Synovial Fluid Biomarkers Associated With Anterior Cruciate Ligament Injury and Reconstruction: A Systematic Review

Background: Synovial fluid biomarkers reflect the inflammatory response after joint injury and surgery. Previous studies have identified synovial fluid biomarker concentrations in the knee after both anterior cruciate ligament (ACL) injury and ACL reconstruction (ACLR). Purpose: To systematically review the literature to summarize reported changes in synovial fluid biomarkers and their concentrations after acute ACL injury/ACLR. Study Design: Systematic review; Level of evidence, 4. Methods: Studies published in the PubMed, EMBASE, and the Cochrane Library databases reporting in English on humans sustaining ACL tears and undergoing ACLR from inception to August 2025 were identified and included if postinjury/preoperative and/or postoperative concentrations of synovial fluid biomarkers were reported. Study quality, risk of bias, and heterogeneity were evaluated. Results: A total of 44 studies were identified, comprising 2428 patients and 4721 synovial fluid profiles. Postinjury (pre-ACLR) biomarker concentrations were reported across 38 studies (N = 2101 patients). Nineteen studies (N = 676 patients) reported mean biomarker concentrations post-ACLR. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-8 (IL-8), interleukin-10 (IL-10), and interleukin-1 receptor antagonist (IL-1Ra) were reported in ≥10 studies (22 studies postinjury; 11 studies post-ACLR). Mean concentrations of all 6 biomarkers were elevated immediately after both injury (pre-ACLR) and surgery (post-ACLR), followed by progressive decrease. Increased mean concentrations for TNF-α and IL-8 were reported from 3 to 6 months after ACL injury (pre-ACLR), with IL-6, TNF-α, and IL-8 remaining elevated over 1 year after injury. Increased mean concentrations of IL-6 and IL-8 were reported from 3 to 6 months after ACLR, with IL-6 and IL-8 remaining elevated over 1 year post-ACLR. Methodological quality was moderate based on Methodological Index for Non-Randomized Studies scores (overall mean, 17.3 range, 10-23). Randomized studies demonstrated low to moderate risk of bias according to the Risk of Bias 2 assessment. Considerable heterogeneity in biomarker concentrations was observed. Conclusion: Immediate elevation of synovial fluid levels of proinflammatory biomarkers occurs after ACL injury and ACLR, followed by a progressive, yet variable, decrease over 1 year. These biomarkers reflect the underlying inflammatory and healing responses within the knee. However, their correlation with subjective and objective measures of knee function, as well as with the risk of secondary osteoarthritis, is unknown.