Highly Integrated Multiplexing and Buffering Electronics for Large Aperture Ultrasonic Arrays.

Large aperture ultrasonic arrays can be implemented by tiling together multiple pretested modules of high-density acoustic arrays with closely integrated multiplexing and buffering electronics to form a larger aperture with high yield. These modular arrays can be used to implement large 1.75D array apertures capable of focusing in elevation for uniform slice thickness along the axial direction which can improve image contrast. An important goal for large array tiling is obtaining high yield and sensitivity while reducing extraneous image artifacts. We have been developing tileable acoustic-electric modules for the implementation of large array apertures utilizing Application Specific Integrated Circuits (ASICs) implemented using 0.35 µ m high voltage (50 V) CMOS. Multiple generations of ASICs have been designed and tested. The ASICs were integrated with high-density transducer arrays for acoustic testing and imaging. The modules were further interfaced to a Verasonics Vantage imaging system and were used to image industry standard ultrasound phantoms. The first-generation modules comprise ASICs with both multiplexing and buffering electronics on-chip and have demonstrated a switching artifact which was visible in the images. A second-generation ASIC design incorporates low switching injection circuits which effectively mitigate the artifacts observed with the first-generation devices. Here, we present the architecture of the two ASIC designs and module types as well imaging results that demonstrate reduction in switching artifacts for the second-generation devices.

A theranostic 3D ultrasound imaging system for high resolution image-guided therapy.

Microbubble contrast agents are a diagnostic tool with broad clinical impact and an increasing number of indications. Many therapeutic applications have also been identified. Yet, technologies for ultrasound guidance of microbubble-mediated therapy are limited. In particular, arrays that are capable of implementing and imaging microbubble-based therapy in three dimensions in real-time are lacking. We propose a system to perform and monitor microbubble-based therapy, capable of volumetric imaging over a large field-of-view. To propel the promise of the theranostic treatment strategies forward, we have designed and tested a unique array and system for 3D ultrasound guidance of microbubble-based therapeutic protocols based on the frequency, temporal and spatial requirements. Methods: Four 256-channel plane wave scanners (Verasonics, Inc, WA, USA) were combined to control a 1024-element planar array with 1.3 and 2.5 MHz therapeutic and imaging transmissions, respectively. A transducer aperture of ~40×15 mm was selected and Field II was applied to evaluate the point spread function. In vitro experiments were performed on commercial and custom phantoms to assess the spatial resolution, image contrast and microbubble-enhanced imaging capabilities. Results: We found that a 2D array configuration with 64 elements separated by λ-pitch in azimuth and 16 elements separated by 1.5λ-pitch in elevation ensured the required flexibility. This design, of 41.6 mm × 16 mm, thus provided both an extended field-of-view, up to 11 cm x 6 cm at 10 cm depth and steering of ±18° in azimuth and ±12° in elevation. At a depth of 16 cm, we achieved a volume imaging rate of 60 Hz, with a contrast ratio and resolution, respectively, of 19 dB, 0.8 mm at 3 cm and 20 dB and 2.1 mm at 12.5 cm. Conclusion: A single 2D array for both imaging and therapeutics, integrated with a 1024 channel scanner can guide microbubble-based therapy in volumetric regions of interest.

Erratum to "Highly Integrated Multiplexing and Buffering Electronics for Large Aperture Ultrasonic Arrays".

[This corrects the article DOI: 10.34133/2022/9870386.].

Co-Integrated PIN-PMN-PT 2-D Array and Transceiver Electronics by Direct Assembly Using a 3-D Printed Interposer Grid Frame.

Tiled modular 2-D ultrasound arrays have the potential for realizing large apertures for novel diagnostic applications. This work presents an architecture for fabrication of tileable 2-D array modules implemented using 1-3 composites of high-bandwidth (BW) PIN-PMN-PT single-crystal piezoelectric material closely coupled with high-voltage CMOS application-specific integrated circuit (ASIC) electronics for buffering and multiplexing functions. The module, which is designed to be operated as a λ -pitch 1.75-D array, benefits from an improved electromechanical coupling coefficient and increased Curie temperature and is assembled directly on top of the ASIC silicon substrate using an interposer backing. The interposer consists of a novel 3-D printed acrylic frame that is filled with conducting and acoustically absorbing silver epoxy material. The ASIC comprises a high-voltage switching matrix with locally integrated buffering and is interfaced to a Verasonics Vantage 128, using a local field programmable gate array (FPGA) controller. Multiple prototype 5 ×6 element array modules have been fabricated by this process. The combined acoustic array and ASIC module was configured electronically by programming the switches to operate as a 1-D array with elements grouped in elevation for imaging and pulse-echo testing. The resulting array configuration had an average center frequency of 4.55 MHz, azimuthal element pitch of [Formula: see text], and exhibited average -20-dB pulsewidth of 592 ns and average -6-dB fractional BW of 77%.

Simultaneous Axial Multifocal Imaging Using a Single Acoustical Transmission: A Practical Implementation.

Standard ultrasound imaging techniques rely on sweeping a focused beam across a field of view; however, outside the transmission focal depth, image resolution and contrast are degraded. High-quality deep tissue in vivo imaging requires focusing the emitted field at multiple depths, yielding high-resolution and high-contrast ultrasound images but at the expense of a loss in frame rate. Recent developments in ultrasound technologies have led to user-programmable systems, which enable real-time dynamic control over the phase and apodization of each individual element in the imaging array. In this paper, we present a practical implementation of a method to achieve simultaneous axial multifoci using a single acoustical transmission. Our practical approach relies on the superposition of axial multifoci waveforms in a single transmission. The delay in transmission between different elements is set such that pulses constructively interfere at multiple focal depths. The proposed method achieves lateral resolution similar to successive focusing, but with an enhanced frame rate. The proposed method uses standard dynamic receive beamforming, identical to two-way focusing, and does not require additional postprocessing. Thus, the method can be implemented in real time on programmable ultrasound systems that allow different excitation signals for each element. The proposed method is described analytically and validated by laboratory experiments in phantoms and ex vivo biological samples.

Theoretical investigation of ultrasound-modulated Cerenkov luminescence imaging for higher-resolution imaging in turbid media.

Cerenkov luminescence imaging (CLI) is an optical technique for imaging radiolabeled molecules in vivo. It has demonstrated utility in both the clinical and preclinical settings and can serve as a substitute for nuclear imaging instrumentation in some cases. However, optical scattering fundamentally limits the resolution and depth of imaging that can be achieved with this modality. In this Letter, we report the numerical results that support the potential for ultrasound-modulated Cerenkov luminescence imaging (USCLI), a new imaging modality that can mitigate optical scattering. The technique uses an acoustic field to modulate the refractive index of the medium and, thus, the intensity of Cerenkov luminescence in a spatially precise manner. This mechanism of contrast has not been reported previously. For a physiologically compatible ultrasound peak pressure of 1 MPa, ∼0.1% of the Cerenkov signal can be modulated. Furthermore, our simulations show that USCLI can overcome the scattering limit of resolution for CLI and provide higher-resolution imaging. For an F18 point source centered in a 1 cm3 simulated tissue phantom with a scattering coefficient of µs'=10 cm-1, <2 mm full width at half-maximum lateral spatial resolution is possible, a resolution three times finer than the same phantom imaged with CLI.

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.

Development of a spherically focused phased array transducer for ultrasonic image-guided hyperthermia.

A 1.5 MHz prolate spheroidal therapeutic array with 128 circular elements was designed to accommodate standard imaging arrays for ultrasonic image-guided hyperthermia. The implementation of this dual-array system integrates real-time therapeutic and imaging functions with a single ultrasound system (Vantage 256, Verasonics). To facilitate applications involving small animal imaging and therapy the array was designed to have a beam depth of field smaller than 3.5 mm and to electronically steer over distances greater than 1 cm in both the axial and lateral directions. In order to achieve the required f number of 0.69, 1-3 piezocomposite modules were mated within the transducer housing. The performance of the prototype array was experimentally evaluated with excellent agreement with numerical simulation. A focal volume (2.70 mm (axial) × 0.65 mm (transverse) × 0.35 mm (transverse)) defined by the -6 dB focal intensity was obtained to address the dimensions needed for small animal therapy. An electronic beam steering range defined by the -3 dB focal peak intensity (17 mm (axial) × 14 mm (transverse) × 12 mm (transverse)) and -8 dB lateral grating lobes (24 mm (axial) × 18 mm (transverse) × 16 mm (transverse)) was achieved. The combined testing of imaging and therapeutic functions confirmed well-controlled local heating generation and imaging in a tissue mimicking phantom. This dual-array implementation offers a practical means to achieve hyperthermia and ablation in small animal models and can be incorporated within protocols for ultrasound-mediated drug delivery.

Photoacoustic-imaging-based temperature monitoring for high-intensity focused ultrasound therapy.

Temperature monitoring during high-intensity focused ultrasound (HIFU) application is necessary to ensure effective therapy while minimizing thermal damage to adjacent tissue. In this study, we demonstrate a noninvasive approach for temperature measurement during HIFU therapy based on photoacoustic imaging (PAI). Because of the dependence of photoacoustic (PA) signal amplitude on temperature of the source tissue and the linearity of the PAI system, changes in temperature will cause changes in PA image intensity. Experiments have been conducted in ex-vivo bovine tissue to characterize the linear dependence of PA image pixel values on temperature and subsequently to convert the PA image to a real-time temperature map.

Flexible integration of high-imaging-resolution and high-power arrays for ultrasound-induced thermal strain imaging (US-TSI).

Ultrasound-induced thermal strain imaging (USTSI) for carotid artery plaque detection requires both high imaging resolution (<100 µm) and sufficient US-induced heating to elevate the tissue temperature (~1°C to 3°C within 1 to 3 cardiac cycles) to produce a noticeable change in sound speed in the targeted tissues. Because the optimization of both imaging and heating in a monolithic array design is particularly expensive and inflexible, a new integrated approach is presented which utilizes independent ultrasound arrays to meet the requirements for this particular application. This work demonstrates a new approach in dual-array construction. A 3-D printed manifold was built to support both a high-resolution 20 MHz commercial imaging array and 6 custom heating elements operating in the 3.5 to 4 MHz range. For the application of US-TSI in carotid plaque characterization, the tissue target site is 20 to 30 mm deep, with a typical target volume of 2 mm (elevation) × 8 mm (azimuthal) × 5 mm (depth). The custom heating array performance was fully characterized for two design variants (flat and spherical apertures), and can easily deliver 30 W of total acoustic power to produce intensities greater than 15 W/cm(2) in the tissue target region.

Noninvasive detection of lipids in atherosclerotic plaque using ultrasound thermal strain imaging: in vivo animal study.

OBJECTIVES: This study sought to examine the feasibility of in vivo detection of lipids in atherosclerotic plaque (AP) by ultrasound (US) thermal (or temporal) strain imaging (TSI). BACKGROUND: Intraplaque lipid content is thought to contribute to plaque stability. Lipid exhibits a distinctive physical characteristic of temperature-dependent US speed compared with water-bearing tissues. As tissue temperature changes, US radiofrequency (RF) echoes shift in time of flight, which produces an apparent strain (thermal or temporal strain [TS]). METHODS: US heating-imaging pulse sequences and transducers were designed and integrated into commercial US scanners for US-TSI of arterial segments. US-RF data were collected while gradually increasing tissue temperature. Phase-sensitive speckle tracking was applied to reconstruct TS maps coregistered to B-scans. Segments from injured atherosclerotic and uninjured nonatherosclerotic common femoral arteries (CFA) in cholesterol-fed New Zealand rabbits, and segments from control normal diet-fed rabbits (N =14) were scanned in vivo at different time points up to 12 weeks. RESULTS: Lipid-rich atherosclerotic lesions exhibited distinct positive TS (+0.19 ± 0.08%) compared with that in nonatherosclerotic (-0.10 ± 0.13%) and control (-0.09 ± 0.09%) segments (p < 0.001). US-TSI enabled serial monitoring of lipids during atherosclerosis development. The coregistered set of morphological and compositional information of US-TSI showed good agreement with histology. CONCLUSIONS: US-TSI successfully detected and longitudinally monitored lipid progression in atherosclerotic CFA. US-TSI of relatively superficial arteries may be a modality that could be integrated into a commercial US system for noninvasive lipid detection in AP.

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.

A radio-frequency coupling network for heating of citrate-coated gold nanoparticles for cancer therapy: design and analysis.

Gold nanoparticles (GNPs) are nontoxic, can be functionalized with ligands, and preferentially accumulate in tumors. We have developed a 13.56-MHz RF-electromagnetic field (RF-EM) delivery system capable of generating high E-field strengths required for noninvasive, noncontact heating of GNPs. The bulk heating and specific heating rates were measured as a function of NP size and concentration. It was found that heating is both size and concentration dependent, with 5 nm particles producing a 50.6 ± 0.2 °C temperature rise in 30 s for 25 µg/mL gold (125 W input). The specific heating rate was also size and concentration dependent, with 5 nm particles producing a specific heating rate of 356 ± 78 kW/g gold at 16 µg/mL (125 W input). Furthermore, we demonstrate that cancer cells incubated with GNPs are killed when exposed to 13.56 MHz RF-EM fields. Compared to cells that were not incubated with GNPs, three out of four RF-treated groups showed a significant enhancement of cell death with GNPs (p<0.05). GNP-enhanced cell killing appears to require temperatures above 50 °C for the experimental parameters used in this study. Transmission electron micrographs show extensive vacuolization with the combination of GNPs and RF treatment.

Noninvasive thermometry assisted by a dual-function ultrasound transducer for mild hyperthermia.

Mild hyperthermia is increasingly important for the activation of temperature-sensitive drug delivery vehicles. Noninvasive ultrasound thermometry based on a 2-D speckle tracking algorithm was examined in this study. Here, a commercial ultrasound scanner, a customized co-linear array transducer, and a controlling PC system were used to generate mild hyperthermia. Because the co-linear array transducer is capable of both therapy and imaging at widely separated frequencies, RF image frames were acquired during therapeutic insonation and then exported for off-line analysis. For in vivo studies in a mouse model, before temperature estimation, motion correction was applied between a reference RF frame and subsequent RF frames. Both in vitro and in vivo experiments were examined; in the in vitro and in vivo studies, the average temperature error had a standard deviation of 0.7°C and 0.8°C, respectively. The application of motion correction improved the accuracy of temperature estimation, where the error range was 1.9 to 4.5°C without correction compared with 1.1 to 1.0°C following correction. This study demonstrates the feasibility of combining therapy and monitoring using a commercial system. In the future, real-time temperature estimation will be incorporated into this system.

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.

A sensitive TLRH targeted imaging technique for ultrasonic molecular imaging.

The primary goals of ultrasound molecular imaging are the detection and imaging of ultrasound contrast agents (microbubbles), which are bound to specific vascular surface receptors. Imaging methods that can sensitively and selectively detect and distinguish bound microbubbles from freely circulating microbubbles (free microbubbles) and surrounding tissue are critically important for the practical application of ultrasound contrast molecular imaging. Microbubbles excited by low-frequency acoustic pulses emit wide-band echoes with a bandwidth extending beyond 20 MHz; we refer to this technique as transmission at a low frequency and reception at a high frequency (TLRH). Using this wideband, transient echo, we have developed and implemented a targeted imaging technique incorporating a multifrequency colinear array and the Siemens Antares imaging system. The multifrequency colinear array integrates a center 5.4-MHz array, used to receive echoes and produce radiation force, and 2 outer 1.5-MHz arrays used to transmit low-frequency incident pulses. The targeted imaging technique makes use of an acoustic radiation force subsequence to enhance accumulation and a TLRH imaging subsequence to detect bound microbubbles. The radiofrequency (RF) data obtained from the TLRH imaging subsequence are processed to separate echo signatures between tissue, free microbubbles, and bound microbubbles. By imaging biotin-coated microbubbles targeted to avidin-coated cellulose tubes, we demonstrate that the proposed method has a high contrast-to-tissue ratio (up to 34 dB) and a high sensitivity to bound microbubbles (with the ratio of echoes from bound microbubbles versus free microbubbles extending up to 23 dB). The effects of the imaging pulse acoustic pressure, the radiation force subsequence, and the use of various slow-time filters on the targeted imaging quality are studied. The TLRH targeted imaging method is demonstrated in this study to provide sensitive and selective detection of bound microbubbles for ultrasound molecularly targeted imaging.

Spatial and temporal-controlled tissue heating on a modified clinical ultrasound scanner for generating mild hyperthermia in tumors.

A new system is presented for generating controlled tissue heating with a clinical ultrasound scanner, and initial in vitro and in vivo results are presented that demonstrate both transient and sustained heating in the mild-hyperthermia range of 37 ( degrees )C-42 ( degrees )C. The system consists of a Siemens Antares ultrasound scanner, a custom dual-frequency three-row transducer array and an external temperature feedback control system. The transducer has two outer rows that operate at 1.5 MHz for tissue heating and a center row that operates at 5 MHz for B-mode imaging to guide the therapy. We compare the field maps obtained using a hydrophone against calculations of the ultrasound beam based on monochromatic and linear assumptions. Using the finite-difference time-domain (FDTD) method, we compare predicted time-dependent thermal profiles to measured profiles for soy tofu as a tissue-mimicking phantom. In vitro results show differential heating of 6 ( degrees )C for chicken breast and tofu. In vivo tests of the system were performed on three mice bearing Met-1 tumors, which is a model of aggressive, metastatic, and highly vascular breast cancer. In superficially implanted tumors, we demonstrate controlled heating to 42 ( degrees )C. We show that the system is able to maintain the temperature to within 0.1 ( degrees )C of the desired temperature both in vitro and in vivo.

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.