Stimuli-Responsive Dual Cross-Linked N-Carboxyethylchitosan Hydrogels with Tunable Dissolution Rate

Abstract

Here, we discuss the applicability of (methylenebis(salicylaldehyde)—MbSA) for the fabrication of the stimuli-responsive N-carboxyethylchitosan (CEC) hydrogels with a tunable dissolution rate under physiological conditions. In comparison with non-covalent salicylimine hydrogels, MbSA cross-linking via covalent bis(‘imine clip’) and non-covalent hydrophobic interactions allowed the fabrication of hydrogels with storage moduli > 1 kPa at ten-fold lower aldehyde/CEC molar ratio with the preservation of pH- and amino-acid responsive behavior. Although MbSA-cross-linked CEC hydrogels were stable at neutral and weakly alkaline pH, their disassembly in cell growth medium (Dulbecco’s modified Eagle’s medium, DMEM) under physiological conditions was feasible due to transimination reaction with amino acids contained in DMEM. Depending on the cross-linking density, the complete dissolution time of the fabricated hydrogels varied from 28 h to 11 days. The cytotoxicity of MbSA cross-linked CEC hydrogels toward a human colon carcinoma cell line (HCT 116) and primary human dermal fibroblasts (HDF) was remarkably lower in comparison with CEC-salicylimine hydrogels. Fast gelation, relatively low cytotoxicity, and tunable stimuli-induced disassembly under physiological conditions make MbSA cross-linked CEC hydrogels promising for drug encapsulation and release, 3D printing, cell culturing, and other biomedical applications.

Biocompatible Chitosan-Based Hydrogels for Bioabsorbable Wound Dressings

“…Considering the structure of the chitosan and 2-FPBA reagents and the imine product which resulted between them, it was estimated that the new H-bonds derived from the intermolecular interactions among the hydroxyl units of 2-FPBA and the amine and hydroxyl units of chitosan on one hand, derived and from the intra- and intermolecular interactions between the hydroxyl groups and the nitrogen atom of the new imine units on the other hand. The stabilization of imine units by imino-boronate bonds [ 25 ] by “imine-clip” stabilization [ 26 , 27 , 28 ] is possible too.…”

“…Considering the structure of the chitosan and 2-FPBA reagents and the imine product which resulted between them, it was estimated that the new H-bonds derived from the intermolecular interactions among the hydroxyl units of 2-FPBA and the amine and hydroxyl units of chitosan on one hand, derived and from the intraand intermolecular interactions between the hydroxyl groups and the nitrogen atom of the new imine units on the other hand. The stabilization of imine units by imino-boronate bonds [25] by "imine-clip" stabilization [26][27][28] is possible too. POM images of the hydrogel showed bright birefringence with a banded texture identified for layered supramolecular architectures, proving that the new formed imine units self-ordered during the hydrogelation into a layered architecture pattern, similar to lyotropic liquid crystals (Figure 4) [29,30].…”

“…Gels 2022, 8, x FOR PEER REVIEW 5 of 15the new imine units on the other hand. The stabilization of imine units by imino-boronate bonds[25] by "imine-clip" stabilization[26][27][28] is possible too.…”

Chitosan Cross-Linking with Acetaldehyde Acetals

“…Hydrogel chemical (hydrolytic) stability was investigated at 25 °C in PBS buffer (PanEco Ldt., Moscow, Russia); the pH in the acidic and basic range was adjusted with H 3 PO 4 and NaOH, respectively. Colloid titration of supernatants was used to determine the content of the polymer, which was released from the hydrogels due to the hydrolysis of the cross-links, as described in [ 31 ]. The experiments were performed as follows: 300 mg of the hydrogel was immersed in 15 mL of PBS solution with adjusted pH value and gently agitated for 24 h using a Biosan PSU-20i orbital shaker (Latvia) at 30 rpm.…”

“…Flow cytometric analyses were conducted after staining using a CytoFLEX flow cytometer (Beckman-Coulter, Brea, CA, USA) connected to a computer running CytExpert software (version 2.4, Beckman-Coulter). A detailed description of cell cultivation and flow cytometrical analysis is given in [ 31 ].…”