Regenerative Peripheral Nerve Interface (RPNI) Surgery for Naturalistic Prosthetic Control

Loss of limb function remains a significant public health challenge affecting millions of people worldwide, causing high rates of disability, unemployment, and chronic pain. Current neuroprosthetic devices are limited by unintuitive control and poor long-term embodiment. While implantable neural interfaces show promise in improving prosthetic function, these often rely on direct implantation into peripheral nerves, which may result in long-term scarring, low signal-to-noise ratios, and difficulty interpreting motor intent. In this review, we will highlight the regenerative peripheral nerve interface (RPNI) as a potential solution to overcome these challenges. RPNI surgery involves implantation of transected peripheral nerves or nerve fascicles into free muscle grafts, which become reinnervated and amplify neural signals. Preclinical studies have demonstrated that RPNIs remain healthy long-term and provide high-fidelity, stable electrophysiologic signal amplification. Clinical studies further confirm the ability of RPNIs to generate selective, robust signals for real-time prosthetic control without the need for recalibration. This review will also highlight derivative constructs such as the dermal sensory RPNI (DS-RPNI) and composite RPNI (C-RPNI) to facilitate sensory feedback from a prosthesis. In addition, we will discuss the muscle cuff RPNI (MC-RPNI) which can be used to interface with intact peripheral nerves for neural signal acquisition and exoskeleton control. These innovations highlight the versatility of RPNI as a stable and clinically meaningful neural interface capable of high-fidelity signaling for intuitive prosthetic control. By improving functional control, RPNIs represent a promising step toward intuitive prosthetic embodiment and improved functional outcomes for patients living with limb loss or neural injury.