Keywords
PANoptosis
Wear particles
Macrophage cell death
Osteoblast dysfunction
Aseptic loosening
Inflammatory bone loss
Orthopedic implant failure
Submitted : 2026-03-15
Accepted : 2026-03-30
Published : 2026-04-14
Abstract
Background: Periprosthetic osteolysis (PPO) is the main cause of aseptic loosening after total joint replacement, which is caused by chronic inflammation induced by wear particles. Apoptosis, pyroptosis, and necroptosis have been studied respectively, but the mechanism of PANoptosis (synergistic inflammatory cell death) integrated by them has not been studied in PPO. Methods: A total of 43 studies that met strict cell death criteria were screened through systematic reviews (PubMed/Web of Sci, 2020–2025). RAW264.7 macrophages were placed under endotoxin-free TC4 titanium particles (100/400 μg/mL, for 24 hours). A rat femoral implant model was established, and Ti particles were injected locally (with a concentration of 5 mg/mL and a volume of 100 μL; there were 8 rats in each group). Analyze the periprosthetic interface membrane tissues of 12 patients with aseptic loosening revision surgery and the control synovial tissues of 8 patients with primary total hip replacement surgery. Detect PANoptosis markers using Western blot and immunohistochemistry (IHC). Results: Through systematic analysis, it can be seen that in all cell types and models, there is consistency in the co-activation of pyroptosis (involving GSDMD, CASP1), apoptosis (involving CASP3, CASP8) and necroptosis (involving p-MLKL, p-RIPK1). In vitro experiments, Ti particles upregulated the three pathway effector molecules in a dose-dependent manner. Exposure to intra-body particles can cause significant periprosthetic bone loss and is accompanied by the expression of PANoptosis markers. In the human interface membrane of failed implants, the level of its effector molecules is higher than that of the control group. Conclusion: This study provides integrated evidence that PANoptosis is activated in wear particle–induced PPO in both experimental and clinical settings. Targeting PANoptosis may become a new method to inhibit inflammation-induced osteolysis and improve the long-term survival rate of implants.
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