Synergistic effects of dual-presenting VEGF- and BDNF-mimetic peptide epitopes from self-assembling peptide hydrogels on peripheral nerve regeneration

The crosstalk between vascularization and nerve regeneration in the peripheral nervous system has recently been suggested to play an important role in the treatment of peripheral nerve injury. Regenerative strategies via synergistic delivery of multiple biochemical cues have received growing attention, especially the combination of pro-angiogenic factors and neurotrophic factors. Here we developed a self-assembling peptide nanofiber hydrogel dual-functionalized with vascular endothelial growth factor (VEGF)- and brain-derived neurotrophic factor (BDNF)-mimetic peptide epitopes for peripheral nerve reconstruction. It could simultaneously present VEGF- and BDNF-mimetic peptide epitopes and provides a three-dimensional (3D) neurovascular microenvironment for endothelial cell and neural cell growth. In vitro cellular experiments showed that the functionalized peptide hydrogel scaffold effectively promoted the pro-myelination of Schwann cell, as well as the adhesion and proliferation of endothelial cell compared with scaffolds presenting VEGF- or BDNF-mimetic peptide epitope alone. When implanted in a rat model to bridge a critical-size sciatic nerve gap in vivo, the functionalized peptide hydrogel significantly improved the number of newly formed blood vessels, the density of regenerating axons, the morphometric analysis of the regenerated muscles and the electrophysiological findings, indicating the synergistic effect of the two bioactive motifs on peripheral nerve regeneration. Collectively, constructing an artificial neurovascular microenvironment in the lesion area by using the functionalized self-assembling peptide nanofiber hydrogel may have a great potential for promoting nerve tissue engineering and regeneration in other tissues.