Treatment of Osteoradionecrosis with Bone Marrow Stromal Cells

简介(由申请人提供)：Akintoye博士对研究和学术牙科的承诺为他作为一名独立的临床医生-宾夕法尼亚大学牙医学院的科学家--的职业生涯做好了准备。这个K08应用程序在Phoebe Leball博士和Marjorie Jeffcoat博士的指导下，寻求应用骨髓基质细胞(BMSC)技术治疗放射性骨坏死并提供翻译研究方面的培训。在口面部，放射性骨坏死是头颈部肿瘤放射治疗的主要并发症，以组织裂开、骨外露、面部畸形、口面部功能受损和生活质量下降为主要特征。目前对放射性骨坏死的非手术治疗是高压氧治疗，可以暂时改善组织的氧合。由于愈合不完全，结果是不同的，在一些患者中是相反的，随后经常需要手术切除受影响的骨。临床资料表明，自体轴骨移植修复颌骨缺损常会导致骨不整合和骨吸收，而口腔颌面部其他部位的骨移植通常更为成功。同样，小天使症和甲状旁腺功能亢进症等疾病仅限于颌骨，在其他部位从未描述过。这些颌骨独有的特性仍然不清楚，需要进一步阐明。它们可能与颅面(神经脊起源)和中轴(中胚层起源)骨的不同胚胎学起源有关，但人类骨髓间充质干细胞的解剖骨骼部位特异性特性尚未确定。从不同骨骼部位移植的体外扩增的BMSC在放射性坏死骨中再生新骨的研究，在人类和动物身上也未见报道。Akintoye博士在第一个特定目标中提出了研究人上颌骨(神经脊来源)和髂骨(中胚层来源)的BMSC的部位特异性、独特的成骨特性和放射敏感性。第二个特定目的将阐明人骨髓间充质干细胞在无菌大鼠自发性放射性骨坏死中的部位特异性再生特性。通过从下颌骨和髂骨中移植正常人骨髓间充质干细胞，他将研究和比较它们作为移植物治疗放射性骨坏死的疗效。需要新的方法来治疗骨缺损；我们建议使用组织工程技术(体外扩增的骨髓间充质干细胞)来治疗放射性骨坏死，这是头颈癌放射治疗相关的顽固性临床问题。这些数据将提供大量新的见解。Akintoye博士的长期目标是最终将这些转化为治疗放射性骨坏死患者的人类临床方案。

DESCRIPTION (provided by applicant): Dr. Akintoye's commitment to research and academic dentistry have prepared him for a career as an independent Clinician-Scientist at the School of Dental Medicine, University of Pennsylvania. This K08 application, under the mentorship of Drs. Phoebe Leboy and Marjorie Jeffcoat, seeks to apply bone marrow stromal cell (BMSC) technology to treat osteoradionecrosis and provide training in translational research. In the oro-facial region, osteoradionecrosis is a major complication of head and neck cancer radiotherapy characterized by tissue dehiscence, bone exposure, facial deformities, compromised oro-facial function and diminished quality of life. Current non-surgical treatment of osteoradionecrosis is hyperbaric oxygen therapy that improves tissue oxygenation transiently. The results are variable as healing is incomplete, it is contra-indicated in some patients and subsequent surgical resection of affected bones is often needed. Clinical data indicate that maxillofacial reconstruction with autologous graft from the axial bones to bridge osseous jaw defects often results in non-integration and graft resorbtion, while grafting bone from other oro-facial sites is usually more successful. Similarly, diseases such as cherubism and hyperparathyroid jaw tumor syndrome are restricted to the jaw bones and never been described in other sites. These properties unique to the jaw bones still remain unclear and need to be further elucidated. They may be related to the different embryological origins of the craniofacial (neural crest origin) and axial (mesodermal origin) bones, but anatomic skeletal site-specific properties of human BMSC have not been conclusively defined. Regeneration of new bone in radionecrotic bone using grafted ex vivo expanded BMSC from different skeletal sites has also not been explored either in humans or animals. Dr. Akintoye has proposed in the first specific aim to investigate site-specific distinctive osteogenic properties and radiosensitivity of human BMSC of the maxilla and mandible (neural crest origin) and ilium (mesodermal origin). The second specific aim will elucidate site-specific regenerative properties of human BMSC in spontaneous osteoradionecrosis in athymic rats. By transplanting normal human BMSC from mandible and iliac crest, he will study and compare their efficacy as graft to heal osteoradionecrosis. New methods are needed to treat osseous defects; we propose the use of tissue engineering technology (ex vivo expanded BMSC) to treat osteoradionecrosis, a recalcitrant clinical problem associated with head and neck cancer radiotherapy. These data will provide substantial new insights. Dr. Akintoye's long term goal is to ultimately translate these into human clinical protocols to treat patients with osteoradionecrosis.