Systemic Interaction

The systemic increase in metal ions following joint arthroplasty can lead to various inflammatory reactions distal to the implant. However, the mechanisms leading to these systemic reactions remain elusive. To address this scientific question, we will modify the murine calvaria model using a particle release system, which, over the course of several weeks, will allow for the systemic increase of serum metal ion concentrations. Our goal is to identify changes not only in the central, peripheral, and mucosal immune system but also in distal long bones and in joints already affected by osteoarthritis. These changes will then be correlated with local wear particle corrosion products. The experimental methods used cover state-of-the-art single-cell RNA sequencing, imaging via µCT to quantify bone loss, histomorphometry to assess alterations in the osteoblast-osteoclast balance, and biochemical assays to evaluate the bone formation and bone resorption metabolites in the serum. Systemic cytokines will be quantified via bead-based multiplex methods, and the cellular immune landscape will be monitored via spectral flow cytometry.

Several case reports have described cardiotoxicity induced by wear and corrosion products, which may result in permanent myocardial damage. Yet, the available data on this topic are unsatisfactory and partly contradictory. Against this background, this subproject aims to address the issue of cardiotoxic effects caused by metallic wear particles and corrosion products through both in vitro and in vivo approaches. In vitro, human cardiomyocytes derived from induced pluripotent stem cells (iPSCs) will be exposed to metal ions and particles as well as to pro-inflammatory conditioned medium from other, corrosion product-stimulated cell types. Subsequently, electrophysiological and pharmacological analyses and single-cell transcriptomics will be conducted. Protein levels will be assessed using flow cytometry and super-resolution immunofluorescence microscopy. Omic analyses in combination with deep learning will allow prospective statements. Additionally, the approach will be transferred to small animal models using hemodynamic and telemetric examinations, as well as small animal cardiac imaging in vivo.

In contrast to local inflammatory processes, systemic reactions due to increased concentrations of wear products have rarely been investigated, particularly with regard to the central and peripheral nervous system. Metal ions are generally considered to be neurotoxic. It has been described that divalent ions promote the formation of reactive oxygen species and can trigger DNA damage in brain tissue. Further, (nano/micro) wear particles can also damage nerve cells. Alternatively, a local tissue reaction can trigger systemic inflammation. This involves the release of inflammatory mediators, the (region-specific) activation of local inflammatory cells (including microglial cells) or damage to the blood-brain barrier. This project will systematically investigate potential differential long-term effects of wear and corrosion products on the peripheral and central nervous system. Special focus is placed on the differentiation of direct vs. indirect (via immune cells/inflammatory mediators) effects as well as the respective understanding of the underlying mechanisms.