MCP-1 and attenuation of the foreign body response

描述(由申请人提供)： 生物材料植入软组织会导致异物反应(FBR)，异物反应干扰植入物的功能，最终导致植入物失败。一般来说，由于FBR，在生物材料和支架周围形成了大量无血管和致密的胶原囊。FBR的一个特点是异物巨细胞(FBGC)在植入物表面的形成和持续，这一过程表明存在慢性炎症反应。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，还提出了FBGC在促进生物材料包埋方面的作用。因此，与自我限制的伤口愈合反应不同，FBR可以持续到植入期。尽管FBGC在植入部位很突出，但对它们在体内的形成知之甚少。我们已经发现，MCP-1基因缺失的小鼠表现出与减少生物材料损伤相关的FBGC形成受损。在这项建议的具体目标1中，我们的目标是全面描述MCP-1基因缺失小鼠的FBR。在特定的目标2中，我们将重点关注单核细胞募集和FBGC的形成，并通过选择性的时间抑制MCP-1，我们将剖析其在这些过程中的贡献。在特定的目标3中，我们将利用体外实验来研究MPC-1缺失对分子和生化信号的影响。最后，在特定的目标4中，将使用基因传递方法来限制FBGC的形成，增加异物包膜新生血管，并将FBR转变为伤口愈合表型。预计向伤口愈合类反应的转变应该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.