Engineering the fourth dimension of cell-instructive hydrogels through dynamic bonding

Dynamic remodeling is a defining feature of native tissues, yet many synthetic biomaterials remain static and exhibit purely elastic mechanics. The extracellular matrix (ECM) continuously evolves through viscoelastic mechanical responses and temporally regulated remodeling processes, and cells are highly sensitive to these time-dependent mechanical cues. Traditional covalently crosslinked hydrogels can recapitulate stiffness and biochemical signals, but often fail to capture the fourth dimension of matrix mechanics-time-operationally defined here as the intrinsic stress relaxation timescale governed by reversible bond-exchange kinetics, and distinct from cell-driven enzymatic remodeling. Recent advances in non-covalent, supramolecular, and dynamic-covalent chemistries have enabled synthetic hydrogels with programmable stress relaxation, yielding, and self-healing across biologically relevant timescales. This review surveys a chemical toolbox spanning ionic and dynamic-covalent networks, host-guest and peptide-based supramolecular matrices, engineered protein association motifs, and DNA-crosslinked hydrogels. These platforms have enabled mechanobiology studies that decouple stiffness from relaxation in understanding cell spreading, proliferation, migration, and differentiation in ways inaccessible using traditional static hydrogels. Rheological and biophysical methods for quantifying frequency-dependent viscoelasticity, stress relaxation, and recovery are also discussed. By integrating molecular-level design with cell-instructive mechanics, dynamic hydrogels provide a versatile synthetic ECM platform for advanced 3D culture, regenerative medicine, and disease modeling.