Evaluating the Potential Cardiac Toxicity of Implant-Derived Metal Ions and Particles Using H9C2 and Stem Cell Model

Abstract

Abstract Total hip replacement (THR) remains a widely performed orthopedic procedure; however, degradation of cobalt-chromium-molybdenum (CoCrMo) alloy components can release leachates containing metallic ions and nanoparticles into the body over time. These metal degradation products (DPs) have been associated with local and systemic toxicity to the vital organs, including potential cardiac complications. This study investigated the biological effects of CoCrMo particles (CoCrMo P), cobalt ions (Co2+), and chromium ions (Cr3+) on cardiac tissue through a combination of in vitro and in vivo approaches focused on three primary aims: (i) in vitro toxicity evaluation using H9C2 myoblasts under static, dynamic, and all-trans retinoic acid (ATRA)-induced cardiac-like conditions; (ii) assessment of functional and structural toxicity in iPSC-derived cardiomyocytes; and (iii) evaluation of particle deposition and inflammation in cardiac tissues of a mouse model treated with DPs. From our investigation, we observed the following: (i) In vitro testing revealed that metal degradation products induced dose- and time-dependent cytotoxicity in H9C2 cells, with CoCrMo particles consistently producing the most severe effects. Dynamic culturing intensified these outcomes, suggesting that fluid shear may exacerbate DP toxicity compared with static conditions. ATRA-treated H9C2 cells expressed cTnT, thereby enabling cardiomyocyte-relevant observations of damage. (ii) In iPSC-derived cardiomyocytes, CoCrMo particle exposure disrupted calcium handling and increased contraction frequency, with accompanying morphological deterioration. (iii) In vivo testing revealed that mice injected with CoCrMo particles showed increased CD3-positive T-cell infiltration and signs of particle deposition in cardiac tissue. These findings support the hypothesis that long-term exposure to metal degradation products may contribute to adverse cardiac effects, demanding further investigation into implant biocompatibility and systemic impact.