cMUT technology developments.

Capacitive micromachined ultrasonic transducer (cMUT) technology has steadily advanced since its advent in the mid-1990's. Though cMUTs have not supplanted piezoelectric transducers for medical ultrasound imaging to date, researchers and engineers are continuing to improve cMUTs and leverage unique cMUT characteristics toward new applications. While not intended to be an exhaustive review of every aspect of cMUT state-of-the-art, this article provides a brief overview of cMUT benefits, challenges, and opportunities, as well as recent progress in cMUT research and translation.

Aberration correction in diagnostic ultrasound: A review of the prior field and current directions.

Medical ultrasound images are reconstructed with simplifying assumptions on wave propagation, with one of the most prominent assumptions being that the imaging medium is composed of a constant sound speed. When the assumption of a constant sound speed are violated, which is true in most in vivoor clinical imaging scenarios, distortion of the transmitted and received ultrasound wavefronts appear and degrade the image quality. This distortion is known as aberration, and the techniques used to correct for the distortion are known as aberration correction techniques. Several models have been proposed to understand and correct for aberration. In this review paper, aberration and aberration correction are explored from the early models and correction techniques, including the near-field phase screen model and its associated correction techniques such as nearest-neighbor cross-correlation, to more recent models and correction techniques that incorporate spatially varying aberration and diffractive effects, such as models and techniques that rely on the estimation of the sound speed distribution in the imaging medium. In addition to historical models, future directions of ultrasound aberration correction are proposed.

Cylindrical Transducer Array for Intravascular Shear Wave Elasticity Imaging: Preliminary Development.

We present an intravascular ultrasound (IVUS) transducer array designed to enable shear wave elasticity imaging (SWEI) of arteries for the detection and characterization of atherosclerotic soft plaques. Using a custom dicing fixture, we have fabricated single-element and axially-segmented array transducer prototypes from 4.6-Fr to 7.6-Fr piezoceramic tubes, respectively. Focused excitation of the array prototype at 4 MHz yielded a focal gain of 5× in intensity, for an estimated 60 mW/cm2 [Formula: see text] and 1.6-MPa negative peak pressure at 4.5-mm range in water. The single-element transducer generated a peak radial displacement of [Formula: see text] in a uniform elasticity phantom, with axial shear waves detectable by an external linear array probe up to 5 mm away from the excitation plane. In a vessel phantom with a soft inclusion, the array prototype generated peak displacements of 2.2 and [Formula: see text] in the soft inclusion and vessel wall regions, respectively. A SWEI image of the vessel phantom was reconstructed, with measured shear wave speed (SWS) of 1.66 ± 0.91 m/s and 0.97 ± 0.59 m/s for the soft inclusion and vessel wall regions, respectively. The array prototype was also used to obtain a SWEI image of an ex vivo porcine artery, with a mean SWS of 3.97 ± 1.12 m/s. These results suggest that a cylindrical intravascular ultrasound (IVUS) transducer array could be made capable of SWEI for atherosclerotic plaque detection in coronary arteries.

Passive Cavitation Mapping by Cavitation Source Localization From Aperture-Domain Signals-Part II: Phantom and In Vivo Experiments.

Passive cavitation mapping (PCM) techniques typically utilize a time-exposure acoustic (TEA) approach, where the received radio frequency data are beamformed, squared, and integrated over time. Such PCM-TEA cavitation maps typically suffer from long-tail artifacts and poor axial resolution with pulse-echo diagnostic arrays. Here, we utilize a recently developed PCM technique based on cavitation source localization (CSL), which fits a hyperbolic function to the received cavitation wavefront. A filtering method based on the root-mean-square error (rmse) of the hyperbolic fit is utilized to filter out spurious signals. We apply a wavefront correction technique to the signals with poor fit quality to recover additional cavitation signals and improve cavitation localization. Validation of the PCM-CSL technique with rmse filtering and wavefront correction was conducted in experiments with a tissue-mimicking flow phantom and an in vivo mouse model of cancer. It is shown that the quality of the hyperbolic fit, necessary for the PCM-CSL, requires an rmse < 0.05 mm2 in order to accurately localize the cavitation sources. A detailed study of the wavefront correction technique was carried out, and it was shown that, when applied to experiments with high noise and interference from multiple cavitating microbubbles, it was capable of effectively correcting noisy wavefronts without introducing spurious cavitation sources, thereby improving the quality of the PCM-CSL images. In phantom experiments, the PCM-CSL was capable of precisely localizing sources on the therapy beam axis and off-axis sources. In vivo cavitation experiments showed that PMC-CSL showed a significant improvement over PCM-TEA and yielded acceptable localization of cavitation signals in mice.

Nondestructive Detection of Targeted Microbubbles Using Dual-Mode Data and Deep Learning for Real-Time Ultrasound Molecular Imaging.

Ultrasound molecular imaging (UMI) is enabled by targeted microbubbles (MBs), which are highly reflective ultrasound contrast agents that bind to specific biomarkers. Distinguishing between adherent MBs and background signals can be challenging in vivo. The preferred preclinical technique is differential targeted enhancement (DTE), wherein a strong acoustic pulse is used to destroy MBs to verify their locations. However, DTE intrinsically cannot be used for real-time imaging and may cause undesirable bioeffects. In this work, we propose a simple 4-layer convolutional neural network to nondestructively detect adherent MB signatures. We investigated several types of input data to the network: "anatomy-mode" (fundamental frequency), "contrast-mode" (pulse-inversion harmonic frequency), or both, i.e., "dual-mode", using IQ channel signals, the channel sum, or the channel sum magnitude. Training and evaluation were performed on in vivo mouse tumor data and microvessel phantoms. The dual-mode channel signals yielded optimal performance, achieving a soft Dice coefficient of 0.45 and AUC of 0.91 in two test images. In a volumetric acquisition, the network best detected a breast cancer tumor, resulting in a generalized contrast-to-noise ratio (GCNR) of 0.93 and Kolmogorov-Smirnov statistic (KSS) of 0.86, outperforming both regular contrast mode imaging (GCNR = 0.76, KSS = 0.53) and DTE imaging (GCNR = 0.81, KSS = 0.62). Further development of the methodology is necessary to distinguish free from adherent MBs. These results demonstrate that neural networks can be trained to detect targeted MBs with DTE-like quality using nondestructive dual-mode data, and can be used to facilitate the safe and real-time translation of UMI to clinical applications.

Cylindrical Transducer for Intravascular ARFI Imaging: Design and Feasibility.

Intravascular acoustic radiation force impulse (IV-ARFI) imaging has the potential to identify vulnerable atherosclerotic plaques and improve clinical treatment decisions and outcomes for patients with coronary heart disease. Our long-term goal is to develop a thin, flexible catheter probe that does not require mechanical rotation to achieve high-resolution IV-ARFI imaging. In this work, we propose a novel cylindrical transducer array design for IV-ARFI imaging and investigate the feasibility of this approach. We present the construction of a 2.2-mm-long, 4.6-Fr cylindrical prototype transducer to demonstrate generating large ARFI displacements from a small toroidal beam, and we also present simulations of the proposed IV-ARFI cylindrical array design using Field II and a cylindrical finite-element model of vascular tissues and soft plaques. The prototype transducer was found to generate peak radial displacements of over [Formula: see text] in soft gelatin phantoms, and simulations demonstrate the ability of the array design to obtain ARFI images and distinguish soft plaque targets from surrounding, stiffer vessel wall tissue. These results suggest that high-resolution IV-ARFI imaging is possible using a cylindrical transducer array.

Extending Retrospective Encoding for Robust Recovery of the Multistatic Data Set.

Robust recovery of multistatic synthetic aperture data from conventional ultrasound sequences can enable complete transmit-and-receive focusing at all points in the field of view without the drawbacks of virtual-source synthetic aperture and further enables more advanced imaging applications, such as backscatter coherence, sound speed estimation, and phase aberration correction. Recovery of the multistatic data set has previously been demonstrated on a steered transmit sequence for phased arrays using an adjoint-based method. We introduce two methods to improve the accuracy of the multistatic data set. We first modify the original technique used for steered transmit sequences by applying a ramp filter to compensate for the nonuniform frequency scaling introduced by the adjoint-based method. Then, we present a regularized inversion technique that allows additional aperture specification and is intended to work for both steered transmit and walking aperture sequences. The ramp-filtered adjoint and regularized inversion techniques, respectively, improve the correlation of the recovered signal with the ground truth from 0.9404 to 0.9774 and 0.9894 in steered transmit sequences and 0.4610 to 0.4733 and 0.9936 in walking aperture sequences.

Unsupervised clustering method to convert high-resolution magnetic resonance volumes to three-dimensional acoustic models for full-wave ultrasound simulations.

Simulations of acoustic wave propagation, including both the forward and the backward propagations of the wave (also known as full-wave simulations), are increasingly utilized in ultrasound imaging due to their ability to more accurately model important acoustic phenomena. Realistic anatomic models, particularly those of the abdominal wall, are needed to take full advantage of the capabilities of these simulation tools. We describe a method for converting fat-water-separated magnetic resonance imaging (MRI) volumes to anatomical models for ultrasound simulations. These acoustic models are used to map acoustic imaging parameters, such as speed of sound and density, to grid points in an ultrasound simulation. The tissues of these models are segmented from the MRI volumes into five primary classes of tissue in the human abdominal wall (skin, fat, muscle, connective tissue, and nontissue). This segmentation is achieved using an unsupervised machine learning algorithm, fuzzy c-means clustering (FCM), on a multiscale feature representation of the MRI volumes. We describe an automated method for utilizing FCM weights to produce a model that achieves ∼ 90 % agreement with manual segmentation. Two-dimensional (2-D) and three-dimensional (3-D) full-wave nonlinear ultrasound simulations are conducted, demonstrating the utility of realistic 3-D abdominal wall models over previously available 2-D abdominal wall models.

Ultrasound/microbubble-mediated targeted delivery of anticancer microRNA-loaded nanoparticles to deep tissues in pigs.

In this study, we designed and validated a platform for ultrasound and microbubble-mediated delivery of FDA-approved pegylated poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with anticancer microRNAs (miRNAs) to deep tissues in a pig model. Small RNAs have been shown to reprogram tumor cells and sensitize them to clinically used chemotherapy. To overcome their short intravascular circulation half-life and achieve controlled and sustained release into tumor cells, anticancer miRNAs need to be encapsulated into nanocarriers. Focused ultrasound combined with gas-filled microbubbles provides a noninvasive way to improve the permeability of tumor vasculature and increase the delivery efficiency of drug-loaded particles. A single handheld, curvilinear ultrasound array was used in this study for image-guided therapy with clinical-grade SonoVue contrast agent. First, we validated the platform on phantoms to optimize the microbubble cavitation dose based on acoustic parameters, including peak negative pressure, pulse length, and pulse repetition frequency. We then tested the system in vivo by delivering PLGA nanoparticles co-loaded with antisense-miRNA-21 and antisense-miRNA-10b to pig liver and kidney. Enhanced miRNA delivery was observed (1.9- to 3.7-fold increase) as a result of the ultrasound treatment compared to untreated control regions. Additionally, we used highly fluorescent semiconducting polymer nanoparticles to visually assess nanoparticle extravasation. Fluorescent microscopy suggested the presence of nanoparticles in the extravascular compartment. Hematoxylin and eosin staining of treated tissues did not reveal tissue damage. The results presented in this manuscript suggest that the proposed platform may be used to safely and noninvasively enhance the delivery of miRNA-loaded nanoparticles to target regions in deep organs in large animal models.

Versatile Low-Cost Volumetric 3-D Ultrasound Platform for Existing Clinical 2-D Systems.

Ultrasound imaging has indications across many areas of medicine, but the need for training and the variability in skill and acquired image quality among 2-D ultrasound users have limited its wider adoption and utilization. Low-cost volumetric ultrasound with a known frame of reference has the potential to lower these operator-dependent barriers and enhance the clinical utility of ultrasound imaging. In this paper, we improve upon our previous research-scanner-based prototype to implement a versatile volumetric imaging platform for existing clinical 2-D ultrasound systems. We present improved data acquisition and image reconstruction schemes to increase quality, streamline workflow, and provide real-time visual feedback. We present initial results using the platform on a Vimedix simulator, as well as on phantom and in vivo targets using a variety of clinical ultrasound systems and probes.

Low-cost Volumetric Ultrasound by Augmentation of 2D Systems: Design and Prototype.

Conventional two-dimensional (2D) ultrasound imaging is a powerful diagnostic tool in the hands of an experienced user, yet 2D ultrasound remains clinically underutilized and inherently incomplete, with output being very operator dependent. Volumetric ultrasound systems can more fully capture a three-dimensional (3D) region of interest, but current 3D systems require specialized transducers, are prohibitively expensive for many clinical departments, and do not register image orientation with respect to the patient; these systems are designed to provide improved workflow rather than operator independence. This work investigates whether it is possible to add volumetric 3D imaging capability to existing 2D ultrasound systems at minimal cost, providing a practical means of reducing operator dependence in ultrasound. In this paper, we present a low-cost method to make 2D ultrasound systems capable of quality volumetric image acquisition: we present the general system design and image acquisition method, including the use of a probe-mounted orientation sensor, a simple probe fixture prototype, and an offline volume reconstruction technique. We demonstrate initial results of the method, implemented using a Verasonics Vantage research scanner.

Intracranial dual-mode IVUS and hyperthermia using circular arrays: preliminary experiments.

In this study, we investigated the feasibility of using 3.5-Fr (3 Fr = 1 mm) circular phased-array intravascular ultrasound (IVUS) catheters for minimally invasive, image-guided hyperthermia treatment of tumors in the brain. Feasibility was demonstrated in two ways: (1) by inserting a 3.5-Fr IVUS catheter through skull burr holes, for 20 MHz brain imaging in the pig model, and (2) by testing a modified circular array for therapy potential with 18.5-MHz and 9-MHz continuous wave (CW) excitation. The imaging transducer's performance was superior to our previous 9-MHz mechanical IVUS prototype. The therapy catheter transducer was driven by CW electrical power at 18.5 MHz, achieving temperature changes reaching +8°C at a depth of 2 mm in a human glioblastoma grown on the flank of a mouse with minimal transducer resistive heating of +2°C. Further hyperthermia trials showed that 9-MHz CW excitation produced temperature changes of +4.5°C at a depth of 12 mm-a sufficient temperature rise for our long-term goal of targeted, controlled drug release via thermosensitive liposomes for therapeutic treatment of 1-cm-diameter glioblastomas.

Dual-mode IVUS transducer for image-guided brain therapy: preliminary experiments.

In this study, we investigated the feasibility of using 3.5-Fr intravascular ultrasound (IVUS) catheters for minimally-invasive, image-guided hyperthermia treatment of tumors in the brain. Feasibility was demonstrated by: (1) retro-fitting a commercial 3.5-Fr IVUS catheter with a 5 × 0.5 × 0.22 mm PZT-4 transducer for 9-MHz imaging and (2) testing an identical transducer for therapy potential with 3.3-MHz continuous-wave excitation. The imaging transducer was compared with a 9-Fr, 9-MHz ICE catheter when visualizing the post-mortem ovine brain and was also used to attempt vascular access to an in vivo porcine brain. A net average electrical power input of 700 mW was applied to the therapy transducer, producing a temperature rise of +13.5°C at a depth of 1.5 mm in live brain tumor tissue in the mouse model. These results suggest that it may be feasible to combine the imaging and therapeutic capabilities into a single device as a clinically-viable instrument.

Dual-mode IVUS catheter for intracranial image-guided hyperthermia: feasibility study.

In this study, we investigated the feasibility of modifying 3-Fr IVUS catheters in several designs to potentially achieve minimally-invasive, endovascular access for image-guided ultrasound hyperthermia treatment of tumors in the brain. Using a plane wave approximation, target frequencies of 8.7 and 3.5 MHz were considered optimal for heating at depths (tumor sizes) of 1 and 2.5 cm, respectively. First, a 3.5-Fr IVUS catheter with a 0.7-mm diameter transducer (30 MHz nominal frequency) was driven at 8.6 MHz. Second, for a low-frequency design, a 220-µm-thick, 0.35 x 0.35-mm PZT-4 transducer--driven at width-mode resonance of 3.85 MHz--replaced a 40-MHz element in a 3.5-Fr coronary imaging catheter. Third, a 5 x 0.5-mm PZT-4 transducer was evaluated as the largest aperture geometry possible for a flexible 3-Fr IVUS catheter. Beam plots and on-axis heating profiles were simulated for each aperture, and test transducers were fabricated. The electrical impedance, impulse response, frequency response, maximum intensity, and mechanical index were measured to assess performance. For the 5 x 0.5-mm transducer, this testing also included mechanically scanning and reconstructing an image of a 2.5-cm-diameter cyst phantom as a preliminary measure of imaging potential.

Dual-mode intracranial catheter integrating 3D ultrasound imaging and hyperthermia for neuro-oncology: feasibility study.

In this study, we investigated the feasibility of an intracranial catheter transducer with dual-mode capability of real-time 3D (RT3D) imaging and ultrasound hyperthermia, for application in the visualization and treatment of tumors in the brain. Feasibility is demonstrated in two ways: first by using a 50-element linear array transducer (17 mm x 3.1 mm aperture) operating at 4.4 MHz with our Volumetrics diagnostic scanner and custom, electrical impedance-matching circuits to achieve a temperature rise over 4 degrees C in excised pork muscle, and second, by designing and constructing a 12 Fr, integrated matrix and linear-array catheter transducer prototype for combined RT3D imaging and heating capability. This dual-mode catheter incorporated 153 matrix array elements and 11 linear array elements diced on a 0.2 mm pitch, with a total aperture size of 8.4 mm x 2.3 mm. This 3.64 MHz array achieved a 3.5 degrees C in vitro temperature rise at a 2 cm focal distance in tissue-mimicking material. The dual-mode catheter prototype was compared with a Siemens 10 Fr AcuNav catheter as a gold standard in experiments assessing image quality and therapeutic potential and both probes were used in an in vivo canine brain model to image anatomical structures and color Doppler blood flow and to attempt in vivo heating.