CELLULAR RESPONSES TO INORGANIC PARTICULATES

描述(改编自调查者摘要)：无菌松动 假体植入装置是全关节置入术后的主要远期并发症 更换(TIR)。局部骨质破坏(骨溶解)是其特征 这种情况可以归因于肉芽肿的诱发。 骨-种植体界面的炎症反应。这种组织反应是 由巨噬细胞的募集和激活而启动和持续 假肢磨损碎片。本应用将集中在物理化学方面 调节细胞对颗粒骨科植入物反应的特性 材料，并将探索内毒素污染在 调节不良细胞反应的一部分。特定目标1将测试 粒子表面化学和晶体结构是 细胞反应模式和大小的关键决定因素。 具有良好表征、大小、形状、表面的荧光标记颗粒 化学和作文将被用来定义特定的影响 理化性质对蛋白质吸附、吸附动力学的影响 颗粒内化和细胞因子释放。这些研究将利用 亚微米级UHMWPE颗粒的独特可用性 与从失败的植入物中回收的真实PE磨损碎屑相似的特性。 《特定目标2》将检验以下假设：脂多糖(LPS) “污染”是颗粒诱导的细胞反应的一个组成部分。 这些研究将定义不同粒子的微分能力 结合脂多糖的表面化学和结晶度，并将评估 颗粒相关内毒素对细胞反应的影响。《特定目标3》将测试 假设：粒子调节IL-1b的分子途径 和肿瘤坏死因子基因不同，颗粒介导的效应涉及内毒素依赖 和-独立的信号转导系统。这些实验方法 将允许对分子机制和信号通路的剖析 外来颗粒物通过这种物质来调节细胞反应。整体而言 这些研究的目标是通过以下方式增加对机制的理解 骨科(和牙科)植入物产生的颗粒磨屑 调节细胞反应，严格定义物理和化学 决定颗粒材料生物活性的特性。 这一信息可能会导致靶向治疗的发展 预防或调节不良细胞和组织的干预措施 对磨损颗粒的反应。此外，定义了具体的 负责细胞激活的物理化学性质可能导致 减少磨屑产生的材料介绍 具有促炎作用。

DESCRIPTION (adapted from the Investigator's abstract): Aseptic loosening of prosthetic implant devices is the major long-term complication after total join replacement (TIR). The local bone destruction (osteolysis) that characterizes this condition can be attributed to the induction of a granulomatous inflammatory reaction at the bone-implant interface. This tissue reaction is initiated and perpetuated by the recruitment and activation of macrophages by prosthetic wear debris. This application will focus on the physical-chemical properties regulating cell responses to particulate orthopedic implant materials, and will explore the potential role of endotoxin contamination in mediating a component of the adverse cell responses. Specific Aim 1 will test the hypothesis that particle surface chemistry and crystal structure are critical determinants of the pattern and magnitude of cell responses. Fluorescent-labeled particles of well characterized, size, shape, surface chemistry and composition will be used to define the influence of specific physical and chemical properties on protein adsorption, the kinetics of particle internalization and cytokine release. These studies will exploit the unique availability of submicron sized UHMWPE particles which exhibit properties similar to authentic retrieved PE wear debris from failed implants. Specific Aim 2 will test the hypothesis that: Lipopolysaccharide (LPS) "contamination" accounts for a component of particle-induced cell responses. These studies will define the differential capacity of particles with different surface chemistry and crystallinity of bind LPS and will assess the effects of particle-associated LPS on cell responses. Specific Aim 3 will test the hypothesis that: the molecular pathways by which particles regulate the IL-1b and TNF- genes differ and that particle-mediated effects involve LPS-dependent and -independent signal transduction systems. These experimental approaches will permit the dissection of the molecular mechanisms and signaling pathways by which foreign particulate materials modulate cell responses. The overall goal of these studies is to increase the understanding of the mechanisms by which particulate wear debris generated from orthopedic (and dental) implants regulate cell responses and to define rigorously the physical and chemical properties that determine the biological activity of the particulate materials. This information could lead to the development of targeted therapeutic interventions for preventing or modulating the adverse cellular and tissue reaction to wear particles. In addition, definition of the specific physical-chemical properties responsible for cell activation could lead to the introduction of materials that generate wear debris with reduced pro-inflammatory properties.