Possible Mechanism for Synchronized Detection of Weak Magnetic Fields by Nerve Cells

We propose that biological systems may detect static and slowly varying magnetic fields by the modification of the timing of firing of adjacent nerve cells through the local influence of the magnetic field generated by current from one cell's firing on its nearest neighbors. The time delay of an adjacent nerve cell pulse with respect to the initial clock nerve cell pulse could serve as a signal for sensing the magnitude and direction of the magnetic field in a direction perpendicular to the current flows in the cells. It has been shown that changes in static magnetic fields modify concentrations of reactive oxygen species, calcium, pH, the growth rates of fibrosarcoma cells, and membrane potentials. These are linked to changes in membrane potentials that can either inhibit or accelerate the firing rate of pacemaker or clock cells. This mechanism may have applications to animals' use of magnetic fields for navigation or other purposes, possibly in conjunction with other mechanisms. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.     

Growth inhibition of Staphylococcus aureus induced by low‐frequency electric and electromagnetic fields

Magnetic field therapy is an established technique in the treatment of pseudarthrosis. In cases of osteomylitis, palliation is also observed. This study focuses on the impact of different electric and electromagnetic fields on the growth of Staphylococcus aureus by in vitro technologies. Cultures of Staphylococcus aureus in fluid and gel‐like medium were exposed to a low‐frequency electromagnetic field, an electromagnetic field combined with an additional electric field, a sinusoidal electric field and a static electric field. In gel‐like medium no significant difference between colony‐forming units of exposed samples and non‐exposed references was detected. In contrast, Staphylococcus aureus concentrations in fluid medium could clearly be reduced under the influence of the four different applied fields within 24 h of experiment. The strongest effects were observed for the direct current electric field which could decrease CFU/ml of 37%, and the low‐frequency electromagnetic field with additional induced electric alternating field with a decrease of Staphylococci concentration by 36%. The effects of the electromagnetic treatment on Staphylococci within fluid medium are significantly higher than in gel‐like medium. The application of low‐frequency electromagnetic fields corroborates clinical situations of bone infections during magnetic field therapy. Bioelectromagnetics 30:270–279, 2009. © 2009 Wiley‐Liss, Inc.     

Tumor treating fields: An emerging treatment modality for thoracic and abdominal cavity cancers

Tumor treating fields (TTFields)-an intermediate-frequency, electric field therapy-has emerged as a promising alternative therapy for the treatment of solid cancers. Since the first publication describing the anticancer effects of TTFields in 2004 there have been numerous follow-up studies by other groups, either to confirm the efficacy of TTFields or to study the primary mechanism of interaction. The overwhelming conclusion from these in vitro studies is that TTFields reduce the viability of aggressively replicating cell lines. However, there is still speculation as to the primary mechanism for this effect; moreover, observations both in vitro and in vivo of inhibited migration and metastases have been made, which may be unrelated to the originally proposed hypothesis of replication stress. Adding to this, the in vivo environment is much more complex spatially, structurally, and involves intricate networks of cell signaling, all of which could change the efficacy of TTFields in the same way pharmaceutical interventions often struggle transitioning in vivo. Despite this, TTFields have shown promise in clinical practice on multiple cancer types, which begs the question: has the primary mechanism carried over from in vitro to in vivo or are there new mechanisms at play? The goal of this review is to highlight the current proposed mechanism of action of TTFields based primarily on in vitro experiments and animal models, provide a summary of the clinical efficacy of TTFields, and finally, propose future directions of research to identify all possible mechanisms in vivo utilizing novel tumor-on-a-chip platforms.     

Microsecond and nanosecond electric pulses in cancer treatments

New local treatments based on electromagnetic fields have been developed as non‐surgical and minimally invasive treatments of tumors. In particular, short electric pulses can induce important non‐thermal changes in cell physiology, especially the permeabilization of the cell membrane. The aim of this review is to summarize the present data on the electroporation‐based techniques: electrochemotherapy (ECT), nanosecond pulsed electric fields (nsPEFs), and irreversible electroporation (IRE). ECT is a safe, easy, and efficient technique for the treatment of solid tumors that uses cell‐permeabilizing electrical pulses to enhance the activity of a non‐permeant (bleomycin) or low permeant (cisplatin) anticancer drug with a very high intrinsic cytotoxicity. The most interesting feature of ECT is its unique ability to selectively kill tumor cells without harming normal surrounding tissue. ECT is already used widely in the clinics in Europe. nsPEFs could represent a drug free, purely electrical cancer therapy. They allow the inhibition of tumor growth, and interestingly, nsPEF can target intracellular organelles. However, many questions remain on the mechanism of action of these pulses. Finally, IRE is a new ablation procedure using pulses that provoke the permanent permeabilization of the cells resulting in their death. This technique does not result in any thermal effect, which is its main advantage in current physical ablation technologies. For both the nsPEF and the IRE, the preservation of the normal tissue, which is characteristic of ECT, has not yet been shown and their safety and efficacy still have to be investigated thoroughly in vivo and in the clinics. Bioelectromagnetics 33:106–123, 2012. © 2011 Wiley Periodicals, Inc.     

The Importance of Subcellular Structures to the Modeling of Biological Cells in the Context of Computational Bioelectromagnetics Simulations

Numerical investigation of the interaction of electromagnetic fields with eukaryotic cells requires specifically adapted computer models. Virtual microdosimetry, used to investigate exposure, requires volumetric cell models, which are numerically challenging. For this reason, a method is presented here to determine the current and volumetric loss densities occurring in single cells and their distinct compartments in a spatially accurate manner as a first step toward multicellular models within the microstructure of tissue layers. To achieve this, 3D models of the electromagnetic exposure of generic eukaryotic cells of different shape (i.e. spherical and ellipsoidal) and internal complexity (i.e. different organelles) are performed in a virtual, finite element method-based capacitor experiment in the frequency range from 10 Hz to 100 GHz. In this context, the spectral response of the current and loss distribution within the cell compartments is investigated and any effects that occur are attributed either to the dispersive material properties of these compartments or to the geometric characteristics of the cell model investigated in each case. In these investigations, the cell is represented as an anisotropic body with an internal distributed membrane system of low conductivity that mimics the endoplasmic reticulum in a simplified manner. This will be used to determine which details of the cell interior need to be modeled, how the electric field and the current density will be distributed in this region, and where the electromagnetic energy is absorbed in the microstructure regarding electromagnetic microdosimetry. Results show that for 5 G frequencies, membranes make a significant contribution to the absorption losses. © 2023 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.     

900 MHz modulated electromagnetic fields accelerate the clathrin‐mediated endocytosis pathway

We report new data regarding the molecular mechanisms of GSM‐induced increase of cell endocytosis rate. Even though endocytosis represents an important physical and biological event for cell physiology, studies on modulated electromagnetic fields (EMF) effects on this process are scarce. In a previous article, we showed that fluid phase endocytosis rate increases when cultured cells are exposed to 900 MHz EMF similar to mobile phones' modulated GSM signals (217 Hz repetition frequency, 576 µs pulse width) and to electric pulses similar to the GSM electrical component. Trying to distinguish the mechanisms sustaining this endocytosis stimulation, we exposed murine melanoma cells to Lucifer Yellow (LY) or to GSM–EMF/electric pulses in the presence of drugs inhibiting the clathrin‐ or the caveolin‐dependent endocytosis. Experiments were performed at a specific absorption rate (SAR) of 3.2 W/kg in a wire patch cell under homogeneously distributed EMF field and controlled temperature (in the range of 28.5–29.5 °C). Thus, the observed increase in LY uptake was not a thermal effect. Chlorpromazine and ethanol, but not Filipin, inhibited this increase. Therefore, the clathrin‐dependent endocytosis is stimulated by the GSM–EMF, suggesting that the cellular mechanism affected by the modulated EMF involves vesicles that detach from the cell membrane, mainly clathrin‐coated vesicles. Bioelectromagnetics 30:222–230, 2009. © 2008 Wiley‐Liss, Inc.     

Phantom Model Testing of Active Implantable Cardiac Devices at 50/60 Hz Electric Field

Exposure to external extremely low-frequency (ELF) electric and magnetic fields induces the development of electric fields inside the human body, with their nature depending on multiple factors including the human body characteristics and frequency, amplitude, and wave shape of the field. The objective of this study was to determine whether active implanted cardiac devices may be perturbed by a 50 or 60 Hz electric field and at which level. A numerical method was used to design the experimental setup. Several configurations including disadvantageous scenarios, 11 implantable cardioverter-defibrillators, and 43 cardiac pacemakers were tested in vitro by an experimental bench test up to 100 kV/m at 50 Hz and 83 kV/m at 60 Hz. No failure was observed for ICNIRP public exposure levels for most configurations (in more than 99% of the clinical cases), except for six pacemakers tested in unipolar mode with maximum sensitivity and atrial sensing. The implants configured with a nominal sensitivity in the bipolar mode were found to be resistant to electric fields exceeding the low action levels, even for the highest action levels, as defined by the Directive 2013/35/EU. Bioelectromagnetics. 2020;41:136–147. © 2020 Bioelectromagnetics Society.     

Effects of low-intensity AC and/or DC electromagnetic fields on cell attachment and induction of apoptosis

Rat tendon fibroblast (RTF) and rat bone marrow (RBM) osteoprogenitor cells were cultured and exposed to AC and/or DC magnetic fields in a triaxial Helmholtz coil in an incubator for up to 13 days. The AC fields were at 60 and 1000 Hz and up to 0.25 mT peak to peak, and the DC fields were up to 0.25 mT. At various combinations of field strengths and frequencies, AC and/or DC fields resulted in extensive detachment of preattached cells and prevented the normal attachment of cells not previously attached to substrates. In addition, the fields resulted in altered cell morphologies. When RTF and RBM cells were removed from the fields after several days of exposure, they partially reattached and assumed more normal morphologies. An additional set of experiments described in the Appendix corroborates these findings and also shows that low-frequency EMF also initiates apoptosis, i.e., programmed cell death, at the onset of cell detachment. Taken together, these results suggest that the electromagnetic fields result in significant alterations in cell metabolism and cytoskeleton structure. Further work is required to determine the relative effect of the electric and magnetic fields on these phenomena. The research has implications for understanding the role of fields in affecting bone healing in fracture nonunions, in cell detachment in cancer metastasis, and in the effect of EMF on organisms generally. Bioelectromagnetics 18:264–272, 1997. © Wiley-Liss, Inc.     

Effects of electromagnetic fields on the motion of Euglena gracilis.

The orientation behavior of Euglena gracilis cultures in electromagnetic fields is shown to agree with the predictions of a model involving only a passive mechanism. The increase in Euglena motor activity with increasing field intensity is demonstrated by measuring various motion parameters by the laser scattering technique. The effect of electric field on the speed of Euglenas is compared with that of temperature. We conclude that the electric field warms up the culture, thus inducing an increase in cell motility.     

Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit

The anti-tumor effects of chemotherapy and radiation are thought to be mediated by triggering G₁/S or G₂/M cell cycle checkpoints, while spindle poisons, such as paclitaxel, block metaphase exit by initiating the spindle assembly checkpoint. In contrast, we have found that 150 kilohertz (kHz) alternating electric fields, also known as Tumor Treating Fields (TTFields), perturbed cells at the transition from metaphase to anaphase. Cells exposed to the TTFields during mitosis showed normal progression to this point, but exhibited uncontrolled membrane blebbing that coincided with metaphase exit. The ability of such alternating electric fields to affect cellular physiology is likely to be dependent on their interactions with proteins possessing high dipole moments. The mitotic Septin complex consisting of Septin 2, 6 and 7, possesses a high calculated dipole moment of 2711 Debyes (D) and plays a central role in positioning the cytokinetic cleavage furrow, and governing its contraction during ingression. We showed that during anaphase, TTFields inhibited Septin localization to the anaphase spindle midline and cytokinetic furrow, as well as its association with microtubules during cell attachment and spreading on fibronectin. After aberrant metaphase exit as a consequence of TTFields exposure, cells exhibited aberrant nuclear architecture and signs of cellular stress including an overall decrease in cellular proliferation, followed by apoptosis that was strongly influenced by the p53 mutational status. Thus, TTFields are able to diminish cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death.     

Setting Guidelines for Electromagnetic Exposures and Research Needs

Current limits for exposures to nonionizing electromagnetic fields (EMF) are set, based on relatively short-term exposures. Long-term exposures to weak EMF are not addressed in the current guidelines. Nevertheless, a large and growing amount of evidence indicates that long-term exposure to weak fields can affect biological systems and might have effects on human health. If they do, the public health issues could be important because of the very large fraction of the population worldwide that is exposed. We also discuss research that needs to be done to clarify questions about the effects of weak fields. In addition to the current short-term exposure guidelines, we propose an approach to how weak field exposure guidelines for long-term exposures might be set, in which the responsibility for limiting exposure is divided between the manufacturer, system operator, and individual being exposed. Bioelectromagnetics. © 2020 Bioelectromagnetics Society     

The Relative Permittivity Changes of EGF by 50 Hz MF Exposure Neither Affect the Interaction of EGF With EGFR Nor Its Biological Effects

The biophysical mechanism of magnetic fields (MFs) acting on living systems is not clear. Previous research showed that, similar to epidermal growth factor (EGF), MF exposure induced EGF receptor (EGFR) clustering and activated EGFR signaling. In this study, we investigated whether MF exposure induced the changes in physical characteristics of EGF and downstream effects of EGF and EGFR interaction. The phase-interrogation surface plasmon resonance (SPR) sensing analyses showed that 50 Hz MF exposure at 4.0 mT for 1 h induced reversible relative permittivity changes of EGF solution. However, compared with sham-exposed EGF solution, the MF-exposed EGF solution did not affect the binding of EGF to EGFR, nor the cell viability and EGFR clustering in human amniotic epithelial cells (FL cells). Our data suggest that cellular EGFR clustering response to MF exposure might not be a result of changes in relative permittivity of EGF in cell culture solution. Bioelectromagnetics. © 2020 Bioelectromagnetics Society     

Design,implementation, and dosimetry analysis of an S‐band waveguide in vitro system for the exposure of cell culture samples to pulsed fields

The interaction between electromagnetic fields and biological media, particularly regarding very high power, short pulses as in radar signals, is not a fully understood phenomenon. In the past few years, many in vitro, cellular communications‐oriented exposure studies have been carried out. This article presents a high‐power waveguide exposure system capable of dealing with monochromatic, multicarrier or pulsed signals between 1.8 and 3.2 GHz (L‐ and S‐band) with a pulse duration as low as 90 ns, minimum pulse repetition of 100 Hz, and maximum instantaneous power of 100 W. The setup is currently being used with a 2.2 GHz carrier modulated by 5 µs pulses with a 100 Hz repetition period and approximately 30 W of instantaneous power. After a worst‐case temperature analysis, which does not account for conduction and convection thermal effects, the experiment's exposure is considered sub‐thermal. Evaluation of the results through the specific absorption rate distribution is not considered sufficient enough in these cases. An electromagnetic field distribution analysis is needed. For monochromatic signals, the representation of the modulus of the electric and magnetic field components is proposed as a suitable method of assessment. Bioelectromagnetics 31:479–487, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of continuous and intermittent exposure to RF fields with a wide range of SARs on cell growth, survival, and cell cycle distribution

To examine the biological effects of radio frequency (RF) electromagnetic fields in vitro, we have examined the fundamental cellular responses, such as cell growth, survival, and cell cycle distribution, following exposure to a wide range of specific absorption rates (SAR). Furthermore, we compared the effects of continuous and intermittent exposure at high SARs. An RF electromagnetic field exposure unit operating at a frequency of 2.45 GHz was used to expose cells to SARs from 0.05 to 1500 W/kg. When cells were exposed to a continuous RF field at SARs from 0.05 to 100 W/kg for 2 h, cellular growth rate, survival, and cell cycle distribution were not affected. At 200 W/kg, the cell growth rate was suppressed and cell survival decreased. When the cells were exposed to an intermittent RF field at 300 W/kg(pk), 900 W/kg(pk) and 1500 W/kg(pk) (100 W/kg(mean)), no significant differences were observed between these conditions and intermittent wave exposure at 100 W/kg. When cells were exposed to a SAR of 50 W/kg for 2 h, the temperature of the medium around cells rose to 39.1 degrees C, 100 W/kg exposure increased the temperature to 41.0 degrees C, and 200 W/kg exposure increased the temperature to 44.1 degrees C. Exposure to RF radiation results in heating of the medium, and the thermal effect depends on the mean SAR. Hence, these results suggest that the proliferation disorder is caused by the thermal effect.     

Environmental magnetic fields inhibit the antiproliferative action of tamoxifen and melatonin in a human breast cancer cell line

We have previously reported that environmental-level magnetic fields (1.2 μT [12 milligauss], 60 Hz) block the growth inhibition of the hormone melatonin (10⁻⁹ M) on MCF-7 human breast cancer cells in vitro. We now report that the same 1.2 μT, 60 Hz magnetic fields significantly block the growth inhibitory action of pharmacological levels of tamoxifen (10⁻⁷ M). In biophysical studies we have taken advantage of Faraday's Law of Current Induction and tested whether the 1.2 μT magnetic field or the associated induced electric field is responsible for this field effect on melatonin and tamoxifen. We observe that the magnetic field component is associated with the field blocking effect on melatonin and tamoxifen function. To our knowledge the tamoxifen studies represent the first experimental evidence for an environmental-level magnetic field modification of drug interaction with human breast cancer cells. Together, these findings provide support to the theory that environmental-level magnetic fields can act to modify the action of a drug or hormone on regulation of cell proliferation. Melatonin and tamoxifen may act through different biological pathways to down-regulate cell growth, and further studies are required to identify a specific biological site of interaction for the 1.2 μT magnetic field. Bioelectromagnetics 18:555–562, 1997. Published 1997 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Modulation of the Cell Membrane Potential and Intracellular Protein Transport by High Magnetic Fields

To explore cellular responses to high magnetic fields (HMF), we present a model of the interactions of cells with a homogeneous HMF that accounts for the magnetic force exerted on paramagnetic/diamagnetic species. There are various chemical species inside a living cell, many of which may have large concentration gradients. Thus, when an HMF is applied to a cell, the concentration‐gradient magnetic forces act on paramagnetic or diamagnetic species and can either assist or oppose large particle movement through the cytoplasm. We demonstrate possibilities for changing the machinery in living cells with HMFs and predict two new mechanisms for modulating cellular functions with HMFs via (i) changes in the membrane potential and (ii) magnetically assisted intracellular diffusiophoresis of large proteins. By deriving a generalized form for the Nernst equation, we find that an HMF can change the membrane potential of the cell and thus have a significant impact on the properties and biological functionality of cells. The elaborated model provides a universal framework encompassing current studies on controlling cell functions by high static magnetic fields. Bioelectromagnetics. 2021;42:27–36. © 2020 Bioelectromagnetics Society.     

Computational simulations establish a novel transducer array placement arrangement that extends delivery of therapeutic TTFields to the infratentorium of patients with brainstem gliomas

Background and PurposeTumor treating fields (TTFields) are a non-invasive, efficacious treatment modality currently approved for supratentorial glioblastomas. Despite their ability to improve overall survival in supratentorial tumors, the current placement of arrays is limited to the supratentorial head, precluding its use in infratentorial tumors. Infratentorial malignancies are in need of new therapy modalities given their poor prognoses in both children and adults. The aim of this research is to determine whether rearrangement of TTFields may allow for management of infratentorial tumors.Materials and methodsDelivery of TTFields using Novocure’s prototype Optune™ device human male head model was simulated based on brain MRIs from patients with brainstem gliomas to develop a novel array layout designed to extend adequate infratentorial coverage.ResultsArray placement on the vertex, bilateral posterolateral occiput, and superior-posterior neck achieved intensities above 1.1 V/cm (average 1.7 V/cm; maximum 2.3 V/cm) in the vertical field direction and above 1 V/cm (average 2 V/cm; maximum 2.8 V/cm) in the horizontal field direction of the infratentorium. The calculated field intensity within the simulated tumors were in the therapeutic range and demonstrated the effective delivery of TTFields to the infratentorial brain.ConclusionsOur findings suggest that rearrangement of the TTFields standard array with placement of electrodes on the vertex, bilateral posterolateral occiput, and superior-posterior neck allows for adequate electric field distribution in the infratentorium that is within the therapeutic range.     

Action of a 50 Hz magnetic field on proliferation of cells in culture

Proliferation of SV40-3T3 mouse fibroblasts and human HL-60 promyelocytes was studied after treatment with a sinusoidal 2 mT_rms 50 Hz magnetic field. A single exposure of 60 minutes caused quasicyclic changes in the cell number of SV40-3T3 cultures as function of time after treatment, which was interpreted to be due to the induction of chronobiological mechanisms by the field. Moreover, small variations in cell cycle distribution were measured during postexposure incubation for both cell lines. To discriminate between the effect of the magnetic vector and the induced electric field, HL-60 cell exposure was also performed on organ culture dishes. These dishes consist of two coaxially centered, isolated compartments in which different electric field levels are induced in the medium during treatment. Cell growth was affected in the outer compartment only where the induced electric field ranged from 8 to 12 mV_peak/meter at 2 mT, but it was not affected in the inner compartment (field range 0–4 mV_peak/meter). This suggests that the effects on cell growth are due to the induced electric field and are expressed only above a threshold of between 4 and 8 mV_peak/meter. Bioelectromagnetics 18:177–183, 1997. © 1997 Wiley-Liss, Inc.     

Assessment of the efficacy and safety of low frequency,low intensity magnetic fields in patients after knee endoprosthesis plasty. Part 1: In vitro safety

The purpose of this in vitro study was to assess the potential influence of low frequency, low intensity magnetic fields (rectangular pulse, 5 mT, 30 Hz) applied in therapy on the temperature, contact electric potential, and magnetization in knee endoprosthesis, which might be dangerous for implantation and stability of knee prosthesis, and later slacking it off, causing postoperative complications. The experimental investigation was carried out on a knee endoprosthesis which had been placed in a container with physiological saline. The prosthesis located inside the container was under the exposure of the magnetic field applied by a solenoid. The results indicated that magnetic fields did not influence thermal and electromagnetic properties of knee endoprosthesis in vitro. The magnetic fields of examined parameters should not be dangerous for implantation and stability of knee endoprosthesis. Bioelectromagnetics 30:159–162, 2009. © 2008 Wiley‐Liss, Inc.     

Analysis of the effect of a 60 Hz AC field on histamine release by rat peritoneal mast cells

Reports have indicated effects of electromagnetic fields on inflammatory processes in vivo. To begin a systematic approach toward separating and examining the many components of such responses, we created and tested a temperature-controlled device to develop 5 mT 60 Hz magnetic fields for studies of the effects of fields on mast cells, a key component in acute inflammatory responses. Such fields have been reported to modulate cell activity, including changes in membrane function, in various systems. The magnetic field was generated using a solenoid and calibrated with an induction probe. Tests of mast cell function were determined by histamine release response to stimulation by compound 48/80, using both an “expose then test” and a “test during exposure” protocol. Aliquots not treated with 48/80 were used to evaluate field treatment effects on spontaneous histamine release. Freshly harvested rat peritoneal mast cells were exposed to the magnetic field for periods of 30 min to 2 h at 37 °C. They showed no significant degranulation during treatment, nor did they show reduced sensitivity to the degranulating agent 48/80. These observations are consistent with a model in which such processes are exclusively reflexive by the cells using field-independent membrane systems. This observation is very useful and was needed before examining longer term exposures in which gene expression in the cells might be influenced; this is the first such report of in vitro exposure of purified mast cells under these conditions and will further the study of the effects of electromagnetic fields on cell types active in acute inflammation. Bioelectromagnetics 19:192–198, 1998. © 1998 Wiley-Liss, Inc.