A hyaluronic acid/silk fibroin/poly-dopamine-coated biomimetic hydrogel scaffold with incorporated neurotrophin-3 for spinal cord injury repair

Bio-factor stimulation is essential for axonal regeneration in the central nervous system. Thus, persistent and efficient factor delivery in the local microenvironment is an ideal strategy for spinal cord injury repair. We developed a biomimetic hydrogel scaffold to load biofactors in situ and release them in a controlled way as a promising therapeutic modality. Hyaluronic acid and silk fibroin were cross-linked as the basement of the scaffolds, and poly-dopamine coating was used to further increase the loading of factors and endow the hydrogel scaffolds with ideal physical and chemical properties and proper biocompatibility. Notably, neurotrophin-3 release from the hydrogel scaffolds was prolonged to 28 days. A spinal cord injury model was constructed for hydrogel scaffold transplantation. After eight weeks, significant NF200-positive nerve fibers were observed extending across the glial scar to the center of the injured area. Due to the release of neurotrophin-3, spinal cord regeneration was enhanced, and the cavity area of the injury graft site and inflammation associated with CD68 positive cells were reduced, which led to a significant improvement in hind limb motor function. The results show that the hyaluronic acid/silk fibroin/poly-dopamine-coated biomimetic hydrogel scaffold achieved locally slow release of neurotrophin-3, thus facilitating the regeneration of injured spinal cord. STATEMENT OF SIGNIFICANCE: Hydrogels have received great attention in spinal cord regeneration. Current research has focused on more efficient and controlled release of bio-factors. Here, we adopted a mussel-inspired strategy to functionalize the hyaluronic acid/silk fibroin hydrogel scaffold to increase the load of neurotrophin-3 and extend the release time. The hydrogel scaffolds have ideal physiochemical properties, proper release rate, and biocompatibility. Owing to the continuous neurotrophin-3 release from implanted scaffolds, cavity formation is reduced, inflammation alleviated, and spinal cord regeneration enhanced, indicating great potential for bio-factor delivery in soft tissue regeneration applications.