Skeletal muscle has a remarkable regenerative capability following mild physical or chemical insult. However, following a critical loss of muscle tissue, the regeneration process is impaired due to the inadequate myogenic activity of muscle resident stem cells (i.e., satellite cells). Laminin (LM) is a heterotrimeric structural protein in the satellite cell niche that is crucial for maintaining its function. In this study, we created hydrogels composed of poly (ethylene glycol) (PEG) and LM-111 to provide an elastic substrate for satellite cell proliferation at the site of injury. The PEG-LM111 conjugates were mixed with 5% and 10% (w/v) pure PEG-diacrylate (PEGDA) and photopolymerized to form 5% and 10% PEGLM gels. Pure 5% and 10% PEGDA gels were used as controls. The modulus of both hydrogels containing 10% (w/v) PEGDA was significantly higher than the hydrogels containing 5% (w/v) PEGDA. The 5% PEGLM hydrogels showed significantly higher swelling in aqueous medium suggesting a more porous structure. CC myoblasts cultured on the softer 5% PEGLM hydrogels showed a flat and spread-out morphology when compared to the rounded, multicell clusters formed on the 5% PEGDA, 10% PEGDA, and 10% PEGLM hydrogels. The 5% PEGLM hydrogels also promoted a significant increase in both vascular endothelial growth factor and interleukin-6 (IL-6) production from the myoblasts. Additionally, the expression of MyoD was significantly higher while that of myogenin and α-actinin trended higher on the 5% PEGLM hydrogels compared to 5% PEGDA on day 5. Our data suggests that the introduction of LM-111 into compliant PEG hydrogels promoted myoblast adhesion, survival, pro-regenerative growth factor production, and myogenic activity.
Volumetric muscle loss (VML) injuries are irrecoverable due to a significant loss of regenerative elements, persistent inflammation, extensive fibrosis, and functional impairment. When used in isolation, previous stem cell and biomaterial‐based therapies have failed to regenerate skeletal muscle at clinically relevant levels. The extracellular matrix (ECM) microenvironment is crucial for the viability, stemness, and differentiation of stem cells. Decellularized‐ECM (D‐ECM) scaffolds are at the forefront of ongoing research to develop a viable therapy for VML. Due to the retention of key ECM components, D‐ECM scaffolds provide an excellent substrate for the adhesion and migration of several cell types. Mesenchymal stem cells (MSCs) possess regenerative and immunomodulatory properties and are currently under investigation in clinical trials for a wide range of medical conditions. However, a major limitation to the use of MSCs in clinical applications is their poor viability at the site of transplantation. In this study, we have fabricated spherical scaffolds composed of gelatin and skeletal muscle D‐ECM for the adhesion and delivery of MSCs to the site of VML injury. These spherical scaffolds termed “gelloids” supported MSC survival, expansion, trophic factor secretion, immunomodulation, and myogenic protein expression in vitro. Future studies would determine the therapeutic efficacy of this approach in a murine model of VML injury.
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