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Implant-derived CoCrMo alloy nanoparticle disrupts DNA replication dynamics in neuronal cells

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Abstract

The complexity of cobalt-chromium-molybdenum (CoCrMo) nanoparticles generated from the hip modular taper interfaces resulted in inconclusive outcomes on the level of toxicity in orthopedic patients. We used a hip simulator to generate physiologically relevant CoCrMo degradation products (DPs) to demonstrate the variation in the level of toxicity in neurons in comparison to processed degradation products (PDPs). The study outcomes indicate that DP induces a higher level of DNA damage in the form of double- and single-stranded DNA breaks and alkaline labile DNA adducts versus PDPs. The scientific advancements of this study are the following: (i) how DPs mimic more closely to the implant debris from hip implants in terms of bioactivity, (ii) how hip implant debris causes local and systemic issues, and (iii) methods to augment the biologic impact of implant debris. We discovered that DP is bioactive compared with PDP, and this should be considered in the toxicity evaluation related to implants.

Graphical abstract

• The physicochemical characteristics of the CoCrMo is a major factor to consider for implant-related cytotoxicity or genotoxicity experimental design.

• Elevated levels of intracellular ROS induced by the physiologically relevant wear particle are detrimental to the neuronal cells.

• The DP can induce variation in DNA replication dynamics compared to PDP.

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Data availability

The data that support the findings of this study are available from the corresponding author, Divya Bijukumar, upon reasonable request.

References

  • Apel W, Stark D, Stark A, O’Hagan S, Ling J. Cobalt-chromium toxic retinopathy case study. Documenta Ophthalmologica. Advances in Ophthalmology. 2013;126(1):69–78.

    PubMed  Google Scholar 

  • Bhabra G, Sood A, Fisher B, Cartwright L, Saunders M, Evans WH, et al. Nanoparticles can cause DNA damage across a cellular barrier. Nat Nanotechnol. 2009;4(12):876–83.

    Article  CAS  Google Scholar 

  • Bijukumar DR, Segu A, Souza JCM, Li X-j, Barba M, Mercuri LG, Jacobs JJ, Mathew MT. Systemic and local toxicity of metal debris released from hip prostheses: A review of experimental approaches. Nanomedicine: Nanotechnology, Biology and Medicine. 2018a; 14(3):951–963

  • Bijukumar DR, Segu A, Mou Y, Ghodsi R, Shokufhar T, Barba M, et al. Differential toxicity of processed and non-processed states of CoCrMo degradation products generated from a hip simulator on neural cells. Nanotoxicology. 2018b;12(9):941–56.

  • Boardman DR, Middleton FR, Kavanagh TG. A benign psoas mass following metal-on-metal resurfacing of the hip. The Journal of Bone and Joint Surgery. British. 2006;88(3):402–4.

    Article  CAS  Google Scholar 

  • Caicedo MS, Pennekamp PH, McAllister K, Jacobs JJ, Hallab NJ. Soluble ions more than particulate cobalt-alloy implant debris induce monocyte costimulatory molecule expression and release of proinflammatory cytokines critical to metal-induced lymphocyte reactivity. Journal of Biomedical Materials Research. Part A. 2010;93(4):1312–21.

  • Case CP, Langkamer VG, Howell RT, Webb J, Standen G, Palmer M, et al. Preliminary observations on possible premalignant changes in bone marrow adjacent to worn total hip arthroplasty implants. Clinical Orthopaedics and Related Research. 1996;(329 Suppl):S269–79.

  • Charette, R.S., Neuwirth, A.L., and Nelson, C.L., n.d. Arthroprosthetic cobaltism associated with cardiomyopathy. Arthroplasty Today

  • Chastain PD, Nakamura J, Rao S, Chu H, Ibrahim JG, Swenberg JA, et al. Abasic sites preferentially form at regions undergoing DNA replication. FASEB J. 2010;24(10):3674–80.

    Article  CAS  Google Scholar 

  • Chatterjee N, Walker GC. Mechanisms of DNA damage, repair and mutagenesis. Environ Mol Mutagen. 2017;58(5):235–63.

    Article  CAS  Google Scholar 

  • Cheng X, Tian X, Wu A, Li J, Tian J, Chong Y, et al. Protein corona influences cellular uptake of gold nanoparticles by phagocytic and nonphagocytic cells in a size-dependent manner. ACS Appl Mater Interfaces. 2015;7(37):20568–75.

    Article  CAS  Google Scholar 

  • Clark MJ, Prentice JR, Hoggard N, Paley MN, Hadjivassiliou M, Wilkinson JM. Brain structure and function in patients after metal-on-metal hip resurfacing. Am J Neuroradiol. 2014;35(9):1753–8.

    Article  CAS  Google Scholar 

  • Collins AR, Oscoz AA, Brunborg G, Gaivão I, Giovannelli L, Kruszewski M, et al. The comet assay: topical issues. Mutagenesis. 2008;23(3):143–51.

    Article  CAS  Google Scholar 

  • Committee on Mutagenicity of chemicals in food, consumer products and the environment, annual report., 2006.

  • Das M, Yi DK, An SSA. Analyses of protein corona on bare and silica-coated gold nanorods against four mammalian cells. Int J Nanomedicine. 2015;10:1521–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Davies AP, Willert HG, Campbell PA, Learmonth ID, Case CP. An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements. The Journal of Bone and Joint Surgery. American. 2005;87(1):18–27.

    Article  CAS  Google Scholar 

  • Doorn PF, Campbell PA, Worrall J, Benya PD, McKellop HA, Amstutz HC. Metal wear particle characterization from metal on metal total hip replacements: transmission electron microscopy study of periprosthetic tissues and isolated particles. J Biomed Mater Res. 1998;42(1):103–11.

    Article  CAS  Google Scholar 

  • Germain MA, Hatton A, Williams S, Matthews JB, Stone MH, Fisher J, et al. Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro. Biomaterials. 2003;24(3):469–79.

    Article  CAS  Google Scholar 

  • Granchi D, Savarino L, Ciapetti G, Cenni E, Rotini R, Mieti M, et al. Immunological changes in patients with primary osteoarthritis of the hip after total joint replacement. The Journal of Bone and Joint Surgery. British. 2003;85(5):758–64.

    Article  Google Scholar 

  • Gyori BM, Venkatachalam G, Thiagarajan PS, Hsu D, Clement M-V. OpenComet: an automated tool for comet assay image analysis. Redox Biol. 2014;2:457–65.

    Article  CAS  Google Scholar 

  • Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic implants. The Journal of Bone and Joint Surgery. American. 2001;83(3):428–36.

  • Hallab NJ, Anderson S, Caicedo M, Skipor A, Campbell P, Jacobs JJ. Immune responses correlate with serum-metal in metal-on-metal hip arthroplasty. J Arthroplast. 2004;19(8 Suppl 3):88–93.

    Article  Google Scholar 

  • Ikeda T, Takahashi K, Kabata T, Sakagoshi D, Tomita K, Yamada M. Polyneuropathy caused by cobalt-chromium metallosis after total hip replacement. Muscle Nerve. 2010;42(1):140–3.

    Article  Google Scholar 

  • Lynch I, Salvati A, Dawson KA. Protein-nanoparticle interactions: what does the cell see? Nat Nanotechnol. 2009;4:546–7.

    Article  CAS  Google Scholar 

  • Madl AK, Kovochich M, Liong M, Finley BL, Paustenbach DJ, Oberdörster G. Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants part II: importance of physicochemical properties and dose in animal and in vitro studies as a basis for risk assessment. Nanomedicine. 2015a;11(5):1285–98.

    Article  CAS  Google Scholar 

  • Madl AK, Liong M, Kovochich M, Finley BL, Paustenbach DJ, Oberdörster G. Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants part I: physicochemical properties in patient and simulator studies. Nanomedicine. 2015b;11(5):1201–15.

    Article  CAS  Google Scholar 

  • Moniz S, Hodgkinson S, Yates P. Cardiac transplant due to metal toxicity associated with hip arthroplasty. Arthroplasty Today. 2017;3(3):151–3.

    Article  Google Scholar 

  • Nowsheen S, Yang ES. The intersection between DNA damage response and cell death pathways. Exp Oncol. 2012;34(3):243–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parry MC, Bhabra G, Sood A, Machado F, Cartwright L, Saunders M, et al. Thresholds for indirect DNA damage across cellular barriers for orthopaedic biomaterials. Biomaterials. 2010;31(16):4477–83.

    Article  CAS  Google Scholar 

  • Ritz S, Schöttler S, Kotman N, Baier G, Musyanovych A, Kuharev J, et al. Protein corona of nanoparticles: distinct proteins regulate the cellular uptake. Biomacromolecules. 2015;16(4):1311–21.

    Article  CAS  Google Scholar 

  • Rizzetti MC, Liberini P, Zarattini G, Catalani S, Pazzaglia U, Apostoli P, et al. Loss of sight and sound. Could it be the hip? Lancet (London, England). 2009;373(9668):1052.

    Article  Google Scholar 

  • Savarino L, Granchi D, Ciapetti G, Stea S, Donati ME, Zinghi G, et al. Effects of metal ions on white blood cells of patients with failed total joint arthroplasties. J Biomed Mater Res. 1999;47(4):543–50.

    Article  CAS  Google Scholar 

  • Schins RPF, Knaapen AM. Genotoxicity of poorly soluble particles. Inhalation Toxicology. 2007;19(sup1):189–98.

    Article  CAS  Google Scholar 

  • Smith PJ, Giroud M, Wiggins HL, Gower F, Thorley JA, Stolpe B, et al. Cellular entry of nanoparticles via serum sensitive clathrin-mediated endocytosis, and plasma membrane permeabilization. Int J Nanomedicine. 2012;7:2045–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Srinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD. ROS and the DNA damage response in cancer. Redox Biol. 2019;25:101084.

    Article  CAS  Google Scholar 

  • Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metals toxicity and the environment. EXS. 2012;101:133–64.

    PubMed  PubMed Central  Google Scholar 

  • Tower SS. Arthroprosthetic cobaltism associated with metal on metal hip implants. BMJ. 2012;344:e430.

    Article  Google Scholar 

  • Wang, Y., Chastain, P., Yap, P.-T., Cheng, J.-Z., Kaufman, D., Guo, L., and Shen, D., 2011. Automated DNA fiber tracking and measurement. In: 2011 IEEE International Symposium on Biomedical Imaging: From Nano to Macro. Presented at the 2011 IEEE International Symposium on Biomedical Imaging: From Nano to Macro, 1349–1352.

  • Zhang Y. Cell toxicity mechanism and biomarker. Clinical and Translational Medicine. 2018;7:34.

    Article  Google Scholar 

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Acknowledgments

The authors acknowledge the financial support provided by the Blazer Foundation for the Nanomedicine Research Lab at the Department of Biomedical Sciences, UIC College of Medicine at Rockford. The authors also acknowledge NIH RO3-R03NS111554 and the Department of Health Science Education (UIC-Rockford) funding for financial support. In addition, the work is financially supported by the Masters in Biotechnology (MBT) program at the Department of Biomedical Sciences at Rockford.

Funding

This work was supported by NIH RO3-R03NS111554 and the Department of Health Science Education (UIC-Rockford) and MBT program, UIC College of Medicine at Rockford.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL, 61107, USA

    Divya Bijukumar, Abhijith Segu, Paul Chastain II & Mathew T. Mathew

  2. Department of Health Sciences Education, University of Illinois College of Medicine at Rockford, Rockford, IL, 61007, USA

    Paul Chastain II

  3. Department of Orthopedics, Rush University Medical Center, Chicago, IL, 61107, USA

    Mathew T. Mathew

Authors
  1. Divya Bijukumar
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  2. Abhijith Segu
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  3. Paul Chastain II
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  4. Mathew T. Mathew
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Abhijith Segu and Paul Chastain. The first draft of the manuscript was written by Divya Bijukumar and Abhijith Segu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Divya Bijukumar.

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Bijukumar, D., Segu, A., Chastain, P. et al. Implant-derived CoCrMo alloy nanoparticle disrupts DNA replication dynamics in neuronal cells. Cell Biol Toxicol 37, 833–847 (2021). https://doi.org/10.1007/s10565-020-09577-7

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