Translational Optimization of Bone Regeneration in the Irradiated Mandible

描述（由申请人提供）：头颈癌（HNC）造成了重大的生物医学负担，每年有8000多人死亡，50000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XRT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xrt诱导的副作用的腐蚀性影响可能是无情的，它们的复杂管理很少是补救的。严重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xrt诱导的病理性骨折和骨放射性坏死的治疗选择。目前的护理标准要求复杂的下颌重建，利用身体其他部位的游离组织移植，需要长期住院治疗。随之而来的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，通过将新颖和更有效的治疗策略带入实际手术室，为xrt诱导的副作用提供了创新的新疗法。牵张成骨术（DO）是通过两个成骨前沿的逐渐分离来产生新骨，从局部基质中产生解剖和功能上的缺损组织替代，在肿瘤切除后重建具有巨大的潜力。然而，XRT极大地损害了骨折愈合，阻碍了DO作为HNC持久重建方法的使用。本研究的核心假设是，XRT对骨形成的有害影响可以减轻，从而使下颌骨成功再生，恢复正常骨愈合的能力。我们进一步假设，新的治疗策略可以结合组织工程技术和药理学优化，以开发可与手术重建同步利用的应用，从根本上改变当前的手术范式。我们的实验室最近证明了在辐照下颌骨愈合界面降低骨质量的具体指标。然后，我们采用了一系列药理学和组织工程策略来减轻XRT引起的损伤的不利影响。我们的每一种疗法都证明了xrt诱导的骨愈合退化的修复。这些实验的结果是能够在以前不可能的情况下产生新的骨形成和骨愈合。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，候选细胞系和基于细胞的疗法可能受益于治疗协同作用，并且可能在手术室中被分离和直接操作，但仍然需要创新的解决方案，以便充分优化转化为临床领域。目前的建议需要发展这些协同作用和创新的解决方案，以便将我们的发现从实验台上转化为手术套件，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.