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Non-invasive surgical approaches, including boiling histotripsy (BH), are currently being developed for the treatment of brain disorders aiming to avoid craniotomy and exposure of intervening tissues, and, thus, minimize associated complications. This work aimed to demonstrate the feasibility of BH for mechanical fractionation of human brain tissues ex vivo under B-mode guidance, with preliminary measurements of tissue stiffness via shear wave elastography. Young's moduli of 25 human autopsy brain samples obtained from de-identified patients of 51–91 y old (median 77 y old) were measured via shear wave elastography prior to BH sonication. Seventeen volumetric BH lesions (1–4 layers of 5 × 5 points with a 1- mm step) were produced near brain surface (n = 10), in white matter (n = 3), in thalamus (n = 2), and globus pallidus (n = 2) using 12 element 1.5 MHz sector transducer under B-mode guidance with 10 ms or 2 ms pulses delivered 10 or 15 times per sonication point with 1% duty cycle. After treatment, the lesions were evaluated grossly through bisection, histologically with hematoxylin and eosin staining, and ultrastructurally via scanning and transmission electron microscopy. Young's moduli of autopsy brain samples were lower in older patients (from 32.9 ± 6.6 kPa in 51 y olds to 10 ± 2 kPa in 91 y olds) and at higher temperature (6%–50% lower at 37°С vs 23°С), and were within the range observed clinically. All tested BH treatments performed near the brain surface (i.e., mostly in gray matter) resulted in formation of well-demarcated rectangular lesions with homogenized content and sharp boundaries, with majority of residual fragments below 100 microns. The use of shorter pulses (2 ms vs 10 ms) accelerated the treatment at least threefold, and the highest liquefaction rate was 568 mm3/min. White matter was more resistant to BH vs gray matter: at least 15 pulses of 2 ms duration were required per each sonication point, and the liquefaction rate was three times lower. The ability of BH to produce lesions in thalamus and globus pallidus was also confirmed. This work presents the first demonstration of BH proof-of-concept in human brain tissues ex vivo under B-mode guidance with clinically relevant treatment rates. [ABSTRACT FROM AUTHOR]

As an alternative to surgical excision and magnetic resonance-guided thermal high-intensity focused ultrasound ablation of uterine leiomyoma, this work was aimed at pilot feasibility demonstration of use of ultrasound-guided boiling histotripsy for non-invasive non-thermal fractionation of human uterine leiomyoma ex vivo. A custom-made sector ultrasound transducer of 1.5-MHz operating frequency and nominal f -number F # = 0.75 was used to produce a volumetric lesion (two layers of 5 × 5 foci with a 1 mm step) in surgically resected human leiomyoma ex vivo. A sequence of 10 ms pulses (P +/ P –/ A s = 157/–25/170 MPa in situ) with 1% duty cycle was delivered N = 30 times per focus under B-mode guidance. The treatment outcome was evaluated via B-mode imaging and histologically with hematoxylin and eosin and Masson's trichrome staining. The treatment was successfully performed in less than 30 min and resulted in formation of a rectangular lesion visualized on B-mode images during the sonication as an echogenic region, which sustained for about 10 min post-treatment. Histology revealed loss of cellular structure, necrotic debris and globules of degenerated collagen in the target volume surrounded by injured smooth muscle cells. The pilot experiment described here indicates that boiling histotripsy is feasible for non-invasive mechanical disintegration of human uterine leiomyoma ex vivo under B-mode guidance, encouraging further investigation and optimization of this potential clinical application of boiling histotripsy. [ABSTRACT FROM AUTHOR]

Tissue susceptibility to histotripsy disintegration has been reported to depend on its elastic properties. This work was aimed at investigation of histotripsy efficiency for liquefaction of human hematomas, depending on their stiffness and degree of retraction over time (0–10 d). As an in vitro hematoma model, anticoagulated human blood samples (200 mL) were recalcified at different temperatures. In one set of samples, the shear modulus was measured by shear wave elastography during blood clotting at 10℃, 22℃ and 37℃, and then daily during further aging. The ultrastructure of the samples was analyzed daily with scanning electron microscopy (SEM). Another set of blood samples (50–200 mL) were recalcified at 37℃ for density and retraction measurements over aging and exposed to histotripsy at varying time points. Boiling histotripsy (2.5 ms pulses) and hybrid histotripsy (0.2 ms pulses) exposures (2 MHz, 1% dc, P +/ P –/ A s = 182/–27/207 MPa in situ) were used to produce either individual cigar-shaped or volumetric (0.8–3 mL) lesions in samples incubated for 3 h, 5 d and 10 d. The obtained lesions were sized, then the lysate aspirated under B-mode guidance was analyzed ultrastructurally and diluted in distilled water for sizing of residual fragments. It was found that clotting time decreased from 113 to 25 min with the increase in blood temperature from 10℃ to 37℃. The shear modulus increased to 0.53 ± 0.17 kPa during clotting and remained constant within 8 d of incubation at 2℃. Sample volumes decreased by 57% because of retraction within 10 d. SEM revealed significant echinocytosis but unchanged ultrastructure of the fibrin meshwork. Liquefaction rate and lesion dimensions produced with the same histotripsy protocols correlated with the increase in the degree of retraction and were lower in retracted samples versus freshly clotted samples. More than 80% of residual fibrin fragments after histotripsy treatment were shorter than 150 µm; the maximum length was 208 µm, allowing for unobstructed aspiration of the lysate with most clinically used needles. The results indicate that hematoma susceptibility to histotripsy liquefaction is not entirely determined by its stiffness, and correlates with the retraction degree. [ABSTRACT FROM AUTHOR]

Boiling histotripsy (BH) is a focused ultrasound technology that uses millisecond-long pulses with shock fronts to induce mechanical tissue ablation. The pulsing scheme and mechanisms of BH differ from those of cavitation cloud histotripsy, which was previously developed for benign prostatic hyperplasia. The goal of the work described here was to evaluate the feasibility of using BH to ablate fresh ex vivo human prostate tissue as a proof of principle for developing BH for prostate applications. Fresh human prostate samples (N = 24) were obtained via rapid autopsy (<24 h after death, institutional review board exempt). Samples were analyzed using shear wave elastography to ensure that mechanical properties of autopsy tissue were clinically representative. Samples were exposed to BH using 10- or 1-ms pulses with 1% duty cycle under real-time B-mode and Doppler imaging. Volumetric lesions were created by sonicating 1-4 rectangular planes spaced 1 mm apart, containing a grid of foci spaced 1-2 mm apart. Tissue then was evaluated grossly and histologically, and the lesion content was analyzed using transmission electron microscopy and scanning electron microscopy. Observed shear wave elastography characterization of ex vivo prostate tissue (37.9 ± 22.2 kPa) was within the typical range observed clinically. During BH, hyperechoic regions were visualized at the focus on B-mode, and BH-induced bubbles were also detected using power Doppler. As treatment progressed, hypoechoic regions of tissue appeared, suggesting successful tissue fractionation. BH treatment was twofold faster using shorter pulses (1 ms vs. 10 ms). Histological analysis revealed lesions containing completely homogenized cell debris, consistent with histotripsy-induced mechanical ablation. It was therefore determined that BH is feasible in fresh ex vivo human prostate tissue producing desired mechanical ablation. The study supports further work aimed at translating BH technology as a clinical option for prostate ablation. [ABSTRACT FROM AUTHOR]

Large-volume soft tissue hematomas are a serious clinical problem, which, if untreated, can have severe consequences. Current treatments are associated with significant pain and discomfort. It has been reported that in an in vitro bovine hematoma model, pulsed high-intensity focused ultrasound (HIFU) ablation, termed histotripsy, can be used to rapidly and non-invasively liquefy the hematoma through localized bubble activity, enabling fine-needle aspiration. The goals of this study were to evaluate the efficiency and speed of volumetric histotripsy liquefaction using a large in vitro human hematoma model. Large human hematoma phantoms (85 cc) were formed by recalcifying blood anticoagulated with citrate phosphate dextrose/saline-adenine-glucose-mannitol solution. Typical boiling histotripsy pulses (10 or 2 ms) or hybrid histotripsy pulses using higher-amplitude and shorter pulses (0.4 ms) were delivered at 1% duty cycle while continuously translating the HIFU focus location. Histotripsy exposures were performed under ultrasound guidance with a 1.5-MHz transducer (8-cm aperture, F# = 0.75). The volume of liquefied lesions was determined by ultrasound imaging and gross inspection. Untreated hematoma samples and samples of the liquefied lesions aspirated using a fine needle were analyzed cytologically and ultrastructurally with scanning electron microscopy. All exposures resulted in uniform liquid-filled voids with sharp edges; liquefaction speed was higher for exposures with shorter pulses and higher shock amplitudes at the focus (up to 0.32, 0.68 and 2.62 mL/min for 10-, 2- and 0.4-ms pulses, respectively). Cytological and ultrastructural observations revealed completely homogenized blood cells and fibrin fragments in the lysate. Most of the fibrin fragments were less than 20 μm in length, but a number of fragments were up to 150 μm. The lysate with residual debris of that size would potentially be amenable to fine-needle aspiration without risk for needle clogging in clinical implementation. [ABSTRACT FROM AUTHOR]