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 THR because of the known toxicities of the metallic elements that comprise the implant alloys. In this long term study, we have been investigating metal release, transport, storage and excretion in patients with total hip and knee replacements. In the current grant period, we have demonstrated that (1) elevations in serum titanium and chromium can be detected in individuals with well functioning total hip and knee replacements; (2) the highest chromium and cobalt levels have been observed in patients with metal-on-metal bearings; (3) passive dissolution from extensively porous coated cobalt- base alloy femoral stems is not a dominant model of metal release; rather, fretting corrosion of femoral components at modular junctions is more closely associated with elevations in serum chromium; (4) cobalt- and titanium-alloy particulate degradation products from TJR commonly disseminate to paraaortic lymph nodes, liver and spleen, particularly in individuals who have had a failed TJR; and (5) there are indications that individuals with elevated serum metal content may have associated liver cell injury. We propose to expand on these studies to (1) quantify metal release in the prospective study group which will be 7 to 12 years postoperative, an interval in which complications related to the implant are more prevalent; (2) prospectively follow patients up to 8 years after revision surgery who have demonstrated significant elevations in serum metal content to determine if serum metal transport diminishes with time; (3) expand our autopsy retrieval program to characterize not only tissue metal levels and systemic distribution of particulate wear debris but also the tissue and cellular localization of these degradation products; and (4) conduct bioavailability and bioreactivity studies of circulating metal-protein complexes which result from corrosion and wear of joint replacement components. This is one of four grants in an Orthopaedic Biomaterials Investigator- Initiated Interactive Research Project Grant entitled "Safety and Efficacy of Permanent Skeletal Replacement Implants". The studies proposed here address safety issues and are deemed critical in order to understand the prospective risks to patients undergoing total joint arthroplasty.