Aldehyde-methacrylate-hyaluronan profited hydrogel system integrating aligned and viscoelastic cues for neurogenesis

Either oriented architecture or viscoelasticity is pivotal to neurogenesis, thus, native neural extracellular matrix derived-hyaluronan hydrogels with nano-orientation and viscoelasticity recapitulated might be instructive for neurogenesis, however it is still unexploited. Herein, based on aldehyde-methacrylate difunctionalized hyaluronan, by integrating imine kinetic modulation and microfluidic biofabrication, we construct a hydrogel system with orthogonal viscoelasticity and nano-topography. We then find the positive synergy effects of matrix nanoorientation and viscoelasticity not only on neurites outgrowth and elongation of neural cells, but also on neuronal differentiation of stem cells. Moreover, by implanting viscoelastic and nano-aligned hydrogels into lesion sites, we demonstrate the enhanced repair of spinal cord injury, including ameliorated pathological microenvironment, facilitated endogenous neurogenesis and functional axons regeneration as well as motor function restoration. This work supplies universal platform for preparing neuronal inducing hyaluronan-based hydrogels which might serve as promising therapeutic strategies for nerve injury.

Automated summary

In this study, we developed a hydrogel system with orthogonal viscoelasticity and nano-topography by modifying hyaluronan. The matrix nanoorientation and viscoelasticity were found to have positive effects on neurites outgrowth, neural cell elongation, and neuronal differentiation. Moreover, implantation of the viscoelastic and nano-aligned hydrogels showed enhanced repair of spinal cord injury, including improved pathological microenvironment, facilitated endogenous neurogenesis, axon regeneration, and motor function restoration.