Engineered regenerative isolated peripheral nerve interface for targeted reinnervation

Abstract A regenerative peripheral nerve interface (RPNI) provides neuroma pain relief through the reinnervation of the native skeletal muscle and represents a promising therapeutic solution for severe nerve injury or amputation. Despite its notable effects, the unsolvable limitation of donor-site morbidity owing to autologous muscle grafts has emphasized the necessity to develop a substantial muscle construct using tissue engineering. However, the current fabrication methods for engineered skeletal muscle constructs have limitations in terms of the mechanical properties of the bioink and surgical manipulation. Therefore, we developed an engineered regenerative isolated peripheral nerve interface (eRIPEN) using three-dimensional skeletal cell printing and direct electrospinning for a nanofiber membrane-envelop with host nerve implantation to facilitate long-term functionality. In our in vivo study, the eRIPEN shows long-term survival, myofiber formation, neuromuscular junction formation, promotion of vascularization, and muscle contractility. More importantly, neuropathic pain was relieved and motor function was restored over 8 months following proper neural regeneration and innervation of the host nerve. These results suggest that the eRIPEN with neural integration can replace the basic RPNI and realize neuroprosthesis control through synaptic connections.