Ultrasound-Mediated Gene Delivery Enhances Tendon Allograft Integration in Mini-Pig Ligament Reconstruction

Maxim Bez, Thomas J. Kremen, Wafa Tawackoli, Pablo Avalos, Dmitriy Sheyn, Galina Shapiro, Joseph C. Giaconi, Shiran Ben David, Jess G. Snedeker, Zulma Gazit, Katherine W. Ferrara, Dan Gazit, Gadi Pelled*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Ligament injuries occur frequently, substantially hindering routine daily activities and sports participation in patients. Surgical reconstruction using autogenous or allogeneic tissues is the gold standard treatment for ligament injuries. Although surgeons routinely perform ligament reconstructions, the integrity of these reconstructions largely depends on adequate biological healing of the interface between the ligament graft and the bone. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would lead to significantly improved ligament graft integration. To test this hypothesis, an anterior cruciate ligament reconstruction procedure was performed in Yucatan mini-pigs. A collagen scaffold was implanted in the reconstruction sites to facilitate recruitment of endogenous mesenchymal stem cells. Ultrasound-mediated reporter gene delivery successfully transfected 40% of cells recruited to the reconstruction sites. When BMP-6 encoding DNA was delivered, BMP-6 expression in the reconstruction sites was significantly enhanced. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to significantly enhanced osteointegration in all animals 8 weeks after surgery. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively improve ligament reconstruction in large animals, thereby addressing a major unmet orthopedic need and offering new possibilities for translation to the clinical setting. Ligament injuries occur frequently, substantially hindering routine daily activities and sports participation in patients. In this issue of Molecular Therapy, Bez et al. (2018) show a novel method of gene delivery using ultrasound to accelerate the integration process between implanted ligaments and bones, offering new possibilities in orthopedic surgeries.

Original languageEnglish
Pages (from-to)1746-1755
Number of pages10
JournalMolecular Therapy
Volume26
Issue number7
DOIs
StatePublished - 5 Jul 2018

Bibliographical note

Publisher Copyright:
© 2018 The American Society of Gene and Cell Therapy

Keywords

  • gene therapy
  • regenerative medicine
  • tissue engineering

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