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.

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.

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.

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.

Experimental studies with a 9F forward-looking intracardiac imaging and ablation catheter.

OBJECTIVE: The purpose of this study was to develop a high-resolution, near-field-optimized 14-MHz, 24-element broad-bandwidth forward-looking array for integration on a steerable 9F electrophysiology (EP) catheter. METHODS: Several generations of prototype imaging catheters with bidirectional steering, termed microlinear (ML), were built and tested as integrated catheter designs with EP sensing electrodes near the tip. The wide-bandwidth ultrasound array was mounted on the very tip, equipped with an aperture of only 1.2 by 1.58 mm. The array pulse echo performance was fully simulated, and its construction offered shielding from ablation noise. Both ex vivo and in vivo imaging with a porcine animal model were performed. RESULTS: The array pulse echo performance was concordant with Krimholtz-Leedom-Matthaei model simulation. Three generations of prototype devices were tested in the right atrium and ventricle in 4 acute pig studies for the following characteristics: (1) image quality, (2) anatomic identification, (3) visualization of other catheter devices, and (4) for a mechanism for stabilization when imaging ablation. The ML catheter is capable of both low-artifact ablation imaging on a standard clinical imaging system and high-frame rate myocardial wall strain rate imaging for detecting changes in cardiac mechanics associated with ablation. CONCLUSIONS: The imaging resolution performance of this very small array device, together with its penetration beyond 2 cm, is excellent considering its very small array aperture. The forward-looking intracardiac catheter has been adapted to work easily on an existing commercial imaging platform with very minor software modifications.

High-frequency ultrasound Doppler system for biomedical applications with a 30-MHz linear array.

In this paper, we report the development of the first high-frequency (HF) pulsed-wave Doppler system using a 30-MHz linear array transducer to assess the cardiovascular functions in small animals. This array-based pulsed-wave Doppler system included a 16-channel HF analog beamformer, a HF pulsed-wave Doppler module, timing circuits, HF bipolar pulsers and analog front ends. The beamformed echoes acquired by the 16-channel analog beamformer were fed directly to the HF pulsed-wave Doppler module. Then the in-phase and quadrature-phase (IQ) audio Doppler signals were digitized by either a sound card or a Gage digitizer and stored in a personal computer. The Doppler spectrogram was displayed on a personal computer in real time. The two-way beamwidths were determined to be 160 microm to 320 microm when the array was electronically focused at different focal points at depths from 5 to 10 mm. A micro-flow phantom, consisting of a polyimide tube with an inner diameter of 127 microm and the wire phantom were used to evaluate and calibrate the system. The results show that the system is capable of detecting motion velocity of the wire phantom as low as 0.1 mm/s, and detecting blood-mimicking flow velocity in the 127-microm tube lower than 7 mm/s. The system was subsequently used to measure the blood flow in vivo in two mouse abdominal superficial vessels, with diameters of approximately 200 microm, and a mouse aorta close to the heart. These results demonstrated that this system may become an indispensable part of the current HF array-based imaging systems for small animal studies.

The acoustic lens design and in vivo use of a multifunctional catheter combining intracardiac ultrasound imaging and electrophysiology sensing.

A multifunctional 9F intracardiac imaging and electrophysiology mapping catheter was developed and tested to help guide diagnostic and therapeutic intracardiac electrophysiology (EP) procedures. The catheter tip includes a 7.25-MHz, 64-element, side-looking phased array for high resolution sector scanning. Multiple electrophysiology mapping sensors were mounted as ring electrodes near the array for electrocardiographic synchronization of ultrasound images. The catheter array elevation beam performance in particular was investigated. An acoustic lens for the distal tip array designed with a round cross section can produce an acceptable elevation beam shape; however, the velocity of sound in the lens material should be approximately 155 m/s slower than in tissue for the best beam shape and wide bandwidth performance. To help establish the catheter's unique ability for integration with electrophysiology interventional procedures, it was used in vivo in a porcine animal model, and demonstrated both useful intracardiac echocardiographic visualization and simultaneous 3-D positional information using integrated electroanatomical mapping techniques. The catheter also performed well in high frame rate imaging, color flow imaging, and strain rate imaging of atrial and ventricular structures.

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.

PMN-PT single crystal, high-frequency ultrasonic needle transducers for pulsed-wave Doppler application.

High-frequency needle ultrasound transducers with an aperture size of 0.4 mm were fabricated using lead magnesium niobate-lead titanate (PMN-33% PT) as the active piezoelectric material. The active element was bonded to a conductive silver particle matching layer and a conductive epoxy backing through direct contact curing. An outer matching layer of parylene was formed by vapor deposition. The active element was housed within a polyimide tube and a 20-gauge needle housing. The magnitude and phase of the electrical impedance of the transducer were 47 omega and -38 degrees, respectively. The measured center frequency and -6 dB fractional bandwidth of the PMN-PT needle transducer were 44 MHz and 45%, respectively. The two-way insertion loss was approximately 15 dB. In vivo high-frequency, pulsed-wave Doppler patterns of blood flow in the posterior portion and in vitro ultrasonic backscatter microscope (UBM) images of the rabbit eye were obtained with the 44-MHz needle transducer.

A high-frame rate high-frequency ultrasonic system for cardiac imaging in mice.

We report the development of a high-frequency (30-50 MHz), real-time ultrasonic imaging system for cardiac imaging in mice. This system is capable of producing images at 130 frames per second (fps) with a spatial resolution of less than 50 microm. A novel mechanical sector probe was developed that utilizes a magnetic drive mechanism and custom-built servo controller for high speed and accuracy. Additionally, a very light-weight (< 0.28 g), single-element transducer was constructed and used to reduce the mass load on the motor. The imaging electronics were triggered according to the angular position of the transducer in order to compensate for the varying speed of the sector motor. This strategy ensured the production of equally spaced scan lines with minimal jitter. Wire phantom testing showed that the system axial and lateral resolutions were 48 microm and 72 microm, respectively. In vivo experiments showed that high-frequency ultrasonic imaging at 130 fps is capable of showing a detailed depiction of a beating mouse heart.

Development of a high-frequency (> 50 mhz) copolymer annular-array, ultrasound transducer.

The development of a high frequency (> 50 MHz) annular array ultrasonic transducer is presented. The array was constructed by bonding a 9 microm P(VDF-TrFE) film to a two-sided polyimide flexible circuit with annuli electrodes on the top layer. Each annulus was separated by a 30 microm kerf and had several electroplated microvias that connected to electrode traces on the bottom side of the flex circuit. In order to improve device sensitivity, each element was electrically matched to an impedance magnitude of 50 omega and 0 degrees phase at resonance using a serial inductor and high impedance coaxial cable. The array's performance was evaluated by measuring the electrical impedance, pulse echo response, and cross talk between elements. The average round trip insertion loss was -33.5 dB after compensating for diffractive and attenuative losses. The measured average center frequency and bandwidth for an element was 55 MHz and 47%, respectively. The measured cross talk between adjacent elements remained below -29 dB at the center frequency in water. A vertical wire phantom was imaged using a single focus transmit beamformer and dynamic focusing receive beamformer. This image showed a significant improvement in lateral resolution over a range of 9 mm after the dynamic focusing receive algorithm was applied. These results correlated well with predictions from a Field II simulation. After beamforming, the minimum lateral resolution achieved by the array (-6 dB) was 108 microm at the focus.

Development of a real-time, high-frequency ultrasound digital beamformer for high-frequency linear array transducers.

A real-time digital beamformer for high-frequency (>20 MHz) linear ultrasonic arrays has been developed. The system can handle up to 64-element linear array transducers and excite 16 channels and receive simultaneously at 100 MHz sampling frequency with 8-bit precision. Radio frequency (RF) signals are digitized, delayed, and summed through a real-time digital beamformer, which is implemented using a field programmable gate array (FPGA). Using fractional delay filters, fine delays as small as 2 ns can be implemented. A frame rate of 30 frames per second is achieved. Wire phantom (20 microm tungsten) images were obtained and -6 dB axial and lateral widths were measured. The results showed that, using a 30 MHz, 48-element array with a pitch of 100 microm produced a -6 dB width of 68 microm in the axial and 370 microm in the lateral direction at 6.4 mm range. Images from an excised rabbit eye sample also were acquired, and fine anatomical structures, such as the cornea and lens, were resolved.

Development of a 35-MHz piezo-composite ultrasound array for medical imaging.

This paper discusses the development of a 64-element 35-MHz composite ultrasonic array. This array was designed primarily for ocular imaging applications, and features 2-2 composite elements mechanically diced out of a fine-grain high-density Navy Type VI ceramic. Array elements were spaced at a 50-micron pitch, interconnected via a custom flexible circuit and matched to the 50-ohm system electronics via a 75-ohm transmission line coaxial cable. Elevation focusing was achieved using a cylindrically shaped epoxy lens. One functional 64-element array was fabricated and tested. Bandwidths averaging 55%, 23-dB insertion loss, and crosstalk less than -24 dB were measured. An image of a tungsten wire target phantom was acquired using a synthetic aperture reconstruction algorithm. The results from this imaging test demonstrate resolution exceeding 50 microm axially and 100 microm laterally.

Design and fabrication of broadband graded ultrasonic transducers with rectangular kerfs.

Broadband ultrasound imaging is capable of achieving superior resolution in clinical applications. An effective and easy way of manufacturing broadband transducers is desired for these applications. In this work, a graded material in which the piezoelectric plate is mechanically graded with rectangular grooves is introduced. Finite element analysis (FEA) demonstrated that the graded piezoelectric material could achieve a broadband, time-domain response resulting from multiple resonant modes. Experimental tests were carried out to validate these theoretical results. Based upon the FEA designs, several single-element transducers were fabricated using either a nondiced ceramic or a diced, graded ceramics. A superior bandwidth of 92% was achieved by the graded transducer when compared to a bandwidth of 56% produced by the nondiced ceramic transducer at the expense of a reduced sensitivity.

Half-thickness inversion layer high-frequency ultrasonic transducers using LiNbO3 single crystal.

Half-thickness inversion layer high-frequency ultrasonic transducers were fabricated using lithium niobate (LiNbO3) single crystal plate. The transducers developed for this study used a 36 degrees rotated Y-cut LiNbO3 thin plate with an active element thickness of 115 microm. The designed center frequency was in the range of 30 to 60 MHz. Half-thickness inversion layer was formed after the sample was annealed at a high temperature, and it is shown that the inversion layer thickness can be controlled by the temperature. Silver powder/epoxy composite and parylene were used as acoustic matching layers. A lossy silver epoxy was used as the backing material. Using an analytical method, the electrical impedance for different inversion layer ratios was determined. The measured resonant frequency was consistent with the modeled data. Even-order higher frequency broadband ultrasonic transducers with a center frequency at 60 MHz was obtained using half-thickness inversion layer of LiNbO3 single crystal.

Fabrication and characterization of micromachined high-frequency tonpilz transducers derived by PZT thick films.

Miniaturized tonpilz transducers are potentially useful for ultrasonic imaging in the 10 to 100 MHz frequency range due to their higher efficiency and output capabilities. In this work, 4 to 10-microm thick piezoelectric thin films were used as the active element in the construction of miniaturized tonpilz structures. The tonpilz stack consisted of silver/lead zirconate titanate (PZT)/lanthanum nickelate (LaNiO3)/silicon on insulator (SOI) substrates. First, conductive LaNiO3 thin films, approximately 300 nm in thickness, were grown on SOI substrates by a metalorganic decomposition (MOD) method. The room temperature resistivity of the LaNiO3 was 6.5 x 10(-6) omega x m. Randomly oriented PZT (52/48) films up to 7-microm thick were then deposited using a sol-gel process on the LaNiO3-coated SOI substrates. The PZT films with LaNiO3 bottom electrodes showed good dielectric and ferroelectric properties. The relative dielectric permittivity (at 1 kHz) was about 1030. The remanent polarization of PZT films was larger than 26 microC/cm2. The effective transverse piezoelectric e31,f coefficient of PZT thick films was about -6.5 C/m2 when poled at -75 kV/cm for 15 minutes at room temperature. Enhanced piezoelectric properties were obtained on poling the PZT films at higher temperatures. A silver layer about 40-microm thick was prepared by silver powder dispersed in epoxy and deposited onto the PZT film to form the tail mass of the tonpilz structure. The top layers of this wafer were subsequently diced with a saw, and the structure was bonded to a second wafer. The original silicon carrier wafer was polished and etched using a Xenon difluoride (XeF2) etching system. The resulting structures showed good piezoelectric activity. This process flow should enable integration of the piezoelectric elements with drive/receive electronics.

Design of efficient, broadband single-element (20-80 MHz) ultrasonic transducers for medical imaging applications.

This paper discusses the design, fabrication, and testing of sensitive broadband lithium niobate (LiNbO3) single-element ultrasonic transducers in the 20-80 MHz frequency range. Transducers of varying dimensions were built for an f# range of 2.0-3.1. The desired focal depths were achieved by either casting an acoustic lens on the transducer face or press-focusing the piezoelectric into a spherical curvature. For designs that required electrical impedance matching, a low impedance transmission line coaxial cable was used. All transducers were tested in a pulse-echo arrangement, whereby the center frequency, bandwidth, insertion loss, and focal depth were measured. Several transducers were fabricated with center frequencies in the 20-80 MHz range with the measured -6 dB bandwidths and two-way insertion loss values ranging from 57 to 74% and 9.6 to 21.3 dB, respectively. Both transducer focusing techniques proved successful in producing highly sensitive, high-frequency, single-element, ultrasonic-imaging transducers. In vivo and in vitro ultrasonic backscatter microscope (UBM) images of human eyes were obtained with the 50 MHz transducers. The high sensitivity of these devices could possibly allow for an increase in depth of penetration, higher image signal-to-noise ratio (SNR), and improved image contrast at high frequencies when compared to previously reported results.

Design, fabrication, and evaluation of high frequency, single-element transducers incorporating different materials.

The performance of high frequency, single-element transducers depends greatly on the mechanical and electrical properties of the piezoelectric materials used. This study compares the design and performance of transducers incorporating different materials. The materials investigated include 1-3 lead zirconate titanate (PZT) fiber composite, lead titanate (PbTiO3) ceramic, poly(vinylidene fluoride) (PVDF) film, and lithium niobate (LiNbO3) single crystal. All transducers were constructed with a 3-mm aperture size and an f-number between 2 and 3. Backing and matching materials were selected based on design goals and fabrication limitations. A simplified coaxial cable tuning method was employed to match the transducer impedance to 50 ohms for the PZT fiber composite and PbTiO3 ceramic transducers. Transducers were tested for two-way loss and -6 dB bandwidth using the pulse/echo response from a flat quartz target. Two-way loss varied from 21 to 46 dB, and bandwidths measured were in the range from 47 to 118%. In vitro ultrasonic backscatter microscope (UBM) images of an excised human eye were obtained for each device and used to compare imaging performance. Both press-focusing and application of a lens proved to be useful beam focusing methods for high frequency. Under equal gain schemes, the LiNbO3 and PbTiO3 transducers provided better image contrast than the other materials.