Biomarkers of Knee Joint Healing in Adolescents Following Anterior Cruciate Ligament Reconstruction: A Systematic Review

BACKGROUND: Anterior cruciate ligament (ACL) injuries are increasing in prevalence by 2.3% annually in adolescents and have been linked to an increased risk for early-onset knee osteoarthritis (OA). Current ACL rehabilitation guidelines do not directly account for the physiological healing process of the knee joint. Instead, the sole focus is on a patients’ perceived function and their ability to meet functional benchmarks in the lower extremities. The physiological healing process could provide prognostic insight for clinicians and physiotherapists when rehabilitating ACL-injured patients. HYPOTHESES/PURPOSE: The purpose of this systematic review was to identify existing literature to determine i) the most prevalent biomarkers for reflecting knee joint healing in patients after ACL reconstruction (ACLR), and ii) the quantity of these studies which include adolescents. Methods: Following PRISMA guidelines, Medline, Embase, SCOPUS and Web of Science databases were searched up until September 2020. Studies were included if they (1) included participants who had sustained a primary ACL injury and undergone a subsequent ACLR, and (2) measured at least one biomarker of knee joint healing at more than one time point. An NIH quality assessment tool was used to assess study quality. The following data were extracted: participant age; biological sample(s); biomarker(s) analyzed. RESULTS: Seven studies met inclusion criteria for this systematic review (Table 1). Interleukin-6 (IL-6) and C-terminal crosslinking telopeptide of type II collagen (CTX-II) were the most prevalent biomarkers used in the literature (3/7 studies). These biomarkers reflected knee joint healing through consistent elevation and/or gradual decrease following ACLR. Six studies evaluated adult populations (age range; Table 1). One study (average age 19.6±4.5) evaluated the effect of age on biomarker levels of knee joint healing and showed a negative correlation between age and CTX-II concentrations (r=-.769, p < 0.001). Conclusions: This systematic review identified (i) seven studies which evaluated healing using biomarkers following ACLR, (ii) IL-6 and CTX-II were most commonly used, and (iii) there is little research evaluating the physiological healing of the knee joint in any cohorts, in particular adolescent patients following ACLR. Adolescents are unique from adults due to growth and sex hormone variation. Therefore, what little biomarker research completed in adults cannot simply be extrapolated to adolescents. In addition to existing biomechanical rehabilitation tasks, we propose that rehabilitation and return to activity assessment following ACLR in adolescents could be informed by the healing status of the knee, improving outcomes and reducing their risk of early-onset knee OA.