Aligned Conductive Core-Shell Biomimetic Scaffolds Based on Nanofiber Yarns/Hydrogel for Enhanced 3D Neurite Outgrowth Alignment and Elongation.

Aligned topographical cue has been demonstrated as a critical role in neuronal guidance, and it is highly beneficial to develop a scaffold with aligned structure for peripheral nerve tissue regeneration. Although considerable efforts have been devoted to guiding neurite alignment and extension, it remains a remarkable challenge for developing a biomimetic scaffold for enhancing 3D aligned neuronal outgrowth. Herein, we present a core-shell scaffold based on aligned conductive nanofiber yarns (NFYs) within the hydrogel to mimic the 3D hierarchically aligned structure of the native nerve tissue. The aligned NFYs assembled by a bundle of aligned nanofibers composed of polycaprolactone (PCL), silk fibroin (SF), and carbon nanotubes (CNTs) are prepared by a developed dry-wet electrospinning method, which has the ability to induce neurite alignment and elongation when PC12 cells and dorsal root ganglia (DRG) cells are cultured on their 3D peripheral surface. Particularly, such an aligned nanofibrous structure also induces aligned neurite extension and cell migration from DRG explants along the direction of nanofibers. 3D core-shell scaffolds are fabricated by encapsulating NFYs within the hydrogel shell after photocrosslinking, and these 3D aligned scaffolds are able to control cellular alignment and elongation of nerve cells in this 3D environment. Our results suggest that such 3D hierarchically aligned core-shell scaffold consists of NFYs that mimic the aligned nerve fiber structure to induce neurite alignment and extension and a hydrogel shell that mimics the epineurium layer to protect nerve cell organization within a 3D environment, which is largely promising for the design of biomimetic scaffolds in nerve tissue engineering. STATEMENT OF SIGNIFICANCE: Designing scaffolds with 3D aligned structure has been paid more attention for peripheral nerve tissue regeneration, because the aligned topographical cue is able to induce neurites alignment and extension. However, developing scaffolds mimicking the hierarchically aligned structure of native nerve tissue for directing 3D aligned neuronal outgrowth without external stimulation remains challenging. This work presented a simple and efficient strategy to prepare a 3D biomimetic core-shell scaffold based on electrospun aligned conductive nanofiber yarns within photocurable hydrogel shell to mimic the hierarchically aligned structure of native nerve tissue. These 3D aligned composite scaffolds performed the ability to direct 3D cellular alignment and elongation of nerve cells along with the nanofiber yarn direction, and the hydrogel shell mimicking the epineurium layer was able to protect nerve cells organization within the 3D environment, which indicated their great potential in peripheral nerve tissue engineering applications.