Advancing the future of prosthetic rehabilitation with Regenerative Peripheral Nerve Interface surgery: Questions and opportunities

INTRODUCTION: Regenerative Peripheral Nerve Interface (RPNI) surgery represents a biologic solution to three major challenges in amputation care: (1) achieving intuitive, high-fidelity prosthetic control, (2) mitigating post-amputation pain, and (3) enabling meaningful sensory feedback. By using denervated autologous tissue as a physiologic target for regenerating axons, RPNI surgery is a promising strategy that permits closed-loop control of prosthetic devices. AREAS COVERED: This review focuses on unanswered questions and emerging opportunities regarding RPNI surgery. We examine three key areas: (1) determining the optimal number of RPNIs, (2) selecting the most appropriate graft tissue type, and (3) leveraging novel RPNI variations to expand clinical impact. To explore these topics, we synthesize preclinical and clinical evidence by systematically searching PubMed/MEDLINE, Embase, and Scopus for studies related to RPNI from inception to date. We aim to identify research priorities that will accelerate the evolution of RPNI surgery to revolutionize neuroprosthetic rehabilitation. EXPERT OPINION: RPNI surgery has evolved from proof-of-concept to a feasible, scalable strategy for treating patients with amputations. Future progress will depend on refining patient- and nerve-specific modifications, developing wireless, bidirectional devices that leverage RPNI signal transduction, and addressing reimbursement and training barriers. With continued interdisciplinary collaboration, RPNI surgery is poised to become a critical component of prosthetic rehabilitation.