# Macrophage Phenotype Transition as the Biological Mechanism of Chronic Wound Healing Treated with Non-Thermal, Non-Cavitational Therapeutic Ultrasound

> **NIH NIH F31** · DREXEL UNIVERSITY · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ ABSTRACT
Chronic wounds affect approximately 6.5 million patients in the United States. Current standard
protocols for wound management do not guarantee healing and focus on maintaining a wound
environment that is conducive to passive self-healing. Hence, there is a need to develop alternative
treatments that promote active healing and shorten healing time leading to reduced costs. We have
previously reported that treatment with low-frequency (20-100 kHz), low-intensity (50-150 mW/cm2)
ultrasound (LFLI US) significantly (p<0.03) reduces venous ulcer size in vivo as compared to wounds
treated with a sham device. This proposal aims at determining the biological mechanisms by which
LFLI US promotes chronic wound healing in vitro. There is evidence that the cause of impaired healing
is the dysregulation of macrophage phenotype, especially the defective transition from pro-
inflammatory (M1) to pro-healing (M2) macrophages. Our characterization of tissue debrided from
chronic wounds has shown that healing chronic wounds contain higher proportions of M1-like than M2-
like macrophages. Additionally, the signaling protein Rac2, downstream of integrin and focal adhesion
kinase activation, is a key regulator of mechanotransduction in macrophages and facilitates the
transition of macrophages from the M1 to M2 phenotype. The proposed study will systematically
examine the effects of LFLI ultrasound on macrophage phenotype, using macrophages cultured in
three-dimensional (3D) scaffolds. We hypothesize that LFLI US directly and indirectly stimulates the
transition of pro-inflammatory M1 macrophages to pro-healing M2 macrophages via Rac2. This project
will enhance our understanding of chronic wound healing and the potential of therapeutic ultrasound to
accelerate healing. Aim 1 will elucidate the direct effects of LFLI US on macrophage function and
phenotype by treating inflammatory macrophages directly with LFLI US and characterizing functional
changes (proliferation, migration, and phagocytosis), protein/cytokine secretion, and gene expression.
Concurrently, we will validate Rac2 as the potential mechanotransduction pathway which promotes M1
to M2 macrophages transition by analyzing integrins, focal adhesion kinases, and Rac2 via confocal
microscopy and RNA characterization. [Aim 2 will validate the in vitro findings from Aim 1 using our
previously developed diagnostic M1/M2 score on debrided tissue from chronic wound patients treated
with LFLI US.] Aim 3 will elucidate the indirect effects of LFLI US on macrophage function and
phenotype via a 3D macrophage fibroblast co-culture. The results of this study will inform the optimal
design of LFLI ultrasound therapy protocols, lead to a personalized, active treatment for chronic
wounds, accelerate chronic wound healing, and contribute to reduced annual wound care costs.

## Key facts

- **NIH application ID:** 10137782
- **Project number:** 5F31AR074847-02
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Olivia Ngo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137782

## Citation

> US National Institutes of Health, RePORTER application 10137782, Macrophage Phenotype Transition as the Biological Mechanism of Chronic Wound Healing Treated with Non-Thermal, Non-Cavitational Therapeutic Ultrasound (5F31AR074847-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10137782. Licensed CC0.

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