Craniofacial skeletal deficiencies involving the mandible, midface, and cranial vault result in a wide range of disabilities including severe airway compromise, malocclusion, inadequate corneal protection, and neurological impairment. Secondary to trauma, tumor resection, or developmental anomalies, these deformities represent a significant reconstructive challenge and account for over $1 billion in annual health care expenditures. While surgical techniques integrating conventional osteotomies with autogenous bone and/or synthetic graft materials can be successful, limitations in donor site morbidity, biocompatibility, and osteoconductivity still remain. As an alternative approach, distraction osteogenesis (DO) offers the ability to promote endogenous bone formation across a mechanically controlled environment, providing anatomical and functional replacement of deficient tissue. The application of DO to the craniofacial skeleton has revolutionized the treatment of many congenital and acquired defects, and for many patients with mandibular deficiency associated with Pierre-Robin sequence, Treacher Collins syndrome, and craniofacial microsomia, distraction osteogenesis has become the treatment choice. We have developed a novel model of mouse mandibular distraction which allows for lineage tracing of cellular contribution to the regenerate and genetic dissection of biomechanical force transduction regulating cell differentiation during guided bone formation. Findings from this proposal will deepen our knowledge of how progenitor cells localize to the regenerate and enhance our understanding of craniofacial distraction. The identification of the cellular source within the DO regenerate, the timeline for progenitor cell response, and determination of how these cells transduce physical stimuli to enact a regenerative response may all facilitate development of improved distraction protocols. Findings from this proposal may provide new and effective strategies for reconstruction of the craniofacial skeleton.
Bone defects of the facial skeleton following trauma, tumor resection, or due to congenital anomalies are challenging to treat, and the many current strategies available reflect the inadequacies of each therapeutic technique. Distraction osteogenesis (DO) offers the ability to promote endogenous bone formation across a mechanically controlled environment without incurring the morbidity associated with bone grafting. While studies in large-animal models have had a significant role in delineating the ultrastructural and histological changes occurring during successful distraction osteogenesis, the underlying biology of this process has remained largely uninvestigated. Therefore, a genetically-dissectible mouse model of mandibular distraction osteogenesis represents an invaluable tool for uncovering the cellular and molecular mechanisms that drive this process, facilitating the development of new approaches to the surgical reconstruction of complex skeletal defects.
| Chan, Charles K F; Gulati, Gunsagar S; Sinha, Rahul et al. (2018) Identification of the Human Skeletal Stem Cell. Cell 175:43-56.e21 |
| Ransom, Ryan C; Foster, Deshka S; Salhotra, Ankit et al. (2018) Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes. Nat Commun 9:2971 |
