Nonlinear Frequency Mixing Ultrasound Imaging of Nanoscale Contrast Agents

Keren T. Karlinsky, Mike Bismuth, Ramona Aronovich, Tali Ilovitsh

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Nanoscale ultrasound contrast agents show promise as alternatives for diagnostics and therapies due to their enhanced stability and ability to traverse blood vessels. Nonetheless, their reduced size limits echogenicity. This study introduces a nanobubble frequency mixing ultrasound imaging method. This method enhances nanobubble imaging by capitalizing on their nonlinear acoustic response to dual-frequency excitation. Methods: A single broadband transducer (L12-3v) controlled by a programmable ultrasound system was used to transmit a dual-frequency single-cycle wavefront. The frequency mixing effect enabled simultaneous transducer capture of nanobubble-generated sum and difference frequencies in real time without the need for additional hardware or post-processing, by substituting the single-frequency wavefront in a standard contrast harmonic pulse inversion imaging protocol, with the dual-frequency wavefront. Results: Optimization experiments were conducted in tissue mimicking phantoms. Among the dual-frequency combinations that were tested, the highest contrast was obtained using 4&8 MHz. The nanobubble contrast improved with increased mechanical index, and achieved a maximal contrast improvement of 8.4±0.5 dB compared to 4 MHz pulse inversion imaging. In a breast cancer tumor mouse model, tumor imaging after a systemic nanobubble injection indicated that the resulted in a higher contrast for the frequency mixing method over standard single-frequency imaging. The contrast was improved by 3.4 ± 1.7, 4.8 ± 1.8, and 6.3 ± 1.6 dB for mechanical indices of 0.04, 0.08, and 0.1, respectively. Conclusion: Nonlinear frequency mixing significantly improved the nanobubble contrast, which facilitated their imaging in-vivo. Significance: This study offers a new avenue to enhance ultrasound imaging utilizing nanobubbles, potentially leading to advancements in other diagnostic applications.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalIEEE Transactions on Biomedical Engineering
DOIs
StateAccepted/In press - 2023

Keywords

  • Cancer diagnosis
  • Contrast harmonic imaging
  • Frequency mixing
  • Harmonic analysis
  • Imaging
  • Nanobubbles
  • Phantoms
  • Standards
  • Transducers
  • Tumors
  • Ultrasonic imaging
  • Ultrasound

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