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Bone marrow-derived mesenchymal stem cell
Bone marrow-derived mesenchymal stem cells (BMMSCs) are another source of pluripotent cells that are
located in the stromal bone marrow compartment. Under specific experimental conditions, they have the
potential to differentiate into mesenchymal lineages, which accounts for their extensive application in cell-
based therapies. The first use of BMMSCs for lower limb nerve regeneration was described by Dezawa et al.
[45]
in 2001 . They observed significant nerve fiber regeneration following administration of genetically
engineered BMMSC to the end of transected sciatic nerve . The same observation was made by Chen et al.
[45]
using BMMSCs from rat models for regeneration of injured sciatic nerve . The experiment resulted in an
[46]
increase in regenerative nerve fibers after differentiation of BMMSCs to Schwann-like cells. Regardless of
their potential beneficial effects, they are limited by their harvesting difficulties, which are usually quite
painful. In addition, bone marrow aspirations provide low amounts of stem cells, most of which may get
lost due to unsuitable post-translational microenvironment.

Adipose-derived stem cells
Contrary to BMMSCs, adipose-derived stem cells (ADSCs) are the preferred method due to the ease of
harvest in great numbers . However, ADSCs are acquired after 2-3 weeks of cell culturing . To address
[37]
[5]
this problem, a stromal vascular fraction (SVF), which is obtained by treating subcutaneous adipose tissue
with collagenase, has emerged as a potential source of ADSCs that are immediately available and do not
require cell culturing [Figure 3] .
[5]
In 2020, Mathot et al. demonstrated enhanced neoangiogenesis of decellularized sciatic nerve graft defects
with ADSCs in rats . Notably, their protocol for cell harvesting is approved for harvesting ADSCs from
[48]
patients as part of a future clinical trial . ADSCs have also shown potential for improving nerve
[48]
regeneration in rat studies when delivered to fibrin and nerve conduits . Furthermore, in another study
[7]
[6]
by Shimizu et al., both ADSCs and SVF were shown to have excellent effects on nerve regeneration in a rat
model with nerve conduits .
[5]
Clinical trials investigating the use of ADSCs are limited by the Food and Drug Association, which has not
approved using ADSCs that have been enzymatically altered . These federal regulations limit the
[49]
availability of ADSCs for research, warranting further investigation into alternative sources . One target
[37]
[50]
source of mesenchymal stem cells is the olfactory nerve . An additional intervention showing potential is
the use of fat grafting as a source of ADSCs . This is an evolving field of research, and more studies are
[37]
needed to investigate patient outcomes .
[49]
ELECTRICAL STIMULATION
An additional intervention to encourage nerve regeneration after PNI is pulsatile ES, which has shown
potential as an adjunct therapy by accelerating axonal regeneration and promoting recovery . Keane et al.
[10]
found that ES accelerated functional recovery when applied at the time of nerve graft surgery in rats .
[8]
Immunohistochemistry of the harvested nerve revealed increased axonal regeneration and macrophage
accumulation . Furthermore, Jo et al. found that ES improved nerve regeneration in a rat model and was
[8]
[9]
comparable to the changes seen with systemic tacrolimus administration .
One challenge in the translation of ES at the time of surgery to a clinical setting is that the current protocol
[10]
tested is one-hour in duration, which adds a significant time and cost burden for clinical trials . Roh et al.
found a possible solution to this problem by investigating the benefit of a 10-minute ES session in a rat
[10]
model . They found accelerated recovery in both the 10- and 60-minute ES groups compared to the
control group, with evidence of early axon regeneration in both groups . While no clinical trials have been
[10]