A facile bioorthogonal chemistry-based reversible to irreversible strategy to surmount the dilemma between injectability and stability of hyaluronic acid hydrogels

Injectable and stable hydrogels have great promise for clinical applications. Fine-tuning the injectability and the stability of the hydrogels at different stages has been challenging due to the limited number of coupling reactions. A distinct "reversible to irreversible" concept using a thiazolidine-based bioorthogonal reaction between 1,2-aminothiols and aldehydes in physiological conditions to surmount the dilemma between injectability and stability is presented for the first time. Upon mixing aqueous solutions of aldehyde-functionalized hyaluronic acid (SA-HA) and cysteine-capped ethylenediamine (DI-Cys), SA-HA/DI-Cys hydrogels formed through reversible hemithioacetal crosslinking within 2 min. The reversible kinetic intermediate facilitated thiol-triggered gel-to-sol transition, shear-thinning and injectability of the SA-HA/DI-Cys hydrogel but then converted to the irreversible thermodynamic network after injection, thereby permitting the resulting gel with improved stability. As compared to the Schiff base hydrogels, the hydrogels generated from this simple, yet effective concept awarded improved protection to the embedded mesenchymal stem cells and fibroblast during injection, retained the cells homogeneously within the gel, and allowed them further proliferation in vitro and in vivo. There is potential for the proposed approach of "reversible to irreversible" based on thiazolidine chemistry to be applied as a general coupling technique for developing injectable and stable hydrogels for biomedical applications.