Endomysium-permeable muscle extracellular matrix composite hydrogel for promoting functional muscle recovery in muscle atrophy

Sarcopenia is an age-related muscle atrophy that has recently been considered a significant factor in deteriorating the quality of life in elderly individuals. However, currently, there are no clinically-approved drugs available for the treatment of sarcopenia due to its complex etiology. Although cell therapies have been attempted to treat muscle atrophy, including sarcopenia, several problems still remain, including the cost and time for cell production, potential immunogenicity, and insufficient efficacy. In this sense, we suggest a cell-free therapeutic approach using a muscle extracellular matrix (MEM)-based composite hydrogel to boost proliferation and differentiation of endogenous cell populations by reconstituting the muscle-specific microenvironment. Here, we combine two components: (1) aldehyde-modified hyaluronic acid conjugated with the pyrogallol group (AH-PG), which enables permeation into the gaps among muscle fibers and in situ self-crosslinking of the hydrogel, and (2) decellularized muscle-derived MEM to provide muscle-specific components and growth factors for muscle restoration. The resultant composite hydrogel can be facilely injected via intramuscular route and stably maintained in the endomysial area where muscle stem cells reside, which changes the impaired atrophic and sarcopenic states to the muscle-regenerative microenvironment. As a result, the composite hydrogel promotes not only muscle mass recovery in disuse and age-induced muscle atrophies, but also muscle maturation accompanying vascularization and innervation, thereby significantly improving muscular function in sarcopenic animals. Together, our hybrid hydrogel can serve as a promising biomaterial for cell-free therapy of muscle atrophy.