The Effect of Stem Cell-Based Therapies on Tendon Graft Healing and Ligamentization after Anterior Cruciate Ligament Reconstruction: A Systematic Review.

Introduction: Successful return to sport after anterior cruciate ligament reconstruction (ACLR) depends on rapid, robust "ligamentization" of the tendon graft. Preclinical and early clinical studies suggest that biologic augmentation with stem cells may accelerate this remodeling process, but the magnitude and consistency of benefit remain uncertain. Therefore, this study systematically reviewed and quantitatively synthesized the available evidence on the efficacy of stem cell-based interventions in enhancing intra-articular ligamentization of tendon grafts following primary ACLR.

Methods: MEDLINE (Ovid), Embase, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and medRxiv were searched from inception to 1 April 2025. Controlled animal or human studies comparing stem-cell therapy (any source or delivery) with standard ACLR were eligible.

Results: Fourteen studies (10 animal, 4 early-phase human; n = 563 specimens/patients) met inclusion criteria. Pooled analysis of four biomechanical studies (n = 150 grafts) demonstrated a large, significant improvement in load-to-failure (SMD = 1.22, 95 % CI 0.89-1.55; p < 0.001; I² = 12 %).

Discussions: Stem cell augmentation improves biomechanical and histological graft maturation in ACL reconstruction, but current subgroup findings are limited by small human study sizes, a lack of patient-centered functional outcomes, and high variability, which restricts clinical applicability and generalizability.

Conclusions: Stem cell therapies, particularly mesenchymal stem cells delivered around or within the graft, improve tendon graft healing and ligamentization robustly in animal models; early safety signals in humans are promising, but definitive clinical benefit remains to be established in adequately powered randomized trials. Routine clinical adoption should await clearer evidence.