Neural stem cell-laden 3D bioprinting of polyphenol-doped electroconductive hydrogel scaffolds for enhanced neuronal differentiation

The development of three-dimensional (3D) bioprinting technology opens a door for constructing bionic nerve tissue scaffolds on demand for nerve injury repair. However, the electrical insulation of the current nerve tissue scaffolds fabricated by 3D bioprinting hinders the bioelectrical signal transmission between cells, limiting the therapeutic effect in nerve tissue repair. To address this issue, we have developed a neural stem cell (NSC)-laden 3D bioprinted electroconductive hydrogel (ECH) scaffold, composed of modified poly(3,4-ethylenedioxythiophene) (PEDOT), gelatin methacrylate/polyethylene glycol diacrylate hydrogel matrix, and NSCs, to promote the electron propagation in the scaffold for enhanced nerve regeneration. In our strategy, PEDOT is modified by doping with chondroitin sulfate and tannic acid (TA) to improve its water-solubility and electric property. With moderate mechanical strength and good electroconductivity, the 3D ECH scaffold provides a benign conductive microenvironment for the adhesion, growth, and proliferation of the encapsulated NSCs. Clearly, in the 3D ECH scaffolds, the NSCs not only maintain high cell viability (>90%) after bioprinting, but also tend to differentiate into neurons with extended neurites. This study testifies for the first time the effect of polyphenol structure belonging to TA on neuronal differentiation of NSCs, and offers a new insight into designing electroconductive biomaterials to induce neuronal regeneration for nerve injury repair and neurodegenerative disease therapy.