Optimization of Bone Regeneration in the Irradiated Mandible

描述（由申请人提供）：美国外科医生报告颅面区域疾病是影响普通人群的最常见健康问题之一。在这些疾病中，仅在美国，毁灭性的头颈癌（HNC）每年就造成8000人死亡，4万多例新病例，给生物医学带来了沉重的负担。这些患者中的大多数将需要手术、放疗和化疗的多模式治疗。虽然放疗提高了生存率，但它也会导致邻近正常组织的损伤，从而导致显著的发病率。这些辐射引起的副作用的腐蚀性影响可能是无情的，其复杂的管理是很少补救。手术治疗HNC提出了一个持续的挑战，因为它是复杂的严重问题的伤口愈合问题，随之而来的辅助放射治疗。目前的护理标准要求利用自由组织移植进行下颌骨重建，需要从身体其他部位（腿、肋骨或手臂）获取骨骼和组织。这些大的、复杂的手术需要延长住院时间，随之而来的并发症往往导致放疗和/或化疗的延迟，危及预后和生活质量。生物技术和手术器械的进步为基础研究和临床研究的合作提供了独特的机会。这项转化性研究有可能通过将新颖和更有效的治疗策略引入临床环境来改变头颈癌的重建。牵张成骨术（DO）用于肿瘤切除后的组织置换或作为放射骨继发性变形的重建选择，可能具有巨大的潜在治疗效果。DO是通过两个成骨前沿的逐渐分离而产生的新骨，从局部基质中产生缺陷组织的解剖和功能替代。辐射严重损害骨愈合，使DO无法作为HNC的持久和可预测的重建方法。本研究要验证的中心假设是，辐射对骨形成的有害影响可以减轻，从而使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啮齿动物DO模型来生成辐照分散下颌骨再生体内骨质量下降的具体指标。然后，我们将采用一系列药理学和组织工程策略来减轻辐射引起的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，这些信息可以从实验室转化为床边，从而改善对这一严重受损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.