An Investigation on Biological Modulation on Anterior Cruciate Ligament Reconstruction- treatments with Intra-operative L-ascorbate and Post-operative Glycyl-Histydyl-Lysine Tripeptide.

摘要

Anterior cruciate ligament (ACL) rupture is a very common sport injury resulting in an unstable knee. As a ruptured ACL does not heal, ACL reconstruction (ACLR) is the standard treatment to restore knee function. Poor graft healing is the major cause leading to ACLR failure and excessive knee laxity. There is ample emphasis on "mechanical" solutions to ACLR, but the biological healing process would be more deterministic for ultimate graft incorporation. If this process can be further enhanced, it will reduce the time of maturation of the graft, and hence earlier returns to full activities and sports. In the present study, the possibilities of biological augmentation of graft healing in ACLR were investigated.;In the first part of the study, research focus was put on the establishment of validated functional outcomes with good clinical relevance in a rat model of ACLR. We developed the measurement of anterior-posterior (AP) translational knee laxity for the rat model of ACLR. Moreover, measurement of limb idleness during walking was developed to measure functional impairments due to ACL deficiency in rats, such as knee pain.;In the second part, the effect of biological modulation of anterior cruciate ligament reconstruction was investigated in the same rat model. As the graft degeneration during post-operative inflammatory phase and graft remodeling (ligamentization) are the key processes that affect the graft integrity in ACLR, we propose to modulate graft degeneration by intra-operative irrigation of L-ascorbate (vitamin C) saline; and for the post-inflammatory phase, we also tested the effect of Glycyl-Histydyl-Lysine tripeptide (GHK), a well-known activator of tissue remodeling, to modulate tissue remodeling in ACLR.;From the result of vitamin C study, vitamin C irrigation at all tested doses significantly reduced the extent of post-operative inflammation. At day 42 post-op, the restoration of AP knee laxity was significantly improved with less graft degeneration by 3 mg/ml vitamin C irrigation. There was no significant difference in limb idleness among different groups at day 28 and 42 post injury. From the result of the GHK-Cu study, we found that a treatment regime of 4 weekly intra-articular injections of 50 il GHK-Cu (0.3mg/ml, week 2-5) could significantly improve AP knee laxity at 6 week post-op, but the failure load of the graft complex was not altered. At a longer time point (12 week post-op), knee laxity in both control and GHK-Cu groups were improved but the group difference was no longer significant. Although GHK treatment did not affect limb idleness as compared to control, repeated intra-articular injections caused significant increase in limb idleness. Combined treatments of effective doses of vitamin C (intra-op) and GHK-Cu (2-5 week post op) did not yield further improvement.;Because of the high safety profile, ease of application and potential benefits, further investigations for the clinical use of vitamin C irrigation saline and GHK-Cu supplementation to promote graft healing in ACLR are well supported by the results of this study.