PARTICULATE BIOMATERIAL INDUCED BONE RESORPTION

用金属和聚合物材料进行全关节置换， 为数百万人提供了戏剧性的疼痛缓解和功能改善 终末期关节炎患者。 尽管联合国的成功 置换手术，存在或不存在假体周围骨溶解 无菌性松动会危及两种骨水泥固定的长期成功， 和非骨水泥全关节置换术。 微粒碎片来自 假体和（当存在时）骨粘固剂被吞噬， 相信这些微粒激活巨噬细胞和成骨细胞 (and可能是成纤维细胞）来产生刺激骨的因子 再吸收 为了支持这一假设，已经证明， 假体周围肉芽肿组织和巨噬细胞系 用微粒刺激产生高水平的细胞因子/生长 与骨增加相关的因子和前列腺素E/2（PGE/2） 器官培养中的再吸收。 我们建议调查这一假设 通过研究分子和细胞水平上的因素， 触发、维持和/或调节颗粒诱导假体周围 骨质溶解 我们将确定最有效的微粒种类 其在体外激活“标准”细胞系并将其关联起来 在活化细胞的体内定位的发现（在存在下 假体周围溶骨性病变中的颗粒）， 选择一组“骨吸收”细胞因子、金属蛋白酶和PGE/2。 此外，将分离假体周围组织的细胞， 表征，然后它们表达骨吸收剂的能力， 将被确定。 这项建议将集中在三个尚未得到充分理解的方面 植入物相关的假体周围骨质溶解：（1）是否有一个主导的 刺激骨吸收的颗粒物质，或者 处理多个颗粒物之间的协同作用？（二） 有没有一种占优势的细胞类型对磨损的刺激作出反应 碎片或颗粒诱导的骨吸收是一种复杂的机制 同时涉及多种细胞类型（巨噬细胞，成纤维细胞， 巨细胞、成骨细胞和破骨细胞）？（3）是否存在一个共同的 在细胞水平的调节机制，导致假体周围 骨水泥型和非骨水泥型全髋关节置换术中的骨质溶解？ 与 关于第一个问题，应该强调的是，答案可能 对未来的植入物设计、制造和 材料选择 关于第二和第三个问题， 是缺乏这种信息，这被认为是至关重要的 发展治疗方式，以预防、延缓或扭转 植入物相关假体周围骨质溶解。

Total joint replacement with metallic and polymeric materials has provided dramatic relief of pain and improvement in function for millions of patients with end stage arthritis. Despite the success of joint replacement surgery, periprosthetic osteolysis in the presence or absence of aseptic loosening jeopardizes the long-term success of both cemented and cementless total joint replacements. Particulate debris derived from the prosthesis and (when present) bone cement is phagocytized, and it is believed that these particulates activate macrophages and osteoblasts (and perhaps fibroblasts) to produce factors which stimulate bone resorption. In support of this hypothesis, it has been demonstrated that cells from the periprosthetic granulomatous tissues and macrophage cell lines stimulated with particulates yield high levels of cytokines/growth factors and prostaglandin E/2 (PGE/2) associated with increased bone resorption in organ cultures. We propose to investigate this hypothesis by studying factors at the molecular and cellular levels which may trigger, maintain and/or regulate particulate-induced periprosthetic osteolysis. We will determine the most effective particulate species which activate "standard" cell lines in vitro and correlate these findings with in vivo localization of activated cells (in the presence of particulates) in the periprosthetic osteolytic lesions measuring a select group of "bone resorbing" cytokines, metalloproteinases and PGE/2. In addition, cells of the periprosthetic tissue will be isolated, characterized and then their ability to express bone resorbing agents will be determined. This proposal will concentrate on three as yet poorly understood aspects of implant-associated, periprosthetic osteolysis: (1) is there a dominant particulate species which is the stimulus to bone resorption or is this process a synergistic interaction among multiple particulate species? (2) Is there a dominant cell type which responds to the stimulus of wear debris or is the particulate-induced bone resorption a complex mechanism involving simultaneously multiple cell types (macrophages, fibroblasts, giant cells, osteoblasts and osteoclasts)?, and (3) is there a common regulatory mechanism at the cellular level which leads to periprosthetic osteolysis in cemented and cementless total hip arthroplasties? With regard to the first question, it should be stressed that the answer may have important implications for future implant design, fabrication and material selection. With regard to the second and third questions, there is a dearth of such information, which is deemed critical for the development of therapeutic modalities to prevent, retard or reverse implant-associated periprosthetic osteolysis.