Extracellular matrix grafts for the treatment of volumetric muscle loss

用于治疗体积肌肉损失的细胞外基质移植物

• 批准号: 577534-2022
• 负责人: Bentzinger, FlorianCF
• 金额: $ 3.28万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762059
• 关键词: Extracellular; matrix; grafts; treatment; volumetric

Musculoskeletal injuries are one of the most frequent reasons for emergency room visits and make up over 75% of battlefield wounds in modern combat. Skeletal muscle, one of the most abundant tissues of the human body, has a remarkable regenerative capacity mediated by tissue resident myogenic progenitors (MPs). However, MPs require an extracellular matrix (ECM) template to efficiently repair damaged muscle tissue. Volumetric muscle loss (VML) is caused by excision of large portions of skeletal muscle as a consequence of injuries or surgery. Due to the absence of an organized ECM and their limited migratory capacity, MPs in unaffected areas of skeletal muscle adjacent to the injury fail to efficiently repopulate and repair the VML site. As a result, VML frequently results in chronic functional deficits and disability that have a considerable socioeconomic impact. Over the recent years we have developed sophisticated methods for decellularization of skeletal muscle tissue. By providing guidance cues for endogenous MPs, these ECM scaffolds hold great therapeutic promise as grafts for VML injuries. Here, we assembled an interdisciplinary team of bioengineers and stem cell biologists to develop a microfabricated polysulfone cell culture chamber system to assess the ability of MPs to migrate into and repopulate fibrin gel embedded ECM scaffolds. These experiments will, for the first time, provide an in-vitro platform to assess the potential of ECM scaffold preparations as grafts for VML injuries. In parallel experiments, we will test the efficiency of our decellularized fibrin embedded skeletal muscle ECM scaffolds to promote the repair of VML injuries in mice. Lastly, in a third, partially interdependent aim, we will test a library of previously identified and novel pro-migratory growth factors for their ability to stimulate the recellularization of ECM scaffolds in our in-vitro system and subsequently in our mouse model of VML. Ultimately, our work will inspire the development of much needed novel therapeutic avenues for the treatment of VML. A surgical intervention that is capable to enhance the repair of VML injuries represents an opportunity to ease the burdens of daily living for thousands of patients each year.

肌肉骨骼损伤是急诊室就诊的最常见原因之一，占现代战斗中战场创伤的75%以上。骨骼肌是人体最丰富的组织之一，具有由组织驻留的肌源性祖细胞（MP）介导的显著的再生能力。然而，MP需要细胞外基质（ECM）模板来有效地修复受损的肌肉组织。肌肉体积损失（VML）是由于损伤或手术切除大部分骨骼肌而引起的。由于缺乏有组织的ECM和它们有限的迁移能力，邻近损伤的骨骼肌未受影响区域中的MP不能有效地重新填充和修复VML位点。因此，VML经常导致慢性功能缺陷和残疾，并产生相当大的社会经济影响。近年来，我们已经开发出复杂的骨骼肌组织脱细胞化方法。通过为内源性MP提供指导线索，这些ECM支架作为VML损伤的移植物具有很大的治疗前景。在这里，我们组建了一个跨学科的生物工程师和干细胞生物学家团队，开发了一种微加工聚砜细胞培养室系统，以评估MP迁移到纤维蛋白凝胶包埋的ECM支架中并重新填充的能力。这些实验将首次提供一个体外平台来评估ECM支架制剂作为VML损伤移植物的潜力。在平行实验中，我们将测试我们的脱细胞纤维蛋白包埋骨骼肌ECM支架促进小鼠VML损伤修复的效率。最后，在第三个部分相互依赖的目标中，我们将测试先前鉴定的和新的促迁移生长因子的文库，以测试它们在我们的体外系统中以及随后在我们的VML小鼠模型中刺激ECM支架再细胞化的能力。最终，我们的工作将激发开发急需的治疗VML的新治疗途径。能够增强VML损伤修复的手术干预是减轻每年数千名患者日常生活负担的机会。