Dual-frequency Ultrasound Transducer Research Articles

Axial Super-Resolution Ultrasound Imaging With Quasi-Monopolar Pulses From a Dual-Frequency Transducer

In biomedical ultrasound imaging, the axial resolution is determined by the pulse length, which reaches the bottleneck for the existing piezoelectric materials. The resonance of piezoelectric materials in conventional ultrasound transducers causes relatively long pulses with multiple wavelengths, which cannot be effectively shortened for decades. The waveform with practically the shortest pulse length is a monopolar half-cycle sinusoidal wave, which is beyond the capability of traditional piezoelectric transducers. Here, we propose a method for generating quasi-monopolar ultrasound pulses by the superposition of two ultrasound signals from a stack-layer dual-frequency ultrasound transducer. In this article, we designed and fabricated a 1+ 3 MHz stack-layer dual-frequency ultrasound transducer, and validated the generation of the quasi-monopolar pulse by specific excitation of each piezoelectric layer. Imaging with the quasi-monopolar pulses on copper wire phantoms demonstrated a pulse length of <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$0.17\lambda $ </tex-math></inline-formula> (85.5 ns referring to 2 MHz), which generates images with superb axial resolution and clearly differentiates the phantom wires separated with 1 mm. This design provides a practical approach for general-purpose super-resolution ultrasound imaging without a contrast agent.

Catheter-mounted dual-frequency ultrasound transducers for intravascular contrast-enhanced superharmonic imaging

Vulnerable atherosclerotic plaques are a source of morbidity and mortality and are hypothesized to be correlated with abnormal development of microvasculature in arterial walls. Thus, there is an interest in assessing microvascularity for the plaque diagnosis. However, conventional catheter-delivered, high-frequency (>20 MHz) intravascular ultrasound imaging is unable to resolve vasa vasorum microvessels. We present here the development of a custom dual-frequency transducer-tipped catheter for contrast-enhanced superharmonic imaging of plaque-associated microvasculature. We exploit our previous design of the miniaturized dual-element, stacked-type needle transducer. A 4/22 MHz dual-frequency transducer with a lateral dimension of 800 μm is assembled with a 70 cm-long drive shaft inside a 4 Fr-catheter. We designed a 4 MHz-transmitter element to generate moderate amplitude (>1 MPa peak-negative-pressure) pulses for bubble excitation. A confocally aligned 22 MHz-receiver element is designed to detect contrast generated superharmonics (>10 MHz) with substantial tissue rejection. We tested the catheter in a tissue-mimicking phantom simulating an arterial lumen with surrounding microvasculature. The in vitro imaging data were acquired through a rotational pull-back (2 mm) imaging procedure with microbubble infusion. The resulting superharmonic images display a clearly defined microvessel with an approximated contrast-to-tissue ratio of 12 dB and an axial resolution of 300 μm.Vulnerable atherosclerotic plaques are a source of morbidity and mortality and are hypothesized to be correlated with abnormal development of microvasculature in arterial walls. Thus, there is an interest in assessing microvascularity for the plaque diagnosis. However, conventional catheter-delivered, high-frequency (>20 MHz) intravascular ultrasound imaging is unable to resolve vasa vasorum microvessels. We present here the development of a custom dual-frequency transducer-tipped catheter for contrast-enhanced superharmonic imaging of plaque-associated microvasculature. We exploit our previous design of the miniaturized dual-element, stacked-type needle transducer. A 4/22 MHz dual-frequency transducer with a lateral dimension of 800 μm is assembled with a 70 cm-long drive shaft inside a 4 Fr-catheter. We designed a 4 MHz-transmitter element to generate moderate amplitude (>1 MPa peak-negative-pressure) pulses for bubble excitation. A confocally aligned 22 MHz-receiver element is designed to detect contra...

Numerical Study and Optimisation of a Novel Single-Element Dual-Frequency Ultrasound Transducer.

A dual-frequency ultrasound transducer (DFUT) is usually preferred for its numerous advantageous applications, especially in biomedical imaging and sensing. However, most of DFUTs are based on the combination of fundamental and harmonic operations, or integration of multiple different single-frequency ultrasound transducers, hindering perfect beam alignment and acoustic impedance matching. A novel single-element DFUT has been proposed in this paper. A small piezoelectric membrane is used as the high-frequency ultrasound transducer, which is stacked on a large non-piezoelectric elastic membrane with a groove used as the low-frequency capacitive ultrasound transducer. Such a capacitive-piezoelectric hybrid structure is theoretically analysed in details, based on the electrostatic attraction force and converse piezoelectric effect. Both the low and high resonance frequencies are independently derived, with a maximum deviation of less than 4% from the finite element simulations. Besides, a lumped-parameter equivalent circuit model of combining both the capacitive and piezoelectric ultrasound transducers was also described. Based on our dual-frequency structure design, a high-to-low frequency ratio of about 2 to more than 20 could be achieved, with easy and independent controllability of two frequencies, and the high-frequency operation shows at least an order-of-magnitude displacement sensitivity improvement compared with the conventional harmonic operations.

Dual-Frequency Ultrasound Transducers for the Detection of Morphological Changes of Deep-Layered Muscles

It is evident that surface electromyography (sEMG)-based sensing approach for human-machine interfaces has some inherent limitations for applications requiring morphological changes information of deep-layered muscles, such as dexterous prosthetic hands. In this paper, the design, simulation, fabrication, and evaluation for a series of novel structured ultrasound transducers are conducted in order to develop a type of A-mode ultrasound transducers that overcome the drawbacks of the sEMG-based sensing. The transducers cover single-frequency and dual-frequency types. Their key parameters, the acoustic impedance and thickness of the matching layer, are simulated and verified by PZFlex. The parameters are designed as 0.3 times of the 1-3 composite piezoelectric's acoustic impedance and 0.25 times of the wavelength, respectively. The characterizations of the dual-frequency transducers significantly outperform single-frequency transducers. The experiments of recognizing dexterous hand gesture are designed to detect morphological changes information of deep-layered muscles. The classification accuracy improvements with linear discrimination analysis are 7.3% and 4.7%, and with support vector machine are 14.1% and 13.4% for the horizontal stacked and annulus array. This preliminary study concludes that the dual-frequency transducers have huge potential for applications that need contraction information of deep-layered muscles over the single-frequency transducers, letting alone sEMG-based sensors.

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model.

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma.

Dual-Frequency Ultrasound Transducer Using Inversion Layer Technique for Therapeutic Ultrasound Surgery

High intensity focused ultrasound surgery still requires relatively a long surgical time due to small size of coagulative necrosis per each sonication. In order to increase a region of coagulative necrosis, dual-frequency ultrasound scheme has been proposed and showed notable results. In this paper, a novel dual-frequency ultrasound transducer based on the inversion layer technique is presented. Finite element analysis simulation was conducted, and the prototype transducer was fabricated to demonstrate the performance of the proposed method. The optimized thickness ratio between the inverted and non-inverted piezoelectric layers was chosen as 0.3:0.7. The proposed transducer with the chosen ratio generated the fundamental (at 1.2 MHz) frequency and the second harmonic frequency (at 2.4 MHz) ultrasound at the same time. The performance of the proposed transducer was numerically and experimentally verified through electrical impedance, pulse-echo response, and beam profile tests.

Abstract 2073: Focused ultrasound-mediated transport of poly(alkyl) cyanoacrylate nanoparticles across the blood-brain barrier in a melanoma brain metastasis model

Abstract Drug delivery into the brain is impeded by the blood-brain barrier (BBB) - a dynamic interface that protects brain homeostasis, but also screens the brain from the vast majority of large and/or hydrophilic drug molecules. Focused ultrasound (FUS) has emerged as one of the promising methods to open the BBB safely and reversibly. We have previously reported FUS-mediated BBB opening using a novel platform consisting of microbubbles surrounded by poly(alkyl cyanoacrylate) nanoparticles that could prospectively be used for FUS- and nanoparticle-mediated drug delivery into the brain (1,2). Here, we have been investigating FUS-mediated BBB opening using a novel ultrasound system capable of generating FUS at two frequencies, 1.1 MHz and 7.8 MHz during the same experiment. This system allows a very precise selection of the exposure area. We used FUS exposure at 1 MHz to open the BBB by cavitation, while exposure at 7.8 MHz was employed to enable the action of acoustic radiation force. This force is caused by a transfer of momentum from acoustic waves to the tissues in which they propagate, and can facilitate nanoparticle transport in the extracellular matrix. FUS-mediated BBB opening was performed in NOD/SCID mice with melanoma brain metastases developed after intracardiac injection of human melanoma brain metastasis cells (3). The cells were fluorescently labeled, which enabled their detection in the brain. Poly(isohexyl) cyanoacrylate (PIHCA) nanoparticle-microbubbles similar to those reported in our earlier works (1,2) were injected immediately before the FUS exposure. Successful opening of the BBB was verified by MRI using a gadolinium-based contrast agent. An optimal window of exposure intensities that allow BBB disruption was found to be close a mechanical index of 0.3. Location of fluorescently labeled nanoparticles relative to blood vessels and tumor cells was determined in frozen sections using confocal microscopy. Tissue damage and FUS-induced changes at the cellular and molecular level were studied using histological and molecular techniques. In conclusion, the dual-frequency ultrasound transducer setup and our novel nanoparticle-microbubble platform showed promising results which will be used to develop a novel treatment of brain metastasis combining dual-frequency FUS with drug delivery using microbubbles. 1. Nanoparticle-stabilized microbubbles for multimodal imaging and drug delivery. Mørch Ý et al. Contrast Media Mol Imaging. 2015 Sep;10(5):356-66 2. Nanoparticle delivery to the brain - By focused ultrasound and self-assembled nanoparticle-stabilized microbubbles. Åslund AK et al. J Control Release. 2015 Oct 28;220(Pt A):287-294 3. Automated tracking of nanoparticle-labeled melanoma cells improves the predicted power of a brain metastasis model. Sundstrøm T et al. Cancer Res. 2013 Feb;73(8):2445-2456. Citation Format: Habib Baghirov, Andreas Åslund, Sofie Snipstad, Sigrid Berg, Rune Hansen, Frits Thorsen, Yrr Mørch, Catharina de Lange Davies. Focused ultrasound-mediated transport of poly(alkyl) cyanoacrylate nanoparticles across the blood-brain barrier in a melanoma brain metastasis model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2073.

Acoustic Angiography: High-Resolution Contrast-Enhanced Ultrasound Imaging of the Microvasculature

Presenting Author: Paul A. Dayton1 Co-authors: Co-authors: Sarah Shelton1, Brooks Lindsey1, Ryan Gessner1, Yueh Z. Lee4, Stephen Aylward2, Mike Lee3, Emmanuel Cherin3, F. Stuart Foster3 Joint Graduate Department of Biomedical Engineering, University of North Carolina and North Carolina State University, NC, USA Kitware Medical Imaging, 101 East Weaver Street, Carrboro, NC Department of Medical Biophysics, Sunnybrook Health Sciences Centre,Toronto, ON, Canada Department of Neuroradiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Contrast enhanced ultrasound is FDA approved in the US for cardiology applications, and has demonstrated substantial utility off-label and in preclinical research studies. However, to date, contrast enhanced ultrasound in patients is largely performed at low frequencies and does not provide sufficient resolution or tissue suppression to visualize structural details of microvasculature blood flow. Through the use of new dual-frequency ultrasound transducer technology, contrast enhanced ultrasound can be performed with unprecedented resolution and contrast-to-tissue ratio, albeit at shallow penetration depths. This imaging technique enables the visualization of microvascular architecture without signal from background tissues, and can simultaneously provide anatomical information for registration. The resulting images are similar to x-ray angiography, and provide a new means to assess microvascular density and structure. Initial results indicate this new imaging modality can provide non-invasive insight into angiogenic processes involved in tumor growth and progression. We demonstrate the application of this imaging technique in evaluation of cancer angiogenesis in pre-clinical models, and provide a report of first in-human use. Presenting Author: Paul A. Dayton1 Co-authors: Co-authors: Sarah Shelton1, Brooks Lindsey1, Ryan Gessner1, Yueh Z. Lee4, Stephen Aylward2, Mike Lee3, Emmanuel Cherin3, F. Stuart Foster3 Joint Graduate Department of Biomedical Engineering, University of North Carolina and North Carolina State University, NC, USA Kitware Medical Imaging, 101 East Weaver Street, Carrboro, NC Department of Medical Biophysics, Sunnybrook Health Sciences Centre,Toronto, ON, Canada Department of Neuroradiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Contrast enhanced ultrasound is FDA approved in the US for cardiology applications, and has demonstrated substantial utility off-label and in preclinical research studies. However, to date, contrast enhanced ultrasound in patients is largely performed at low frequencies and does not provide sufficient resolution or tissue suppression to visualize structural details of microvasculature blood flow. Through the use of new dual-frequency ultrasound transducer technology, contrast enhanced ultrasound can be performed with unprecedented resolution and contrast-to-tissue ratio, albeit at shallow penetration depths. This imaging technique enables the visualization of microvascular architecture without signal from background tissues, and can simultaneously provide anatomical information for registration. The resulting images are similar to x-ray angiography, and provide a new means to assess microvascular density and structure. Initial results indicate this new imaging modality can provide non-invasive insight into angiogenic processes involved in tumor growth and progression. We demonstrate the application of this imaging technique in evaluation of cancer angiogenesis in pre-clinical models, and provide a report of first in-human use.

Acoustic Angiography: A New Imaging Modality for Assessing Microvasculature Architecture

The purpose of this paper is to provide the biomedical imaging community with details of a new high resolution contrast imaging approach referred to as “acoustic angiography.” Through the use of dual-frequency ultrasound transducer technology, images acquired with this approach possess both high resolution and a high contrast-to-tissue ratio, which enables the visualization of microvascular architecture without significant contribution from background tissues. Additionally, volumetric vessel-tissue integration can be visualized by using b-mode overlays acquired with the same probe. We present a brief technical overview of how the images are acquired, followed by several examples of images of both healthy and diseased tissue volumes. 3D images from alternate modalities often used in preclinical imaging, contrast-enhanced micro-CT and photoacoustics, are also included to provide a perspective on how acoustic angiography has qualitatively similar capabilities to these other techniques. These preliminary images provide visually compelling evidence to suggest that acoustic angiography may serve as a powerful new tool in preclinical and future clinical imaging.

Dynamics of Sonoporation Correlated with Acoustic Cavitation Activities

Sonoporation has been exploited as a promising nonviral strategy for intracellular delivery of drugs and genes. The technique utilizes ultrasound application, often facilitated by the presence of microbubbles, to generate transient, nonspecific pores on the cell membrane. However, due to the complexity and transient nature of ultrasound-mediated bubble interaction with cells, no direct correlation of sonoporation with bubble activities such as acoustic cavitation, i.e., the ultrasound-driven growth and violent collapse of bubbles, has been obtained. Using Xenopus oocytes as a model system, this study investigated sonoporation in a single cell affected by colocalized cavitation in real time. A confocally and collinearly-aligned dual-frequency ultrasound transducer assembly was used to generate focused ultrasound pulses (1.5MHz) to induce focal sonoporation while detecting the broadband cavitation acoustic emission within the same focal zone. Dynamic sonoporation of the single cell was monitored via the transmembrane current of the cell under voltage-clamp. Our results demonstrate for the first time, to our knowledge, the spatiotemporal correlation of sonoporation with cavitation at the single-cell level.