Gene Expression Changes in Therapeutic Ultrasound-Treated Human Chronic Wound Tissue

Abstract

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/cm2) ultrasound compared to a sham treatment in an effort to better understand the potential biological mechanisms. 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 different between the ultrasound and sham groups using cut-off values of p<0.05 and fold change of 2. 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 one 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.

Analyzing Gene Expression After Administration of Low‐Intensity Therapeutic Ultrasound in Human Islet Cells

“…Additionally, we hypothesized that ultrasound application would stimulate transcription of other genes, such as amylin and glucagon—indicating that ultrasound could indeed regulate gene transcription and protein production. While therapeutic ultrasound has shown the ability to influence gene expression in certain contexts, 39 here we report that no significant changes in insulin or glucagon mRNA levels were detected. The lack of observable changes in gene regulation following low‐intensity ultrasound treatment can be attributed to several factors.…”