How Might Consideration of Cell Polarity Aect
Daily Therapeutic Practices?
A Literature Review
Hamid Reza Ravanbod1
1 Podiatric Surgery, Australian Podiatry Association, Melbourne, Australia
GMJ.2023;12:e2970
www.gmj.ir
Correspondence to:
Hamid Reza Ravanbod, Podiatric Surgery, Australian
Podiatry Association, Melbourne, Australia.
Telephone Number: +61398196616
Email Address: hamidravan@yahoo.com.au
Received 2023-03-07
Revised 2023-03-20
Accepted 2023-04-05
Abstract
Background: In addition to biochemical gradients and transcriptional networks, cell be-
haviour is controlled by endogenous bioelectrical signals resulting from the action of ion
channels and pumps. Cells are regulated not only by their own membrane resting potential
(Vmem) but also by the Vmem of neighbouring cells, establishing networks through electrical
synapses known as gap junctions. V mem is the primary factor in producing a polarity that
can regulate cell assimilation of various substances. This article aimed to examine how cell
polarity can change and how variations in cell polarity may lead to clinical demonstrations.
Materials and Methods: Using Cochrane Central, PubMed, Scopus, Web of Sci-
ence (WOS), and Embase, a comprehensive qualitative literature review was con-
ducted from February 1, 2018, to February 1, 2023, to identify studies addressing bio-
electric, cell polarity, and electroceuticals in patients with foot and ankle problems.
Results: Out of 1,281 publications, 27 were included. One study investigated bioelectric
wound-healing. Twenty-ve studies examined bioelectric nerve cell growth, whereas one
study evaluated bioelectricity-induced cellular dierentiation in the treatment of arteriopathies.
Conclusion: The author of this systematic review support addressing the predisposing fac-
tors and healing impediments for a disease, thereby enhancing the healing process and re-
ducing the likelihood of recurrence or parallel conditions. This method of treatment has pro-
vided a summary of evidence indicating that cell polarity could be addressed for the treat-
ment and prevention of most if not all, foot and ankle problems. However, owing to the
limitations of V mem and bioelectricity measurement and the direct or indirect involvement
of genetics and chemical gradients, further studies are required to conrm these results.
[GMJ.2023;12:e2970] DOI:10.31661/gmj.v12i0.2970
Keywords: Bioelectricity; Cell Polarity; Bioelectric; Action Potential
Introduction
Bioelectricity is an electrical phenomenon
that is induced or supplied to cells to aect
their phenotype. In the context of this term,
an electrical phenomenon refers to functions
or activities in living cells that depend on the
separation of charges (voltage), which gener-
ally occurs when ions separate, or move
(current), typically via channels and pumps.
This electrical eect is generated by a liv-
ing cell that expends energy to accomplish
this. In other words, the dead cells do not
generate bioelectricity. However, they can
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Ravanbod HR, et al. Cell Polarity and Therapeutic Practice
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change the quality and quntity of bioelec-
tricity in the adjacent cells. A “cell” accord-
ing to this denition could be a single cell
or a group of cells. A cell’s phenotype con-
sists of its shape, size, location of charges
in space and time, physiology, and gene ex-
pression. The phenotype covers the condi-
tion of the cell, including polarisation. Polar-
isation is the disruption of a region’s charge
distribution by an electric eld (EF) [1-3].
Evidence demonstrates that bioelectrical
changes are fundamental to cellular dierenti-
ation and wound-healing [4].
Additionally, the application of physiologi-
cal strength and transepithelial EFs can alter
nerve cell migration, orientation, and growth
[5]. However, the benets of bioelectricity
may extend well beyond these three uses. For
instance, breakthroughs in molecular-level
techniques [1] have identied a unique prop-
erty of bioelectricity that governs the activi-
ty of single cells and coordinates the cellular
development and regenerative repair of com-
plex structures. This indicates that changes in
bioelectricity and cell polarity can alter cel-
lular programming, resulting in the develop-
ment of new symptoms or the disappearance
of undesirable symptoms. This review aims
to address some of the well-known or com-
monly accepted uses of bioelectricity and cell
polarity in the pathophysiology and treatment
of foot and ankle disorders. In addition, it pro-
vides new perspectives on the potential of bio-
electricity and cell polarity to prevent diseases
and improve the treatment of foot and ankle
disorders [6].
Materials and Methods
Protocol and Registration
The protocol was developed according to the
Preferred Reporting Items for Systematic Re-
views and Meta-Analysis (PRISMA) Check-
list [7] and was retrospectively registered on
08/02/2023 with the Open Science Frame-
work (Registration number: osf.io/ehbtk).
Eligibility Criteria
A comprehensive literature review was con-
ducted using various databases including
Cochrane Central, PubMed, Scopus, Web of
Science (WOS), and Embase from February
1, 2018, to February 1, 2023. To identify addi-
tional studies, Google Scholar was also used.
Key search terms and their synonyms, includ-
ing bioelectric, cell polarity, electroceuticals,
and foot and ankle diseases were combined
using Boolean operators (AND, OR, and *). If
full articles were not available or information
was missing, we contacted the corresponding
authors to request additional data. The review
excluded papers that did not focus on the
treatment of diseases that addressed non-hu-
man specimens or diseases other than foot and
ankle.
In addition, lecture notes, dissertations, and
papers not published in peer-reviewed jour-
nals have been removed due to accessibility
issues. Finally, the eligible papers were sort-
ed into three main topics for evaluation: a)
Wound-healing, b) Nerve healing, and c) Cel-
lular dierentiation and the reparative regen-
eration of complex structures.
Results
Study Selection
We retrieved 1,281 studies from electronic
databases and excluded 104 duplicate stud-
ies. Reading titles and abstracts, 1,133 papers
were discarded, and the remaining 44 full-text
articles were retrieved for potential inclusion.
The author assessed citations, abstracts, and-
full-text publications based on the inclusion
criteria. From these 44 articles, 17 studies
were removed for various reasons, such as
discussing devices instead of disease treat-
ment (three articles), including complicated
contributing factors (12 articles), or focusing
only on hands and organs other than foot and
ankle (two articles). The study selection pro-
cess is shown in the PRISMA diagram (Fig-
ure-1)
Characteristics of the Included Studies
Eligible studies with dierent designs were
grouped into three categories:
a) One study focused on wound-healing [8].
b) A total of 25 studies examined transepithe-
lial EFs and their inuence on cell migration,
orientation, and nerve growth [9-28].
c) Another study explored the aspect of bio-
electricity that regulate cellular dierentiation
and diabetic arteriopathy [19].
Cell Polarity and Therapeutic Practice Ravanbod HR, et al.
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3
Description of Studies and Their Character-
istics
A total of 1,281 citations were retrieved
through a database search, and 27 studies
were identied that addressed the topics of
this analysis. Of these studies, three showed
no statistically signicant dierences be-
tween the use of electric stimulators (ES) and
conventional approaches [25, 12, 29]. These
studies focused on reducing muscular spasms
following a stroke or multiple sclerosis (MS).
The remaining 24 trials revealed a statistical-
ly signicant eect of ES on symptom relief,
but the studies considered possible changes
in the bioelectricity or examined bioelectrical
changes to determine device ecacy.
Intervention Types Employed
The available evidence about bioelectricity
were analysed using descriptive qualitative
analysis and coded by the author. As a result,
three overarching categories were identied:
Category 1: Wound-Healing
Research indicates that bioelectrical signal-
ling is a crucial aspect of the wound-healing
process [8]. Understanding and eectively
using this process is essential for improved
wound-healing and regeneration. During this
process, individual cell behaviours coordinate
migration to the wound centre to address mild
or severe barrier deciencies [30]. One of the
most critical processes involved in restoring
Figure 1. PRISMA ow diagram
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Ravanbod HR, et al. Cell Polarity and Therapeutic Practice
the skin barrier is the migration of epithelial
cells as a continuous sheet structure. When
skin is injured, weakened epithelial barri-
ers create endogenous EFs, sustained by ion
channels and cell junctions, with the cathodal
pole at the centre of the incision [31]. In re-
sponse to electrical impulses, epithelial cells
recognize minute EFs and move in a desig-
nated direction [32]. It has long been hypoth-
esised that naturally occurring EFs promote
wound-healing by directing cell migration
[33], and experimentally gathered evidence
indicates that extensive epithelial sheets of
keratinocytes or corneal epithelial cells col-
lectively respond to applied EFs [8]. Although
some mechanisms of collective cell migra-
tion are similar to those employed by solitary
cells, the coordinated movement of the cohe-
sive sheet is governed by distinct [8].
Category 2: Nerve Growth
The use of ES in neural tissue engineering is
a promising therapeutic approach [34]. ES
positively aects four major cell types in-
volved in peripheral nerve healing: neurones,
endothelial cells, macrophages, and Schwann
cells [34]. ES promotes more rapid neurite
extension, cellular alignment, and cell phe-
notypic modications linked with enhanced
regeneration and functional recovery. Materi-
als including hydrogel-based electrically con-
ductive nerve guidance conduits (NGCs) can
bridge gaps in the peripheral nervous system
and further enhance nerve generation [35].
In vitro, the enhanced electrical conductivity
of the hydrogel plays a vital role in the ex-
tension of dorsal root ganglion (DRG) axons
[36]. Therefore, any environment that pro-
vides ES can alter cellular polarisation, hence
regulating and enhancing cell activity in the
nervous system towards the repair of the dam-
aged cells. This can result in improvement of
stretching muscles and reduction in spasticity,
improvement in gait, balance, and prevention
of muscle atrophy [12, 15, 18, 21, 26, 37]. In
practice, applying ES reduces pain score after
orthopaedic surgeries [38].
Category 3: Cellular Dierentiation
Chemical gradients, gene regulatory net-
works, and endogenous ion uxes (bioelec-
tricity) are the three major regulators of cel-
lular activity [39]. Bioelectric signals provide
crucial information on early structural growth
and the restoration of normal patterns follow-
ing damage [39]. Decoding bioelectric signals
can change gene expression and even change
genetic patterns [40].
Bioelectrical networks can process morphoge-
netic information that aects gene expression,
allowing cell collectives to make large-scale
growth and shape decisions [41]. All tissues
have ion channel and gap junction-generated
membrane potentials creating bioelectrical
networking [41]. Altering bioelectric circuits
through channels can eectively govern cel-
lular collectives’ work toward appropriate
changes. For instance, applying bioelectricity
to the foot and ankle area improves diabetic
arteriopathies, as ES can change vascular de-
velopment. This will minimise chronic pain
through enhancement of the arterial, and ve-
nous and lymphatic-ow [19].
Discussion
Summary of Evidence
The current review assessed several applica-
tions of cell polarity in foot and ankle prob-
lems. This study consisted of 27 papers that
addressed the inuence of bioelectricity on
wound-healing, neural development, and cel-
lular dierentiation.
It is well known that the ion gradient across
cell and organelle semipermeable membranes
drives electrical signalling. This electrical sig-
nalling produces the electrical potential of the
cell’s plasma membrane at rest, called Vmem
[1]. Vmem is mainly determined by the K+
and Na+ concentrations on both sides of the
membrane. Diverse ion channels, uctuating
expression of channels and isoforms with dif-
ferent response properties and ion anities,
and post-translational modications of chan-
nels maintain both steady-state Vmem and dy-
namic responses to environmental and other
stimuli. Accordingly, Vmem varies consider-
ably during dierent phases, such as cellular
proliferation, resting membrane potential, and
developmental potential [4]. The relationship
between membrane polarisation and prolifera-
tion phases have been established [4]. Accord-
ingly, various cell types exhibit varying de-
grees of polarisation. For instance, metastatic
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Cell Polarity and Therapeutic Practice Ravanbod HR, et al.
cancer cells are hypopolarised, while the volt-
ages of myoblasts and neural crest cells vary
between 10 and 35 mV. Therefore, membrane
polarisation and proliferative capacity are re-
lated [4].
Based on this connection, the research has
shown that bioelectrical signalling is vital to
the healing process [31]. This healing process
has been discussed in three primary sections
in the foot and ankle areas: regeneration and
mending of the wound [8], treatment of a
damaged nervous system [14], and modica-
tion of arteriopathies through changes in the
cellular proliferation or expression and pat-
tern of genes [19]. The three main regulato-
ry networks controlling cellular activities are
chemical gradients, gene regulatory networks,
and bioelectricity [4].
Connections exist in these networks. For in-
stance, bioelectric signals dictate early struc-
tural development and robust pattern resto-
ration following an injury [4]. Chemical gra-
dients can modify bioelectricity through ion
uxes, and bioelectric impulses can change
the expression and patterns of genes by pro-
ducing cell polarities and endogenous EFs
[42]. Enforcing a dierent ES to the cells,
EFs can be modied and controlled or cell
function will be enhanced [42]. Changes in
bioelectrical networks may also interpret
morphogenetic information that aects gene
expression and enable cell collectives to make
large-scale decisions regarding development
and shape [42].
Hence, among the three major regulatory net-
works, bioelectrical changes may have the
greatest eect on cell activity and can regu-
late a large number of diseases in the foot and
ankle. Moreover, applying ES or modifying
the chemical gradients [16] can modify cell
polarity. Therefore, understanding cell polar-
ity and its possible roles can help practitioners
nd more eective ways to treat and prevent
diseases[16].
For a specic disease, practitioners have ac-
cess to multiple levels of symptom manage-
ment. However, symptom management is not
necessarily a treatment for the underlying
causes. For instance, in the case of painful
calf cramps, a practitioner may focus on pain
treatment using analgesics, muscle relaxants,
muscle stretching, calcium, and magnesium or
address potential risks for calcium and mag-
nesium deciency, including malabsorption,
wasting, or over-demand for these minerals
[43]. Some measures, including analgesics,
can relieve patient discomfort but usually can-
not prevent predisposing factors and sources
of pain. However, it is generally preferable
to be aware of predisposing factors and heal-
ing obstructors, as well as their proportional
eects on the current disease. Developing a
comprehensive treatment plan involves as-
sessing the risk and benets of treating vari-
ables (intrinsic and extrinsic) while monitor-
ing symptom improvement [44]. These pre-
disposing variables in the case of calf muscle
cramps may include hormonal changes, trau-
ma, tension, and electrolyte imbalance [43].
The issue with this method of addressing
predisposing variables is that the assessment
of these variables and their potential impact
on the symptoms cannot always be validated
[45]. The author argues that measuring bio-
electricity and cell polarity can help validate
in vitro variable eects. For instance, in calf
spasms, dierent variables can alter the bio-
electricity of sarcomeres from normal. There-
fore, their capacity to absorb nutrients, includ-
ing calcium and magnesium, will change and
this can produce muscle spasms in the nal
stage [45].
Achilles tendonitis is another example, in-
ammation of surrounding the tendon cells
and perhaps their insertion into the calcaneus
[46].
In this scenario, the authors declare that sev-
eral intrinsic and extrinsic factors including
the strain from a short calf muscle, might alter
the cell polarity in the region. This alteration
could be towards the polarity that absorbs
more white blood cells or calcium and bro-
blasts, processing inammation, tendon inju-
ry, and brosis.
Bunion development is yet another example
that can occur due to rotational alterations
in the rst metatarsal bone, or expansion of
the rst metatarsal bone’s head. Several ge-
netic or acquired hazards may be involved in
the development of bunions [47]. However,
the author argues that real expansion in the
head of the 1st metatarsal bone is impossible
without alterations in the cell polarity in that
location. Changes in the bioelectric and cell
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Ravanbod HR, et al. Cell Polarity and Therapeutic Practice
polarity can boost the absorption of minerals
and allow the tissue to overcome mechanisms
that try to control excessive development in
the metatarsal bone [1]. Alternately, ion al-
terations and cell polarity changes in the sur-
rounding muscles of some individuals can
lead to muscular imbalance and changes in
the anatomic position of the rst metatarsal,
including its rotation. These changes are clas-
sied as bunion [48].
Cell polarity and bioelectricity at the cellular
level can play a role in the ageing process. Ag-
ing is often characterised by widespread mus-
cle loss and cognitive impairments. During
the ageing process, there is a steady decline in
physical and mental function, an increase in
the risk of disease, inammatory conditions,
and ultimately increased mortality [49].
In the elderly, muscles are wasted in the pres-
ence of protein, and there is the possibility of
protein malabsorption at the cellular level.
This malabsorption may be caused by physi-
cal and social environments or personal char-
acteristics such as hormonal shifts, inamma-
tion, heredity, and environmental and social
variables, which vary from individual to in-
dividual [49].
The author argues that any of the above intrin-
sic or extrinsic variables will have an eect
on ageing based on the amount of direct or
indirect alterations they can impose on cel-
lular polarity. For example, a psychological
condition can modify cellular polarity through
both humeral changes in the body and elec-
tric changes in the nerve terminals. Although
these fundamental factors cannot always be
studied, it is easier and more practical to mea-
sure changes in cell polarity. Additionally,
changes in cell polarity and bioelectricity can
inuence the ageing process independently of
genetics and other risk factors. By restoring
normal cell polarity, inammatory cells will
be less attracted to other tissues, reducing
age-related inammatory changes [1].
Onychomycosis is an intriguing example of a
fungal infection that aects the toenails, and
it is usually treated with antifungals. This
type of infection is contagious and can easily
spread to other toenails. Various factors such
as family history, advancing age, poor health,
previous injuries, warm environment, partic-
ipation in tness activities, immunosuppres-
sive drugs or diseases (e.g., HIV), communal
bathing, occlusive footwear, and decreased
blood ow can predispose individuals to this
condition [50].
Determining the spread pattern of onychomy-
cosis on a single foot can be challenging. For
instance, it can be dicult to understand why a
nearby toenail with more predisposing factors
is healthy, while a distant toenail with fewer
predisposing elements is infected [50]. The
author argues that predisposing variables can
alter the cellular polarity of toenail cells, mak-
ing certain toenails more susceptible to fungal
infection. Thus, predisposing factors are only
important when they can change the cell po-
larity and attract the fungus agent due to the
new cell polarity.
Overall, to develop eective treatment ap-
proaches for symptomatic individuals, it is
essential to create a treatment plan consider-
ing all potential predisposing variables and
healing impediments [44]. Evaluating and
individualizing treatment options for each
patient is necessary. Using accurate instru-
ments evaluating cell polarity and bioelectric-
ity can help validate the probable inuence
of these variables. Additionally, it is possi-
ble to bypass these risk factors by adjusting
the bioelectricity, directly. Of the three pri-
mary networks that govern cell activity and
growth – chemical gradients, bioelectricity,
and genetics – changes in bioelectricity and
cell polarity are the most ecient and useful
[1]. Therefore, understanding the potential in-
volvement of bioelectricity and cell polarity
in the pathophysiology of most diseases is im-
portant to develop more eective treatments
that concentrate on altering cell polarity [1].
Clinical Relevance
Cell polarity plays an essential role in sever-
al aspects of clinical practice, including dis-
ease prevention and treatment. Practitioners
need a thorough treatment plan that considers
all relevant aspects and causes and compares
the risk-benet of addressing them to basic
symptom control to treat diseases eective-
ly [2]. The authors claim that it is possible
to examine the impact of dierent variables
on bioelectricity to develop an ecient treat-
ment approach. The polarity of the adequate
number of cells can play a role in attracting
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Cell Polarity and Therapeutic Practice Ravanbod HR, et al.
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This approach can help doctors and research-
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Limitations
According to the author's understanding, this
is the rst study to comprehensively cover
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sequently, it is unclear if ES’s observed eca-
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imitating a pure neural response.
Conclusion
This review provides valuable information on
treatment and prevention strategies for foot
and ankle diseases. It emphasizes incorpo-
rating cell polarity and considering possible
factors and relevant contributing factors to re-
duce the risk of recurrence or other issues in
patients. However, given the lack of precision
in measuring bioelectricity and the inclusion
of other gradients, future studies with larg-
er sample sizes are necessary to corroborate
these ndings.
Conict of Interest
None to declare.
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