Liver Histotripsy Mediated Abscopal Effect-Case Report.

We present a case report that shows an abscopal effect in the context of a safety and efficacy clinical trial for histotripsy as ablation technique in liver tumors. The abscopal effect appears in the form of reduction in the volume of nontreated tumor lesions in the same organ, as well as sustained reduction of tumor marker [carcinoembryonic antigen (CEA)] that extends weeks away of the procedure. Histotripsy is a novel noninvasive, nonthermal, and nonionizing precise ablation technique for tissue destruction guided by ultrasonography. We discuss the feasibility of this technique compared with other focal therapies and its possibilities as immune system enhancer.

Contrast-Enhanced Ultrasound: A Useful Tool to Study and Monitor Hepatic Tumors Treated With Histotripsy.

Histotripsy is a novel noninvasive nonthermal, nonionizing, and precise treatment technique for tissue destruction. Contrast-enhanced ultrasound (CEUS) improves the detection, characterization, and follow-up of hepatic lesions because it depicts accurately the vascular perfusion of both normal hepatic tissue and hepatic tumors. We present the spectrum of imaging findings of CEUS after histotripsy treatment of hepatic tumors. CEUS provides real-time information, a close approximation to the dimension of the lesion, and a clear definition of its margins. Hepatic tumors detected by ultrasound can be potentially treated using B-mode ultrasound-guided histotripsy and characterized and monitored with CEUS. CEUS has shown to be very useful after tissue treatment to monitor and assess the evolution of the treated zone. Histotripsy treated zones are practically isoechogenic and slightly heterogeneous, and their limits are difficult to establish using standard B-mode ultrasound. The use of CEUS after histotripsy showing uptake of contrast protruding into the treated zone is clinically relevant to identify residual tumors and establish the most appropriate management strategy avoiding unnecessary treatments. We here describe CEUS findings after histotripsy for hepatic tumors.

In vivo histotripsy brain treatment.

OBJECTIVE: Histotripsy 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. METHODS: Following 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. RESULTS: Histotripsy 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. CONCLUSIONS: Histotripsy 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.

Robotically Assisted Sonic Therapy as a Noninvasive Nonthermal Ablation Modality: Proof of Concept in a Porcine Liver Model.

Purpose To determine the feasibility of creating a clinically relevant hepatic ablation (ie, an ablation zone capable of treating a 2-cm liver tumor) by using robotically assisted sonic therapy (RAST), a noninvasive and nonthermal focused ultrasound therapy based on histotripsy. Materials and Methods This study was approved by the institutional animal use and care committee. Ten female pigs were treated with RAST in a single session with a prescribed 3-cm spherical treatment region and immediately underwent abdominal magnetic resonance (MR) imaging. Three pigs (acute group) were sacrificed immediately following MR imaging. Seven pigs (chronic group) were survived for approximately 4 weeks and were reimaged with MR imaging immediately before sacrifice. Animals underwent necropsy and harvesting of the liver for histologic evaluation of the ablation zone. RAST ablations were performed with a 700-kHz therapy transducer. Student t tests were performed to compare prescribed versus achieved ablation diameter, difference of sphericity from 1, and change in ablation zone volume from acute to chronic imaging. Results Ablation zones had a sphericity index of 0.99 ± 0.01 (standard deviation) (P < .001 vs sphericity index of 1). Anteroposterior and transverse dimensions were not significantly different from prescribed (3.4 ± 0.7; P = .08 and 3.2 ± 0.8; P = .29, respectively). The craniocaudal dimension was significantly larger than prescribed (3.8 ± 1.1; P = .04), likely because of respiratory motion. The central ablation zone demonstrated complete cell destruction and a zone of partial necrosis. A fibrous capsule surrounded the ablation zone by 4 weeks. On 4-week follow-up images, ablation zone volumes decreased by 64% (P < .001). Conclusion RAST is capable of producing clinically relevant ablation zones in a noninvasive manner in a porcine model. © RSNA, 2018.

An improved wave-vector frequency-domain method for nonlinear wave modeling.

In this paper, a recently developed wave-vector frequency-domain method for nonlinear wave modeling is improved and verified by numerical simulations and underwater experiments. Higher order numeric schemes are proposed that significantly increase the modeling accuracy, thereby allowing for a larger step size and shorter computation time. The improved algorithms replace the left-point Riemann sum in the original algorithm by the trapezoidal or Simpson's integration. Plane waves and a phased array were first studied to numerically validate the model. It is shown that the left-point Riemann sum, trapezoidal, and Simpson's integration have first-, second-, and third-order global accuracy, respectively. A highly focused therapeutic transducer was then used for experimental verifications. Short high-intensity pulses were generated. 2-D scans were conducted at a prefocal plane, which were later used as the input to the numerical model to predict the acoustic field at other planes. Good agreement is observed between simulations and experiments.

Experimental verification of transient nonlinear acoustical holography.

This paper presents an experimental study on nonlinear transient acoustical holography. The validity and effectiveness of a recently proposed nonlinear transient acoustical holography algorithm is evaluated in the presence of noise. The acoustic field measured on a post-focal plane of a high-intensity focused transducer is backward projected to reconstruct the pressure distributions on the focal and a pre-focal plane, which are shown to be in good agreement with the measurement. In contrast, the conventional linear holography produces erroneous results in this case where the nonlinearity involved is strong. Forward acoustic field projection was also carried out to further verify the algorithm.

Crosstalk reduction for high-frequency linear-array ultrasound transducers using 1-3 piezocomposites with pseudo-random pillars.

The goal of this research was to develop a novel diced 1-3 piezocomposite geometry to reduce pulse-echo ring down and acoustic crosstalk between high-frequency ultrasonic array elements. Two PZT-5H-based 1-3 composites (10 and 15 MHz) of different pillar geometries [square (SQ), 45° triangle (TR), and pseudo-random (PR)] were fabricated and then made into single-element ultrasound transducers. The measured pulse-echo waveforms and their envelopes indicate that the PR composites had the shortest -20-dB pulse length and highest sensitivity among the composites evaluated. Using these composites, 15-MHz array subapertures with a 0.95λ pitch were fabricated to assess the acoustic crosstalk between array elements. The combined electrical and acoustical crosstalk between the nearest array elements of the PR array subapertures (-31.8 dB at 15 MHz) was 6.5 and 2.2 dB lower than those of the SQ and the TR array subapertures, respectively. These results demonstrate that the 1-3 piezocomposite with the pseudo-random pillars may be a better choice for fabricating enhanced high-frequency linear-array ultrasound transducers; especially when mechanical dicing is used.

Development of a flexible implantable sensor for postoperative monitoring of blood flow.

We have developed a blood flow measurement system using Doppler ultrasound flow sensors fabricated of thin and flexible piezoelectric-polymer films. These flow sensors can be wrapped around a blood vessel and accurately measure flow. The innovation that makes this flow sensor possible is the diffraction-grating transducer. A conventional transducer produces a sound beam perpendicular to its face; therefore, when placed on the wall of a blood vessel, the Doppler shift in the backscattered ultrasound from blood theoretically would be 0. The diffraction-grating transducer produces a beam at a known angle to its face; therefore, backscattered ultrasound from the vessel will contain a Doppler signal. Flow sensors were fabricated by spin coating a poly(vinylidene fluoride-trifluoroethylene) copolymer film onto a flexible substrate with patterned gold electrodes. Custom-designed battery-operated continuous wave Doppler electronics along with a laptop computer completed the system. A prototype flow sensor was evaluated experimentally by measuring blood flow in a flow phantom and the infrarenal aorta of an adult New Zealand White rabbit. The flow phantom experiment demonstrated that the error in average velocity and volume blood flow was less than 6% for 30 measurements taken over a 2.5-hour period. The peak blood velocity through the rabbit infrarenal aorta measured by the flow sensor was 118 cm/s, within 1.7% of the measurement obtained using a duplex ultrasound system. The flow sensor and electronics operated continuously during the course of the 5-hour experiment after the incision on the animal was closed.

First in vivo use of a capacitive micromachined ultrasound transducer array-based imaging and ablation catheter.

OBJECTIVES: The primary objective was to test in vivo for the first time the general operation of a new multifunctional intracardiac echocardiography (ICE) catheter constructed with a microlinear capacitive micromachined ultrasound transducer (ML-CMUT) imaging array. Secondarily, we examined the compatibility of this catheter with electroanatomic mapping (EAM) guidance and also as a radiofrequency ablation (RFA) catheter. Preliminary thermal strain imaging (TSI)-derived temperature data were obtained from within the endocardium simultaneously during RFA to show the feasibility of direct ablation guidance procedures. METHODS: The new 9F forward-looking ICE catheter was constructed with 3 complementary technologies: a CMUT imaging array with a custom electronic array buffer, catheter surface electrodes for EAM guidance, and a special ablation tip, that permits simultaneous TSI and RFA. In vivo imaging studies of 5 anesthetized porcine models with 5 CMUT catheters were performed. RESULTS: The ML-CMUT ICE catheter provided high-resolution real-time wideband 2-dimensional (2D) images at greater than 8 MHz and is capable of both RFA and EAM guidance. Although the 24-element array aperture dimension is only 1.5 mm, the imaging depth of penetration is greater than 30 mm. The specially designed ultrasound-compatible metalized plastic tip allowed simultaneous imaging during ablation and direct acquisition of TSI data for tissue ablation temperatures. Postprocessing analysis showed a first-order correlation between TSI and temperature, permitting early development temperature-time relationships at specific myocardial ablation sites. CONCLUSIONS: Multifunctional forward-looking ML-CMUT ICE catheters, with simultaneous intracardiac guidance, ultrasound imaging, and RFA, may offer a new means to improve interventional ablation procedures.

Design and characterization of dual-curvature 1.5-dimensional high-intensity focused ultrasound phased-array transducer.

A dual-curvature focused ultrasound phased-array transducer with a symmetric control has been developed for noninvasive ablative treatment of tumors. The 1.5-D array was constructed in-house and the electro-acoustic conversion efficiency was measured to be approximately 65%. In vitro experiments demonstrated that the array uses 256 independent elements to achieve 2-D wide-range high-intensity electronic focusing.

A high-frequency linear ultrasonic array utilizing an interdigitally bonded 2-2 piezo-composite.

This paper describes the development of a high-frequency 256-element linear ultrasonic array utilizing an interdigitally bonded (IB) piezo-composite. Several IB composites were fabricated with different commercial and experimental piezoelectric ceramics and evaluated to determine a suitable formulation for use in high-frequency linear arrays. It was found that the fabricated fine-scale 2-2 IB composites outperformed 1-3 IB composites with identical pillar- and kerf-widths. This result was not expected and lead to the conclusion that dicing damage was likely the cause of the discrepancy. Ultimately, a 2-2 composite fabricated using a fine-grain piezoelectric ceramic was chosen for the array. The composite was manufactured using one IB operation in the azimuth direction to produce approximately 19-µm-wide pillars separated by 6-µm-wide kerfs. The array had a 50 µm (one wavelength in water) azimuth pitch, two matching layers, and 2 mm elevation length focused to 7.3 mm using a polymethylpentene (TPX) lens. The measured pulse-echo center frequency for a representative array element was 28 MHz and -6-dB bandwidth was 61%. The measured single-element transmit -6-dB directivity was estimated to be 50°. The measured insertion loss was 19 dB after compensating for the effects of attenuation and diffraction in the water bath. A fine-wire phantom was used to assess the lateral and axial resolution of the array when paired with a prototype system utilizing a 64-channel analog beamformer. The -6-dB lateral and axial resolutions were estimated to be 125 and 68 µm, respectively. An anechoic cyst phantom was also imaged to determine the minimum detectable spherical inclusion, and thus the 3-D resolution of the array and beamformer. The minimum anechoic cyst detected was approximately 300 µm in diameter.

Multimodal characterization of compositional, structural and functional features of human atherosclerotic plaques.

Detection of atherosclerotic plaque vulnerability has critical clinical implications for avoiding sudden death in patients with high risk of plaque rupture. We report on multimodality imaging of ex-vivo human carotid plaque samples using a system that integrates fluorescence lifetime imaging (FLIM), ultrasonic backscatter microscopy (UBM), and photoacoustic imaging (PAI). Biochemical composition is differentiated with a high temporal resolution and sensitivity at the surface of the plaque by the FLIM subsystem. 3D microanatomy of the whole plaque is reconstructed by the UBM. Functional imaging associated with optical absorption contrast is evaluated from the PAI component. Simultaneous recordings of the optical, ultrasonic, and photoacoustic data present a wealth of complementary information concerning the plaque composition, structure, and function that are related to plaque vulnerability. This approach is expected to improve our ability to study atherosclerotic plaques. The multimodal system presented here can be translated into a catheter based intraluminal system for future clinical studies.

The feasibility of using thermal strain imaging to regulate energy delivery during intracardiac radio-frequency ablation.

A method is introduced to monitor cardiac ablative therapy by examining slope changes in the thermal strain curve caused by speed of sound variations with temperature. The sound speed of water-bearing tissue such as cardiac muscle increases with temperature. However, at temperatures above about 50°C, there is no further increase in the sound speed and the temperature coefficient may become slightly negative. For ablation therapy, an irreversible injury to tissue and a complete heart block occurs in the range of 48 to 50°C for a short period in accordance with the well-known Arrhenius equation. Using these two properties, we propose a potential tool to detect the moment when tissue damage occurs by using the reduced slope in the thermal strain curve as a function of heating time. We have illustrated the feasibility of this method initially using porcine myocardium in vitro. The method was further demonstrated in vivo, using a specially equipped ablation tip and an 11-MHz microlinear intracardiac echocardiography (ICE) array mounted on the tip of a catheter. The thermal strain curves showed a plateau, strongly suggesting that the temperature reached at least 50°C.

Development of a 64 channel ultrasonic high frequency linear array imaging system.

In order to improve the lateral resolution and extend the field of view of a previously reported 48 element 30 MHz ultrasound linear array and 16-channel digital imaging system, the development of a 256 element 30 MHz linear array and an ultrasound imaging system with increased channel count has been undertaken. This paper reports the design and testing of a 64 channel digital imaging system which consists of an analog front-end pulser/receiver, 64 channels of Time-Gain Compensation (TGC), 64 channels of high-speed digitizer as well as a beamformer. A Personal Computer (PC) is used as the user interface to display real-time images. This system is designed as a platform for the purpose of testing the performance of high frequency linear arrays that have been developed in house. Therefore conventional approaches were taken it its implementation. Flexibility and ease of use are of primary concern whereas consideration of cost-effectiveness and novelty in design are only secondary. Even so, there are many issues at higher frequencies but do not exist at lower frequencies need to be solved. The system provides 64 channels of excitation pulsers while receiving simultaneously at a 20-120 MHz sampling rate to 12-bits. The digitized data from all channels are first fed through Field Programmable Gate Arrays (FPGAs), and then stored in memories. These raw data are accessed by the beamforming processor to re-build the image or to be downloaded to the PC for further processing. The beamformer that applies delays to the echoes of each channel is implemented with the strategy that combines coarse (8.3 ns) and fine delays (2 ns). The coarse delays are integer multiples of the sampling clock rate and are achieved by controlling the write enable pin of the First-In-First-Out (FIFO) memory to obtain valid beamforming data. The fine delays are accomplished with interpolation filters. This system is capable of achieving a maximum frame rate of 50 frames per second. Wire phantom images acquired with this system show a spatial resolution of 146 µm (lateral) and 54 µm (axial). Images with excised rabbit and pig eyeball as well as mouse embryo were also acquired to demonstrate its imaging capability.

Photoacoustic imaging with a commercial ultrasound system and a custom probe.

Building photoacoustic imaging (PAI) systems by using stand-alone ultrasound (US) units makes it convenient to take advantage of the state-of-the-art ultrasonic technologies. However, the sometimes limited receiving sensitivity and the comparatively narrow bandwidth of commercial US probes may not be sufficient to acquire high quality photoacoustic images. In this work, a high-speed PAI system has been developed using a commercial US unit and a custom built 128-element piezoelectric-polymer array (PPA) probe using a P(VDF-TrFE) film and flexible circuit to define the elements. Since the US unit supports simultaneous signal acquisition from 64 parallel receive channels, PAI data for synthetic image formation from a 64- or 128-element array aperture can be acquired after a single or dual laser firing, respectively. Therefore, two-dimensional (2-D) B-scan imaging can be achieved with a maximum frame rate up to 10 Hz, limited only by the laser repetition rate. The uniquely properties of P(VDF-TrFE) facilitated a wide -6 dB receiving bandwidth of over 120% for the array. A specially designed 128-channel preamplifier board made the connection between the array and the system cable, which not only enabled element electrical impedance matching but also further elevated the signal-to-noise ratio (SNR) to further enhance the detection of weak photoacoustic signals. Through the experiments on phantoms and rabbit ears, the good performance of this PAI system was demonstrated.

A high-frequency annular-array transducer using an interdigital bonded 1-3 composite.

This paper reports the design, fabrication, and characterization of a 1-3 composite annular-array transducer. An interdigital bonded (IB) 1-3 composite was prepared using two IB operations on a fine-grain piezoelectric ceramic. The final composite had 19-µm-wide posts separated by 6-µm-wide polymer kerfs. A novel method to remove metal electrodes from polymer portions of the 1-3 composite was established to eliminate the need for patterning and aligning the electrode on the composite to the electrodes on a flexible circuit. Unloaded epoxy was used for both the matching and backing layers and a flexible circuit was used for interconnect. A prototype array was successfully fabricated and tested. The results were in reasonable agreement with those predicted by a circuit-analogous model. The average center frequency estimated from the measured pulse-echo responses of array elements was 33.5 MHz and the -6-dB fractional bandwidth was 57%. The average insertion loss recorded was 14.3 dB, and the maximum crosstalk between the nearest-neighbor elements was less than -37 dB. Images of a wire phantom and excised porcine eye were obtained to show the capabilities of the array for high-frequency ultrasound imaging.

A dual-modality probe utilizing intravascular ultrasound and optical coherence tomography for intravascular imaging applications.

We have developed a dual-modality biomedical imaging probe utilizing intravascular ultrasound (IVUS) and optical coherence tomography (OCT). It consists of an OCT probe, a miniature ultrasonic transducer and a fixed mirror. The mirror was mounted at the head of the hybrid probe 45° relative to the light and the ultrasound beams to change their propagation directions. The probe was designed to be able to cover a larger area in blood vessel by IVUS and then visualize a specific point at a much finer image resolution using OCT. To demonstrate both its feasibility and potential clinical applications, we used this ultrasound-guide OCT probe to image a rabbit aorta in vitro. The results offer convincing evidence that the complementary natures of these two modalities may yield beneficial results that could not have otherwise been obtained.

Dual-focus therapeutic ultrasound transducer for production of broad tissue lesions.

In noninvasive high-intensity focused ultrasound (HIFU) treatment, formation of a large tissue lesion per sonication is desirable for reducing the overall treatment time. The goal of this study is to show the feasibility of enlarging tissue lesion size with a dual-focus therapeutic ultrasound transducer (DFTUT) by increasing the depth-of-focus (DOF). The proposed transducer consists of a disc- and an annular-type element of different radii of curvatures to produce two focal zones. To increase focal depth and to maintain uniform beamwidth of the elongated DOF, each element transmits ultrasound of a different center frequency: the inner element at a higher frequency for near field focusing and the outer element at a lower frequency for far field focusing. By activating two elements at the same time with a single transmitter capable of generating a dual-frequency mixed signal, the overall DOF of the proposed transducer may be extended considerably. A prototype transducer composed of a 4.1 MHz inner element and a 2.7 MHz outer element was fabricated to obtain preliminary experimental results. The feasibility the proposed technique was demonstrated through sound field, temperature and thermal dose simulations. The performance of the prototype transducer was verified by hydrophone measurements and tissue ablation experiments on a beef liver specimen. When several factors affecting the length and the uniformity of elongated DOF of the DFTUT are optimized, the proposed therapeutic ultrasound transducer design may increase the size of ablated tissues in the axial direction and, thus, decreasing the treatment time for a large volume of malignant tissues especially deep-seated targets.

A high-frequency, high frame rate duplex ultrasound linear array imaging system for small animal imaging.

High-frequency (HF) ultrasound imaging has been shown to be useful for non-invasively imaging anatomical structures of the eye and small animals in biological and pharmaceutical research, achieving superior spatial resolution. Cardiovascular research utilizing mice requires not only realtime B-scan imaging, but also ultrasound Doppler to evaluate both anatomy and blood flow of the mouse heart. This paper reports the development of an HF ultrasound duplex imaging system capable of both B-mode imaging and Doppler flow measurements, using a 64-element linear array. The system included an HF pulsed-wave Doppler module, a 32-channel HF B-mode imaging module, a PC with a 200 MS/s 14-bit A/D card, and real-time LabView software. A 50 dB SNR and a depth of penetration of larger than 12 mm were achieved using a 35-MHz linear array with 50 µm pitch. The two-way beam widths were determined to be 165 to 260 µm and the clutter-energy-to-total-energy ratio (CTR) were 9.1 to 12 dB when the array was electronically focused at different focal points at depths from 4.8 to 9.6 mm. The system is capable of acquiring real-time B-mode images at a rate greater than 400 frames per second (fps) for a 4.8 x 13 mm field of view, using a 30- MHz 64-element linear array with 100 µm pitch. Sample in vivo cardiac high frame rate images and duplex images of mouse hearts are shown to assess its current imaging capability and performance for small animals.

High-resolution photoacoustic imaging of ocular tissues.

Optical coherence tomography (OCT) and ultrasound (US) are methods widely used for diagnostic imaging of the eye. These techniques detect discontinuities in optical refractive index and acoustic impedance, respectively. Because these both relate to variations in tissue density or composition, OCT and US images share a qualitatively similar appearance. In photoacoustic imaging (PAI), short light pulses are directed at tissues, pressure is generated due to a rapid energy deposition in the tissue volume and thermoelastic expansion results in generation of broadband US. PAI thus depicts optical absorption, which is independent of the tissue characteristics imaged by OCT or US. Our aim was to demonstrate the application of PAI in ocular tissues and to do so with lateral resolution comparable to OCT. We developed two PAI assemblies, both of which used single-element US transducers and lasers sharing a common focus. The first assembly had optical and 35-MHz US axes offset by a 30 degrees angle. The second assembly consisted of a 20-MHz ring transducer with a coaxial optics. The laser emitted 5-ns pulses at either 532 nm or 1064 nm, with spot sizes at the focus of 35 microm for the angled probe and 20 microm for the coaxial probe. We compared lateral resolution by scanning 12.5 microm diameter wire targets with pulse/echo US and PAI at each wavelength. We then imaged the anterior segment in whole ex vivo pig eyes and the choroid and ciliary body region in sectioned eyes. PAI data obtained at 1064 nm in the near infrared had higher penetration but reduced signal amplitude compared to that obtained using the 532 nm green wavelength. Images were obtained of the iris, choroid and ciliary processes. The zonules and anterior cornea and lens surfaces were seen at 532 nm. Because the laser spot size was significantly smaller than the US beamwidth at the focus, PAI images had superior resolution than those obtained using conventional US.