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. Author manuscript; available in PMC: 2026 Oct 14.
Published before final editing as: Ultrasound Med Biol. 2026 Oct 8:S0301-5629(26)00300-5. doi: 10.1016/j.ultrasmedbio.2026.07.025

Characterization of Bubble Cloud Formation and Tissue Ablation using a High Frequency Endoscopic Histotripsy System

Victor A Lopez 1,*, Jessica Gannon 1,*, Amber Keith 2, Tamalika Paul 3, Thomas G Landry 4,5, Jeffrey K Woodacre 4, Jeremy A Brown 4,5, Irving C Allen 3, Eli Vlaisavljevich 1,ǂ
PMCID: PMC13660375  NIHMSID: NIHMS2199631  PMID: 42850155

Abstract

Objective:

Histotripsy is a non-thermal focused ultrasound ablation strategy to non-invasively destroy tissue by generating a cavitation bubble cloud. Prior work has established the potential of histotripsy for many applications including the non-invasive treatment of liver tumors. In order to expand histotripsy beyond the currently available clinical systems for targeting deep abdominal tumors, recent work has developed miniaturized high frequency devices capable of higher precision using devices within an endoscopic form factor. This work investigates the use of one of these high-frequency histotripsy devices to evaluate cavitation generation and ablation capacity in a variety of ex vivo porcine tissues (brain, liver, kidney, pancreas, lymph node) and in vivo murine liver.

Methods:

A 6.3 MHz histotripsy transducer with an aperture of 10 mm and focal length of 7 mm was co-registered with a 30 MHz ultrasound imaging array. Optical imaging was used to identify cloud formation for different pulsing cycles while ultrasound imaging was used to monitor ex vivo and in vivo histotripsy ablations in tissue. Histological sections were examined, and statistical analyses were performed on imaging data.

Results:

Well-defined bubble clouds ranging from 0.54 ± 0.12 mm to 0.82 ± 0.12 mm (axial) were maintained over the course of 10,000 pulses for 3, 5, 8, and 12 cycles for peak negative pressures (p-) of 33–42 MPa. Larger bubble clouds were generated at higher p- for all cycles. Pearson Correlation Coefficients above 0.8 for all cases indicated strong correlation between US and optical imaging. Histotripsy bubble clouds were identified and maintained on US imaging with hypoechoic zones seen immediately post-treatment for all tissue types in both ex vivo and in vivo treatments. Histological results showed complete ablation of the targeted regions in excised porcine brain, kidney, pancreas, and lymph node. Ex vivo porcine liver exhibited extensive loss of hepatocytes but did retain subtle lobular architecture due to remnants of portal connective tissue. In vivo murine liver showed partial ablation, suggesting higher treatment doses are required.

Conclusions:

Results demonstrate the potential of miniaturized high-frequency histotripsy devices for precise and effective histotripsy ablation of a wide range of potential applications and establish the potential of this device for use in preclinical murine histotripsy studies.

Keywords: Histotripsy, cavitation, ablation, high frequency

INTRODUCTION

Histotripsy is a focused ultrasound (FUS) tissue ablation modality that is noninvasive, non-ionizing, non-thermal, and image-guided1. Histotripsy transducers are designed to have a focus where high-pressure ultrasound waves come together and generate sufficient peak negative pressure (p-) to induce acoustic cavitation2. During this process, once the cavitation threshold in the tissue is exceeded, intrinsic gas nuclei in tissue expand and collapse rapidly, resulting in a cavitation bubble cloud capable of mechanically ablating the tissue into acellular debris1,2. To date, clinical trials have been conducted for the treatment of benign prostatic hyperplasiae3, liver tumors4,5, kidney tumors6, and pancreatic tumors7,8. As of October 2023, the United States Food and Drug Administration (FDA) has approved histotripsy for the ablation of liver cancer9. In addition, histotripsy is currently being developed for additional applications with preclinical studies showing promise for many applications including musculoskeletal tumors10–12, deep vein thrombosis (DVT)13,14, brain15,16, breast cancers17, bacteria18,19, and uterine fibroids20.

Current clinical histotripsy systems are large, cart-based devices that have been optimized for treating intra-abdominal organs5,6,8. Most preclinical histotripsy systems that have previously been developed consist of relatively large FUS transducers in order to generate the high pressures needed for applying histotripsy to deep tissues non-invasively7,21,22. For example, histotripsy transducers developed for treating deep abdominal targets have apertures ranging from 10 to 20 cm and typically operate at frequencies of 500kHz to 1 MHz7,23,24. Similarly, histotripsy transducers developed for transcranial treatments and prostate cancer are large, low frequency devices that were designed to treat at depths ~4–10 cm15,22. Although these previously developed systems have shown promise for non-invasively targeting different organs throughout the body with histotripsy, there are some critical limitations that result from the relatively large size and low frequency of these transducers. In particular, the lower frequency of these devices, which is needed to enable depth penetration, ultimately limits the treatment precision that is achievable with histotripsy due to the larger focal size. Similarly, image-guidance with ultrasound imaging can be limited in many of these cases due to the treatment depth and gas blockage from intervening tissues. Developing high frequency histotripsy transducers with an endoscopic form factor, guided by high frequency US imaging, would allow for more precise targeting and therapeutic delivery.

To address these limitations of current histotripsy systems, recent studies have developed miniaturized high frequency histotripsy (~2–6 MHz) transducers capable of treating shallow and/or endoscopic targets with high precision25–27. These miniaturized high-frequency devices have been designed using as small as 8 mm apertures25–27, with initial studies focused on demonstrating the feasibility of high precision rodent brain tissue ablation25,28 in order to overcome the challenges of bone obstruction exhibited with large MRI-guided transcranial histotripsy arrays24,29. The high frequency therapeutic transducers previously developed have also been co-registered with a coaxially aligned high-resolution 30 MHz ultrasound imaging probe, providing real-time treatment guidance and monitoring26,28. Although these systems have only been tested for rodent brain tissue ablation to date, they have potential to improve small rodent studies. They also have potential for a large number of additional clinical applications that require high precision endoscopic or intraoperative devices, such as the treatment of oral cancer, lymph nodes, thyroid nodules, skin cancer, and other indications.

This study explores the use of a high frequency histotripsy device in an endoscopic form factor, examining its ability to generate cavitation and its capacity for tissue ablation. Previous studies have investigated the effects of transducer frequency on the histotripsy bubble cloud, with results showing that the size of the bubble cloud, as well as the expansion of individual bubbles within the cloud, is inversely proportional to the frequency, with larger bubble clouds and larger individual bubbles observed at lower frequencies30,31. Studies have also shown an increase in bubble cloud density (number of bubbles per unit area within the cloud) when the frequency is increased, due to a process of bubble induced pressure saturation30,32. Due to these differences, prior studies have shown a slight reduction in treatment efficiency at higher frequency, which is hypothesized to be due to the smaller bubble clouds and decreased bubble expansion, resulting in less strain being applied to the surrounding tissue30,31. Although higher frequency histotripsy was shown to be slightly less efficient than lower frequencies, previous studies have demonstrated histotripsy ablation was still achieved at frequencies up to 3MHz in tissue phantoms containing a layer of red blood cells30,33,34 and up to 6MHz in brain tissue. These studies have also shown a reduction in off-target damage, suggesting higher frequency histotripsy can be used to increase precision due to the smaller bubble cloud and reduced risk of generating off-target cavitation33,34.

We hypothesize that high frequency histotripsy can enable precise ablation of a wide range of tissue types with sub-millimeter treatment precision. This hypothesis is supported by previous studies using our 6.3MHz histotripsy device for the treatment of brain tissue, which is the only tissue type treated to date. Here, we investigate the cavitation behavior and tissue ablation in a wider range of tissue types in order to establish the potential of high frequency histotripsy for additional indications. This study is important to demonstrate the potential of these high frequency systems for applications outside of the brain, which is a very soft tissue, since previously studies have established that histotripsy susceptibility is dependent on tissue mechanical properties35,36. We hypothesize that the high frequency system will be able to precisely ablate a number of excised tissue types including porcine brain, liver, kidney, pancreas, and lymph nodes. Finally, it is hypothesized that the high frequency histotripsy transducer will be able to target and ablate murine liver in vivo, serving as an improved preclinical histotripsy device for conducting studies in murine models.

METHODS

Transducer Fabrication and Calibration

A high-frequency 6.3 MHz histotripsy system (MicroSonic Lab, Dalhousie University, Halifax, NS, Canada) with a 30 MHz coaxially aligned US imaging probe (Sagacity 200127, Daxsonics Ultrasound Inc., Halifax, NS, Canada) was evaluated for cavitation cloud formation and tissue ablation in a variety of tissue types27. The 6.3 MHz histotripsy transducer has a circular aperture with a f-number of 0.7, where the aperture is 10 mm and the focal length of 7 mm. Compared to most previous histotripsy systems, this transducer (Fig. 1) is significantly smaller and incorporates a notably higher frequency US imaging probe enabling precise histotripsy application as well as high resolution treatment monitoring. Transducer fabrication followed previously established methods27,28. The average peak negative pressure (PNP) per volt was estimated to be 0.22 MPa/V at the focal spot for ≥ 3 cycles based on calibrations and computational modeling, as described previously28.

Figure 1: In Vitro Optical Imaging, Ex Vivo and In Vivo Setup.

Figure 1:

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(A – In Vitro Setup) The histotripsy transducer is placed perpendicular to the surface of a phantom gel. A high-speed camera was oriented perpendicular to the transducer and backlit with a strobe light. (B – In Vivo Setup) Volumetric ablations were applied using a motorized positioning system and a custom MATLAB code. Transducer coupling involved adhering a plastic drape with an opening to the mouse’s skin, supported by a stage and filled with degassed water (<30% O2).

Optical Imaging and Analysis of Bubble Cloud

A high-speed camera (Photron Nova S12 monochrome, Proprietary Design Advanced CMOS, Photron USA, Inc., San Diego, California, USA) was used to obtain optical imaging of the histotripsy bubble cloud with a 25 mm F2.8 5× Ultra Macro lens at 4.8 : 1 (LAOWA, Hefei, China) attached, giving a resolution of ~5.2 μm per pixel (Fig. 1). A continuous light source (GS Vitec Multi-LED QT Light, Multi-LED G8 controller, 320 W power supply, Soden-Salmünster, Germany) was used to backlight images. Using soft-tissue-mimicking 1% agarose gel35,37,38, histotripsy was applied at 1 kHz pulse repetition frequency (PRF) with images captured at a 6.74 μs delay from the end of the pulse, as preliminary testing consistently showed fully formed bubble clouds at this timepoint for a variety of pulsing schemes. Photron FASTCAM Viewer software (PFV4) was used to record and save frames and videos of the cloud. Images were analyzed across the range of parameters tested in previous in vivo studies including 3–12 cycle pulses applied at different peak negative pressures ranging from ~22–44 MPa with a step size of 10 (~2.2 MPa p-). This setup follows the same procedure previously used28. For each cycle parameter and pressure level, 25 pulses were applied to three separate agarose phantoms for a total of 75 bubble cloud images for each pressure level and cycle parameter to reduce the effects of tissue phantom liquefaction. The cloud length was determined by measuring the distance between the closest edge of the bubble nearest to the transducer and the furthest edge of the bubble farthest from the transducer. Likewise, the cloud width was measured as the distance from the uppermost point of the bubble at the highest position in the positive transverse direction to the lowermost point of the bubble at the deepest position in the negative transverse direction30. A one-way analysis of variance (ANOVA) was performed to determine differences in bubble cloud lengths and widths among the 4 different cycle parameters. If a difference was detected, a Tukey’s Honestly Significant Difference (HSD) Post-Hoc test was used to identify the specific pairs of groups with significant differences. For all comparisons, p-values less than 0.05 were considered significant. Similarly, the same tests were performed for identifying differences in lengths and widths across the pressure levels within a given cycle group. Additionally, ultrasound images were collected with optical imaging simultaneously in two agarose phantoms. Using the ultrasound imaging frame rate, 790 images were processed using the same grayscale threshold technique used with optical imaging to now measure ultrasound cloud dimensions. After cloud lengths and widths were measured for ultrasound images, they were compared to the optical images by performing a Pearson’s correlation coefficient analysis.

Ex Vivo Porcine Tissue Ablations

Histotripsy was tested in excised porcine brain, liver, kidney, pancreas, and lymph node tissues ex vivo. Tissue was collected from healthy pigs either from other Institutional Care and Animal Use Committee (IACUC) approved research studies or from the Virginia Tech Meat Center. After harvest, tissues were placed in 0.9% saline or Dulbecco’s Modified Eagle’s Medium for preservation. Each sample was degassed and embedded in gelatin phantoms using 7.5 g of porcine gelatin (Gelatin from porcine skin powder, gel strength −300 g Bloom, Sigma-Aldrich, St. Louis, MO, USA) per 100 mL of 0.9% saline. All samples were treated within 48 hours of sample collection. Histotripsy was applied as a single point treatment or scanned through a cubic volume. For single point testing, 10,000 histotripsy pulses were applied at 8 cycles with a PRF of 1000 Hz which was previously used for rat brain ablations28. Volumetric ablations ranged from 37.5 – 45 mm3. A PRF of 1000 Hz with 10 cycles was applied for 1 second dwell times per treatment location to deliver 1000 pulses per point. These parameters fall within the range previously used for histotripsy28,39. Once cavitation was confirmed with the device, volumetric treatments were applied at pressures 20% above the point ablation thresholds to achieve a robust bubble cloud40,41. After histotripsy treatment, tissues were placed in 10% formalin for at least 48 hours before sectioning. Hematoxylin and eosin (H&E) staining were used to characterize the histotripsy ablation.

In Vivo Murine Tissue Ablations

In order to investigate the feasibility of using our 6.3 MHz histotripsy transducer coaxially aligned with a 30 MHz US imaging probe to treat mice, healthy murine liver was targeted in vivo. Before applying histotripsy, the transducer focus was found on the US imaging platform by firing the transducer in a beaker filled with degassed water (<30% O2) and marking where the cavitation bubble cloud was located. Following an IACUC approved research protocol, healthy C57/BL6 mice (n=3) were placed under general anesthesia with inhaled isoflurane gas. Prior to beginning the histotripsy ablation, hair covering the treatment site was removed using hair removal cream for approximately 3–5 minutes (Nair Hair Remover Lotion, Naircare, Ewing, NJ, USA). A plastic drape was secured to the treatment site using eyelash adhesive (Everlasting Lash Glue, IONI Cosmetics, Los Angeles, CA, USA) and filled with degassed water (<30% dissolved 02), as seen in Figure 1B. The histotripsy transducer was then submerged and positioned over the mouse using a custom, motorized positioning system. The mouse liver was identified and targeted using anatomical markers and US imaging by the research animal caretaker and the first author (Biomedical Engineering PhD student). The transducer focus was positioned in the center of the liver that was within the available acoustic window. Next, the pressure was increased gradually until a cavitation bubble cloud was confirmed to determine the cavitation threshold prior to treatment. The treatment pressure was set to 20% above the cavitation threshold. Cubic volumetric ablations of 18 mm3 were applied at 1000 Hz PRF with 10 cycles, a 0.5 second dwell time for a dose of 500 pulses per point using a custom MATLAB code. Mice were euthanized after treatment and a necropsy was performed. Liver tissues were excised and placed in 10% formalin for a minimum of 48 hours before sectioning. Histotripsy ablation was characterized using H&E staining.

RESULTS

Bubble Cloud Images and Cloud Size

Optical imaging revealed well-defined focal bubble clouds generated with consistent cavitation occurring over the course of 10,000 pulses for 3–12 cycle pulses applied at p- of 33–42 MPa (Fig. 2). Individual bubbles appeared to grow in size with increasing number of pulses, likely due to breakdown of the agarose tissue phantom over the course of the applied histotripsy exposure (Fig. 2, supplemental video 1). Images of histotripsy bubble clouds generated at p- ranging from 33–42 MPa showed larger bubble clouds were generated at higher p- for all cycle conditions..

Figure 2: Bubble Cloud Images for Cycle vs. Pressure.

Figure 2:

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All bubble clouds were maintained across 10,000 total pulses. Pulse 1 shown in still frame with ultrasound propagation from left to right.

The measured axial cloud length dimensions shown in Figure 3 ranged from 0.54 ± 0.12 mm to 0.79 ± 0.07 mm for 3 cycles, 0.49 ± 0.11 mm to 0.84 ± 0.09 mm for 5 cycles, 0.46 ± 0.13 to 0.81 ± 0.09 mm for 8 cycles, and 0.44 ± 0.15 to 0.82 ± 0.12 mm for 12 cycles. The measured transverse cloud width dimensions ranged from 0.21 ± 0.05 mm to 0.34 ± 0.03 mm for 3 cycles, 0.20 ± 0.04 mm to 0.40 ± 0.03 mm or 5 cycles, 0.19 ± 0.05 mm to 0.41 ± 0.05 mm for 8 cycles, and 0.19 ± 0.06 mm to 0.40 ± 0.05 mm for 12 cycles (Fig. 3). Results from the one-way ANOVA revealed no significant differences in cloud dimensions across the four tested cycle parameters, but did show differences in cloud dimensions across pressure levels within each cycle parameter. Tukey’s HSD Post-Hoc test revealed a significant difference in cloud length and width between 33 and 44 MPa p- for each cycle group, further supporting the increase in cloud size with increasing pressure level which is consistent with previous studies30.

Figure 3: Plots of Bubble Cloud Length and Width.

Figure 3:

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Measured cloud dimensions at varying cycles and pressures.

Bubble cloud dimensions were also measured using the US imaging (Fig. 4) where measured bubble cloud lengths on US imaging ranged from 0.37 ± 0.084 mm to 0.62 ± 0.16 mm for 3 cycles, 0.50 ± 0.12 mm to 0.92 ± 0.11 mm for 5 cycles, 0.63 ± 0.15 mm to 0.85 ± 0.20 mm for 8 cycles, and 0.58 ± 0.13 mm to 0.90 ± 0.15 mm for 12 cycles. Measured transverse cloud width dimensions on US imaging ranged from 0.37 ± 0.05 mm to 0.40 ± 0.04 mm for 3 cycles, 0.40 ± 0.05 mm to 0.44 ± 0.03 mm for 5 cycles, 0.43 ± 0.06 mm to 0.49 ± 0.05 mm for 8 cycles, and 0.46 ± 0.06 to 0.61 ± 0.08 mm for 12 cycles. Comparing the measured cloud dimensions on US imaging to optical imaging, a Pearson Correlation Coefficient was determined for cloud length of 0.96, 0.99, 0.93, and 0.88 for 3, 5, 8, and 12 cycles, respectively. For cloud width, optical images and US imaging had a Pearson Correlation Coefficient of 0.97, 0.96, 0.94, and 0.95 for 3, 5, 8, and 12 cycles, respectively. Having Pearson Correlation Coefficients above 0.8 for all cases indicates strong correlation between US imaging and optical imaging.

Figure 4: Comparison of Optical Imaging and Ultrasound Imaging.

Figure 4:

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Bubble cloud area for optical imaging and B-mode ultrasound imaging (8 cycles, representative). At 33 MPa, the imaging probe has high resolution to capture the space between the bubbles within the cloud area. Only showing one frame from the optical and US imaging (see videos). Ultrasound propagation is from top-down.

Ex-Vivo Point and Volumetric Ablations

Healthy excised porcine tissues (brain, liver, kidney, pancreas, and lymph node) were treated ex vivo within 48 hours of harvest. Single point treatments showed the histotripsy bubble cloud could be identified on US imaging as a bright hyperechoic region during sonication. Immediately after treatment, a hypoechoic region was seen in the same location, indicating ablation for all tissue types (Fig. 5). For volumetric treatments, well-defined histotripsy bubble clouds were visualized and maintained on US imaging throughout the applied volumetric ablation (Fig. 6, supplemental video 2). A clear hypoechoic region was observed in the ablation zone post treatment for all tissue types, suggesting the liquification and ablation of the targeted tissue42 (Fig. 6).

Figure 5: Ex Vivo Tissue Point Ablation.

Figure 5:

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Cavitation was generated inside all porcine tissue types and was visualized on B-mode ultrasound imaging (red arrows). Immediately after point cavitation a hypoechoic zone was observed (yellow dashed ellipse).

Figure 6: Ex Vivo Volumetric Ablations.

Figure 6:

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Ultrasound images of healthy excised porcine tissue before and after histotripsy treatment using a 6.3 MHz histotripsy transducer coaxially aligned with a 30 MHz ultrasound imaging transducer. Volumetric ablations of 1000 Hz pulse repetition frequency (PRF) at 10 cycles with a 1 second dwell time for a dose of 1000 pulses per point was applied to all tissue types.

The planned treatment volumes (X × Y × Z) for each tissue type were 4 × 4 × 1 mm for brain, 6 × 5 × 1.5 for liver, 5 × 5 × 1.5 for kidney, 5 × 6 × 1.5 for pancreas, and 4 × 4 × 2.5 for lymph node. Since the US imaging shows a 2D plane, the X and Z measurements of the treatment volume were measured and compared to the planned X-Z dimensions. The measured X-Z dimensions were 4.2 × 1.5 mm for brain, 5.9 × 2.1 mm for liver, 5.3 × 2.1 mm for kidney, 4.9 × 2 mm for pancreas, and 4 × 3.3 for lymph node tissue. The calculated percent difference between the treated and planned axial X-dimension was 40.0%, 33.3%, 28.6%, and 27.6% for the brain, liver and kidney, pancreas, and lymph node tissues, respectively. It’s important to note this is sub-millimeter so the measured US treatment dimensions across all tissues on average were within 0.6 ± 0.12 mm for the axial dimension. The calculated percent difference between the treated and planned transverse Z-dimensions was 4.9%, 1.7%, 5.8%, 2.0%, and 0% for brain, liver, kidney, pancreas, and lymph node tissue, respectively. These measured US transverse treatment dimensions across all tissues on average were within 0.14 ± 0.11 mm.

Since treatments were delivered in a top-down orientation (Fig. 6), the transducer applied compressive force to the tissue during therapy. After treatment, the “After” images were captured with the transducer repositioned to include a standoff between its face and the tissue surface. This allowed the tissue to decompress, resulting in slightly larger axial dimensions compared to transverse. The compression during treatment likely accounts for the reduced agreement in axial measurements of the treatment zones relative to the transverse dimensions. Additionally, the axial dimension on the cloud could be inducing streaming effects on the surrounding tissue making these treated dimensions larger. Analyzing the cross-section histological samples of the ablation zone and comparing them to the planned treatment dimensions, the measured treatment dimensions were within 0.56 ± 0.36 mm and 0.50 ± 0.29 mm for the transverse and axial directions, respectively. Across all samples, histological results showed that treatments led to precise, well-defined areas of ablation that were abruptly demarcated from the adjacent, untreated and otherwise intact tissue (Fig. 7). Treated areas were characterized by varying but often near complete loss of normal tissue architecture with replacement by amphophilic, fibrillar to granular material (interpreted as edema or fluid) and varying amounts of fragmented, nuclear debris. Sections of brain, kidney, pancreas, and lymph node often exhibited the most significant and near complete loss of normal tissue architecture. Sections of liver exhibited extensive loss of hepatocytes but did retain subtle lobular architecture due to remnants of portal connective tissues.

Figure 7: Histological Volumetric Treatment Results.

Figure 7:

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Varying healthy porcine tissues were treated at 1000 Hz pulse repetition frequency (PRF). Ablation dimensions were similar to those of the planned treatment dimensions. Clear, delineated boundaries between treated and untreated regions were seen across all tissues. Sections of brain, kidney, pancreas, and lymph node showed pronounced and nearly complete loss of normal tissue architecture. The liver demonstrated extensive hepatocyte loss but retained subtle lobular organization, preserved by remnants of portal connective tissue.

In-Vivo Ablations

Histotripsy volumetric ablation treatments were completed in three C57/BL6 mice, targeting the liver in vivo, in order to demonstrate the feasibility of using this high frequency device for precise targeting of histotripsy in murine models. A distinct cavitation bubble cloud was clearly visualized within the liver on real-time US imaging, appearing as a dynamically changing hyperechoic region throughout the duration of the treatment (Fig. 8). A slight hypoechoic region was observed in the treatment zone post treatment on US imaging, implying tissue ablation. Necropsy showed no off-target damage in the lungs or any neighboring structures, offering a significant improvement over prior in vivo liver ablation studies in mouse and rat models43. Additionally, no evidence of skin damage was observed. The ablation zone was observed grossly as hemorrhage with delineated boundaries prior to staining and sectioning for histological analysis. Histology results showed complete ablation of cells in regions closer to the liver surface within the treatment zone, with no remaining viable cells. Regions of hemorrhage were also observed within the treatment zone. Treated regions in deeper regions of the planned treatment zone showed only partial ablation with degenerative extracellular matrix but intact nuclei, likely due to the bubble cloud being intermittently generated in these deeper regions of the volumetric ablation, which was observed during treatment on ultrasound imaging.

Figure 8: Murine Liver Ultrasound and Tissue Histology.

Figure 8:

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Ultrasound imaging of in vivo mouse liver during histotripsy treatment (A). The bubble cloud is clearly visualized and contained within the liver during treatment. The treatment zone (B) correlates closely with the planned dimensions. Untreated cells (C) showed intact nuclei and cell membrane. Regions closer to the liver edge (D) showed complete ablation with no viable cells. Hemorrhage was observed throughout the treatment zone. Deeper regions within the treatment zone (F) showed partial ablations with degenerative extracellular matrix but intact nuclei.

DISCUSSION

In this study, the cavitation cloud of a high frequency endoscopic histotripsy transducer was collected via high-speed imaging and the device’s ablation capabilities were evaluated in both ex vivo and in vivo tissue. Optical imaging results showed sustained well-defined clouds for all conditions, supporting the use of the device for high precision histotripsy. Additionally, there was a strong correlation between US images of the cloud and optical images. The US imaging bubble cloud was mostly larger than the optical dimensions, this may be attributed to a combination of reasons. The US imaging is not synchronized with the pulses being delivered, showing an average of multiple frames across the lifespan of the bubble cloud. This suggests the US imaging may also be imaging residual nuclei instead of just the actual histotripsy bubbles that are not imaged during maximum expansion. There may also be streaming effects occurring in the ablated phantom that is more apparent under US imaging compared to optical imaging. Additionally, dark regions were observed in B-mode US imaging, but are most likely not actual hypoechoic regions and are due to an active-enhancement algorithm, affecting the contrast or brightness through beamforming settings, in the display software. Another factor that may contribute to the differences is less precise lateral US resolution compared to optical imaging. A recent study characterizing the 30MHz US imager showed it had lower lateral resolution compared to axial resolution44. Despite these slight differences, there was still a strong correlation between the bubble cloud dimensions of US images and optical images. These results highlight the resolution of the co-axially aligned high frequency 30 MHz imaging probe to resolve the bubble cloud, which is important for cases requiring high precision of therapy and imaging. Results from the ex vivo tissue experiments revealed that a bubble cloud was generated for all tissue types, which establishes that this device can be developed for use in a large number of future clinical applications. Near complete ablation was observed for brain, liver, kidney, and lymph node on histology. Although a clear hypoechoic zone could be seen on US imaging, it was difficult to obtain a clear treatment zone on histology for pancreas samples due to the tissue lacking structural integrity which has also been observed in previous in vivo porcine pancreas ablations45. However, the overall results from this study suggest high frequency histotripsy can be used for effective ablation across the full range of tissue types tested, suggesting further exploration is warranted in order to develop endoscopic and surgical histotripsy devices for these applications.

The results from this study are promising for endoscopic and intraoperative tissue ablation using histotripsy, opening the door for the development of this technique for clinical applications that require high precision ablation. Histotripsy has currently been used as a non-invasive tissue ablation modality using an extracorporeal approach. The device evaluated here shows the potential for an endoscopic focused ultrasound transducer for gastrointestinal cancers such as in the esophagus, stomach, intestines, and pancreas. The device can potentially overcome gas interference that can limit effective targeting in the extracorporeal approach while also providing high precision within these critical structures. For instance, another version of this device specifically designed for pancreatic tumors could be developed for targeting the pancreas through the stomach wall. This histotripsy device may enable more precise and complete ablation of pancreatic tumors while reducing the risks of off-target bowel injury, which has previously been shown to be a concern when targeting the pancreas non-invasively7. Many other applications using high frequency histotripsy, such as the treatment of lymph nodes or the targeting of tumors using endoscopic devices, could be achieved using these miniaturized high frequency devices. For instance, the well-confined bubble clouds and miniature size of this transducer shows promise for ear, nose, and throat (ENT) indications such as lymphoma, tongue ablation (sleep apnea), thyroid nodules, and oral tumors. Moreover, this study highlights the potential of surgical histotripsy tools in applications requiring high precision. For example, the device could enable targeted pancreatic tumor ablation near vessel walls during laparoscopic Whipple procedures. It may also prove valuable in spinal interventions where preserving nearby nerves is critical. Ongoing studies are currently underway by our groups to investigate these applications with high-frequency histotripsy transducers.

In addition to opening the door to new clinical applications, having a miniaturized histotripsy system enables better precision for pre-clinical small animal studies, reducing the risk of off-target injury within the beam path, offering a significant improvement compared to the commonly used 1MHz small animal histotripsy transducers used in prior rodent studies46. For instance, prior small animal histotripsy studies have been primarily limited to the partial ablation of subcutaneous tumors in mice or orthotopic tumors in rats due to the lack of treatment precision and risks of injury to critical tissue structures outside of the targeted region43,47,48. An improved high frequency pre-clinical small animal histotripsy platform using the device evaluated in this study would enable improved treatments of orthotopic tumors in mouse models and allow for studies evaluating complete tumor ablation instead of just partial ablation of the targeted tumors. This improved small animal histotripsy platform would improve a large number of histotripsy studies evaluating the systemic oncologic and immune responses to histotripsy in various murine cancer models49–52, which is essential to optimizing histotripsy treatment parameters for specific clinical applications. Future work by our group is underway to develop these transducers into an integrated small animal histotripsy device.

Although the results of this study are promising for the use of high frequency histotripsy, there are some limitations with this study that should be noted. First, there is calibration uncertainty with this device at a high frequency, leading to overestimation of the peak negative pressure which has previously been observed53,54. Future work should focus on developing a more sensitive fiber-optic hydrophone for high-frequency histotripsy systems, which will ultimately facilitate the evaluation of new preclinical devices and accelerate their path to clinical approval. Additionally, the volumetric treatments in this study highlight the limitation of targeting a large volume within clinically relevant treatment times without further improvements. For instance, while high precision sub-millimeter cavitation was effectively produced using this device, ablation of a 45 mm3 volume took approximately one hour to complete. Since many applications using this device may require the targeting of larger tissue volumes, future work should investigate strategies for enhancing treatment efficiency while preserving the high precision demonstrated in this study. One potential approach to address this limitation is the development of steerable high-frequency array transducers that can electronically scan the focus through the depth of the tissue and thereby speed up the treatment similar to prior work using electronic focal steering24,55. Another limitation of the high frequency histotripsy system used in this study was the limited targeting depth, demonstrating the potential tradeoff in developing high precision and endoscopic histotripsy systems that need to be considered for each clinical application. Finally, another limitation of this work is that the tissue types targeted primarily consisted of healthy soft tissues. Although these tissues represent a range typical of most clinical histotripsy applications, they did not account for applications that require the ablation of stiffer or very fibrous tissues, such as cancers, uterine fibroids or fibroadenoma, suggesting future studies are needed to evaluate the use of these devices for fibrous tissue ablation.

CONCLUSION

The results of this study demonstrate the potential of high-frequency histotripsy devices for ultra-precise treatments of ex vivo and in vivo soft tissues. Results from optical imaging showed a sub-millimeter bubble cloud strong correlation of cloud size between optical imaging and US imaging, highlighting the high-resolution imaging quality of this device. Results from ex vivo treatments demonstrated clear bubble cloud visualization on US and tissue ablation in healthy porcine brain, liver, kidney, pancreas, and lymph node. In vivo treatments of murine liver exhibited clear bubble cloud formation and visualization on US, maintaining a bubble cloud within the liver without any off target or adverse effects. Histology showed regions of complete liver ablation and regions of partial ablation with degenerative extracellular matrix and intact nuclei. Overall, this study highlights the potential of high frequency histotripsy devices for ultra-precise tissue ablation, and suggests that future work is warranted to improve these devices for faster, more clinically relevant treatments.

Supplementary Material

1
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2
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ACKNOWLEDGEMENTS

This work was funded in part by grants from the Focused Ultrasound Foundation and NIH (R01CA269811-01, R01CA262474).

Footnotes

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CONFLICT OF INTEREST STATEMENT

Dr. Eli Vlaisavljevich is a co-founder of Sound Blade Medical, Inc. and Helix Acoustics, LLC. He also has an ongoing research partnership with HistoSonics, Inc. Dr. Jeremy A. Brown is a co-founder of Sound Blade Medical, Inc. and Daxsonics Ultrasound Inc.

DECLARATION OF GENERATIVE AI AND AI-ASSISTED TECHNOLOGIES IN THE WRITING PROCESS

During the preparation of this work the authors used OpenAI’s GPT-5 language model (ChatGPT) in order to improve readability and suggest alternative phrasings. After using this tool, the authors reviewed and edited the content as need and take full responsibility for the content of the publication.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

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Supplementary Materials

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Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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