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To determine whether histotripsy can create human-scale transcostal ablations in porcine liver without causing severe thermal wall injuries along the beam path. Histotripsy was applied to the liver using a preclinical prototype robotic system through a transcostal window in six female swine. A 3.0 cm spherical ablation zone was prescribed. Duration of treatment (75 min) was longer than a prior subcostal treatment study (24 min, 15 s) to minimize beam path heating. Animals then underwent contrast-enhanced MRI, necropsy, and histopathology. Images and tissue were analyzed for ablation zone size, shape, completeness of necrosis, and off-target effects. Ablation zones demonstrated complete necrosis with no viable tissue remaining in 6/6 animals by histopathology. Ablation zone volume was close to prescribed (13.8 ± 1.8 cm3 vs. prescribed 14.1 cm3). Edema was noted in the body wall overlying the ablation on T2 MRI in 5/5 (one animal did not receive MRI), though there was no gross or histologic evidence of injury to the chest wall at necropsy. At gross inspection, lung discoloration in the right lower lobe was present in 5/6 animals (mean size: 1 × 2 × 4 cm) with alveolar hemorrhage, preservation of blood vessels and bronchioles, and minor injuries to pneumocytes noted at histology. Transcostal hepatic histotripsy ablation appears feasible, effective, and no severe injuries were identified in an acute porcine model when prolonged cooling time is added to minimize body wall heating.

OBJECTIVES—: To quantify the bias of shear wave speed (SWS) measurements between different commercial ultrasonic shear elasticity systems and a magnetic resonance elastography (MRE) system in elastic and viscoelastic phantoms. METHODS—: Two elastic phantoms, representing healthy through fibrotic liver, were measured with 5 different ultrasound platforms, and 3 viscoelastic phantoms, representing healthy through fibrotic liver tissue, were measured with 12 different ultrasound platforms. Measurements were performed with different systems at different sites, at 3 focal depths, and with different appraisers. The SWS bias across the systems was quantified as a function of the system, site, focal depth, and appraiser. A single MRE research system was also used to characterize these phantoms using discrete frequencies from 60 to 500 Hz. RESULTS—: The SWS from different systems had mean difference 95% confidence intervals of ±0.145 m/s (±9.6%) across both elastic phantoms and ± 0.340 m/s (±15.3%) across the viscoelastic phantoms. The focal depth and appraiser were less significant sources of SWS variability than the system and site. Magnetic resonance elastography best matched the ultrasonic SWS in the viscoelastic phantoms using a 140 Hz source but had a − 0.27 ± 0.027-m/s (−12.2% ± 1.2%) bias when using the clinically implemented 60-Hz vibration source. CONCLUSIONS—: Shear wave speed reconstruction across different manufacturer systems is more consistent in elastic than viscoelastic phantoms, with a mean difference bias of < ±10% in all cases. Magnetic resonance elastographic measurements in the elastic and viscoelastic phantoms best match the ultrasound systems with a 140-Hz excitation but have a significant negative bias operating at 60 Hz. This study establishes a foundation for meaningful comparison of SWS measurements made with different platforms.

Nonlinear mechanical properties of breast tissue can be employed to diagnose and differentiate breast tumors. To obtain such nonlinear mechanical properties, it is necessary to track tissue motion under large deformation. In this study, a multi-compression strategy was utilized to produce large tissue deformation and a method to estimate three-dimensional (3D) motion of tissue under large deformation was introduced. Given multiple volumes of ultrasound data, the proposed method first estimates volume-to-volume incremental displacements using a 3D region-growing motion-tracking method. Then, possible outliers among all incremental displacements are removed to avoid error accumulation. Once large displacement errors have been removed, all incremental displacements are registered together to obtain accumulated displacements under large tissue deformation (e.g. > 10%). The proposed method was tested with one set of in vivo tumor-bearing ultrasound data acquired from a human subject. A total of 10 small-strain deformation steps were performed to obtain the final accumulated displacement field, in which the breast lesion and its surrounding were deformed by approximately 6% and 16%, respectively. The contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of the elasticity images obtained with the proposed method are all higher than those with a 2D tracking method. Furthermore, in three orthogonal views of accumulated axial strain images, the breast lesion was clearly visible with good correspondence between the axial strain and B-mode images.

Quantitative ultrasound estimates different intrinsic tissue properties, which can be used for tissue characterization. Among different tissue properties, the effective number of scatterers per resolution cell is an important parameter, which can be estimated by the echo envelope. Assuming the signal is stationary and coherent, if the number of scatterers per resolution cell is above approximately 10, envelope signal is considered to be fully developed speckle (FDS) and otherwise they are from low scatterer number density (LSND). Two statistical parameters named R and S are often calculated from envelope intensity to classify FDS from LSND. The main problem is that limited data from small patches often renders this classification inaccurate. Herein, we propose two techniques based on neural networks to estimate the effective number of scatterers. The first network is a multi-layer perceptron (MLP) that uses the hand-crafted features of R and S for classification. The second network is a convolutional neural network (CNN) that does not need hand-crafted features and instead utilizes spectrum and the envelope intensity directly. We show that the proposed MLP works very well for large patches wherein a reliable estimation of R and S can be made. However, its classification becomes inaccurate for small patches, where the proposed CNN provides accurate classifications.

The objective of quantitative ultrasound (QUS) is to characterize tissue microstructure by parametrizing backscattered radiofrequency (RF) signals from clinical ultrasound scanners. Herein, we develop a novel technique based on dynamic programming (DP) to simultaneously estimate the acoustic attenuation, the effective scatterer size (ESS), and the acoustic concentration (AC) from ultrasound backscattered power spectra. This is achieved through two different approaches: (1) using a Gaussian form factor (GFF) and (2) using a general form factor (gFF) that is more flexible than the Gaussian form factor but involves estimating more parameters. Both DP methods are compared to an adaptation of a previously proposed least-squares (LSQ) method. Simulation results show that in the GFF approach, the variance of DP is on average 88%, 75% and 32% lower than that of LSQ for the three estimated QUS parameters. The gFF approach also yields similar improvements.

Studies in animal models have demonstrated that long exposures to anesthetics can induce apoptosis in the newborn and young developing brain. These effects have not been confirmed in humans due to the lack of a non-invasive, practical in vivo imaging tool with the ability to detect these changes. Following the success of using Ultrasound Backscatter Spectroscopy (UBS) to monitor in vivo cell death in breast tumors, we aimed at applying UBS to assess neurotoxicity of the anesthetic Sevoflurane (SEVO) in a non-human primate (NHP) model. Sixteen 2–7 day-old Rhesus macaques were exposed for 5 hours to SEVO. Ultrasound scanning was done with a phased array transducer on a clinical ultrasound scanner operated at 10 MHz. Data consisting of 10–15 frames of radiofrequency (RF) echo signals from coronal views of the thalamus were obtained at 0.5 and 6.0 h after initiating exposure. The UBS parameter “Effective Scatterer Size” (ESS) was estimated by fitting a scattering form factor (FF) model to the FF measured from RF echo signals. The approach involved analyzing the frequency-dependence of the measured FF to characterize scattering sources and selecting the FF model based on a χ(2) goodness of fit criterion. To assess data quality, a rigorous acceptance criterion based on the analysis of prevalence of diffuse scattering (an assumption in the estimation of ESS) was established. ESS changes after exposure to SEVO were compared to changes in a control group of 5 primates for which ultrasound data were acquired at 0 min and 10 min (no apoptosis expected). Over the entire data set, the average measured FF at 0.5 h and 6.0 h monotonically decreased with frequency, justifying fitting a single form factor over the analysis bandwidth. χ(2) values of an (inhomogeneous continuum) Gaussian FF model were one fifth those of the discrete fluid sphere model, suggesting that a continuum scatterer model better represents ultrasound scattering in the young Rhesus brain. After applying the data quality criterion, only 5 out of 16 subjects from the apoptotic group, and 5 out of 5 subjects from the control group, fulfilled the acceptance criteria. All of the subjects in the apoptotic group that passed the acceptance criterion showed a significant ESS reduction at 6.0 h. These changes (−6.4% [95% Confidence Interval −14.3% to −3.3%]) were larger than those in the control group (−0.8% [95% Confidence Interval −2.0% to 1.5%]). Data with low prevalence of diffuse scattering corresponded to possibly biased results. Thus, ESS has potential to detect changes in brain microstructure related to anesthesia-induced apoptosis.

Efforts to develop quantitative ultrasound biomarkers would benefit from comparisons between ultrasound data and higher-resolution images of the tissue microstructure, such as from optical microscopy. However, only a few studies have used these methods for multiscale-imaging because it is difficult to register low-resolution (>100μm) ultrasound images to high-resolution (

Acoustic aberrations caused by natural heterogeneities of biological soft-tissue are a substantial problem for histotripsy, a therapeutic ultrasound technique that uses acoustic cavitation to mechanically fractionate and destroy unwanted target tissue without damaging surrounding tissue. These aberrations, primarily caused by sound speed variations, result in severe defocusing of histotripsy pulses thereby decreasing treatment efficacy. The gold standard for aberration correction (AC) is to place a hydrophone at the desired focal location to directly measure phase aberrations, which is a method that is infeasible in vivo. We hypothesized that the acoustic cavitation emission (ACE) shockwaves from the initial expansion of inertially cavitating microbubbles generated by histotripsy can be used as a point source for AC. In this study, a 500-kHz, 112-element histotripsy phased array capable of transmitting and receiving ultrasound on all channels was used to acquire ACE shockwaves. These shock-waves were first characterized optically and acoustically. It was found that the shockwave pressure increases significantly as the source changes from a single bubble to a dense cavitation cloud. The first arrival of the shockwave received by the histotripsy array was from the outer-most cavitation bubbles located closest to the histotripsy array. Hydrophone and ACE AC methods were then tested on ex vivo porcine abdominal tissue samples. Without AC, the focal pressure is reduced by 49.7% through the abdominal tissue. The hydrophone AC approach recovered 55.5% of the lost pressure. Using the ACE AC method, over 20% of the lost pressure was recovered, and the array power required to induce cavitation was reduced by approximately 31.5% compared to without AC. These results supported our hypothesis that the ACE shockwaves coupled with a histotripsy array with transmit and receive capability can be used for aberration correction for histotripsy through soft-tissue.

Residual bubbles produced after collapse of a cavitation cloud provide cavitation nuclei for subsequent cavitation events, causing cavitation to occur repeatedly at the same discrete set of sites. This effect, referred to as cavitation memory, limits the efficiency of histotripsy soft tissue fractionation. Besides passively mitigating cavitation memory by using a low pulse repetition frequency (~ 1 Hz), an active strategy was developed by our group. In this strategy, low-amplitude ultrasound sequences were used to stimulate coalescence of residual bubbles. The goal of this work is to remove cavitation memory and achieve rapid, homogeneous lesion formation using a single phased array transducer. A 1 MHz integrated histotripsy and bubble coalescing (HBC) transducer system with a specialized electronic driving system was built in house. High amplitude (P- >= 30 MPa) histotripsy pulses and subsequent low amplitude (~1-2 MPa) bubble coalescing (BC) sequences were applied to a red blood cell (RBC) tissue-mimicking phantom at a single focal site. Significant reduction of the cavitation memory effect and increase in the fractionation rate were observed by introducing BC sequence. Effects of BC pulsing parameters were further studied. The optimal BC parameters were then utilized to homogenize a 10 × 10 mm region at high rate.

Histotripsy is a minimally invasive ultrasound therapy that has shown rapid liquefaction of blood clots through human skullcaps in an in-vitro intracerebral hemorrhage (ICH) model. However, the efficiency of these treatments can be compromised if the skull induced aberrations are uncorrected. We have developed a catheter hydrophone which can perform aberration correction and drain the liquefied clot following histotripsy treatment. Histotripsy pulses were delivered through an excised human skullcap using a 256-element, 500 kHz hemisphere array transducer with a 15 cm focal distance. A custom hydrophone was fabricated using a 0.5 × 0.5 × 0.3 mm PZT-5h crystal interfaced to a coaxial cable and integrated into a drainage catheter. An aberration correction algorithm was developed to correct the aberrations introduced between histotripsy pulses from each array element. Increases in focal pressure of up to 60% were achieved at the geometric focus and 27 – 62% across a range of electronic steering locations. The sagittal and axial −6 dB beam widths decreased from 4.6 to 2.2 mm in the sagittal direction and 8 to 4.4 mm in the axial direction, compared to 1.5 mm and 3 mm in the absence of aberration. After performing aberration correction, lesions with diameters ranging from 0.24 mm to 1.35 mm were generated using electronic steering over a 10 × 10 mm grid in a tissue mimicking phantom. An average volume of 4.07 ± 0.91 mL was liquefied and drained after using electronic steering to treat a 4.2 mL spherical volume in in-vitro bovine clots through the skullcap.

This in-vitro study investigated the effects of ultrasound frequency and focal spacing on blood clot liquefaction via transcranial histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30 cm aperture diameters. A 4 cm diameter spherical volume of in-vitro blood clot was treated through three excised human skullcaps by electronically steering the focus with frequency proportional focal spacing: λ/2, 2λ/3 and λ with 50 pulses per location. The pulse repetition frequency (PRF) across the volume was 200 Hz, corresponding to a duty cycle of 0.08% (250 kHz) and 0.04% (500 kHz) for each focal location. Skull heating during treatment was monitored. Liquefied clot was drained via catheter and syringe in range of 6–59 mL in 0.9–42.4 minutes. The fastest rate was 16.6 mL/min. The best parameter combination was λ spacing at 500 kHz which produced large liquefaction through three skullcaps (23.1 ± 4.0, 37.1 ± 16.9 and 25.4 ± 16.9 mL) with the fast rates (3.2 ± 0.6, 5.1 ± 2.3 and 3.5 ± 0.4 mL/min). The temperature rise through the 3 skullcaps remained below 4 °C.

Ultrasound elasticity imaging has demonstrated utility in breast imaging, but it is typically performed with handheld transducers and two-dimensional imaging. Two-dimensional (2D) elastography images tissue stiffness of only a plane and hence suffers from errors due to out-of-plane motion, whereas three-dimensional (3D) data acquisition and motion tracking can be used to track out-of-plane motion that is lost in 2D elastography systems. A commercially-available automated breast volume scanning system that acquires 3D ultrasound data with precisely controlled elevational movement of the 1D array ultrasound transducer was employed in this study. A hybrid, guided 3D motion tracking algorithm was developed that first estimated the displacements in one plane using a modified quality-guided search method, and then performed an elevational guided-search for displacement estimation in adjacent planes. To assess the performance of the method, 3D radiofrequency echo data were acquired with this system from a phantom and from an in vivo human breast. For both experiments, the axial displacement fields were smooth and high cross-correlation coefficients were obtained in most of the tracking region. The motion tracking performance of the new method was compared with a correlation-based exhaustive search method on six consecutive volumes (five consecutive volume pairs) of radiofrequency echo data acquired during in vivo scanning of the breast of one subject. For all five motion tracking volume pairs, the average motion-compensated cross-correlation values (between pre-deformation and motion-compensated post-deformation echo fields) obtained by the guided-search motion tracking method were equivalent to those by the exhaustive search method, and the computation time was about a factor of 10 less. Therefore, the proposed 3D ultrasound elasticity imaging method was a more efficient approach to produce a high quality of 3D ultrasound strain image.

Objective and Impact Statement . This is the first longitudinal study investigating the effects of histotripsy on local tumor progression in an in vivo orthotopic, immunocompetent rat hepatocellular carcinoma (HCC) model. Introduction . Histotripsy is the first noninvasive, nonionizing, nonthermal, mechanical ablation technique using ultrasound to generate acoustic cavitation to liquefy the target tissue into acellular debris with millimeter accuracy. Previously, histotripsy has demonstrated in vivo ablation of noncancerous liver tissue. Methods . N1-S1 HCC tumors were generated in the livers of immunocompetent rats ( n = 6 , control; n = 15 , treatment). Real-time ultrasound-guided histotripsy was applied to ablate either 100 % tumor volume + up to 2 mm margin ( n = 9 , complete treatment) or 50-75% tumor volume ( n = 6 , partial treatment) by delivering 1-2 cycle histotripsy pulses at 100 Hz PRF (pulse repetition frequency) with p − ≥ 30 MPa using a custom 1 MHz transducer. Rats were monitored weekly using MRI (magnetic resonance imaging) for 3 months or until tumors reached ~25 mm. Results . MRI revealed effective post-histotripsy reduction of tumor burden with near-complete resorption of the ablated tumor in 14/15 (93.3%) treated rats. Histopathology showed Conclusion . Complete and partial histotripsy ablation resulted in effective tumor removal for 14/15 rats, with no evidence of local tumor progression or recurrence.

Shock scattering histotripsy (SSH) involves a complex interaction between positive and negative phases of an acoustic burst to initiate a robust cavitation bubble cloud. To more precisely study these effects and optimize SSH therapy, we constructed a frequency compounding transducer to generate pseudo-monopolar ultrasound pulses. The transducer consisted of 113 individual piezoelectric elements with various resonant frequencies (250 kHz, 500 kHz, 750 kHz, 1 MHz, 1.5 MHz, 2 MHz, and 3 MHz). For each resonant frequency, a nearly 1.5-cycle pulse could be generated. Pseudo-monopolar peak positive pulses were generated by aligning the principal peak positive pressures of individual frequency components temporally so that they added constructively, and destructive interference occurred outside the peak-positive-overlapped temporal window. After inverting the polarity of the excitation signals, pseudo-monopolar peak negative pulses were generated similarly by aligning principal peak negative pressures. Decoupling the positive and negative acoustic phases could have significant advantages for therapeutic applications enhancing precision, avoiding cavitation at tissue interfaces, and reducing the acoustic aperture required for effective therapy. For example, we show that 16 SSH bubble clouds can be generated using only peak positive pulses following a single peak negative pulse. This results in a precise elongated lesion within red-blood-cell phantoms. Shock scattering histotripsy (SSH) involves a complex interaction between positive and negative phases of an acoustic burst to initiate a robust cavitation bubble cloud. To more precisely study these effects and optimize SSH therapy, we constructed a frequency compounding transducer to generate pseudo-monopolar ultrasound pulses. The transducer consisted of 113 individual piezoelectric elements with various resonant frequencies (250 kHz, 500 kHz, 750 kHz, 1 MHz, 1.5 MHz, 2 MHz, and 3 MHz). For each resonant frequency, a nearly 1.5-cycle pulse could be generated. Pseudo-monopolar peak positive pulses were generated by aligning the principal peak positive pressures of individual frequency components temporally so that they added constructively, and destructive interference occurred outside the peak-positive-overlapped temporal window. After inverting the polarity of the excitation signals, pseudo-monopolar peak negative pulses were generated similarly by aligning principal peak negative pressures. Decouplin...

Transcatheter interventions for structural heart disease demand real-time visualization of catheter devices and their relationship to cardiac anatomy. Co-registration of x-ray fluoroscopy with echocardiography has been proposed to provide the necessary device and soft tissue visualization for these procedures. Development of real-time 3D x-ray/echo registration systems with device tracking has been hampered by the lack of a suitable test model. This study presents a phantom that is compatible with x-ray, CT, transthoracic (TTE), and transesophageal echo (TEE) for testing the feasibility and accuracy of new registration solutions. The phantom consists of a 20.3-cm diameter, 15-cm tall cylindrical shell with acoustic windows for TTE and an access port for a TEE probe. The interior contains 24 dual-modality targets, 5-mm in diameter, suspended in a three-turn helix occupying a volume that is similar to an adult heart. An ultrasound-compatible, tissue-mimicking slurry medium fills the remainder of the phantom. The dual-modality targets are agar based with barium sulfate (BaSO4) powder and glass beads added to generate contrast in both x-ray and ultrasound. Appropriate concentrations of these additives were determined experimentally with contrast measurements in x-ray, CT, and ultrasound. Selected concentrations were 150 mg/mL BaSO4 and 100 mg/mL of 53-63 μm diameter glass beads. Average target contrast (± SD) was 16% ± 2% in x-ray fluoroscopy (90 kV) and 1805 ± 99 HU in CT (100 kV). In ultrasound, target CNR was 4.30 ± 0.62 in 2D B-mode and 4.03 ±1.06 in 4D-mode images acquired at a center frequency of 2.8 MHz.

Tissue mechanics is central to pregnancy, during which maternal anatomic structures undergo continuous remodeling to serve a dual function to first protect the fetus in utero while it develops and then facilitate its passage out. In this study of normal pregnancy using biomechanical solid modeling, we used standard clinical ultrasound images to obtain measurements of structural dimensions of the gravid uterus and cervix throughout gestation. 2-dimensional ultrasound images were acquired from the uterus and cervix in 30 pregnant subjects in supine and standing positions at four time points during pregnancy (8-14, 14-16, 22-24, and 32-34 weeks). Offline, three observers independently measured from the images of multiple anatomic regions. Statistical analysis was performed to evaluate inter-observer variance, as well as effect of gestational age, gravity, and parity on maternal geometry. A parametric solid model developed in the Solidworks computer aided design (CAD) software was used to convert ultrasonic measurements to a 3-dimensional solid computer model, from which estimates of uterine and cervical volumes were made. This parametric model was compared against previous 3-dimensional solid models derived from magnetic resonance frequency images in pregnancy. In brief, we found several anatomic measurements easily derived from standard clinical imaging are reproducible and reliable, and provide sufficient information to allow biomechanical solid modeling. This structural dataset is the first, to our knowledge, to provide key variables to enable future computational calculations of tissue stress and stretch in pregnancy, making it possible to characterize the biomechanical milieu of normal pregnancy. This vital dataset will be the foundation to understand how the uterus and cervix malfunction in pregnancy leading to adverse perinatal outcomes.

High-frequency quantitative ultrasound is a potential non-invasive source of imaging cell-tissue scale biomarkers for major diseases such as heart disease, cancer, and preterm birth. However, one of the barriers to developing such biomarkers is that it is labor-intensive to compare quantitative ultrasound images to optical images of the tissue structure. We have previously developed a multiscale imaging system that can obtain registered qualitative ultrasound and optical images, but there are further technical challenges to obtaining quantitative data: System-specific details of obtaining and processing data with Verasonics high-frequency transducers; the need for high-frequency reference phantoms; and off-axis clutter from imaging above a glass coverslip. This paper provides a characterization of the Verasonics ultrasound system with the 18.5 MHz L22-14v and 28.5 MHz L38-22v transducers, describes the construction of high-frequency reference phantoms, and details methods for reducing off-axis clutter. The paper features a demonstration multiscale image of a wild type mouse mammary gland that incorporates quantitative ultrasound with both transducers and second harmonic generation microscopy. These advances demonstrate a way to obtain, on a single system with a cohesive and integrated pipeline, quantitative ultrasound data that is correlated with optical imaging without the need for extensive sample preparation.

Changes in the multi-level physical structure of biological features going from cellular to tissue level composition is a key factor in many major diseases. However, we are only beginning to understand the role of these structural changes because there are few dedicated multiscale imaging platforms with sensitivity at both the cellular and macrostructural spatial scale. A single platform reduces bias and complications from multiple sample preparation methods and can ease image registration. In order to address these needs, we have developed a multiscale imaging system using a range of imaging modalities sensitive to tissue composition: Ultrasound, Second Harmonic Generation Microscopy, Multiphoton Microscopy, Optical Coherence Tomography, and Enhanced Backscattering. This paper details the system design, the calibration for each modality, and a demonstration experiment imaging a rabbit eye.

After the collapse of a cavitation bubble cloud, residual microbubbles can persist for up to seconds and function as weak cavitation nuclei for subsequent pulses in a phenomenon known as cavitation memory effect. In histotripsy, the cavitation memory effect can cause bubble clouds to repeatedly form at the same discrete set of sites. This effect limits the efficacy of histotripsy-based tissue fractionation. Our previous studies have indicated that low-amplitude bubble-coalescing (BC) ultrasound sequences interleaved with high-amplitude histotripsy pulses can coalesce the residual bubbles into one large bubble quickly. This reduces the cavitation memory effect and may increase treatment efficacy. Histotripsy has been investigated for thrombolysis by breaking up clots into debris smaller than red blood cells. However, this treatment has low efficacy for aged or retracted clots. In this study, we investigate the use of histotripsy with BC to improve the efficacy of treatment of retracted clots. An integrated histotripsy and bubble-coalescing (HBC) transducer system with specialized electronic driving system was built in-house. One high-amplitude (32 MPa), one-cycle histotripsy pulse followed by 36 low-amplitude (2.4 MPa), one-cycle BC pulses formed one HBC sequence. Results indicate that HBC sequences successfully generated a flow channel through the retracted clots at scan speeds of 0.2–0.5 mm/s. The channel size created using the HBC sequence was 128% to 480% larger than that created using histotripsy alone. The clot debris particles generated during HBC treatments were within the tolerable range. These results illustrate the concept that BC improves the treatment efficacy of histotripsy thrombolysis for retracted clots.

Histotripsy is a tissue ablation method that utilizes focused, high-amplitude ultrasound to generate a cavitation bubble cloud that mechanically fractionates tissue. Effective histotripsy depends on the initiation, control, and maintenance of cavitation bubble clouds in the targeted area. In this study, we hypothesized that a low-pressure acoustic pulse sequence applied before and/or during histotripsy therapy would increase the cavitation initiation pressure threshold and the growth of cavitation bubble clouds. This technique could shrink or “sharpen” the focal zone during histotripsy to produce more precise and well-defined lesions with minimal collateral damage. It may also be a way to actively protect the soft tissue from cavitation damage during lithotripsy by increasing the pressure threshold for bubble cloud initiation. We applied these low-amplitude acoustic pulse sequences before and during histotripsy treatments with the pulse repetition frequency of 1 and 100 Hz, in three different mediums: water, tissue phantom agarose gel, and bovine liver in vitro . Acoustic backscatter signals and optical imaging were used to detect and monitor the initiation, maintenance, and growth of the resulting cavitation bubble cloud. The results demonstrated that the use of low-amplitude acoustic pulse sequences could increase the cavitation pressure amplitude threshold by 20% in the targeted area.

Histotripsy fractionates tissue through a mechanical, non-invasive ultrasonic ablation process that precisely controls acoustic cavitation while utilizing real-time ultrasound (US) imaging guidance. This study investigates the potential, feasibility and tumor volume reduction effects of histotripsy for liver cancer ablation in a subcutaneous in vivo murine Hepatocellular Carcinoma (HCC) model. Hep3B tumors were generated in the right flanks of 14 NSG and 7 NOD-SCID mice. The mice were grouped as follows: A (acute, NSG with n=9 treatment and n=1 control), B (chronic, NSG with n=2 treatment and n=2 control) and C (chronic NODSCID, with n=6 treatment and n=1 control). Treatment was performed when the tumor diameters reached >5 mm. 1-2 cycle histotripsy pulses at 100 Hz PRF (p- >30 MPa) were delivered using a custom built 1 MHz therapy transducer attached to a motorized positioner, which scanned the transducer focus to traverse the targeted tumor volume, guided by real-time US imaging. Tumor ablation effectiveness was assessed by obtaining T1, T2 and T2* weighted MR images. Post euthanasia, treated tumor, brain, and lung tissue samples were harvested for histology. Histology of acute group A showed fractionation of targeted region with a sharp boundary separating it from untreated tissue. Groups B and C demonstrated effective tumor volume reduction post treatment on MRI as the homogenate and edema were resorbed within 23 weeks. However, as the tumor was subcutaneous, it was not possible to set adequate treatment margin and since the mice were immune-compromised, residual viable tumor cells eventually developed into tumor regrowth at 3-9 weeks after histotripsy. Groups B and C showed no signs of metastasis in the lung and brain. Our study successfully demonstrated the potential of histotripsy for non-invasive HCC ablation in a subcutaneous murine model. Additional work is ongoing to study the response of histotripsy in immune-competent orthotopic liver tumor models.

Medical ultrasound systems are capable of monitoring a variety of health conditions while avoiding invasive procedures. However, this function is complicated by ultrasound contrast of the tissue varying with contact pressure exerted by the probe. The knowledge of the contact pressure is beneficial for a variety of screening and diagnostic procedures involving ultrasound. This paper introduces a solid-state sensor array, which measures the contact pressure distribution between the probe and the tissue marginally affecting the ultrasound imaging capabilities. The probe design utilizes the dielectrostriction mechanism, which relates the change in dielectric properties of the sensing layer to deformation. The concept, structure, fabrication, and performance of this sensor array are discussed. The prototype device is highly tolerant to overloads (>1 MPa tested) and provides stress measurements in the range of 0.14–10 kPa. Its loss of ultrasound transmissivity is less 3 dB at 9-MHz ultrasound frequency. This performance is satisfactory for clinical and biomedical research in ultrasound image formation and interpretation, however, for commercial product, a higher ultrasound transmissivity is desired. Directions for improving the sensor ultrasound transparency and electrical performance are discussed. The sensor array described in this paper has been specifically developed for ultrasound diagnosis during breast cancer screening. However, the same sensing mechanism, the similar configuration, and the sensor array structure can be applied to other applications involving ultrasound tools for medical diagnostics.

Remanent bubble nuclei generated by primary cavitation collapse can limit the efficiency of histotripsy softtissue fractionation. When these residual bubbles persist from one histotripsy pulse to the next, they can seed the repetitive nucleation of cavitation bubbles at a discrete set of sites within the focal volume. This effect—referred to as cavitation memory— manifests in inefficient lesion formation, because certain sites within the focal volume are overtreated whereas others remain undertreated. Although the cavitation memory effect can be passively mitigated by using a low pulse repetition frequency (PRF) that affords remanent nuclei sufficient time for dissolution between successive pulses, this low PRF also results in slow lesion production. As such, it would be highly desirable to maintain the high per-pulse efficiency associated with low pulse rates when much higher PRFs are utilized. In this vein, we have developed a strategy for the active removal of the remanent bubble nuclei following primary cavitation collapse, using low-amplitude ultrasound sequences (termed bubble-removal sequences) to stimulate the aggregation and subsequent coalescence of these bubbles. In this study, bubbleremoval sequences were incorporated in high-PRF histotripsy treatment (100 Hz) of a red blood cell tissue-mimicking phantom that allows for the visualization of lesion development in real time. A series of reference treatments were also conducted at the low PRF of 1 Hz to provide a point of comparison for which cavitation memory effects are minimal. It was found that bubble-removal sequences as short as 1 ms are capable of maintaining the efficacious lesion development characteristics associated with the low PRF of 1 Hz when the much higher pulse rate of 100 Hz is used. These results were then extended to the treatment of a large volume within the tissue phantom, and optimal bubble-removal sequences identified for the singlefocal- spot case were utilized to homogenize a 10 × 10 mm region at high rate.

Objectives The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) atlas for ultrasound (US) qualitatively describes the echogenicity and attenuation of a mass, where fat lobules serve as a standard for comparison. This study aimed to estimate acoustic properties of breast fat under clinical imaging conditions to determine the degree to which properties vary among patients. Methods Twenty-four women with solid breast masses scheduled for biopsy were scanned with a Siemens S2000 scanner and 18L6 linear array transducer (Siemens Medical Solutions, Malvern, PA). Offline analysis estimated the attenuation coefficient and backscatter coefficients (BSCs) from breast fat using the reference phantom method. The average BSC was calculated over 6 to 12 MHz to objectively quantify the BI-RADS US echo pattern descriptor, and effective scatterer diameters were also estimated. Results A power law fit to the attenuation coefficient versus frequency yielded an attenuation coefficient of 1.28 dB·cm(-1) MHz(-0.73). The mean attenuation coefficient versus frequency slope ± SD at 7 MHz was 0.73 ± 0.23 dB·cm(-1) MHz(-1), in agreement with previously reported values. The BSC versus frequency showed close agreement among all patients, both in magnitude and frequency dependence, with a power law fit of (0.6 ± 0.25) ×10(-4) sr(-1) cm(-1) MHz(-2.49). The average backscatter in the 6-12-MHz range was 0.004 ± 0.002 sr(-1) cm(-1). The mean effective scatterer diameter for fat was 60.2 ± 9.5 μm. Conclusions The agreement in parameter estimates for breast fat among these patients supports the use of fat as a standard for comparison with tumors. Results also suggest that objective quantification of these BI-RADS US descriptors may reduce subjectivity when interpreting B-mode image data.

The efficacy of ultrasound therapies such as shock wave lithotripsy and histotripsy can be compromised by residual cavitation bubble nuclei that persist following the collapse of primary cavitation. In our previous work, we have developed a unique strategy for mitigating the effects of these residual bubbles using low amplitude ultrasound pulses to stimulate their aggregation and subsequent coalescence—effectively removing them from the field. Here, we further develop this bubble removal strategy through an investigation of the effect of frequency on the consolidation process. Bubble removal pulses ranging from 0.5 – 2 MHz were used to sonicate the population of residual nuclei produced upon collapse of a histotripsy bubble cloud. For each frequency, mechanical index (MI) values ranging from 0 to approximately 1.5 were tested. Results indicated that, when evaluated as a function of bubble removal pulse MI, the efficacy of bubble removal shows markedly similar trends for all frequencies tested. This behavior divides into three distinct regimes (with provided cutoffs being approximate): (1) MI < 0.2: Minimal effect on the population of remnant cavitation nuclei; (2) 0.2 < MI < 1: Aggregation and subsequent coalescence of residual bubbles, the extent of which trends toward a maximum; (3) MI > 1: Bubble coalescence is compromised as bubble removal pulses induce high magnitude inertial cavitation of residual bubbles. The major distinction in these trends came for bubble removal pulses applied at 2 MHz, which were observed to generate the most effective bubble coalescence of all frequencies tested. We hypothesize that this is a consequence of the secondary Bjerknes force being the major facilitator of the consolidation process, the magnitude of which increases when the bubble size distribution is far from resonance such that the phase difference of oscillation of individual bubbles is minimal.

Quantitative ultrasound estimates based on the backscatter coefficient (BSC) have demonstrated the ability to detect and classify disease beyond the capabilities of traditional B-mode imaging. Quantitative ultrasound has been able to differentiate live from apoptotic cells or oncotic cells in vitro with high-frequency ultrasound,1,2 monitor changes in tissue microstructure due to high-intensity focused ultrasound at high frequencies in a preclinical model,3 and monitor changes due to chemotherapy clinically at 6 MHz.4 Tumors have been characterized and differentiated using quantitative ultrasound at high frequencies in preclinical models of thyroid cancer,5 at high frequencies in clinical applications for ocular tumors,6,7 and at clinical frequencies in human patients for breast tumors8 and prostate cancers.9,10 Also, the BSC has been proven valuable for diagnosing fatty liver disease clinically11 and for monitoring physiologic and pharmacologic responses in renal function at clinical frequencies in an animal model.12,13 One of the BSC features that is often cited as an advantage is its system independence; ie, the same BSC value for a given tissue can be estimated from any imaging platform. Previous studies have demonstrated system independence of BSC estimates in well-characterized phantoms.14–17 These investigations applied single-element imaging systems measuring backscatter levels for strong glass bead scatterer phantoms (1–12 MHz),14,15 single-element imaging systems for probing weakly scattering agar-in-agar phantoms (1–13 MHz),16 and clinical array imaging systems for estimating BSC for phantoms with glass bead scatterers (1–15 MHz).17 Parametric estimates based on the BSC have demonstrated the ability to differentiate different types of orthotopic mouse tumors ex vivo (16–24 MHz),18 to identify regions of micrometastases within resected lymph nodes clinically (26.5 MHz center),19 and to identify dominant sources of backscattering in the renal cortex (frequencies covering 2.5–15 MHz).12,13,20,21 The frequency ranges in these studies cover the range being investigated in this study: namely, from the clinical frequencies to the lower end of the small-animal pre-clinical imaging frequencies, covering, for example, 1 to 21 MHz. This study addresses the need for demonstrating that in vivo interlaboratory measurements can be used to distinguish different types of tumors, while being able to obtain consistent BSC results from all systems. Previous studies22,23 examined BSC agreement across single-element and clinical imaging systems for an in vivo rodent fibroadenoma model over a frequency range of 1 to 14 MHz. The heterogeneity of the benign fibroadenomas provided a near worst-case scenario to evaluate quantitative ultrasound performance. The study presented herein seeks to expand on this work using clinical and preclinical array imaging systems to test their capability to detect known tissue differences while maintaining good agreement in BSC values across all systems. Mouse (4T1) and rat (MAT) mammary tumor models were used in a comparative experiment with 3 array-based ultrasound imaging systems (Siemens, Ultrasonix, and VisualSonics) and 5 different transducers covering a range of frequency bandwidths. Backscatter coefficient agreement between systems was assessed, as well as the ability to differentiate the two tumor types.

Histotripsy has been shown to be an effective treatment for model kidney stones, eroding their surface to tiny particulate debris via a cavitational bubble cloud. However, similar to shock wave lithotripsy, histotripsy stone treatments display a rate-dependent efficacy, with pulses applied at a low rate generating more efficient stone erosion in comparison with those applied at a high rate. This is hypothesized to be the result of residual cavitation bubble nuclei generated by bubble cloud collapse. Although the histotripsy bubble cloud only lasts on the order of 100 μs, these microscopic remnant bubbles can persist on the order of 1 s, inducing direct attenuation of subsequent histotripsy pulses and influencing bubble cloud dynamics. In an effort to mitigate these effects, we have developed a novel strategy to actively remove residual cavitation nuclei from the field using low-amplitude ultrasound pulses. Previous work has demonstrated that with selection of the appropriate acoustic parameters these bubble removal pulses can stimulate the aggregation and subsequent coalescence of microscopic bubble nuclei, effectively deleting them from the target volume. Here, we incorporate bubble removal pulses in histotripsy treatment of model kidney stones. It was found that when histotripsy is applied at low rate (1 Hz), bubble removal does not produce a statistically significant change in erosion. At higher pulse rates of 10, 100, and 500 Hz, incorporating bubble removal results in 3.7-, 7.5-, and 2.7-fold increases in stone erosion, respectively. High-speed imaging indicates that the introduction of bubble removal pulses allows bubble cloud dynamics resulting from high pulse rates to more closely approximate those generated at the low rate of 1 Hz. These results corroborate previous work in the field of shock wave lithotripsy regarding the ill effects of residual bubble nuclei, and suggest that high treatment efficiency can be recovered at high pulse rates through appropriate manipulation of the cavitation environment surrounding the stone.

OBJECTIVEHistotripsy is an ultrasound-based treatment modality relying on the generation of targeted cavitation bubble clouds, which mechanically fractionate tissue. The purpose of the current study was to investigate the in vivo feasibility, including dosage requirements and safety, of generating well-confined destructive lesions within the porcine brain utilizing histotripsy technology.METHODSFollowing a craniectomy to open an acoustic window to the brain, histotripsy pulses were delivered to generate lesions in the porcine cortex. Large lesions with a major dimension of up to 1 cm were generated to demonstrate the efficacy of histotripsy lesioning in the brain. Gyrus-confined lesions were generated at different applied dosages and under ultrasound imaging guidance to ensure that they were accurately targeted and contained within individual gyri. Clinical evaluation as well as MRI and histological outcomes were assessed in the acute (≤ 6 hours) and subacute (≤ 72 hours) phases of recovery.RESULTSHistotripsy was able to generate lesions with a major dimension of up to 1 cm in the cortex. Histotripsy lesions were seen to be well demarcated with sharp boundaries between treated and untreated tissues, with histological evidence of injuries extending ≤ 200 µm from their boundaries in all cases. In animals with lesions confined to the gyrus, no major hemorrhage or other complications resulting from treatment were observed. At 72 hours, MRI revealed minimal to no edema and no radiographic evidence of inflammatory changes in the perilesional area. Histological evaluation revealed the histotripsy lesions to be similar to subacute infarcts.CONCLUSIONSHistotripsy can be used to generate sharply defined lesions of arbitrary shapes and sizes in the swine cortex. Lesions confined to within the gyri did not lead to significant hemorrhage or edema responses at the treatment site in the acute or subacute time intervals.

A three-dimensional (3D) region-growing motion tracking (RGMT) method for ultrasound elasticity imaging is described. This 3D RGMT method first estimates the displacements at a sparse subset of points, called seeds, uses an objective measure to determine, among those seeds, which displacement estimates to trust, and then performs RGMT in 3D to estimate displacements for the remaining points in the field. During the growing process in 3D, the displacement estimate at one grid point is employed to guide the displacement estimation of its neighboring points using a 3D small search region. To test this algorithm, volumetric ultrasound radiofrequency echo data was acquired from a phantom and five in vivo human breasts. Displacement estimates obtained with the 3D RGMT method were compared with a published two-dimensional (2D) RGMT method via the motion-compensated cross correlation (MCCC) of pre- and post-deformation radiofrequency echo signals. For data from experiments with the phantom, the average MCCC values in the entire tracking region of interest (ROI) were approximately 0.95 and the contrast to noise ratios were 4.6 for both tracking methods. For all 5 human subjects, the average MCCC values within the ROI obtained with the 3D RGMT were consistently higher than those obtained with the 2D RGMT method. These results demonstrated that the 3D RGMT algorithm has the ability to track displacements with increased accuracy and generate higher-quality 3D elasticity images than the 2D RGMT method.

The non-pregnant cervix is composed of layers of pseudo-aligned collagen wrapped circumferentially around the cervical canal. Studies in rodents have shown that this structure disorganizes and breaks down throughout normal pregnancy. There is evidence to suggest that layered, pseudo-aligned collagen fibers in the non-pregnant cervix induce an angle-dependence (anisotropy) in backscattered ultrasound power. We therefore hypothesize that quantification of backscattered power anisotropy can track (ab)normal changes in the cervix collagen structure that precede (pre)term parturition. To test our hypothesis, we longitudinally measured backscattered power anisotropy throughout gestation in the cervix of a non-human primate model.

Current liver cancer ablation methods are mainly thermal-based and inherently exhibit inconsistent tissue ablation due to irregular heat dissipation. Histotripsy is a non-thermal ultrasound (US) ablation method that fractionates tissue through the precise control of acoustic cavitation. This paper studies the feasibility and chronic effects of non-invasive histotripsy for liver cancer ablation in an in vivo murine HCC model.

One of the main objectives of this study is to develop active tissue protection techniques for histotripsy treatment by modulating the pressure threshold of bubble cloud initiation and focal sharpening using bubble suppressing pulses. Histotripsy is a cavitation based ultrasound therapy that can achieve tissue fractionation through a mechanical process using controlled cavitation bubble clouds. In this study, we investigate the effect of applying bubble suppressing pulses before and during shock scattering histotripsy on the cavitation initiation pressure threshold. This threshold is expected to increase by reducing the probability of having an appropriate initial nuclei presence at the focus. Bubble suppressing pulses are utilized to sharpen the focus and produce a dense bubble cloud at the focus with minimized cavitation events in the peripheral zones.

Histotripsy uses high-pressure, microsecond-long ultrasound pulses to generate a cloud of cavitation to fractionate cells in target tissues such as tumors, blood clots and brain applications. B-mode ultrasound has been used to detect the cavitation and tissue fractionation generated by histotripsy, but it requires a separate imaging probe and can only detect substantial amounts of tissue fractionation. In this study, a specialized circuit and digitizer was designed to allow all the elements of a 112-element array to transmit extremely high-pressure (>40MPa) histotripsy pulses and receive the low-pressure Acoustic Cavitation Emission (ACE) signals. ACE feedback can be achieved via the histotripsy array itself and may have a high sensitivity to detect tissue fractionation.

Histotripsy is a noninvasive ultrasound therapy that fractionates target tissues via cavitation. Our group has previously demonstrated that histotripsy can be delivered transcranially through excised human skulls to rapidly liquefy large volume clots for catheter aspiration using electronic focal steering (up to 40mL in 20 min) in an ex vivo ICH model. Transcranial MRgFUS has been investigated for ICH treatment, but is much slower (40mL in 3 hours), and limited to deep targets due to prefocal skull heating. The objective of this study was to demonstrate the feasibility of using histotripsy to liquefy clots for catheter aspiration in an in vivo porcine ICH model.

Purpose Elastography has emerged as a new tool for detecting and diagnosing many types of diseases including breast cancer. To date, most clinical applications of elastography have utilized two-dimensional strain images. The goal of this paper is to present a new quasi-static elastography technique that yields shear modulus images in three dimensions Methods An automated breast volume scanner was used to acquire ultrasound images of the breast as it was gently compressed. Cross-correlation between successive images was used to determine the displacement within the tissue. The resulting displacement field was filtered of all but compressive motion through principal component analysis. This displacement field was usedto infer spatial distribution of shear modulus by solving a 3D elastic inverse problem. Results Three dimensional shear modulus images of benign breast lesions for two subjects were generated using the techniques described above. It was found that the lesions were visualized more clearly in images generated using the displacement data de-noised through the use of principal components. Conclusions We have presented experimental and algorithmic techniques that lead to three dimensional imaging of shear modulus using quasi-static elastography. This work demonstrates feasibility of this approach, and lays the foundation for images of other, more informative, mechanical parameters. This article is protected by copyright. All rights reserved.

The aim of this study was to assess the ability of shear wave elasticity imaging (SWEI) to detect changes in cervical softness between early and late pregnancy. Using a cross-sectional study design, shear wave speed (SWS) measurements were obtained from women in the first trimester (5-14 wk of gestation) and compared with estimates from a previous study of women at term (37-41 wk). Two sets of five SWS measurements were made using commercial SWEI applications on an ultrasound system equipped with a prototype catheter transducer (128 elements, 3-mm diameter, 14-mm aperture). Average SWS estimates were 4.42 ± 0.32 m/s (n = 12) for the first trimester and 2.13 ± 0.66 m/s (n = 18) for the third trimester (p

There has been an emerging interest in high intensity focused ultrasound (HIFU) for therapeutic applications. By means of its thermal or mechanical effects, HIFU is able to serve as a direct tool for tissue ablation, or an indirect moderating medium to manipulate microbubbles or perform heating (hyperthermia) for the purpose of targeted drug delivery. The development and testing of HIFU based phased arrays is favorable as their elements allow for individual phasing to steer and focus the beam. While FDA has already approved tissue ablation by HIFU for the treatment of uterine fibroids (2004) and pain from bone metastases (2012), development continues on other possible applications that are less forgiving of incomplete treatment, such as thermal necrosis of malignant masses. Ideally, each element, of such an array must have its own fully programmable electrical driving channel, which allows the control of delay, phase, and amplitude of the output from each element. To enable full control, each channel needs a waveform generator, an amplification device, and an impedance matching circuit between driver and acoustic element. Similar projects utilizing this approach to drive therapeutic arrays include a 512-channel therapy system which was built at the University of Michigan using low cost Field-Programmable Gate Arrays (FPGA) microcontroller and highly efficient MOSFET switching amplifiers [1]. However, this system lacks the ability to drive both, continuous wave (CW) and transient short duty-cycle high power pulses. This paper presents a hybrid system, which is able to perform CW and transient short duty-cycle high power excitation. In the following we will describe the design, programming, fabrication, and evaluation of this radiofrequency (RF) driver system as used in our laboratory for a 1.5 MHz center frequency, 298-element array (Imasonic SA, Besancon, France) [2], FPGA-controlled amplifier boards and matching circuitry. Advantages of our design include: 1. Inexpensive components (

Microscopic residual bubble nuclei can persist on the order of 1 second following a cavitation event. These bubbles can limit the efficacy of ultrasound therapies such as shock wave lithotripsy and histotripsy, as they attenuate pulses that arrive subsequent to their formation and seed repetitive cavitation activity at a discrete set of sites (cavitation memory). Here, we explore a strategy for the removal of these residual bubbles following a cavitation event, using low amplitude ultrasound pulses to stimulate bubble coalescence. All experiments were conducted in degassed water and monitored using high speed photography. In each case, a 2 MHz histotripsy transducer was used to initiate cavitation activity (a cavitational bubble cloud), the collapse of which generated a population of residual bubble nuclei. This residual nuclei population was then sonicated using a 1 ms pulse from a separate 500 kHz transducer, which we term the ‘bubble removal pulse.’ Bubble removal pulse amplitudes ranging from 0 to 1.7 MPa were tested, and the backlit area of shadow from bubbles remaining in the field following bubble removal was calculated to quantify efficacy. It was found that an ideal amplitude range exists (roughly 180 – 570 kPa) in which bubble removal pulses stimulate the aggregation and subsequent coalescence of residual bubble nuclei, effectively removing them from the field. Further optimization of bubble removal pulse sequences stands to provide an adjunct to cavitation-based ultrasound therapies such as shock wave lithotripsy and histotripsy, mitigating the effects of residual bubble nuclei that currently limit their efficacy.

In diagnostic ultrasound, broadband transducers capable of short acoustic pulse emission and reception can improve axial resolution and provide sufficient bandwidth for harmonic imaging and multi-frequency excitation techniques. In histotripsy, a cavitation-based ultrasound therapy, short acoustic pulses (

Objectives To explore spatial variability within the cervix and the sensitivity of shear wave speed (SWS) to assess softness/stiffness differences in ripened (softened) vs unripened tissue. Methods We obtained SWS estimates from hysterectomy specimens (n = 22), a subset of which were ripened (n = 13). Multiple measurements were made longitudinally along the cervical canal on both the anterior and posterior sides of the cervix. Statistical tests of differences in the proximal vs distal, anterior vs posterior and ripened vs unripened cervix were performed with individual two-sample t-tests and a linear mixed model. Results Estimates of SWS increase monotonically from distal to proximal longitudinally along the cervix, they vary in the anterior compared to the posterior cervix and they are significantly different in ripened vs unripened cervical tissue. Specifically, the mid position SWS estimates for the unripened group were 3.45 ± 0.95 m/s (anterior; mean ± SD) and 3.56 ± 0.92 m/s (posterior), and 2.11 ± 0.45 m/s (anterior) and 2.68 ± 0.57 m/s (posterior) for the ripened group (P

We report here the results of a longitudinal study of cervix stiffness during pregnancy. Thirty women, ages ranging from 19 to 37 years, were scanned with ultrasound at five time points beginning at their normal first-trimester screening (8–13 weeks) through term pregnancy (nominally 40 week) using a clinical ultrasound imaging system modified with a special ultrasound transducer and system software. The system estimated the shear wave speed (its square proportional to the shear modulus under idealized conditions) in the cervix. We found a constant fractional reduction (about 4% per week) in shear wave speed with increasing gestational age. We also demonstrated a spatial gradient in shear wave speed along the length of the cervix (softest at the distal end). Results were consistent with our previous ex vivo and in vivo work in women. Shear wave elasticity imaging may be a potentially useful clinical tool for objective assessment of cervical softening in pregnancy.

The uterine cervix softens, shortens, and dilates throughout pregnancy in response to progressive disorganization of its layered collagen microstructure. This process is an essential part of normal pregnancy, but premature changes are associated with preterm birth. Clinically, there are no reliable noninvasive methods to objectively measure cervical softening or assess cervical microstructure. The goal of these preliminary studies was to evaluate the feasibility of using an intracavity ultrasound array to generate acoustic radiation force impulse (ARFI) excitations in the uterine cervix through simulation, and to optimize the acoustic radiation force (ARF) excitation for shear wave elasticity imaging (SWEI) of the tissue stiffness. The cervix is a unique soft tissue target for SWEI because it has significantly greater acoustic attenuation (α = 1.3 to 2.0 dB·cm(-1)·MHz(-)1) than other soft tissues, and the pathology being studied tends to lead to an increase in tissue compliance, with healthy cervix being relatively stiff compared with other soft tissues (E ≈ 25 kPa). Additionally, the cervix can only be accessed in vivo using a transvaginal or catheter-based array, which places additional constraints on the excitation focal characteristics that can be used during SWEI. Finite element method (FEM) models of SWEI show that larger-aperture, catheter-based arrays can utilize excitation frequencies up to 7 MHz to generate adequate focal gain up to focal depths 10 to 15 mm deep, with higher frequencies suffering from excessive amounts of near-field acoustic attenuation. Using full-aperture excitations can yield ~40% increases in ARFI-induced displacements, but also restricts the depth of field of the excitation to ~0.5 mm, compared with 2 to 6 mm, which limits the range that can be used for shear wave characterization of the tissue. The center-frequency content of the shear wave particle velocity profiles ranges from 1.5 to 2.5 kHz, depending on the focal configuration and the stiffness of the material being imaged. Overall, SWEI is possible using catheter-based imaging arrays to generate adequate displacements in cervical tissue for shear wave imaging, although specific considerations must be made when optimizing these arrays for this shear wave imaging application.

Histotripsy is an ultrasound ablation method that depends on the initiation of a cavitation bubble cloud to fractionate soft tissue. Although previous work has provided significant insight into the process of intrinsic threshold histotripsy, the majority of these studies have used highly focused (i.e. f-number

Objective To compare the number and density of lung metastases in histotripsy-treated and control subjects. Histotripsy is a noninvasive, nonthermal, pulsed ultrasound technology that produces targeted mechanical tissue fractionation. Histotripsy ablation of renal implanted VX-2 tumor has been previously demonstrated; however, concerns have been raised that mechanical forces associated with histotripsy might result in unwanted metastatic dissemination of tumor. Methods VX-2 tumor was implanted into the left kidneys of New Zealand White rabbits. Twenty rabbits were treated with histotripsy on day 13; 8 were maintained as controls. All rabbits underwent left nephrectomy on day 14. Lungs were harvested and processed for histopathologic inspection on day 19. Whole-mount coronal lung sections were examined to determine the number of metastases and metastatic density. Results Tumors grew after implantation in all 28 cases and were localized with ultrasound in 19 of 20 subjects before treatment. Histology confirmed fractionation of tumor in all treatment rabbits. The number of lung metastases (88.7 vs 72.5; P = .29) and the metastatic density (8.9 vs 7.0 mets/cm2; P = .22) were not statistically different between treatment and control rabbits. Conclusion Histotripsy of renal implanted VX-2 tumor in an in-vivo rabbit model did not produce a statistically significant increase in number or density of lung metastasis. Data suggesting a trend toward increased metastases after histotripsy are overwhelmed by the high baseline rate of metastases in this aggressive tumor model. Further investigation using less aggressive tumor models is indicated to clarify this relationship.

The strain image contrast of some in vivo breast lesions changes with increasing applied load. This change is attributed to differences in the nonlinear elastic properties of the constituent tissues suggesting some potential to help classify breast diseases by their nonlinear elastic properties. A phantom with inclusions and long-term stability is desired to serve as a test bed for nonlinear elasticity imaging method development, testing, etc. This study reports a phantom designed to investigate nonlinear elastic properties with ultrasound elastographic techniques. The phantom contains four spherical inclusions and was manufactured from a mixture of gelatin, agar and oil. The phantom background and each of the inclusions has distinct Young’s modulus and nonlinear mechanical behavior. This phantom was subjected to large deformations (up to 20%) while scanning with ultrasound, and changes in strain image contrast and contrast-to-noise ratio (CNR) between inclusion and background, as a function of applied deformation, were investigated. The changes in contrast over a large deformation range predicted by the finite element analysis (FEA) were consistent with those experimentally observed. Therefore, the paper reports a procedure for making phantoms with predictable nonlinear behavior, based on independent measurements of the constituent materials, and shows that the resulting strain images (e.g., strain contrast) agrees with that predicted with nonlinear FEA.

Histotripsy is a cavitation-based ultrasound therapy that mechanically fractionates soft solid tissues into fluid-like homogenates. This paper investigates the feasibility of imaging the tissue elasticity change during the histotripsy process as a tool to provide feedback for the treatments. The treatments were performed on agar tissue phantoms and ex vivo kidneys using 3-cycle ultrasound pulses delivered by a 750-kHz therapeutic array at peak negative/positive pressure of 17/108 MPa and a repetition rate of 50 Hz. Lesions with different degrees of damage were created with increasing numbers of therapy pulses from 0 to 2000 pulses per treatment location. The elasticity of the lesions was measured with ultrasound shear wave elastography, in which a quasi-planar shear wave was induced by acoustic radiation force generated by the therapeutic array, and tracked with ultrasound imaging at 3000 frames per second. Based on the shear wave velocity calculated from the sequentially captured frames, the Young’s modulus was reconstructed. Results showed that the lesions were more easily identified on the shear wave velocity images than on B-mode images. As the number of therapy pulses increased from 0 to 2000 pulses/location, the Young’s modulus decreased exponentially from 22.1 ± 2.7 to 2.1 ± 1.1 kPa in the tissue phantoms (R2 = 0.99, N = 9 each), and from 33.0 ± 7.1 to 4.0 ± 2.5 kPa in the ex vivo kidneys (R2 = 0.99, N = 8 each). Correspondingly, the tissues transformed from completely intact to completely fractionated as examined via histology. A good correlation existed between the lesions’ Young’s modulus and the degree of tissue fractionation as examined with the percentage of remaining structurally intact cell nuclei (R2 = 0.91, N = 8 each). These results indicate that lesions produced by histotripsy can be detected with high sensitivity using shear wave elastography. Because the decrease in the tissue elasticity corresponded well with the morphological and histological change, this study provides a basis for predicting the local treatment outcomes from tissue elasticity change.

Cavitation memory effects occur when remnants of cavitation bubbles (nuclei) persist in the host medium and act as seeds for subsequent events. In pulsed cavitational ultrasound therapy, or histotripsy, this effect may cause cavitation to repeatedly occur at these seeded locations within a target volume, producing inhomogeneous tissue fractionation or requiring an excess number of pulses to completely homogenize the target volume. We hypothesized that by removing the cavitation memory, i.e., the persistent nuclei, the cavitation bubbles could be induced at random locations in response to each pulse; therefore, complete disruption of a tissue volume may be achieved with fewer pulses. To test the hypothesis, the cavitation memory was passively removed by increasing the intervals between successive pulses, ∆t, from 2, 10, 20, 50 and 100, to 200 ms. Histotripsy treatments were performed in red blood cell tissue phantoms and ex vivo livers using 1-MHz ultrasound pulses of 10 cycles at P-/P+ pressure of 21/59 MPa. The phantom study allowed for direct visualization of the cavitation patterns and the lesion development process in real time using high-speed photography; the ex vivo tissue study provided validation of the memory effect in real tissues. Results of the phantom study showed an exponential decrease in the correlation coefficient between cavitation patterns in successive pulses from 0.5 ± 0.1 to 0.1 ± 0.1 as ∆t increased from 2-200 ms; correspondingly, the lesion was completely fractionated with significantly fewer pulses for longer ∆ts. In the tissue study, given the same number of therapy pulses, complete and homogeneous tissue fractionation with well-defined lesion boundaries was achieved only for ∆t ≥ 100 ms. These results indicated that the removal of the cavitation memory resulted in more efficient treatments and homogeneous lesions.