Dynamic cell-adaptable hydrogels with a moderate level of elasticity promote 3D development of encapsulated cells

Abstract Hydrogels stabilized by dynamic reversible crosslinks provide a more permissive three-dimensional (3D) microenvironment to support various behaviors of encapsulated cells. Compared with hydrogels based on dynamic covalent crosslinks, supramolecular hydrogels based on host–guest interactions generally possess higher structural dynamics but lower elasticity due to the highly dynamic nature of the host–guest interactions. Herein, we first preassemble thiolated β-cyclodextrin (CD-SH) with adamantane-grafted hyaluronic acid (HA-Ada) before reacting with maleimide-grafted HA (HA-Mal) via the thiol–ene click reaction to fabricate host–guest hydrogels (HAHG) with a highly dynamic network. Furthermore, a minor fraction of covalent crosslinking can be easily incorporated into the hydrogel network by using multivalent CD-SH as the crosslinker to produce HAHG hydrogels with varying residual elasticity (RE) while keeping the hydrogel chemical composition unchanged. We demonstrated that HAHG hydrogels with a moderate level of RE best support the 3D spreading and intercellular interactions of encapsulated stem cells. This work provides an easy strategy to prepare cell-adaptable dynamic hydrogels with tunable network elasticity to study the effects of biophysical properties of hydrogel networks on cellular behavior in 3D environments.