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Phase aberration induced by soft tissue inhomogeneities often complicates high-intensity focused ultrasound (HIFU) therapies by distorting the field and, previously, we designed and fabricated a bilayer gel phantom to reproducibly mimic that effect. A surface pattern containing size scales relevant to inhomogeneities of a porcine body wall was introduced between gel materials with fat- and muscle-like acoustic properties—ballistic and polyvinyl alcohol gels. Here, the phantom design was refined to achieve relevant values of ultrasound absorption and scattering and make it more robust, facilitating frequent handling and use in various experimental arrangements. The fidelity of the interfacial surface of the fabricated phantom to the design was confirmed by three-dimensional ultrasound imaging. The HIFU field distortions—displacement of the focus, enlargement of the focal region, and reduction of focal pressure—produced by the phantom were characterized using hydrophone measurements with a 1.5 MHz 256-element HIFU array and found to be similar to those induced by an ex vivo porcine body wall. A phase correction approach was used to mitigate the aberration effect on nonlinear focal waveforms and enable boiling histotripsy treatments through the phantom or body wall. The refined phantom represents a practical tool to explore HIFU therapy systems capabilities.

Inertial cavitation induced by pulsed high-intensity focused ultrasound (pHIFU) has previously been shown to successfully permeabilize tumor tissue and enhance chemotherapeutic drug uptake. In addition to HIFU frequency, peak rarefactional pressure ( ${p}^{-}$ ), and pulse duration, the threshold for cavitation-induced bioeffects has recently been correlated with asymmetric distortion caused by nonlinear propagation, diffraction and formation of shocks in the focal waveform, and therefore with the transducer ${F}$ -number. To connect previously observed bioeffects with bubble dynamics and their attendant physical mechanisms, the dependence of inertial cavitation behavior on shock formation was investigated in transparent agarose gel phantoms using high-speed photography and passive cavitation detection (PCD). Agarose phantoms with concentrations ranging from 1.5% to 5% were exposed to 1-ms pulses using three transducers of the same aperture but different focal distances ( ${F}$ -numbers of 0.77, 1.02, and 1.52). Pulses had central frequencies of 1, 1.5, or 1.9 MHz and a range of ${p}^{-}$ at the focus varying within 1–18 MPa. Three distinct categories of bubble behavior were observed as the acoustic power increased: stationary near-spherical oscillation of individual bubbles, proliferation of multiple bubbles along the pHIFU beam axis, and fanned-out proliferation toward the transducer. Proliferating bubbles were only observed under strongly nonlinear or shock-forming conditions regardless of frequency, and only where the bubbles reached a certain threshold size range. In stiffer gels with higher agarose concentrations, the same pattern of cavitation behavior was observed, but the dimensions of proliferating clouds were smaller. These observations suggest mechanisms that may be involved in bubble proliferation: enhanced growth of bubbles under shock-forming conditions, subsequent shock scattering from the gel–bubble interface, causing an increase in the repetitive tension created by the acoustic wave, and the appearance of a new growing bubble in the proximal direction. Different behaviors corresponded to specific spectral characteristics in the PCD signals: broadband noise in all cases, narrow peaks of backscattered harmonics in the case of stationary bubbles, and broadened, shifted harmonic peaks in the case of proliferating bubbles. The shift in harmonic peaks can be interpreted as a Doppler shift from targets moving at speeds of up to 2 m/s, which correspond to the observed bubble proliferation speeds.

Graphene oxide (GO) is a promising membrane system for chemical separation applications due to its 2-D nanofluidics properties and an ability to control interplanar spacing for selectivity. The permeance of water, methanol (MeOH) and isopropyl alcohol (IPA) through 5 µm thick membranes was found to be 0.38 ± 0.15, 0.33 ± 0.16 and 0.42 ± 0.31 LMH/bar (liter/m2·h·bar), respectively. Interestingly, the permeance of a water–alcohol mixture was found to be dramatically lower (~0.01 LMH/bar) than any of its components. Upon removing the solvent mixture, the transmembrane flux of the pure solvent was recovered to near the original permeance. The interlayer space of a dried GO membrane was found to be 8.52 Å, which increased to 12.19 Å. 13.26 Å and 16.20 Å upon addition of water, MeOH and IPA. A decrease in d-space, about 2 Å, was consistently observed when adding alcohol to water wetted GO membrane and an optical color change and reduction in permeance. A newly proposed mechanism of a partial reduction of GO through a catalytic reaction with the water–alcohol mixture is consistent with experimental observations.

Phase aberrations induced by heterogeneities in body wall tissues introduce a shift and broadening of the high-intensity focused ultrasound (HIFU) focus, associated with decreased focal intensity. This effect is particularly detrimental for HIFU therapies that rely on shock front formation at the focus, such as boiling histotripsy (BH). In this article, an aberration correction method based on the backscattering of nonlinear ultrasound pulses from the focus is proposed and evaluated in tissue-mimicking phantoms. A custom BH system comprising a 1.5-MHz 256-element array connected to a Verasonics V1 engine was used as a pulse/echo probe. Pulse inversion imaging was implemented to visualize the second harmonic of the backscattered signal from the focus inside a phantom when propagating through an aberrating layer. Phase correction for each array element was derived from an aberration-correction method for ultrasound imaging that combines both the beamsum and the nearest neighbor correlation method and adapted it to the unique configuration of the array. The results were confirmed by replacing the target tissue with a fiber-optic hydrophone. Comparing the shock amplitude before and after phase-aberration correction showed that the majority of losses due to tissue heterogeneity were compensated, enabling fully developed shocks to be generated while focusing through aberrating layers. The feasibility of using a HIFU phased-array transducer as a pulse-echo probe in harmonic imaging mode to correct for phase aberrations was demonstrated.

Aberrations induced by soft tissue inhomogeneities often complicate high-intensity focused ultrasound (HIFU) therapies. In this work, a bilayer phantom made from polyvinyl alcohol hydrogel and ballistic gel was built to mimic alternating layers of water-based and lipid tissues characteristic of an abdominal body wall and to reproducibly distort HIFU fields. The density, sound speed, and attenuation coefficient of each material were measured using a homogeneous gel layer. A surface with random topographical features was designed as an interface between gel layers using a 2D Fourier spectrum approach and replicating different spatial scales of tissue inhomogeneities. Distortion of the field of a 256-element 1.5 MHz HIFU array by the phantom was characterized through hydrophone measurements for linear and nonlinear beam focusing and compared to the corresponding distortion induced by an ex vivo porcine body wall of the same thickness. Both spatial shift and widening of the focal lobe were observed, as well as dramatic reduction in focal pressures caused by aberrations. The results suggest that the phantom produced levels of aberration that are similar to a real body wall and can serve as a research tool for studying HIFU effects as well as for developing algorithms for aberration correction.

Boiling histotripsy (BH) is a high intensity focused ultrasound method that induces mechanical tissue liquefaction and relies on the formation of a mm-sized vapor bubble at the focus. One challenge of transcutaneous BH is to confirm the presence of such bubble and to differentiate it from prefocal cavitation. Strong prefocal cavitation can shield the focus, prevent initiation of boiling, and lead to unsuccessful treatment, although an echogenic region would still be present on B-mode ultrasound images. Here, a methodology for real-time monitoring of different bubble activity during BH treatment is proposed. Custom BH systems of 1 and 1.5 MHz with inline ultrasound imaging probes connected to a Verasonics V1 system were used for BH treatments in pigs in vivo and in ex vivo tissues. Backscattered signals arriving to the imaging probe were recorded during the 10 ms BH pulses delivered at 1 Hz and passive cavitation imaging (PCI) reconstruction was performed and displayed on top of the B-mode images to identify and classify the regions of bubble activity. Spectral analysis of the PCI signals promoting prefocal cavitation and lack thereof was performed to identify the spectral features corresponding to prefocal cavitation and vapor bubble formation. [Work supported by NIH R01EB007643, R01GM122859, and R01EB25187.]

Aberrations induced by soft tissue inhomogeneities distort acoustic fields and often complicate HIFU therapies. An aberration-generating phantom was designed and fabricated to mimic the acoustic effects of a porcine body wall. A rippled surface pattern replicating inhomogeneities of size scales relevant to the porcine body wall was transferred to a large phantom made of fat-like and muscle-like gel materials. The acoustic distortions produced by the phantom and an ex vivo porcine body wall were characterized by hydrophone measurements with a 256-element 1.5 MHz focused ultrasound array (diameter = 144 mm, F# = 0.83). Insertion of the phantom generated large distortions for both linear and nonlinear beam focusing including displacement of the focus (up to 0.3 mm transversely), enlargement of the focal region, and reduction in focal pressures due to aberration (up to 2.5-fold peak positive pressure reduction). The phantom and porcine body wall produced similar levels of aberration and attenuation effects. An aberration correction approach was leveraged to isolate the quantitative effect of aberration and to restore shocks in nonlinear waveforms in the focus. Boiling histotripsy treatments through the phantom or body wall were subsequently demonstrated in a hematoma sample. [This work was supported by NIH R01EB7643 and R01EB25187, and RSF 20-12-00145.]

The development of new clinical applications of therapeutic ultrasound has been accompanied by efforts to standardize simulation methods for predicting nonlinear ultrasound fields. Although software tools for simulating nonlinear ultrasound propagation are increasingly available, computational burdens remain high, especially for fields characterized by strong focusing and significant harmonic content. Because nonlinear effects in such fields accumulate primarily over a short axial distance within the focal lobe, the nonlinear field can be approximated by considering an equivalent source with a similarly shaped focal lobe in the linearly focused beam. If an axisymmetric equivalent source can be identified, even strongly nonlinear fields can be accurately simulated with minimal computational burden using the Khokhlov-Zabolotskaya- Kuznetsov model. This approach has been implemented and validated in water for several real sources using only a simple set of linear field measurements to characterize the focal lobe of each source. To demonstrate the breadth of utility of this approach, holograms of non-axisymmetric fields distorted by phantoms were also used to define equivalent sources and estimate in situ nonlinear fields. Fast holography measurements combined with equivalent-source simulations can efficiently characterize the impact of different phantom geometries on nonlinear fields. [Work supported by NIH R01EB025187 and R01EB007643, and RSF 19-12-00148.]

High intensity focused ultrasound (HIFU) therapies are often affected by aberrations, which can severely limit treatments. For multi-element arrays, applying phase corrections for each element could mitigate these effects. Here, an aberration correction method based on cross-correlation of nonlinear HIFU waves, backscattered from the focus is proposed and tested. A spherically focused 1.5 MHz 256-element HIFU array powered by Verasonics system was used for both emitting and receiving backscattered ultrasound waves. A short (3-cycle) high-amplitude pulse was transmitted through an aberrating layer into an ex vivo clotted bovine blood sample. The backscattered signal was recorded by individual array elements and high-pass filtered at 4 MHz. The layer introduced different acoustic path lengths for individual elements leading to a decrease in the peak-positive pressure of ~70%. The time delay required for each element to restore the nonlinear waveform at the focus was calculated based on the cross-correlation between the backscattered filtered signals. The results were confirmed by replacing the sample with a hydrophone. Using the corrected time delays, peak-positive focal pressure increased over 75% from uncorrected aberrated levels. These results demonstrate that the proposed focal “nonlinear beacon” can be used for phase correction feedback in HIFU treatments of soft tissue. [Work supported by NIH R01GM122859, R01EB007643, and RSF19-12-00148.]

Applications of high intensity therapeutic ultrasound (HITU) rely on the accurate delivery of ultrasound to targeted tissues. However, because in situ measurement of 3-D ultrasound fields in tissue is not possible, knowledge of such fields depends upon some form of calculation. Standard approaches utilize measurements in water to characterize the ultrasound source, with fields in tissue estimated by derating or numerical simulation. To evaluate the accuracy of numerical models, simulations and measurements have been performed based on tissue phantoms with known geometries and physical properties. In this work, holography measurements were used to characterize a 256-element HITU transducer in water and to measure directly the 3-D fields behind soft-tissue phantoms designed to introduce refraction, attenuation, and/or aberration. Using synchronization between a waveform digitizer and a computer-controlled positioner, accelerated recording of each hologram (representing over 40 000 points) was performed in about an hour by continuously scanning a capsule hydrophone line-by-line in the measurement plane. Linear measurements are compared with simulations performed using the k-Wave toolbox, and various uncertainties are quantified. It is shown that holography-based modeling accurately represents fields distorted by inhomogeneous layers mimicking body wall. [Funding support by NIH R01-EB025187, R01-EB007643, R01-R01GM122859, and RSF Grant No. 19-12-00148.]

Pulsed HIFU-induced inertial cavitation can be used to permeabilize tissue for promoting drug extravasation and penetration. In addition to HIFU frequency, peak rarefactional pressure (p-), and pulse duration, the threshold for inducing inertial cavitation has recently been correlated with nonlinear distortion of the focal waveform. Here, the effect of nonlinear distortion and HIFU frequency within the range of 0.28–1.9 MHz were investigated in transparent gel phantoms with simultaneous high-speed photography and passive cavitation detection (PCD). Transducers with different F-numbers (0.77–1.5) delivered 1 ms-long pulses with varying p- (1–15 MPa) at 1 Hz pulse rate. For all frequencies, increasing acoustic power and nonlinear distortion led to bubble behaviors changing both quantitatively and qualitatively from isolated, stationary bubbles to sparse bubble clouds that proliferated slowly towards the transducer. Different behaviors corresponded to specific spectral characteristics of the PCD signals. Exposures corresponding to particular behaviors at 1 MHz and 0.3 MHz frequencies were then applied to surgically exposed porcine liver, kidney, and pancreas in vivo with concurrent administration of Evans Blue Dye (EBD). Exposures with spectral signatures of proliferating bubbles on PCD corresponded to enhanced EBD extravasation and hemorrhagic injury to all tissues. [Work supported by NIH R01EB023910 and R01CA154451.]