A novel glucose-responsive controlled drug release system based on pH sensitive cationic chitosan hydrogel (HTCC) with different degree of substitution (DS) was successfully prepared. The composition and structure of HTCC were analyzed by FTIR, H-1 NMR and theological evaluation. With increasing DS of HTCC hydrogels, the network mesh size (L-c) increased and the crosslinking density decreased, and in the meantime the swelling ratio and pH-sensitivity of the hydrogel increased. In a narrow pH variation range (pH-6.8 to 7.4), a considerable difference in the cumulative release of BSA was observed with distinct sensitivity, while the resulting electrostatic repulsion between the protonated cationic groups of the hydrogel with high zeta potentials weakened the inter- and intra-molecular hydrogen bonding of HTCC molecules, and much loose network structure formed at subacid environment. FITCC hydrogels presented an obvious glucose concentration-dependent response release behavior, and the steplike release behavior for incremental doses of glucose clearly showed the versatility of the system to respond to the sequential addition of glucose. Korsmeyer-Peppas model was used for describing BSA release kinetics of HTCC hydrogels under different pH values and glucose concentrations, which corresponded to a Fickian release behavior. (C) 2015 Elsevier B.V. All rights reserved.