Tuning the rheological properties of dynamic covalent hydrogels through crosslinking bond exchange kinetics for biomedical applications

The dynamic properties of the natural extracellular matrix (ECM) allows for a continuous exchange of information with resident cells that changes over time. In addition, the dynamic properties of ECM polymers provide mechanical stress relaxation, thereby protecting and enhancing cell function. Despite the importance of matrix dynamics, nearly all commercially available cell culture platforms are static in nature or have limited control over viscoelasticity. Within this context, we developed a poly(ethylene glycol) (PEG) hydrogel platform using a fast reversible thia-conjugate addition crosslinking chemistry to impart viscoelastic properties at physiologic conditions. By controlling the aromatic substituents on a benzalcyanoacetamide, we demonstrate that we can preferentially control the forward reaction kinetics, which contributes to the overall modulus of the hydrogel. Importantly, we can perform these manipulations with minimal effect on the reverse reaction rate kinetics, thereby holding the stress relaxation properties of the hydrogel relatively constant. Furthermore, we showed the kinetics of bond exchange are tuned over several orders of magnitude with pH and that the developed hydrogels exhibit a regime of shear thickening under continuous shear. Finally, our data indicate good cytocompatibility with encapsulated fibroblasts and human mesenchymal stem cells, which promise suitability for cellular applications such as injectable cell delivery vehicles to localize delivery of therapeutics to a specific site. Overall, these data suggest a route to decoupling forward and reverse reaction rate kinetics in dynamic covalent PEG hydrogels, thereby expanding the toolbox for viscoelastic ECM mimics.