{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:46:06Z","timestamp":1793144766019,"version":"4.5.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Low-frequency, low-intensity ultrasound has been previously shown to promote healing of chronic wounds in humans, but mechanisms behind these effects are poorly understood. The purpose of this study was to evaluate gene expression differences in debrided human venous ulcer tissue from patients treated with low-frequency (20 kHz), low-intensity (100 mW\/cm<jats:sup>2<\/jats:sup>) ultrasound compared to a sham treatment in an effort to better understand the potential biological mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Debrided venous ulcer tissue was collected from 32 subjects one week after sham treatment or low-frequency, low-intensity ultrasound treatment. Of these samples, 7 samples (3 ultrasound treated and 4 sham treated) yielded sufficient quality total RNA for analysis by ultra-high multiplexed PCR (Ampliseq) and expression of more than 24,000 genes was analyzed. 477 genes were found to be significantly differentially expressed between the ultrasound and sham groups using cut-off values of <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.05 and fold change of 2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Discussion<\/jats:title><jats:p>The top differentially expressed genes included those involved in regulation of cell metabolism, proliferation, and immune cell signaling. Gene set enrichment analysis identified 20 significantly enriched gene sets from upregulated genes and 4 significantly enriched gene sets from downregulated genes. Most of the enriched gene sets from upregulated genes were related to cell-cell signaling pathways. The most significantly enriched gene set from downregulated genes was the inflammatory response gene set. These findings show that therapeutic ultrasound influences cellular behavior in chronic wounds as early as 1 week after application. Considering the well-known role of chronic inflammation in impairing wound healing in chronic wounds, these results suggest that a downregulation of inflammatory genes is a possible biological mechanism of ultrasound-mediated venous chronic wound healing. Such increased understanding may ultimately lead to the enhancement of ultrasound devices to accelerate chronic wound healing and increase patient quality of life.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2023.1144182","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T07:03:56Z","timestamp":1680159836000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Gene expression changes in therapeutic ultrasound-treated venous leg ulcers"],"prefix":"10.3389","volume":"10","author":[{"given":"Olivia","family":"Boerman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahidur","family":"Abedin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose Ann","family":"DiMaria-Ghalili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Weingarten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Neidrauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Lewin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara L.","family":"Spiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.jaad.2007.08.048","article-title":"Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings","volume":"58","author":"Fonder","year":"2008","journal-title":"J Am Acad Dermatol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2544","DOI":"10.3390\/ijms19092544","article-title":"Chronic venous disorders: the dangerous, the good, and the diverse","volume":"19","author":"Ligi","year":"2018","journal-title":"Int J Mol Sci"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.3390\/ijms17122085","article-title":"Inflammation in chronic wounds","volume":"17","author":"Zhao","year":"2016","journal-title":"Int J Mol Sci"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s12325-020-01219-y","article-title":"The Most severe stage of chronic venous disease: an update on the Management of Patients with venous leg ulcers","volume":"37","author":"Nicolaides","year":"2020","journal-title":"Adv Ther"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1067\/mjd.2001.111633","article-title":"Chronic venous insufficiency and venous leg ulceration","volume":"44","author":"Valencia","year":"2001","journal-title":"J Am Acad Dermatol"},{"key":"ref6","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 practices","volume":"25","author":"Franks","year":"2016","journal-title":"J Wound Care"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1046\/j.1524-475X.1997.50107.x","article-title":"Low-frequency ultrasound treatment of chronic venous ulcers","volume":"5","author":"Weichenthal","year":"1997","journal-title":"Wound Repair Regen"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1121\/1.4812875","article-title":"Low-frequency (<100 kHz), low-intensity (<100 mW\/cm(2)) ultrasound to treat venous ulcers: a human study and in vitro experiments","volume":"134","author":"Samuels","year":"2013","journal-title":"J Acoust Soc Am"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e2100785","DOI":"10.1002\/adhm.202100785","article-title":"Flexible ultrasonic patch for accelerating chronic wound healing","volume":"10","author":"Lyu","year":"2021","journal-title":"Adv Healthc Mater"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1109\/TUFFC.2018.2836311","article-title":"Development of low frequency (20-100 kHz) clinically viable ultrasound applicator for chronic wound treatment. 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