Photoresponsive Granular Hydrogels Enable Spatiotemporal Control of Matrix Mechanics and MSC Behavior

Abstract

ABSTRACT Granular hydrogels offer a powerful platform for engineering porous, cell‐instructive scaffolds with tunable mechanical, structural, and biochemical properties, yet introducing spatial and functional heterogeneity typically requires multiple microgel populations or complex fabrication strategies. Here, we present a programmable, photoresponsive granular hydrogel platform that enables post‐assembly spatiotemporal control of scaffold mechanics and cell microenvironments from a single microgel formulation. Poly(ethylene glycol) microgels containing photolabile allyl sulfide moieties were synthesized via strain‐promoted azide‐alkyne cycloaddition and assembled into granular scaffolds capable of light‐mediated remodeling through radical addition‐fragmentation chain transfer. This chemistry afforded dynamic, on‐demand, and spatially defined tuning of mechanical properties (G′ = 0.7–3.7 kPa) while maintaining scaffold porosity (∼20%). High‐resolution photopatterning across multiple length (6 µm‐1 mm) and timescales enabled precise modulation of local microenvironments. Human mesenchymal stem/stromal cells embedded in these scaffolds responded to spatiotemporal modulation of matrix mechanics as observed by changes in morphology, yes‐associated protein 1 (YAP) nuclear localization, and secretory profiles. Together, these results establish a versatile and broadly applicable strategy for programming mechanical heterogeneity and regulating cell behavior in granular hydrogels through photolabile moieties.