿命来提高生物相容性。总的来说，这个应用程序 提出了一种新的靶向FBR的方法，主要是通过选择性靶向宿主衍生的分子， 流程.

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.