Fibronectin Tethering as a Shear-thinning Bio-Annealing Strategy for Granular Hydrogels

Granular hydrogel scaffolds (GHS) are injectable, integrative biomaterials built from hydrogel microparticles that permit rapid cell infiltration independent of scaffold degradation. Microporous annealed particle (MAP) scaffolds, a sub-class of GHS, use inter-microparticle crosslinks to anneal adjacent particles, providing greater mechanical stability than purely jammed assemblies. A growing range of inter-particle crosslinking strategies-including covalent photo-initiated radical polymerization and reversible guest-host chemistries, some intended to mimic extracellular matrix (ECM) viscoelasticity-focus on mechanical stabilization, while surface bioactivity is typically added separately via orthogonally tethered cell-adhesion ligands such as RGD, a peptide derived from fibronectin (FN), a key mediator of cell-ECM and ECM-ECM interactions. Here, we present an alternative that unifies these functions: coating MAP microparticle building blocks with covalently bound fibronectin to create fibronectin-modified MAP (FN-MAP). FN-MAP exhibits shear-thinning annealing with complete recovery of scaffold mechanics after physical mixing. Human lung fibroblasts respond favorably, adopting spread morphologies with high viability. Translationally, FN-MAP shows proof-of-principle promise for 3D bioprinting (greater stability and higher print resolution) and wound healing (increased epidermal closure in a diabetic mouse model). FN-MAP thus delivers both increased scaffold strength and bioactivity without exogenous soluble linkers or mixed particle populations.

Porous scaffolds encourage tissue regeneration but typically need separate components to be both strong and bioactive. By coating granular hydrogel scaffolds with fibronectin, a natural protein central to wound repair, we simultaneously boost material strength and cell-instructive signaling. This single-protein strategy produces stronger, more printable scaffolds, promotes healthy cell activity, and enhances wound closure in a challenging diabetic mouse model.