2025 Theses Doctoral

The Role of the Ligament Sheath in Anterior Cruciate Ligament Maintenance and Repair

Rogot, James

The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee, with over 100,000 ruptures every year, particularly amongst the athlete and active populations. The current gold standard treatment for ACL injuries is a surgical reconstruction, where a tendon graft is used to replace the native ACL. This technique was first developed because the intra-articular (IA) ACL was historically characterized as unable to heal itself when the torn ends were anastomosed together in a primary repair. While effective at preventing excessive anterior translation and varus-valgus rotation of the tibia in relation to the femur, the reconstructive surgery does not fully restore proprioception and mechanical strength of the ACL. Furthermore, injuries often lead to post-traumatic osteoarthritis (PTOA) - a long-term, progressively degenerative disease of the articular cartilage - regardless of surgical intervention to fix the ACL.

To address these shortcomings, innovations in ACL repair technique aimed at preserving the native ACL tissue have evolved. Specifically, a suture-based repair method called Bridge Enhanced ACL Repair (BEAR), that uses a platelet-rich biomaterial to bridge the ruptured ligament ends, has resurrected clinical interest in primary ACL repair. This repair strategy has shown promise in a clinical setting, although not yet superior to the classical reconstruction in preventing PTOA. In the context of developing complementary strategies to promote primary ACL repair, we considered literature reports that primary repair in human and canine models was more successful when the ACL sheath (ACL-s), a loose synovial-like lining the covers the surface of the ACL, is intact.

However, the structure-function relationship of the ACL-s relative to the central ACL core (ACL-c) was previously uncharacterized. Aim 1 will compare the function of the ACL-s and ACL-c in terms of its synovial lineage through differences in RNA sequencing, histology, solute diffusivity, and protein expression.
Cells isolated from the ACL-c have less propensity to migrate than cells from an extra-synovial ligament that may contribute to the disparate healing capacity. The key difference between the native sheath and core environments is the presence of synovial fluid that contains hyaluronic acid (HA), which serves as an IA load bearing and lubricating molecule. While HA injections have been used clinically to lubricate the IA space and prevent painful adhesions, they may also inhibit the formation of focal adhesions in the wound healing process. When the ACL ruptures the ACL-s is violated, exposing the ACL-c to the HA in synovial fluid. We posit that this exposure contributes to the slower migration of fibroblasts and wound healing of the ACL. Aim 2 will explore the negative effects of HA on the wound closure and focal adhesion formation in ACL fibroblasts.

Local supplementation of corticosteroids has been shown to be chondroprotective and may even be a disease-modifying agent against degeneration associated with OA secondary to an ACL rupture. Sustained delivery of a clinically relevant dosage is a challenge in the knee as there is a high clearance rate of solutes from the IA space. Previous work in our laboratory and by others has addressed this shortcoming using drug-loaded degradable polymer microspheres with an extended, steady payload release rate. Aim 3 will propose a biomaterial scaffold that simultaneously recapitulates the ACL-s following a rupture and co-localizes corticosteroid sustained releasing microspheres to address PTOA development. Together these Aims will outline the role of the ACL-s, help elucidate the mechanism(s) that contributes to poor ACL healing, and introduce a dual-purpose biomaterial to enhance ACL regeneration and mitigate long-term degeneration of the knee.