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Page 2 of 9 Burke et al. Plast Aesthet Res 2022;9:48 https://dx.doi.org/10.20517/2347-9264.2022.26

[1]
self-perception and quality of life . Recent innovations in robotic technology have led to the development
of upper extremity prosthetic devices that are capable of emulating precise finger, hand, and wrist
[2]
movements . However, persons with upper extremity amputations continue to reject these advanced
devices at high rates, preferring conventional (i.e., body-powered or myoelectric) prosthetic limbs that
provide little functional recovery . This finding is largely due to a lack of an intuitive, functional neural
[3]
interface that can provide high-fidelity control signals for efferent motor control. The majority of current
experimental peripheral nerve interfaces are limited by several disadvantages, including iatrogenic nerve
injury from electrode insertion, insufficient signal selectivity and reproducibility, substantial signal
degradation over time, and an inability to prevent neuroma formation .
[4,5]

To overcome the limitations of current neural interfacing strategies, our laboratory has developed the
regenerative peripheral nerve interface (RPNI) to provide reliable, high-fidelity signal transduction from the
residual limb for optimal prosthetic activation and volitional control [6-11] . The RPNI is composed of a
[12]
transected peripheral nerve, or peripheral nerve fascicle, that is implanted into a free skeletal muscle graft
[Figure 1]. After the free muscle graft is secured around the terminal end of the fascicle or nerve, the graft
undergoes a process of regeneration, revascularization, and reinnervation by the implanted peripheral
nerve . This process creates a biologically stable peripheral nerve bioamplifier that produces high-
[13]
amplitude EMG signals [6-8,13] . An epimysial electrode is then implanted in the RPNI to record specific
efferent motor action potentials , which serves as an interface that can be utilized for prosthetic
[13]
control [6-8,13,14] . This surgical approach has numerous benefits, including decreased neuroma formation,
improved signal-to-noise ratio (SNR) by means of neuromuscular signal amplification, as well as avoidance
of iatrogenic axonal injury that occurs with direct neural interfacing approaches . Furthermore, because
[14]
RPNIs can be created with individual fascicles, specific and selective prosthetic device control supporting
multiple degrees of freedom is possible, potentially resulting in a more intuitive and enhanced experience
when compared to other neuroprosthetic control techniques . In addition to neuroprosthetic control,
[15]
RPNIs may have the potential for providing sensory feedback from the prosthetic to the sensory afferents in
patients with upper extremity amputations . Lastly, RPNI surgery is indicated for effective prevention and
[16]
treatment of neuromas and postamputation pain . The purpose of this article is to review the multiple
[17]
applications of the RPNI.

REGENERATIVE PERIPHERAL NERVE INTERFACE DEVELOPMENT
Development of the RPNI began with extensive preliminary testing of RPNIs in animal models [6-8,11,13,18] .
Initial testing in rodents utilized free skeletal muscle grafts of the extensor digitorum longus (EDL) muscle
neurotized by the divided common peroneal nerve for the creation of RPNIs . Following the three-month
[13]
regeneration, revascularization, and reinnervation process, RPNIs were shown to generate high-amplitude
compound muscle action potentials (CMAPs) that could be readily recorded . Further experimentation
[13]
confirmed the biologic stability of the interface and provided histologic evidence of axonal regeneration and
synaptogenesis within the construct [Figure 2].
[11]

Subsequent testing revealed reliable RPNI signal transduction in real-time during voluntary muscle
activation [8,11] . These experiments showed that RPNI EMG activity could be selectively recorded without
electrical interference and signal contamination from adjacent active muscles or RPNIs [8,11] . In addition,
results from these experiments revealed that RPNIs had high SNR when compared to a control group
without RPNIs . Substantiated by these findings, this rodent model was used to further investigate the
[11]
long-term stability of RPNIs along with their ability to transduce efferent motor action potentials into
CMAPs . Signals were measured up to 14 months postoperatively and demonstrated large-amplitude
[18]
CMAPs without evidence of RPNI degeneration or signal degradation over time . Together, these findings
[18]