Focused Ultrasound Crosslinkable Granular Hydrogels

Minimally invasive delivery of biomaterials for tissue regeneration can be achieved using biomaterials delivered by injection that rapidly stabilize at the delivery site. Tissue regeneration has been shown to be dependent on material properties, with porosity strongly supporting revascularization and tissue regrowth. Here, a highly porous granular hydrogel system was designed that is compatible with the unique strengths of highly penetrating, minimal invasive focused ultrasound (FUS), to address this challenge. FUS offers well-defined spatial and temporal control over hydrogel crosslinking. We developed a composite granular hydrogel scaffold composed of two polyethylene glycol (PEG)-based components, microgels and fibers with FUS-responsive chemistry, and a pore-defining gelatin microgel component. Upon applying FUS, the bulk granular hydrogel stabilized through the formation of crosslinks between PEG components, with porosity designed by gelatin microgel melting. FUS-crosslinking parameters were determined that resulted in crosslinking both in vitro and a mouse cadaver model of minimally invasive delivery. The resulting granular hydrogels stability depended on the presence of fibers and exhibited viscoelastic properties comparable to granular hydrogels that were photocrosslinked. Hydrogels were highly porous and cytocompatible. This work defines a FUS-responsive granular system and extends the potential of FUS as a novel, noninvasive method for crosslinking regenerative hydrogel systems.