MCP-1 and attenuation of the foreign body response

MCP-1和异物反应的衰减

• 批准号: 7027107
• 负责人: THEMIS R KYRIAKIDES
• 金额: $ 29.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027107
• 关键词: biomaterial interface interaction; bone marrow; complementary DNA; flow cytometry; gene expression; genetically modified animals; immune response; implant; integrins; laboratory mouse; leukocyte activation /transformation; macrophage; membrane proteins; monocyte chemoattractant protein 1; protein structure function; thrombospondins; transforming growth factors

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.

描述（由申请人提供）： 将生物材料植入软组织会导致异物反应（FBR）的发生，从而干扰植入物的功能并最终导致植入物失败。一般来说，由于 FBR，生物材料和支架周围会形成大量无血管且致密的胶原胶囊。 FBR 的一个标志是植入物表面异物巨细胞 (FBGC) 的形成和持续存在，这一过程表明存在慢性炎症反应。此外，FBGC 已被证明会对多种生物材料造成广泛的表面损伤，并导致释放具有毒性​​作用的微粒。此外，还提出了 FBGC 在促进生物材料封装中的作用。因此，与自限性的伤口愈合反应不同，FBR 可以在植入期间持续。尽管 FBGC 在植入部位很重要，但人们对它们在体内的形成知之甚少。我们发现 MCP-1 缺失小鼠表现出 FBGC 形成受损，这与生物材料损伤减少有关。在本提案的具体目标 1 中，我们的目标是全面表征 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，并通过选择性暂时抑制 MCP-1，我们将剖析其对这些过程的贡献。在特定目标 3 中，我们将利用体外测定来研究受 MPC-1 缺乏影响的分子和生化线索。最后，在具体目标 4 中，将采用基因传递方法来限制 FBGC 形成，增加异物囊新生血管形成并将 FBR 转向伤口愈合表型。预计向类似伤口愈合的反应的转变应该通过防止损坏和延长植入物的使用寿命来增强生物相容性。总的来说，该申请提出了一种靶向 FBR 的新方法，主要是通过选择性靶向宿主衍生的分子过程。