Biological consequences of exposure to prosthetic nanoparticles

Hip replacement surgery can transform the lives of people crippled with arthritis and ther are thousands of hip replacement procedures performed every year in the UK. Recently there has been an increase in the use of hips made from metal articulating on metal since these hips enable younger recipients to continue to participate in active sports activities. These metal on metal hips however produce millions of very small (nanometre sized) metal particles with every step taken and these particles will travel around the body. The particles may have no effect whatsoever if the body can dispose of them through normal excretion. On the other hand, the particles have the potential to cause changes to cells in different parts of the body which may lead to diseases such as metal allergy or even cancer. The aims of this study are to investigate the biological consequences of exposure to these particles in a mouse model that can be translated into the human situation. This will enable scientists and clinicians to better understand what the consequences of the use of metal on metal hips might be. This will mean that clinicians and patients can make better informed descisions when choosing the type of hip replacement by balancing the benefits against the potential risks.

There are currently around 46,000 total hip or surface replacement procedures performed annually in the UK. Globally the figure is around 1 million. There is increasing use of metal on metal (MoM) articulations in young active patients. MoM articulations generate nanometre sized cobalt chromium (CoCr) wear particles and high systemic levels of metal ions. The consequences of endogenous exposure to these nanoparticles and metal ions have not been adequately investigated and both the Department of Health and NICE have called for studies in this area. The aims of this study are to investigate the biological consequences of exposure to physiological levels of prosthetic CoCr wear particles in a mouse intra-articular model that can be translated to human exposure. CoCr nanoparticles will be generated in MoM hip joint simulations. Four groups of mice will be exposed to two doses of CoCr nanoparticles, in the physiological range, one dose of micrometer sized CoCr particles (for direct comparison) and vehicle (control) over a 5 month period to model clinical MoM bedding in wear. Particles will be delivered by intra-articular injection into the knee joint. The extent of dissemination to bodily organs, histopathological consequences, genotoxic, immunotoxic and lymphocyte sensitisation consequences of exposure will be determined over a period of 10 months. Analyses will include determination of metal ion concentration in, and histological evaluation of, all major bodily organs and tissues, cytogenetic analysis (M-FISH) of peripheral blood lymphocytes, ovaries, testes and bone marrow cells, DNA damage in bone marrow cells, numbers of CD4+, CD8+ T-cells, B-cells, lymphocyte transformation response to Co, Cr and Ni ions and analysis of responding T-cell phenotype by ELISpot. These studies will indicate any specific immune reaction or genotoxic effects caused by nanoparticle compared to microparticle exposure together with the extent and consequences of dissemination of the particles systemically. These studies will address important gaps in knowledge that are preventing the orthopaedic community from answering fundamental questions.