BMP-7 and Bone Regeneration: Evaluation of Dose-Response in a Rodent Segmental Defect Model.

Abstract

To develop and validate a translatable and reproducible rodent critical-sized defect (CSD) model and to determine the optimal dose of recombinant human bone morphogenetic protein (BMP)-7 required to consistently heal the CSD in the new model. Rats with 6-mm CSDs stabilized with a commercial radiolucent plate and screws with angular stability were randomly assigned to 4 treatment groups with varied doses of recombinant human BMP-7 (25, 50, 75, and 100 μg) on absorbable collagen sponge and a single control group (absorbable collagen sponge alone). Bone formation was evaluated by radiographs, micro-computed tomography, histology, and biomechanics. All the rats treated with 100 μg of BMP-7 with CSDs were united by 4 weeks and all 75- and 50-μg-group rats united by 6 weeks. None of the animals in the 25-μg BMP-7 group or the control group were healed at the time of killing. Bone volume, bone mineral density, the ratio of bone volume to total volume, stiffness, and ultimate load to failure were maximal in the 50-μg group. Total callus volume progressively increased with increasing BMP dose. Histologic analysis demonstrated increased callus width with increasing BMP-7 doses above 50 μg, but the bone seemed structurally abnormal. There was a 100% union rate in the 50-, 75-, and 100-μg BMP-7-treated groups. None of the control or 25-μg-dose rats united. The biomechanical data demonstrated that 50 μg of BMP-7 produced the highest mechanical strength in the bone regenerate. These data also suggest that administration of BMP-7 above 50 μg does not improve bone regeneration and actually seems to produce lower quality bone with diminished biomechanical properties.