Flowable and microporous granular grafts made from decellularized extracellular matrix microgels for tissue repair

Decellularized extracellular matrix (dECM) scaffolds are widely used in tissue engineering, primarily due to their inherent bioactivity and cell-instructive properties. ECM scaffolds are conventionally prepared as monolithic and rigid sheet-like constructs, and while these form factors are generally sutured at the defect site it can be challenging to achieve even filling of the defect volume, where flowable scaffolds may be beneficial. Although infusible and injectable dECM formulations have been developed, optimizing for high mechanical strength and a porous microstructure that permits integration with host tissue remains difficult. Here, we report the fabrication of granular dECMs, which are flowable and microporous biomaterials that are assembled through the packing of crosslinked dECM microgels. A feature of these dECM microgels is their crosslinking through dityrosine photochemistry, which circumvents the need for chemical modification of the dECM with synthetic functional groups. Granular dECMs show tunable porosity through optimization of microgel packing, and shear-responsive rheological behaviors that impart extrudability from syringe needles. When tested in a mouse model of volumetric muscle loss and compared against no treatment negative controls, bioinert granular controls made with poly(ethylene glycol) diacrylate, and bulk dECM implants, granular dECMs showed improved wound healing properties and support robust angiogenesis and myogenesis at a structural level. Data from longitudinal muscle force measurements carried out over 12 weeks showed comparable levels of functional recovery across all groups. Collectively, these results showcase the potential promise of dityrosine crosslinked granular dECMs in supporting tissue repair. These hydrogels may be broadly applicable as acellular injectable grafts for reconstructive surgery and wound healing applications. STATEMENT OF SIGNIFICANCE: Acellular biomaterial grafts made with decellularized tissues are commercially available and clinically used for reconstructive and wound healing applications. Their rigid design and low malleability has motivated the development of injectable and infusible dECM hydrogels. However, it has remained challenging to co-optimize their mechanical properties and microporosity for tisue repair applications. This work presents a granular dECM graft technology that uses light-activated crosslinking of tyrosine groups naturally present in protein-rich tissues to fabricate dECM microgels that are then assembled into microporous scaffolds that flow under strain and can be extruded via syringe into irregularly shaped tissue defects. Using a clinically relevant mouse model of muscle injury, we highlight the regenerative potential of granular dECM grafts in supporting rapid vascularization and myogenesis at the defect site. This advanced design of injectable and flowable dECM biomaterials is likely to find broad utility in reconstructive surgery and tissue engineering applications.