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Updated: Jul 20, 2026

Multi-timescale Microscopy Methods for the Characterization of Fluorescently-labeled Microbubbles for Ultrasound-Triggered Drug Release
Published on: June 12, 2021
Difference frequency and its harmonic emitted by microbubbles under dual frequency excitation
Shigao Chen1, Randall Kinnick, James F Greenleaf
1Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 200 First ST. SW., Rochester, MN 55905, USA. chen.shigao@mayo.edu <chen.shigao@mayo.edu>
Harmonic acoustic emission (HAE) is generated by microbubbles using vibro-acoustography. This elasticity imaging technique shows HAE is highly sensitive to microbubble size, enabling selective detection.
Area of Science:
- Medical Imaging
- Acoustic Physics
Background:
- Vibro-acoustography uses dual ultrasound frequencies to detect acoustic emission (AE) at the difference frequency.
- This method is sensitive to bubble nonlinearity, but harmonic acoustic emission (HAE) has not been fully explored.
Purpose of the Study:
- To investigate harmonic acoustic emission (HAE) at twice the difference frequency from bubbles.
- To determine the conditions under which HAE is generated and its potential for microbubble detection.
Main Methods:
- A perturbation method based on the dynamic bubble equation was used to derive AE and HAE.
- Simulations and experiments were conducted using dual frequency ultrasound waves to excite bubbles.
Main Results:
- HAE is generated only by microbubbles resonant with incident ultrasound frequencies.
- AE is more sensitive to resonance at the difference frequency, relevant for larger bubbles.
- Experiments confirmed HAE from microbubbles (Optison) but not larger air bubbles.
Conclusions:
- Harmonic acoustic emission is a distinct phenomenon present in microbubbles.
- HAE is highly sensitive to microbubble size, offering potential for selective microbubble detection in elasticity imaging.
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