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High-intensity focused ultrasound (HIFU) has been widely used in tumor ablation in clinical settings. Meanwhile, there is great potential to increase the therapeutic efficiency of temporary cavitation due to enhanced thermal effects and combined mechanical effects from nonlinear vibration and collapse of the microbubbles. In this study, dual-frequency (1.1 and 5 MHz) HIFU was used to produce acoustic droplet vaporization (ADV) microbubbles from activatable perfluoropentane-loaded polymer nanoparticles (PFP@Polymer NPs), which increased the therapeutic outcome of the HIFU and helped realize tumor theranostics with ultrasound contrast imaging. Combined with PFP@Polymer NPs, dual-frequency HIFU changed the shape of the damage lesion and reduced the acoustic intensity threshold of thermal damage significantly, from 216.86 to 62.38 W/cm2. It produced a nearly 20 °C temperature increase in half the irradiation time and exhibited a higher tumor inhibition rate (84.5% ± 3.4%) at a low acoustic intensity (1.1 MHz: 23.77 W/cm2, 5 MHz: 0.35 W/cm2) in vitro than the single-frequency HIFU (60.2% ± 11.9%). Moreover, compared with the traditional PFP@BSA NDs, PFP@Polymer NPs showed higher anti-tumor efficacy (81.13% vs. 69.34%, * p &lt, 0.05) and better contrast-enhanced ultrasound (CEUS) imaging ability (gray value of 57.53 vs. 30.67, **** p &lt, 0.0001), probably benefitting from its uniform and stable structure. It showed potential as a highly efficient tumor theranostics approach based on dual-frequency HIFU and activatable PFP@Polymer NPs.

A novel histotripsy approach based on fundamental and second harmonic superposition and incorporating hundred-microsecond-long pulses and two-stage pulse protocol is proposed in this study to rapidly generate mechanically homogenized lesions. Two pulse stages were applied: stage 1, pulses with a pulse duration of 500-600 μs and pulse repetition frequency of 100 Hz, and stage 2, multiple periods, each composed of multiple pulses with the same pulse duration and pulse repetition frequency as those in stage 1, but with an off-time of 600 ms between periods. A custom-designed 1.1/2.2-MHz two-element confocal-annular array, with an f-number of 0.69, and lateral and axial full width at half-maximum pressure dimensions of approximately 1.0 and 6.0 mm, was used. The peak positive/negative pressures at the focus were +22/-7 MPa for 1.1 MHz and +56/-14 MPa with shock wave for 2.2 MHz. To investigate the feasibility of this approach, experiments were designed and performed in tissue-mimicking polyacrylamide gel phantoms with bovine serum albumin and in ex vivo porcine tissues. Cavitation and boiling activities were observed through high-speed photography, and the corresponding acoustic emissions were recorded through passive cavitation detection. Ex vivo experimental results revealed that complete tissue homogeneous regions with regular long tear shape and typical dimensions of 5.80 ± 0.19 mm in axial and 2.20 ± 0.26 mm in lateral were successfully generated in porcine kidney samples. The hematoxylin and eosin staining evidenced that the lesions were thoroughly homogenized and sharply demarcated from untreated regions. These results indicated that the histotripsy approach using fundamental and second harmonic superposition combined with hundred-microsecond pulses and two-stage pulse protocol can efficiently obtain a mechanical disruption of soft tissues with spatial precision, and this approach may have the potential to be developed as a useful tool for precise tumor treatment.

The viscoelastic properties of tissues can reflect human physiological and pathological conditions. During and after the high-intensity focused ultrasound (HIFU) treatment, measuring the viscoelasticity of HIFU ablated tissue is important for therapy evaluation. Two-dimensional Fourier transform (2DFT) method has been reported to quantify elasticity and viscosity. However, a deviation is induced by under-sampling in practical application. This work proposes an approach based on the convolution theorem and model fitting to solve the finite spatial data problem. A model using the convolution theorem was constructed, and mean-square error (MSE) was calculated to determine the optimal fitting between the model and experimental data. For validation, HIFU therapeutic experiments were conducted in polyacrylamide-bovine serum (BAS) transparent tissue-mimicking phantoms. This approach was used to quantify the viscoelasticity of HIFU ablation and untreated phantoms. Acoustic-radiation-force (ARF) shear wave was generated by the same HIFU therapeutic transducer, and laser Doppler vibrometer (LDV) was used for the high-resolution measurement of shear wave signals. Results suggest that the shear elasticity and viscosity of untreated phantoms are generally smaller than those of HIFU ablation. Thus, the proposed method may be helpful for HIFU treatment monitoring.

Intracerebral hemorrhage is a life-threatening acute cerebrovascular disease characterized by a 30-d mortality rate of 40% and substantial disability for those who survive. The objective of this study is to investigate the feasibility of histotripsy-mediated efficient and fine liquefaction of large-volume hematoma by utilizing a protocol of millisecond-length ultrasound pulse groups combined with fundamental and second harmonic superposition. Experiments were initially performed in an in vitro hematoma phantom, using a two-element confocal-annular array. Results showed that a single ellipsoid shape, histotripsy lesion with major dimensions of 10.8 ± 1.2 mm axially and 4.8 ± 0.2 mm laterally was successfully generated. Controllability of the lesion shape and size could be realized by modulating treatment parameters in single-spot experiments. Large-volume hematomas were efficiently and finely liquefied through multisonications via a treatment strategy under the relatively optimized treatment parameters. Liquefied contents were evacuated and analyzed using a particle sizing system. The size of the lysates for the most part ranged from 4-8 μm, with more than 99% of them being smaller than 10 μm. Experiments were then conducted in an optically transparent tissue phantom to explore the liquefaction mechanisms. The phantom was composed of polyacrylamide hydrogel, embedded with bovine serum albumin (BSA), and a thin phantom layer consisted of red blood cells in the BSA polyacrylamide gel was inlayed in the BSA gel phantom. The related mechanisms, such as the frequent boiling that occurred at multiple positions and the enhanced cavitation, revealed the quick development of the lesion in the phantom and the efficient liquefaction of the clot. These results indicated that the proposed histotripsy approach is feasible for the efficient, precise and fine liquefaction of large-volume hematoma and may be developed as a useful tool for intracerebral hemorrhage treatment.

In this study, we propose a strategy of using a 4-element sector array, fundamental and second harmonic pressure superposition, and waveform of hundred-microsecond pulses and two stages. Hopefully, the rapid histotripsy process can be achieved through increasing one-spot lesion volume, enhancing pressure from cavitation reflection and multi boiling bubbles. A custom-designed 4-element sector array operated at 1.2 and 2.4 MHz with 146 mm aperture, 100 mm geometric focal length. In our initial experiments, we used the one focus pattern with acoustic focus dimension of 0.7 mm by 3 mm (lateral by axial length) and the peak negative pressure of each frequency exceeding −10 MPa. The histotripsy waveform scheme of hundred-microsecond pulses and two stages was used: stage 1, pulses with a pulse duration (PD) of 350 μs and pulse repetition frequency (PRF) of 100 Hz; stage 2, same PD and PRF as those in stage 1 and 1 % duty factor. The experiments were implemented in gel-phantom with bovine serum albumin (BSA), ex vivo porcine kidneys, monitored via high speed camera or passive cavitation detection (PCD). As expected, the experiments achieved successfully the disintegrated lesions with typical dimension of 5.5 mm by 7.5 mm (lateral by axial length) in porcine kidneys. The slide of H&E stained shows the lesion region where tissue fractionates into acellular debris with sharp boundary. The filtered-PCD mean square waveform indicates the enhanced inertial cavitation energy. The selected images from high speed imaging show the cavitation cloud structure and cavitation-bubble-layer reflection effects toward to transducer in prefocal region. The large sized lesion with wider 5.5-mm lateral dimension generated in prefocal region can attribute to dual-frequency parallel beams with shock waves, strong cavitation-bubble-layer reflection effects, and the parallel boiling bubbles of two frequencies.

The previous study has demonstrated that pulsed HIFU with tens of microseconds pulse duration and 10kHz pulse repetition frequency is effective for cavitation generation. With the assistance of perfluorocarbon (PFC) nano-droplets, cavitation can be further enhanced. But despite higher efficiency, we also need precisely controlled cavitation for sake of therapeutic safety. In this work, we propose a combinatorial ultrasound wave sequence to realize precisely controlled cavitation in PFC nano-droplets assisted HIFU ablation. The applied combinatorial wave sequence was composed of a preconditioned continuous wave sustained for several seconds, then a pause and eventually the pulsed waves. We employed sonoluminescence (SL) to visualize the cavitation active spots. The luminous area and mean light intensity were measured to represent cavitation area and intensity, respectively. High-speed photography was utilized to record the thermal ablation development process. The results showed that cavitation distribution space became more confined and less stretched when sonicated by the combinatorial sequence. The SL area decreased about 60%. Meanwhile, no obvious change in the mean intensity. Higher efficient and better-controlled cavitation and ablation were achieved through applying the combinatorial ultrasound wave sequence.

A novel hundred-microsecond histotripsy treatment method is proposed. This method utilizes the confocal dual-frequency of second harmonic superimposition control approach. A custom-designed transducer consisting of two confocal spherical-annular element arrays is used. The frequencies of the transducer are 1.1 and 2.2 MHz, and the peak negative pressures are 5 MPa and 12 MPa with shock wave. Due to the dual-frequency superimposition, inertial cavitation threshold can be significantly decreased and inertial cavitation activity can be enhanced. By controlling the ratio of the dual-frequency acoustic power, the superimposition of two frequency pressures results in nine split foci along a beam axis within the confocal region, and the maximal peak intensity of the split foci can reach approximately twice the sum of the two frequency intensities, indicating strong wave interference. Experiments were conducted on BSA gel phantoms and on porcine liver tissues ex vivo. Target tissue could be mechanically disintegrated into long-tear-shape lesion with smooth borders. Lesion inception time, boiling bubble emergence time, and first stage treatment time were decreased to nearly 1/6, 1/7, and 1/2 of the single-frequency monofocal mode. The boiling bubbles occurred frequently at multiple foci in each lesion formation, beneficiating shorten the treatment time. The inertial-cavitation-energy waveform revealed that the energetic inertial cavitation activity dominated the entire histotripsy treatment and the occurrence of boiling activity significantly increased the filtered-PCD signal amplitude in the frequency-domain. These results demonstrated that the hundred-microsecond dual-frequency of second harmonic superimposition had potential value being used in improvement of histotripsy treatment efficiency.

Confocal fundamental and harmonic superimposition can greatly lower the cavitation threshold and enhance cavitation activity via wave interference. In this study, a histotripsy protocol of using dual frequency of fundamental and harmonic superimposition combined with hundred-microsecond-length pulses and two stages is proposed and testified to get good use of the nonlinear regimes of enhanced cavitation and boiling effects. Each hundred-microsecond-long pulse consists of 400–600μs. Much higher 4–6% duty cycles will be used in stage 1 to induce boiling and at the same time partially homogenize tissue, and 1% duty cycles be used in second stage. Each two-element transducer for either 1.1/3.3 MHz or 1.1/2.2 MHz dual frequencies consists of two confocal-annular-element arrays. The experiments were implemented in gel phantom with BSA, ex vivo of bovine eye lens and porcine kidneys, monitored via high speed camera or passive cavitation detect, PCD. The harmonic pressures in focal region appeared shocks. As expected, the experiment of porcine kidney produced successfully a completely tissue homogenate region (sharply demarcated from untreated tissue) with typical dimension of 7.8 mm×2 mm (axial × lateral). The key reasons to enhance treatment efficiency may boiling generate a lot of times in multi positions within focal region.

Rapid and effective determination of biomechanical properties is important in examining and diagnosing skin thermal injury. Among the methods used, viscoelasticity quantification is one of the most effective methods in determining such properties. This study aims to rapidly determine skin viscoelasticity by optically tracking the local surface wave. New elastic and viscous coefficients were proposed to indicate skin viscoelasticity based on a single impulse response of the skin. Experiments were performed using fresh porcine skin samples. Surface wave was generated in a single impulse using a vibrator with a ball-tipped device and was detected using a laser Doppler vibrometer. The motions along the depth direction were monitored using an ultrasound system. The ultrasound monitoring results indicated the multi-layered viscoelasticity of the epidermis and dermis. The viscoelastic coefficients from four healthy samples show a potential viscoelasticity variation of porcine skin. In one sample, the two coefficients were evidently higher than those in a healthy area if the skin was slightly burned. These results indicate that the proposed method is sensitive, effective, and quick in determining skin viscoelasticity.

A novel approach combining dual frequency and split focus approaches is proposed to substantially enhance heating in treatment by using a prototype broadband splitfocus transducer. Using a dual-frequency mode in which the higher frequency is twice the lower frequency, the superimposition of two frequency pressures in the confocal region can enhance nucleation cavitation and inertial cavitation activity. Ex vivo liver or gel phantom experiments using the dual frequencies of 1.2 and 2.4 MHz confirmed a lesion size about two times larger than that obtained using a single 1.6 MHz frequency. The mean square indicating inertial cavitation energy from filtered passive cavitation detection (PCD) data demonstrated that the inertial cavitation activity dominated the enhanced heating rate and that the extra frequency components in the dual-frequency case contributed to increasing the lesion size. The dual-frequency, split-focus protocol takes great advantages of temporally and spatially enhanced-cavitation heating. The results revealed that the dual-frequency, split-focus method enhanced the heating rate one order of magnitude more than other methods. The inertial cavitation energy waveform revealed that the strong inertial cavitation action was involved in enhanced heating in the entire 22 s treatment. The greater spatial area of preformed bubble-layer surface reflection (or scatter ultrasound) regime in the dual-frequency, split-focus protocol enhanced the proximal acoustic field and enlarged the enhanced-pressure field toward the transducer about 3 times in the axial original-focal dimension, as well as laterally. This regime supported the sustained inertial cavitation during a 22 s treatment. An increased pulse-repetition frequency (PRF) protocol was formed using dual frequency and split focus, increasing PRF from 1 to 10, 20, and 40 Hz to take advantage of pulse-induced cavitation. The experiments demonstrated that the lesion size with 20 Hz PRF was about 2.5 times that obtained with 1 Hz PRF, and possessed quick 0.2 s lesioninception time. Within the high-frequency band, the inertialcavitation frequency integral was approximately proportional to the lesion size of 1, 10, 20, and 40 Hz PRF respectively, indicating higher frequency contribution to enhanced heating.

In this paper, based on a programmable diagnostic ultrasound scanner, a combined approach was proposed, in which a variable-sized focal region wherein the acoustic pressure is above the ultrasound contrast agents (UCA) fragmentation threshold is synthesized by reasonably matching the excitation voltage and the transmit aperture of the linear array at 5MHz, the UCAs’ temporal and spatial distribution before and after the microbubbles fragmentation is monitored using the plane-wave transmission and reception at 400Hz and, simultaneously, the broadband noise emission during the microbubbles fragmentation is extracted using the backscattering of focused release bursts (destruction pulse) themselves on the linear array. Then, acquired radio frequency (RF) data are processed to draw parameters which can be correlated with the indicator of broadband noise emission level, namely inertial cavitation dose (ICD) and microbubble fragmentation efficiency, namely decay rate of microbubbles.

We proposed that high efficiency high-intensity focused ultrasound (HIFU) could be achieved by using a splitting transducer with various frequencies and focusing patterns, and explored the feasibility of using ultrafast active cavitation imaging (UACI), pulse inversion (PI) sub-harmonic cavitation imaging and bubble wavelet transform imaging for monitoring of cavitation during HIFU, as well as the ultrasonic B-mode images, differential integrated backscatter (IBS) images, Nakagami images and elastography for monitoring HIFU-induced lesion. The use of HIFU splitting transducer had the potential to increase the size of the thermal lesion in a shorter duration and may improve the ablation efficiency of HIFU and would shorten the exposure duration significantly. The spatial-temporal evolution of residual cavitation bubbles at the tissue-water interface was obtained by UACI and the results showed that the UACI had a frame rate high enough to capture the transient behavior of the cavitation bubbles. The experim...

To substantially enhance heating in HIFU treatment, several methods such as split foci, multi foci, and dual-frequency modes are used. The enhanced-cavitation heating protocols are implemented experimentally in BSA gel-phantom using four-element split-focus array. Using dual frequency of 1.2 and 2.4 MHz, the superimposing of two frequency pressures at confocal region can enhance nucleation cavitation and inertial cavitation activity. When using 135° phase shift combined with dual frequency of 1.2 and 2.4 MHz, the peak negative pressure reach maximum due to peak-negative pressures of two frequencies occur at same time, resulting strong cavitation activities. When using dual frequency of 1.2 and 2.4 MHz, 25-Hz pulse-repetition frequency (PRF), both 135° and 180° phase shift protocols, the experiment results show the largest lesion size of 10.5 × 10.5 × 11 mm3, quickest lesion inception time of less than 0.2 s, therefore, both 135° and 180° phase shift protocols are most efficient in enhanced-cavitation heat...

A two-stage treatment was performed to explore the feasibility of generating histotripsy using hundred-microsecond pulses. A single-element 1.06-MHz transducer was used at 8 MPa peak negative pressure with shockwaves. Stage 1 was performed to accelerate the rupture of local tissue structure by boiling bubbles. The pulse group had 500-µs/400-µs pulse duration (PD) and 100-Hz pulse repetition frequency (PRF) with 4.9%/3.9% duty cycle (DC). Stage 2 involved the mechanical homogenization of the lesion by inertial cavitation. Several locations in the lesion axial direction were treated simultaneously by the bubble clusters induced by multiple reflection of shocks. The pulse group had 500-µs/400-µs PD with 100-Hz PRF and 200-µs PD with 200-Hz PRF with 1%/0.88% DC. Experiments were conducted on polyacrylamide phantoms with bovine serum albumin and on rabbit liver tissues ex vivo. Final lesions had a cylindrical shape with smooth borders and total homogenate inside. These results demonstrated that hundred-microsecond pulses enabled controllable histotripsy with a lower acoustic pressure.

This study aims at enhancing cavitation heating by using dual-frequency modes of second-harmonic and third-harmonic superimposition for high-efficient focused-ultrasound surgery. By controlling the ratio of dual-frequency acoustic powers, the superimposing of two frequency pressures result in split foci along beam axial within confocal region, and the maximal peak intensity of split focus can reach about 2 times the sum of two frequency intensities, indicating strong wave interference. The 1.1 MHz/3.3 MHz and 1.1 MHz/2.2 MHz experiments implemented in BSA gel-phantom, and lesion inception time is about 0.3 s, which is 10 times shorter than that in single frequency mode. The boiling bubbles occur frequently in each lesion formation, beneficiating increase the lesion size. In 1.1 MHz/3.3 MHz modes, lesions developed in a symmetrical manner in ellipsoid shapes. The 12-s lesion size of 1.1 MHz/3.3 MHz modes is nearly two times as large as the lesion size of 1.1 MHz/2.2 MHz modes. Although in 20% DC case, the acoustic power dose is only a half that used in 80% DC case, the 12-s lesion size with 20% DC is nearly same as that with 80% DC for both 1.1 MHz/3.3 MHz and 1.1 MHz/2.2 MHz conditions. The inertial-cavitation-energy waveforms reveal that the strong inertial-cavitation activities involve in all cases.

A new strategy is proposed in this study to rapidly generate mechanical homogenized lesions using hundred-microsecond-long pulses. The pulsing scheme was divided into two stages: generating sufficient bubble seed nuclei via acceleration by boiling bubbles and efficiently forming a mechanically homogenized and regularly shaped lesion with a homogenate inside via inertial cavitation. The duty cycle was set at 4.9%/3.9% in stage 1 and 1%/0.88% in stage 2 by changing the pulse duration (PD) and off-time independently. The pulse sequence was 500-μs/400-μs PD with a 100-Hz pulse repetition frequency (PRF) in stage 1, followed by 500-μs/400-μs PD with a 100-Hz PRF and 200-μs PD with a 200-Hz PRF in stage 2. Experiments were conducted on polyacrylamide phantoms with bovine serum albumin and on ex vivo porcine kidney tissues using a single-element 1.06-MHz transducer at an 8-MPa peak negative pressure with shock waves. The lesion evolution and dynamic elastic modulus variation in the phantoms and the histology in the tissue samples were investigated. The results indicate that the two-stage treatment using hundred-microsecond-long pulses can efficiently produce mechanically homogenized lesions with smooth borders, long tear shapes and the total homogenate inside. The time to generate a single mechanically homogenized lesion is shortened from >50 s to 17.1 s.