Abstract
Many strategies, including various growth factors and gene transfer, have been used to augment healing after anterior cruciate ligament (ACL) reconstruction. The biological environment regulated by the growth factors during the stage of tendon-bone healing was considered important in controlling the integrating process. The purpose of this study was to evaluate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) on healing after ACL reconstruction. BMSCs were infected with an adenoviral vector encoding BMP2 (AdBMP2) or bFGF (AdbFGF). Then, the infected BMSCs were surgically implanted into the tendon-bone interface. At 12 weeks postoperatively, the formation of abundant cartilage-like cells, smaller tibial bone tunnel and significantly higher ultimate load and stiffness levels, through histological analysis, micro-computed tomography and biomechanical testing, were observed. In addition, the AdBMP2-plus-AdbFGF group had the smallest bone tunnel and the best mechanical properties among all the groups. The addition of BMP2 or bFGF by gene transfer resulted in better cellularity, new bone formation and higher mechanical property, which contributed to the healing process after ACL reconstruction. Furthermore, the co-application of these two genes was more powerful and efficient than either single gene therapy.
Highlights
That endogenous bFGF and BMP2 were both found at the tendon-to-bone interface after Anterior cruciate ligament (ACL) reconstruction in a rabbit model[15]: in their findings, bFGF was expressed at the first 3 weeks of graft incorporation, but was absent at the 12 weeks, which contributed to fibrous integration between the tendon and bone via vascularization during the early postoperative phases
This report is the first demonstration of the therapeutic potential of gene therapy using adenoviral-mediated bone marrow-derived mesenchymal stem cells (BMSCs) expressing BMP2 and bFGF for healing after ACL reconstruction
The effects of combinatorial BMP2 and bFGF gene therapy were more powerful than those of single gene therapy in accelerating tendon-to-bone healing. These findings suggest the potential of the co-application of growth factors in gene therapy to biologically and functionally improve the regeneration of the tendon-to-bone interface
Summary
That endogenous bFGF and BMP2 were both found at the tendon-to-bone interface after ACL reconstruction in a rabbit model[15]: in their findings, bFGF was expressed at the first 3 weeks of graft incorporation, but was absent at the 12 weeks, which contributed to fibrous integration between the tendon and bone via vascularization during the early postoperative phases. Low levels of growth factors might be partly responsible for the slow or weak healing responses in the injured tendons. These discoveries indicated that a combination of these beneficial genes might have additive roles to achieve optimal efficacy in the molecular network system of the tendon-bone interface. It was reasonable for us to hypothesize that sustained delivery of bFGF and BMP2 by gene transfer at the tendon-to-bone insertion site could achieve the best biological and biochemical effects on healing after ACL reconstruction. We hypothesized that transplanted cells genetically modified with either bFGF alone or the combination of BMP2 and bFGF would significantly enhance the healing process and that the combined growth factors would achieve the best effects
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