Early Graft Tunnel Healing After Anterior Cruciate Ligament Reconstruction With Intratunnel Injection of Bone Marrow Mesenchymal Stem Cells and Vascular Endothelial Growth Factor

Abstract

Background:Bone marrow mesenchymal stem cells (BM-MSCs) are multipotent adult stem cells and have become an important source of cells for engineering tissue repair and cell therapy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and contributes fibrous integration between tendon and bone during the early postoperative stage. Both MSCs and VEGF can stimulate cell proliferation, differentiation, and matrix deposition by enhancing angiogenesis and osteogenesis of the graft in the tunnel.Hypothesis:Injection of intratunnel BM-MSCs and VEGF enhances the early healing process of a tendon graft.Study Design:Controlled laboratory study.Methods:In this controlled animal laboratory study, each of 4 groups of rabbits underwent unilateral anterior cruciate ligament (ACL) reconstruction with use of the ipsilateral semitendinosus tendon. The rabbits received intratunnel injection of BM-MSCs and VEGF with a fibrin glue seal covering the distal tunnel at the articular site. Evaluation using magnetic resonance imaging (MRI), collagen type III expression, and biomechanical analyses were performed at 3- and 6-week intervals.Results:All parameters using MRI, collagen type III expression, and biomechanical analysis of pullout strength of the graft showed that application of intratunnel BM-MSCs and VEGF enhanced tendon-to-bone healing after ACL reconstruction.Conclusion:Intratunnel injections of BM-MSCs and VEGF after ACL reconstruction enhanced graft tunnel healing. Overall, the femoral tunnel that received BM-MSCs and VEGF had better advanced healing with increased collagen type III fibers and better outcomes on MRI and biomechanical analysis. MRI is the most reliable tool for clinical use in evaluating stages of ACL healing after reconstruction, since biopsy is an invasive procedure.

Bioactive Tape With BMP-2 Binding Peptides Captures Endogenous Growth Factors and Accelerates Healing After Anterior Cruciate Ligament Reconstruction

“…7 Therefore, GFs that enhance bone healing, such as bone morphogenetic proteins (BMPs), are becoming promising candidates to promote osteointegration of the graft, with special attention being given to the use of BMP-2. 6,9,16,26,28,30,32 However, the administration of soluble GFs is clinically challenging because of their low stability in the body and diffusion-related problems, which lead to the need for supraphysiological concentrations and systemic administration to achieve the desired result. 27 Additionally, Thomopoulos et al 34 showed that the addition of BMP-2 did not improve bone formation and mechanical properties when compared with a control in a canine flexor tendon.…”

Biological modulations to facilitate graft healing in anterior cruciate ligament reconstruction (ACLR), when and where to apply? A systematic review

“…Besides, the fibrin glue applied in the graft-tunnel interface by Setiawati et al. [ 41 ] improved the graft press-fit to the walls of the femoral tunnel and reduced tunnel widening. Fibrin glue [ 42 ] was also useful to blend MSCs from bone to allograft to enhance the effect of MSCs and accelerated the osteointegration.…”

Stem cell therapies in tendon-bone healing

“…They proved that the combination of BMSCs and PRP synergistically stimulates tendon bone healing through stronger signals associated with angiogenesis, bone formation, and in situ tendon generation. Setiawati et al [ 64 ] then tested whether injecting BMSCs and vascular endothelial growth factor (VEGF) into the bone tunnel of rabbits after ACL reconstruction would improve the early healing process of a tendon graft. They found a higher mean collagen type III score, a higher value for the final tensile strength, as well as improved signal intensity for magnetic resonance imaging (MRI) in the group BMSCs + VEGF.…”