Dynamic Hyaluronan Hydrogels with Temporally Modulated High Injectability and Stability Using a Biocompatible Catalyst

Injectable and biocompatible hydrogels have become increasingly important for cell transplantation to provide mechanical protection of cells during injection and a stable scaffold for cell adhesion post‐injection. Injectable hydrogels need to be easily pushed through a syringe needle and quickly recover to a gel state, thus generally requiring noncovalent or dynamic cross‐linking. However, a dilemma exists in the design of dynamic hydrogels: hydrogels with fast exchange of cross‐links are easier to eject using less force, but lack long‐term stability; in contrast, slow exchange of cross‐links improves stability, but compromises injectability and thus the ability to protect cells under flow. A new concept to resolve this dilemma using a biocompatible catalyst to modulate the dynamic properties of hydrogels at different time points of application to have both high injectability and high stability is presented. Hyaluronic acid based hydrogels are formed through dynamic covalent hydrazone cross‐linking in the presence of a biocompatible benzimidazole‐based catalyst. The catalyst accelerates the formation and exchange of hydrazone bonds, enhancing injectability, but rapidly diffuses away from the hydrogel after injection to retard the exchange and improve the long‐term stability for cell culture. Temporally modulating the injectability and stability of dynamically cross‐linked hyaluronic acid–hydrazone hydrogels is achieved using a biocompatible organocatalyst. The incorporated catalyst renders the hydrogels with easier injection and better cell protection, while rapid diffusion of the catalyst out of the hydrogels post‐injection improves their stability, thus achieving high injectability and stability, two often conflicting yet highly desired properties for dynamic injectable hydrogels.