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.

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.

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.].

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.

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%.

Intraluminal fluorescence spectroscopy catheter with ultrasound guidance.

We demonstrate the feasibility of a time-resolved fluorescence spectroscopy (TRFS) technique for intraluminal investigation of arterial vessel composition under intravascular ultrasound (IVUS) guidance. A prototype 1.8-mm (5.4 Fr) catheter combining a side-viewing optical fiber (SVOF) and an IVUS catheter was constructed and tested with in vitro vessel phantoms. The prototype catheter can locate a fluorophore in the phantom vessel wall, steer the SVOF in place, perform blood flushing under flow conditions, and acquire high-quality TRFS data using 337-nm wavelength excitation. The catheter steering capability used for the coregistration of the IVUS image plane and the SVOF beam produce a guiding precision to an arterial phantom wall site location of 0.53+/-0.16 mm. This new intravascular multimodal catheter enables the potential for in vivo arterial plaque composition identification using TRFS.

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.

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.

Efficient array design for sonotherapy.

New linear multi-row, multi-frequency arrays have been designed, constructed and tested as fully operational ultrasound probes to produce confocal imaging and therapeutic acoustic intensities with a standard commercial ultrasound imaging system. The triple-array probes and imaging system produce high quality B-mode images with a center row imaging array at 5.3 MHz and sufficient acoustic power with dual therapeutic arrays to produce mild hyperthermia at 1.54 MHz. The therapeutic array pair in the first probe design (termed G3) utilizes a high bandwidth and peak pressure, suitable for mechanical therapies. The second multi-array design (termed G4) has a redesigned therapeutic array pair which is optimized for a high time-averaged power output suitable for mild hyperthermia applications. The 'thermal therapy' design produces more than 4 W of acoustic power from the low-frequency arrays with only a 10.5 degrees C internal rise in temperature after 100 s of continuous use with an unmodified conventional imaging system or substantially longer operation at lower acoustic power. The low-frequency arrays in both probe designs were examined and contrasted for real power transfer efficiency with a KLM model which includes all lossy contributions in the power delivery path from system transmitters to the tissue load. Laboratory verification was successfully performed for the KLM-derived estimates of transducer parallel model acoustic resistance and dissipation resistance, which are the critical design factors for acoustic power output and undesired internal heating, respectively.

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.

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.

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.

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.

An integrated semicompliant balloon ultrasound catheter for quantitative feedback and image guidance during stent deployment.

An integrated balloon ultrasound catheter prototype was designed to image from inside the balloon for real-time guidance during stent deployment. It was fabricated using a semicompliant balloon material (polyethylene) and a 20 MHz, 64-element circumferential ultrasound array. A commercial stent, nominally 4.4 mm in diameter and 12 mm in length, was used for a phantom study and placed along the length of the integrated balloon ultrasound catheter. A rubber phantom was created with an elastic modulus of 175 kPa with a 4.36 mm diameter lumen. Real-time balloon pressure measurements were recorded using a digital pressure sensor, and real-time radio-frequency (RF) data were captured as the balloon was inflated. The slope of the area-pressure ratio (APR) was compared to a reference measure of the balloon and stent expanded in water to determine a measure for optimal stent deployment. The results clearly indicate stent deployment at 11.1 atm using this metric. The APR slope could serve as quantitative feedback parameter for guiding stent deployment to reduce arterial injury and subsequent restenosis. After the stent deployment experiment, RF data were captured as the balloon catheter was moved along the length of the stent in pullback mode to confirm successful stent deployment. Ultimately, an integrated balloon ultrasound catheter could serve as a single catheter intervention device by providing real-time intravascular ultrasound (IVUS) imaging and quantitative feedback during stent deployment.

Optimizing the beam pattern of a forward-viewing ring-annular ultrasound array for intravascular imaging.

Intravascular ultrasound (IVUS) imaging systems using circumferential arrays mounted on cardiac catheter tips fire beams orthogonal to the principal axis of the catheter. The system produces high resolution cross-sectional images but must be guided by conventional angioscopy. A real-time forward-viewing array, integrated into the same catheter, could greatly reduce radiation exposure by decreasing angiographic guidance. Unfortunately, the mounting requirement of a catheter guide wire prohibits a full-disk imaging aperture. Given only an annulus of array elements, prior theoretical investigations have only considered a circular ring of point transceivers and focusing strategies using all elements in the highly dense array, both impractical assumptions. In this paper, we consider a practical array geometry and signal processing architecture for a forward-viewing IVUS system. Our specific design uses a total of 210 transceiver firings with synthetic reconstruction for a given 3-D image frame. Simulation results demonstrate this design can achieve side-lobes under -40 dB for on-axis situations and under -30 dB for steering to the edge of a 80 degrees cone.

Coded excitation with spectrum inversion (CEXSI) for ultrasound array imaging.

In this paper, a scheme called coded excitation with spectrum inversion (CEXSI) is presented. An established optimal binary code whose spectrum has no nulls and possesses the least variation is encoded as a burst for transmission. Using this optimal code, the decoding filter can be derived directly from its inverse spectrum. Various transmission techniques can be used to improve energy coupling within the system pass-band. We demonstrate its potential to achieve excellent decoding with very low (< 80 dB) side-lobes. For a 2.6 micros code, an array element with a center frequency of 10 MHz and fractional bandwidth of 38%, range side-lobes of about 40 dB have been achieved experimentally with little compromise in range resolution. The signal-to-noise ratio (SNR) improvement also has been characterized at about 14 dB. Along with simulations and experimental data, we present a formulation of the scheme, according to which CEXSI can be extended to improve SNR in sparse array imaging in general.

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.

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.

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.