Journal of experimental orthopaedics · 2026
Patients with cyclops syndrome exhibit elevated synovial fluid interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels and disorganized collagen remodelling within the lesion: A histological and molecular study.
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Morici Luca, Tscholl Philippe M, Skau Eline L, Eyer Klaus, Clerc Lukas, Gauthier Morgan, Nikolic Ines
Аннотация
PURPOSE: Cyclops syndrome is a clinically relevant complication of anterior cruciate ligament (ACL) reconstruction characterized by the formation of a fibrotic nodule (cyclops lesion) that causes extension loss and often requires a revision surgery. Biological mechanisms underlying lesion formation remain poorly understood. The purpose of this study is to characterize the tissue architecture, cellular composition, inflammatory profile and single-cell cytokine secretion patterns of patient-derived biopsies to gain mechanistic insight into disease pathogenesis.
METHODS: This prospective observational comparative study included three patient groups: patients undergoing revision surgery for cyclops syndrome (n = 10), patients undergoing primary ACL reconstruction with subsequent successful recovery (n = 10) and patients undergoing revision surgery for ACL graft re-rupture (n = 2). Tissue biopsies and synovial fluid samples were collected intraoperatively and used for histological, cellular and cytokine analyses.
RESULTS: Histological analyses demonstrated that cyclops lesions exhibited disorganized collagen architecture, neovascularization and infiltration of immune cells. Flow cytometry identified activated FAP+CD54+ fibroblasts as the predominant cell population (~80%), accompanied by CD206+ pro-fibrotic macrophages. Synovial fluid from cyclops patients contained significantly elevated IL-6 and TNF-α concentrations, whereas IL-1β levels did not differ among the groups. Looking at the cells, single-cell cytokine secretion profiles revealed detectable IL-6 secretion in up to 11% of cells, while IL-1β, TNF-α and TGF-β secretion were not detected, indicating that at least the source of TNF-α has to be found elsewhere.
CONCLUSIONS: Our preliminary data from a small patient cohort show that cyclops syndrome may be observed as an active fibro-inflammatory process rather than a purely mechanical post-operative complication. Patient-derived samples revealed persistent inflammatory activity characterized by immune cell infiltration, elevated levels of pro-inflammatory mediators, and sustained activation of fibroblasts. The absence of detectable TGF-β secretion despite established fibrosis suggests that lesion persistence may be maintained through alternative fibrotic pathways (non-TGF-β/non-canonical pathways), which requires further investigation.
LEVEL OF EVIDENCE: N/A.
METHODS: This prospective observational comparative study included three patient groups: patients undergoing revision surgery for cyclops syndrome (n = 10), patients undergoing primary ACL reconstruction with subsequent successful recovery (n = 10) and patients undergoing revision surgery for ACL graft re-rupture (n = 2). Tissue biopsies and synovial fluid samples were collected intraoperatively and used for histological, cellular and cytokine analyses.
RESULTS: Histological analyses demonstrated that cyclops lesions exhibited disorganized collagen architecture, neovascularization and infiltration of immune cells. Flow cytometry identified activated FAP+CD54+ fibroblasts as the predominant cell population (~80%), accompanied by CD206+ pro-fibrotic macrophages. Synovial fluid from cyclops patients contained significantly elevated IL-6 and TNF-α concentrations, whereas IL-1β levels did not differ among the groups. Looking at the cells, single-cell cytokine secretion profiles revealed detectable IL-6 secretion in up to 11% of cells, while IL-1β, TNF-α and TGF-β secretion were not detected, indicating that at least the source of TNF-α has to be found elsewhere.
CONCLUSIONS: Our preliminary data from a small patient cohort show that cyclops syndrome may be observed as an active fibro-inflammatory process rather than a purely mechanical post-operative complication. Patient-derived samples revealed persistent inflammatory activity characterized by immune cell infiltration, elevated levels of pro-inflammatory mediators, and sustained activation of fibroblasts. The absence of detectable TGF-β secretion despite established fibrosis suggests that lesion persistence may be maintained through alternative fibrotic pathways (non-TGF-β/non-canonical pathways), which requires further investigation.
LEVEL OF EVIDENCE: N/A.