Fast Absorbent and Highly Bioorthogonal Hydrogels Developed by IEDDA Click Reaction for Drug Delivery Application

In this work, we engineered highly biocompatible and fast absorbent injectable hydrogels derived from norbornene (Nb)-functionalized hyaluronic acid (HA-Nb) and a water-soluble cross-linker possessing tetrazine (Tz) functional groups on both ends of polyethylene glycol (PEG-DTz). The by-product (nitrogen gas) of the inverse electron demand Diels–Alder (IEDDA) cross-linking reaction carved porosity in the resulting hydrogels. By varying the molar ratio of HA-Nb and PEG-DTz (Nb:Tz = 10:10, 10:5, 10:2.5), we were able to formulate hydrogels with tunable porosity, gelation time, mechanical strength, and swelling ratios. The hydrogels formed quickly (gelation time < 100 s), offering a possibility to use them as an injectable drug delivery system. The experimental data showed rapid swelling and a high swelling ratio thanks to the existence of PEG chains and highly porous architectures of the hydrogels. The hydrogels were able to encapsulate a high amount of curcumin (~99%) and released the encapsulated curcumin in a temporal pattern. The PEG-DTz cross-linker, HA-Nb, and the resulting hydrogels showed no cytotoxicity in HEK-293 cells. These fast absorbent hydrogels with excellent biocompatibility fabricated from HA-Nb and the IEDDA click-able cross-linker could be promising drug carriers for injectable drug delivery applications.