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Berberoglu et al. Plast Aesthet Res 2024;11:14 https://dx.doi.org/10.20517/2347-9264.2023.101 Page 3 of 10

Figure 1. The Regenerative Peripheral Nerve Interface (RPNI) construct. (A) Intraoperative dissection and isolation of median, ulnar,
and radial nerves (B) Implantation of six RPNIs, two each for the median nerve, ulnar nerve, and radial nerve (Burke KL, Kung TA,
Hooper RC, Kemp SWP, Cederna PS. Regenerative peripheral nerve interfaces (RPNIs): current status and future direction [8] .

Following the procedure, denervated muscle fibers undergo robust reinnervation by regenerating axons,
revascularization, and eventually mature RPNI formation . The transition process to a prosthetic limb is
[18]
supported by training, which involves the control of a real physical or virtual avatar prosthetic limb. Efforts
to contract the muscles in the missing limb generate neural signals that allow prosthetic control of
corresponding movements. However, recording signals directly from peripheral nerves is challenging
because nerve signal amplitudes are small and produce low signal-to-noise ratios (SNRs). Each RPNI has
the ability to serve as a biological amplifier without causing iatrogenic nerve injury while providing high
amplitude and reliable signals with high SNRs [15,21] . In a rat model, RPNIs with an implanted electrode
remained viable over 7 months and the reinnervated muscle graft transduced high-amplitude compound
muscle action potentials (CMAPs) from low-amplitude efferent motor action potentials . Further studies
[17]
in both rodents and non-human primates confirmed the biological stability of the interface and
demonstrated successful axonal regeneration and reinnervation by providing histologic evidence [21-24] . In a
[22]
first-in-human pilot study, four participants with upper extremity amputations underwent RPNI surgery .
Two individuals with distal transradial amputations elected to undergo surgical implantation of indwelling
intramuscular bipolar electrodes into their RPNIs, 3 years and 12 months after the initial RPNI surgery. The
SNRs measured in RPNIs of two patients had mean values of 68.9 and 21.0 decibels (dB) . The variation
[22]
may be due to the difference in duration between RPNI surgery and electrode implantation since additional
years may prolong the period of RPNI maturation and reinnervation . In a follow-up clinical study,
[22]
researchers further investigated the longevity of the RPNI by assessing the signal reliability from chronically
implanted RPNIs . RPNIs with indwelling bipolar electrodes produced SNRs that remained consistently
[24]
high, ranging from 15 to 250 dB across sessions for up to 276 days and 1,054 days, respectively . The
[24]
difference in SNR magnitude between sessions was likely due to the variability of the electromyography
[24]
(EMG) signals rather than shifts in electrode noise . Despite the variation, both SNRs remained
significantly higher than the SNR range from 2 to 20 typically recorded from surface EMG, intraneural
probes, and nerve cuff electrodes [22,24] . Additionally, by obtaining motor control signals from RPNI, both
participants completed functional and real-world tasks (e.g., coffee task, box, and block task) that require
[24]
various arm positions and grip movements over a period of 16 months without a need for recalibration .
This study further showed the potential of RPNIs as a long-term interface for enhanced control of
prosthetic devices. By providing individuals with a more intuitive experience and improving quality of life,
RPNIs hold promise for significantly advancing prosthetic technology in the future. The high adaptability of
this simple and effective surgery has subsequently led to the development of multiple modifications and