Bone Regeneration in a Mouse Model of Masquelet's Induced Membrane Technique

Masquelet 诱导膜技术小鼠模型的骨再生

• 批准号: 10426512
• 负责人: SARAH H MCBRIDE-GAGYI
• 金额: $ 20.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426512
• 关键词: Adjuvant; Adult; Amputation; Amputees; Animals; Autologous; Biochemical; Biological; Biological Assay; Biology; Blood Vessels; Bone Regeneration; Bone Transplantation; Cells; Characteristics; Clinical; Communities; Defect; Development; Diagnostic; Environment; Foreign Bodies; Future; Gene Expression; Generations; Genes; Genetic; Goals; Harvest; Health Care Costs; Histology; Imaging Techniques; Implant; Infection; Isogenic transplantation; Label; Lead; Limb structure; Location; Malignant Neoplasms; Membrane; Modeling; Mus; Natural regeneration; Operative Surgical Procedures; Osteoblasts; Osteocytes; Osteogenesis; Pathway interactions; Patient Care; Patients; Population; Procedures; Process; Rattus; Reagent; Regimen; Reporting; Research; Research Design; Resort; Roentgen Rays; Role; Structure; Techniques; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; base; body system; bone; bone repair; cell type; clinical application; clinical practice; cohort; cost; design; experimental study; healing; implantation; improved; microCT; mouse model; novel; osteogenic; patient population; pediatric patients; protein expression; reconstruction; regenerative; regenerative biology; sample fixation; success; tissue regeneration; tool

Project Summary/Abstract Large bone defects caused by trauma, infection, or cancer lead to thousands of amputees and millions of dollars in costs. Recently, a two-staged surgical regimen, Masquelet’s Induced Membrane Technique (MIMT), has presented a revolutionary way to reconstruct critical-sized defects that is more ideal than the current standards and could serve a wider patient population. More importantly, it presents a unique opportunity to discover new bone regeneration biology which could be applied to other bone formation situations (i.e. non- union, fusions) and possibly other tissues. The key feature of MIMT is an autologous foreign-body membrane that forms around an implanted bone cement spacer. Weeks to months later during a second surgery, the spacer is removed and the membrane compartment is filled with morselized bone graft. The technique can heal defects as large as 25 cm, more than triple the traditional maximum volume treatable via grafting without the membrane. However, MIMT’s regeneration mechanisms are completely unknown. All that is certain is that the membrane is necessary. Its critical functions have not yet been defined, so there is no evidence to improve its clinical application or harness the biological principles for other tissue regeneration scenarios. A critical barrier to investigating MIMT’s mechanisms is that it has only been thoroughly established in rats and larger animals. The number of genetic tools and reagents available for these species are far fewer than those available for mice. Thus, establishing a mouse-based MIMT model would be very powerful and allow much more in depth study and manipulation. To date, only one study has used a mouse for MIMT, but the second stage was not attempted and the first stage study design did not mirror well what has been done in other species. The goals of this proposal are to establish a mouse-based MIMT model, compare/contrast this model with what is known in other species, and use tools only available in mice to answer some fundamental MIMT questions. We hypothesize that a mouse model is feasible and that host cells, specifically osteoblasts, are mainly responsible for new bone generation. To test this hypothesis, we will first compare/contrast membrane formation and bone regeneration dynamics in normal C57BL/6J mice with what is already known from other species – most specifically rats. After establishing that a mouse MIMT model is feasible, we will use transgenic C57BL/6J mice to determine the contributions of host/graft cells to regeneration. Information gained from these experiments will be combined to target specific cells/genes/pathways in host/graft mouse tissues in a future R01.

项目摘要/摘要 由创伤，感染或癌症引起的大骨缺损导致成千上万的截肢者和数百万 美元成本。最近，一种两阶段的外科手术方案，Masquelet的诱导膜技术（MIMT）， 已经提出了一种革命性的方式来重建关键大小的缺陷，这比当前更理想 标准，可以为更广泛的患者人群提供服务。更重要的是，它提供了一个独特的机会 发现可以应用于其他骨形成情况的新骨再生生物学（即非 - 联合，融合）和可能的其他组织。 MIMT的主要特征是自体外国膜 在植入的骨水泥垫片周围形成。几周到几个月后，在第二次手术中，垫片 去除，膜室充满了圆形的骨移植。该技术可以治愈缺陷 多达25厘米，超过三倍的传统最大体积可以通过嫁接无膜处理。 但是，MIMT的再生机制是完全未知的。所有可以肯定的是 膜是必要的。它的关键功能尚未定义，因此没有证据可以改善其 临床应用或利用其他组织再生方案的生物学原理。一个关键的障碍 调查MIMT的机制是仅在大鼠和大型动物中彻底确定它。 这些物种可用的遗传工具和试剂的数量少于可用的遗传工具和试剂的数量 老鼠。这是建立基于鼠标的MIMT模型的功能非常强大，并允许更深入 研究和操纵。迄今为止，只有一项研究已将鼠标用于MIMT，但第二阶段不是 尝试和第一阶段的研究设计并不能很好地反映其他物种所做的事情。 该建议的目标是建立基于鼠标的MIMT模型，将该模型与什么比较/对比 在其他物种中是已知的，并且只使用小鼠可用的工具来回答一些基本的MIMT问题。我们 假设小鼠模型是可行的，并且宿主细胞，特别是成骨细胞，主要是 负责新的骨骼产生。为了检验该假设，我们将首先比较/对比膜 正常C57BL/6J小鼠的形成和骨再生动力学与其他已经知道的 物种 - 最特别的老鼠。确定鼠标MIMT模型是可行的后，我们将使用转基因 C57BL/6J小鼠确定宿主/移植细胞对再生的贡献。 从这些实验中获得的信息将合并到目标特定细胞/基因/途径中 未来R01中的宿主/移植小鼠组织。