Translational Optimization of Bone Regeneration in the Irradiated Mandible

照射下颌骨骨再生的平移优化

• 批准号: 8657300
• 负责人: STEVEN R BUCHMAN
• 金额: $ 3.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657300
• 关键词: Accounting; Adipose tissue; Adverse effects; Aftercare; Amifostine; Biotechnology; Blood Vessels; Body part; Bone Injury; Bone Marrow; Bone Regeneration; Bone Tissue; Cell physiology; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Corrosives; Deferoxamine; Disease; Distraction Osteogenesis; Engineering; Excision; Fostering; Fracture; Fracture Healing; Generations; Goals; Harvest; Head and Neck Cancer; Healed; Hospitalization; Incidence; Individual; Injury; Knowledge; Laboratories; Lead; Maintenance; Mandible; Mediating; Medical; Methods; Metric; Modality; Morbidity - disease rate; Natural regeneration; Normal tissue morphology; Operating Rooms; Operative Surgical Procedures; Osteogenesis; Osteoradionecrosis; Outcome; Pathologic; Pathological fracture; Patients; Preparation; Process; Property; Quality of Care; Quality of life; Radiation; Radiation therapy; Radio; Radiosurgery; Replacement Therapy; Research; Research Proposals; Series; Skeleton; Societies; Solutions; Stem cells; Structure; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Translating; Translations; Transplantation; Treatment Protocols; United States; Vascular blood supply; Work; Wound Healing; bench to bedside; bone; bone healing; bone quality; cancer diagnosis; chemotherapy; clinically relevant; craniofacial; design; functional restoration; head and neck cancer patient; healing; improved; innovation; named group; novel; operation; osteogenic; outcome forecast; patient population; radiation effect; reconstruction; remediation; repaired; research study; soft tissue; standard of care; tissue repair; treatment strategy; tumor

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.

头颈癌（HNC）每年造成8000多例死亡和40,000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、放疗和化疗的多模式治疗。虽然放射治疗提高了生存率，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努力，以及治疗辐射诱导的病理性骨折和放射性骨坏死的选择。目前的护理标准要求利用身体其他部位的游离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，联合收割机的知识，从基础和临床研究，创新新的治疗方案，辐射引起的副作用，使新的和更有效的治疗策略进入临床设置。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是通过两个成骨前沿的逐渐分离产生新骨，从局部基质产生缺陷组织的解剖和功能替代。放射严重损害骨愈合，排除使用DO作为HNC的持久和可预测的重建方法。本提案中要测试的中心假设是，可以减轻辐射对骨形成的有害影响，以实现下颌骨的功能恢复和成功再生，并恢复正常骨愈合的能力。我们实验室最近的工作表明，在愈合的骨折和受照射下颌骨的分散区域内，骨质下降的具体指标。然后，我们采用了一系列的药理学和组织工程学的策略，以减轻放射性损伤的不良影响，以优化重建和修复。我们的每种疗法都证明了对辐射诱导的骨愈合退化的部分补救。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。尽管骨愈合的关键指标显著增强，但它们并未完全恢复，因此尚未优化用于临床竞技场。目前的建议需要将我们有效的个体治疗方案结合到精心设计的计划中，以最大限度地发挥治疗协同作用，实现更强大和可预测的重建。该提案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旁信息，从而改善这一严重受损患者人群的治疗方式。