Semi-Interpenetrating Polymer Network of Hyaluronan and Chitosan Self-Healing Hydrogels for Central Nervous System Repair

The repair of the central nervous system (CNS) is a major challenge because of the difficulty for neurons or axons to regenerate after damages. Injectable hydrogels have been developed to deliver drugs or cells for neural repair, but these hydrogels usually require conditional stimuli or additional catalysts to control the gelling process. Self-healing hydrogels, which can be injected locally to fill tissue defects after stable gelation, are attractive candidates for CNS treatment. In the current study, the self-healing hydrogel with a semi-interpenetrating polymer network (SIPN) was prepared by incorporation of hyaluronan (HA) into the chitosan-based self-healing hydrogel. The addition of HA allowed the hydrogel to pass through a narrow needle much more easily. As the HA content increased, the hydrogel showed a more packed nanostructure and a more porous microstructure verified by coherent small-angle X-ray scattering and scanning electron microscopy. The unique structure of SIPN hydrogel enhanced the spreading, migration, proliferation, and differentiation of encapsulated neural stem cells in vitro. Compared to the pristine chitosan-based self-healing hydrogel, the SIPN hydrogel showed better biocompatibility, CNS injury repair, and functional recovery evaluated by the traumatic brain injury zebrafish model and intracerebral hemorrhage rat model. We proposed that the SIPN of HA and chitosan self-healing hydrogel allowed an adaptable environment for cell spreading and migration and had the potential as an injectable defect support for CNS repair.