Macroporous Alginate–PEG Hybrid Double Network Cryogels: Tuning Mechanics, Porosity, and Long-Term Growth Factor Release via Polymer Concentration, Ice Nucleation, and Sulfation

Cryogels are macroporous hydrogel scaffolds with promising applications in tissue engineering; however, conventional systems often suffer from inadequate mechanical strength, limited porosity, and biocompatibility concerns due to the use of free radical initiators and organic solvents. In this study, we report the engineering of a hybrid double-network (HDN) cryogel scaffold composed of alginate and poly(ethylene glycol) (PEG), designed for tissue engineering applications. The scaffolds were fabricated via simultaneous cross-linking of alginate and PEG networks at subzero temperatures using a solvent-free and initiator-free biocompatible approach. We systematically investigated the influence of polymer concentration, ice nucleating agents, and sulfation of alginate on the resulting cryogel structure, porosity, and mechanical properties. The optimized HDN cryogels exhibited a highly interconnected macroporous architecture, improved compressive strength, and enhanced elasticity while maintaining cytocompatibility. These findings highlight the potential of HDN cryogels as robust and biocompatible scaffolds for soft tissue engineering and regenerative medicine applications.