Biological modulations to facilitate graft healing in anterior cruciate ligament reconstruction (ACLR), when and where to apply? A systematic review

Background: When and where to apply the biological modulations is effective to promote healing in the anterior cruciate ligament (ACL) reconstruction remains unclear. Purpose: To perform a systematic review of preclinical animal studies on biological modulation in anterior cruciate ligament reconstruction (ACLR) concerning the time and site of delivery. Study design: Systematic review of controlled laboratory studies. Methods: PubMed, Ovid, and Scopus were searched until December 2020 using a combination of keywords and their synonym to retrieve all animal studies about biological modulation in ACLR. Studies that assessed me-chanical strength after ACLR and compared with negative control were included. The methodological quality of animal studies was evaluated. Results: 33 studies were included in this review and the majority reported mechanical strength improvement. 79 % of studies applied the biological modulations intra-operatively with different delivery systems used. For 21 % of post-operative delivery studies, intermittent delivery was tried. 21 of the included studies directly applied the biological modulations in the bone tunnels, 5 studies applied intra-articularly while 7 studies applied both in the bone tunnels and intra-articular part. Biological modulations applied intra-operatively and those applied in both parts showed better mechanical strength increase. A shift of the failure mode of pull-out from the bone tunnel in the early healing phase, to mid-substance rupture in the later phase was observed in most studies. Conclusion: The improvement of the mechanical strength depends on how the biological modulations (delivery phase, delivery site, delivery form) are applied. The intra-operative delivery showed an overall higher mechanical strength increase and bone tunnel only delivery or intra-articular and bone tunnel both delivery are preferred than intra-articular only delivery. In addition, intra-articular and bone tunnel both delivery can have better mechanical strength increase for a long follow-up time. Thus, intra-operative application with a carrier to control release rate in both parts should be recommended. Further studies are needed to achieve a better healing outcome and more attention should be given to the intra-articular remodeling of the graft along with the tendon bone healing to increase the final mechanical strength. The Translational potential of this article: Here, a systematic review of preclinical evidence of the time, site and the method the biological modulations being applied for ACLR to improve the graft healing would be performed. After reviewing the available studies, a choice of when and where to apply the biological modulations can achieve better mechanical strength after ACLR can be obtained. It provides evidence for both researchers and clinicians to decide when and where to apply the biological modulations can achieve their best effectiveness for ACLR before implementing. Promoting graft healing with targeted time and targeted site may reduce the risk of graft failure, safeguard return to sport.