4.1 Summary of evidence
The current review assessed some of the applications of cell polarity in the foot and ankle problems. This study comprised 27 papers centred on the influence of bioelectricity in wound healing, nerve development and cellular differentiation.
It is well known that the ion gradient across cell and organelle semipermeable membranes drives electrical signalling. This electrical signalling produces cell's plasma membrane's electrical potential at rest which we call it Vmem(1). Vmem is mainly determined by K and Na concentrations on each side of the membrane. Diverse ion channels, fluctuating expression of channels and isoforms with different response properties and ion affinities, and post-translational modification of channels sustain both steady-state Vmem and dynamic responses to environmental and other stimuli. Proliferation of cells, resting membrane potential, and the developmental potential of Vmem vary considerably(4). The relationship between membrane polarisation and proliferative potential has been established(4). This may be deduced from the fact that various cell types exhibit varying degrees of polarisation. For instance, metastatic cancer cells are hypo polarized, while the voltage of myoblasts and neural crest cells varies between 10 and 35 mV. Therefore, membrane polarisation and proliferative capacity are connected(4).
Based on this connection, the research shows that bioelectrical signalling is vital to the healing process(36). In the foot and ankle area, this healing process has been discussed in three primary sections: Regeneration and mending of wound(8), treatment of a damaged nervous system(14), and modification of arteriopathies through changes in the cellular proliferation or expression and pattern of genes(19).
Three main regulatory networks which control cellular activities are chemical gradients, gene regulatory networks, and bioelectricity(1). There are connections between these networks. For instance, after an injury, bioelectric signals dictate early structural development and robust pattern restoration(1). Chemical gradients can modify bioelectricity through ion fluxes, and bioelectric impulses can change the expression and pattern of genes by producing cell polarities and endogenous electric fields (EF)(46). Enforcing a different electrical stimulation (ES) to the cells can modify EFs and control or enhance cell function(46). Changes in the bioelectrical networks may interpret morphogenetic information that affects gene expression and enable cell collectives to make large-scale decisions regarding development and shape, as well(46).
Hence, among the three major regulatory networks, bioelectrical changes may have the greatest effect on cell activity and regulate a large number of the foot and ankle illnesses. Moreover, it is possible to make changes to the cell polarity by applying electrical stimulation or modifying the chemical gradients(16). Therefore, understanding cell polarity and its possible roles can aid practitioners to find more effective ways of treating and preventing illnesses(16).
Practitioners can tackle a particular ailment in multiple levels and yet fix the symptoms. For instance, in the case of painful calf cramps, a practitioner may focus on pain treatment with analgesics, muscle relaxants, muscle stretching, calcium, and magnesium, or address the potential risks for calcium and magnesium deficiency, such as malabsorption, wasting, or overdemand for calcium and magnesium (47). Some measures, such as the use of analgesics, can alleviate patient discomfort and circumvent predisposing factors and sources of pain. However, it is typically preferable to be aware of predisposing factors and healing obstructors, as well as their proportional effects on the current disease, and to develop a thorough treatment plan by assessing the risk and benefit of treating variables (intrinsic and extrinsic) while monitoring the improvement of symptoms(48). These predisposing variables in the case of calf muscle cramps may include hormonal changes, trauma, tension, and electrolyte imbalance(47).
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. The author argues that measuring bioelectricity and cell polarity can help to validate in vitro variable effects (49). For instance, in the calf spasm, different variables can alter the bioelectricity of sarcomeres from normal; therefor, their capacity to absorb nutrients, including calcium and magnesium, will change and this can produce muscle spasm in the final stage(49).
In another example, Achilles tendonitis, is an inflammation surrounding the tendon cells and perhaps their insertion into the calcaneus(50). In this scenario, the author argues that several intrinsic and extrinsic factors, such as the strain from a short calf muscle, might alter the cell polarity in the region, toward the polarity which absorb more white blood cells or calcium and fibroblasts, and process inflammation, tendon injury, and fibrosis (50).
Bunion development is another example, which can happen by rotational alterations in the first metatarsal bone or expansion of the first metatarsal bone's head. Several genetic or acquired hazards may be implicated in the development of bunion (51). However, the author argues that a real expansion in the head of the 1st Metatarsal bone is impossible without alterations in the cell polarity in that location. Changes in the bioelectrics and cell polarity can boost absorption from minerals and allow the tissue to overcome mechanisms which try to regulate excessive development in the metatarsal bone (1). Alternately, the ion alterations and cell polarity changes in the surrounding muscles of some individuals can lead to muscular imbalance and changes in the anatomic position of the first metatarsal, including its rotation, which are nonetheless classified as bunion (52).
Cell polarity and bioelectricity at the cellular level can play a role in the ageing process, as well. Aging is often characterised by widespread muscle loss and cognitive impairments. The process of ageing is caused by the accumulation of a wide variety of molecular and cellular damage over time. This results in a steady decline in physical and mental function, an increase in the risk of disease, and finally mortality(53). At the elderly age muscles are being wasted in the presence of protein. There is the possibility of protein malabsorption at the cellular level. This malabsorption, which may be caused by physical and social environments or personal characteristics such as hormonal shifts, inflammation, heredity, and environmental and social variables, varies from individual to individual (53). The author argues that any of the intrinsic or extrinsic variables listed above will have an effect on ageing based on the amount of direct or indirect alterations they can make to cellular polarity. For example, psychological condition can modify the cellular polarity through both humeral changes in the body and electric changes in the nerve terminals. Although it is not always possible to examine these basic factors, measuring changes in cell polarity appears to be simpler and more practical. According to some ideas, changes in cell polarity associated with ageing might attract inflammatory cells, which are also essential for ageing (1).
Onychomycosis is an interesting example. Onychomycosis, which is a fungal infection of the toenails is usually being treated with antifungals. Fungal infection is contagious and can spread to other toenails. Family history, growing age, poor health, past trauma, warm environment, engagement in fitness activities, immunosuppression (e.g., HIV or drug-induced), communal bathing, and occlusive footwear, and decreased blood flow are predisposing variables that might increase the likelihood of fungus development (54). Sometimes it is difficult to determine the pattern of onychomycosis spread on a single foot. For instance, why a nearby toenail with certain predisposing variables is healthy but a distant toenail with fewer predisposing factors gets infected(54). The author argues that predisposing variables will be successful when they are able to alter the cellular polarity of toenail cells. Consequently, certain toenails on the same foot will be susceptible to fungal infection while others may contain additional variables.
Overall, it is essential to formulate an informed treatment approach for individuals with presenting symptoms(48). In order to create an effective treatment plan, it is necessary to evaluate all potential predisposing variables and healing impediments for a disease with their potential impacts, then individualize the treatment. Using precise instruments to evaluate cell polarity and bioelectricity can assist to validate the probable influence of these variables. Of the three primary networks that govern cell activity and growth (chemical gradients, bioelectricity, and genetics), changes in bioelectricity and cell polarity appear to be the most efficient and useful(1). Therefore, it is essential to be aware of the possible involvement of bioelectricity and cell polarity in the pathophysiology of the majority of diseases and try to develop more effective future treatments by concentrating on alterations in cell polarity (1).
4.3 Limitations
According to the author's understanding, this is the first study of its sort to comprehensively cover the clinical implications of cell polarity in foot and ankle illnesses; nevertheless, there are concerns that certain studies may have been omitted from this review. In addition, since it is not always possible to quantify cell polarity and bioelectricity, it is likely that sections of the present research will alter as a result of advancements in measuring instruments, bringing them closer to reality (55).
The relationship between Cell Vmem, and proliferative potentials is confusing since there is no obvious functional link between Vmem and the cell cycle (56). Therefore, this part needs further investigation.
Additionally, our bodies utilise several types of energy, including chemical, electrical, mechanical, and electromagnetic energy(46). Only the form of energy known as electrical energy or electricity has been explored in this article. Although we briefly discussed the relationship between electrical and magnetic energies or chemical energy and the production of electrical energy, further research is required to determine the effects of other types of energy on each other or on the symptoms themselves.
Finally, despite the fact that the bulk of accessible research explore symptoms of various diseases and randomise the influence of various medications on the treatment of these symptoms, these studies seldom evaluate potential predisposing variables and associated impact factors. Therefore, it is too soon to consider cell polarity as a combining point for all predisposing factors.
A few investigations revealed that the use of neuromuscular electric stimulation (NMES), electric stimulation (ES), or devices for electrical stimulation of the peroneal nerve were ineffective in suppressing muscular spasms (12, 25, 31); however, these papers were based on trial and error, and it is unclear if the use of such devices may alter the bioelectric. In other words, neither bioelectric nor cell polarities were measured, but we know that timing and amplitude vary between devices and changes in bioelectric are sensitive to timing and amplitude of the devices(24).
In the majority of investigations (9–33), ES was used to restimulate the nervous system, and its efficacy was evaluated using the trial-and-error method; however, bioelectricity and cell polarity changes were not observed. Consequently, it is unclear if the observed efficacy in ES is a result of bioelectric effects or imitating a pure neural response.
Nonetheless, the present review is a valuable addition to therapeutic efficacy. In addition, it gives researchers with guidelines to follow if they conduct low-risk experiments in the future.