A catechol-chitosan-based adhesive and injectable hydrogel resistant to oxidation and compatible with cell therapy

Abstract

Injectable hydrogels designed for cell therapy need to be adhesive to the surrounding tissues to maximize their retention and the communication between the host and the encapsulated cells. Catechol grafting is an efficient and well-known strategy to improve the adhesive properties of various polymers, including chitosan. However, catechol groups are also known to be cytotoxic as they oxidize into quinones in alkaline environments. Usually, hydrogels made from catechol-grafted chitosan (cat-CH) oxidize quickly, which tends to limit adhesion and prevent cell encapsulation. In this work, we limited oxidation and improved the cytocompatibility of cat-CH hydrogels by grafting chitosan with dihydroxybenzoic acid (DHBA), a small cat-bearing molecule known to have a high resistance to oxidation. We show that DHBA-grafted CH (dhba-CH) oxidized significantly slower and to a lesser extent that cat-CH made with hydrocaffeic acid (hca-CH). By combining dhba-CH with sodium bicarbonate and phosphate buffer, we fabricated thermosensitive injectable hydrogels with higher mechanical properties, quicker gelation and significantly lower oxidation than previously designed cat-CH systems. The resulting gels are highly adhesive on inorganic substrates and support L929 fibroblast encapsulation with high viability (≥90% after 24 hours), something that was not possible in any previously designed cat-CH gel system. These properties make the dhba-CH hydrogels excellent candidates for minimally invasive and targeted cell therapy in applications that require high adhesive strength.