Granular Hydrogels Improve Myogenic Invasion and Repair after Volumetric Muscle Loss

Skeletal muscle injuries including volumetric muscle loss (VML) lead to excessive tissue scarring and permanent functional disability. Despite its high prevalence, there is currently no effective treatment for VML. Bioengineering interventions such as biomaterials that fill the VML defect to support cell and tissue growth are a promising therapeutic strategy. However, traditional biomaterials developed for this purpose lack the pore features needed to support cell infiltration. The present study investigates for the first time, the impact of granular hydrogels on muscle repair - hypothesizing that their flowability will permit conformable filling of the defect site and their inherent porosity will support the invasion of native myogenic cells, leading to effective muscle repair. Small and large microparticle fragments are prepared from photocurable hyaluronic acid polymer via extrusion fragmentation and facile size sorting. In assembled granular hydrogels, particle size and degree of packing significantly influence pore features, rheological behavior, and injectability. Using a mouse model of VML, it is demonstrated that, in contrast to bulk hydrogels, granular hydrogels support early-stage (satellite cell invasion) and late-stage (myofiber regeneration) muscle repair processes. Together, these results highlight the promising potential of injectable and porous granular hydrogels in supporting endogenous repair after severe muscle injury.