Systemic Implications of Total Joint Replacement

描述(申请人提供)：越来越多的人认识到，从长远来看，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程不良组织反应有关。人们对TJR的金属降解产物特别感兴趣，因为构成植入合金的金属元素具有已知的毒性。在这项长期研究中，研究了TJRS HABS患者的金属释放、运输、储存和排泄。在目前的授权期内，已经证明：(1)在功能良好的全髋关节和膝关节置换术后长达84个月的患者中，可以检测到血清钛、钴和铬的升高；(2)在金属对金属轴承的患者中，观察到最高的铬和钴水平；(3)从广泛多孔的涂层钴基合金股骨柄中被动溶解不是金属释放的主要方式；相反，模块接合处股骨假体的微动腐蚀与血清铬的升高更密切相关；(4)在TJR和血清金属浓度升高的患者中，发现两个分子范围结合铬(约70kD和约180kD)，而单个分子范围(约70kD)结合钛；(5)全髋关节翻修术失败后，循环金属水平下降，但持续升高至翻修后60个月；(6)钴和钛合金颗粒降解产物，通常来自轴承表面以外的来源，通常扩散到腹主动脉旁淋巴结、肝和脾，特别是在TJR失败的患者；(7)金属降解产物的生物反应性受其物理化学性质和蛋白质加合物的控制：在这些研究中，含铬180kD的金属-蛋白质络合物最具刺激性。这项建议通过解决以下具体目标来扩展这些发现：(1)量化预期的原发THR研究组的金属释放，这将是术后10-15年，与假体相关的并发症更为普遍的时间间隔；(2)前瞻性地跟踪接受钴合金金属对金属置换的患者，以确定金属过敏的患病率与血清和尿液中金属含量的相关性；(3)扩大尸检检索程序，以表征：不仅是颗粒磨损碎片的系统分布，而且还有组织金属水平和细胞定位；以及(4)对关节置换部件的腐蚀和磨损引起的循环金属-蛋白质络合物进行生物利用度和生物反应性研究。

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.