Autologous Stem Cell-Augmented Mandibular Distraction Osteogenesis

描述(申请人提供)：大型头面部骨骼缺陷或缺陷严重危及患者的生活，并仍然具有挑战性的治疗。牵张成骨(DO)是一种机械诱导的内源性骨再生方法，已被用作一种主要的治疗方式。虽然目前的DO方法在骨再生方面是可靠的，但它的效率很低，因为它主要依赖于机械刺激，因此需要大量延长治疗时间，并增加感染、矫治器损坏、不依从性和治疗失败的风险。与NIDCR目前在组织工程和再生医学方面的使命一致，该项目的总体目标是通过使用机械刺激和基于自体干细胞的组织工程方法来增强颌骨再生。假说是在牵张前通过支架植入自体骨髓间充质干细胞(BM-MSCs)，并在固位期加强BM-MSC注射，可以显著加速下颌骨DO。与通常接受头面部DO治疗的年轻人密切相关的年轻猪将被使用。该项目将首先使用我们经过验证的猪下颌骨DO模型在对照动物中建立基线参数。目的1研究将确定将细胞引入DO部位的两个关键方面，即使用未分化或成骨分化的BM-MSCs，以及是否包含或排除骨髓来源的内皮祖细胞(BM-EPC)。这两个方面都与骨再生所需的成骨和血管生成高度相关，但到目前为止还没有研究同时在DO部位对它们进行评估。细胞移植后的骨再生将与对照组的基线参数进行比较，以确定铅促进成骨的组合。下一步，该项目将确定在巩固阶段注射BM-MSCs是否进一步促进骨再生(目标2)。与仅进行初始细胞移植相比，初始细胞移植和助推剂注射后的骨再生将是不同的。使用自体富含血小板血浆(PRP)携带BM-MSCs用于注射的效果也将通过比较注射中包含PRP的DO部位和没有PRP的DO部位来确定。来自目标1和目标2的组合数据将被用来创建最优治疗方案，以便在具有更快的分散和更短的巩固的加速DO方案中进行评估(目标3)。这些研究将确定，与没有细胞增强的常规DO相比，优化的自体干细胞介入DO是否可以显著缩短DO治疗时间(缩短数周)，同时实现类似质量和数量的骨再生。总体而言，该项目有可能建立一种新的范例，利用牵引成骨技术治疗大型颅面骨缺损性或缺损性疾病。

DESCRIPTION (provided by applicant): Large craniofacial skeletal defects or deficiencies significantly compromise patient's life and remain challenging to treat. Distraction osteogenesis (DO), a mechanically-induced endogenous bone-regeneration approach, has been used as a major treatment modality. Though reliable in bone regeneration, the current DO approach is inefficient because it relies mostly on mechanical stimulation, hence requiring a substantially prolonged treatment time with heightened risks of infection, appliance breakage, noncompliance, and treatment failures. Consistent with the current NIDCR's mission on tissue engineering and regenerative medicine, this project has an overall goal to augment jaw bone regeneration by using mechanical stimulation combined with autologous stem cell-based tissue engineering approaches. The hypothesis is that mandibular DO can be significantly accelerated by the introduction of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) through scaffolds before distraction and booster BM-MSC injections during the consolidation phase. Young pigs, closely relevant to young humans who constitute the population commonly receiving craniofacial DO treatments, will be used. The project will first establish baseline parameters in control animals using our validated pig mandibular DO model. Aim 1 studies will then determine two critical aspects of introducing cells to the DO site, i.e., the use of undifferentiated or osteogenic-differentiated BM-MSCs, and the inclusion or exclusion of bone marrow-derived endothelial progenitor cells (BM-EPCs). Both of these aspects are highly relevant to osteogenesis and angiogenesis needed for bone regeneration, but no study to date has concurrently evaluated them in a DO site. Bone regeneration following cell transplantation will be compared to the baseline parameters derived from the controls in order to identify the lead osteogenic promoting combination. Next, the project will determine whether booster injection of BM-MSCs during the consolidation phase further improves bone regeneration (Aim 2). Bone regeneration following initial cell transplantation together with booster injections will e compared to that only with initial cell transplantation. The effects of using autologous platelet-rich plasma (PRP) to carry BM-MSCs for injections will also be determined by comparing the DO sites with PRP included in the injections versus DO sites without PRP. The combined data from Aim 1 and 2 will be employed to create an optimal treatment scheme to be evaluated in an accelerated DO protocols with a faster distraction and a shorter consolidation (Aim 3). These studies will determine whether or not an optimized DO with autologous stem cell intervention can substantially shorten (by several weeks) the DO treatment time while achieving similar quality and quantity of bone regeneration, compared to regular DO without cell augmentation. Overall, this project has the potential to establish a new paradigm for the management of large craniofacial bone deficiencies or defects using distraction osteogenesis.