CELLULAR RESPONSES TO INORGANIC PARTICULATES

细胞对无机颗粒的反应

• 批准号: 6511933
• 负责人: STEVEN GOLDRING
• 金额: $ 49.65万
• 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/6511933
• 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（改编自调查员的摘要）：无菌松动 普体植入设备是总和后的主要长期并发症 替换（TIR）。特征的局部骨骼破坏（骨溶解） 这种情况可以归因于颗粒的诱导 骨植入术界面处的炎症反应。这种组织反应是 由 假体磨损碎片。该应用将重点放在物理化学上 调节细胞对颗粒骨科植入物的响应的特性 材料，并将探索内毒素污染在 介导不良细胞反应的组成部分。具体目标1将测试 颗粒表面化学和晶体结构是 细胞反应的模式和大小的关键决定因素。 荧光标记的颗粒具有良好的特征，大小，形状，表面 化学和组成将用于定义特定的影响 物理和化学特性，对蛋白质吸附，动力学 粒子内在化和细胞因子释放。这些研究将利用 表现出的亚微米尺寸UHMWPE颗粒的独特可用性 类似于从失败植入物中检索到的PE磨损碎屑的特性。 特定目标2将检验以下假设：脂多糖（LPS） “污染”解释了粒子诱导的细胞反应的成分。 这些研究将定义不同的粒子的差异能力 结合LP的表面化学和结晶度，将评估 粒子相关的LPS在细胞反应上。特定目标3将测试 假设：颗粒调节IL-1b的分子途径 tnf-基因不同，颗粒介导的作用涉及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 外来颗粒物材料调节细胞反应。总体 这些研究的目标是通过通过 哪些颗粒物戴着骨科（和牙科）植入物产生的碎屑 调节细胞反应并严格定义物理和化学物质 决定颗粒物质的生物学活性的特性。 这些信息可能导致有针对性的治疗的发展 预防或调节不良细胞和组织的干预措施 穿着颗粒的反应。此外，特定的定义 负责细胞激活的物理化学特性可能导致 引入产生磨损碎屑并减少的材料 促炎性特性。