RESUMEN
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.
RESUMEN
BACKGROUND: Volumetric muscle loss (VML) causes pain and disability in patients who sustain traumatic injury from invasive surgical procedures, vehicle accidents, and battlefield wounds. Clinical treatment of VML injuries is challenging and although options such as free-flap autologous grafting exist, patients inevitably develop excessive scarring and fatty infiltration, leading to muscle weakness and reduced quality of life. SUMMARY: New bioengineering approaches, including cell therapy, drug delivery, and biomaterial implantation, have emerged as therapies to restore muscle function and structure to pre-injury levels. Of these, acellular biomaterial implants have attracted wide interest owing to their broad potential design space and high translational potential as medical devices. Implantable biomaterials fill the VML defect and create a conduit that permits the migration of regenerative cells from intact muscle tissue to the injury site. Invading cells and regenerating myofibers are sensitive to the biomaterial's structural and biochemical properties, which can play instructive roles in guiding cell fate and organization into functional tissue. KEY MESSAGES: Many diverse biomaterials have been developed for skeletal muscle regeneration with variations in biophysical and biochemical properties and while many have been tested in vitro, few have proven their regenerative potential in clinically relevant in vivo models. Here, we provide an overview of recent advances in the design, fabrication, and application of acellular biomaterials made from synthetic or natural materials for the repair of VML defects. We specifically focus on biomaterials with rationally designed structural (i.e., porosity, topography, alignment) and biochemical (i.e., proteins, peptides, growth factors) components, highlighting their regenerative effects in clinically relevant VML models.