Neurophilic peptide-reinforced dual-fiber-network bioactive hydrogels for spinal cord injury repair

Spinal cord injury (SCI) is a challenging central nervous system disorder that characterized by microenvironmental disturbances following injury, which can be addressed by simulating the microenvironment of the spinal cord regeneration. Herein, we report the design and synthesis of bioactive hydrogels with a dual-fiber-network (DFN) porous structure, using self-assembled peptide nanofibers (PNFs) and natural cellulose nanofibers (CNFs). A neurophilic peptide is further introduced to enhance nervous regeneration capability of the pre-prepared PNF/ CNF hydrogels, which then exhibit excellent neuro-affinity, self-healing ability, biodegradability, and biocompatibility, facilitating targeted SCI repair and regeneration through the hydrogel injection. The in vitro experiments reveal that the DFN hydrogel can enhance the proliferation and migration of bone marrow mesenchymal stem cells, and induce neural stem cell (NSC) proliferation with enhanced neuronal differentiation and axonal growth. Additionally, the in vivo studies validate that the hydrogel attenuates the post-SCI inflammation, inhibits reactive astrocyte proliferation, and facilitates endogenous NSC proliferation and migration, as well as promotes neuronal growth and axonal regeneration. The potential mechanism of SCI repair is ascribed to the hydrogelinduced activation of the PI3K/AKT/mTOR pathway, which alleviates inflammatory response, inhibits excessive reactive response of glial cells, and promotes NSC differentiation into neurons. This neurophilic peptidereinforced DFN bioactive hydrogel system, with its comprehensive approach to SCI repair, holds great potential for clinical applications.