Practical Guide to the Design of Granular Hydrogels for Customizing Complex Cellular Microenvironments

Granular hydrogels are a novel class of microporous platforms for cell culture and delivery, formed as macroscopic aggregates through the bottom-up assembly of microgels. Given their flexibility and diversity, granular scaffolds have attracted extensive attention as emerging materials replicating the complex, heterogeneous environments found in natural tissues. This review outlines the design principles of granular hydrogels, highlighting critical intra-microgel and inter-microgel factors that determine the final physicochemical properties of the entire system for creating a biomimetic cellular microenvironment. Intra-microgel factors represent the intrinsic properties of microgels, while inter-microgel factors primarily focus on the interactions between microgels. A comprehensive analysis is conducted on each intra- and inter-microgel factor, elaborating on their definitions, classifications, and regulation strategies. Subsequently, the final properties of granular hydrogels, such as porosity, mechanical characteristics, degradability, heterogeneity, drug loading, and cellular incorporation strategy, are discussed in detail with an emphasis on their effects on cellular behavior. Finally, the current technical challenges in granular hydrogel design are discussed along with potential opportunities for further development.