Effect of a novel nonviral gene delivery of BMP-2 on bone healing.

P Schwabe,J Eberhart,B Wildemann,G Schmidmaier,K Dähn,A Stemberger,R Ganzert,S Greiner,C Plank

doi:10.1100/2012/560142

Abstract

Background. Gene therapeutic drug delivery approaches have been introduced to improve the efficiency of growth factors at the site of interest. This study investigated the efficacy and safety of a new nonviral copolymer-protected gene vector (COPROG) for the stimulation of bone healing. Methods. In vitro, rat osteoblasts were transfected with COPROG + luciferase plasmid or COPROG + hBMP-2 plasmid. In vivo, rat tibial fractures were intramedullary stabilized with uncoated versus COPROG+hBMP-2-plasmid-coated titanium K-wires. The tibiae were prepared for biomechanical and histological analyses at days 28 and 42 and for transfection/safety study at days 2, 4, 7, 28, and 42. Results. In vitro results showed luciferase expression until day 21, and hBMP-2-protein was measured from day 2 – day 10. In vivo, the local application of hBMP-2-plasmid showed a significantly higher maximum load after 42 days compared to that in the control. The histomorphometric analysis revealed a significantly less mineralized periosteal callus area in the BMP-2 group compared to the control at day 28. The rt-PCR showed no systemic biodistribution of luciferase RNA. Conclusion. A positive effect on fracture healing by nonviral BMP-2 plasmid application from COPROG-coated implants could be shown in this study; however, the effect of the vector may be improved with higher plasmid concentrations. Transfection showed no biodistribution to distant organs and was considered to be safe.

Highlights

Gene therapeutic drug delivery approaches have been introduced to improve the efficiency of growth factors at the site of interest
A positive effect on fracture healing by nonviral BMP-2 plasmid application from copolymer-protected gene vector (COPROG)-coated implants could be shown in this study; the effect of the vector may be improved with higher plasmid concentrations
After discovery of the osteoinductive properties of demineralised bone matrix by Urist and Mclean in 1965 [1] rhBMP-2 and rhBMP-7 are approved by the U.S Food and Drug Administration (FDA) for restricted clinical use in open tibial fractures and anterior spinal fusion

Summary

Introduction

Gene therapeutic drug delivery approaches have been introduced to improve the efficiency of growth factors at the site of interest. This study investigated the efficacy and safety of a new nonviral copolymer-protected gene vector (COPROG) for the stimulation of bone healing. The local application of hBMP-2-plasmid showed a significantly higher maximum load after 42 days compared to that in the control. A positive effect on fracture healing by nonviral BMP-2 plasmid application from COPROG-coated implants could be shown in this study; the effect of the vector may be improved with higher plasmid concentrations. The stimulation of bone healing with application of several recombinant growth factors has moved into scientific and clinical focus. The important issue when accessing growth factors for local bone repair maintains to identify the ideal drug delivery carrier which assures a sufficient concentration and effect of the protein at the application site for the duration of

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Conclusion