TY - JOUR
T1 - Direct percutaneous gene delivery to enhance healing of segmental bone defects
AU - Betz, Oliver B.
AU - Betz, Volker M.
AU - Nazarian, Ara
AU - Pilapil, Carmencita G.
AU - Vrahas, Mark S.
AU - Bouxsein, Mary L.
AU - Gerstenfeld, Louis C.
AU - Einhorn, Thomas A.
AU - Evans, Christopher H.
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
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U2 - 10.2106/JBJS.E.00464
DO - 10.2106/JBJS.E.00464
M3 - Article
C2 - 16452748
AN - SCOPUS:31844454557
SN - 0021-9355
VL - 88
SP - 355
EP - 365
JO - Journal of Bone and Joint Surgery
JF - Journal of Bone and Joint Surgery
IS - 2
ER -