Periprosthetic inflammation is a crucial factor contributing to aseptic loosening, the leading cause of implant failures. Metallic debris, including nanoparticles, sub-micron particles, and ions, plays a central role in triggering inflammatory responses around orthopedic implants. Exposure to the debris activates macrophages via toll-like receptors and nucleotide-binding and oligomerization domain-like receptors, which in turn leads to the production of pro-inflammatory cytokines. This signaling cascade subsequently drives osteoclast activation, resulting in periprosthetic bone loss and, ultimately, implant loosening. Recent research has focused on strategies to prevent aseptic loosening by targeting the inflammation induced by metallic particles/ions. Pharmacological interventions aimed at modulating macrophage activation and inhibiting specific inflammatory pathways have shown promise in reducing osteoclast activity and excessive bone resorption. This review provides a comprehensive overview of the processes involved in the pathogenesis of periprosthetic inflammation, beginning with the release of metallic debris and its recognition by immune cells, followed by the inflammatory reactions that lead to osteoclastogenesis and bone loss. A detailed understanding of these molecular mechanisms is essential for the development of targeted approaches to prevent aseptic loosening, improve long-term patient outcomes, and alleviate the economic burden on healthcare systems.

Department of Pathophysiology Faculty of Medicine Masaryk University 625 00 Brno Czech Republic

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