Injury to the anterior cruciate ligament (ACL) is one of the most devastating and frequent injuries of the knee. Surgical reconstruction is the current standard of care for treatment of ACL injuries in active patients. The widespread adoption of ACL reconstruction over primary repair was based on early perception of the limited healing capacity of the ACL. Although the majority of ACL reconstruction surgeries successfully restore gross joint stability, post-traumatic osteoarthritis is commonplace following these injuries, even with ACL reconstruction. The development of new techniques to limit the long-term clinical sequelae associated with ACL reconstruction has been the main focus of research over the past decades. The improved knowledge of healing, along with recent advances in tissue engineering and regenerative medicine, has resulted in the discovery of novel biologically augmented ACL-repair techniques that have satisfactory outcomes in preclinical studies. This instructional review provides a summary of the latest advances made in ACL repair. Cite this article: Bone Joint Res 2014;3:20–31.

The anterior cruciate ligament (ACL) fails to heal after suture repair. One hypothesis for this failure is the premature loss of the fibrin clot, or provisional scaffolding, between the two ligament ends in the joint environment. To test this hypothesis, a substitute provisional scaffold of collagen–platelet rich plasma (PRP) hydrogel was used to fill the ACL wound site at the time of suture repair and the structural properties of the healing ACLs evaluated 4 weeks after surgery. Bilateral ACL transections were performed in five 30‐kg Yorkshire pigs and treated with suture repair. In each animal, one of the repairs was augmented with placement of a collagen–PRP hydrogel at the ACL transection site, while the contralateral knee had suture repair alone. In addition, six control knees with intact ACLs from three additional animals were used as a control group. No postoperative immobilization was used. After 4 weeks the animals underwent in vivo magnetic resonance imaging to assess the size of the healing ACL, followed by biomechanical testing to determine tensile properties. The supplementation of suture repair with a collagen–PRP hydrogel resulted in significant improvements in load at yield, maximum load, and linear stiffness at 4 weeks. We conclude that use of a stabilized provisional scaffold, such as a collagen–PRP hydrogel, to supplement primary repair of the ACL can result in improved biomechanical properties at an early time point. Further studies to determine the long‐term effect of primary repair enhancement are needed. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:81–91, 2007

The anterior cruciate ligament (ACL) of the knee is an intra‐articular ligament that fails to heal after primary repair. The medial collateral ligament (MCL) of the knee is an extra‐articular ligament that heals uneventfully in the majority of cases. Why these two ligaments have such different responses to injury remains unclear. In this article, we address two hypotheses: first, that the histologic response to injury is different in intra‐articular and extra‐articular ligaments, and second, that the response of the intra‐articular ligaments can be altered by placing a collagen–platelet‐rich plasma (collagen‐PRP) hydrogel in the wound site. Wounds were created in extra‐articular ligaments (MCL and/or patellar ligament) and an intra‐articular ligament (ACL) in canine knees, and the histologic response to injury evaluated at 3 days (n = 3), 7 days (n = 4), 3 weeks (n = 5), and 6 weeks (n = 5). In the 3‐week (n = 5) and 6‐week (n = 5) animals, bilateral central wounds were made in the ACLs and the wounds in one knee of each animal treated with a collagen‐PRP hydrogel while the contralateral side was untreated. Extra‐articular ligament wounds had greater filling of the wound site and increased presence in the wound site of fibrinogen, fibronectin, PDGF‐A, TGF‐β1, FGF‐2, and von Willebrand's factor when compared to intra‐articular ligament wounds. Treatment of the intra‐articular wound with a collagen‐PRP hydrogel resulted in increased filling of the wound site with repair tissue that had similar profiles of growth factor and protein expression to the extra‐articular ligament wounds. The use of a collagen‐PRP scaffold can ameliorate histologic differences noted between healing extra‐articular ligamentous wounds and nonhealing intra‐articular ligamentous wounds. This study supports the hypothesis that premature scaffold failure may play a key role in the normally expected failure of the ACL to heal after injury. Published by Wiley Periodicals, Inc. J Orthop Res 25:1007–1017, 2007

Background: Platelet-rich plasma (PRP) has been increasingly used in sports medicine applications. Platelets are thought to release growth factors important in wound healing, including transforming growth factor (TGF-β1), platelet-derived growth factor (PDGF-AB), and vascular endothelial growth factor (VEGF). However, little is known about the effect of platelet activator choice on growth factor release kinetics. Hypothesis: The choice of platelet activator would affect the timing and level of growth factor release from PRP. Study Design: Controlled laboratory study. Methods: Platelet-rich plasma aliquots were activated with either thrombin or collagen. A control group of whole blood aliquots was clotted with thrombin. Supernatant containing the released growth factors was collected daily for 1 week. Levels of TGF-β1, PDGF-AB, and VEGF were measured using enzyme-linked immunosorbent assay (ELISA). Results: The use of thrombin as an activator resulted in immediate release of TGF-β1 and PDGF-AB, while the collagen-activated PRP clots released similar amounts each day for 5 days. The use of collagen as an activator resulted in an 80% greater cumulative release of TGF-β1 from the PRP aliquots over 7 days (P < .001). Concentrating platelets to 3 times the systemic blood level resulted in a 3-fold higher release of TGF-β1, 2.5-fold greater release of PDGF, and 5-fold greater release of VEGF (all P < .0001) when compared with whole blood control clots, but no significant differences in the timing of release were noted. Conclusion: These experiments demonstrated that the choice of platelet activator can significantly influence the release kinetics of cytokines from PRP, with thrombin resulting in an immediate release and collagen having a more sustained release pattern. Clinical Relevance: The level and rate of growth factor release depends on the selected platelet activator, a factor that should be considered when selecting a PRP system for a given application.

The anterior cruciate ligament (ACL) of the knee fails to heal after primary repair. Here we hypothesize that a beneficial biologic repair response can be induced by placing a collagen‐platelet rich plasma (collagen‐PRP) material into a central ACL defect. A collagen‐PRP scaffold was used to treat a central ACL defect in vivo. In the first experiment, the histologic response in treated and untreated defects was evaluated at 3 (n = 5) and 6 weeks (n = 5). In the second experiment, biomechanical testing of the treated ligaments (n = 8) was performed at 6 weeks and compared with the results of biomechanical testing of untreated defects at the same time‐point (n = 6). The percentage filling of the defects in the treated ACLs was significantly higher at both the 3‐ and 6‐week time‐points when compared with the untreated contralateral control defects (50 ± 21% vs. 2 ± 2% at 3 weeks, and 43 ± 11% vs. 23 ± 11 at 6 weeks; all values mean ± SEM. Biomechanically, the treated ACL defects had a 40% increase in strength at 6 weeks, which was significantly higher than the 14% increase in strength previously reported for untreated defects (p < 0.02). Placement of a collagen‐PRP bridging scaffold in a central ACL defect can stimulate healing of the ACL histologically and biomechanically. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:820–830, 2006

Background: The anterior cruciate ligament (ACL) fails to heal after traumatic rupture. Furthermore, large-animal models have recently shown that 1-month functional ACL healing is augmented after suture repair when a bioactive scaffold is placed in the tear site. Hypothesis: At the time of suture repair, placement of a bioactive scaffold in the ACL wound site would improve the structural properties of the tissue. Study Design: Controlled laboratory study. Methods: Twenty-seven knees in immature pigs underwent ACL transection and suture repair. A collagen-platelet composite (CPC) was used to supplement the repair in 14 knees. Knees were harvested at 4 weeks, 6 weeks, and 3 months. Mechanical testing and histologic analysis were performed. Results: The addition of a CPC to a suture repair resulted in improvements in yield load and linear stiffness of the repair tissue at 3 months, as well as a significant increase in cell density. A reduction in yield load and stiffness occurred at the 6-week time point in both groups, a phase when revascularization was noted. Conclusion: The addition of a CPC to a suture repair enhanced the structural properties of the ACL, and the improvement was associated with increased cellularity within the healing ligament. Clinical Relevance: The addition of a bioactive scaffold to the wound site improved the functional healing of the ACL after suture repair. The decreased repair strength during revascularization may indicate a need to protect the repair site through this period.