The Effect of Pulsed Electromagnetic Fields on Angiogenesis.

A pulsed electromagnetic field (PEMF) has been used to treat inflammation-based diseases such as osteoporosis, neurological injury, and osteoarthritis. Numerous animal experiments and in vitro studies have shown that PEMF may affect angiogenesis. For ischemic diseases, in theory, blood flow may be richer by increasing the number of blood vessels which supply blood to ischemic tissue. PEMF plays a role in enhancing angiogenesis, and their clinical application may go far beyond the current scope. In this review, we analyzed and summarized the effects and possible mechanisms of PEMF on angiogenesis. Most studies have shown that PEMF with specific parameters can promote angiogenesis, which is manifested by an increased vascular growth rate and increased capillary density. The potential mechanisms consist of promoting vascular endothelial cell proliferation, migration, and tube formation, and increasing the expression level of vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), angiopoietin-2 (Ang-2), and other angiogenic growth factors. Additionally, PEMF has an impact on the activation of voltage-gated calcium channels (VGCC). Bioelectromagnetics. © 2021 Bioelectromagnetics Society.

Co-treatment effect of pulsed electromagnetic field (PEMF) with human dental pulp stromal cells and FK506 on the regeneration of crush injured rat sciatic nerve.

PURPOSE: The purpose of this study was to determine whether crush injured rat sciatic nerve could be benefit from pulsed electromagnetic field (PEMF) combined with human dental pulp stromal cells (hDPSCs), with FK506 (Tacrolimus) for immune suppression and neuropromotion. MATERIALS AND METHODS: Male Sprague-Dawley rats (200-250 g, 6 week old) were distributed into 6 groups (n = 18 each): control, PEMF, FK506, PEMF + hDPSCs, PEMF + FK506, and PEMF + hDPSCs + FK506 groups. hDPSCs (cell = 1 × 106/10 µl/rat) were injected at the crush site immediate after injury. FK506 was administered 3 weeks in FK506 group (0.5 mg/kg/d) while pre-op 1 d and post-op 7 d in PEMF + FK506 and PEMF + hDPSCs + FK506 group; cell tracking was done with PKH26-labeled hDPSCs (cell = 1 × 106/10 µl/rat). The rats were follow-up for 3 weeks. RESULTS: PEMF + FK506 and PEMF + hDPSCs + FK506 group showed a sharp increase in sciatic function index (SFI), axon counts, densities, and labeled neurons in dorsal root ganglia (DRG) than control at 3 weeks. Other three treatment groups also showed higher axon counts, densities, and labeled neurons than control. Higher axon counts and densities were found in PEMF + FK506 and PEMF + hDPSCs + FK506 groups comparing with PEMF group. Brain-derived neurotrophic factor (BDNF) mRNA expression pattern in nerve segment and DRG was almost same. Higher expression level in all the treatment groups was discovered in the follow-up period, but there was no significant difference. CONCLUSIONS: All treatment groups can improve regeneration of neurons following crushed injury, PEMF + FK506 and PEMF + hDPSCs + FK506 groups showed higher regeneration ability than other three groups. FK506 plays an important role during hDPSCs transplantation.

Influence of pulsed electromagnetic and pulsed vector magnetic potential field on the growth of tumor cells.

AIMS AND BACKGROUND: Tumor diseases cause 20% of deaths in Europe and they are the second most common cause of death and morbidity after cardiovascular diseases. Thus, tumor cells are target of many therapeutic strategies and tumor research is focused on searching more efficient and specific drugs as well as new therapeutic approaches. One of the areas of tumor research is an issue of external fields. In our work, we tested influence of a pulsed electromagnetic field (PEMF) and a hypothetic field of the pulsed vector magnetic potential (PVMP) on the growth of tumor cells; and further the possible growth inhibition effect of the PVMP. METHODS: Both unipolar and bipolar PEMF fields of 5 mT and PVMP fields of 0 mT at frequencies of 15 Hz, 125 Hz and 625 Hz were tested on cancer cell lines derived from various types of tumors: CEM/C2 (acute lymphoblastic leukemia), SU-DHL-4 (B-cell lymphoma), COLO-320DM (colorectal adenocarcinoma), MDA-BM-468 (breast adenocarcinoma), and ZR-75-1 (ductal carcinoma). Cell morphology was observed, proliferation activity using WST assay was measured and simultaneous proportion of live, early apoptotic and dead cells was detected using flow cytometry. RESULTS: 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, i.e. COLO-320DM and ZR-75-1. In contrast, any of employed methods did not confirm a significant inhibitory effect of hypothetic PVMP field on tumor cells.

Clinical effectiveness of pulsed electromagnetic field therapy as an adjunct treatment to eccentric exercise for Achilles tendinopathy: a randomised controlled trial.

BACKGROUND: The Achilles tendon is the largest and strongest tendon in the human body. Achilles tendinopathy (AT) is a common clinical problem with Achilles overuse. Eccentric exercise is often used as an initial treatment for these patients. Most patients with AT experienced moderate to severe pain, limiting the incentive to perform eccentric exercise. It is difficult for them to complete eccentric exercise for 3 months consecutively to obtain significant improvements. Using PEMF as an adjunct, there could be immediate pain relief and improved response to eccentric exercise by modulating the mechanical properties of the Achilles tendon. Participants may experience less pain while performing eccentric exercises to increase compliance with the rehabilitation programme. METHODS: This prospective randomised double-blinded, placebo-controlled trial aims to investigate the treatment effects of PEMF for participants with AT. All participants are randomised into two groups: the intervention group (n = 20; active PEMF treatment and eccentric exercise) and the control group (n = 20; sham treatment and eccentric exercise). Researchers perform self-reported, functional and ultrasonographic outcomes during baseline assessment, 4 weeks, 8 weeks follow-ups, and 3 and 6 months follow-ups after the commencement of the PEMF treatment. DISCUSSION: AT is a common clinical condition affecting athletes and sedentary populations. It is essential to investigate treatment adjuncts to improve rehabilitation outcomes for these patients. This trial may demonstrate the effectiveness of PEMF in relieving pain, improving function, and restoring mechanical changes of the tendon in participants with AT. TRIAL REGISTRATION: ClinicalTrials.gov NCT05316961. Registered on 7th April 2022.

Pulsed Electromagnetic Field Enhances Healing of a Meniscal Tear and Mitigates Posttraumatic Osteoarthritis in a Rat Model.

BACKGROUND: Meniscal tears in the avascular region are thought to rarely heal and are a considerable challenge to treat. Although the therapeutic effects of a pulsed electromagnetic field (PEMF) have been extensively studied in a variety of orthopaedic disorders, the effect of a PEMF on meniscal healing has not been reported. HYPOTHESIS: PEMF treatment would promote meniscal healing and prevent osteoarthritis progression. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 72 twelve-week-old male Sprague-Dawley rats with full-thickness longitudinal medial meniscal tears in the avascular region were divided into 3 groups: control (Gcon), treatment with a classic signal PEMF (Gclassic), and treatment with a high-slew rate signal PEMF (GHSR). Macroscopic observation and histological analysis of the meniscus and articular cartilage were performed to evaluate the meniscal healing and progression of osteoarthritis. The synovium was harvested for histological and immunofluorescent analysis to evaluate the intra-articular inflammation. Meniscal healing, articular cartilage degeneration, and synovitis were quantitatively evaluated according to their scoring systems. RESULTS: Dramatic degenerative changes of the meniscus and articular cartilage were noticed during gross observation and histological evaluation in Gcon at 8 weeks. However, the menisci in the 2 treatment groups were restored to normal morphology, with a smooth surface and shiny white color. Particularly, the HSR signal remarkably enhanced the fibrochondrogenesis and accelerated the remodeling process of the regenerated tissue. The meniscal healing scores of the PEMF treatment groups were significantly higher than those in Gcon at 8 weeks. Specifically, the HSR signal showed a significantly higher meniscal repair score than did the classic signal at week 8 (P < .01). Additionally, the HSR signal significantly downregulated the secretion levels of interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in the meniscus and synovium as compared with the control group. When compared with the 2 treatment groups, Gcon had significantly higher degeneration scores (Gcon vs Gclassic, P < .0001; Gcon vs GHSR, P < .0001). The HSR signal also exhibited significantly lower synovitis scores compared with the other two groups (Gcon vs Gclassic, P < .0001; Gclassic vs GHSR, P = .0002). CONCLUSION: A PEMF promoted the healing of meniscal tears in the avascular region and restored the injured meniscus to its structural integrity in a rat model. As compared with the classic signal, the HSR signal showed increased capability to promote fibrocartilaginous tissue formation and modulate the inflammatory environment, therefore protecting the knee joint from posttraumatic osteoarthritis development. CLINICAL RELEVANCE: Adjuvant PEMF therapy may offer a new approach for the treatment of meniscal tears attributed to the enhanced meniscal repair and ameliorated osteoarthritis progression.

Effect of pulsed electromagnetic field as an intervention for patients with quadriceps weakness after anterior cruciate ligament reconstruction: a double-blinded, randomized-controlled trial.

BACKGROUND: The ultimate goal of anterior cruciate ligament reconstructions (ACLR) is to fulfil the return-to-play (RTP) criteria. Quadriceps muscle strength is one of the key determinants for a patient's successful return-to-play after ACLR. Quadriceps muscle atrophy can persist beyond the completion of the rehabilitation program in almost half the patients and the reason behind this is still unknown. There are emerging evidences showing that pulsed electromagnetic field (PEMF) can modulate mitochondrial activities for muscle gain. PEMF exposure on top of regular exercise training may promote muscle regeneration and tissue healing. METHODS: This is a double-blinded, randomized controlled trial to investigate the effects of PEMF treatment during the postoperative period on quadriceps muscle strength in ACL injured patient. Adult patients (aged 18-30) with a unilateral ACL injury, total quadriceps muscle volume is equal or more than 7% deficit on involved leg compared with uninvolved leg, sporting injury with a Tegner score of 7+, and both knees without a history of injury/prior surgery will be recruited. To estimate the improvement of patients, isokinetic muscle assessment, ultrasound imaging and MRI for quadriceps muscle thickness, self-reported outcomes with questionnaires, KT-1000 for knee laxity and biomechanical analysis, and Xtreme CT for bone mineral density will be performed. To investigate the mechanism of PEMF therapy on increasing quadriceps strength, samples of blood serum will be drawn before and after intervention. DISCUSSION: This is the first trial evaluating the effects of PEMF on quadriceps muscle recovery after ACLR. The proposed study addresses a huge research gap by evaluating practical use of PEMF as part of rehabilitation. The proposed study will provide much needed scientific support in the use of this noninvasive treatment modality to facilitate recovery of quadriceps strength after PEMF. TRIAL REGISTRATION: ClinicalTrials.gov NCT05184023. Registered on 5 January 2022.

Pulsed Electromagnetic Fields Modulate miRNAs During Osteogenic Differentiation of Bone Mesenchymal Stem Cells: a Possible Role in the Osteogenic-angiogenic Coupling.

Despite the high intrinsic ability of bone tissue to regenerate, bone healing fails in some pathological conditions and especially in the presence of large defects. Due to the strong relationship between bone development and vascularization during in vivo bone formation and repair, strategies promoting the osteogenic-angiogenic coupling are crucial for regenerative medicine. Increasing evidence shows that miRNAs play important roles in controlling osteogenesis and bone vascularization and are important tool in medical research although their clinical use still needs to optimize miRNA stability and delivery. Pulsed electromagnetic fields (PEMFs) have been successfully used to enhance bone repair and their clinical activity has been associated to their ability to promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this study we investigated the potential ability of PEMF exposure to modulate selected miRNAs involved in the osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs). We show that, during in vitro hBMSC differentiation, PEMFs up-modulate the expression of miR-26a and miR-29b, which favor osteogenic differentiation, and decrease miR-125b which acts as an inhibitor miRNA. As PEMFs promote the expression and release of miRNAs also involved in angiogenesis, we conclude that PEMFs may represent a noninvasive and safe strategy to modulate miRNAs with relevant roles in bone repair and with the potential to regulate the osteogenic-angiogenic coupling.

The Use of Pulsed Electromagnetic Field to Modulate Inflammation and Improve Tissue Regeneration: A Review.

Pulsed electromagnetic field (PEMF) is emerging as innovative treatment for regulation of inflammation, which could have significant effects on tissue regeneration. PEMF modulates inflammatory processes through the regulation of pro- and anti-inflammatory cytokine secretion during different stages of inflammatory response. Consistent outcomes in studies involving animal and human tissue have shown promise for the use of PEMF as an alternative or complementary treatment to pharmaceutical therapies. Thus, PEMF treatment could provide a novel nonpharmaceutical means of modulating inflammation in injured tissues resulting in enhanced functional recovery. This review examines the effect of PEMF on immunomodulatory cells (e.g., mesenchymal stem/stromal cells [MSCs] and macrophages [MΦ]) to better understand the potential for PEMF therapy to modulate inflammatory signaling pathways and improve tissue regeneration. This review cites published data that support the use of PEMF to improve tissue regeneration. Our studies included herein confirm anti-inflammatory effects of PEMF on MSCs and MΦ.

Targeting Mesenchymal Stromal Cells/Pericytes (MSCs) With Pulsed Electromagnetic Field (PEMF) Has the Potential to Treat Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovium (synovitis), with inflammatory/immune cells and resident fibroblast-like synoviocytes (FLS) acting as major players in the pathogenesis of this disease. The resulting inflammatory response poses considerable risks as loss of bone and cartilage progresses, destroying the joint surface, causing joint damage, joint failure, articular dysfunction, and pre-mature death if left untreated. At the cellular level, early changes in RA synovium include inflammatory cell infiltration, synovial hyperplasia, and stimulation of angiogenesis to the site of injury. Different angiogenic factors promote this disease, making the role of anti-angiogenic therapy a focus of RA treatment. To control angiogenesis, mesenchymal stromal cells/pericytes (MSCs) in synovial tissue play a vital role in tissue repair. While recent evidence reports that MSCs found in joint tissues can differentiate to repair damaged tissue, this repair function can be repressed by the inflammatory milieu. Extremely-low frequency pulsed electromagnetic field (PEMF), a biophysical form of stimulation, has an anti-inflammatory effect by causing differentiation of MSCs. PEMF has also been reported to increase the functional activity of MSCs to improve differentiation to chondrocytes and osteocytes. Moreover, PEMF has been demonstrated to accelerate cell differentiation, increase deposition of collagen, and potentially return vascular dysfunction back to homeostasis. The aim of this report is to review the effects of PEMF on MSC modulation of cytokines, growth factors, and angiogenesis, and describe its effect on MSC regeneration of synovial tissue to further understand its potential role in the treatment of RA.

Low frequency pulsed electromagnetic field promotes differentiation of oligodendrocyte precursor cells through upregulation of miR-219-5p in vitro.

AIM: Spinal cord injury (SCI) is a common demyelinating disorder of the central nervous system. The differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), which induce myelination, plays a critical role in the functional recovery following SCI. In this study, the effect of low frequency pulsed electromagnetic field (PEMF) on the differentiation of OPCs and the potential underlying mechanisms were investigated. MAIN METHODS: OPCs were randomly divided into the PEMF and non-PEMF (NPEMF) groups. Immunofluorescence and western blot assays were performed to assess the expression levels of OLs stage-specific markers after 3, 7, 14, and 21 days of PEMF or NPEMF exposure. qRT-PCR was used to further assess the expression levels of miR-219-5p, miR-338, miR-138, and miR-9, which are associated with OPCs differentiation, and the expression levels of genes associated with miR-219-5p. Finally, following PEMF or NPEMF exposure, qRT-PCR and western blot assays were performed to explore the relationship between miR-219-5p and Lingo1 and between miR-219-5p and PEMF in promoting OPCs differentiation. KEY FINDINGS: 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. Under PEMF exposure, miR-219-5p targeted Lingo1 and reversed the inhibitory effect of miR-219-5p inhibitor on OPCs differentiation. In addition, PEMF synergized with miR-219-5p to promote OPCs differentiation. SIGNIFICANCE: Our results, for the first time, indicated that PEMF promoted OPCs differentiation by regulating miR-219-5p activity in vitro.

Global Responses of Il-1ß-Primed 3D Tendon Constructs to Treatment with Pulsed Electromagnetic Fields.

Tendinopathy is accompanied by a cascade of inflammatory events promoting tendon degeneration. Among various cytokines, interleukin-1ß plays a central role in driving catabolic processes, ultimately resulting in the activation of matrix metalloproteinases and a diminished collagen synthesis, both of which promote tendon extracellular matrix degradation. Pulsed electromagnetic field (PEMF) therapy is often used for pain management, osteoarthritis, and delayed wound healing. In vitro PEMF treatment of tendon-derived cells was shown to modulate pro-inflammatory cytokines, potentially limiting their catabolic effects. However, our understanding of the underlying cellular and molecular mechanisms remains limited. We therefore investigated the transcriptome-wide responses of Il-1ß-primed rat Achilles tendon cell-derived 3D tendon-like constructs to high-energy PEMF treatment. RNASeq analysis and gene ontology assignment revealed various biological processes to be affected by PEMF, including extracellular matrix remodeling and negative regulation of apoptosis. Further, we show that members of the cytoprotective Il-6/gp130 family and the Il-1ß decoy receptor Il1r2 are positively regulated upon PEMF exposure. In conclusion, our results provide fundamental mechanistic insight into the cellular and molecular mode of action of PEMF on tendon cells and can help to optimize treatment protocols for the non-invasive therapy of tendinopathies.

The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy.

Neuropathic pain is usually defined as a chronic pain state caused by peripheral or central nerve injury as a result of acute damage or systemic diseases. It remains a difficult disease to treat. Recent studies showed that the frequency of action potentials in nociceptive afferents is affected by the activity of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) family. In the current study, we used a neuropathy rat model induced by chronic constriction injury (CCI) of sciatic nerve to evaluate the change of expression of HCN1/HCN2 mRNA in peripheral nerve and spinal cord. Rats were subjected to CCI with or without pulsed electromagnetic field (PEMF) therapy. It was found that CCI induced neural cell degeneration while PEMF promoted nerve regeneration as documented by Nissl staining. CCI shortened the hind paw withdrawal latency (PWL) and hind paw withdrawal threshold (PWT) and PEMF prolonged the PWL and PWT. In addition, CCI lowers the expression of HCN1 and HCN2 mRNA and PEMF cannot restore the expression of HCN1 and HCN2 mRNA. Our results indicated that PEMF can promote nerve regeneration and could be used for the treatment of neuropathic pain.

Novel protective effects of pulsed electromagnetic field ischemia/reperfusion injury rats.

Extracorporeal pulsed electromagnetic field (PEMF) has shown the ability to regenerate tissue by promoting cell proliferation. In the present study, we investigated for the first time whether PEMF treatment could improve the myocardial ischaemia/reperfusion (I/R) injury and uncovered its underlying mechanisms.In our study, we demonstrated for the first time that extracorporeal PEMF has a novel effect on myocardial I/R injury. The number and function of circulating endothelial progenitor cells (EPCs) were increased in PEMF treating rats. The in vivo results showed that per-treatment of PEMF could significantly improve the cardiac function in I/R injury group. In addition, PEMF treatment also reduced the apoptosis of myocardial cells by up-regulating the expression of anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and down-regulating the expression of pro-apoptosis protein (Bax). In vitro, the results showed that PEMF treatment could significantly reduce the apoptosis and reactive oxygen species (ROS) levels in primary neonatal rat cardiac ventricular myocytes (NRCMs) induced by hypoxia/reoxygenation (H/R). In particular, PEMF increased the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS), which might be closely related to attenuated cell apoptosis by increasing the releasing of nitric oxide (NO). Therefore, our data indicated that PEMF could be a potential candidate for I/R injury.