The Role of Biomarkers in Predicting Outcomes of Anterior Cruciate Ligament Reconstruction: A Systematic Review

BACKGROUND: Anterior cruciate ligament (ACL) injury is frequently associated with injuries to other parts of the knee, including the menisci and articular cartilage. After ACL injury and reconstruction, there may be progressive chondral degradation. Biomarkers in blood, urine, and synovial fluid can be measured after ACL injury and reconstruction and have been proposed as a means of measuring the associated cellular changes occurring in the knee. PURPOSE: To systematically review the literature regarding biomarkers in urine, serum, or synovial fluid that have been associated with an outcome measure after ACL reconstruction. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: This review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The MEDLINE, Embase, CINAHL, and Web of Science databases were searched to identify studies published before September 2023 that reported on patients undergoing ACL reconstruction where a biomarker was measured and related to an outcome variable. Of 9360 results, 16 studies comprising 492 patients were included. Findings were reported as descriptive summaries synthesizing the available literature. RESULTS: A total of 45 unique biomarkers or biomarker ratios were investigated (12 serum, 3 urine, and 38 synovial fluid; 8 biomarkers were measured from >1 source). Nineteen different outcome measures were identified, including the International Knee Documentation Committee Subjective Knee Form, Knee injury and Osteoarthritis Outcome Score, numeric pain scores, radiological outcomes (magnetic resonance imaging and radiography), rates of arthrofibrosis and cyclops lesions, and gait biomechanics. Across the included studies, 17 biomarkers were found to have a statistically significant association (P < .05) with an outcome variable. Serum interleukin 6 (s-IL-6), serum and synovial fluid matrix metalloproteinase-3 (s-MMP-3 and sf-MMP-3), urinary and synovial fluid C-terminal telopeptide of type 2 collagen (u-CTX-II and sf-CTX-II), and serum collagen type 2 cleavage product (s-C2C) showed promise in predicting outcomes after ACL reconstruction, specifically regarding patient-reported outcome measures (s-IL-6 and u-CTX-II), gait biomechanical parameters (s-IL-6, sf-MMP-3, s-MMP-3, and s-C2C), pain (s-IL-6 and u-CTX-II), and radiological osteoarthritis (ratio of u-CTX-II to serum procollagen 2 C-propeptide). CONCLUSION: The results highlight several biomarkers that have been associated with clinically important postoperative outcome measures and may warrant further research to understand if they can provide meaningful information in the clinical environment.