Translational Optimization of Bone Regeneration in the Irradiated Mandible

描述(申请人提供)：头颈部癌症(HNC)造成巨大的生物医学负担，每年造成超过8000人死亡和50,000例新病例。HNC患者通常需要手术、放射治疗(XRT)和化疗的综合治疗。虽然XRT提高了存活率，但它也会对邻近的正常组织造成损害，导致显着的发病率。这些XRT引起的副作用的腐蚀性影响可能是无情的，其复杂的管理很少得到补救。严重的伤口愈合问题影响了重建努力，以取代肿瘤切除后移除的骨和软组织，以及治疗XRT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免费组织移植。随之而来的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，通过将新颖和更有效的治疗策略引入实际手术区，来创新XRT引起的副作用的新疗法。牵张成骨(DO)是通过逐渐分离两个成骨前沿形成新骨，在解剖和功能上替代局部基质中的缺陷组织，在肿瘤切除后具有巨大的重建潜力。然而，XRT严重损害了骨折的愈合，排除了DO作为一种持久的重建方法用于HNC的可能性。在这项建议中要检验的中心假设是，XRT对骨形成的有害影响可以减轻，以允许成功地再生下颌骨，恢复正常的骨愈合能力。我们进一步认为，可以设计新的治疗策略，将组织工程技术和药理学优化结合起来，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外科模式。我们的实验室最近证实了照射后下颌骨愈合界面的骨质量降低的具体指标。然后，我们采用了一系列的药理学和组织工程学策略来减轻XRT引起的损伤的不良影响。我们的每一种疗法都证明了XRT导致的骨愈合退化的修复作用。这些实验的后续发现是，在以前不可能的情况下，能够产生新的骨形成和骨愈合。尽管成功地增强了骨愈合的关键指标，但它们并没有完全恢复，候选细胞系和基于细胞的药物可以受益于治疗协同作用，并且可能在手术室中分离和直接操作，仍然需要创新的解决方案，以便完全优化转换为临床AENA。目前的建议需要开发这些协同效应和创新的解决方案，以便将我们的发现从替补席上转化为手术套件，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.