Microscale Mechanical Cues in Hydrogels: Engineering Strategies to Modulate Cell Fates in Three Dimensions

Recent advances in hydrogel design and mechanobiology have underscored the importance of extracellular matrix mechanical cues in guiding cell fates in 3D. However, most studies focus on bulk mechanical properties, which can differ markedly from the microscale mechanical cues that cells experience. Within a 3D hydrogel network, cells actively exert forces to push, pull, and remodel their immediate surroundings. Increasing evidence suggests that these local mechanical properties are dominant regulators of cell fates. This review summarizes recent advances in hydrogel engineering strategies, including crosslinking mechanisms and polymer architectures, that offer control over microscale matrix mechanics at the cellular scale. It synthesizes current understanding of how microscale mechanical cues modulate biological outcomes in 3D, spanning regenerative medicine and disease progression. Key techniques for measuring microscale mechanics and associated outstanding technical challenges are discussed. Finally, future directions for defining the mechanisms linking local hydrogel mechanics to long-term biological outcomes are discussed.