MCP-1 and attenuation of the foreign body response

MCP-1和异物反应的衰减

基本信息

批准号：
7628682
负责人：
THEMIS R KYRIAKIDES
金额：
$ 28.91万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7628682
关键词：
Alginates Alveolar Macrophages Amino Acids Angiogenesis Inhibitors Animal Model Animals Antibodies Biochemical Biocompatible Materials Biological Assay Blocking Antibodies Bone Marrow CD47 Antigen CD47 gene Cell Surface Receptors Cells Characteristics Chronic Collagen Complementary DNA Coupled Cues DNA DNA delivery Deposition Development Dominant-Negative Mutation Enzymes Event Extracellular Matrix Failure Flow Cytometry Foreign Bodies Foreign-Body Giant Cells Gene Delivery Genes Granuloma Harvest Human Implant In Vitro Inflammation Inflammatory Response Injection of therapeutic agent Integrins Interleukin-4 Knockout Mice Lead Length Ligands Longevity Marrow Matrix Metalloproteinases Mediating Mediator of activation protein Modeling Molecular Monocyte Chemoattractant Protein-1 Monocyte Chemoattractant Proteins Mus Nature Peritoneum Phase Phenotype Plasmids Play Polyvinyl Alcohol Porifera Principal Investigator Process Protein Tyrosine Phosphatase Proteins Reaction Recombinants Recruitment Activity Regulation Research Personnel Role Series Signal Pathway Site Src homology 2 domain-containing, transforming protein 1 Surface System Thioglycolates Tissue Engineering Tissues Toxic effect Transforming Growth Factors Wild Type Mouse Wound Healing angiogenesis attenuation base biomaterial compatibility capsule cell motility chemokine cytokine granulocyte implantable device implantation in vitro Assay in vivo inter-alpha-inhibitor intraperitoneal macrophage monocyte monocyte chemoattractant protein 1 receptor monocyte colony stimulating factor neovascularization novel strategies overexpression peripheral blood prevent programs receptor response scaffold soft tissue subcutaneous thrombospondin 2

项目摘要

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外国反应（FBR）的发展，该反应会干扰植入物的功能并最终导致植入物衰竭。通常，由于FBR，在生物材料和脚手架周围形成了很大程度上的血管和密集的胶原胶囊。 FBR的标志是植入物表面上异物巨细胞（FBGC）的形成和持久性，这一过程表明了慢性炎症反应。此外，FBGC已被证明会对多种生物材料造成广泛的表面损害，并导致可能具有毒性作用的微粒释放。此外，已经提出了FBGC在促进生物材料封装中的作用。因此，与自我限制的伤口愈合反应不同，FBR可以在植入期间持续使用。尽管FBGC在植入部位具有突出性，但对它们在体内的形成知之甚少。我们发现，MCP-1-NULL小鼠显示出损害与生物材料损伤减少有关的FBGC形成。在该提案的特定目的1中，我们旨在充分表征MCP-1-NULL小鼠中的FBR。在特定目标2中，我们将重点关注单核细胞募集和FBGC形成，并通过选择性的时间抑制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法研究受MPC-1缺乏影响的分子和生化线索。最后，在特定的目标4中，将采用一种基因递送方法来限制FBGC的形成，增加外国体囊新血管形成，并将FBR转移到伤口愈合表型中。可以预期，向伤口愈合样反应的转变应通过防止损害并延长植入物的寿命来提高生物相容性。总体而言，该应用提出了一种针对FBR的新方法，主要是通过选择性靶向宿主衍生的分子过程的方法。