Granular hydrogels improve myogenic invasion and repair after volumetric muscle loss

Abstract

Skeletal muscle injuries including volumetric muscle loss (VML) are marked by excessive scarring and functional disability that inherent regenerative mechanisms are unable to reverse. Despite high prevalence in civilian and military populations, there is currently no effective treatment for VML but bioengineering interventions such as biomaterials that fill the VML defect to support tissue growth and repair are a promising strategy. However, traditional biomaterials developed for this purpose are rigid, non-porous constructs that hinder cell infiltration. In the present study, we test the effects of granular hydrogels on muscle repair - hypothesizing that their inherent porosity will support the invasion of native myogenic cells and their flowability will permit conformable filling of the defect site, leading to effective muscle repair. We used photocurable hyaluronic acid crosslinked with matched muscle stiffness to prepare small or large particle fragments via extrusion fragmentation and facile size sorting. In assembled granular hydrogels, particle size and degree of packing significantly influenced pore features including porosity, pore size, and pore density, as well as rheological behavior including storage moduli and yield strain. We tested the ability of granular hydrogels to support early-stage (satellite cell invasion) and late-stage (myofiber invasion) muscle repair compared to bulk hydrogels in a VML injury model in the tibialis anterior (TA) muscles of 12-14 week old mice. Histological evaluation revealed granular hydrogels supported these regenerative processes while control bulk hydrogels restricted them to the gel-tissue interface in line with the absence of invading cells. Together, these results highlight the promising potential of injectable and porous granular hydrogels in supporting endogenous repair after severe muscle injury.

Cell-scale porosity in microporous annealed particle (MAP) scaffolds modulates immune response and promotes formation of innervated muscle fibers in volumetric muscle loss injuries

“…A wide variety of biomaterial-based approaches have been used to support VML recovery, including decellularized matrices [8][9][10] , electrospun scaffolds 11 , bioactive glass 12 , nanomaterials 11,[13][14][15][16][17][18] , and hydrogels [19][20][21][22][23][24][25][26] . While biomaterial-assisted therapies are promising tools to provide a guided healing environment for the restoration of lost tissue and function in VML, they have yet to achieve clinical significance.…”

“…Of the biomaterial classes listed above, hydrogels are one of the most commonly used for VML due to their chemical and physical versatility, which allow them to match skeletal tissue properties. Hydrogels for muscle regeneration have been made from natural and synthetic polymers, and have been applied in various forms (e.g., bioprinting [19][20][21] , electrospinning 22 , sponges [23][24][25] , and granular hydrogels 26 ). Like other biomaterials, hydrogels face an additional obstacle in the form of a foreign body reaction (FBR), which is a form of chronic inflammation that occurs at the interface of the implant and ultimately causes its fibrotic encapsulation.…”