Multiscale Structure–Property Relationships in Gelatin-Based Granular Hydrogel Scaffolds

Granular hydrogel scaffolds (GHS) are macroporous biomaterials composed of interlinked jammed hydrogel particles, particularly microgels. Each microgel is a crosslinked polymer network, typically with nanoscale pores. Among macromolecules, proteins such as gelatin and its derivatives are commonly used in GHS research, as their physicochemical characteristics and biological properties are well established. The hierarchical architecture of gelatin-based GHS, spanning from the nanoscale macromolecular network within microgels to jammed microgels with macroscale interstitial pores, provides modular control over the structural and functional properties of scaffolds, enabling unique biomedical applications. This Viewpoint highlights how gelatin chemistry at the molecular scale, microscale hydrogel particle design, and macroscale scaffold assembly regulate the overall behavior of gelatin-based GHS. At the molecular scale, the chemical composition of gelatin-based polymers modulates crosslinking mechanisms, degradation kinetics, and bioactivity, influencing microgel stability and mechanical behavior. At the microscale, particle size, stability, shape/porosity, and stiffness are key design factors that regulate GHS pore architecture, mechanical integrity, and cell- and tissue-biomaterial interactions, which, in turn, influence the overall properties of GHS at the macroscale. The interconnected macroporous network of GHS, tuned via microgel properties, guides cell infiltration and tissue integration, enabling applications in vascularization, immunomodulation, tissue regeneration, and 3D bioprinting. By mapping structure-property relationships from macromolecules to microgel features to scaffold properties, this Viewpoint may open new opportunities for the rational design and optimization of gelatin-based GHS for broad biomedical applications.