Phase-Templated Poly(ethylene glycol) Sponges for Programmable Porosity and Bone Regeneration

Synthetic hydrogels rarely form the porous, cell-permissive architectures required for effective tissue regeneration. Here, we report a poly(ethylene glycol) (PEG) sponge hydrogel whose macroporous network is pre-programmed through gel–gel phase separation (GGPS) and stabilized by freeze–thaw processing. This mechanism generates fully interconnected pores up to 150 μm in size, larger than those typically achieved in conventional PEG hydrogels, while preserving mechanical resilience and eliminating swelling. The resulting architecture supports infiltration and three-dimensional expansion of human mesenchymal stem cells and directs lineage specification through pore-geometry–dependent mechanotransduction. When functionalized with osteoinductive cues, the sponge promotes robust regeneration of critical-sized cranial defects. By coupling polymer phase behavior with precise structural control, this strategy establishes a scalable route to architecturally defined synthetic scaffolds for regenerative medicine.