Histotripsy methods in mechanical disintegration of tissue: Towards clinical applications

Abstract

Purpose In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently, there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Material and Methods Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapor cavity causes tissue disintegration. Results Recent pre-clinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumors, kidney stone fragmentation, enhancing antitumor immune response, and tissue decellularization for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Conclusions Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilize different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of noninvasive surgery.

Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy

“…Tissue liquefaction through BH produced complete tissue disintegration into subcellular debris, with occasional intact nuclei observed in the lysate, but no other structurally intact cells or organelles. As is consistent with previous studies (16), this treatment appeared to be tissue selective: Some larger connective tissue structures in the treated region (eg, blood vessels) remained intact, while the tumor cells that surrounded the vessels were liquefied. Permeabilization treatment resulted in largely intact tumor tissue, with some damaged adjacent tumor cells and scattered areas of petechial hemorrhage.…”

“…Pulsed focused ultrasound allows induction of such mechanical tissue disruption locally and noninvasively, while minimizing off-target effects (16). With pulsed focused ultrasound, short bursts of high-amplitude ultrasound waves are used from an extracorporeal source.…”

“…The maximum plasma abundance for biomarkers, with increases ranging from threefold to 32-fold for miR-34c, miR-100, miR-129-5p, and miR-196a within [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] addition to Caenorhabditis elegans miR-NA cel-miR-39, were obtained (Applied Biosystems). Oligoribonucleotides that corresponded to the mature sequence of each miRNA were synthesized (Integrated DNA Technologies, Coralville, Iowa) and serially diluted as standard curves (23).…”

The influence of gas diffusion on bubble persistence in shock-scattering histotripsy

“…1 Unlike thermal ultrasound therapies, shock-scattering histotripsy relies on the formation of a bubble cloud to ablate tissue. 2 Bubbles thought to be nucleated from nanoscale sources expand tens of micrometers in diameter under the tensile phase of the histotripsy pulse.…”

Ultrasound: The versatile energy source

“…There are a number of differences between imaging and therapy ultrasound exposures which explain these differences in biological response. Imaging generally uses very short (a few ms long) pulses, powers of 5300 mW, and pressure amplitudes 57 MPa [1], whereas therapy applications most often employ longer pulse trains (4ms long), and higher powers (4500 mW), or ms pulses and extremely high pressure amplitudes (412 MPa) [2].…”