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Page 4 of 10 Berberoglu et al. Plast Aesthet Res 2024;11:14 https://dx.doi.org/10.20517/2347-9264.2023.101

expanded its applications to different clinical settings, such as musculoskeletal injuries and advanced
control of exoskeleton devices.

RPNIs are also an effective surgical intervention in both the prevention and treatment of postamputation
pain resulting from symptomatic neuroma [8,16,18,19] . Following amputation, regenerating peripheral nerves
without a distal target can cause disorganized bulbous axonal sprouting, leading to subsequent neuroma
formation [12,16] . These neuromas may cause spontaneous ectopic neural activity, resulting in hyperalgesia,
allodynia, and eventually, chronic neuropathic pain [11,12] . By providing a distal target for regenerating axons,
RPNIs may prevent the formation of symptomatic neuromas. In a pilot clinical study, sixteen patients with
amputations underwent RPNI surgery for symptomatic postamputation neuromas . Using the numeric
[25]
pain rating scale, an average reduction of neuroma pain score by 71% and phantom limb pain score by 53%
was reported postoperatively. In addition, 75% of patients were satisfied with RPNI surgery and 94% would
choose to undergo surgery again when asked on the questionnaire . When RPNIs were implanted
[25]
prophylactically at the time of amputation, the results indicated a significantly lower incidence of both
neuroma and phantom limb pain compared to the control cohort . In this study, postoperative outcomes
[19]
were evaluated in a total of 90 patients. Forty-five patients underwent RPNI implantation at the time of
primary amputation, and 45 control patients underwent amputation without RPNI. Six control patients
(13.3 percent) developed symptomatic neuromas in the postoperative period compared with zero (0.0
percent) in the prophylactic RPNI group (P = 0.026). Twenty-three RPNI patients (51.1 percent) reported
phantom limb pain, compared with 41 control patients (91.1 percent).

DERMAL SENSORY REGENERATIVE PERIPHERAL NERVE INTERFACE (DS-RPNI)
Sensory feedback is of great importance for efficient motor planning, execution, and accomplishing daily
tasks . A prosthesis that lacks sensory and positional feedback is often experienced as foreign to
[26]
[26]
individuals with amputations and may result in user dissatisfaction and abandonment of these devices .
Providing a prosthetic device that can restore sensory information to individuals with amputations is,
therefore, a critical need. However, currently available prosthetic devices cannot accurately translate sensor-
derived information into meaningful, somatotopically matched sensory feedback [9,27] . This was supported by
a survey in which prosthetic users reported sensory feedback as one of the main features missing in current
[27]
devices . Similarly, absence of physiologic feedback is seen in the generation of phantom limb pain. PLP is
often burdensome to patients, resulting in displeasure among prosthetic users and subsequent rejection of
their prosthetic device [26,27] . Although the mechanism is still unclear, studies have shown improvements in
PLP when provided with sensory stimulation [26,27] . Therefore, reestablishing sensory feedback could
significantly reduce PLP and relieve the burden of individuals with amputation.

To overcome these limitations, the RPNI has been modified to develop the Dermal Sensory Regenerative
Peripheral Nerve Interface (DS-RPNI). The DS-RPNI consists of a residual sensory nerve implanted into a
[9]
deepithelialized skin graft measuring 0.5 × 1.0 cm [Figure 2] . The construct is placed subcutaneously, and
the graft is reinnervated by the sensory afferents in two months. A single DS-RPNI can be created for each
sensory nerve. To allow for sensory feedback from various distinct locations, multiple sensory nerves can be
[9]
implanted into independent deepithelialized skin grafts . So far, results from the preclinical study in
rodents showed robust revascularization and viable free dermal flap two months after fabrication.
Sando et al. achieved successful regeneration and reinnervation of the DS-RPNI dermal grafts by the sural
nerve with no evidence of neuroma formation . Mechanical and electrical stimuli applied to glabrous skin
[9]
[9]
grafts evoked highly reproducible and graded sensory nerve action potentials . Larger compound sensory
nerve action potential (CSNAP) amplitudes were obtained when electrical stimuli were applied to the DS-
RPNI compared to directly stimulating the nerves. Thus, the DS-RPNI has the potential to provide sensory