Optimization of Bone Regeneration in the Irradiated Mandible

描述(由申请人提供)：美国卫生局局长报告说，颅面部疾病是影响普通民众的最常见的健康问题之一。在这些疾病中，毁灭性的头颈癌(HNC)单枪匹马就造成了巨大的生物医学负担，仅在美国每年就造成8000人死亡和4万多新病例。这些患者中的大多数将需要手术、放疗和化疗的综合治疗。虽然放射治疗提高了存活率，但它也会损害邻近的正常组织，导致显着的发病率。这些辐射引起的副作用的腐蚀性影响可能是无情的，其复杂的管理很少得到补救。HNC的手术治疗是一个持续的挑战，因为它因辅助放射治疗而导致的严重的伤口愈合问题而复杂化。目前的护理标准要求利用自由组织移植进行下颌骨重建，要求从身体其他部位(腿、肋骨或手臂)采集骨骼和组织。这些庞大、复杂和复杂的手术需要延长住院时间，伴随的并发症往往会导致延迟开始放疗和/或化疗，危及预后和生活质量。生物技术和手术器械的进步为合作努力提供了一个独特的机会，将基础和临床研究的知识结合起来进行转化性研究。这项转化性研究有可能通过将新的和更有效的治疗策略引入临床环境来改变头颈部癌症的重建。利用牵张成骨(DO)进行肿瘤切除后的组织替代，或作为放疗后继发畸形的重建选择，可能具有巨大的潜在治疗分支。DO是通过逐渐分离两个成骨前沿而产生的新骨，从解剖和功能上替代了局部基质中的缺陷组织。放射治疗严重损害骨愈合，阻碍了DO作为一种持久和可预测的重建方法应用于HNC。在这项建议中要检验的中心假设是，辐射对骨形成的有害影响可以减轻，以实现下颌骨的功能恢复和成功再生。为了验证这一假设，我们将利用一种新的DO啮齿动物模型来产生辐射牵张下颌骨再生过程中骨质量下降的特定指标。然后，我们将采用一系列的药理学和组织工程学策略来缓解辐射损伤对新骨形成和愈合的不利影响，以优化重建和修复。这项提议的长期目标是提供基本信息，这些信息可以从替补席上翻译到床边，以改善对这一严重受损的患者群体的治疗方式。

DESCRIPTION (provided by applicant): The US Surgeon General has reported that diseases of the craniofacial region are among the most common health problems affecting the general population. Among these maladies, devastating head and neck cancers (HNC) single-handedly impose a significant biomedical burden by accounting for 8000 deaths and over 40,000 new cases each year in the U.S. alone. Most of these patients will require multimodality treatment with surgery, radiation, and chemotherapy. Although radiotherapy has increased survival it also results in damage to adjacent normal tissues leading to significant morbidity. The corrosive impact of these radiation induced side effects can be unrelenting and their complex management is rarely remedial. Surgical treatment of HNC poses an ongoing challenge as it is complicated by the severely problematic wound healing issues consequent to adjuvant radiation therapy. Standard of care currently dictates mandibular reconstruction utilizing free tissue transfer, requiring the harvest of bone and tissue from other parts of the body (leg, rib, or arm). These large, involved, and complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of radiation and/or chemotherapy jeopardizing prognosis as well as quality of life. Advances in biotechnology and surgical instrumentation have afforded a unique opportunity for collaborative efforts combining knowledge from both basic and clinical investigation to conduct translational research. This translational research has the potential to transform head and neck cancer reconstruction by bringing novel and more effective therapeutic strategies into clinical settings. The utilization of Distraction Osteogenesis (DO) for tissue replacement after oncologic resection or as a reconstructive option for deformations secondary to irradiated bone could have immense potential therapeutic ramifications. DO, the creation of new bone by the gradual separation of two osteogenic fronts, generates an anatomical and functional replacement of deficient tissue from local substrate. Radiation drastically impairs bone healing, precluding the utilization of DO as a durable and predictable reconstructive method for HNC. The central hypothesis to be tested in this proposal is that the deleterious effects of radiation on bone formation can be mitigated to allow functional restoration and successful regeneration of the mandible. To test this hypothesis we will utilize a novel rodent model of DO to generate specific metrics of diminished bone quality within the regenerate of irradiated distracted mandibles. We will then employ a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of radiation induced injury on new bone formation and healing in order to optimize reconstruction and repair. The long term goal of this proposal is to provide fundamental information that can be translated from the bench to the bedside to lead to improved treatment modalities to this severely compromised patient population.