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Biopatterned Recombinant Human Bone Morphogenetic Protein 2 Does Not Induce Pansynostosis or Growth Restriction in the Immature Craniofacial Skeleton
Sameer Shakir, BS1, Osama Basri, DMD1, James J. Cray, PhD2, Sanjay Naran, MD1, Darren M. Smith, MD3, Zoe M. MacIsaac, MD1, Seth M. Weinberg, PhD1, Joseph E. Losee, MD1, Mark P. Mooney, PhD1, Gregory M. Cooper, PhD1.
1University of Pittsburgh, Pittsburgh, PA, USA, 2Medical University of South Carolina, Charleston, SC, USA, 3The Hospital for Sick Children, Toronto, ON, Canada.

Purpose:
Efficacy of rhBMP-2 therapy in the skeletally immature patient remains unknown. Current off-label applications of rhBMP-2 far supersede physiologic concentrations and may contribute to problematic side effects. Biopatterning technology allows delivery of spatially controlled, low dose growth factors, which may circumvent reported side effects of rhBMP-2 that continue to limit widespread clinical translation. The study compared the effects of rhBMP-2 dose on cranial growth with the hypothesis that higher dose rhBMP-2 negatively affects growth.
Methods:
Juvenile rabbits underwent bicoronal suturectomies treated with 0.4-mg/mL rhBMP-2, 100-ug/mL biopatterned rhBMP-2, or left empty. Amalgam markers were placed to track cranial growth at 10, 25, and 42 days of age. Sutures were qualitatively assessed using micro–computed tomographic (microCT) scanning 42 days postoperatively.
Results:
Treatment with 0.4-mg/mL rhBMP-2 resulted in significant growth changes and fusion of the coronal sutures bilaterally, anterior sagittal suture, and frontonasal suture by cephalometric analyses 42 days postoperatively (p<0.05). Frontonasal changes appeared greatest (F=3.832, p=0.013). No significant differences in cranial growth were noted with use of 100-ug/mL biopatterned rhBMP-2 when compared to empty defects. MicroCT analyses revealed comparable bony defect healing between rhBMP2 groups. 0.4-mg/mL rhBMP-2 resulted in pansynostosis upon uCT analysis, yet 100-ug/mL biopatterned rhBMP-2 regenerated bone without evidence of extra-sutural invasion.
Conclusions:
Use of rhBMP-2 results in unwanted craniofacial changes in a dose-dependent manner. Pansynostosis and growth restriction continue to limit translation of high dose rhBMP-2 formulations. Low dose, biopatterned rhBMP-2 regenerates bone without these contraindications, thereby enhancing potential clinical efficacy in the immature craniofacial skeleton.


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