Study of Disulfide-exchange Dynamic Cross-linking Mechanism for Controlled Construction of Hydrogels

Hydrogels, as a kind of three-dimensional (3D) network of polymer chains constructed by physical or chemical crosslinkers, possess significant potentials in wound healing, drug delivery, and tissue engineering. In recent years, stimuli-responsive hydrogels have received increasing interests on account of their fundamentally architectural features and controllably functional performances under various external stimuli, such as pH, temperature, electricity, redox, and light. Wherein, various hydrogels embedded with dynamic covalent crosslinking networks have been widely developed for high-performance functional materials since dynamic covalent bond could break and reform reversibly under suitable conditions, combining the reversibility of supramolecular non-covalent bond and the robustness of covalent bond. Herein, we demonstrate a facile and universal approach to create "living" controlled in situ gelling systems based on a thiol-disulfide exchange reaction. Thiol-disulfide exchange reaction is reversibly activated or terminated by deprotonating free thiols or protonating thiolates under different pH conditions with an "on/off" function, resulting in dissociation of shells and cross-linking of cores, and thus dynamically optimizing hydrogel structures: from solution to loose and compact hydrogels in macroscopic dimensions. This "living" controlled in situ gelation process can be optionally activated, controllably terminated and interrupted, and reinitiated by external stimuli whenever needed. Associated with an inverse emulsion technique, the controlled cross-linking strategy can be utilized to produce micro/nanoscale hydrogels in a confined space with flexible architectures and designable performances. Under this circumstance, multilayered hydrogel particles with each tailor-made layer are also prepared using the controlled in situ gelation method in association with a seed emulsion technique. By tailoring thiol-disulfide exchange reaction rate in a dilute aqueous solution, a dynamic and programmable morphology and size evolution is well-performed via a hierarchical self-assembly strategy, providing unique advantages to fabricate intelligent drug carriers with high loading efficiency. Furthermore, UV-triggered thiol-disulfide exchange reaction has been developed to prepare the hydrogels with a radical-centered disulfide exchange mechanism, opening up another cross-linking strategy for precise spatiotemporal control on a photochemical gelation process by varying irradiation time. Since these hydrogels are formed through disulfide shuffling of the cores that can be easily cleaved in response to glutathione, these tailor-made hydrogels are biocompatible, biodegradable, and easily fabricated with desired shapes, sizes, and properties in controllable drug delivery systems. In this contribution, we summarize and review this disulfide-exchange-based cross-linking strategy on acquisition of smart hydrogels with adjustable structures and fine-tunable properties in widely biomedical applications.