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Plastic response of macrophages to metal ions and nanoparticles in time mimicking metal implant body environment

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The paradigm of using metal biomaterials could be viewed from two sides — treatment of wide spectrum of degenerative diseases, and debris release from materials. After implant insertion, metal nanoparticles (NPs) and ions are released not only upon the first contact with cells/tissues, but in continual manner, which is immediately recognized by immune cells. In this work, the effects of metal nanoparticles (TiO2, Ni) and ions (Ni2+, Co2+, Cr3+, Mo6+) on primary human M0 macrophages from the blood samples of osteoarthritic patients undergoing total arthroplasty were studied in order to monitor immunomodulatory effects on the cells in a real-time format. The highest NiNPs concentration of 10 µg/ml had no effect on any of macrophage parameters, while the Ni2+ ions cytotoxicity limit for the cells is 0.5 mM. The cytotoxic effects of higher Ni2+ concentration revealed mitochondrial network fragmentation leading to mitochondrial dysfunction, accompanied by increased lysosomal activity and changes in pro-apoptotic markers. The suppression of M2 cell formation ability was connected to presence of Ni2+ ions (0.5 mM) and TiO2NPs (10 µg/ml). The immunomodulatory effect of Mo6+ ions, controversially, inhibit the formation of the cells with M1 phenotype and potentiate the thread-like shape M2s with increased chaotic cell movement. To summarize, metal toxicity depends on the debris form. Both, metal ions and nanoparticles affect macrophage size, morphological and functional parameters, but the effect of ions is more complex and likely more harmful, which has potential impact on healing and determines post-implantation reactions.

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The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.


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This study was funded by The Ministry of Health Foundation under the project no. NU20-08–00149.

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Authors and Affiliations



All authors contributed to the study conception and design. Patient sample collection was performed by Jan Emmer, Tomas Tomas, Jan Burda and Ludek Ryba. Material preparation, data collection and analyses were performed by Polina Navratilova, Tomas Loja, Jana Veverkova and Lucie Valkova. The first draft of the manuscript was written by Polina Navratilova and Monika Pavkova Goldbergova and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Tomas Tomas.

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Ethics approval

In this study, the whole blood samples obtained from osteoarthritic patients were used. This study was approved by the Ethics Committee of the Faculty of Medicine of Masaryk University (Brno, Czech Republic), the Ethics Committee of the St. Anne’s University Hospital (Brno, Czech Republic) and the Ethics Committee of the University Hospital Brno Bohunice (Brno, Czech Republic).

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Each patient signed an informed consent to participate in this study.

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Each patient signed an informed consent to publish the obtained results.

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The authors declare no competing interests.

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Responsible Editor: Mohamed M. Abdel-Daim

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• High TiO2NP and Ni2+ concentrations cause polarization ratio shift with M1 increase.

• Mo6+ ions potentiate M2 polarization and healing effect.

• Ni2+ cytotoxicity is caused by mitochondria dysfunction and cell-death activation.

• Ni2+ ions cause more complex and harmful effects compared to nanoparticles.

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Navratilova, P., Emmer, J., Tomas, T. et al. Plastic response of macrophages to metal ions and nanoparticles in time mimicking metal implant body environment. Environ Sci Pollut Res 31, 4111–4129 (2024).

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