Aligned fibrous hydrogels capable of recruiting endogenous neural stem/progenitor cells (NSPCs) show great promise in spinal cord injury (SCI) repair. However, the hydrogels suffer from severe issues in close contact with the transected nerve stumps and harnessing the NSPC fate in the lesion microenvironment. Herein, we report aligned collagen-fibrin (Col-FB) fibrous hydrogels with stretchable property, adhesive behavior, and stromal cell-derived factor-1α (SDF1α)/paclitaxel (PTX) spatiotemporal delivery capability. The resultant Col-FB fibrous hydrogels exhibited 1.98 times longer elongation at break (230%), 2.55 times lower Young's modulus (17.93 ± 1.16 KPa), and 2.21 times greater adhesive strength (3.45 ± 0.48 KPa) than collagen (Col) fibrous hydrogels. The soft aligned fibrous hydrogels simulate the oriented microstructure and soft tissue feature of a natural spinal cord and provide elasticity and adhesivity to ensure a persistent close contact with host stumps. The repair of complete transection SCI in rats demonstrates that "middle-tobilateral" SDF1α gradient release induced endogenous NSPC migration to the lesion site in 10 days, and SDF1α/PTX sequential release promoted neuronal differentiation of the recruited NSPCs over 8 weeks, leading to hind limb locomotion recovery. The presented strategy was proved to be efficient for harnessing endogenous NSPCs, which facilitate SCI repair significantly.

Aligned topography and biomolecular gradients exist in various native tissues and play pivotal roles in a set of biological processes. Scaffolds that recapitulate the complex structure and microenvironment show great potential in promoting tissue regeneration and repair. We begin with a discussion on the fabrication of aligned scaffolds, followed by how biomolecular gradients can be immobilized on aligned scaffolds. In particular, we emphasize how electrospinning, freeze drying, and 3D printing technology can accomplish aligned topography and biomolecular gradients flexibly and robustly. We then highlight several applications of aligned scaffolds and biomolecular gradients in regenerative medicine including nerve, tendon/ligament, and tendon/ligament-to-bone insertion regeneration. Finally, we finish with conclusions and future perspectives on the use of aligned scaffolds with biomolecular gradients in regenerative medicine.