Real-time ultrasound angiography using superharmonic dual-frequency (2.25MHz/30MHz) cylindrical array: In vitro study.

Recent studies suggest that dual-frequency intravascular ultrasound (IVUS) transducers allow detection of superharmonic bubble signatures, enabling acoustic angiography for microvascular and molecular imaging. In this paper, a dual-frequency IVUS cylindrical array transducer was developed for real-time superharmonic imaging. A reduced form-factor lateral mode transmitter (2.25MHz) was used to excite microbubbles effectively at 782kPa with single-cycle excitation while still maintaining the small size and low profile (5Fr) (3Fr=1mm) for intravascular imaging applications. Superharmonic microbubble responses generated in simulated microvessels were captured by the high frequency receiver (30MHz). The axial and lateral full-width half-maximum of microbubbles in a 200-µm-diameter cellulose tube were measured to be 162µm and 1039µm, respectively, with a contrast-to-noise ratio (CNR) of 16.6dB. Compared to our previously reported single-element IVUS transducers, this IVUS array design achieves a higher CNR (16.6dBvs 11dB) and improved axial resolution (162µmvs 616µm). The results show that this dual-frequency IVUS array transducer with a lateral-mode transmitter can fulfill the native design requirement (∼3-5Fr) for acoustic angiography by generating nonlinear microbubble responses as well as detecting their superharmonic responses in a 5Fr form factor.

High Resolution Ultrasound Superharmonic Perfusion Imaging: In Vivo Feasibility and Quantification of Dynamic Contrast-Enhanced Acoustic Angiography.

Mapping blood perfusion quantitatively allows localization of abnormal physiology and can improve understanding of disease progression. Dynamic contrast-enhanced ultrasound is a low-cost, real-time technique for imaging perfusion dynamics with microbubble contrast agents. Previously, we have demonstrated another contrast agent-specific ultrasound imaging technique, acoustic angiography, which forms static anatomical images of the superharmonic signal produced by microbubbles. In this work, we seek to determine whether acoustic angiography can be utilized for high resolution perfusion imaging in vivo by examining the effect of acquisition rate on superharmonic imaging at low flow rates and demonstrating the feasibility of dynamic contrast-enhanced superharmonic perfusion imaging for the first time. Results in the chorioallantoic membrane model indicate that frame rate and frame averaging do not affect the measured diameter of individual vessels observed, but that frame rate does influence the detection of vessels near and below the resolution limit. The highest number of resolvable vessels was observed at an intermediate frame rate of 3 Hz using a mechanically-steered prototype transducer. We also demonstrate the feasibility of quantitatively mapping perfusion rate in 2D in a mouse model with spatial resolution of ~100 µm. This type of imaging could provide non-invasive, high resolution quantification of microvascular function at penetration depths of several centimeters.

Ex Vivo Porcine Arterial and Chorioallantoic Membrane Acoustic Angiography Using Dual-Frequency Intravascular Ultrasound Probes.

The presence of blood vessels within a developing atherosclerotic plaque has been found to be correlated with increased plaque vulnerability and ensuing cardiac events, however, detection of coronary intraplaque neovascularization poses a significant challenge in the clinic. We describe here a new in vivo intravascular ultrasound imaging method using a dual-frequency transducer to visualize contrast flow in microvessels with high specificity. This method uses a specialized transducer capable of exciting contrast agents at a low frequency (5.5 MHz) while detecting their nonlinear superhamonics at a much higher frequency (37 MHz). In vitro evaluation of the approach was performed in a microvascular phantom to produce 3-D renderings of simulated vessel patterns and to determine image quality metrics as a function of depth. Furthermore, we describe the ability of the system to detect microvessels both ex vivo using porcine arteries and in vivo using the chorioallantoic membrane of a developing chicken embryo with optical confirmation. Dual-frequency contrast-specific imaging was able to resolve vessels similar in size to those found in vulnerable atherosclerotic plaques at clinically relevant depths. The results of this study add to the support for further evaluation and translation of contrast-specific imaging in intravascular ultrasound for the detection of vulnerable plaques in atherosclerosis.

Adaptive windowing in contrast-enhanced intravascular ultrasound imaging.

Intravascular ultrasound (IVUS) is one of the most commonly-used interventional imaging techniques and has seen recent innovations which attempt to characterize the risk posed by atherosclerotic plaques. One such development is the use of microbubble contrast agents to image vasa vasorum, fine vessels which supply oxygen and nutrients to the walls of coronary arteries and typically have diameters less than 200µm. The degree of vasa vasorum neovascularization within plaques is positively correlated with plaque vulnerability. Having recently presented a prototype dual-frequency transducer for contrast agent-specific intravascular imaging, here we describe signal processing approaches based on minimum variance (MV) beamforming and the phase coherence factor (PCF) for improving the spatial resolution and contrast-to-tissue ratio (CTR) in IVUS imaging. These approaches are examined through simulations, phantom studies, ex vivo studies in porcine arteries, and in vivo studies in chicken embryos. In phantom studies, PCF processing improved CTR by a mean of 4.2dB, while combined MV and PCF processing improved spatial resolution by 41.7%. Improvements of 2.2dB in CTR and 37.2% in resolution were observed in vivo. Applying these processing strategies can enhance image quality in conventional B-mode IVUS or in contrast-enhanced IVUS, where signal-to-noise ratio is relatively low and resolution is at a premium.

An Integrated System for Superharmonic Contrast-Enhanced Ultrasound Imaging: Design and Intravascular Phantom Imaging Study.

OBJECTIVE: Superharmonic contrast-enhanced ultrasound imaging, also called acoustic angiography, has previously been used for the imaging of microvasculature. This approach excites microbubble contrast agents near their resonance frequency and receives echoes at nonoverlapping superharmonic bandwidths. No integrated system currently exists could fully support this application. To fulfill this need, an integrated dual-channel transmit/receive system for superharmonic imaging was designed, built, and characterized experimentally. METHOD: The system was uniquely designed for superharmonic imaging and high-resolution B-mode imaging. A complete ultrasound system including a pulse generator, a data acquisition unit, and a signal processing unit were integrated into a single package. The system was controlled by a field-programmable gate array, on which multiple user-defined modes were implemented. A 6-, 35-MHz dual-frequency dual-element intravascular ultrasound transducer was designed and used for imaging. RESULT: The system successfully obtained high-resolution B-mode images of coronary artery ex vivo with 45-dB dynamic range. The system was capable of acquiring in vitro superharmonic images of a vasa vasorum mimicking phantom with 30-dB contrast. It could detect a contrast agent filled tissue mimicking tube of 200 µm diameter. CONCLUSION: For the first time, high-resolution B-mode images and superharmonic images were obtained in an intravascular phantom, made possible by the dedicated integrated system proposed. The system greatly reduced the cost and complexity of the superharmonic imaging intended for preclinical study. Significant: The system showed promise for high-contrast intravascular microvascular imaging, which may have significant importance in assessment of the vasa vasorum associated with atherosclerotic plaques.

Design factors of intravascular dual frequency transducers for super-harmonic contrast imaging and acoustic angiography.

Imaging of coronary vasa vasorum may lead to assessment of the vulnerable plaque development in diagnosis of atherosclerosis diseases. Dual frequency transducers capable of detection of microbubble super-harmonics have shown promise as a new contrast-enhanced intravascular ultrasound (CE-IVUS) platform with the capability of vasa vasorum imaging. Contrast-to-tissue ratio (CTR) in CE-IVUS imaging can be closely associated with low frequency transmitter performance. In this paper, transducer designs encompassing different transducer layouts, transmitting frequencies, and transducer materials are compared for optimization of imaging performance. In the layout selection, the stacked configuration showed superior super-harmonic imaging compared with the interleaved configuration. In the transmitter frequency selection, a decrease in frequency from 6.5 MHz to 5 MHz resulted in an increase of CTR from 15 dB to 22 dB when receiving frequency was kept constant at 30 MHz. In the material selection, the dual frequency transducer with the lead magnesium niobate-lead titanate (PMN-PT) 1-3 composite transmitter yielded higher axial resolution compared to single crystal transmitters (70 µm compared to 150 µm pulse length). These comparisons provide guidelines for the design of intravascular acoustic angiography transducers.

Dual-frequency piezoelectric transducers for contrast enhanced ultrasound imaging.

For many years, ultrasound has provided clinicians with an affordable and effective imaging tool for applications ranging from cardiology to obstetrics. Development of microbubble contrast agents over the past several decades has enabled ultrasound to distinguish between blood flow and surrounding tissue. Current clinical practices using microbubble contrast agents rely heavily on user training to evaluate degree of localized perfusion. Advances in separating the signals produced from contrast agents versus surrounding tissue backscatter provide unique opportunities for specialized sensors designed to image microbubbles with higher signal to noise and resolution than previously possible. In this review article, we describe the background principles and recent developments of ultrasound transducer technology for receiving signals produced by contrast agents while rejecting signals arising from soft tissue. This approach relies on transmitting at a low-frequency and receiving microbubble harmonic signals at frequencies many times higher than the transmitted frequency. Design and fabrication of dual-frequency transducers and the extension of recent developments in transducer technology for dual-frequency harmonic imaging are discussed.

Acoustic characterization of contrast-to-tissue ratio and axial resolution for dual-frequency contrast-specific acoustic angiography imaging.

Recently, dual-frequency transducers have enabled high-spatial-resolution and high-contrast imaging of vasculature with minimal tissue artifacts by transmitting at a low frequency and receiving broadband superharmonic echoes scattered by microbubble contrast agents. In this work, we examine the imaging parameters for optimizing contrast-to-tissue ratio (CTR) for dual-frequency imaging and the relationship with spatial resolution. Confocal piston transducers are used in a water bath setup to measure the SNR, CTR, and axial resolution for ultrasound imaging of nonlinear scattering of microbubble contrast agents when transmitting at a lower frequency (1.5 to 8 MHz) and receiving at a higher frequency (7.5 to 25 MHz). Parameters varied include the frequency and peak negative pressure of transmitted waves, center frequency of the receiving transducer, microbubble concentration, and microbubble size. CTR is maximized at the lowest transmission frequencies but would be acceptable for imaging in the 1.5 to 3.5 MHz range. At these frequencies, CTR is optimized when a receiving transducer with a center frequency of 10 MHz is used, with the maximum CTR of 25.5 dB occurring when transmitting at 1.5 MHz with a peak negative pressure of 1600 kPa and receiving with a center frequency of 10 MHz. Axial resolution is influenced more heavily by the receiving center frequency, with a weak decrease in measured pulse lengths associated with increasing transmit frequency. A microbubble population containing predominately 4-µm-diameter bubbles yielded the greatest CTR, followed by 1- and then 2-µm bubbles. Varying concentration showed little effect over the tested parameters. CTR dependence on transmit frequency and peak pressure were confirmed through in vivo imaging in two rodents. These findings may lead to improved imaging of vascular remodeling in superficial or luminal cancers such as those of the breast, prostate, and colon.

Current status and prospects for microbubbles in ultrasound theranostics.

Encapsulated microbubbles have been developed over the past two decades to provide improvements both in imaging as well as new therapeutic applications. Microbubble contrast agents are used currently for clinical imaging where increased sensitivity to blood flow is required, such as echocardiography. These compressible spheres oscillate in an acoustic field, producing nonlinear responses which can be uniquely distinguished from surrounding tissue, resulting in substantial enhancements in imaging signal-to-noise ratio. Furthermore, with sufficient acoustic energy the oscillation of microbubbles can mediate localized biological effects in tissue including the enhancement of membrane permeability or increased thermal energy deposition. Structurally, microbubbles are comprised of two principal components--an encapsulating shell and an inner gas core. This configuration enables microbubbles to be loaded with drugs or genes for additional therapeutic effect. Application of sufficient ultrasound energy can release this payload, resulting in site-specific delivery. Extensive preclinical studies illustrate that combining microbubbles and ultrasound can result in enhanced drug delivery or gene expression at spatially selective sites. Thus, microbbubles can be used for imaging, for therapy, or for both simultaneously. In this sense, microbubbles combined with acoustics may be one of the most universal theranostic tools.