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.

Authors

Luca Morici, Philippe M Tscholl, Eline L Skau, Klaus Eyer, Lukas Clerc, Morgan Gauthier, Ines Nikolic

Published in

Journal of experimental orthopaedics. Volume 13. Issue 4. Pages e70953. Epub Oct 17, 2026.

Abstract

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.
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.
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.
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.
N/A.

PMID:
42893231
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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