Morris, Jodie L., Letson, Hayley L., McEwen, Peter C., and Dobson, Geoffrey P. (2025) Delayed Surgery and Adenosine, Lidocaine, and Mg2+Immunomodulatory Therapy Improve Joint Recovery in a Sex-Specific Manner After Anterior Cruciate Ligament Reconstruction in a Rat Model. American Journal of Sports Medicine, 53 (13). pp. 3166-3181.

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Abstract

Background: The timing for anterior cruciate ligament (ACL) reconstruction (ACLR) and strategies to enhance postoperative healing remain controversial, with little known regarding potential sex-specific differences. Perioperative adenosine, lidocaine, and Mg²⁺(ALM) therapy has been shown to promote joint tissue healing in an experimental model of early ACLR; however, an early-late comparison of ALM’s effects on postoperative recovery remains to be investigated. Purpose: To examine the effect of delayed surgery in males and females, and the effect of ALM therapy to augment joint tissue healing. Study Design: Controlled laboratory study. Methods: After noninvasive ACL rupture, adult male (n = 38) and female (n = 39) Sprague-Dawley rats were randomly divided into early (3-day delay) or delayed (14-day delay) ACLR surgery groups, and to receive ALM therapy or saline. During ACLR, an ALM or saline intravenous 1-hour infusion was commenced before first incision, and an intra-articular bolus of ALM or saline was administered at surgery end. Animals were monitored to 28 days postoperatively, and pain, functional recovery, inflammation and joint tissue repair markers, and histopathology were assessed. Results: In the first postoperative week, delayed ACLR was associated with a lymphocyte-driven immune response, with less systemic inflammation compared with early ACLR. This response was associated with faster recovery of body weight, and less joint pain and swelling in both sexes. At 28 days postoperatively, graft and adjacent joint tissue healing appeared more advanced in females than males, regardless of surgical timing. In both sexes, ALM blunted synovial levels of inflammatory mediators (tumor necrosis factor–α and interleukin-1β), reduced injury markers in articular cartilage, and improved graft healing, evidenced from increased expression of tissue repair markers and bony ingrowth at the graft-tunnel interface. Conclusion: Delayed versus early ACLR improves joint recovery, and ALM further augments healing by blunting the early immunoinflammatory response in both sexes, irrespective of surgical timing. Clinical Relevance: Delaying ACLR has the advantage of reducing the pre- and postoperative joint inflammatory environment, with improved outcomes. Perioperative ALM therapy may augment joint healing in both sexes after ACLR.

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