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The objective for this substudy of the IN BALANCE RCT VLU trial was to characterize and compare the NLFU treatment group and patients receiving standard of care (SOC) with respect to the effect of the assigned study treatment on content\/quantity of inflammatory cytokines and fibrinogen as well as bacteria. Higher mean wound area reduction was observed in the NLFU treatment group (67.0%) compared to the SOC group (41.6%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Hypertension, diabetes type II, coronary artery disease, and anemia were identified as the most common comorbidities of the Chronic venous leg ulcer (CVLU) patients included in the study. <jats:italic>Pseudomonas<\/jats:italic>, <jats:italic>Corynebacterium<\/jats:italic>, and unclassified <jats:italic>Enterobacteriaceae<\/jats:italic> were dominant in the highest number of samples. <jats:italic>Anaerococcus<\/jats:italic>, <jats:italic>Peptoniphilus<\/jats:italic>, and <jats:italic>Finegoldia<\/jats:italic>, had the highest median proportion in the samples overall. <jats:italic>Peptoniphilus<\/jats:italic> abundance decreased more in the NLFU treatment group relative to SOC; similar trends were observed for <jats:italic>Anaerococcus<\/jats:italic> and <jats:italic>Finegoldia<\/jats:italic>. Progression of mediators like TNF\u2010alpha, IL\u20101beta, IL\u20106, IL\u20108, and IL\u201010 as well as PF4, TGF\u2010beta, and fibrinogen was monitored and trends for several of the mediators were identified. Fibrinogen amounts were significantly reduced over time in the NLFU treatment group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). IL\u20108 levels declined in wound fluid from NLFU responders as well as SOC responders. Bacterial load (total bacterial abundance) determined local parameters of ulcer inflammation. If a bioburden of\u2009\u2265\u200910E<jats:sup>5<\/jats:sup> was found compared to\u2009&lt;\u200910E<jats:sup>5<\/jats:sup>, levels of IL\u20101beta, IL\u20108, and TNF\u2010alpha were significantly higher. In conclusion, NLFU treatment is an effective adjuvant tool for CVLU therapy. This study demonstrates that it improves wound healing by equally inhibiting abundant levels of pro\u2010inflammatory cytokines as well as by reducing the overall bacterial burden.<\/jats:p>","DOI":"10.1111\/wrr.12595","type":"journal-article","created":{"date-parts":[[2017,11,3]],"date-time":"2017-11-03T05:16:59Z","timestamp":1509686219000},"page":"871-882","source":"Crossref","is-referenced-by-count":20,"title":["Does noncontact low\u2010frequency ultrasound therapy contribute to wound healing at the molecular level?"],"prefix":"10.1111","volume":"25","author":[{"given":"Cornelia","family":"Wiegand","sequence":"first","affiliation":[{"name":"Department of Dermatology University Hospital Jena Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Bittenger","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert D.","family":"Galiano","sequence":"additional","affiliation":[{"name":"Division of Plastic Surgery, Department of Surgery Northwestern University Feinberg School of Medicine Chicago Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vickie R.","family":"Driver","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Brown University Providence Rhode Island"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary W.","family":"Gibbons","sequence":"additional","affiliation":[{"name":"Center for Wound Healing South Shore Hospital Weymouth Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,12,8]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.311.7001.370"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2005-921948"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-4632.2004.02276.x"},{"key":"e_1_2_6_5_1","first-page":"CD002303","article-title":"Compression for preventing recurrence of venous ulcers","volume":"4","author":"Nelson EA","year":"2000","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198005223022105"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/413604"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(00)00379-X"},{"key":"e_1_2_6_9_1","first-page":"16","article-title":"A prospective, randomized, controlled trial comparing the effects of noncontact, low\u2010frequency ultrasound to standard care in healing venous leg ulcers","volume":"61","author":"Gibbons GW","year":"2015","journal-title":"Ostomy Wound Manage"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/iwj.12389"},{"key":"e_1_2_6_11_1","first-page":"14","article-title":"High\u2010frequency and noncontact low\u2010frequency ultrasound therapy for venous leg ulcer treatment: a randomized, controlled study","volume":"59","author":"Olyaie M","year":"2013","journal-title":"Ostomy Wound Manage"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-481X.2012.00944.x"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/iwj.12005"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-481X.2011.00921.x"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.7547\/0970095"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASW.0000266660.88900.38"},{"key":"e_1_2_6_17_1","first-page":"24","article-title":"Ultrasound therapy for recalcitrant diabetic foot ulcers: results of a randomized, double\u2010blind, controlled, multicenter study","volume":"51","author":"Ennis WJ","year":"2005","journal-title":"Ostomy Wound Manage"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAI.0b013e31821fc8cd"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.f.303"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq461"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01996-06"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp636"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009490"},{"key":"e_1_2_6_24_1","unstructured":"R Core Team(2016). 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