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.

项目概要/摘要 由外伤、感染或癌症引起的大骨缺损导致数以千计的截肢者和数以百万计的人 最近，一种两阶段的手术​​方案，马斯奎莱诱导膜技术（MIMT）， 提出了一种革命性的方法来重建临界尺寸的缺陷，比当前的方法更理想 更重要的是，它提供了一个独特的机会 发现新的骨再生生物学，可应用于其他骨形成情况（即 MIMT 的关键特征是自体异物膜。 数周至数月后，在第二次手术期间，在植入的骨水泥垫片周围形成垫片。 移除膜室并用颗粒状骨移植物填充该技术可以治愈缺损。 最大可达 25 厘米，是传统无膜嫁接处理最大体积的三倍多。 然而，MIMT 的再生机制完全未知。 膜是必要的。其关键功能尚未确定，因此没有证据可以改进其。 临床应用或利用生物学原理进行其他组织再生的一个关键障碍。 研究 MIMT 机制的一个重要原因是，它仅在大鼠和大型动物身上得到了彻底的证实。 可用于这些物种的遗传工具和试剂的数量远远少于可用于这些物种的遗传工具和试剂的数量。 因此，建立基于小鼠的 MIMT 模型将非常强大，并且可以进行更深入的研究。 迄今为止，只有一项研究使用小鼠进行 MIMT，但第二阶段并未使用小鼠。 尝试过，第一阶段的研究设计并没有很好地反映在其他物种中所做的事情。 该提案的目标是建立一个基于鼠标的 MIMT 模型，将该模型与其他模型进行比较/对比 在其他物种中是已知的，并且我们使用仅在小鼠中可用的工具来回答一些基本的 MIMT 问题。 小鼠模型是可行的，并且宿主细胞，特别是成骨细胞，主要是 为了检验这个假设，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知的 在确定小鼠 MIMT 模型可行后，我们将使用转基因动物。 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被结合起来以针对特定的细胞/基因/途径 未来 R01 中的宿主/移植小鼠组织。