Aligned fibrin/functionalized self-assembling peptide interpenetrating nanofiber hydrogel presenting multi-cues promotes peripheral nerve functional recovery

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.