Customizable topological neuro-mimetic hydrogels based on mechanical training for functional recovery following peripheral nerve injury

After peripheral nerve injury, nerve guidance conduits (NGCs) offer an effective alternative to autologous nerve grafting for repairing nerve defects. However, without a well-defined topological structure, peripheral nerve regeneration often results in disorganized growth. Because the regeneration site is subject to bodily movement, the conduits must possess sufficient mechanical integrity to function within this dynamic environment. We prepared double-network hydrogel films from polyvinyl alcohol (PVA) and gelatin for nerve regeneration applications. Using freeze-thaw crystallization, the Hofmeister effect, borate bonding, and incorporating poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), along with continuous optimization of the formulation, the hydrogel achieved excellent mechanical properties. With repeated mechanical training, the hydrogel surface developed a fibrous-like topological structure and could also carry and gradually release nerve growth factor (NGF). The hydrogel could be shaped by cutting and origami folding, and was then firmly attached to the nerve defect via chitosan stitching adhesives, providing a foundation for nerve regeneration. The conduit exhibited a degradation rate closely matching the nerve regeneration process and excellent biocompatibility, while also promoting the oriented growth and differentiation of PC12 cells. In vivo evaluation in a rat sciatic nerve defect model demonstrated that the conduit suppressed inflammation, activated calcium signaling and PPAR pathways in the early regenerative phase, and promoted axon regeneration, remyelination, and functional recovery.