Dynamically Crosslinked Hydrogels Composed of Carboxymethyl Chitosan and Tannic Acid for Sustained Release of Encapsulated Protein

Abstract Polysaccharide‐based hydrogels are promising for biomedical applications such as drug delivery owing to their biocompatibility, biodegradability, and bioactivities. In particular, there is a need for hydrogels with injectability for minimally invasive therapies and controlled sustained release for sustained drug effect. Hydrogels made from carboxymethyl chitosan (CMC) and tannic acid (TA) (CMC‐TA) contain dynamic covalent bonds owing to autoxidation between CMC and TA, and interact with proteins via TA, elucidation of the detailed mechanism of dynamic covalent bonding in CMC‐TA hydrogels will facilitate stable loading and zero‐order release of proteins. Herein, the physical properties of oxidized CMC‐TA (Oxi‐CMC‐TA) prepared for the encapsulation and sustained release of proteins are explored. Following incubation at 37 °C for 24 h, CMC‐TA undergoes secondary crosslinking by autoxidation to produce Oxi‐CMC‐TA. Notably, CMC‐TA is viscoelastic and shear‐thinning, allowing for injection and 3D bioprinting. Indeed, CMC‐TA can be 3D‐printed with green fluorescent protein (GFP) encapsulated in its matrix. Oxi‐CMC‐TA also exhibits an affinity for protein owing to its gallol groups, enabling Oxi‐CMC‐TA to collect GFP in aqueous solutions against a concentration gradient. Moreover, Oxi‐CMC‐TA releases GFP over 15 days. Injectable, 3D‐printable, protein‐collecting, and zero‐order sustained‐releasing Oxi‐CMC‐TA has the potential to make a significant contribution to drug delivery.