The Development and Rescue of an Atrophic Nonunion Model

项目摘要/摘要 骨不连被定义为骨愈合的永久性失败，需要手术治疗。 以达到治愈的目的[1]。骨不连有肥厚型和萎缩型两种类型，在2018年国际拳击比赛中。 在骨折修复学会(ISFR)，对萎缩性骨不连新模型的需求被确认。动物模型 萎缩性骨不连早在1999年就已经出现，提供了骨骼的活体表现 无法愈合，导致骨不连[1，2]。然而，大多数用于复制的动物模型 骨不连包括截骨术、骨膜剥离、骨髓摘除、断流术或创伤性骨不连 关键尺寸的缺陷。虽然所有的方法都会导致骨不连，但这种侵入性方法并不能代表 许多临床骨不连，骨再生因代谢障碍而受阻 路径[3，4]。相反，萎缩性骨不连中所见的“生物学上的失败”应该与那些 临床上可见骨痂减少/缺失。因此，仍然需要开发一种更多的 相关的临床前骨不连模型，以测试治疗干预措施。 在Jilka等人之前的一项研究中。[5]、3.6Col1a1-tk(col1-tk)小鼠 成骨细胞系细胞可以通过核苷类似物更昔洛韦(GCV)的作用而被消融。在……里面 在我们实验室的初步研究中，我们观察到了对Col1-tk小鼠增殖的成骨细胞的消融 导致无法形成愈伤组织。我们假设对受损的愈合情况进行更全面的评估 Col1-tk小鼠可能会导致其成为一种有用的萎缩性骨不连模型。此外，在萎缩性 骨不连，骨愈合停滞，加上生物制剂，如植骨， 通常是诱导再生所必需的。我们提出了一种组织工程支架介导的基因 高表达成骨转基因的骨髓间充质干细胞(MSC)群的构建 骨形态发生蛋白-2(BMP-2)将在骨不连部位诱导成骨[6-10]。这项研究是 这不仅对建立与临床相关的萎缩性骨不连模型具有重要意义，而且对探索新的救治方法具有重要意义。 在NIAMS完成治疗肌肉骨骼损伤和疾病的任务后，恢复愈合的技术。

PROJECT SUMMARY/ABSTRACT Nonunion is defined as the permanent failure of a bone to heal, where surgical intervention is required to achieve healing [1]. There are two types of nonunion, hypertrophic and atrophic, and at the 2018 Intl. Society of Fracture Repair (ISFR), a need for new models of atrophic nonunion was identified. Animal models of atrophic nonunion have been around as early as 1999, providing an in vivo representation of the bone's inability to heal, resulting in nonunion [1, 2]. However, the majority of the animal models used to replicate nonunion involve osteotomy, periosteal stripping, bone marrow removal, devascularization, or the creation of a critical-sized defect. While all approaches result in nonunion, such invasive methods are not representative of many clinical nonunions where osseous regeneration has been arrested by a disturbance of metabolic pathways [3, 4]. The “failure of biology” seen in atrophic nonunion should, instead, be modeled closely to those seen clinically with a reduced/absent callus. Thus, there remains a need for the development of a more relevant, pre-clinical nonunion model to test therapeutic interventions. In a previous study by Jilka et al. [5], 3.6Col1a1-tk (Col1-tk) mice were developed in which proliferating osteoblast lineage cells can be ablated through exposure to the nucleoside analog ganciclovir (GCV). In preliminary studies in our lab, we have observed that ablation of proliferating osteoblasts in the Col1-tk mice causes a failure to form a callus. We posit that a more comprehensive assessment of the impaired healing in the Col1-tk mice may lead to its establishment as a useful atrophic nonunion model. Further, in atrophic nonunion, the bone healing has become stagnant and the addition of a biological agent, such as a bone graft, is often necessary to induce regeneration. We propose that a tissue-engineered scaffold-mediated gene delivery of a bone marrow mesenchymal stem cell (MSC) population overexpressing the osteogenic transgene bone morphogenetic protein-2 (BMP-2) will induce osteogenesis at the site of nonunion [6-10]. This research is significant to not only establish a clinically relevant model of atrophic nonunion, but also explore a novel rescue technique to restore healing, following the NIAMS mission of treating musculoskeletal injury and disease.