Tuning Hydrogels by Mixing Dynamic Cross‐Linkers: Enabling Cell‐Instructive Hydrogels and Advanced Bioinks

Rational design of hydrogels that balance processability and extracellular matrix (ECM) biomimicry remains a challenge for tissue engineering and biofabrication. Hydrogels suitable for biofabrication techniques, yet tuneable to match the mechanical (static and dynamic) properties of native tissues remain elusive. Dynamic covalent hydrogels possessing shear‐thinning/self‐healing (processability) and time‐dependent cross‐links (mechanical properties) provide a potential solution, yet can be difficult to rationally control. Here, the straightforward modular mixing of dynamic cross‐links with different timescales (hydrazone and oxime) is explored using rheology, self‐healing tests, extrusion printing, and culture of primary human dermal fibroblasts. Maintaining a constant polymer content and cross‐linker concentration, the stiffness and stress relaxation can be tuned across two orders of magnitude. All formulations demonstrate a similar flow profile after network rupture, allowing the separation of initial mechanical properties from flow behavior during printing. Furthermore, the self‐healing nature of hydrogels with high hydrazone content enables recyclability of printed structures. Last, a distinct threshold for cell spreading and morphology is observed within this hydrogel series, even in multi‐material constructs. Simple cross‐linker mixing enables fine control and is of general interest for bioink development, targeting viscoelastic properties of specific cellular niches, and as an accessible and flexible platform for designing dynamic networks. Dynamic hydrogels are an important tool for the development of advanced bioinks. Individually, dynamic cross‐linkers introduce time‐dependent properties including shear thinning, self‐healing, and stress relaxation. By mixing oxime and hydrazone cross‐links in an oxidized alginate hydrogel, hybrid networks can combine desirable properties of both, leading to tunable mechanical properties, improved processability and printability, and the ability to control fibroblast morphology.