Development of an in vivo model to assess immune and angiogenic responses to metallic implants using Humanized TLR-4 mice

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Abstract Metal on metal(MOM) hips often fail due to inappropriate inflammation and angiogenesis which may be due to localized concentrations of metal ions and/or MOM wear particles in the joint. Critically, human, but not mouse TLR-4 receptors, are responsive to nickel, cobalt and MOM particles. Therefore, we are using humanized, hTLR-4 mice in these studies. MOM hips are predominately cobalt, so our initial experiments were focused upon this ion. Spleen cells of hTLR -4 mice were exposed to 3 concentrations of CoCl2 (2.5μM, 25μM, 250μM) for 3 and 6 days. The cultures were analyzed for endothelial cell markers, (MADCAM and CD31)and T cell markers, (CD4 and CD8). A dose dependent induction of endothelial markers was seen on day 3 with a dose dependent reduction on day 6, with no changes in CD4 or CD8 expression. Next, spleen cells of TLR-4 mice were exposed to 3 different ratios of cell to MOM particles (1:5, 1:50, 1:500 per cell) for 3 and 6 days. Endothelial markers were induced, but it was not dose dependent, however the endothelial cell numbers increased between 3 and 6 days. Again, T cell markers were not altered. To assess the in-vivo responses to MOM particles, nude mice were implanted with angioreactors containing MOM particles (2.5×105 and 2.5 × 106). On day 12, the angioreactors were removed and the was a dose dependent increase in endothelial cells. Currently, we are extending the MOM angiogenesis studies in hTLR-4 mice. In sum, both CoCl2 and MOM particles induced endothelial cells and angiogenesis. The hTLR-4 mouse model will greatly aid in the evaluating the angiogenic and immunotoxicological profile of ions and MOM wear debris, particularly during menopause. Funded by FDA Office of Women’s Health.

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