Growth Factors and Other New Methods for Graft-Healing Enhancement

Modern intra-articular anterior cruciate ligament (ACL) reconstructive techniques produce clinically stable ligament reconstruction in the majority of cases. In ACL reconstruction, however, the strength of the grafted tendon is reduced in the early phase after surgery, and then it gradually increases. A problem is that this graft remodeling occurs very slowly. The slow graft maturation may result in graft failure or elongation during the postoperative rehabilitation period due to unknown causes. In addition, a firm attachment of a tendon graft to the bone is a significant factor for success in ACL reconstruction. In procedures using a hamstring tendon graft, however, the anchoring strength of the soft tissue in a bone tunnel is the weakest in the femur–graft–tibia complex in the early phase after surgery. To improve these problems after ACL reconstruction in the near future, we should try to develop a new strategy to accelerate the intra-articular and intraosseous remodeling of the tendon graft. This may enable more aggressive rehabilitation and an earlier return to rigorous sports for patients with ACL reconstruction. In this chapter, the authors will review recent studies that are intended to enhance intra-articular and intraosseous graft healing after ACL reconstruction using growth factors, gene therapy, and cell-based therapy.

Basic Knowledge To Enhance the Graft Remodeling in Anterior Cruciate Ligament Reconstruction

In ACL reconstruction, intrinsic fibroblasts of the tendon graft are necrotized immediately after transplantation, and then numerous extrinsic fibroblasts infiltrate the graft with revascularization. Delay et al. reported a clinical case in which the core portion of the patellar tendon graft still remained necrotic even at the 18-month period after ligament reconstruction. On the other hand, biomechanically, the mechanical properties of the graft deteriorate in the early phase after transplantation and then are very gradually restored over a long period.

Concerning the graft deterioration mechanism, the fibroblast necrosis itself does not deteriorate the mechanical properties of the tendon matrix, but extrinsic fibroblasts proliferating after the necrosis reduce the strength properties. In the extrinsic fibroblasts, type III collagen is overexpressed, even under physiological stress in areas where extrinsic fibroblasts infiltrate. In the matrix of the autograft after transplantation, ultrastructurally, fibrils having a diameter less than 90 nm predominantly increase in the graft matrix, and these fibrils with small diameters still remain predominant at the 4-year period after surgery. Such ultrastructural changes due to type III collagen production are considered to be one of the causes of mechanical deterioration of autografts.

What molecular mechanisms control the autograft remodeling? In a rabbit ACL reconstruction model, vascular endothelial growth factor (VEGF) is overexpressed in the extrinsic fibroblasts at 2 weeks after graft implantation, followed by vascular formation at 3 weeks. On the other hand, basic fibroblast growth factor, transforming growth factor (TGF)-β, and platelet-derived growth factor (PDGF) are overexpressed in the autogenous patellar tendon graft used to reconstruct the ACL in the canine model, reaching their greatest expression 3 weeks after implantation. This fact suggests that a complex growth factor network controls the fibroblasts, resulting in remodeling of the graft matrix, and implies that control of the fibroblasts using growth factors is a potential strategy to accelerate the graft remodeling after ACL reconstruction.

Enhancement of Graft Healing with Growth Factors

Intra-articular Healing

Platelet-Derived Growth Factor-BB

It has been known that PDGF-BB enhances proliferation and migration of ligament fibroblasts. Woo et al. and Hildebrand et al. described that 20-μg PDGF-BB is the most effective agent to enhance the extra-articular medial collateral ligament healing in the rabbit. Regarding intra-articular ACL reconstruction, Weiler et al. showed that the PDGF-BB application significantly increased the load to failure and vascular density of the graft at 6 weeks after ACL reconstruction, although they found no significant effects at 24 weeks. Nagumo et al. investigated the effect of PDGF-BB using fibrin sealant as a carrier on the in situ frozen-thawed rabbit ACL, an idealized intra-articular autograft model. They reported that an application of 4-μg PDGF-BB did not significantly affect the mechanical properties of the frozen-thawed ACL at 12 weeks. Therefore the effect of PDGF-BB in ACL reconstruction is controversial.

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