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The main risk factors for aseptic loosening and implant failure are wear and corrosion of metal implants. Despite a passive oxygen layer forming on many implant materials, electrochemical reactions can occur [1]. Oxidation and reduction reactions take place, resulting in a constant exchange of electrons and ions between the metal and the surrounding fluid [2]. The release of metal ions in different oxidation states can be promoted by the acidic pH caused by specific cells [3]. This in turn may have direct effects on the surrounding tissue and its cells [4]. The cytotoxic effects of nickel, cobalt, and chromium are mainly manifested by apoptosis, necrosis, and inhibition of DNA repair mechanisms [2,5]. However, the various metal ions differ in their local and systemic effects [2,3]. It is known that some metallic corrosion products can induce an inflammatory response in the implant periphery [4]. In this context, signal transduction processes influenced by metallic corrosion products may have an impact on cellular differentiation and immune response. The aim of this study is to better evaluate the low-threshold, "adapted" cellular responses.
In the present study, we treated mesenchymal stem/stromal cells (MSC) in vitro with different metal ion concentrations (starting with 10 µM nickel(II) chloride, NiCl2; cobalt(II) chloride, CoCl2, and chromium(III) chloride, CrCL3) and subsequently analyzed cell number and metabolic activity. In addition, the influence of the non-toxic metal ion concentrations (10 and 100 µM) on energy metabolism (more specifically, mitochondrial activity and extracellular acidification) was investigated by the Seahorse Analyzer (Agilent).
When exposed to higher ion concentrations (100 µM and above), the number of cells was reduced over the 3-day period with no evidence of cell death. This decrease correlated with relative metabolic activity (determined by MTS conversion assay). Specific examination of energy metabolism showed a reduction in basal respiration upon treatment with the metal salts CoCl2 and NiCl2. The trivalent chromium salt had no effect on basal respiration. In contrast, extracellular acidification, indicating glycolytic energy metabolism, was shown to be increased by NiCl2 and CoCl2 in a concentration-dependent manner over the course of the 3-day treatment. Again, CrCl3 exposure had no marked effect.
These in vitro results demonstrate that metal ions, as potential corrosion products of metal implants, can have a significant effect on cells even at non-toxic concentrations. Therefore, in order to prevent or treat aseptic loosening, the complex mechanisms of corrosion-induced biological reactions should be fully elucidated.
This work was financially supported by funds from the Rostock University Medical Center (KOBE project "Entzündungsmodulierende Eigenschaften metallischer Korrosionsprodukte") and the European Union as well as the Federal State Mecklenburg-Vorpommern (EFRE project-No. TBI-V-1-141-VBW-116).
References:
1. Matusiewicz, H. et al., Acta Biomater. 10, 2379–2403 (2014)
2. Sansone, V. et al., Clin. Cases Miner Bone Metab. 10, 34–40 (2013)
3. Scharf, B. et al. Sci. Rep. 4, 5729 (2014)
4. Jonitz-Heincke, A. et al. Materials 12, 2771 (2019)
5. Gibon, E. et al. J. Biomed. Mater. Res. B Appl. Biomater. 105, 2162–2173 (2016)
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