title: A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.
abstract: Non-contact low-frequency ultrasound (NCLF-US) devices have been increasingly used for the treatment of chronic non-healing wounds. The appropriate dose for NCLF-US is still in debate. The aims of this pilot study were to evaluate the relationship between dose and duration of treatment for subjects with non-healing diabetic foot ulcers (DFUs) and to explore the correlation between wound healing and change of cytokine/proteinase/growth factor profile. This was a prospective randomised clinical study designed to evaluate subjects with non-healing DFUs for 5 weeks receiving standard of care and/or NCLF-US treatment. Subjects were randomly assigned to one of the three groups: application of NCLF-US thrice per week (Group 1), NCLF-US once per week (Group 2) and the control (Group 3) that received no NCLF-US. All subjects received standard wound care plus offloading for a total of 4 weeks. Percent area reduction (PAR) of each wound compared with baseline was evaluated weekly. Profiles of cytokines/proteinase/growth factors in wound fluid and biopsied tissue were quantified to explore the correlation between wound healing and cytokines/growth factor expression. Twelve DFU patients, 2 (16·7%) type 1 and 10 (83·3%) type 2 diabetics, with an average age of 58 ± 10 years and a total of 12 foot ulcers were enrolled. Average ulcer duration was 36·44 ± 24·78 weeks and the average ABI was 0·91 ± 0·06. Group 1 showed significant wound area reduction at weeks 3, 4 and 5 compared with baseline, with the greatest PAR, 86% (P < 0·05); Groups 2 and 3 showed 25% PAR and 39% PAR, respectively, but there were no statistically significant differences between Groups 2 and 3 over time. Biochemical and histological analyses indicated a trend towards reduction of pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α and GM-CSF), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF-US consistent with wound reduction, when compared with control group subjects. This proof-of-concept pilot study demonstrates that NCLF-US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro-inflammatory cytokines in chronic wound and improving tissue regeneration. Therapeutic application of NFLU, thrice (3) per week, renders the best wound area reduction.
authors.affiliation: Limb Preservation and Wound Care Research, Department of Surgery, Center for Restorative and Regenerative Medicine, VA New England Health Care Division, Providence, RI, USA; Department of Surgery, Boston University Medical Center, School of Medicine, Boston, MA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.forename: Hatice
authors.initials: H
authors.lastname: Hasturk
authors.forename: Alpdogan
authors.initials: A
authors.lastname: Kantarci
authors.forename: Guosheng
authors.initials: G
authors.lastname: Gu
authors.forename: Silvia
authors.initials: S
authors.lastname: Garcia-Lavin
authors.forename: Matteo
authors.initials: M
authors.lastname: Fabbi
authors.forename: Nanjin
authors.initials: N
authors.lastname: Park
authors.forename: Hisae
authors.initials: H
authors.lastname: Hayashi
authors.forename: Khaled
authors.initials: K
authors.lastname: Attala
authors.forename: Michael A
authors.initials: MA
authors.lastname: French
authors.forename: Vickie R
authors.initials: VR
authors.lastname: Driver
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017719:Diabetic Foot / Q000378:metabolism / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D016896:Treatment Outcome; D014464:Ultrasonic Therapy / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9