Translational Optimization of Bone Regeneration in the Irradiated Mandible

描述（由申请人提供）：头颈部癌症（HNC）每年造成8000多例死亡和50，000例新发病例，造成了重大的生物医学负担。HNC患者通常需要手术、放疗（XRT）和化疗的多模式治疗。尽管XRT增加了存活率，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XRT引起的副作用的腐蚀性影响可能是无情的，其复杂的管理很少是补救性的。严重的伤口愈合问题影响了通过肿瘤摘除术替换骨和软组织的重建工作以及治疗XRT诱导的病理性骨折和放射性骨坏死的选择。目前的护理标准规定了复杂的下颌骨重建，利用需要延长住院时间的身体其他部位的游离组织移植。伴随的并发症通常导致治疗开始延迟，危及预后以及生活质量。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实际的手术室来创新XRT引起的副作用的新疗法。牵张成骨（DO），通过两个成骨前沿的逐渐分离产生新骨，从局部基质中产生缺陷组织的解剖和功能替代，并且在肿瘤切除后具有巨大的重建潜力。然而，XRT严重损害骨折愈合，排除了使用DO作为HNC的持久重建方法。在本提案中要测试的中心假设是，XRT对骨形成的有害影响可以减轻，以允许下颌骨的成功再生并恢复正常骨愈合的能力。我们进一步证实，可以设计新的治疗策略，将联合收割机组织工程技术和药理学优化相结合，以开发可与手术重建同步使用的应用，从根本上改变当前的手术模式。我们的实验室最近证明了在辐照下颌骨的愈合界面处骨质降低的具体指标。然后，我们采用了一系列的药理学和组织工程学的策略，以减轻XRT诱导的损伤的不利影响。我们的每种疗法都证明了XRT诱导的骨愈合退化的补救。这些实验的结果是在以前不可能的情况下产生新骨形成和骨愈合的能力。尽管骨愈合的关键指标得到了成功的增强，但它们并没有完全恢复，并且可以从治疗协同作用中受益并可能在手术室中直接分离和操作的候选细胞系和基于细胞的补救措施仍然需要创新的解决方案，以便完全优化转化为临床aena。目前的提案需要开发这些协同作用和创新的解决方案，以便将我们的研究结果从实验室转化为手术室，以改善对这一严重受损患者群体的治疗。

DESCRIPTION (provided by applicant): Head and neck cancers (HNC) impose a significant biomedical burden by accounting for over 8000 deaths and 50,000 new cases each year. HNC patients often require multimodality treatment with surgery, radiation (XRT), and chemotherapy. Although XRT has increased survival it also results in damage to adjacent normal tissues leading to significant morbidity. The corrosive impact of these XRT-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 and the options to treat XRT-induced pathologic fractures and osteoradionecrosis. Standard of care currently dictates complex mandibular reconstruction utilizing free tissue transfer from other parts of the body requiring extended hospitalizations. Attendant 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 innovate new remedies for XRT-induced side effects by bringing novel and more effective therapeutic strategies into the actual operating theater. Distraction Osteogenesis (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 and could have immense potential for reconstruction after oncologic resection. XRT drastically impairs fracture healing, however, precluding the utilization of DO as a durable reconstructive method for HNC. The central hypothesis to be tested in this proposal is that the deleterious effects of XRT on bone formation can be mitigated to allow successful regeneration of the mandible and restore the capacity for normal bone healing. We further posit that new treatment strategies can be designed to combine tissue engineering techniques and pharmacological optimization in order to develop applications that can be utilized synchronously with operative reconstruction, to fundamentally transform current surgical paradigms. Our laboratory recently demonstrated specific metrics of diminished bone quality at the healing interface of irradiated mandibles. We then employed a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of XRT induced injury. Each of our therapies demonstrated remediation of the XRT-induced degradation of bone healing. The consequential finding of these experiments was the ability to generate new bone formation and a bony union in scenarios where this was not previously possible. Although, the key metrics of bone healing were successfully enhanced, they were not completely restored and candidate cell lines and cell-based remedies that could benefit from therapeutic synergies and potentially be isolated and manipulated directly in the operating room still require innovative solutions in order to be fully optimized for translation to the clinical aena. The current proposal entails developing those synergies and innovative solutions in order to translate our findings from the bench to the operative suite to improve the treatment for this severely compromised patient population.