Extracellular matrix grafts for the treatment of volumetric muscle loss

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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.