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Adenosine receptors (ARs) have an important role in the regulation of inflammation and their activation is involved in the inhibition of pro-inflammatory cytokine release. The effects of pulsed electromagnetic fields (PEMFs) on inflammation have been reported and we have demonstrated that PEMFs increased A2A and A3AR density and functionality in different cell lines. Chondrocytes and osteoblasts are two key cell types in the skeletal system that play important role in cartilage and bone metabolism representing an interesting target to study the effect of PEMFs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-inflammatory effect of A2A and/or A3ARs in T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. Immunofluorescence, mRNA analysis and saturation binding assays revealed that PEMF exposure up-regulated A2A and A3AR expression. A2A and A3ARs were able to modulate cAMP production and cell proliferation. The activation of A2A and A3ARs resulted in the decrease of some of the most relevant pro-inflammatory cytokine release such as interleukin (IL)-6 and IL-8, following the treatment with IL-1β as an inflammatory stimuli. In human chondrocyte and osteoblast cell lines, the inhibitory effect of A2A and A3AR stimulation on the release of prostaglandin E2 (PGE2), an important lipid inflammatory mediator, was observed. In addition, in T/C-28a2 cells, the activation of A2A or A3ARs elicited an inhibition of vascular endothelial growth factor (VEGF) secretion. In hFOB 1.19 osteoblasts, PEMF exposure determined an increase of osteoprotegerin (OPG) production. The effect of the A2A or A3AR agonists in the examined cells was enhanced in the presence of PEMFs and completely blocked by using well-known selective antagonists. These results demonstrated that PEMF exposure significantly increase the anti-inflammatory effect of A2A or A3ARs suggesting their potential therapeutic use in the therapy of inflammatory bone and joint disorders.

Vincenzi F, Targa M, Corciulo C, Gessi S, Merighi S, Setti S, Cadossi R, Goldring MB, Borea PA, Varani K. Pulsed electromagnetic fields increased the anti-inflammatory effect of A₂A and A₃ adenosine receptors in human T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. PLoS One. 2013 May 31;8(5):e65561. doi: 10.1371/journal.pone.0065561. PMID: 23741498; PMCID: PMC3669296.

[Purpose] To determine the efficacy of high intensity laser therapy (HILT) versus pulsed electromagnetic field (PEMF) in the treatment of primary dysmenorrhea. [Subjects and Methods] This was a randomized clinical trial that included 52 girls diagnosed with primary dysmenorrhea and who were assigned randomly into two groups of equal numbers. The treatment was three sessions every cycle for three consecutive cycles where group (A) included those participants treated with HILT 15 min/session and group (B) those who were treated with PEMF 30 min/session. All patients were evaluated before starting the treatment as well as after the end of treatment by present pain intensity scale and the prostaglandin level in blood and pain relief scale at the end of treatment for both groups. [Results] The results showed a significant decrease in the severity of pain, statistically significant decrease in prostaglandin level in blood, and a statistically significant pain alleviation in both groups. With comparison between both groups there was a statistically significant decrease in the severity of pain, significant decrease in the blood levels of PGF2α, in group (A) than group (B). [Conclusion] Both HILT and PEMF are effective in the treatment of primary dysmenorrhea with HILT being superior to PEMF.

Thabet AAE, Elsodany AM, Battecha KH, Alshehri MA, Refaat B. High-intensity laser therapy versus pulsed electromagnetic field in the treatment of primary dysmenorrhea. J Phys Ther Sci. 2017 Oct;29(10):1742-1748. doi: 10.1589/jpts.29.1742. Epub 2017 Oct 21. PMID: 29184281; PMCID: PMC5684002.

The value of pulsed electromagnetic fields (PEMF) for the treatment of persistent rotator cuff tendinitis was tested in a double-blind controlled study in 29 patients whose symptoms were refractory to steroid injection and other conventional conservative measures. The treated group (15 patients) had a significant benefit compared with the control group (14 patients) during the first 4 weeks of the study, when the control group received a placebo. In the second 4 weeks, when all patients were on active coils, no significant differences were noted between the groups. This lack of difference persisted over the third phase, when neither group received any treatment for 8 weeks. At the end of the study 19 (65%) of the 29 patients were symptomless and 5 others much improved. PEMF therapy may thus be useful in the treatment of severe and persistent rotator cuff and possibly other chronic tendon lesions.

Binder A, Parr G, Hazleman B, Fitton-Jackson S. Pulsed electromagnetic field therapy of persistent rotator cuff tendinitis. A double-blind controlled assessment. Lancet. 1984 Mar 31;1(8379):695-8. doi: 10.1016/s0140-6736(84)92219-0. PMID: 6143039.

To determine the effect of a 72 Hz pulsating electromagnetic field (PEMF) on bone density of the radii of osteoporosis-prone women, the nondominant forearms of 20 subjects were exposed to PEMF 10 h daily for a period of 12 weeks. Bone density before, during, and after the exposure period was determined by use of a Norland-Cameron bone mineral analyzer. Bone mineral densities of the treated radii measured by single-photon densitometry increased significantly in the immediate area of the field during the exposure period and decreased during the following 36 weeks. A similar but weaker response occurred in the opposite arm, suggesting a "cross-talk" effect on the nontreated radii, from either possible arm proximity during sleep or very weak general field effects. The data suggest that properly applied PEMFs, if scaled for whole-body use, may have clinical application in the prevention and treatment of osteoporosis.

Tabrah F, Hoffmeier M, Gilbert F Jr, Batkin S, Bassett CA. Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J Bone Miner Res. 1990 May;5(5):437-42. doi: 10.1002/jbmr.5650050504. PMID: 2195843.

The present study investigated the impact of 12 weeks of pulsed electromagnetic field (PEMF) therapy on peripheral vascular function, blood pressure (BP), and nitric oxide in hypertensive individuals. Thirty hypertensive individuals (SBP > 130 mm Hg and/or MAP > 100 mm Hg) were assigned to either PEMF group (n = 15) or control group (n = 15). During pre‐assessment, participants underwent measures of flow‐mediated dilation (FMD), BP, and blood draw for nitric oxide (NO). Subsequently, they received PEMF therapy 3x/day for 12 weeks and, at conclusion, returned to the laboratory for post‐assessment. Fifteen participants from the PEMF group and 11 participants from the control group successfully completed the study protocol. After therapy, the PEMF group demonstrated significant improvements in FMD and FMDNOR (normalized to hyperemia), but the control group did not (P = .05 and P = .04, respectively). Moreover, SBP, DBP, and MAP were reduced, but the control group did not (P = .04, .04, and .03, respectively). There were no significant alterations in NO in both groups (P > .05). Twelve weeks of PEMF therapy may improve BP and vascular function in hypertensive individuals. Additional studies are needed to identify the mechanisms by which PEMF affects endothelial function.

Stewart GM, Wheatley-Guy CM, Johnson BD, Shen WK, Kim CH. Impact of pulsed electromagnetic field therapy on vascular function and blood pressure in hypertensive individuals. J Clin Hypertens (Greenwich). 2020 Jun;22(6):1083-1089. doi: 10.1111/jch.13877. Epub 2020 May 13. PMID: 32401418; PMCID: PMC8030044.

The aim of the present study was to investigate on the effects of a low-frequency pulsed electromagnetic field (LF-PEMF) in an experimental cell model of Alzheimer's disease (AD) to assess new therapies that counteract neurodegeneration. In recent scientific literature, it is documented that the deep brain stimulation via electromagnetic fields (EMFs) modulates the neurophysiological activity of the pathological circuits and produces clinical benefits in AD patients. EMFs are applied for tissue regeneration because of their ability to stimulate cell proliferation and immune functions via the HSP70 protein family. However, the effects of EMFs are still controversial and further investigations are required. Our results demonstrate the ability of our LF-PEMF to modulate gene expression in cell functions that are dysregulated in AD (i.e., BACE1) and that these effects can be modulated with different treatment conditions. Of relevance, we will focus on miRNAs regulating the pathways involved in brain degenerative disorders.

Capelli E, Torrisi F, Venturini L, Granato M, Fassina L, Lupo GFD, Ricevuti G. Low-Frequency Pulsed Electromagnetic Field Is Able to Modulate miRNAs in an Experimental Cell Model of Alzheimer's Disease. J Healthc Eng. 2017;2017:2530270. doi: 10.1155/2017/2530270. Epub 2017 May 2. PMID: 29065581; PMCID: PMC5434238.

It has been reported that skin aging is associated with a downregulation in collagen synthesis and an elevation in matrix metalloproteinase (MMP) expression. This study investigated the potential of light-emitting diode (LED) treatments with a 660 nm sequentially pulsed illumination formula in the photobiomodulation of these molecules. Histological and biochemical changes were first evaluated in a tissue-engineered Human Reconstructed Skin (HRS) model after 11 sham or LED light treatments. LED effects were then assessed in aged/photoaged individuals in a split-face single-blinded study. Results yielded a mean percent difference between LED-treated and non-LED-treated HRS of 31% in levels of type-1 procollagen and of -18% in MMP-1. No histological changes were observed. Furthermore, profilometry quantification revealed that more than 90% of individuals showed a reduction in rhytid depth and surface roughness, and, via a blinded clinical assessment, that 87% experienced a reduction in the Fitzpatrick wrinkling severity score after 12 LED treatments. No adverse events or downtime were reported. Our study showed that LED therapy reversed collagen downregulation and MMP-1 upregulation. This could explain the improvements in skin appearance observed in LED-treated individuals. These findings suggest that LED at 660 nm is a safe and effective collagen-enhancement strategy.

Barolet D, Roberge CJ, Auger FA, Boucher A, Germain L. Regulation of skin collagen metabolism in vitro using a pulsed 660 nm LED light source: clinical correlation with a single-blinded study. J Invest Dermatol. 2009 Dec;129(12):2751-9. doi: 10.1038/jid.2009.186. Epub 2009 Jul 9. PMID: 19587693.

Extremely low-frequency electromagnetic field (ELF-EMF) exposures influence many biological systems. These effects are mainly related to the intensity, duration, frequency, and pattern of the ELF-EMF. Our intent was to characterize the effect of specific pulsed electromagnetic fields on the in vitro proliferation of MCF-7 adenocarcinoma and MDA-MB-231 breast cancer cell lines and one non-cancerous M10 breast epithelial cell line. The following four important parameters of ELF-EMF were examined: frequencies (7.83 ± 0.3, 23.49 ± 0.3, and 39.15 ± 0.3 Hz), flux density (0.5 and 1 mT), exposure duration (12, 24, and 48 h), and the exposure methodology (continuous exposure versus switching exposure). The viability of MDA-MB-231 cells exposed to the optimized ELF-EMF pattern (7.83 ± 0.3 Hz, 1 mT, and 6 h switching exposure) was 40.1%. By contrast, the optimized ELF-EMF parameters that were most cytotoxic to breast cancer MDA-MB-231 cells were not damaging to normal M10 cells. In vitro studies also showed that exposure of MDA-MB-231 cells to the optimized ELF-EMF pattern promoted Ca2+ influx and resulted in apoptosis. These data confirm that exposure to this specific ELF-EMF pattern can influence cellular processes and inhibit cancer cell growth. The specific ELF-EMF pattern determined in this study may provide a potential anti-cancer treatment in the future.

Wang MH, Chen KW, Ni DX, Fang HJ, Jang LS, Chen CH. Effect of extremely low frequency electromagnetic field parameters on the proliferation of human breast cancer. Electromagn Biol Med. 2021 Jul 3;40(3):384-392. doi: 10.1080/15368378.2021.1891093. Epub 2021 Feb 25. PMID: 33632057.

Arthritis refers to more than 100 disorders of the musculoskeletal system. The existing pharmacological interventions for arthritis offer only symptomatic relief and they are not definitive and curative. Magnetic healing has been known from antiquity and it is evolved to the present times with the advent of electromagnetism. The original basis for the trial of this form of therapy is the interaction between the biological systems with the natural magnetic fields. Optimization of the physical window comprising the electromagnetic field generator and signal properties (frequency, intensity, duration, waveform) with the biological window, inclusive of the experimental model, age and stimulus has helped in achieving consistent beneficial results. Low frequency pulsed electromagnetic field (PEMF) can provide noninvasive, safe and easy to apply method to treat pain, inflammation and dysfunctions associated with rheumatoid arthritis (RA) and osteoarthritis (OA) and PEMF has a long term record of safety. This review focusses on the therapeutic application of PEMF in the treatment of these forms of arthritis. The analysis of various studies (animal models of arthritis, cell culture systems and clinical trials) reporting the use of PEMF for arthritis cure has conclusively shown that PEMF not only alleviates the pain in the arthritis condition but it also affords chondroprotection, exerts anti-inflammatory action and helps in bone remodeling and this could be developed as a viable alternative for arthritis therapy.

Ganesan K, Gengadharan AC, Balachandran C, Manohar BM, Puvanakrishnan R. Low frequency pulsed electromagnetic field--a viable alternative therapy for arthritis. Indian J Exp Biol. 2009 Dec;47(12):939-48. PMID: 20329696.

Objective:

to compare the effects of pulsed electromagnetic field (PEMF) therapy and sham treatment on DOMS-related variables in elbow flexors at 24, 48 and 72 h after delayed onset muscle soreness (DOMS) induction exercise.

Design:

randomized, double-blind, placebo-controlled study.

Main outcome measures:

Muscle soreness, peak torque, median frequency (MDF) and electromechanical delay (EMD) during isometric contraction at 24, 48 and 72 h after DOMS induction exercise.

Results:

Overall, the application of the PEMF was found to be effective in reducing the physiological deficits associated with DOMS, including improved recovery of perceived muscle soreness, MDF, and EMD during isometric contraction. Our results did not show that PEMF treatment was mechanically more effective for isometric peak torque generation compared to the sham group.

Conclusion:

this study indicates that PEMF may be useful as a modality to reduce DOMS symptoms. However, further well-designed experiments are required to determine optimal treatment dosage and duration, and to investigate the physiological and clinical mechanisms of PEMF on DOMS.

Jeon HS, Kang SY, Park JH, Lee HS. Effects of pulsed electromagnetic field therapy on delayed-onset muscle soreness in biceps brachii. Phys Ther Sport. 2015 Feb;16(1):34-9. doi: 10.1016/j.ptsp.2014.02.006. Epub 2014 Mar 7. PMID: 24906295.

In animal and clinical trials low-level laser therapy (LLLT) using red, infrared and mixed wavelengths has been shown to delay the development of skeletal muscle fatigue. However, the parameters employed in these studies do not allow a conclusion as to which wavelength range is better in delaying the development of skeletal muscle fatigue. With this perspective in mind, we compared the effects of red and infrared LLLT on skeletal muscle fatigue. A randomized double-blind placebo-controlled crossover trial was performed in ten healthy male volunteers. They were treated with active red LLLT, active infrared LLLT (660 or 830 nm, 50 mW, 17.85 W/cm(2), 100 s irradiation per point, 5 J, 1,785 J/cm(2) at each point irradiated, total 20 J irradiated per muscle) or an identical placebo LLLT at four points of the biceps brachii muscle for 3 min before exercise (voluntary isometric elbow flexion for 60 s). The mean peak force was significantly greater (p < 0.05) following red (12.14%) and infrared LLLT (14.49%) than following placebo LLLT, and the mean average force was also significantly greater (p < 0.05) following red (13.09%) and infrared LLLT (13.24%) than following placebo LLLT. There were no significant differences in mean average force or mean peak force between red and infrared LLLT. We conclude that both red than infrared LLLT are effective in delaying the development skeletal muscle fatigue and in enhancement of skeletal muscle performance. Further studies are needed to identify the specific mechanisms through which each wavelength acts.

de Almeida P, Lopes-Martins RA, De Marchi T, Tomazoni SS, Albertini R, Corrêa JC, Rossi RP, Machado GP, da Silva DP, Bjordal JM, Leal Junior EC. Red (660 nm) and infrared (830 nm) low-level laser therapy in skeletal muscle fatigue in humans: what is better? Lasers Med Sci. 2012 Mar;27(2):453-8. doi: 10.1007/s10103-011-0957-3. Epub 2011 Jul 22. PMID: 21814736; PMCID: PMC3282894.

Photobiomodulation (PBM) describes the use of red or near-infrared (NIR) light to vstimulate, heal, and regenerate damaged tissue. Both pre-conditioning (light delivered to muscles before exercise) and PBM applied after exercise can increase sports performance in athletes. This review covers the effects of PBM on human muscle tissue in clinical trials in volunteers related to sports performance and in athletes. The parameters used were categorized into those with positive effects or no effects on muscle performance and recovery. Randomized controlled trials and case-control studies in both healthy trained and untrained participants, and elite athletes were retrieved from MEDLINE up to 2016. Performance metrics included fatigue, number of repetitions, torque, hypertrophy; measures of muscle damage and recovery such as creatine kinase and delayed onset muscle soreness. Searches retrieved 533 studies, of which 46 were included in the review (n=1045 participants). Studies used single laser probes, cluster of laser-diodes, LED-clusters, mixed clusters (lasers and LEDs), and flexible LED arrays. Both red, NIR, and red/NIR mixtures were used. PBM can increase muscle mass gained after training, and decrease inflammation and oxidative stress in muscle biopsies. We raise the question of whether PBM should be permitted in athletic competition by international regulatory authorities.

Ferraresi C, Huang YY, Hamblin MR. Photobiomodulation in human muscle tissue: an advantage in sports performance? J Biophotonics. 2016 Dec;9(11-12):1273-1299. doi: 10.1002/jbio.201600176. Epub 2016 Nov 22. PMID: 27874264; PMCID: PMC5167494.

For the histological study, the bilateral sciatic nerves were transected, and the left proximal stump and the right distal stump were inserted into the opposite ends of a silicone chamber, leaving a 10-mm gap. Light from an LED device (660 nm, 7.5 mW/cm(2)) was irradiated for 1 h per day. At 3 weeks after surgery, regenerated tissue was fixed and examined by light microscopy. For the antioxidation assay of chamber fluid, the left sciatic nerve and a 2-mm piece of nerve from the proximal stump were transected and inserted into opposite sides of a silicone chamber leaving a 10-mm gap. LEDs were irradiated using the same parameters as those described in the histological study. At 1, 3, and 7 days after surgery, antioxidation of the chamber fluid was measured using an OXY absorbent test.

Chamber fluid is produced from nerve stumps after nerve injury. This fluid contains neurotrophic factors that may accelerate axonal growth. Red to near-infrared LEDs have been shown to promote mitochondrial oxidative metabolism. In this study, LED irradiation improved nerve regeneration and increased antioxidation levels in the chamber fluid. Therefore, we propose that antioxidation induced by LEDs may be conducive to nerve regeneration.

Ishiguro M, Ikeda K, Tomita K. Effect of near-infrared light-emitting diodes on nerve regeneration. J Orthop Sci. 2010 Mar;15(2):233-9. doi: 10.1007/s00776-009-1438-4. Epub 2010 Apr 1. PMID: 20358337.

It has been reported that skin aging is associated with a downregulation in collagen synthesis and an elevation in matrix metalloproteinase (MMP) expression. This study investigated the potential of light-emitting diode (LED) treatments with a 660 nm sequentially pulsed illumination formula in the photobiomodulation of these molecules. Histological and biochemical changes were first evaluated in a tissue-engineered Human Reconstructed Skin (HRS) model after 11 sham or LED light treatments. LED effects were then assessed in aged/photoaged individuals in a split-face single-blinded study. Results yielded a mean percent difference between LED-treated and non-LED-treated HRS of 31% in levels of type-1 procollagen and of -18% in MMP-1. No histological changes were observed. Furthermore, profilometry quantification revealed that more than 90% of individuals showed a reduction in rhytid depth and surface roughness, and, via a blinded clinical assessment, that 87% experienced a reduction in the Fitzpatrick wrinkling severity score after 12 LED treatments. No adverse events or downtime were reported. Our study showed that LED therapy reversed collagen downregulation and MMP-1 upregulation. This could explain the improvements in skin appearance observed in LED-treated individuals. These findings suggest that LED at 660 nm is a safe and effective collagen-enhancement strategy.

Barolet D, Roberge CJ, Auger FA, Boucher A, Germain L. Regulation of skin collagen metabolism in vitro using a pulsed 660 nm LED light source: clinical correlation with a single-blinded study. J Invest Dermatol. 2009 Dec;129(12):2751-9. doi: 10.1038/jid.2009.186. Epub 2009 Jul 9. PMID: 19587693.

Introduction

Several clinical trials have demonstrated that low-level light therapy (LLLT), a method of photobiomodulation, is an effective analgetic treatment. However, the mechanism of action has not yet been finally clarified. In particular, unanswered questions include whether it only affects peripheral or whether it also affects the spinal or supraspinal level. This study aimed to evaluate the effect of low-level light therapy on primary and secondary hyperalgesia in a human pain model.

Methods

This study was planned as a randomized, sham-controlled, and double-blinded trial with repeated measures within subject design. Capsaicin was applied on both forearms of ten healthy volunteers to induce peripheral and central sensitization. One forearm was treated with low-level light therapy; the other served as sham control.

Results

Low-level light therapy significantly increased the mechanical pain threshold, heat pain threshold, and decreased pain intensity.

Conclusions

Our data indicate that low-level light therapy is effective at reducing the heat and mechanical pain threshold in a human pain model, pointing to a significant modulating effect on peripheral and central sensitization. These effects—especially in the absence of reported side effects—make low-level light therapy a promising tool in pain management. The application of low-level light therapy to treat chronic pain should be considered for further clinical trials.

Lang-Illievich K, Winter R, Rumpold-Seitlinger G, Schicho K, Dorn C, Klivinyi C, Bornemann-Cimenti H. The Effect of Low-Level Light Therapy on Capsaicin-Induced Peripheral and Central Sensitization in Healthy Volunteers: A Double-Blinded, Randomized, Sham-Controlled Trial. Pain Ther. 2020 Dec;9(2):717-726. doi: 10.1007/s40122-020-00205-0. Epub 2020 Oct 10. PMID: 33040311; PMCID: PMC7547817.