{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:25:16Z","timestamp":1791048316299,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T00:00:00Z","timestamp":1712275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Venous leg ulcers are one of the most common nonhealing conditions and represent an important clinical problem. The application of pulsed radiofrequency electromagnetic fields (PRF-EMFs), already applied for pain, inflammation, and new tissue formation, can represent a promising approach for venous leg ulcer amelioration. This study aims to evaluate the effect of PRF-EMF exposure on the inflammatory, antioxidant, cell proliferation, and wound healing characteristics of human primary dermal fibroblasts collected from venous leg ulcer patients. The cells\u2019 proliferative and migratory abilities were evaluated by means of a BrdU assay and scratch assay, respectively. The inflammatory response was investigated through TNF\u03b1, TGF\u03b2, COX2, IL6, and IL1\u03b2 gene expression analysis and PGE2 and IL1\u03b2 production, while the antioxidant activity was tested by measuring GSH, GSSG, tGSH, and GR levels. This study emphasizes the ability of PRF-EMFs to modulate the TGF\u03b2, COX2, IL6, IL1\u03b2, and TNF\u03b1 gene expression in exposed ulcers. Moreover, it confirms the improvement of the proliferative index and wound healing ability presented by PRF-EMFs. In conclusion, exposure to PRF-EMFs can represent a strategy to help tissue repair, regulating mediators involved in the wound healing process.<\/jats:p>","DOI":"10.3390\/bioengineering11040357","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T09:31:23Z","timestamp":1712568683000},"page":"357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pulsed Radiofrequency Electromagnetic Fields as Modulators of Inflammation and Wound Healing in Primary Dermal Fibroblasts of Ulcers"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-4226","authenticated-orcid":false,"given":"Erica","family":"Costantini","sequence":"first","affiliation":[{"name":"Department of Medicine and Aging Sciences, University \u201cG. d\u2019Annunzio\u201d, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4541-1842","authenticated-orcid":false,"given":"Lisa","family":"Aielli","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, University \u201cG. d\u2019Annunzio\u201d, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1640-6609","authenticated-orcid":false,"given":"Giulio","family":"Gualdi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, University \u201cG. d\u2019Annunzio\u201d, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Baronio","sequence":"additional","affiliation":[{"name":"Pediatrics Clinic and Institute for Molecular Medicine A. Novivelli, Department of Clinical and Expermental Sciences, University of Brescia and ASST-Spedali Civili of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Monari","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Spedali Civili of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-9672","authenticated-orcid":false,"given":"Paolo","family":"Amerio","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, University \u201cG. d\u2019Annunzio\u201d, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4164-8781","authenticated-orcid":false,"given":"Marcella","family":"Reale","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, University \u201cG. d\u2019Annunzio\u201d, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,5]]},"reference":[{"key":"ref_1","first-page":"143","article-title":"Prevalence of venous leg ulcer: The importance of the data collection method","volume":"15","year":"2008","journal-title":"Phlebolymphology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mohamady, H.M., Taha, M.M., Aneis, Y.M., Aldhahi, M.I., and Attalla, A.F. (2023). Effect of Combined Electromagnetic Field and Plantar Flexion Resistance Exercise on Wound Healing in Patients with Venous Leg Ulcers: A Randomized Controlled Trial. Medicina, 59.","DOI":"10.3390\/medicina59061157"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2300556","DOI":"10.1002\/adhm.202300556","article-title":"Updates on Recent Clinical Assessment of Commercial Chronic Wound Care Products","volume":"12","author":"Sharma","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1590\/0034-7167-2017-0516","article-title":"Impact of venous ulcers on patients\u2019 quality of life: An integrative review","volume":"71","author":"Joaquim","year":"2018","journal-title":"Rev. Bras. Enferm."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gualdi, G., Costantini, E., Reale, M., and Amerio, P. (2021). Wound Repair and Extremely Low Frequency-Electromagnetic Field: Insight from In Vitro Study and Potential Clinical Application. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22095037"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"407","DOI":"10.12968\/jowc.2013.22.8.407","article-title":"Wound healing and the role of fibroblasts","volume":"22","author":"Bainbridge","year":"2013","journal-title":"J. Wound Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"918223","DOI":"10.3389\/fimmu.2022.918223","article-title":"Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1177\/0268355513476844","article-title":"Inflammation in chronic venous ulcers","volume":"28","author":"Raffetto","year":"2013","journal-title":"Phlebology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhao, R., Liang, H., Clarke, E., Jackson, C., and Xue, M. (2016). Inflammation in Chronic Wounds. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122085"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1089\/wound.2013.0520","article-title":"The Role of Hypoxia-Inducible Factor in Wound Healing","volume":"3","author":"Hong","year":"2014","journal-title":"Adv. Wound Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.12968\/jowc.2016.25.Sup6.S1","article-title":"Management of Patients With Venous Leg Ulcers: Challenges and Current Best Practice","volume":"25","author":"Franks","year":"2016","journal-title":"J. Wound Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1742-481X.2010.00668.x","article-title":"Biofilms and bacterial imbalances in chronic wounds: Anti-Koch","volume":"7","author":"Percival","year":"2010","journal-title":"Int. Wound J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Aleksandrowicz, H., Owczarczyk-Saczonek, A., and Placek, W. (2021). Venous Leg Ulcers: Advanced Therapies and New Technologies. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111569"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Flatscher, J., Pavez Lori\u00e8, E., Mittermayr, R., Meznik, P., Slezak, P., Redl, H., and Slezak, C. (2023). Pulsed Electromagnetic Fields (PEMF)-Physiological Response and Its Potential in Trauma Treatment. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411239"},{"key":"ref_15","first-page":"3115154","article-title":"Physiotherapeutic Reduction of Orofacial Pain Using Extremely Low-Frequency Electromagnetic Field and Light-Emitting Diode Therapy-A Pilot Study","volume":"2022","author":"Ardan","year":"2022","journal-title":"Pain. Res. Manag."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Guarino, M., Bacci, S., P\u00e9rez Gonz\u00e1lez, L.A., Bermejo-Mart\u00ednez, M., Cecilia-Matilla, A., and Hern\u00e1ndez-Bule, M.L. (2023). The Role of Physical Therapies in Wound Healing and Assisted Scarring. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087487"},{"key":"ref_17","first-page":"CD002933","article-title":"Electromagnetic therapy for treating venous leg ulcers","volume":"2015","author":"Aziz","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1007\/s00266-023-03450-8","article-title":"Combined Pulsed Magnetic Field and Radiofrequency Electromagnetic Field Enhances MMP-9, Collagen-4, VEGF Synthesis to Improve Wound Healing Via Hif-1\u03b1\/eNOS Pathway","volume":"47","author":"Asci","year":"2023","journal-title":"Aesthetic Plast. Surg."},{"key":"ref_19","first-page":"59","article-title":"Effect of pulsed electromagnetic field treatment on programmed resolution of inflammation pathway markers in human cells in culture","volume":"8","author":"Kubat","year":"2015","journal-title":"J. Inflamm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Costantini, E., Aielli, L., Serra, F., De Dominicis, L., Falasca, K., Di Giovanni, P., and Reale, M. (2022). Evaluation of Cell Migration and Cytokines Expression Changes under the Radiofrequency Electromagnetic Field on Wound Healing In Vitro Model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042205"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/bem.22271","article-title":"Effectiveness of Pulsed Electromagnetic Fields on Bone Healing: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"41","author":"Peng","year":"2020","journal-title":"Bioelectromagnetics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1742-481X.2010.00758.x","article-title":"Nested graft in chronic wounds: A new solution for an old problem","volume":"8","author":"Gualdi","year":"2011","journal-title":"Int. Wound J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1111\/iwj.12415","article-title":"The nested graft acts by inducing the process of de-senescence of the fibroblasts in chronic venous ulcers","volume":"13","author":"Gualdi","year":"2016","journal-title":"Int. Wound J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/S0741-5214(98)70064-3","article-title":"Fibroblasts cultured from venous ulcers display cellular characteristics of senescence","volume":"28","author":"Mendez","year":"1998","journal-title":"J. Vasc. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1007\/s11033-022-08107-4","article-title":"Role of fibroblast plasticity and heterogeneity in modulating angiogenesis and healing in the diabetic foot ulcer","volume":"50","author":"Rai","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Blyakhman, F.A., Melnikov, G.Y., Makarova, E.B., Fadeyev, F.A., Sedneva-Lugovets, D.V., Shabadrov, P.A., Volchkov, S.O., Mekhdieva, K.R., Safronov, A.P., and Fern\u00e1ndez Armas, S. (2020). Effects of Constant Magnetic Field to the Proliferation Rate of Human Fibroblasts Grown onto Different Substrates: Tissue Culture Polystyrene, Polyacrylamide Hydrogel and Ferrogels \u03b3-Fe2O3 Magnetic Nanoparticles. Nanomaterials, 10.","DOI":"10.3390\/nano10091697"},{"key":"ref_28","unstructured":"Costantini, E., Sinjari, B., D\u2019Angelo, C., Murmura, G., Reale, M., and Caputi, S. (2021). Human Gingival Fibroblasts Exposed to Extremely Low-Frequency Electromagnetic Fields: In Vitro Model of Wound-Healing Improvement. Int. J. Mol. Sci., 22."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3109\/15368378.2015.1076452","article-title":"Investigation on the effect of static magnetic field up to 30\u2009mT on viability percent, proliferation rate and IC50 of HeLa and fibroblast cells","volume":"34","author":"Zafari","year":"2015","journal-title":"Electromagn. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3109\/00365517209080244","article-title":"Biosynthesis and metabolism of prostaglandin E 2 in human skin","volume":"29","author":"Jonsson","year":"1972","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0005-2760(70)90246-8","article-title":"A sensitive method for the determination of prostaglandins by gas chromatography with electron-capture detection","volume":"202","author":"Jouvenaz","year":"1970","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"613170","DOI":"10.3389\/fimmu.2020.613170","article-title":"Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease","volume":"11","author":"Pyrillou","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8836","DOI":"10.7150\/thno.63396","article-title":"Role of prostaglandin E2 in tissue repair and regeneration","volume":"11","author":"Cheng","year":"2021","journal-title":"Theranostics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/978-1-60761-756-3_18","article-title":"Measurement of oxidized\/reduced glutathione ratio","volume":"648","author":"Owen","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1038\/jid.2008.114","article-title":"Fibroblast dysfunction is a key factor in the non-healing of chronic venous leg ulcers","volume":"128","author":"Wall","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"580117","DOI":"10.3389\/fimmu.2020.580117","article-title":"Non-inflammatory Physiology of \u201cInflammatory\u201d Mediators\u2014Unalamation, a New Paradigm","volume":"11","author":"Maddipati","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"153712","DOI":"10.1016\/j.phymed.2021.153712","article-title":"Cascade of immune mechanism and consequences of inflammatory disorders","volume":"91","author":"Megha","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1186\/s13287-020-01755-y","article-title":"Proinflammatory cytokines regulate epidermal stem cells in wound epithelialization","volume":"11","author":"Xiao","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1089\/wound.2017.0761","article-title":"Immune Regulation of Skin Wound Healing: Mechanisms and Novel Therapeutic Targets","volume":"7","author":"Larouche","year":"2018","journal-title":"Adv. Wound Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"179","DOI":"10.21037\/atm-22-75","article-title":"IL-1B can serve as a healing process and is a critical regulator of diabetic foot ulcer","volume":"10","author":"Gan","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1042\/CS20200240","article-title":"Attack of the NETs! NETosis primes IL-1\u03b2-mediated inflammation in diabetic foot ulcers","volume":"134","author":"Lee","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1172\/JCI112283","article-title":"Modulation of keratinocyte proliferation in vitro by endogenous prostaglandin synthesis","volume":"77","author":"Pentland","year":"1986","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5811","DOI":"10.4049\/jimmunol.168.11.5811","article-title":"Lipopolysaccharide-dependent prostaglandin E(2) production is regulated by the glutathione-dependent prostaglandin E(2) synthase gene induced by the Toll-like receptor 4\/MyD88\/NF-IL6 pathway","volume":"168","author":"Uematsu","year":"2002","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.4049\/jimmunol.1102762","article-title":"Prostaglandin E\u2082 induces oncostatin M expression in human chronic wound macrophages through Axl receptor tyrosine kinase pathway","volume":"189","author":"Ganesh","year":"2012","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1046\/j.1524-475X.2002.10803.x","article-title":"Role of glutathione redox dysfunction in diabetic wounds","volume":"10","author":"Mudge","year":"2002","journal-title":"Wound Repair. Regen."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29371","DOI":"10.1038\/srep29371","article-title":"Evaluation of physiological risk factors, oxidant-antioxidant imbalance, proteolytic and genetic variations of matrix metalloproteinase-9 in patients with pressure ulcer","volume":"6","author":"Latifa","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/bab.1495","article-title":"Effect of extremely low-frequency electromagnetic fields on antioxidant activity in the human keratinocyte cell line NCTC 2544","volume":"64","author":"Calcabrini","year":"2017","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Martinelli, I., Cinato, M., Keita, S., Marsal, D., Antoszewski, V., Tao, J., and Kunduzova, O. (2022). Cardiac Cell Exposure to Electromagnetic Fields: Focus on Oxdative Stress and Apoptosis. Biomedicines, 10.","DOI":"10.3390\/biomedicines10050929"}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/11\/4\/357\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:24:00Z","timestamp":1760106240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/11\/4\/357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,5]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["bioengineering11040357"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering11040357","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,5]]}}}