In a rat study, giving the copper‑bound peptide GHK‑Cu directly into the knee joint after ACL surgery helped the graft heal a bit faster in the first six weeks, making the joint a little more stable and the graft a bit stiffer. However, these benefits vanished by twelve weeks once the injections stopped, and the grafts still broke in the same way as the control group.

After anterior cruciate ligament reconstruction (ACLR), the biological healing of the graft is a rate-limiting step which can contribute to graft failure. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu) is a well-known activator of tissue remodeling. We investigated whether GHK-Cu can improve graft healing following ACLR. Seventy-two rats underwent unilateral ACLR were randomized to saline, 0.3 or 3 mg/ml GHK-Cu groups (n = 24). Post-operational intra-articular injections were given from week 2, once a week, for 4 weeks. Gait analysis was performed pre-injury and at harvesting time. At 6 or 12 weeks post-operation, knee specimens were harvested for knee laxity test, graft pull-out test, and histology. At 6 weeks post-ACLR, GHK-Cu groups resulted in a smaller side-to-side difference in knee laxity as compared to the saline group (p = 0.009), but there was no significant difference at 12 weeks post-operation. The graft complex in the 0.3 mg/ml GHK-Cu group had higher stiffness than saline group at 6 weeks post-operation (p = 0.026), but there was no significant difference in ultimate load, gait parameters, and histological scores among treatment groups. All grafts failed mid-substance during pull-out test. Intra-articular supplementation with a bioactive small molecule GHK-Cu improved graft healing following ACLR in rat, but the beneficial effects could not last as treatment discontinued.