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Page 6 of 13 Chi et al. Plast Aesthet Res 2023;10:56 https://dx.doi.org/10.20517/2347-9264.2023.48

Figure 2. Areas of recent study for FK506 and electrostimulation summarized.

ELECTROSTIMULATION FOR PERIPHERAL NERVE INJURY
Early studies
The potential role of electromagnetic fields to interact with regenerating cells was first described in the early
1900s as nerve growth in cell culture exposed to electric fields was observed . Subsequent studies
[50]
characterized cellular changes such as nucleolar enlargement and depletion of Nissl bodies, indicative of the
cellular response to axonotmesis and preparation for regeneration, after electrostimulation to peripheral
nerves [51,52] . Further electrical studies of dorsal root ganglion cells of various species found that neurons
would preferentially align to face the cathode and sprout new axons with greater branching towards the
cathode [53,54] . Given these studies in the normal uninjured nerve, attention was turned towards the role of
electrostimulation in injured nerves.

This work was expanded in animal models, starting with Hoffman, who demonstrated increased nerve
sprouting at partially denervated muscles when electrostimulation was applied for 10-60 min [51,55] . Others
were able to show improved muscle twitch and contractile strength recovery after nerve injury when
continuous electrostimulation was applied [55,56] . Likewise, quicker recovery of the toe flexion reflex with
electrostimulation, in some cases with as little as 5 min of electrostimulation therapy, was seen by Pockett
[57]
and Gavin . Pulsed electromagnetic stimulation following rat median nerve transection injury was found
[58]
to improve resulting axon counts and nerve conduction . Improved functional recovery in rabbits
following soleus nerve crush injury after continuous electrostimulation with implanted nerve electrodes
resulted in muscle twitch and force contraction significantly earlier than in unstimulated nerves .
[56]
Electrostimulation also increased the rate of central nervous system regeneration with improved functional
parameters following spinal cord hemisection in both guinea pigs and dogs [59,60] . Fluorescent dye labeling of
motor neurons showed that a single treatment of 1-hour electrostimulation led to accelerated axonal
regeneration of repaired femoral nerve transection by 3 weeks compared to 8-10 weeks in sham-stimulated
[61]
rats . Additionally, electrostimulation appeared to increase the accuracy of targeted axonal regeneration
with motor neurons preferentially regenerating into motor end-targets.

Mechanism of action
Complete signaling pathways following electrostimulation remain incompletely elucidated, but it is known
that electrostimulation induces the expression of regeneration-associated genes necessary for axonal
regeneration, such as the previously described GAP-43, brain-derived neurotrophic factor (BDNF) encoded