Biological Strategies to Mitigate the Adverse Effects of Polymeric Wear Particles

减轻聚合物磨损颗粒不利影响的生物策略

• 批准号: 8514518
• 负责人: STUART B GOODMAN
• 金额: $ 33.59万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514518
• 关键词: Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Area; Arthritis; Attenuated; Beds; Biological; Bioluminescence; Cell Line; Cells; Characteristics; Chemotaxis; Chronic; Clinical; Coronary; Development; Foreign-Body Giant Cells; Generations; Goals; Grant; Histology; Human; Imaging Techniques; Implant; In Vitro; Infiltration; Inflammation; Inflammatory; Infusion procedures; Interleukin-4; Long Term Survivorship; Longevity; Macrophage Activation; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Mus; Operative Surgical Procedures; Orthopedics; Osseointegration; Osteoclasts; Osteolysis; Outcome; Patients; Pharmaceutical Preparations; Phase; Phenotype; Polyethylenes; Polymers; Positron-Emission Tomography; Prevention; Prevention strategy; Prosthesis; Proteins; Reaction; Replacement Arthroplasty; Retrieval; Role; Signal Transduction; Staging; Stents; Surface; System; Techniques; Testing; Tissues; Titania; Titanium; angiogenesis; bone; bone loss; chemokine; cytokine; improved; in vivo; macrophage; migration; monocyte; morphometry; mutant; nanocoating; novel; novel strategies; particle; peri-implant osteolysis; retinal rods; tissue regeneration; trafficking

DESCRIPTION (provided by applicant): Total joint replacement (TJR) is a highly successful surgical procedure however the long-term survivorship is limited by wear of the bearing surfaces. Monocyte Chemoattractant Protein-1 (MCP-1) is the most important chemokine regulating systemic and local trafficking of monocyte/macrophages in inflammation. In vitro, in vivo and tissue retrieval studies have demonstrated a critical role for MCP-1 in wear particle-induced inflammation. The goals of this grant proposal are twofold 1) to develop, functionalize and validate a novel orthopaedic implant nano-coating that will deliver anti-MCP-1 protein therapy to the implant-bone interface and 2) to modulate macrophage polarization at the interface from an M1 (pro-inflammatory) to an M2 (pro- tissue remodeling and angiogenesis) phenotype with local infusion of the anti-inflammatory cytokine Interleukin-4 (IL-4). Both of these strategies will decrease chronic inflammation near the implant, improve bone apposition, and decrease particle-induced bone loss due to continuous local infusion of wear particles using our established in vivo murine model. Specific Aim #1: To construct, optimize and validate a local delivery system in which mutant anti-MCP-1 protein (called 7ND protein) is eluted from a titanium rod in vitro. Specific Aim #2: To demonstrate that local delivery of 7ND protein decreases systemic macrophage trafficking to the protein eluting titanium implant, thereby improving bone apposition and decreasing peri- implant osteolysis, using the murine continuous polyethylene particle infusion model. Specific Aim #3: To demonstrate that transformation of macrophages located at the bone-implant interface in the presence of continuously infused polyethylene particles from an M1 (pro-inflammatory) to an M2 (pro- tissue remodeling and angiogenesis) phenotype with local delivery of IL-4 will decrease bone loss and improve bone apposition adjacent to the implant. The proposed studies aspire to modulate the inflammatory reaction to polymer wear particles using a murine model of continuous polyethylene particle infusion, similar to the clinical scenario in humans. Strategies which target macrophage migration (delivery of a mutant MCP-1 protein near the implant) and alter the phenotype of local peri-implant macrophages to one supporting tissue remodeling and angiogenesis (local infusion of IL-4) will be tested. The techniques of bioluminescence, microCT and micro PET scanning, histology and morphometry will be used to delineate systemic trafficking of macrophages to the particles, the characteristics of the local inflammatory reaction, and development or prevention of osteolysis. Both of the biological strategies proposed are novel, mechanistic and directly translational; they should result in decreased peri-implant inflammation, improved bone apposition and decreased particle-induced bone loss, potentially extending the lifetime of joint replacements.

描述（由申请人提供）：全关节置换术（TJR）是一种非常成功的外科手术，但长期生存率受到关节面磨损的限制。单核细胞趋化蛋白-1（MCP-1）是炎症反应中调节单核/巨噬细胞系统和局部运输的最重要的趋化因子。体外、体内和组织修复研究已经证明MCP-1在磨损颗粒诱导的炎症中起关键作用。这项赠款提案的目标是双重的1）发展，功能化并验证一种新型骨科植入物纳米涂层，该涂层将向植入物-骨界面提供抗MCP-1蛋白治疗，2）调节M1-MCP-1界面处的巨噬细胞极化（促炎性）至M2（促组织重塑和血管生成）表型，局部输注抗炎细胞因子白细胞介素-4（IL-4）。这两 这些策略将减少植入物附近的慢性炎症，改善骨沉积，并减少由于使用我们建立的体内小鼠模型连续局部注入磨损颗粒而导致的颗粒诱导的骨丢失。具体目标1：构建、优化和验证一种体外洗脱突变型抗MCP-1蛋白（称为7 ND蛋白）的局部给药系统。具体目标#2：使用小鼠连续聚乙烯颗粒输注模型，证明局部递送7 ND蛋白可减少全身巨噬细胞向蛋白洗脱钛植入物的运输，从而改善骨沉积并减少植入物-骨溶解。具体目标#3：证明在存在连续输注聚乙烯颗粒的情况下，骨-植入物界面处的巨噬细胞从M1（促炎性）转化为M2（促组织重塑和血管生成）表型，局部输送IL-4，将减少骨丢失并改善植入物附近的骨沉积。拟定的研究旨在使用持续聚乙烯颗粒输注的小鼠模型调节对聚合物磨损颗粒的炎症反应，类似于人类的临床情况。将测试靶向巨噬细胞迁移（在植入物附近递送突变MCP-1蛋白）并将局部植入物周围巨噬细胞的表型改变为支持组织重塑和血管生成（局部输注IL-4）的策略。将使用生物发光、microCT和microPET扫描、组织学和形态学技术来描述巨噬细胞向颗粒的全身运输、局部炎症反应的特征以及骨质溶解的发生或预防。提出的两种生物学策略都是新颖的、机械的和直接转化的;它们应导致植入物周围炎症减少、骨沉积改善和颗粒诱导的骨丢失减少，从而可能延长关节置换的寿命。