Cellular and Mechanical Mechanisms Regulating Mandibular Distraction Osteogenesis

项目摘要 累及下颌、面中部和颅穹隆的颅面部骨骼缺陷会导致各种残疾，包括严重的呼吸道损害、错牙合、角膜保护不足和神经功能障碍。继发于创伤、肿瘤切除或发育异常，这些畸形是一个重大的重建挑战，占每年医疗保健支出的10亿美元以上。虽然将传统截骨术与自体骨和/或合成移植物材料相结合的外科技术可以取得成功，但在供骨部位发病率、生物相容性和骨传导性方面仍存在局限性。作为一种替代方法，牵张成骨(DO)提供了在机械控制的环境中促进内源性骨形成的能力，为缺乏的组织提供解剖和功能上的替代。DO在颅面骨中的应用使许多先天和后天缺陷的治疗发生了革命性的变化，对于许多伴有Pierre-Robin序列、Treacher Collins综合征和头面部矮小的下颌骨缺陷患者来说，牵引成骨已经成为治疗的选择。我们开发了一种新的小鼠下颌骨牵张模型，该模型允许追踪细胞对再生的贡献，并对引导骨形成过程中调节细胞分化的生物机械力传导进行遗传解剖。这一提议的发现将加深我们对祖细胞如何定位于再生的了解，并增强我们对颅面牵张的理解。识别DO再生中的细胞源，祖细胞反应的时间表，以及确定这些细胞如何转导物理刺激以产生再生反应，这些都可能促进改进的分心方案的发展。这一研究结果可能为颅面骨架的重建提供新的有效策略。

Project Summary 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.