Direct percutaneous gene delivery to enhance healing of segmental bone defects

Oliver B. Betz, Volker M. Betz, Ara Nazarian, Carmencita G. Pilapil, Mark S. Vrahas, Mary L. Bouxsein, Louis C. Gerstenfeld, Thomas A. Einhorn, Christopher H Evans

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108 Scopus citations

Abstract

Background: Healing of segmental bone defects can be induced experimentally with genetically modified osteoprogenitor cells, an ex vivo strategy that requires two operative interventions and substantial cost. Direct transfer of osteogenic genes offers an alternative, clinically expeditious, cost-effective approach. We evaluated its potential in a well-established, critical-size, rat femoral defect model. Methods: A critical-size defect was created in the right femur of forty-eight skeletally mature Sprague-Dawley rats. After twenty-four hours, each defect received a single, intralesional, percutaneous injection of adenovirus carrying bone morphogenetic protein-2 (Ad.BMP-2) or luciferase cDNA (Ad.lue) or it remained untreated. Healing was monitored with weekly radiographs. At eight weeks, the rats were killed and the femora were evaluated with dual-energy x-ray absorptiometry, micro-computed tomography, histological analysis, histomorphometry, and torsional mechanical testing. Results: Radiographically, 75% of the Ad.BMP-2-treated femora showed osseous union. Bone mineral content was similar between the Ad.BMP-2-treated femora (0.045 ± 0.020 g) and the contralateral, intact femora (0.047 ± 0.003 g). Histologically, 50% of the Ad.BMP-2-treated defects were bridged by lamellar, trabecular bone; the other 50% contained islands of cartilage. The control (Ad.luc-treated) defects were filled with fibrous tissue. Histomorphometry demonstrated a large difference in osteogenesis between the Ad.BMP-2 group (mean bone area, 3.25 ± 0.67 mm2) and the controls (mean bone area, 0.65 ± 0.67 mm2). By eight weeks, the Ad.BMP-2-treated femora had approximately one-fourth of the strength (mean, 0.07 ± 0.04 Nm) and stiffness (mean, 0.5 ± 0.4 Nm/rad) of the contralateral femora (0.3 ± 0.08 Nm and 2.0 ± 0.5 Nm/rad, respectively). Conclusions: A single, percutaneous, intralesional injection of Ad.BMP-2 induces healing of critical-size femoral bone defects in rats within eight weeks. At this time, the repair tissue is predominantly trabecular bone, has normal bone mineral content, and has gained mechanical strength. Clinical Relevance: Direct administration of adenovirus carrying BMP-2 could provide a straightforward and cost-effective treatment for large osseous defects with adequate surrounding soft-tissue support. This local in vivo gene-therapy approach avoids the cost and complexity of ex vivo methods that require artificial scaffolds and autologous cell culture.

Original languageEnglish (US)
Pages (from-to)355-365
Number of pages11
JournalJournal of Bone and Joint Surgery - Series A
Volume88
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Surgery
  • Orthopedics and Sports Medicine

Cite this

Betz, O. B., Betz, V. M., Nazarian, A., Pilapil, C. G., Vrahas, M. S., Bouxsein, M. L., Gerstenfeld, L. C., Einhorn, T. A., & Evans, C. H. (2006). Direct percutaneous gene delivery to enhance healing of segmental bone defects. Journal of Bone and Joint Surgery - Series A, 88(2), 355-365. https://doi.org/10.2106/JBJS.E.00464