Systemic Implications of Total Joint Replacement

描述（由申请人提供）：越来越多的人认识到，从长期来看，全关节置换术（TJR）可能与假体材料降解产物介导的局部和远端不良组织反应相关。由于构成植入物合金的金属元素的已知毒性，因此对TJR的金属降解产物特别感兴趣。在这项长期研究中，研究了TJR患者的金属释放、转运、储存和排泄。在当前的资助期内，已经证明：（1）在功能良好的全髋关节和膝关节置换术后84个月内，可以检测到血清Ti、Co和Cr的升高;（2）在金属对金属关节面患者中观察到最高的Cr和Co水平;（3）大面积多孔涂层钴基合金股骨柄的被动溶解不是金属释放的主要模式;相反，组配式连接处股骨部件的微动腐蚀与血清Cr升高更密切相关;（4）在TJR和血清金属浓度升高的患者中，发现两种分子量范围的Cr（在大约70 kD和大约180 kD），而单一分子量范围（约70 kD）与钛结合;（5）在全髋关节置换术失败的翻修手术后，循环金属水平降低，但在翻修后60个月内仍长期升高;（6）钴和钛合金颗粒降解产物，通常来自关节面以外的来源，通常扩散到主动脉旁淋巴结、肝脏和脾脏，特别是在TJR失败的个体中;（7）金属降解产物的生物活性受其理化性质和蛋白质加合物的控制：含Cr的180 kD金属-蛋白质复合物在这些研究中是最具刺激性的。该提案通过解决以下具体目标扩展了这些发现：（1）量化前瞻性初次THR研究组中的金属释放，这些研究组将在术后10至15年，这是与植入物相关的并发症更普遍的时间段;（2）前瞻性随访钴合金金属对金属髋关节置换术，以确定与血清和尿液金属含量相关的金属过敏症的患病率;（3）扩大尸检检索程序，以表征：不仅颗粒磨损碎屑的全身分布，而且组织金属水平和细胞定位;以及（4）对关节置换部件腐蚀和磨损导致的循环金属-蛋白质复合物进行生物利用度和生物活性研究。

DESCRIPTION (provided by applicant): There is an increasing recognition that, in the long-term, total joint replacement (TJR) may be associated with adverse local and remote tissue responses that are mediated by the degradation products of prosthetic materials. There has been particular interest in the metallic degradation products of TJR because of the known toxicities of the metallic elements that comprise implant alloys. In this long-term study, metal release, transport, storage and excretion in patients with TJRs habs been investigated. In the current grant period, it has been demonstrated that (1) elevations in serum Ti, Co and Cr can be detected in individuals with well functioning total hip and knee replacements up to 84 months postoperative; (2) the highest Cr and Co levels have been observed in patients with metal-on-metal bearings; (3) passive dissolution from extensively porous coated Co-base alloy femoral stems is not a dominant mode of metal release; rather, fretting corrosion of femoral components at modular junctions is more closely associated with elevations in serum Cr; (4) in patients with TJR and elevated serum metal concentrations, two molecular weight ranges were found to bind Cr (at approximately 70 kD and approximately 180 kD) whereas a single molecular weight range (at approximately 70 kD) was found to bind Ti; (5) following revision surgery for a failed total hip replacement, circulating metal levels diminish, but remain chronically elevated up to 60 months post-revision; (6) Co- and Ti-alloy particulate degradation products, usually from sources other than the bearing surface, commonly disseminate to paraaortic lymph nodes, liver and spleen, particularly in individuals who have had a failed TJR; and (7) the bioreactivity of metal degradation products is governed by its' physiochemical nature and protein adducts: a Cr-containing 180 kD metal-protein complex was the most stimulatory in these studies. This proposal expands on these findings by addressing the following Specific Aims: (1) to quantify metal release in the prospective primary THR study groups which will be 10 to 15 years postoperative, an interval in which complications related to the implant are more prevalent; (2) to prospectively follow patients with Co-alloy metal-on-metal hip replacements to determine the prevalence of metal hypersensitivity in correlation with the serum and urine metal content; (3) to expand the autopsy retrieval program to characterize not: only the systemic distribution of particulate wear debris but also the tissue metal levels and the cellular localization; and (4) to conduct bioavailability and bioreactivity studies of circulating metal-protein complexes which result from corrosion and wear of joint replacement components.