Translational Optimization of Bone Regeneration in the Irradiated Mandible

头颈癌（HNC）造成了重大的生物医学负担，每年造成8000多例死亡和4万例新病例。HNC患者通常需要多模式治疗，包括手术、放疗和化疗。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。严重有问题的伤口愈合问题影响了肿瘤切除后的骨和软组织的重建工作，以及治疗辐射引起的病理性骨折和骨放射性坏死的选择。目前的治疗标准是利用身体其他部位的游离组织进行下颌骨重建。这些复杂的手术需要延长住院时间，其并发症往往导致延迟开始治疗，危及预后和生活质量。生物技术的进步提供了一个独特的机会，通过将新的和更有效的治疗策略引入临床环境，将基础和临床研究的知识结合起来，创新新的治疗方案，以治疗放射引起的副作用。利用牵张成骨术（DO）进行肿瘤切除后的组织置换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，以及恢复正常骨愈合的能力。我们实验室最近的工作证明了在愈合骨折和受辐射下颌骨分散区域内骨质量下降的具体指标。然后，我们采用一系列药理学和组织工程策略来减轻辐射损伤的不利影响，以优化重建和修复。我们的每一种疗法都证明了放射诱导的骨愈合退化的部分修复。这些实验的结果是能够在以前不可能的情况下产生骨愈合。虽然，骨愈合的关键指标显着增强，但它们并未完全恢复，因此尚未优化转化为临床领域。目前的建议需要将我们有效的个体治疗方案结合到一个精心设计的计划中，以最大限度地发挥治疗协同作用，以实现更稳健和可预测的重建。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。

Head and neck cancers (HNC) impose a significant biomedical burden by accounting for over 8000 deaths and 40,000 new cases each year. HNC patients often 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. Severely problematic wound healing issues impact the reconstructive efforts to replace the bone and soft tissue removed by tumor extirpation as well as the options to treat radiation induced pathologic fractures and osteoradionecrosis. Standard of care currently dictates mandibular reconstruction utilizing free tissue transfer from other parts of the body. These complex operations entail extended hospitalizations and their complications often lead to delays in initiation of therapy jeopardizing prognosis as well as quality of life. Advances in biotechnology have afforded a unique opportunity to combine knowledge from both basic and clinical investigation to innovate new treatment regimens for radiation induced side effects by bringing novel and more effective therapeutic strategies into clinical settings. The utilization of Distraction Osteogenesis (DO) for tissue replacement after oncologic resection 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 both functional restoration and successful regeneration of the mandible as well as restore the capacity for normal bone healing. Recent work in our laboratory demonstrated specific metrics of diminished bone quality within healing fractures and distracted regions of irradiated mandibles. We then employed a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of radiation induced injury in order to optimize reconstruction and repair. Each of our therapies demonstrated partial remediation of the radiation induced degradation of bone healing. The consequential finding of these experiments was the ability to generate a bony union in scenarios where this was not previously possible. Although, the key metrics of bone healing were significantly enhanced, they were not completely restored and therefore not yet optimized for translation to the clinical arena. The current proposal entails combining our efficacious individual treatment regimens into a carefully designed plan engineered to maximize therapeutic synergies to achieve a more robust and predictable reconstruction. 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.