| Summary: | Joint replacements have been used for over 30 years with considerable success as treatment for bone diseases. As a surgical alternative to metal on metal (MoM) total hip replacement, hip resurfacing was developed using Cobalt-Chromium (CoCr) alloys. However, debris particles are generated by wear at the articulating CoCr surfaces. The nanoparticles and ions produced disseminate throughout the body and interact with different cell types. In order to evaluate the effects of CoCr particles and ions released from MoM implants, U937 cells and primary human lymphocytes were exposed in vitro to artificially produced wear debris derived from an ASRTM MoM hip resurfacing. MoM implants release both Cr and Co ions into patients' circulation, with the latter ion being more mobile, and disseminating more widely in the body. U937 cells were treated with Co ions before being exposed to wear debris to investigate the scenario of patients undergoing revision surgery or receiving a second implant. In addition to this, metal ion levels were measured in clinical whole blood samples of patients with MoM hip implants and the relationship between those levels and the expression of key genes involved in the process of bone remodelling was explored. The findings from this study demonstrated that exposure to high concentrations of CoCr wear debris led to decrease in U937 cell viability after 120h but increased cell proliferation of primary human lymphocytes. Moreover, assessment of apoptosis revealed that metal debris, but not low concentrations of Co ions (0.1μM), induced apoptosis in both U937 cells and primary human lymphocytes. Additionally, results showed that whereas cytokine production by U937 cells is affected by both metal debris and metal ions, it is mainly affected by metal debris in primary human lymphocytes. Changes in human general toxicology-related gene expression in response CoCr wear and Co ions exposure was also evaluated in U937 cells. Real time PCR analysis indicated that CoCr particles were more effective as an inducer of changes in gene expression when cells were pre-treated with Co ions. Together, results seemed to suggest that the toxicity of Co ions in macrophages could be related to nitric oxide metabolic processes and apoptosis and to IL-2 production modulation in lymphocytes. ICP-MS analysis of culture medium from cells exposed to increasing concentration of CoCr wear debris demostrated increasing Co and Cr ion levels representing the corrosion process of the metal debris. Since metal wear debris corrodes under physiological conditions, the ions released may play an important role in the cellular response at the peri-implant tissues. Finally, whole blood Co and Cr ion levels from patients with MoM implants were also analysed by ICP-MS. The ion levels measured were elevated compared to patients without implants, and one patient had levels that were just above the 7μg/l(7ppb)threshold recommended by the Medicines and Health care products Regulatory Agency (MHRA) for Co+Cr in the circulation. A correlation between the ion levels measured and gene expression changes could not be established, due to the low number of patients available for this study. Results from this investigation showed that metal debris tends to be more toxic and has a greater influence on gene expression in the presence of Co ion pre-treatment. This could have great health implications as it potentially means that patients undergoing revision surgery or receiving a second implant may be at higher risk of adverse tissue response and implant failure.
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