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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.