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) 造成巨大的生物医学负担，每年导致 8000 多人死亡和 40,000 例新病例。 HNC 患者通常需要手术、放疗和化疗等多学科治疗。尽管放疗提高了生存率，但它也会导致邻近正常组织受损，从而导致显着的发病率。这些辐射引起的副作用的腐蚀性影响可能是无情的，并且其复杂的管理很少能得到补救。严重的伤口愈合问题影响着替换因肿瘤摘除而去除的骨骼和软组织的重建工作，以及治疗辐射引起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利用从身体其他部位转移的游离组织进行下颌重建。这些复杂的手术需要延长住院时间，其并发症通常会导致治疗开始延迟，从而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，可以将基础研究和临床研究的知识结合起来，通过将新颖且更有效的治疗策略引入临床环境，创新放射引起的副作用的新治疗方案。利用牵引成骨（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，通过逐渐分离两个成骨前沿来产生新骨，从局部基质中产生有缺陷的组织的解剖学和功能性替代。放射会严重损害骨愈合，从而妨碍将 DO 作为 HNC 的持久且可预测的重建方法。该提案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，以及恢复正常骨愈合的能力。我们实验室最近的工作证明了骨折愈合和受辐射下颌骨分散区域内骨质量下降的具体指标。然后，我们采用了一系列药理学和组织工程策略来减轻辐射引起的损伤的不利影响，以优化重建和修复。我们的每种疗法都证明可以部分修复辐射引起的骨愈合退化。这些实验的结果是能够在以前不可能的情况下生成骨结合。尽管骨愈合的关键指标显着增强，但它们并未完全恢复，因此尚未针对临床领域的转化进行优化。当前的提案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，旨在最大限度地发挥治疗协同作用，以实现更稳健和可预测的重建。该提案的长期目标是提供可以从实验室转化为临床的基本信息，从而改进针对这一严重受损患者群体的治疗方式。