The application of genetically modified mesenchymal stem cells (MSCs) for Anterior Cruciate Ligament (ACL) reconstruction

Luke Villamaria

 Introduction.  The Anterior Cruciate Ligament (ACL) is one of four major ligaments of the knee and plays an important role in stability of the knee upon movement.  ACL rupture is a common sports injury with a  prevalence estimated to be 1 in 3500 in the United States.1 Surgical reconstruction using soft tissue autografts, including hamstring and patellar bone tendon has been the standard of care for a torn ACL.2 However, slow  and incomplete healing of the tendon-to-bone interface has caused low-grade functional rehabilitation.  Thus, gene transfer of therapeutic factors using mesenchymal stem cells (MSCs) has been intensively developed to accelerate the healing of the tendon-to-bone interface.3  More specifically, numerous studies have reported that basic fibroblast growth factor (bFGF) and bone morphogenic protein 2 (BMP2) have had positive effects on the healing process after ACL reconstruction in animal models and could suggest promising therapy for ACL recovery in the future. Methods. Bone marrow was harvested from four New Zealand rabbits and collected together to obtain MSCs.  BMP2, bFGF, EGFP, and BMP2-plus-bFGF were separately inserted into the MSCs using an adenoviral vector.  Thirty-Two New Zealand rabbits underwent ACL reconstruction surgery in which the ACL was excised from femoral and tibial insertions. Based on the different MSC treatments, rabbits were randomly allocated to four groups.  MSCs correlating with groupings were evenly injected into the tendon-to- bone interface of the rabbits and specimens were harvested from each group at 4 and 12 weeks postoperatively.  The specimens were evaluated for new cellular formation, tibial bone tunnel size, and load and stiffness levels.3  Results.  Upon histological and CT evaluation at 12 weeks post-surgery, a transition from initial tendon to non-mineralized fibrocartilage and mineralized cartilage was observed in BMP2, bFGF, and BMP2-plus-bFGF groups.  In addition, the areas of tibial bone tunnel for the BMP2 and BMP2-plus-bFGF groups were substantially smaller than that of the control and EGFP group.  Upon mechanical evaluation, the maximum loads and mean stiffness values for BMP2, bFGF, and BMP2-plus-bFGF groups were significantly higher than that of the control and EGFP groups.  Furthermore, the co-application of BMP2 and bFGF was more efficient and provided more significant bone formation and mechanical properties than either single gene therapy.3  Conclusion.  The application of genetically modified MSCs with growth factors such as BMP2 and bFGF can be effective in altering the structural environment following ACL reconstruction to promote the integration of tendon-bone interface and provide structural and mechanical benefits in animal models. The application of genetically modified MSCs may enhance recovery time for patients with ACL reconstruction and provide more long term structural and mechanical viability to the ACL after injury.

  1. Friedberg, “Anterior Cruciate Ligament Injury.” Anterior Cruciate Ligament Injury. UpToDate, 20 Apr. 2017. Web.
  2. Dong Y, Zhang Q, Li Y, Jiang J, Chen Enhancement of Tendon–Bone Healing for Anterior Cruciate Ligament (ACL) Reconstruction Using Bone Marrow-Derived Mesenchymal Stem Cells Infected with BMP-2. International Journal of Molecular Sciences. 2012;13(12):13605-13620. doi:10.3390/ijms131013605.
  3. Chen B, Li B, Qi Y-J, et al. Enhancement of tendon-to-bone healing after anterior cruciate ligament reconstruction using bone marrow-derived mesenchymal stem cells genetically modified with bFGF/BMP2. Scientific Reports. 2016;6(1). doi:10.1038/srep2