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: 8762272
• 负责人: STUART B GOODMAN
• 金额: $ 17.68万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762272
• 关键词: Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Area; Arthritis; Beds; Biological; Biomechanics; Carrying Capacities; Cell Line; Cells; Characteristics; Chemotaxis; Chronic; Clinical; Development; Evaluation; Foreign-Body Giant Cells; Fracture; Generations; Goals; Grant; Histology; Human; Image; Imaging Techniques; Implant; In Vitro; Inflammation; Inflammatory; Infusion procedures; Interleukin-4; Lead; Long Term Survivorship; Longevity; Macrophage Activation; Mechanics; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Mus; Operative Surgical Procedures; Orthopedics; Osseointegration; Osteoclasts; Osteolysis; Outcome; Patients; Phase; Phenotype; Polyethylenes; Polymers; Prevention; Prevention strategy; Property; Prosthesis; Proteins; Reaction; Replacement Arthroplasty; Retrieval; Risk; Role; Signal Transduction; Staging; Surface; System; Testing; Tissues; Titania; Titanium; angiogenesis; bone; bone loss; chemokine; cytokine; improved; in vivo; insight; macrophage; migration; monocyte; morphometry; mutant; nanocoating; novel; novel strategies; particle; peri-implant osteolysis; public health relevance; retinal rods; sample fixation; 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. In vitro, in vivo and tissue retrieval studies have demonstrated a critical role for Monocyte Chemoattractant Protein-1 (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 (known as 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 a M1 (pro-inflammatory) to a 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. Specific Aim #4: To demonstrate using biomechanical evaluation that coating titanium implants with 7ND protein or local delivery of IL-4 improves implant fixation and bone structural properties in the presence of continuously infused polyethylene particles. 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. Imaging, histology, morphometry, and mechanical testing 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. The biological strategies proposed are novel, mechanistic and directly translational; they should result in decreased peri-implant inflammation, enhanced bone apposition, decreased particle-induced bone loss and improved biomechanical properties, potentially extending the lifetime of TJRs.

描述(申请人提供)：全关节置换术(TJR)是一种非常成功的外科手术，但其长期存活受到轴承表面磨损的限制。体外、体内和组织修复研究表明，单核细胞趋化蛋白-1(MCP-1)在磨粒诱导的炎症反应中起重要作用。这项赠款提案的目标有两个：1)开发、功能化和验证一种新型的整形外科植入物纳米涂层，该涂层将向植入物-骨界面提供抗MCP-1蛋白疗法；2)通过局部输注抗炎细胞因子白介素4(IL-4)，将界面处的巨噬细胞极化从M1(促炎)调整为M2(促组织重塑和血管生成)表型。使用我们建立的体内小鼠模型，这两种策略都将减少种植体周围的慢性炎症，改善骨对位，并减少由于持续局部注射磨损颗粒而导致的骨丢失。具体目标1：构建、优化和验证一种局部递送系统，在该系统中突变的抗MCP-1蛋白(称为7ND蛋白)可在体外从钛棒中洗脱出来。具体目的#2：使用小鼠持续聚乙烯颗粒输注模型，证明局部输送7ND蛋白减少了系统巨噬细胞向蛋白洗脱钛种植体的转运，从而改善了骨附着，减少了种植体周围骨溶解。具体目的#3：证明在持续注入聚乙烯颗粒的情况下，位于骨-种植体界面的巨噬细胞从M1(促炎)表型转变为M2(促组织重塑和血管生成)表型并局部输送IL-4将减少骨丢失并改善种植体附近的骨附着。具体目标#4：利用生物力学评估，证明在持续注入聚乙烯颗粒的情况下，在钛种植体表面涂覆7ND蛋白或局部输送IL-4可以改善种植体固定和骨结构性能。这项拟议的研究旨在通过连续输注聚乙烯颗粒的小鼠模型来调节对聚合物磨损颗粒的炎症反应，类似于人类的临床情景。针对巨噬细胞迁移(在种植体附近传递突变的MCP-1蛋白)和将种植体周围局部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)的策略将进行测试。影像、组织学、形态计量学和力学测试将被用来描述巨噬细胞向颗粒的全身性运输、局部炎症反应的特征以及骨溶解的发展或预防。所提出的生物学策略是新颖的、机械的和直接平移的；它们应该能够减少种植体周围炎症，增强骨对接，减少颗粒诱导的骨丢失，并改善生物力学性能，潜在地延长TJR的寿命。