High-Intensity Focused Ultrasound: A Review of Mechanisms and Clinical Applications

Abstract

High Intensity Focused Ultrasound (HIFU) is an emerging and increasingly useful modality in the treatment of cancer and other diseases. Although traditional use of ultrasound at lower frequencies has primarily been for diagnostic imaging purposes, the development of HIFU has allowed this particular modality to expand into therapeutic use. This non-invasive and acoustic method involves the use of a piezoelectric transducer to deliver high-energy pulses in a spatially coordinated manner, while minimizing damage to tissue outside the target area. This review describes the history of the development of diagnostic and therapeutic ultrasound and explores the biomedical applications utilizing HIFU technology including thermally ablative treatment, therapeutic delivery mechanisms, and neuromodulatory phenomena. The application of HIFU across various tumor types in multiple organ systems is explored in depth, with particular attention to successful models of HIFU in the treatment of various medical conditions. Basic mechanisms, preclinical models, previous clinical use, and ongoing clinical trials are comparatively discussed. Recent advances in HIFU across multiple medical fields reveal the growing importance of this biomedical technology for the care of patients and for the development of possible pathways for the future use of HIFU as a commonplace treatment modality.

Keywords: Ablation; Drug delivery; Focused ultrasound; Neuromodulation; Sonoporation.

Figure 1:

Illustrative depictions of HIFU applications, © 2021 Johns Hopkins University All rights reserved. Ian Suk.

Figure 2.

Focused ultrasound-gated propofol release is potent enough to silence seizure activity. (A) Schematic of rat positioning for this demonstration of in vivo efficacy. Rats were placed supine on the bed of a focused ultrasound transducer and underwent seizure induction, coupled to the transducer via degassed water (light blue), a Kapton membrane filled with degassed water (orange-brown), and ultrasound gel (not pictured). Expected location of the two sonication foci are overlaid onto ex vivo MRI images with the red ellipse indicating the fwhm of the sonication focus, located ~5 mm caudal to bregma. (B) Schematic of experiment timing for seizure induction, particle administration, and FUS application. (C) Sample traces of EEG voltage from one rat receiving propofol-loaded particles before and after seizure-induction and focused ultrasound application at the indicated pressures. (D) Total EEG power normalized by baseline averaged across rats receiving particles loaded with either propofol (blue) or no drug (blank, red) across experiment time (N = 7 propofol, 5 blank). Gray bars indicate time of FUS application. (E) Mean ± SD of normalized total (left) and theta band (right) EEG power in the indicated time period across rats receiving propofol-loaded particles or blank particles (N = 7 propofol, 5 blank). (F) Mean ± SD of the HPLC-quantified serum propofol concentration of samples from N = 4 rats taken immediately after propofol-loaded particle administration, immediately after sonication, and 10 min post sonication, compared to a blank serum sample. There was no appreciable serum propofol peak for the post sonication samples. Figure reproduced with permission from Nano Lett. 2017, 17, 2, 652–659, Publication Date: January 17, 2017, https://doi.org/10.1021/acs.nanolett.6b03517, Copyright © 2017 American Chemical Society.

Figure 3.

Preoperative and postoperative enhanced MRI. (A) Enhanced MRI of adenomyosis before treatment which shows the thickening of the myometrium in fundus of uterus and rich blood supply. (B) Enhanced MRI from a patient with adenomyosis 1 day after HIFU treatment, which shows non-perfused area in the lesion. Reprinted from Ultrasonics Sonochemistry, Vol. 27, Shui L, Mao S, Wu Q, et al. High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results, Pages 677-681 (2015) with permission from Elsevier.

Figure 4.

Preoperative ultrasound shear wave elastography and prostate histoscanning and dynamics of prostate-specific antigen (PSA) before and after hemiablation. Representative MRI control findings of the pathological focus (arrows) before HIFU hemiablation (a) and its disappearance 3 months after the procedure (b). (C) demonstrates a box plot showing changes in PSA level before and after HIFU hemiablation (n=35), The line indicated the mean, the box indicated the interquartile range, and whiskers indicate the maximum and minimum values. The final, published version of this article is available at https://www.karger.com/Article/Fulltext/499739 .

Figure 5.

Fluorescence images from the delivery of Cy5-DNA-Au NPs across the BBB using focused ultrasound. There is a size-dependency associated with the delivery of Cy5-DNA-Au NPs across the BBB using focused ultrasound, with the smallest NPs tested in this study (A) delivered across the BBB six times more efficiently than the larger/largest NPs tested (B/C). A spot-like distribution of fluorescence was observed in the left thalamus, while no fluorescence signal is detected in the right thalamus. Reprinted with permission from John Wiley and Sons .