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生 (FBR)会干扰植入物的功能，最终导致植入物失败。总体而言, 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。一个 异物巨细胞(FBGC)的形成和存留是FBR的特点。 植入，这是一个慢性炎症反应的过程。此外，还展示了FBGC 对各种生物材料造成广泛的表面损伤，并导致微粒释放，这些微粒可以 有毒害作用。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 植入期。尽管FBGC在植入部位很突出，但人们对它们的情况知之甚少 在体内形成。我们已经发现，MCP-1基因缺失的小鼠表现出FBGC形成的损害，即 与减少生物材料损害有关。在本提案的具体目标1中，我们的目标是充分说明 MCP-1基因缺失小鼠的FBR。在具体目标2中，我们将重点关注单核细胞募集和FBGC 并且，通过选择性的时间抑制MCP-1，我们将剖析它在这些过程中的贡献。 在特定目标3中，我们将利用体外测试来研究分子和生化线索，这些线索是 受缺乏MPC-1的影响。最后，在具体目标4中，将使用基因递送方法来 限制FBGC的形成，增加异物包膜新生血管，并将FBR移向伤口 愈合表型。预计向伤口愈合样反应的转变应该会增强 通过防止损伤和延长植入物的寿命来实现生物兼容性。总体而言，此应用程序 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.