Facile Synthesis of Chitosan-Based Hydrogels and Microgels through Thiol–Ene Photoclick Cross-Linking

Polysaccharide-based microgels are effective vectors for the delivery of biopharmaceutics and functional components in tissue engineering due to their bioactivity and biocompatibility. Currently, the synthesis of chemically cross-linked microgels typically requires long reaction times and a high-energy input and are low yielding due to low volumes of the water phase used. Herein, we report the synthesis of norbornene-derived chitosan (CS-nbn-COOH), which can undergo rapid gelation in the presence of a thiolated cross-linker through the highly efficient thiol-ene photoclick reaction. This water-soluble photo-cross-linkable derivative, synthesized on scale via a single step from native chitosan and commercially available carbic anhydride, represents the first example of a norbornene-functionalized CS to the best of our knowledge. Microgels with controlled cross-linking densities and diameters varying between 100 and 400 nm were obtained via a low-energy water-in-oil nanoemulsion templating method at room temperature, with photo-cross-linking initiated in a flow reactor powered with a domestic UV-A lamp, a method that is suitable for the scale-up synthesis of the microgels. We also demonstrate that the resulting microgels were nontoxic to human dermofibroblasts (HDF) cell lines and that residual norbornene groups could be reacted in a late stage through tetrazine ligation, highlighting the potential of these microgels as scaffolds for functional nanomaterials with biomedical applications.