Development of a Small-Footprint 50 MHz Linear Array: Fabrication and Micro-Ultrasound Imaging Demonstration.

Compact high-frequency arrays are of interest for clinical and preclinical applications in which a small-footprint or endoscopic device is needed to reach the target anatomy. However, the fabrication of compact arrays entails the connection of several dozens of small elements to the imaging system through a combination of flexible printed circuit boards at the array end and micro-coaxial cabling to the imaging system. The methods currently used, such as wire bonding, conductive adhesives, or a dry connection to a flexible circuit, considerably increase the array footprint.

Adaptation of a Clinical High-Frequency Transrectal Ultrasound System for Prostate Photoacoustic Imaging: Implementation and Pre-clinical Demonstration.

Objective: High-frequency, high-resolution transrectal micro-ultrasound (micro-US: ≥15 MHz) imaging of the prostate is emerging as a beneficial tool for scoring disease risk and accurately targeting biopsies. Adding photoacoustic (PA) imaging to visualize abnormal vascularization and accumulation of contrast agents in tumors has potential for guiding focal therapies. In this work, we describe a new imaging platform that combines a transrectal micro-US system with transurethral light delivery for PA imaging.

Micro-ultrasound based characterization of cerebrovasculature following focal ischemic stroke and upon short-term rehabilitation.

Notwithstanding recanalization treatments in the acute stage of stroke, many survivors suffer long-term impairments. Physical rehabilitation is the only widely available strategy for chronic-stage recovery, but its optimization is hindered by limited understanding of its effects on brain structure and function. Using micro-ultrasound, behavioral testing, and electrophysiology, we investigated the impact of skilled reaching rehabilitation on cerebral hemodynamics, motor function, and neuronal activity in a rat model of focal ischemic stroke.

Superharmonic and Microultrasound Imaging With Plane Wave Beamforming Techniques.

Superharmonic contrast imaging (SpHI) suppresses tissue clutter and allows high-contrast visualization of the vasculature. An array-based dual-frequency (DF) probe has been developed for SpHI, integrating a 21-MHz, 256-element microultrasound imaging array with a 2-MHz, 32-element array to take advantage of the broadband nonlinear responses from microbubble (MB) contrast agents. In this work, ultrafast imaging with plane waves was implemented for SpHI to increase the acquisition frame rate.

The CathEye: A Forward-Looking Ultrasound Catheter for Image-Guided Cardiovascular Procedures.

Catheter based procedures are typically guided by X-Ray, which suffers from low soft tissue contrast and only provides 2D projection images of a 3D volume. Intravascular ultrasound (IVUS) can serve as a complementary imaging technique. Forward viewing catheters are useful for visualizing obstructions along the path of the catheter.

High-frequency quantitative ultrasound for the assessment of the acoustic properties of engineered tissues in vitro.

Acoustic properties of biomaterials and engineered tissues reflect their structure and cellularity. High-frequency ultrasound (US) can non-invasively characterize and monitor these properties with sub-millimetre resolution. We present an approach to estimate the speed of sound, acoustic impedance, and acoustic attenuation of cell-laden hydrogels that accounts for frequency-dependent effects of attenuation in coupling media, hydrogel thickness, and interfacial transmission/reflection coefficients of US waves, all of which can bias attenuation estimates.

Fine Pitch Flexible Printed Circuit Board Patterning for Miniaturized Endoscopic MicroUltrasound Arrays.

Microultrasound (micro-US) has become an invaluable tool for preclinical research and in emerging applications in clinical diagnosis and treatment guidance. Several such applications can benefit from arrays with a small footprint and endoscopic form factor. However, critical challenges arise in making electrical connections to array elements in such spatial constraints.

Acoustic Molecular Imaging Beyond the Diffraction Limit In Vivo.

Ultrasound molecular imaging (USMI) is a technique used to noninvasively estimate the distribution of molecular markers by imaging microbubble contrast agents (MCAs) that have been modified to target receptors of interest on the vascular endothelium. USMI is especially relevant for preclinical and clinical cancer research and has been used to predict tumor malignancy and response to treatment. In the last decade, methods that improve the resolution of contrast-enhanced ultrasound by an order of magnitude and allow researchers to noninvasively image individual capillaries have emerged.

Implementation of a Novel 288-Element Dual-Frequency Array for Acoustic Angiography: In Vitro and In Vivo Characterization.

Acoustic angiography is a superharmonic contrast-enhanced ultrasound imaging method that produces high-resolution, 3-D maps of the microvasculature. Previous acoustic angiography studies have used twoelement, annular,mechanicallyactuated transducers(called "wobblers") to image microvasculature in preclinical tumor models with high contrast-to-tissue ratio and resolution, but these earlywobbler transducerscould not achieve the depth and sensitivity required for clinical acoustic angiography. In this work, we present a system for performing acoustic angiography with a novel dual-frequency(DF) transducer-a coaxially stacked DF array (DFA).

Characterization of an Array-Based Dual-Frequency Transducer for Superharmonic Contrast Imaging.

Superharmonic imaging with dual-frequency imaging systems uses conventional low-frequency ultrasound transducers on transmit, and high-frequency transducers on receive to detect higher order harmonic signals from microbubble contrast agents, enabling high-contrast imaging while suppressing clutter from background tissues. Current dual-frequency imaging systems for superharmonic imaging have been used for visualizing tumor microvasculature, with single-element transducers for each of the low- and high-frequency components. However, the useful field of view is limited by the fixed focus of single-element transducers, while image frame rates are limited by the mechanical translation of the transducers.

High-Frequency Array-Based Nanobubble Nonlinear Imaging in a Phantom and In Vivo.

There has been growing interest in nanobubbles (NBs) for vascular and extravascular ultrasound contrast imaging and therapeutic applications. Studies to date have generally utilized low frequencies (<12 MHz), high concentrations (>10 mL), and uncalibrated B-mode or contrast-mode on commercial systems without reporting investigations on NB signatures upon which the imaging protocols should be based. We recently demonstrated that low concentrations (10 mL) of porphyrin-lipid-encapsulated NBs scatter nonlinearly at low (2.

High frequency ultrasound nonlinear scattering from porphyrin nanobubbles.

Emerging contrast imaging studies have highlighted the potential of nanobubbles for both intravascular and extravascular applications. Reports to date on nanobubbles have generally utilized low frequencies (<12 MHz), high concentrations (>10 mL), and B-mode or contrast-mode on preclinical and clinical systems. However, none of these studies directly examined nanobubble acoustic signatures systematically to implement nonlinear imaging schemes in a methodical manner based on nanobubble behaviour.

30/80 MHz Bidirectional Dual-Frequency IVUS Feasibility Evaluated In Vivo and for Stent Imaging.

Although intravascular ultrasound (IVUS) is an important tool in guiding complex coronary interventions, the resolution of existing commercial IVUS devices is considerably poorer than that of optical coherence tomography. Dual-frequency IVUS (DF IVUS), incorporating a second, higher frequency transducer, has been proposed as a possible method of overcoming this limitation. Although preliminary studies have shown that DF IVUS can produce complementary images, including large-scale morphology and high detail of superficial features, it has not yet been determined that this approach would be feasible in a more clinically relevant environment.

Superharmonic Ultrasound for Motion-Independent Localization Microscopy: Applications to Microvascular Imaging From Low to High Flow Rates.

Recent advances in high frame rate biomedical ultrasound have led to the development of ultrasound localization microscopy (ULM), a method of imaging microbubble (MB) contrast agents beyond the diffraction limit of conventional coherent imaging techniques. By localizing and tracking the positions of thousands of individual MBs, ultrahigh resolution vascular maps are generated which can be further analyzed to study disease. Isolating bubble echoes from tissue signal is a key requirement for super-resolution imaging which relies on the spatiotemporal separability and localization of the bubble signals.

In Vitro Superharmonic Contrast Imaging Using a Hybrid Dual-Frequency Probe.

Superharmonic imaging is an ultrasound contrast imaging technique that differentiates microbubble echoes from tissue through detection of higher-order bubble harmonics in a broad frequency range well above the excitation frequency. Application of superharmonic imaging in three dimensions allows specific visualization of the tissue microvasculature with high resolution and contrast, a technique referred to as acoustic angiography. Because of the need to transmit and receive across a bandwidth that spans up to the fifth harmonic of the fundamental and higher, this imaging approach requires imaging probes comprising dedicated transducers for transmit and receive.

Development of a 3 French Dual-Frequency Intravascular Ultrasound Catheter.

Coronary plaque morphology, including plaque size and fibrous cap thickness, is thought to contribute to the risk of plaque rupture and future cardiac events. Dual-frequency intravascular ultrasound has been proposed as a possible technique to visualize both large-scale features and superficial detail of coronary plaque; however, it has not been found to be feasible within the constraints of a clinically functional intravascular ultrasound catheter. In this study, we describe the design and fabrication of a dual-frequency catheter using a bidirectional transducer stack with center frequencies of approximately 30 and 80 MHz.

Acoustic Behavior of Halobacterium salinarum Gas Vesicles in the High-Frequency Range: Experiments and Modeling.

Gas vesicles (GVs) are a new and unique class of biologically derived ultrasound contrast agents with sub-micron size whose acoustic properties have not been fully elucidated. In this study, we investigated the acoustic collapse pressure and behavior of Halobacterium salinarum gas vesicles at transmit center frequencies ranging from 12.5 to 27.

Image-Guided Ultrasound Characterization of Volatile Sub-Micron Phase-Shift Droplets in the 20-40 MHz Frequency Range.

Phase-shift perfluorocarbon droplets are designed to convert from the liquid to the gas state by the external application of acoustic or optical energy. Although droplet vaporization has been investigated extensively at ultrasonic frequencies between 1 and 10 MHz, few studies have characterized performance at the higher frequencies commonly used in small animal imaging. In this study, we use standard B-mode imaging sequences on a pre-clinical ultrasound platform to both image and activate sub-micron decafluorobutane droplet populations in vitro and in vivo at center frequencies in the range of 20-40 MHz.

Design of a Subtarsal Ultrasonic Transducer for Mild Hyperthermia Treatment of Dry Eye Disease.

Dry eye disease is a disorder of the ocular surface that causes pain and low vision in a significant portion of the adult population. A common cause is obstructive Meibomian gland dysfunction, whereby the Meibomian glands secrete abnormal meibum with a melting point elevated by 3°C-4°C; hence, hyperthermia is the typical treatment. A design is proposed for an ultrasound hyperthermia device made of a transducer contained inside a contact lens with an internal air gap.

Quantification of Microvascular Tortuosity during Tumor Evolution Using Acoustic Angiography.

The recent design of ultra-broadband, multifrequency ultrasound transducers has enabled high-sensitivity, high-resolution contrast imaging, with very efficient suppression of tissue background using a technique called acoustic angiography. Here we perform the first application of acoustic angiography to evolving tumors in mice predisposed to develop mammary carcinoma, with the intent of visualizing and quantifying angiogenesis progression associated with tumor growth. Metrics compared include vascular density and two measures of vessel tortuosity quantified from segmentations of vessels traversing and surrounding 24 tumors and abdominal vessels from control mice.

Characterization of submicron phase-change perfluorocarbon droplets for extravascular ultrasound imaging of cancer.

Because many tumors possess blood vessels permeable to particles with diameters of 200 nm, it is possible that submicron perfluorocarbon droplets could constitute a novel extravascular ultrasound contrast agent capable of selectively enhancing tumors. Under exposure to bursts of ultrasound of sufficient rarefactional pressure, droplets can undergo vaporization to form echogenic microbubbles. In this study, phase-change thresholds of 220-nm-diameter droplets composed of perfluoropentane were studied in polyacrylamide gel phantoms maintained at temperatures of 21-37°C, exposed to high-pressure bursts of ultrasound with frequencies ranging from 5-15 MHz and durations of 1 μs to 1 ms.

The effect of binding on the subharmonic emissions from individual lipid-encapsulated microbubbles at transmit frequencies of 11 and 25 MHz.

Targeted microbubble imaging at ultrasound frequencies above 5 MHz has applications in both a preclinical context for a range of disease processes and clinically for the assessment of atherosclerosis and superficial tumors. Although the feasibility of ultrasound molecular imaging has been well demonstrated for a range of target molecules, little work has examined the effects of binding on microbubble oscillations, which is of potential relevance to improving the sensitivity, specificity, and quantification of bound-bubble detection. In this study we investigated the influence of binding on the subharmonic response of bubbles at transmit frequencies of 11 and 25 MHz.

Investigating the subharmonic response of individual phospholipid encapsulated microbubbles at high frequencies: a comparative study of five agents.

There are a range of contrast ultrasound applications above 10 MHz, a frequency regime in which nonlinear microbubble behavior is poorly understood. Lipid-encapsulated microbubbles have considerable potential for use at higher frequencies because they have been shown to exhibit pronounced nonlinear activity at frequencies up to 40 MHz. The objective of this work was to investigate the influence of agent formulation on the subharmonic response of lipid-encapsulated microbubbles at high frequencies with a view to providing information relevant to improving contrast agent design and imaging performance.

A new transducer receive transfer function calibration method: application to microbubble backscattering cross-section measurements at high frequency.

When comparing acoustic scattering experiments with theory, the relationship between the pressure generated by a scatterer at the surface of a transducer and the induced voltage must be known. Methods have been previously proposed to measure the receive transfer function that rely on several assumptions. A new, experimental method for measuring the acoustic response of a spherically-focused transducer, using a hydrophone at twice the focal distance, is proposed that requires a minimum number of assumptions and calculations.