A Mouse Model of Mandibular Distraction Osteogenesis
Ryan C. Ransom, B.A., Tripp Leavitt, B.S., B.A., Leandra A. Barnes, B.A., Clement D. Marshall, M.D., Derrick C. Wan, M.D., Michael T. Longaker, M.D., M.B.A..
Stanford University, Stanford, CA, USA.
PURPOSE: Distraction osteogenesis (DO) is a powerful method of endogenous bone tissue engineering that has been applied to the craniofacial skeleton with great success. However, the cellular and molecular signaling that governs this process of de novo bone formation is not well understood. We aimed to establish a rigorous mandibular distraction model that is genetically dissectable, using C57/B6 mice, the most common background strain of inbred transgenic mice.
METHODS: Mandibular distraction devices were manufactured using computer-aided design (CAD) software and 3D printing. Animals were divided into four groups in this study: sham-operated (n = 6 per time point), fracture (n = 6 per time point), acutely lengthened (n = 8 per time point) and gradually distracted (n = 8 per time point) right hemimandibles. Gradual distraction was performed at a rate of 0.15 mm every 12 h over the course of 10 days whereas acute lengthening was performed at a single time point. The total amount of distraction (3 mm) was maintained across both groups. Specimens were harvested at mid-consolidation (POD 29) and end consolidation (POD 43) time points for μCT and histological analysis.
RESULTS: Detailed serial histology of gradually distracted mandibles revealed patterns of bone formation identical to those seen in our rat DO model. Two weeks into consolidation (POD 29), greater than half of the distraction gap was filled with trabecular bone. No cartilage was seen within the distraction gap, indicating that the regenerate was produced through direct intramembranous bone formation. At the end of consolidation (POD 43), trabecular bone completely bridged the distraction gap of all gradually distracted specimens. Trabecular bone along the edges of the osteotomies was remodeled to lamellar, cortical bone. Three-dimensional reconstruction of the μCT images of gradually distracted specimens clearly showed complete osseous bridging of the osteotomy gap. In marked contrast to the above data, the distraction gap of all mandibles undergoing acute lengthening was filled with fibrous tissue at end-consolidation and there was minimal evidence of new bone formation at the osteotomized bone histologically or radiologically.
CONCLUSION: We have developed and characterized a model of mandibular DO in C57BL/6 mice, which faithfully reproduces the ultrastructural and histological changes seen in larger animal models. Experiments utilizing this unique mouse model will offer valuable insight into the biology of de novo bone formation and the mechanical forces guiding distraction osteogenesis, speeding the development of clinically applicable therapies.
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