Biological Strategies to Mitigate the Adverse Effects of Polymeric Wear Particles

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，但长期存活受到承载表面磨损的限制。体外、体内和组织回收研究已经证明单核细胞化学引诱蛋白-1 （MCP-1）在磨损颗粒诱导的炎症中起着关键作用。该资助提案的目标有两个：1)开发、功能化和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)通过局部输注抗炎细胞因子白细胞介素-4 (IL-4)，调节界面巨噬细胞从M1（促炎症）到M2（促组织重塑和血管生成）表型的极化。在我们建立的小鼠体内模型中，这两种策略都可以减少种植体附近的慢性炎症，改善骨附着，并减少颗粒引起的骨丢失，这是由于持续局部注入磨损颗粒造成的。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，从体外钛棒中洗脱突变抗mcp -1蛋白（称为7ND蛋白）。特定目的#2：通过小鼠连续聚乙烯颗粒输注模型，证明7ND蛋白的局部递送可减少全身巨噬细胞向蛋白洗脱钛种植体的运输，从而改善骨附着并减少种植体周围的骨溶解。特定目标#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（促炎症）表型转化为M2（促组织重塑和血管生成）表型，并局部传递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：通过生物力学评估证明，在持续注入聚乙烯颗粒的情况下，用7ND蛋白涂覆钛植入物或局部递送IL-4可改善植入物的固定和骨结构特性。拟议的研究希望通过连续注入聚乙烯颗粒的小鼠模型来调节聚合物磨损颗粒的炎症反应，类似于人类的临床情况。将测试针对巨噬细胞迁移（在植入物附近递送突变的MCP-1蛋白）和改变局部植入物周围巨噬细胞表型的策略，以支持组织重塑和血管生成（局部输注IL-4）。影像学、组织学、形态计量学和力学测试将用于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溶解的发展或预防。提出的生物学策略新颖、机制、可直接翻译；它们会减少种植体周围的炎症，增强骨附着，减少颗粒引起的骨质流失，改善生物力学性能，潜在地延长TJRs的寿命。

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.