The Effect of Laminin-111 Hydrogels on Muscle Regeneration in a Murine Model of Injury

Volumetric muscle loss (VML) is characterized by a critical loss of muscle tissue that is accompanied by severe functional impairment and often long-term disability. Clinical therapies currently used in the treatment of VML are ineffective at regenerating lost muscle and restoring function. In this study, we used a novel hydrogel composed of fibrinogen and laminin-111, to promote regeneration and recovery of VML-traumatized muscle. Our previous study showed that these hydrogels exhibit a fibrous structure and Young's modulus of ∼2 kPa, while supporting C2C12 myoblast proliferation, myogenic marker expression, and proregenerative growth factor secretion in vitro. In a murine model of VML injury, the implantation of these hydrogels showed significant improvements in muscle weights and heightened infiltration of endothelial, hematopoietic, and immune cells at 2 weeks postinjury compared to the untreated muscles. At 4 weeks postinjury, the hydrogel-treated muscle showed increased myogenic activity, acetylcholine receptor clustering, and induction of the anti-inflammatory M2-like macrophage phenotype. However, improvements in muscle weights and force production were not observed at 4 weeks. An adjunct therapy such as physical rehabilitation or codelivery of stem cells may be required for the effective treatment of VML. Overall, these results will inform and guide the development of a successful tissue engineering strategy for the regeneration of skeletal muscle following trauma. Extremity injuries make up the most common survivable injuries in vehicular accidents and modern military conflicts. A majority of these injuries involve volumetric muscle loss (VML). The potential for donor site morbidity may limit the clinical use of autologous muscle grafts for VML injuries. Treatments that can improve the regeneration of functional muscle tissue are critically needed to improve limb salvage and reduce the rate of delayed amputations. The development of a laminin-111-enriched fibrin hydrogel will offer a potentially transformative and “off-the-shelf” clinically relevant therapy for functional skeletal muscle regeneration.