Translational Optimization of Bone Regeneration in the Irradiated Mandible

照射下颌骨骨再生的平移优化

基本信息

批准号：
9178639
负责人：
STEVEN R BUCHMAN
金额：
$ 24.47万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178639
关键词：
Accounting Adipose tissue Adverse effects Amifostine Anatomy Biotechnology Blood Vessels Body part Bone Injury Bone Marrow Bone Regeneration Bone Tissue Cell Line Cell Survival Cell Therapy Cell physiology Cells Cessation of life Clinical Clinical Trials Combined Modality Therapy Complex Consequentialism Corrosives Deferoxamine Disease Distraction Osteogenesis Engineering Excision Fostering Fracture Healing Generations Head and Neck Cancer Hospitalization Impairment Incidence Individual Injury Institution Joints Laboratories Lead Maintenance Mandible Mediating Medical Methods Morbidity - disease rate Natural regeneration Normal tissue morphology Operating Rooms Operative Surgical Procedures Osteogenesis Osteoradionecrosis PTH gene Pathologic Pathological fracture Patients Pharmacology Property Quality of Care Quality of life Radiation Radiation therapy Radio Replacement Therapy Research Series Skeleton Societies Stem cells Stromal Cells Structure Techniques Testing Therapeutic Tissue Engineering Tissues Translating Translations Treatment Efficacy Treatment Protocols United States Vascular blood supply Work Wound Healing angiogenesis base bone bone healing bone quality cancer diagnosis chemotherapy clinical translation clinically relevant craniofacial design experimental study functional restoration head and neck cancer patient healing improved innovation named group new technology novel osteogenic outcome forecast patient population public health relevance reconstruction remediation repaired restoration soft tissue standard of care synergism tissue repair trait treatment strategy tumor

项目摘要

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.

描述（由申请人提供）：头颈癌 (HNC) 每年造成 8000 多人死亡和 50,000 例新病例，造成重大的生物医学负担。 HNC 患者通常需要手术、放疗 (XRT) 和化疗等多学科治疗。尽管 XRT 提高了存活率，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 XRT 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 XRT 引起的病理性骨折和放射性骨坏死的选择。目前的护理标准要求利用需要长期住院的身体其他部位的游离组织移植来进行复杂的下颌重建。随之而来的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。生物技术的进步为 XRT 引起的副作用创新新疗法提供了独特的机会，将新颖且更有效的治疗策略引入实际手术室。牵引成骨（DO）是通过两个成骨前沿的逐渐分离来产生新骨，从解剖学和功能上替代局部基底的缺陷组织，并且在肿瘤切除后具有巨大的重建潜力。然而，XRT 会极大地损害骨折愈合，从而妨碍了 DO 作为 HNC 的持久重建方法。该提案要测试的中心假设是，XRT 对骨形成的有害影响可以减轻，从而使下颌骨成功再生并恢复正常骨愈合的能力。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相结合，以开发可与手术重建同步使用的应用程序，从根本上改变当前的手术范例。我们的实验室最近展示了受辐射下颌骨愈合界面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 XRT 引起的损伤的不利影响。我们的每种疗法都证明可以修复 XRT 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产生新骨形成和骨结合。尽管骨愈合的关键指标得到了成功增强，但它们并没有完全恢复，候选细胞系和基于细胞的疗法仍然需要创新的解决方案，这些细胞系和细胞疗法可以受益于治疗协同作用，并有可能在手术室中直接分离和操作。充分优化以转化为临床领域。当前的提案需要开发这些协同作用和创新解决方案，以便将我们的研究结果从实验室转化为手术套件，以改善对这一严重受损患者群体的治疗。