Magnesium-Encapsulated Injectable Hydrogel and 3D-Engineered Polycaprolactone Conduit Facilitate Peripheral Nerve Regeneration

Peripheral nerve injury is a challenging orthopedic condition that can be treated by autograft transplantation, a gold standard treatment in the current clinical setting. Nevertheless, limited availability of autografts and potential morbidities in donors hampers its widespread application. Bioactive scaffold-based tissue engineering is a promising strategy to promote nerve regeneration. Additionally, magnesium (Mg) ions enhance nerve regeneration; however, an effectively controlled delivery vehicle is necessary to optimize their in vivo therapeutic effects. Herein, a bisphosphonate-based injectable hydrogel exhibiting sustained Mg²⁺ delivery for peripheral nerve regeneration is developed. It is observed that Mg²⁺ promoted neurite outgrowth in a concentration-dependent manner by activating the PI3K/Akt signaling pathway and Sema5b. Moreover, implantation of polycaprolactone (PCL) conduits filled with Mg²⁺-releasing hydrogel in 10 mm nerve defects in rats significantly enhanced axon regeneration and remyelination at 12 weeks post-operation compared to the controls (blank conduits or conduits filled with Mg²⁺-absent hydrogel). Functional recovery analysis reveals enhanced reinnervation in the animals treated with the Mg²⁺-releasing hydrogel compared to that in the control groups. In summary, the Mg²⁺-releasing hydrogel combined with the 3D-engineered PCL conduit promotes peripheral nerve regeneration and functional recovery. Thus, a new strategy to facilitate the repair of challenging peripheral nerve injuries is proposed.