A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay.

The objective of this preliminary study was to evaluate the threshold for immune stimulation in mice following local exposure to metal particles and ions representative of normal-functioning cobalt-chromium (CoCr) metal-on-metal (MoM) hip implants. The popliteal lymph node assay (PLNA) was used in this study to assess immune responses in BALB/c mice following treatment with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3 and NiCl2), or Cr2O3 particles together with metal salts using single-dose exposures representing approximately 10days (0.000114mg), 19years (0.0800mg), and 40years (0.171mg) of normal implant wear. The immune response elicited following treatment with Cr2O3 particles together with metal salts was also assessed at four additional doses equivalent to approximately 1.5months (0.0005mg), 0.6years (0.0025mg), 2.3years (0.01mg), and 9.3years (0.04mg) of normal implant wear. Mice were injected subcutaneously (50µL) into the right hind foot with the test article, or with the relevant vehicle control. The proliferative response of the draining lymph node cells (LNC) was measured four days after treatment, and stimulation indices (SI) were derived relative to vehicle controls. The PLNA was negative (SI<3) for all Cr2O3 particle doses, and was also negative at the lowest dose of the metal salt mixture, and the lowest four doses of the Cr2O3 particles with metal salt mixture. The PLNA was positive (SI>3) at the highest two doses of the metal salt mixture and the highest three doses of the Cr2O3 particles with the metal salt mixture. The provisional NOAEL and LOAEL values identified in this study for immune activation corresponds to Co and Cr concentrations in the synovial fluid approximately 500 and 2000 times higher than that reported for normal-functioning MoM hip implants, respectively. Overall, these results indicate that normal wear conditions are unlikely to result in immune stimulation in individuals not previously sensitized to metals.

Data on the histological and immune cell response in the popliteal lymph node in mice following exposure to metal particles and ions.

Hip implants containing cobalt-chromium (CoCr) have been used for over 80 years. In patients with metal-on-metal (MoM) hip implants, it has been suggested that wear debris particles may contribute to metal sensitization in some individuals, leading to adverse reactions. This article presents data from a study in which the popliteal lymph node assay (PLNA) was used to assess immune responses in mice treated with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3, and NiCl2) or Cr2O3 particles with metal salts ("A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay" (B.E. Tvermoes, K.M. Unice, B. Winans, M. Kovochich, E.S. Fung, W.V. Christian, E. Donovan, B.L. Finley, B.L. Kimber, I. Kimber, D.J. Paustenbach, 2016) [1]). Data are presented on (1) the chemical characterization of TiO2 particles (used as a particle control), (2) clinical observations in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (3) PLN weight and weight index (WI) in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (4) histological changes in PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (5) percentages of immune cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, and (6) percentages of proliferating cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts.