Does noncontact low-frequency ultrasound therapy contribute to wound healing at the molecular level?

Noncontact low-frequency ultrasound (NLFU) is used to treat various types of chronic wounds including venous, diabetic, and pressure ulcers. 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%, p < 0.05). 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. Pseudomonas, Corynebacterium, and unclassified Enterobacteriaceae were dominant in the highest number of samples. Anaerococcus, Peptoniphilus, and Finegoldia, had the highest median proportion in the samples overall. Peptoniphilus abundance decreased more in the NLFU treatment group relative to SOC; similar trends were observed for Anaerococcus and Finegoldia. Progression of mediators like TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 as well as PF4, TGF-beta, 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 (p < 0.05). IL-8 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 ≥ 10E5 was found compared to < 10E5 , levels of IL-1beta, IL-8, and TNF-alpha 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-inflammatory cytokines as well as by reducing the overall bacterial burden.