Associations of IL-6, COMP, and MMP-3 With Recovery After ACL Injury or Reconstruction: A Systematic Review

This systematic review examines evidence on the associations of interleukin-6 (IL-6), cartilage oligomeric matrix protein (COMP), and matrix metalloproteinase-3 (MMP-3) with recovery-related outcomes following anterior cruciate ligament (ACL) injury or reconstruction. Ten primary studies published between 2010 and 2025 were included. Outcomes encompassed patient-reported function, knee biomechanics, cartilage imaging, inflammatory responses, and longitudinal biomarker changes. Because study populations, specimen types, sampling times, outcomes, and reported effect measures differed substantially, findings were synthesized qualitatively rather than through meta-analysis. COMP findings varied across biomechanical, patient-reported, and imaging outcomes. IL-6 findings primarily concerned inflammatory responses, with limited evidence directly addressing functional recovery. MMP-3 findings were limited and heterogeneous. The review concludes that the available evidence is insufficient to establish these biomarkers as validated predictors of functional recovery after ACL injury or reconstruction. This manuscript is shared as an independent research preprint and has not undergone journal peer review.