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1. Introduction
Electromagnetic fields (EMFs) are composed of magnetic and electric fields that influence each other [1]. There are many EMF subtypes with varying frequency rates, and they can cause either positive or detrimental biological effects. For medical purposes, they can be used in diagnostic modality and be considered as a potential therapeutic option as well. On the other hand, EMFs can penetrate tissues without experiencing intensity decrement [2], pass through the cell membrane, and affect cell responses. Consequently, cells may experience diverse pathophysiological disorders like cancer, thus, elevating one’s concern during the course of using EMFs for therapeutic purposes [3]. However, despite many findings, the carcinogenic role of EMF is still unclear.
Among subtypes of EMFs, low-frequency fields with specific amplitudes and waveforms are referred to as pulsed EMFs (PEMFs) [4]. Being a promising strategy and a type of the noninvasive and inexpensive physical approaches, PEMFs have exhibited therapeutic potential for treating various diseases [5]. It has already been shown that they can make changes to cell cycle, apoptosis, cell proliferation, and differentiation. Indeed, they are able to affect and alter the cell function by inducing forced vibration for free ions on the cell membrane surfaces due to an external oscillating field [6]. Irregular gating of ion channels triggered by this situation can certainly disturb the balance of transmembrane proteins and, consequently, disrupt cell function [7]. It has also been proposed that the effect of PEMFs may be propagated and amplified along the whole signal transduction pathway, thereby changing cell behavior [8]. In some studies, it has been reported that PEMFs can modulate both downstream signal transduction pathway and cell surface receptor expression/activation [8, 9]. As a result, homeostatic cell functions such as differentiation, viability, proliferation, interaction with components of extracellular matrix (ECM), and communication with neighboring cells could be restored [10]. In addition, PEMFs could enhance both the neurogenic differentiation of mesenchymal stem cells (MSCs) and osteogenic differentiation. Because EMFs easily permeate through cells [4] and change the electric field of the inner cell membrane, they can induce biological changes. In particular, they can induce changes in the Ca2+ efflux and, consequently, modulate various biological effects such as nitric oxide signaling, growth factor secretion, and Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Regulated Kinase (ERK) [11]. It has been hypothesized that the production of second messengers is stimulated by the direct effect of PEMF on phospholipids within the plasma membrane, and subsequently, multiple intracellular signal transduction pathways are initiated [12].
There are many factors affecting the biological responses. To clarify PEMF impacts, studies have reported that signal characteristics play a crucial role in determining the type of biological responses including amplitude and frequency of exposure to the applied PEMF [13]. Indeed, to deliver a therapeutic PEMF, it is necessary to optimize these important parameters [6]. In addition, a large volume of evidence has revealed that some kinds of cells appear exquisitely sensitive to PEMF, while other types appear relatively unresponsive. For instance, undifferentiated PC12 cells are more sensitive to PEMF exposure, while differentiated PC12 cells are more resistant to stress [14]. Consequently, cell properties are of vital importance in establishing a biological response to PEMF in vitro.
Despite a relatively long history of using PEMFs in medicine, little is known about the biological mechanism of such therapies. To develop a reliable working principle of PEMF therapies, it is worth investigating the experimentally observed biological effects caused by these fields alone. Thus, in this study, a meta-analysis was performed using 3249 in vitro experimental observations available in 92 scientific journals (1999-2019) in order to determine the potential effects of PEMF on different cell types of both human and rat/mouse. Our analysis scrutinized the published experiments that had considered the effects of exposure to PEMFs (cytogenetic, gene, and protein expression analysis) on cell types from rats, mice, and humans to gain a more explicit and evidence-based conclusion on the association between PEMFs and cell responses.
2. Material and Methods
In Tables 1–15, the characteristics of experimental protocols and variables are presented. In this paper, cellular response (presence or absence) in human, mouse, or rat cells is defined as changes due to exposure to PEMFs. We analyzed the reported studies based on the different experimental readouts/endpoints which they used for their studies and the physiological variables they measured. These studies are shown in Figures 1–3, (human cells), Figure 4 (rat/mouse cells), and Figure 5 (other species), separately.
Table 1
Statistically significant difference cell groups from Figures 1–3.
Exposure detail | Total | Studies with statistical significant cellular response | |
Presence | Absence | ||
Human | 14 | 3 (21.43%) | 11 (78.57%) |
Rat/mouse | 5 | 2 (40%) | 3 (60%) |
Other species | 0 | 0 | 0 |
Total cells | 19 | 5 (23.81%) | 14 (76.19%) |
Table 2
Human cell studies: PEMFs exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response | Result | Year | First author |
1 | Retinal pigment epithelial (RPE) cells | Frequency of 50 Hz | Cell proliferation, cell death, and gene expression | Transcript levels of proangiogenic genes (HIF-1α, VEGFA, VEGFR-2, CTGF, cathepsin D TIMP-1, E2F3, MMP-2, and MMP-9) increased | 2019 | Oladnabi et al. [56] |
2 | Adipose-derived mesenchymal stem cells (AD-MSCs) | Frequency of 5 Hz | Cell proliferation | PEMF can be beneficial to tissue-derived stem cell proliferation | 2018 | Daish et al. [16] |
3 | Adipose-derived stem cells (ASCs) | Frequency of 50 Hz | Cell proliferation, cell differentiation | PEMF could promote cell proliferation and osteogenic differentiation. | 2018 | Yin et al. [17] |
4 | Human adipose-derived mesenchymal stromal cells (hAMSC) | Frequencies:10, 16, 20.6, 23.8, 26, 33, 49.9, 52.3, 75.6, and 90.6 Hz | Cell proliferation, gene expression | PEMF showed significant upregulations of collagen I, alkaline phosphatase, and osteocalcin | 2018 | Poh et al. [18] |
5 | H4 glioma cells | Frequency of 7 Hz | Cell apoptosis | LFPEMF stimulation of H4 glioma cell cultures induced apoptosis in exposed cells. | 2018 | Kaszuba-Zwoińska et al. [38] |
6 | Mesenchymal stem cells (hMSCs) | Frequency of 75 Hz, the intensity peak of 1.5 mT | Gene expression | The exposure to PEMFs did not produce any change on notch-related genes | 2017 | Bagheri et al. [20] |
7 | Human umbilical vein endothelial cells (HUVECs) | The frequency of 50 Hz | Cell proliferation | Proteins and mRNA expression levels of Akt, mTOR, and TGF-β1 were elevated | 2017 | Cheng et al. [59] |
8 | Human mesenchymal stem cells (MSCs) | Frequency of 15 Hz | Gene expression | Brief and single exposures to low amplitude PEMFs were most effective at stimulating MSC chondrogenesis. | 2017 | Parate et al. [21] |
Table 3
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
9 | MCF-7 | Frequencies of 2122.24, 1970.56, 2072.32, and 2648.64 Hz | Cell viability | There was a significant effect on MCF-7 cells after treatment with PEMF at the resonant frequencies of the genes of RICTOR, PPARG, and NBN CHEK2 | 2017 | Alcantara et al. [43] |
10 | U937 cells (leukemia cell line) | Frequency of 50 Hz | Cell viability protein expression | There were no significant differences in the expression level of calmodulin between control- and only MF-treated samples | 2017 | Wojcik-Piotrowicz et al. [46] |
11 | Human bone marrow stromal cells (hBMSCs) | Pulse frequency of 3.8 kHz | Enzyme activity | PEMF regulated preosteoblast gene expression, and notably, the transforming growth factor-beta (TGF-β) signaling pathway and microRNA 21 (miR21) were the most highly regulated | 2017 | Selvamurugan et al. [25] |
25 | Peripheral blood mononuclear cells (PBMCs) | Frequency of 75 Hz | Gene expression | LF-PEMF modulated gene expression. | 2017 | Capelli et al. [57] |
12 | Human bone marrow mesenchymal stem cells (hBM-MSCs) | Frequency of 60 Hz | Protein expression | After exposure to only PEMF, the expression of proteins slightly increased, but there was no significant difference when compared to the nonexposed groups. | 2016 | Choi et al. [26] |
13 | Human glioblastoma U87 cell line | Frequencies of 50 Hz and 100 Hz intensities of 10 mT and 5 mT | Cell viability | A significant increase in the number of cells after 24 h exposure to 50 Hz, 100 G. | 2016 | Akbarnejad et al. [3] |
14 | Human glioblastoma cell line (T98G). | Frequency of 75 Hz | Cell proliferation, cell apoptosis | miR-421 expression significantly increased over the control after PEMF alone. | 2016 | Pasi et al. [39] |
Table 4
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
15 | Periodontal ligament stem cells (PDLSCs) | Pulsed burst frequency of 15 Hz | Cell proliferation | No influence on cell proliferation. | 2016 | Wang et al. [32] |
16 | Human mesenchymal stem cells (MSCs) | Frequency of 50 Hz | Cell viability | PEMFs upregulated genes related to Ca2+ signaling, proliferation, and neurogenic differentiation | 2016 | Lim et al. [11] |
17 | Human tendon stem cells (hTSCs) | Frequency of 10–30 Hz | Cell morphology | PEMF did not cause any significant changes in proliferation, viability, and morphology. | 2016 | Randelli et al. [33] |
18 | Human dental pulp stem cells (hDPSCs) | Frequency of 50 Hz | Gene expression | Group treated to PEMF showed significantly greater P75NTR mRNA expression than the control group | 2016 | Hei et al. [34] |
19 | HeLa, HEK293, MCF7, and AGS | Frequency of 75 Hz | Cell proliferation | Cell proliferations of all four different cell lines also showed an increase in PEMF exposure until 4 mT, but not at 6 mT. | 2016 | Cho et al. [44] |
20 | Human annulus fibrosus (AF) cells | Frequency of 3,850 Hz | Gene expression | PEMF alone had no effect on gene expression. | 2016 | Miller et al. [62] |
Table 5
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
21 | Human dermal fibroblasts (HDF), human epidermal keratinocytes (HEK), and human mononuclear cells (HMNC) | Pulse frequency of 1 kHz, intensity of 6.7 A/m | Gene expression | PEMF treatment changed the relative amount of messenger (m) RNA encoding enzymes involved in heme catabolism and removal of reactive oxygen species. | 2015 | Kubat et al. [60] |
22 | Acute lymphoblastic leukemia (CEM/C2), B-cell lymphoma (SU-DHL-4), colorectal adenocarcinoma (COLO-320DM), breast adenocarcinoma (MDABM-468), and ductal carcinoma (ZR-75-1) | Frequencies of 15 Hz, 125 Hz, and 625 Hz intensity of 5 mT | Cell morphology, cell viability, and cell apoptosis | A PEMF of 125 Hz and 625 Hz for 24 h–48 h increased proliferation activity in the 2 types of cancer cell lines used | 2015 | Loja et al. [48] |
23 | Human neuroblastoma SH-SY5Y cells | Frequency of 75 Hz | Enzymatic activity, cell proliferation, cell viability, and cell apoptosis | Basal MnSOD specific activity was higher in PEMF stimulated cells when compared to cells not treated with PEMF | 2015 | Osera et al. [42] |
24 | Human bone marrow stromal cells (hBMSCs) | Frequency of 200 Hz | Cell proliferation | Proliferation and the osteogenic differentiation of hBMSCs were increased | 2014 | Fu et al. [31] |
25 | Human amniotic epithelial cells (AECs) | Frequency of 50 Hz | Cell differentiation | The PEMF stimulation could induce osteogenic differentiation, as shown by the expression of osteoblast-specific genes and proteins including alkaline phosphatase and osteocalcin | 2014 | Wang et al. [35] |
Table 6
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
26 | Human tendon cells (hTCs) | Intensities of 1.5 and 3 mT | Cell viability | Proliferation and the viability of hTCs were enhanced by PEMF | 2014 | de Girolamo et al. [61] |
27 | Human umbilical cord-derived | Frequency of 75 Hz, intensity of 1.8-3 mT | Cell morphology | Morphological data showed that the treatment with PMEF reduced the time to obtain cell differentiation. | 2013 | Esposito et al. [36] |
28 | Human disc cells | Frequency of 15 Hz. Intensity of 1.6 mT | Gene expression | BMP-7 and BMP-2 were upregulated by PEMF | 2013 | Okada et al. [63] |
29 | Tendon cells (TCs) (human) | Frequency of 75 Hz, intensity of 1.5 mT | Cell morphology, cell viability, cell apoptosis, and gene expression | PEMF exposure is not cytotoxic and is able to stimulate TCs’ proliferation | 2013 | de Girolamo et al. [15] |
30 | Human disc cells (intervertebral disc (IVD)) | Frequency of 15 Hz | Gene expression | mRNA expression of BMP-2 was upregulated by PEMF alone | 2013 | Okada et al. [64] |
31 | MCF7, MCF10 | Frequencies of 20 and 50 Hz | Cell apoptosis | MCF7 cancer cells were particularly vulnerable to 3 mT PEMFs. | 2013 | Crocetti et al. [45] |
32 | Bone marrow MSCs (BM-MSCs) | Frequency of 75 Hz, intensity of 2 mT | Cell viability | After PEMF exposure, in comparison with ASCs, BM-MSCs showed an increase in cell proliferation | 2013 | Ceccarelli et al. [19] |
33 | Human osteogenic sarcoma SaOS-2 | Frequency of 15 Hz, intensity of 0.1 mT | Cell proliferation | PEMF caused a minor increase in expression of osteogenic markers of MSCs | 2012 | Kaivosoja et al. [50] |
Table 7
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
34 | Human mesenchymal stem cell osteoblast | Frequencies of 5, 25, 50, 75, 100, and 150 Hz, intensity of 1.1 mT, | Cell differentiation | Levels of human mesenchymal stem cell differentiation changed by PEMF | 2012 | Luo et al. [37] |
35 | Stromal cells of human bone marrow (BMSC) | Frequency of 75 Hz, intensity of 1.8-3 mT | Gene expression, cell differentiation | The cells treated with PEMF began differentiation earlier than untreated cells. | 2012 | Esposito et al. [24] |
36 | Human breast carcinoma cells (T47D) | Frequencies of 100, 217 Hz intensity of 0.1 mT | Cell proliferation, cell viability, cell morphology, protein expression, and ROS production | PEMF induced a time-dependent decrease in cell growth after 72 h | 2012 | Sadeghipour et al. [49] |
37 | Human peripheral blood mononuclear cell (PBMC) | Frequency of 7 Hz flux density of 30 mT | Cell apoptosis | PEMF induced apoptosis in PBMC | 2011 | Kaszuba-Zwoińska et al. [58] |
38 | Bone marrow mesenchymal stem cells (BMMSCs) | Frequency of 15 Hz flux density of 1.8 mT | Cell proliferation | PEMF treated cells also showed greater MMP-2 expression compared to unstimulated cells. | 2011 | Griffin et al. [27] |
39 | Human bone marrow-derived stromal cell (BMSC) | Frequency of 15 Hz | Cell proliferation | PEMF treatment increased mRNA levels of bone morphogenetic protein 2, transforming growth factor-beta 1, osteoprotegerin, matrix metalloproteinase-1 and -3, osteocalcin, and bone sialoprotein | 2010 | Jansen et al. [28] |
40 | Osteoblast-like cell cultures (MG-63) | Frequency of 75 Hz | Gene expression | PEMFs induced the upregulation of important genes related to bone formation genes, however, PEMF induced downregulation of genes related to the degradation of extracellular matrix | Sollazzo et al. [53] |
Table 8
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
41 | Human osteoblast-like Saos-2 cells | Frequency of 15 Hz flux density of 2 mT | Gene expression | PEMF induced increase in RANKL mRNA expression | 2010 | Borsje et al. [51] |
42 | Bone marrow mesenchymal stem cells (BMMSCs) | Frequency of 15 Hz flux density of 1.8 mT | Cell proliferation | Exposure of BMMSCs to PEMFs increased cell proliferation | 2010 | Sun et al. [29] |
43 | Human mesenchymal stem cells (hMSCs) | Frequency of 7.5 Hz flux density of 0.13 mT | Cell proliferation | The expressions of osteogenic genes, including Runx2/Cbfa1 and ALP, were modulated by PEMF exposure. | 2009 | Tsai et al. [22] |
44 | Human bone marrow mesenchymal stem cells (BMMSC) | Frequency of 15 Hz flux density of 1.8 mT | Cell morphology | PEMF exposure could enhance the BMMSC cell proliferation | 2009 | Sun et al. [30] |
45 | SaOS-2 osteoblast-like cells | Frequency of 15 Hz | Cell viability | PEMF stimulation did not affect cell number, however, increased ALP activity | 2008 | Martino et al. [7] |
46 | Human chondrocyte | Frequency of 21.2 MHz | Cell viability | PEMF exposure increase cell viability | 2007 | Štolfa et al. [66] |
47 | Primary human mesenchymal stem cells (MSCs), human chondrocyte | Frequency of 30 Hz, intensity of 35 μT | Gene expression | PEMF altered the gene expression of a limited number of gene products in human mesenchymal stem cells and human chondrocytes. | 2007 | Walther et al. [23] |
48 | Human promyelocytic leukemia HL-60 cells | Frequency of 0.25 Hz 0.25–4.5 T peak magnetic field strength | Cell viability signal transduction | PEMF did not alter the cell viability or content of cAMP | 2006 | Sontag and Kalka [47] |
49 | A human osteosarcoma (cell line) SaOS-2 | Frequency of 15 Hz | Cell Proliferation | PEMF reduced proliferation and increased differentiation in SaOS-2 cell line | 2005 | Hannay et al. [52] |
50 | MG-63 human osteosarcoma cells | Frequency of 75 Hz, intensity of 2.3 mT | Cell proliferation | The PEMF increased [3H]-thymidine incorporation | 2005 | Mattei et al. [54] |
Table 9
Human cell studies: PEMF exposure conditions used in in vitro studies.
No. | Cell line | Frequencies and intensities | Cell response analysis | Result | Year | First author |
51 | Human astrocytoma cell line U-373 MG | Frequency of 50 Hz, intensity of 3 mT | Cell proliferation | PEMF did not cause cell proliferation or cell death | 2001 | Pessina et al. [40] |
52 | Sympathetic neuronal-like PC6 cells | Frequency of 2 Hz, intensity of 0.3 mT | Cell proliferation, cell differentiation | Proliferation was unaffected by PEMF | 2001 | Shah et al. [67] |
53 | Human atrophic nonunion cell culture | Frequency of 15 Hz, intensity of 1.8 mT | Cell morphology | PEMF resulted in a change in morphologic features of cells. | 2001 | Guerkov et al. [65] |
54 | Human astrocytoma cell line | Frequency of 50 Hz, intensity of 3 mT | Cell proliferation | After the cells were exposed to EMFs, the basal [Ca2+]i levels increased | 2000 | Aldinucci et al. [41] |
55 | TE-85 human osteosarcoma cells | Frequency of 15 Hz, intensity of 1.8 mT | Cell proliferation | The cells increase their proliferation when exposed to PEMF | 1999 | De Mattei et al. [55] |
56 | MG63 human osteoblast-like cells | Frequency of 75 Hz, intensity of 2.3 mT | Cell proliferation, cell differentiation | PEMF caused a reduction in cell proliferation and an increase ALP activity | 1999 | Lohmann et al. [4] |
Table 10
Rat/mouse cells: cellular response (presence or absence) for cultured rat/mouse cells.
No. | Cell line | Frequency and intensity | Cell response analysis | Result | Year | Authors |
57 | MC3T3-E1 | Flux density of either 0.1 or 0.4 mT. Frequency of 10 Hz. | Signal transduction pathway, cell proliferation, cell differentiation | The activation of mTOR, increased, BrdU uptake was increased, and ALPase activity was not observed. | 2019 | Miyamoto et al. [91] |
58 | RAW264.7 | Frequency of 75 Hz, flux density of 1 mT. | Cell viability, cell differentiation, gene expression, protein expression | The results revealed no significant difference between groups stimulated by PEMF alone and control group. | 2019 | Pi et al. [78] |
59 | Oligodendrocyte precursor cells (OPCs) | Frequency of 50 Hz, intensity of 1.8 mT. | Cell differentiation, protein expression, gene expression | PEMF promoted the differentiation of OPCs. PEMF upregulated the expression level of miR-219-5p and downregulated the expression level of Lingo1 during the differentiation of OPCs. | 2019 | Yao et al. [5] |
60 | Tendon stem and progenitor cells (TDSPCs) | Frequency of 125 kHz, intensity of 82 mT | Cell viability, cell apoptosis | The exposure to PEMF alone did not effect on the viability and apoptosis of cells | 2019 | Gehwolf et al. [70] |
61 | MC3T3-E1 subclone 4 cells | Frequency of 50 Hz, intensity of 0.60 mT | Cell morphology, cell viability, cell proliferation, Ca2+ concentration, gene expression | PEMF influenced cell proliferation, did not significantly influence cellular viability, and affected osteogenic differentiation on mRNA level | 2019 | Suryani et al. [92] |
62 | Bone marrow-derived mesenchymal stem cells (BMSCs) (rat) | 50 Hz, 1 mT | Cell proliferation, gene expression | S100, GFAP, and NGF mRNA expression levels were higher on days 5, 7, and 10 of culture. | Seo et al. [73] | |
63 | C3H10T1/2 mesenchymal cells | Frequency of 30 Hz, intensities of 0.1, 1, 2, or 10 mT | Cell proliferation, cell differentiation, Ca2+ concentration, gene expression, protein expression | Cell proliferation was promoted, and intracellular Ca2+ during the process of cell differentiation was increased. The expression of ALP, OSX, Wnt1, phospho-Lrp6, and b-catenin was increased | 2018 | Wu et al. [71] |
Table 11
Rat/mouse cells: cellular response (presence or absence) for cultured rat/mouse cells.
No. | Cell line | Frequency and intensity | Cell response analysis | Result | Year | Authors |
64 | RAW264.7 cells | Frequency of 15 Hz intensities of 0.5, 1, 2, and 3 mT | Cell apoptosis, gene expression | Gene expression of RANK, NFATc1, TRAP, CTSK, BAX, and BAX/BCL was significantly decreased by 0.5 mT PEMF, but increased by 3 mT | 2017 | Wang et al. [79] |
65 | Spermatogonia germ cell line, (GC-1), spermatocyte cell line (GC-2) | Frequencies of 2, 50, and 120 Hz, intensity of 2.5 mT | Cell proliferation, cell morphology, cellular oxidative stress, protein expression, cell viability | PEMF resulted in elongated and fibroblast-like shapes in GC-1 spg cells. PEMF increased the total p53 protein level in GC-2 spd cells. | 2017 | Solek et al. [83] |
66 | Adipose-derived stem cells (ADSCs) isolated | Frequency of 7 Hz, flux density of 30 mT | Cell apoptosis | Exposure to PEMF resulted in a significant increase in the proportion of apoptotic cells | 2017 | Baranowska et al. [69] |
67 | Primary rat nucleus pulposus cells | Frequency of 2 Hz, intensities of 0.5, 1.0, 2.0, and 3.0 A/m | Cell morphology, cell viability, protein expression | Stimulation of nucleus pulposus cells with LF-PEMFs did not appear to affect cell morphology or nucleus pulposus cell IL-1β and TNF-α expression levels. | 2017 | Zou et al. [84] |
68 | Mouse osteosarcoma cell line (LM8 cells) | Frequency of 200 Hz, flux density of 5 mT | Ca2+ concentration, cell apoptosis | The level of intracellular Ca2+ after PEMF treatment was significantly higher. | 2017 | Muramatsu et al. [85] |
69 | C2C12 myoblasts | Frequency of 100 Hz, flux density of 1 mT | Cell proliferation, cell apoptosis, signal transduction, pathway, protein expression | Increase of proliferation, no influence on the apoptosis the phosphorylation level of extracellular, signal-regulated kinase (ERK) was significantly increased, while p38 MAPK and c-Jun N-terminal kinase (JNK) pathways were not affected. | 2016 | Xu et al. [96] |
70 | Bone marrow stem cells (BMSCs) | Frequency of 20 Hz, flux density of 2 mT | Gene expression, cell differentiation | PEMFs significantly promoted the activity of ALP in the BMSCs and mRNA expression of osteogenic proteins | 2015 | Lu et al. [74] |
Table 12
Rat/mouse cells: cellular response (presence or absence) for cultured rat/mouse cells.
No. | Cell line | Frequency and intensity | Cell response analysis | Result | Year | Authors |
71 | Rat bone marrow-derived stem cells | Frequency of 75 Hz | Cell proliferation | PEMF stimulation did not cause significant changes in rat BMSC proliferation | 2015 | Wang et al. [75] |
72 | The murine MN9D dopaminergic cell line | Frequency of 5 Hz | Cell morphology | PEMF signals increased cell body width | 2014 | Lekhraj et al. [68] |
73 | Primary culture osteoblastic cells | Intensities of 0.06 and 0.2 mT | Cell proliferation | Control group had a higher cell proliferation than 0.06 and 0.2 mT PEMF groups | 2013 | Emes et al. [86] |
74 | RAW 264.7 macrophage-like cells (murine) | Frequencies of 5.1 Hz, 7.8 Hz, 10.8 Hz, 15.6 Hz, 20.8 Hz, 23.4 Hz, or 30 Hz. | Signaling pathways | Cells exposed to PEMF demonstrated changes in the downregulation of NFkB | 2013 | Ross and Harrison [80] |
75 | PC12 and NR8383 rat alveolar macrophages | Frequency of 0.172 Hz | Signal pathway | PEMF induced activation of ERK1/2 in PC12 cells | 2013 | Tada-Aki et al. [81] |
76 | Rat brain cortical neurons, PC12, U87MG cells | Frequency of 75 Hz, intensity of 1.5 mT | Gene expression | PEMF treatment induced an upregulation of A3ARs, A2ARs | 2012 | Vincenzi et al. [82] |
77 | C3H10T1/2 cells | Frequency of 1000 Hz | Cell differentiation | PEMF stimulation augmented osteopontin and osteocalcin expression | 2012 | Teven et al. [72] |
78 | Mesenchymal stem cells (MSCs) | Frequency of 50 Hz, intensity of 10 mT | Cell viability, cell proliferation | PEMF increases the proliferation of MSC cells. | 2012 | Li et al. [76] |
Table 13
Rat/mouse cells: cellular response (presence or absence) for cultured rat/mouse cells.
No. | Cell line | Frequency and intensity | Cell response analysis | Result | Year | Authors |
79 | The murine osteoblast-like cell line MC3T3-E1 | Frequency of 0.5 Hz, intensities of 0.17 mT and 1.33 mT | Cell proliferation | The proliferation and differentiation of cells in PEMF exposure groups changed, COL-I and Cbfa1 mRNA expression and BMP2/4 and Smad1/5/8 protein expression did not change. | 2011 | Li et al. [93] |
80 | Rat basophilic leukemia cells (RBL-2H3) | Frequency of 8 kHz, intensity of 200 mT | Cell morphology | PEMF | 2010 | Choi et al. [97] |
81 | Rat bone marrow cells | Frequency of 8 Hz, intensity of 3.8 mT | Gene expression | No statistically significant difference was found between the PEMF group and the control group | 2010 | Chen et al. [98] |
82 | Neural stem cells (NSCs) | Frequency of 0.1 Hz, intensities of 0.5, 1.0, 3.0, 4.0, 5.0, 6.0, 8.0, and 10.0 T | Cell proliferation | Exposure of NSCs to PEMFs changed cell proliferation | 2009 | Meng et al. [77] |
83 | Osteoblast-like MC3T3-E1 cells | Frequency of 48 Hz | Cell proliferation | PEMF treatment accelerated the cell proliferation and promoted cell differentiation of the primary osteoblast cell. | 2008 | Wei et al. [87] |
84 | Rat primary osteoblastic cells | Frequency of 3.8 kHz | Cell proliferation | Continuous daily 4 h treatment with PEMF alone increased expression of osteoblast marker genes | 2007 | Selvamurugan et al. [88] |
85 | A rat osteogenic cell line | Physio-stim® PEMF signals | Signal pathway | PEMF induced rapid phosphorylation reactions of Intracellular signaling molecules | 2006 | Schnoke and Midura [89] |
86 | Murine | Frequency of 3850 Hz | Signal transduction pathway | mTOR pathway was activated within minutes of PEMF exposure | 2006 | Patterson et al. [95] |
Table 14
Rat/mouse cells: cellular response analysis for cultured rat/mouse cells.
No. | Cell line | Frequency and intensity | Cell response analysis | Result | Year | Authors |
87 | Pheochromocytoma cells (PC12) | Frequency of 0.25 Hz | Cell viability | PEMF did not alter the cell viability or content of cAMP | 2006 | Sontag and Kalka [47] |
88 | Osteoblast-like cells | Frequency of 15 Hz, intensity of 0.1 mT | Cell proliferation | PEMF of osteoblasts accelerated cellular proliferation, but did not affect the cellular differentiation | 2004 | Chang et al. [90] |
89 | MLO-Y4 osteocyte-like cells | Frequency of 15 Hz, intensity of 1.6 mT | Cell proliferation, cell differentiation | PEMF did not affect cell number, osteocalcin mRNA, or osteocalcin protein | 2003 | Lohmann et al. [101] |
90 | Osteoblast-like MC3T3-E1 cell line | Frequency of 15 Hz, intensity of 7 mT | Cell proliferation | PEMF treatment accelerated cellular proliferation and enhanced cellular differentiation. | 2002 | Diniz et al. [94] |
Table 15
Other species cell studies.
No. | Cell line | Frequency and intensity | Cell response analysis | Result | Year | Authors |
91 | Intervertebral discs (IVDs) from bovine caudal spines | Pulse frequency of 3850 Hz | Protein expression, signal pathway | Overall p65 expression was increased, and P38 expression was not influenced. | 2019 | Tang et al. [99] |
92 | Rabbit adipose-derived mesenchymal stem cells (AD-MSCs) | Frequencies of 25 Hz and 50 Hz, intensity of 1.6 mT | Cell proliferation | PEMF did not cause any significant increase in SOX9 mRNA productions | 2016 | Kavand et al. [100] |
2.1. Collection of Raw Data
An electronic literature search of databases including Web of Sciences and PubMed was conducted for publications in English from 1999 up to 2019. The key terms introduced in the search engines included “pulsed electromagnetic fields” and “cell.” The process of selecting the papers was carried out by reading the titles and abstracts of the studies as well as the full article when necessary. Upon omitting duplicate titles, full-text versions of the selected papers were obtained.
We excluded those experiments that (1) targeted direct animal or human exposure followed by the analysis of individual cells and (2) applied the combination of PEMFs and other effective treatments, e.g., chemotherapy. After screening many research studies, 92 papers with different designs were eligible for meta-analysis.
For data analysis, the cell responses were classified as “presence” (PEMF exposure changed the cell response statistically significantly in comparison to the control group regardless of direction) and “absence” (no significant PEMF effect).
For each included study, the following data were extracted: type of cells, pulse frequency of exposure, exposure flux density, time of exposure, waveform, and assayed cell responses (cells, cell function, and DNA). Bibliographic details of the studies including the first author and year of publication were also retrieved.
2.2. Analysis of Raw Data
According to the above explanations, given that the frequency and intensity of the mentioned exposure differ across studies, achieving different biological responses would not be unexpected. In this respect, we pooled the retrieved experimental data based on used pulse frequencies and flux densities. Our analysis considered the effect of several subgroups of pulse frequency and flux density as follows: (a)
2.3. Statistical Analysis
Microsoft Excel was used to organize the initial data and build a database. Meta-analysis combined the results obtained from separate studies with a similar outcome. The pooled results were obtained based on cell type, frequency, and intensity. A random-effect model was used to facilitate conducting the analysis, through which
3. Results
A number of publications are analyzed in Figure 6, which provides an overview of the years of publication. Cellular response (presence or absence) was observed in human cells (2441 experiments in Figures 1–3), rat or mouse cells (854 experiments in Figure 4), and other species (11 experiments in Figure 5). The results indicated that most of the experiments were carried out on human cells, among which stem cells drew greater experimental attention. Of not, in case the analysis incorporated such parameters as exposure to PEMFs and individual cell types, the potential effects of PEMFs on cell types, such as bone marrow mesenchymal stem cells (BM-MSCs) (based on 559 reported experiments,
[figure omitted; refer to PDF]
We categorized different experimental techniques as follows: (a) cell structure (cell viability, cell morphology, apoptosis, cell proliferation, and cell differentiation), (b) cell functions (calcium concentration, signal transductions, enzyme activity, membrane potential, and membrane stability), and (c) DNA (gene expression, protein expression, ROS production, chromosome aberration, micronucleus assay, DNA damage, oxidative stress, DNA single-strand breaks, DNA double-strand breaks, and genotoxicity) in Figure 7. Our analysis of the reported results (Figure 8) suggests that most of the experiments used experimental techniques for DNA including gene expression, protein expression, and ROS production for assaying the effect of PEMFs on cells.
[figure omitted; refer to PDF]
We also considered the effects of different pulse frequencies of PEMFs and intensity. To do so, we pooled experimental data based on the frequencies (Figure 9), intensity levels (Figure 10), time of exposure (Figure 11), and waveforms (Figure 12) used in each experiment of the 92 publications Among subgroups of frequencies, significant effects were observed at
[figure omitted; refer to PDF]
The cells exposed to PEMFs in in vitro experiments, which reported results (cellular response, either presence, or absence Table 1) under different exposure conditions, are shown as follows: (a) classification of experimental techniques in Figure 8, (b) frequency of PEMFs in Figure 13, (c) intensity levels in Figure 14, (d) time of exposure in Figure 15, and (e) waveform in Figure 16. It should be noted that our statistical test only reports the presence or absence of cellular responses in the literature, and it is not concerned with the increased or reduced effect of the mentioned responses.
[figure omitted; refer to PDF]
Our findings demonstrated that in in vitro studies, nearly 50% of human cells (Figure 17) would undergo changes due to PEMFs, whereas fewer number of cells in rats/mice (44.61%) and other species (18.18%) were influenced by PEMFs. Thus, a large number of experiments on cells in rats/mice and other species pointed out the absence of any effect caused by PEMFs. Among the studies conducted on human cells, most of them were performed on stem cells. According to the results, it seems that the type of stem cell plays as an effective factor in intracellular processes affected by PEMFs. Especially, in the field of bone tissue engineering in which mesenchymal stem cells are activated by EMF, this finding would be considerable.
Another significant finding of our study was among osteoblast-like cells, MG-63 human osteosarcoma cells seem to be very sensitive to PEMFs (86.1%). The studies have shown that these fields could alter activity through changes in local factor production [4]. However, in human osteogenic sarcoma SaOS-2, the absence of cell response to PEMFs alone was greater in degree than the presence of cell response (75%). PEMFs appeared to have little effect on the phenotype and number of SaOS-2 cells [7].
The potential effects of PEMFs on tendon cells showed that these fields (87.74%), focusing on the potential applicability of this cell source for regenerative medicine purpose, could be effective in the treatment of tendon disorders. In fact, these fields could influence the proliferation, release of anti-inflammatory cytokines, tendon-specific marker expression, and angiogenic factor in healthy human TCs culture models [15].
Analysis of the results of other related studies concerning the effect of PEMFs on the cells of blood cancers like leukemia and lymphoma in human (and on basophilic leukemia cells in rats/mice) showed that these cells were not affected to PEMFs. Thus, it seems that these fields alone are not an effective treatment for blood cancers. Further investigations are required to examine the responsiveness of different types of blood cancer cells to PEMFs. Evaluation of different experimental techniques used in the studies showed that most of the experiments were carried out on the expression of genes and proteins, because PEMFs could verifiably promote bone fracture healing and enhance the maturation of osteoblastic cells. Also, most of studies have examined the effect of osteogenic differentiation of these fields on mRNA level.
Another part of this study focused on evaluating the role of intensity and frequency of PEMFs in stimulating cellular responses in the subgroups. This research was subject to some constraints; first, some of the related experimental studies did not provide sufficient descriptions of exposure signal characteristics, especially in expressing waveform, which in turn made us unable to interpret the results fully. Nevertheless, analysis of frequencies of PEMFs used in the studies showed that different frequencies corresponded to different levels of cellular response. In the subgroups, frequencies higher than 100 Hz and intensities between 1 and 10 mT seemed to be more effective in establishing a cellular response. In addition, the analysis of times of exposure showed that in chronic exposure to PEMF more than 10 days may observe the effect of these fields (presence: 57.66%, absence: 42.34%;
It is worth noting that we may be able to find optimal parameters of PEMF in future studies in the effective ranges obtained from the present study to achieve the most effective response, depending on the desired effect.
Basically, in vitro studies use cells to investigate the interaction mechanisms better by breaking down the complexity of a whole organism into a controllable system. Indeed, each cell with a model system of its own could be suitable for a specific biological aspect. Therefore, although it cannot be expected that humans respond to PEMFs, studies of simple biological systems can advance our understanding about which systems in the body are more susceptible to PEMFs. Therefore, conducting an analysis similar to the present meta-analysis could be useful as a reference for many epidemiological studies or in vivo experiments using the whole organism animal models.
6. Conclusion
To the best of our knowledge, no other meta-analysis has investigated the effects of PEMF on cell responses in vitro. The findings of this study provided us insight into that which cell types could be more responsive to PEMFs. Additionally, we determined the range of frequencies and intensities which PEMFs appeared more effective. Future research would need to explore the effects of other variables on cell response in vitro and to investigate the effectiveness of PEMFs in vivo.
Acknowledgments
The author would like to thank Prof. Marjan Mansourian, an expert in systematic review and meta-analysis, for insightful biostatistical comments.
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Abstract
Pulsed electromagnetic field (PEMF) therapy is a type of physical stimulation that affects biological systems by producing interfering or coherent fields. Given that cell types are significantly distinct, which represents an important factor in stimulation, and that PEMFs can have different effects in terms of frequency and intensity, time of exposure, and waveform. This study is aimed at investigating if distinct positive and negative responses would correspond to specific characteristics of cells, frequency and flux density, time of exposure, and waveform. Necessary data were abstracted from the experimental observations of cell-based in vitro models. The observations were obtained from 92 publications between the years 1999 and 2019, which are available on PubMed and Web of Science databases. From each of the included studies, type of cells, pulse frequency of exposure, exposure flux density, and assayed cell responses were extracted. According to the obtained data, most of the experiments were carried out on human cells, and out of 2421 human cell experiments, cell changes were observed only in 51.05% of the data. In addition, the results pointed out the potential effects of PEMFs on some human cell types such as MG-63 human osteosarcoma cells (
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1 Department of Medical Physics, Faculty of Medicine, Isfahan University of Medical Science, Isfahan, Hezar Jerib Avenue, Isfahan, Iran
2 Department of Medical Physics, Faculty of Medical Science, Isfahan University of Medical Science, Isfahan, Hezar Jerib Street, Isfahan, Iran