Optimization of Bone Regeneration in the Irradiated Mandible

照射下颌骨骨再生的优化

• 批准号: 7666080
• 负责人: STEVEN R BUCHMAN
• 金额: --
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666080
• 关键词: Accounting; Adjuvant; Adverse effects; Affect; Aftercare; Amifostine; Biomechanics; Biotechnology; Body part; Bone Marrow; Bone Marrow Transplantation; Bone Regeneration; Bone Tissue; Cell physiology; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Corrosives; Country; Disease; Distraction Osteogenesis; Excision; Fracture; General Population; Generations; Goals; Harvest; Head and Neck Cancer; Healed; Health; Hospitalization; Impairment; Incidence; Injury; Knowledge; Laboratories; Lead; Leg; Maintenance; Malignant Neoplasms; Mandible; Measures; Mediating; Methods; Metric; Modality; Morbidity - disease rate; Natural regeneration; Normal tissue morphology; Operative Surgical Procedures; Osteoclasts; Osteogenesis; Outcome; Parathyroid Hormones; Pathologic; Pathological fracture; Patients; Procedures; Property; Quality of life; Radiation; Radiation therapy; Radio; Radiosurgery; Replacement Therapy; Reporting; Research Personnel; Research Proposals; Rodent Model; Secondary to; Series; Signal Transduction; Skeleton; Stromal Cells; Surgeon; Techniques; Testing; Therapeutic; Tissue Engineering; Tissues; Translating; Translational Research; Upper arm; Work; Wound Healing; Zoledronic Acid; bench to bedside; bone; bone healing; bone quality; chemotherapy; clinically relevant; craniofacial; design; functional restoration; healing; human PTH protein; improved; instrumentation; irradiation; novel; osteogenic; outcome forecast; patient population; programs; radiation effect; reconstruction; repaired; rib bone structure; soft tissue; standard of care; treatment strategy

DESCRIPTION (provided by applicant): The US Surgeon General has reported that diseases of the craniofacial region are among the most common health problems affecting the general population. Among these maladies, devastating head and neck cancers (HNC) single-handedly impose a significant biomedical burden by accounting for 8000 deaths and over 40,000 new cases each year in the U.S. alone. Most of these patients 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. Surgical treatment of HNC poses an ongoing challenge as it is complicated by the severely problematic wound healing issues consequent to adjuvant radiation therapy. Standard of care currently dictates mandibular reconstruction utilizing free tissue transfer, requiring the harvest of bone and tissue from other parts of the body (leg, rib, or arm). These large, involved, and complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of radiation and/or chemotherapy jeopardizing prognosis as well as quality of life. Advances in biotechnology and surgical instrumentation have afforded a unique opportunity for collaborative efforts combining knowledge from both basic and clinical investigation to conduct translational research. This translational research has the potential to transform head and neck cancer reconstruction by bringing novel and more effective therapeutic strategies into clinical settings. The utilization of Distraction Osteogenesis (DO) for tissue replacement after oncologic resection or as a reconstructive option for deformations secondary to irradiated bone 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 functional restoration and successful regeneration of the mandible. To test this hypothesis we will utilize a novel rodent model of DO to generate specific metrics of diminished bone quality within the regenerate of irradiated distracted mandibles. We will then employ a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of radiation induced injury on new bone formation and healing in order to optimize reconstruction and repair. 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.

描述（由申请人提供）：美国卫生局局长报告称，颅面部疾病是影响普通人群的最常见健康问题之一。在这些疾病中，毁灭性的头颈癌 (HNC) 仅在美国每年就造成 8,000 例死亡和 40,000 多例新病例，造成了巨大的生物医学负担。这些患者中的大多数需要手术、放疗和化疗等综合治疗。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。 HNC 的手术治疗面临着持续的挑战，因为辅助放射治疗导致严重的伤口愈合问题，使手术治疗变得更加复杂。目前的护理标准规定利用游离组织移植进行下颌重建，需要从身体其他部位（腿部、肋骨或手臂）获取骨骼和组织。这些大型、复杂且复杂的手术需要延长住院时间，并且随之而来的并发症通常会导致放疗和/或化疗延迟，从而危及预后和生活质量。生物技术和手术器械的进步为结合基础和临床研究知识进行转化研究的合作提供了独特的机会。这项转化研究有可能通过将新颖且更有效的治疗策略引入临床环境来改变头颈癌的重建。利用牵引成骨 (DO) 进行肿瘤切除后的组织置换或作为继发于辐照骨骼变形的重建选择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。为了检验这一假设，我们将利用一种新型的 DO 啮齿动物模型来生成受辐射下颌骨再生过程中骨质量下降的具体指标。然后，我们将采用一系列药理学和组织工程策略来减轻辐射引起的损伤对新骨形成和愈合的不利影响，以优化重建和修复。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。