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Page 2 of 5 Sears et al. Plast Aesthet Res 2024;11:31 https://dx.doi.org/10.20517/2347-9264.2024.04

reconstruction that prioritizes the care of peripheral nerves, residual bone, and muscle to reduce post-
[2-4]
amputation pain and improve prosthetic control . From a reconstructive surgery perspective, the focal
point of innovation for amputation has been the prevention and treatment of terminal neuromas. Terminal
neuromas are non-tumorigenic, bulbous masses that form at the distal end of amputated nerves in a vain
attempt to reinnervate the now absent distal target. As one of the most common sequelae accompanying
amputation, the prevention and treatment of terminal neuromas have historically been described as
unsatisfactory . To address these complications, surgeons have sought to identify new targets for
[5,6]
transected nerves. Their search produced novel techniques such as targeted muscle reinnervation (TMR)
and regenerative peripheral nerve interface (RPNI), which resolve the problems of nerve transection by
embedding the transected nerve end into muscle. This coupling of biologically compatible tissues provides
the damaged nerve somewhere to go and something to do . In addition to circumventing painful neuroma
[3,4]
formation, the newly innervated muscle amplifies neural signals, providing an opportunity to record
efferent motor activity via electromyography (EMG) and translate it into commands for a coupled
prosthetic device. Both TMR and RPNI rely on the innate regenerative capacity of nerves to innervate new
biological targets. The term innervation generally means to supply an organ or tissue with nerves, but do
terminal targets need to be biological in order to form functional units? In the digital age, we have the
technology to provide advanced robotic limb substitutes and the neural interfaces to control them, and so
the philosophical question becomes: what constitutes innervation in the 21 century? In this opinion piece,
st
we explore the concept of innervation as it relates to the field of neuroprosthetics, and the integral roles
plastic surgeons may play in innovating innervation.

DISCUSSION
One class of devices capable of redefining innervation is the regenerative sieve electrode Figure 1. Like TMR
and RPNI, sieve electrodes rely on axonal regeneration; however, rather than form functional
neuromuscular junctions or cutaneous sensory receptors, sieve electrodes allow axonal regeneration
through porous electrodes Table 1. These porous electrode structures enable greater isolation of axons into
[7,8]
separate channels for highly selective recording and stimulation Figure 2 . Maximization of axonal contact
cements this class as the most selective electrodes available, with improvements such as double layering
[9]
allowing for upwards of 64 recording channels for even greater specificity . Implementing guidance
materials with cuff electrode functionality bolsters interface stability and selectivity . Additionally,
[10]
contemporary sieve electrodes boast substantial chronic viability; their thin polyimide build is highly
[11]
flexible, reducing the risk of axonopathy commonly seen in their silicon variants . Incorporating
polyimide significantly reduced the immune response to the electrode with no signs of inflammation at 12
months of implantation in a rat model . Once supplied with nerves, these electrodes can chronically
[12]
interface with the user's nervous system to actuate a sophisticated prosthesis . This formation of long-term
[10]
functional neural connections with a synthetic target contends with the current definition of innervation,
which holds the distal site of reinnervation to be exclusively biological.

Regenerative sieve electrodes have demonstrated a trajectory of increasing selectivity and stability, but
implantation’s predication on the transection of an intact nerve categorizes these electrodes as the most
invasive. This categorization is symptomatic of experimental methodology, which evaluates invasivity via
[13]
traditional neurorrhaphy models, comparing repair methods restoration of function to an intact limb .
While nerve transection is a prerequisite to regenerative electrode application, in an amputation and
neuroma repair model, neurotmesis would have already occurred, significantly reducing the invasivity of
electrode implantation. Srinivasan et al. . validated the chronic viability of regenerative electrodes in a rat
[14]
amputation model, exhibiting spontaneous, sensory-evoked, and electrically evoked action potentials in the
sciatic nerve at five months. However, electrode implantation is not without risk, and despite the improved