Sonoporation increases therapeutic efficacy of inducible and constitutive BMP2/7 in vivo gene delivery

Georg A Feichtinger*, Anna T Hofmann, Paul Slezak, Sebastian Schuetzenberger, Martin Kaipel, Ernst Schwartz, Anne Neef, Nikolitsa Nomikou, Thomas Nau, Martijn van Griensven, Anthony P McHale, Heinz Redl

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


An ideal novel treatment for bone defects should provide regeneration without autologous or allogenous grafting, exogenous cells, growth factors, or biomaterials while ensuring spatial and temporal control as well as safety. Therefore, a novel osteoinductive nonviral in vivo gene therapy approach using sonoporation was investigated in ectopic and orthotopic models. Constitutive or regulated, doxycycline-inducible, bone morphogenetic protein 2 and 7 coexpression plasmids were repeatedly applied for 5 days. Ectopic and orthotopic gene transfer efficacy was monitored by coapplication of a luciferase plasmid and bioluminescence imaging. Orthotopic plasmid DNA distribution was investigated using a novel plasmid-labeling method. Luciferase imaging demonstrated an increased trend (61% vs. 100%) of gene transfer efficacy, and micro-computed tomography evaluation showed significantly enhanced frequency of ectopic bone formation for sonoporation compared with passive gene delivery (46% vs. 100%) dependent on applied ultrasound power. Bone formation by the inducible system (83%) was stringently controlled by doxycycline in vivo, and no ectopic bone formation was observed without induction or with passive gene transfer without sonoporation. Orthotopic evaluation in a rat femur segmental defect model demonstrated an increased trend of gene transfer efficacy using sonoporation. Investigation of DNA distribution demonstrated extensive binding of plasmid DNA to bone tissue. Sonoporated animals displayed a potentially increased union rate (33%) without extensive callus formation or heterotopic ossification. We conclude that sonoporation of BMP2/7 coexpression plasmids is a feasible, minimally invasive method for osteoinduction and that improvement of bone regeneration by sonoporative gene delivery is superior to passive gene delivery.

Original languageEnglish
Pages (from-to)57-71
Number of pages15
JournalHuman Gene Therapy Methods
Issue number1
Publication statusPublished - Feb 2014
Externally publishedYes


  • Animals
  • Bone Morphogenetic Protein 2/genetics
  • Bone Morphogenetic Protein 7/genetics
  • Bone Regeneration
  • Bone and Bones/diagnostic imaging
  • Doxycycline/pharmacology
  • Female
  • Fractures, Bone/therapy
  • Gene Expression/drug effects
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors/genetics
  • Male
  • Mice
  • Mice, Nude
  • Muscle, Skeletal/pathology
  • Osteogenesis
  • Rats
  • Rats, Sprague-Dawley
  • Sonication
  • Stem Cell Niche
  • Tomography, X-Ray Computed


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