| Summary: | Nerve guidance conduits with hollow lumen fail to regenerate critical-sized peripheral nerve defects (15 mm in rats and 25 mm in humans), which can be improved by a beneficial intraluminal microenvironment. However, individual cues provided by intraluminal filling materials are inadequate to eliminate the functional gap between regenerated nerves and normal nerves. Herein, an aligned fibrin/functionalized self-assembling peptide (AFG/fSAP) interpenetrating nanofiber hydrogel that exerting synergistic topographical and biochemical cues for peripheral nerve regeneration is constructed via electrospinning and molecular self-assembly. The hydrogel possesses an aligned structure, high water content, appropriate mechanical properties and suitable biodegradation capabilities for nerve repair, which enhances the alignment and neurotrophin secretion of primary Schwann cells (SCs) in vitro, and successfully bridges a 15-mm sciatic nerve gap in rats in vivo. The rats transplanted with the AFG/fSAP hydrogel exhibit satisfactory morphological and functional recovery in myelinated nerve fibers and innervated muscles. The motor function recovery facilitated by the AFG/fSAP hydrogel is comparable with that of autografts. Moreover, the AFG/fSAP hydrogel upregulates the regeneration-associated gene expression and activates the PI3K/Akt and MAPK signaling pathways in the regenerated nerve. Altogether, the AFG/fSAP hydrogel represents a promising approach for peripheral nerve repair through an integration of structural guidance and biochemical stimulation.
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