Extracellular matrix grafts for the treatment of volumetric muscle loss

肌肉骨骼损伤是急诊室最常见的原因之一，在现代战斗中占战场创伤的75%以上。骨骼肌是人体内含量最丰富的组织之一，在组织驻留的肌源性祖细胞(MPS)的介导下具有显著的再生能力。然而，MPS需要细胞外基质(ECM)模板来有效修复受损的肌肉组织。容积性肌肉丢失(VML)是由于损伤或手术而切除大部分骨骼肌而引起的。由于缺乏有组织的ECM及其有限的迁移能力，损伤附近骨骼肌未受影响区域的MPS无法有效地重新填充和修复VML部位。因此，VML经常导致慢性功能缺陷和残疾，具有相当大的社会经济影响。近年来，我们开发了用于骨骼肌组织脱细胞的复杂方法。通过为内源性MPS提供指导线索，这些ECM支架作为VML损伤的移植物具有巨大的治疗前景。在这里，我们召集了一个由生物工程师和干细胞生物学家组成的跨学科团队来开发一种微米级聚砜细胞培养箱系统，以评估MPS迁移到纤维蛋白凝胶嵌入的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，以评估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嵌入骨骼肌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，我们将测试一个先前识别的和新的促迁移生长因子库，以确定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支架重新细胞化的能力。最终，我们的工作将激励开发急需的治疗VML的新治疗途径。一种能够加强VML损伤修复的外科干预措施为每年数千名患者提供了减轻日常生活负担的机会。

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.