Translational Optimization of Bone Regeneration in the Irradiated Mandible

头颈部癌症(HNC)造成巨大的生物医学负担，每年造成8000多人死亡和4万新病例。HNC患者通常需要手术、放疗和化疗等多种治疗手段。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。严重有问题的伤口愈合问题影响到重建努力，以取代肿瘤切除后移除的骨和软组织，以及治疗辐射引起的病理性骨折和骨放射性坏死的选择。目前的护理标准规定了利用来自身体其他部位的自由组织移植进行下颌骨重建。这些复杂的手术需要延长住院时间，其并发症往往导致治疗开始的延迟，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，将基础研究和临床研究的知识结合起来，创新辐射副作用的新治疗方案。利用牵张成骨(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得到缓解，以实现下颌骨的功能恢复和成功再生，并恢复正常的骨愈合能力。我们实验室最近的工作表明，在愈合的骨折和受照射的下颌骨的牵张区域内，骨质量下降的具体指标。然后，我们采用了一系列的药理学和组织工程学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辐射导致的骨愈合退化的部分修复作用。这些实验的后续发现是，在以前不可能的情况下，能够产生骨性愈合。尽管骨愈合的关键指标显著增强，但它们并未完全恢复，因此尚未优化应用于临床。目前的提议需要将我们有效的个别治疗方案结合到一个精心设计的计划中，该计划旨在最大限度地发挥治疗的协同作用，以实现更强大和可预测的重建。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。

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.