Cross‐Linker Architectures Impact Viscoelasticity in Dynamic Covalent Hydrogels

Abstract Dynamic covalent cross‐linked (DCC) hydrogels represent a significant advance in biomaterials for regenerative medicine and mechanobiology, offering viscoelasticity, and self‐healing properties that more closely mimic in vivo tissue mechanics than traditional, predominantly elastic, covalent hydrogels. However, the effects of varying cross‐linker architecture on DCC hydrogel viscoelasticity have not been thoroughly investigated. This study introduces hydrazone‐based alginate hydrogels to explore how cross‐linker architectures impact stiffness and viscoelasticity. In hydrogels with side‐chain cross‐linker (SCX), higher cross‐linker concentrations enhance stiffness and decelerate stress relaxation, while an off‐stoichiometric hydrazine‐to‐aldehyde ratio reduces stiffness and shortens relaxation time. In hydrogels with telechelic cross‐linking, maximal stiffness and relaxation time occurs at intermediate cross‐linker mixing ratio for both linear cross‐linker (LX) and star cross‐linker (SX), with higher cross‐linker valency further enhancing these properties. Further, the ranges of stiffness and viscoelasticity accessible with the different cross‐linker architectures are found to be distinct, with SCX hydrogels leading to slower stress relaxation relative to the other architectures, and SX hydrogels providing increased stiffness and slower stress relaxation versus LX hydrogels. This research underscores the pivotal role of cross‐linker architecture in defining hydrogel stiffness and viscoelasticity, providing insights for designing DCC hydrogels with tailored mechanical properties for specific biomedical applications.