Age-Dependent Variations in Knee Synovial Fluid Biomarker Type and Concentration Predict 5- to 10-Year Outcomes After Anterior Cruciate Ligament Reconstruction

Background: Synovial fluid biomarkers reflect the intra-articular response to an anterior cruciate ligament (ACL) rupture and may provide insight into biological processes associated with posttraumatic joint degeneration. While increasing age has been associated with inferior clinical outcomes after ACL reconstruction, age-dependent differences in biomarker expression and their relationship to longer term outcomes remain unclear. Purpose/Hypothesis: The purpose of this study was to evaluate the association between patient age and preoperative synovial biomarker concentrations after an ACL injury to determine whether age modifies biomarker-outcome relationships at longer term follow-up. The authors hypothesized that increasing age would be associated with an elevated inflammatory response and modify biomarker-outcome associations. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing ACL reconstruction between July 2011 and December 2020 were prospectively enrolled. Synovial fluid was aspirated before incision, and concentrations of proinflammatory and anti-inflammatory biomarkers were quantified. Patients completed patient-reported outcome (PRO) measures, including the visual analog scale for pain, Lysholm scale, Tegner Activity Scale, and Knee injury and Osteoarthritis Outcome Score–Physical Function Short Form, at a minimum of 5 years postoperatively. Multivariable regression assessed associations between age and biomarker concentrations. Conditional process analysis evaluated moderation by symptom duration and mediation by cartilage injury severity. Associations between age and long-term PROs were assessed using multivariable regression and minimal clinically important difference analyses. Results: A total of 100 patients were included (mean age, 30.8 ± 9.5 years). Increasing age was independently associated with lower preoperative synovial TIMP-1 concentrations (β = −0.0775; P = .014). This association was moderated by symptom duration, with significant effects at <3.0 and >8.5 months. Cartilage injury severity did not mediate age-biomarker associations. Increasing age was associated with worse long-term PROs and the decreased likelihood of achieving the minimal clinically important difference for pain, function, and activity. After adjusting for age, higher MIP-1β concentrations were associated with worse functional outcomes, higher MMP-3 concentrations were associated with greater pain, higher TIMP-2 concentrations were associated with lower activity levels, and higher bFGF concentrations were associated with improved physical function. Significant age-dependent interactions were observed for TIMP-1, TIMP-2, and MIP-1β with selected PROs. Age-stratified analysis demonstrated heterogeneous biomarker-outcome associations. Conclusion: Patient age at the time of ACL reconstruction was associated with selective alterations in synovial biomarker expression and long-term clinical outcomes. Age modified the prognostic significance of key biomarkers, highlighting the importance of incorporating age into biomarker interpretation and risk stratification after an ACL injury.