CELLULAR RESPONSES TO INORGANIC PARTICULATES

细胞对无机颗粒的反应

• 批准号: 6375146
• 负责人: STEVEN GOLDRING
• 金额: $ 46.11万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-22 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375146
• 关键词: biomaterial compatibility; biomaterial interface interaction; cellular immunity; clinical research; collagenase; cytokine; dental implants; fluorescent dye /probe; human subject; implant; interleukin 1; joint prosthesis; lipopolysaccharides; medical implant science; particle; silicates; surface property; tumor necrosis factor alpha

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.

描述（改编自研究者摘要）： 假体植入装置是全关节置换术后的主要长期并发症 更换（TIR）。局部骨破坏（骨质溶解）的特征是 这种情况可归因于肉芽肿性 骨-植入物界面的炎症反应。这种组织反应 通过巨噬细胞的募集和激活启动和持续， 假肢磨损碎片。本申请将侧重于物理化学 调节细胞对颗粒矫形植入物反应的性质 材料，并将探讨内毒素污染在 介导不利细胞反应的组分。具体目标1将测试 假设颗粒表面化学和晶体结构 细胞反应的模式和幅度的关键决定因素。 具有良好表征、尺寸、形状、表面 化学和组成将被用来定义特定的影响， 蛋白质吸附的物理和化学性质，动力学， 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， 性质与从失败植入物中回收的真实PE磨损碎片相似。 具体目标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颗粒的微分电容， 结合LPS的表面化学和结晶度，并将评估 颗粒相关的LPS对细胞反应的影响。第3章测试 假设：颗粒调节IL-1b的分子途径 和TNF-α基因不同，颗粒介导的效应涉及LPS依赖性 和非依赖性信号转导系统。这些实验方法 将允许解剖分子机制和信号通路 外来颗粒物质通过其调节细胞反应。整体 这些研究的目的是通过以下方式增加对机制的理解： 该颗粒状磨损碎屑由矫形（和牙科）植入物产生， 调节细胞反应，并严格定义物理和化学反应， 确定颗粒材料的生物活性的性质。 这些信息可能会导致靶向治疗的发展 用于预防或调节不利的细胞和组织的干预 对磨损颗粒的反应。此外，具体的定义 负责细胞活化的物理化学性质可能导致 引入产生磨损碎屑的材料， 促炎特性。