Neural-enhancing PRP/Alg/GelMA triple-network hydrogel for neurogenesis and angiogenesis after spinal cord injury via PI3K/AKT/mTOR signaling pathway.

Rational: Spinal cord injury (SCI) is among the most devastating conditions affecting the central nervous system. Nerve regeneration and vascular regeneration are two important strategies for SCI. While platelet-rich plasma (PRP) gel is a bio-hydrogel enriched with a large number of growth factors. It has an excellent ability to promote blood vessel regeneration, but its role in nerve repair needs to be further enhanced. In addition, its weak mechanical properties and rapid release of components have limited its efficacy. Method: In this study, we cleverly applied the dual effects of activation and cross-linking of calcium ions to construct a novel PRP/ sodium alginate (Alg)/ gelatin methacrylate (GelMA) triple-networked hydrogel and enhanced the hydrogel's function in promoting nerve regeneration using brain-derived neurotrophic factor (BDNF). Results: In vitro experiments, we verified the biomimetic, injectable, biodegradable, biocompatible, vascular regenerative and neural regenerative properties of the neural-enhancing triple-network hydrogel by involving endothelial cells and neural stem cells (NSCs). When implanted into SCI rats, this hydrogel significantly improved its motor function. It promotes neuronal differentiation, inhibits astrocyte differentiation, supports axonal regeneration, and enhances the migration of endogenous NSCs and vascular regeneration. In addition, this hydrogel may facilitate neurogenesis and angiogenesis via activating the PI3K/AKT/mTOR signaling pathway. Conclusions: The neural regeneration-enhanced triple-network hydrogel we developed has excellent dual biological functions of neural regeneration and angiogenesis, and it is a straightforward, viable, and promising therapeutic strategy for SCI regeneration.