Simultaneous transrectal ultrasound and photoacoustic human prostate imaging.

Imaging technologies that simultaneously provide anatomical, functional, and molecular information are emerging as an attractive choice for disease screening and management. Since the 1980s, transrectal ultrasound (TRUS) has been routinely used to visualize prostatic anatomy and guide needle biopsy, despite limited specificity. Photoacoustic imaging (PAI) provides functional and molecular information at ultrasonic resolution based on optical absorption. Combining the strengths of TRUS and PAI approaches, we report the development and bench-to-bedside translation of an integrated TRUS and photoacoustic (TRUSPA) device. TRUSPA uses a miniaturized capacitive micromachined ultrasonic transducer array for simultaneous imaging of anatomical and molecular optical contrasts [intrinsic: hemoglobin; extrinsic: intravenous indocyanine green (ICG)] of the human prostate. Hemoglobin absorption mapped vascularity of the prostate and surroundings, whereas ICG absorption enhanced the intraprostatic photoacoustic contrast. Future work using the TRUSPA device for biomarker-specific molecular imaging may enable a fundamentally new approach to prostate cancer diagnosis, prognostication, and therapeutic monitoring.

Radiation Force as a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina.

Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5-43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal responses and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the dominant physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina and propose that the control of standing waves is a new potential method to modulate these effects.SIGNIFICANCE STATEMENT Ultrasonic neurostimulation is a promising noninvasive technology that has potential for both basic research and clinical applications. The mechanisms of ultrasonic neurostimulation are unknown, making it difficult to optimize in any given application. We studied the physical mechanism by which ultrasound is converted into an effective energy form to cause neurostimulation in the retina and find that ultrasound acts via radiation force leading to a mechanical displacement of tissue. We further show that standing waves have a strong modulatory effect on activity. Our quantitative model by which ultrasound generates radiation force and leads to neural activity will be important in optimizing ultrasonic neurostimulation across a wide range of applications.

High-Efficiency Output Pressure Performance Using Capacitive Micromachined Ultrasonic Transducers with Substrate-Embedded Springs.

Capacitive micromachined ultrasonic transducers (CMUTs) with substrate-embedded springs offer highly efficient output pressure performance over conventional CMUTs, owing to their nonflexural parallel plate movement. The embedded silicon springs support thick Si piston plates, creating a large nonflexural average volume displacement efficiency in the operating frequency range from 1⁻3 MHz. Static and dynamic volume displacements of the nonflexural parallel plates were examined using white light interferometry and laser Doppler vibrometry. In addition, an output pressure measurement in immersion was performed using a hydrophone. The device showed a maximum transmission efficiency of 21 kPa/V, and an average volume displacement efficiency of 1.1 nm/V at 1.85 MHz with a low DC bias voltage of 55 V. The device element outperformed the lead zirconate titanate (PZT) ceramic HD3203, in the maximum transmission efficiency or the average volume displacement efficiency by 1.35 times. Furthermore, its average volume displacement efficiency reached almost 80% of the ideal state-of-the-art single-crystal relaxor ferroelectric materials PMN-0.33PT. Additionally, we confirmed that high-efficiency output pressure could be generated from the CMUT device, by quantitatively comparing the hydrophone measurement of a commercial PZT transducer.

Lamb Wave Multitouch Ultrasonic Touchscreen.

Touchscreen sensors are widely used in many devices such as smart phones, tablets, and laptops with diverse applications. We present the design, analysis, and implementation of an ultrasonic touchscreen system that utilizes the interaction of transient Lamb waves with objects in contact with the screen. It attempts to improve on the existing ultrasound technologies, with the potential of addressing some of the weaknesses of the dominant technologies, such as the capacitive or resistive ones. Compared with the existing ultrasonic and acoustic modalities, among other advantages, it provides the capability of detecting several simultaneous touch points and also a more robust performance. The localization algorithm, given the hardware design, can detect several touch points with a very limited number of measurements (one or two). This in turn can significantly reduce the manufacturing cost.

Ex Vivo HIFU Experiments Using a $32 \times 32$ -Element CMUT Array.

High-intensity focused ultrasound (HIFU) has been used as noninvasive treatment for various diseases. For these therapeutic applications, capacitive micromachined ultrasonic transducers (CMUTs) have advantages that make them potentially preferred transducers over traditional piezoelectric transducers. In this paper, we present the design and the fabrication process of an 8 ×8 -mm 2 32 ×32 -element 2-D CMUT array for HIFU applications. To reduce the system complexity for addressing the 1024 transducer elements, we propose to group the CMUT array elements into eight HIFU channels based on the phase delay from the CMUT element to the targeted focal point. Designed to focus at an 8-mm depth with a 5-MHz exciting frequency, this grouping scheme was realized using a custom application-specific integrated circuit. With a 40-V dc bias and a 60-V peak-to-peak ac excitation, the surface pressure was measured 1.2 MPa peak-to-peak and stayed stable for a long enough time to create a lesion. With this dc and ac voltage combination, the measured peak-to-peak output pressure at the focus was 8.5 MPa, which is expected to generate a lesion in a minute according to the temperature simulation. The following ex vivo tissue experiments successfully demonstrated its capability to make lesions in both bovine muscle and liver tissue.

Singulation for imaging ring arrays of capacitive micromachined ultrasonic transducers.

Singulation of MEMS is a critical step in the transition from wafer-level to die-level devices. As is the case for capacitive micromachined ultrasound transducer (CMUT) ring arrays, an ideal singulation must protect the fragile membranes from the processing environment while maintaining a ring array geometry. The singulation process presented in this paper involves bonding a trench-patterned CMUT wafer onto a support wafer, deep reactive ion etching (DRIE) of the trenches, separating the CMUT wafer from the support wafer and de-tethering the CMUT device from the CMUT wafer. The CMUT arrays fabricated and singulated in this process were ring-shaped arrays, with inner and outer diameters of 5 mm and 10 mm, respectively. The fabricated CMUT ring arrays demonstrate the ability of this method to successfully and safely singulate the ring arrays and is applicable to any arbitrary 2D shaped MEMS device with uspended microstructures, taking advantage of the inherent planar attributes of DRIE.

GPU-based real-time volumetric ultrasound image reconstruction for a ring array.

Synthetic phased array (SPA) beamforming with Hadamard coding and aperture weighting is an optimal option for real-time volumetric imaging with a ring array, a particularly attractive geometry in intracardiac and intravascular applications. However, the imaging frame rate of this method is limited by the immense computational load required in synthetic beamforming. For fast imaging with a ring array, we developed graphics processing unit (GPU)-based, real-time image reconstruction software that exploits massive data-level parallelism in beamforming operations. The GPU-based software reconstructs and displays three cross-sectional images at 45 frames per second (fps). This frame rate is 4.5 times higher than that for our previously-developed multi-core CPU-based software. In an alternative imaging mode, it shows one B-mode image rotating about the axis and its maximum intensity projection, processed at a rate of 104 fps . This paper describes the image reconstruction procedure on the GPU platform and presents the experimental images obtained using this software.

Integrated circuits for volumetric ultrasound imaging with 2-D CMUT arrays.

Real-time volumetric ultrasound imaging systems require transmit and receive circuitry to generate ultrasound beams and process received echo signals. The complexity of building such a system is high due to requirement of the front-end electronics needing to be very close to the transducer. A large number of elements also need to be interfaced to the back-end system and image processing of a large dataset could affect the imaging volume rate. In this work, we present a 3-D imaging system using capacitive micromachined ultrasonic transducer (CMUT) technology that addresses many of the challenges in building such a system. We demonstrate two approaches in integrating the transducer and the front-end electronics. The transducer is a 5-MHz CMUT array with an 8 mm × 8 mm aperture size. The aperture consists of 1024 elements (32 × 32) with an element pitch of 250 µm. An integrated circuit (IC) consists of a transmit beamformer and receive circuitry to improve the noise performance of the overall system. The assembly was interfaced with an FPGA and a back-end system (comprising of a data acquisition system and PC). The FPGA provided the digital I/O signals for the IC and the back-end system was used to process the received RF echo data (from the IC) and reconstruct the volume image using a phased array imaging approach. Imaging experiments were performed using wire and spring targets, a ventricle model and a human prostrate. Real-time volumetric images were captured at 5 volumes per second and are presented in this paper.

Volumetric real-time imaging using a CMUT ring array.

A ring array provides a very suitable geometry for forward-looking volumetric intracardiac and intravascular ultrasound imaging. We fabricated an annular 64-element capacitive micromachined ultrasonic transducer (CMUT) array featuring a 10-MHz operating frequency and a 1.27-mm outer radius. A custom software suite was developed to run on a PC-based imaging system for real-time imaging using this device. This paper presents simulated and experimental imaging results for the described CMUT ring array. Three different imaging methods--flash, classic phased array (CPA), and synthetic phased array (SPA)--were used in the study. For SPA imaging, two techniques to improve the image quality--Hadamard coding and aperture weighting--were also applied. The results show that SPA with Hadamard coding and aperture weighting is a good option for ring-array imaging. Compared with CPA, it achieves better image resolution and comparable signal-to-noise ratio at a much faster image acquisition rate. Using this method, a fast frame rate of up to 463 volumes per second is achievable if limited only by the ultrasound time of flight; with the described system we reconstructed three cross-sectional images in real-time at 10 frames per second, which was limited by the computation time in synthetic beamforming.

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.

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.

Miniaturized ultrasound imaging probes enabled by CMUT arrays with integrated frontend electronic circuits.

Capacitive micromachined ultrasonic transducer (CMUT) arrays are conveniently integrated with frontend integrated circuits either monolithically or in a hybrid multichip form. This integration helps with reducing the number of active data processing channels for 2D arrays. This approach also preserves the signal integrity for arrays with small elements. Therefore CMUT arrays integrated with electronic circuits are most suitable to implement miniaturized probes required for many intravascular, intracardiac, and endoscopic applications. This paper presents examples of miniaturized CMUT probes utilizing 1D, 2D, and ring arrays with integrated electronics.

CMUT With Substrate-Embedded Springs For Non-Flexural Plate Movement.

A conventional capacitive micromachined ultrasonic transducer (CMUT) is composed of many cells connected in parallel. Since the plate in each CMUT cell is anchored at its perimeter, the average displacement is several times smaller than the displacement of an equivalent ideal piston transducer. In addition, the post areas, where the plates are anchored to, are non-active and, thus, do not contribute to the transduction. We propose a CMUT structure that resembles an ideal capacitive piston transducer, where the movable top plate only undergoes translation rather than deflection. Our proposed CMUT structure is composed of a rigid plate connected to a substrate using relatively long and narrow posts, providing the spring constant for the movement of the plate. Rather than the flexure of the plate as in a conventional CMUT, this device operates based on the compression of the compliant posts. For a capacitive transducer, a thin electrostatic gap is provided under the top plate. We used finite element analysis (FEA) to design and verify the structure's functionality. The simulation results show a fractional bandwidth of over 100% in immersion for all the designs. They also confirm that the average displacement of the top plate is above 90% of its peak displacement. We fabricated the first prototype based on this idea, which only requires a simple 3-mask fabrication process. In addition to 128-element 1-D arrays, we fabricated a variety of 240 µm × 240 µm, single-element transducers with different post configurations. We successfully measured the electrical input impedance of the fabricated devices and confirmed their resonant behavior in air. Further, we measured the acoustic pressure using a calibrated hydrophone at a known distance. Using this measurement, we calculated a peak-to-peak pressure of 1.5 MPa at the face of the transducer. Our results show that it is possible to fabricate CMUTs that exhibit ideal piston-like plate movement. Because of the substrate-embedded spring elements, the plate does not need to be operated in flexural mode, as in a conventional CMUT, resulting in a significantly improved fill-factor, and, thus, a more efficient device.

A family of intracardiac ultrasound imaging devices designed for guidance of electrophysiology ablation procedures.

Our Bioengineering Research Partnership grant, -High Frequency Ultrasound Arrays for Cardiac Imaging", including the individuals cited at the end of this paper - Douglas N. Stephens (UC Davis), Matthew O'Donnell (UW Seattle), Kai Thomenius (GE Global Research), Aaron M. Dentinger (GE Global Research), Douglas Wildes (GE Global Research), Peter Chen (St. Jude Medical), K. Kirk Shung (University of Southern California), Jonathan M. Cannata (University of Southern California), Butrus (Pierre) T. Khuri-Yakub (Stanford University), Omer Oralkan (Stanford University), Aman Mahajan (UCLA School of Medicine), Kalyanam Shivkumar (UCLA School of Medicine) and David J. Sahn (Oregon Health & Science University) - is in its sixth year of NIH funding, having proposed to develop a family of high frequency miniaturized forward and side-looking ultrasound imaging devices equipped with electrophysiology mapping and localization sensors and eventually to include a family of capactive micromachined ultrasonic transducer (cMUT) devices - a forward-looking cMUT MicroLinear array and a ring array capable of 3-dimensional imaging and a 5Fr lumen large enough to admit an electrode and ablation devices.

An integrated circuit with transmit beamforming flip-chip bonded to a 2-D CMUT array for 3-D ultrasound imaging.

State-of-the-art 3-D medical ultrasound imaging requires transmitting and receiving ultrasound using a 2-D array of ultrasound transducers with hundreds or thousands of elements. A tight combination of the transducer array with integrated circuitry eliminates bulky cables connecting the elements of the transducer array to a separate system of electronics. Furthermore, preamplifiers located close to the array can lead to improved receive sensitivity. A combined IC and transducer array can lead to a portable, high-performance, and inexpensive 3-D ultrasound imaging system. This paper presents an IC flip-chip bonded to a 16 x 16-element capacitive micromachined ultrasonic transducer (CMUT) array for 3-D ultrasound imaging. The IC includes a transmit beamformer that generates 25-V unipolar pulses with programmable focusing delays to 224 of the 256 transducer elements. One-shot circuits allow adjustment of the pulse widths for different ultrasound transducer center frequencies. For receiving reflected ultrasound signals, the IC uses the 32-elements along the array diagonals. The IC provides each receiving element with a low-noise 25-MHz-bandwidth transimpedance amplifier. Using a field-programmable gate array (FPGA) clocked at 100 MHz to operate the IC, the IC generated properly timed transmit pulses with 5-ns accuracy. With the IC flip-chip bonded to a CMUT array, we show that the IC can produce steered and focused ultrasound beams. We present 2-D and 3-D images of a wire phantom and 2-D orthogonal cross-sectional images (Bscans) of a latex heart phantom.

Forward-looking intracardiac ultrasound imaging using a 1-D CMUT array integrated with custom front-end electronics.

Minimally invasive catheter-based electrophysiological (EP) interventions are becoming a standard procedure in diagnosis and treatment of cardiac arrhythmias. As a result of technological advances that enable small feature sizes and a high level of integration, nonfluoroscopic intracardiac echocardiography (ICE) imaging catheters are attracting increasing attention. ICE catheters improve EP procedural guidance while reducing the undesirable use of fluoroscopy, which is currently the common catheter guidance method. Phased-array ICE catheters have been in use for several years now, although only for side-looking imaging. We are developing a forward-looking ICE catheter for improved visualization. In this effort, we fabricate a 24-element, fine-pitch 1-D array of capacitive micromachined ultrasonic transducers (CMUT), with a total footprint of 1.73 mm x 1.27 mm. We also design a custom integrated circuit (IC) composed of 24 identical blocks of transmit/ receive circuitry, measuring 2.1 mm x 2.1 mm. The transmit circuitry is capable of delivering 25-V unipolar pulses, and the receive circuitry includes a transimpedance preamplifier followed by an output buffer. The CMUT array and the custom IC are designed to be mounted at the tip of a 10-Fr catheter for high-frame-rate forward-looking intracardiac imaging. Through-wafer vias incorporated in the CMUT array provide access to individual array elements from the back side of the array. We successfully flip-chip bond a CMUT array to the custom IC with 100% yield. We coat the device with a layer of polydimethylsiloxane (PDMS) to electrically isolate the device for imaging in water and tissue. The pulse-echo in water from a total plane reflector has a center frequency of 9.2 MHz with a 96% fractional bandwidth. Finally, we demonstrate the imaging capability of the integrated device on commercial phantoms and on a beating ex vivo rabbit heart (Langendorff model) using a commercial ultrasound imaging system.

Dynamic analysis of capacitive micromachined ultrasonic transducers.

Electrostatic transducers are usually operated under a DC bias below their collapse voltage. The same scheme has been adopted for capacitive micromachined ultrasonic transducers (cMUTs). DC bias deflects the cMUT membranes toward the substrate, so that their centers are free to move during both receive and transmit operations. In this paper, we present time-domain, finite element calculations for cMUTs using LS-DYNA, a commercially available finite element package. In addition to this DC bias mode, other new cMUT operations (collapse and collapse-snapback) have recently been demonstrated. Because cMUT membranes make contact with the substrate in these new operations, modeling of these cMUTs should include contact analysis. Our model was a cMUT transducer consisting of many hexagonal membranes; because it was symmetrical, we modeled only one-sixth of a hexagonal cell loaded with a fluid medium. The finite element results for both conventional and collapse modes were compared to measurements made by an optical interferometer; a good match was observed. Thus, the model is useful for designing cMUTs that operate in regimes where membranes make contact with the substrate.