Histotripsy: A Method for Mechanical Tissue Ablation with Ultrasound

Abstract

Histotripsy is a relatively new therapeutic ultrasound technology to mechanically liquefy tissue into subcellular debris using high-amplitude focused ultrasound pulses. In contrast to conventional high-intensity focused ultrasound thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using ultrasound imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immunostimulation. The technology is being evaluated in small and large animal models for treating cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; and neurological applications. Histotripsy has been recently approved by the US Food and Drug Administration to treat liver tumors, with clinical trials undertaken for benign prostatic hyperplasia and renal tumors. This review outlines the physical principles of various types of histotripsy; presents major parameters of the technology and corresponding hardware and software, imaging methods, and bioeffects; and discusses the most promising preclinical and clinical applications.

Keywords: HIFU; boiling; cavitation; focused ultrasound surgery; high-intensity focused ultrasound; histotripsy; mechanical bioeffects; nonlinear waves.

Figure 1

Schematic illustration of histotripsy treatment. (a) A pulsed beam is focused through the skin and translated either mechanically or electronically over the target volume to liquefy tissue. (b) Sonication is visualized in real time as an echogenic region due to the presence of bubbles. (c) The posttreatment region is hypoechogenic due to the loss of scatterers. (d) The shape and dimensions of the liquefied lesion agree well with brightness-mode visualization and (e) histology.

Figure 2

Representative histotripsy transducers. (a) A 6.8-MHz, 10-mm shock scattering cavitational histotripsy (CH) transducer with a 4-mm square hole in the center for a high-frequency imaging probe (79). (b) A 750-kHz truncated circular aperture array transducer (165 × 234-mm aperture and 142-mm focal distance) for intrinsic threshold CH in liver and kidney (77). (c) A 1.5-MHz, 256-element array (144-mm aperture and 120-mm focal distance) for boiling histotripsy and hybrid histotripsy (18). (d) A 2-MHz transrectal transducer for boiling histotripsy of prostate tissue.

Figure 3

Imaging guidance. (a,b) Ultrasound brightness-mode images of in vivo porcine liver during and after shock scattering cavitational histotripsy (CH) treatment (103). A hyperechoic-zone cavitation bubble cloud was seen during treatment (a), and a hypoechoic region of the histotripsy ablation zone was seen after treatment (b). (c) Ultrasound color Doppler images in myocardium tissue treated by boiling histotripsy (BH) taken immediately after the first and fifteenth pulses (78). (d) Acoustic cavitation map generated by a transmit-and-receive-capable transcranial histotripsy array overlaid on a T2-weighted magnetic resonance (MR) image of a human cadaveric brain. (e) Axial postcontrast portal venous phase MR image demonstrating an ablation zone within the right hepatic lobe (red arrow) of in vivo porcine liver after shock scattering CH treatment (68).

Figure 4

Histotripsy cancer treatment and immunostimulation. (a) Immunohistochemistry staining for CD8⁺ T cells (brown color, arrowheads) of kidney tumor in spontaneous bilateral Eker rat model 48 h following boiling histotripsy (BH) ablation of 50% of a tumor (K = normal kidney; T = tumor). Enhanced CD8⁺ T cell infiltration was observed not only in the residual treated tumor and adjacent kidney tissue but also in the contralateral nontreated tumor and not in untreated controls. (b) A rodent McA-RH7777 liver tumor model with spontaneous intrahepatic metastasis and intact immune system in an untreated control case (top row) and a histotripsy-treated case (bottom row) (42). Partial treatment (50–75% of the tumor volume) using microtripsy led to complete tumor regression and reduced risk of metastasis development. (c) Microtripsy cavitational histotripsy (CH) ablation of B16F10 melanoma flank tumors caused abscopal reduction in the number and size of distant, nonablated pulmonary metastases (black lesions) (47). Panel a adapted from Reference .

Figure 5

Histotripsy for preclinical blood clot and brain applications. (a,b) Color Doppler ultrasound images of an in vivo porcine femoral vein with deep vein thrombosis before and after microtripsy (34). (a) The blood clot occluded the vein before treatment. (b) The clot was removed and the vein recanalized by microtripsy after treatment. (c) Hematoxylin and eosin stained slide and (d) T1-weighted magnetic resonance (MR) image of an in vivo pig brain treated by MR-guided histotripsy through an excised human skull (29).

Figure 6

Results from clinical trials. (a) An image of the ultrasound image–guided clinical prototype histotripsy system (Edison^™ platform; HistoSonics, Inc.). (b–e) Magnetic resonance (MR) images from the THERESA histotripsy liver tumor clinical trial (51). (b,c) MR images of the targeted tumor 5 mm adjacent to the hepatic vessel branch (b) before and (c) after shock scattering cavitational histotripsy, showing effective ablation of the liver tumor (tumor indicated by the yellow arrow in panel b) with a margin (ablation indicated by the yellow arrow in panel c) and intact hepatic vessel (indicated by the red line in panel c). (d,e) MR images of nontargeted tumors (red ovals) (d) before and (e) 8 weeks after histotripsy treatment, showing the abscopal response as a size reduction.