The Development and Rescue of an Atrophic Nonunion Model

萎缩性骨不连模型的开发和挽救

• 批准号: 10007577
• 负责人: Katherine Hixon
• 金额: $ 6.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007577
• 关键词: Ablation; Address; Affect; Animal Model; Atrophic; Biological; Biological Products; Biology; Biomechanics; Bone Marrow; Bone Regeneration; Bone Transplantation; Bone callus; Cartilage; Cell Lineage; Cell Proliferation; Chondrocytes; Clinical; Defect; Development; Environment; Excision; Exposure to; Extracellular Matrix; Failure; Fracture; Ganciclovir; Gene Delivery; Goals; Immature Bone; Impaired healing; Individual; Infection; Intervention; Lead; Mechanics; Mediating; Mesenchymal Stem Cells; Metabolic Pathway; Methods; Mission; Modeling; Mus; Musculoskeletal Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteotomy; Pathway interactions; Patients; Periosteum; Polymers; Porifera; Proliferating; Reporting; Research; Role; Site; Societies; Source; Structure; Techniques; Temperature; Testing; Therapeutic Intervention; Time; Tissue Engineering; Transgenes; Transgenic Mice; Treatment Cost; United States; Withdrawal; Work; bone; bone healing; bone morphogenetic protein 2; clinically relevant; cost; crosslink; cryogel; design; gene delivery system; healing; improved; in vivo; lentiviral-mediated; mouse model; musculoskeletal injury; novel; nucleoside analog; osteochondral tissue; osteogenic; osteoprogenitor cell; overexpression; pre-clinical; prevent; progenitor; recruit; regenerative; repaired; scaffold; stem cell population; stem cells; therapeutic evaluation; transgene expression; treatment strategy

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.

项目总结/摘要 骨不连定义为骨永久性愈合失败，需要手术干预 治愈之道[1]。有两种类型的骨不连，肥大性和萎缩性，在2018年国际骨不连。 骨折修复学会（ISFR），需要新的模型萎缩性骨不连被确定。动物模型 早在1999年，萎缩性骨不连的研究就已经开始， 不能愈合，导致不愈合[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、骨髓清除、血管离断术或创建 临界尺寸缺陷虽然所有方法都会导致骨不连，但这种侵入性方法并不代表骨不连。 许多临床骨不连，其中骨再生已被代谢紊乱抑制， 路径[3，4]。相反，萎缩性骨不连中所见的“生物学失败”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有效的方法， 相关的临床前骨不连模型，以测试治疗干预措施。 在Jilka等人的先前研究中[5]，开发了3.6Col1a1-tk（Col 1-tk）小鼠，其中增殖的 成骨细胞谱系细胞可以通过暴露于核苷类似物更昔洛韦（GCV）来消除。在 在我们实验室的初步研究中，我们已经观察到，在Col 1-tk小鼠中， 导致无法形成愈伤组织。我们认为，一个更全面的评估受损愈合， Col 1-tk小鼠可作为一种有用的萎缩性骨不连模型。此外，在萎缩 骨不连时，骨愈合变得停滞，并且加入生物制剂，例如骨移植物， 是诱导再生所必需的。我们提出一种组织工程支架介导的基因 递送过表达成骨转基因的骨髓间充质干细胞（MSC）群 骨形态发生蛋白-2（BMP-2）将在骨不连部位诱导骨生成[6-10]。本研究是 不仅建立了与临床相关的萎缩性骨不连模型， NIAMS的使命是治疗肌肉骨骼损伤和疾病。