A translational framework for peripheral nerve stimulating electrodes: Reviewing the journey from concept to clinic

The purpose of this review article is to describe the underlying methodology for successfully translating novel interfaces for electrical modulation of the peripheral nervous system (PNS) from basic design concepts to clinical applications and chronic human use. Despite advances in technologies to communicate directly with the nervous system, the pathway to clinical translation for most neural interfaces is not clear. FDA guidelines provide information on necessary evidence which should be generated and submitted to allow the agency evaluate safety and efficacy of a new medical device. However, a knowledge gap exists on translating neural interfaces from pre-clinical studies into the clinical domain. Our article is intended to inform the field on some of the key considerations for such a transition process specific to neural interfaces that may not be already covered by FDA guidances. This framework focuses on non-penetrating peripheral nerve stimulating electrodes that have been proven effective for motor and sensory neural prostheses and successfully transitioned from pre-clinical through first-in-human and chronic clinical deployment. We discuss the challenges of moving these neural interfaces along the translational continuum and ultimately through FDA approval for human feasibility studies. Specifically, we describe a translational process involving: quantitative human anatomy, neural modeling and simulation, acute intraoperative testing and verification, clinical demonstration with temporary percutaneous access, and finally chronic clinical deployment and functional performance. To clarify and demonstrate the importance of each step of this translational framework, we present case studies from electrodes developed at Case Western Reserve University (CWRU), specifically the spiral cuff, the Flat Interface Nerve Electrode (FINE), and the Composite FINE (C-FINE). In addition, we demonstrate that success along this translational pathway can be further expedited by: appropriate selection of well-characterized materials, validation of fabrication and sterilization protocols, well-implemented quality control measures, and quantification of impact on neural structure, health, and function. The issues and approaches identified in this review for the peripheral nervous system may also serve to accelerate the dissemination of any new neural interface into clinical practice, and consequently advance the performance, utility, and clinical value of new neural prostheses or neuromodulation systems.