Ultrasound Contrast Imaging: Fundamentals and Emerging Technology
- 1Department of Physics, Concordia University, Montreal, QC, Canada
- 2Department of Biology, Concordia University, Montreal, QC, Canada
The development of microbubble contrast agents has broadened the scope of medical ultrasound imaging. Along with dedicated imaging techniques, these agents provide enhanced echoes from the blood pool and have enabled diagnostic ultrasound to assess and quantify microvascular blood flow. Contrast-enhanced ultrasound is currently used worldwide with clinical indications in cardiology and radiology, and it continues to evolve and develop through innovative technological advancements. In this review article, we present an overview of the basic microbubble physics and bubble-specific imaging techniques that enable this modality, and follow this with a discussion on new and emerging applications.
Ultrasound imaging is a well-established clinical tool for the morphological assessment of soft tissues, employed frequently in obstetrics, cardiology, and radiology . As an ultrasonic wave (which is a longitudinal wave) is transmitted into the body, reflections are generated from tissue interfaces that are characterized by different acoustic properties, i.e., speed of sound and density. These scattered signals are recorded by the same transmitting transducer and used to generate an image. At typical diagnostic frequencies (
Ultrasound contrast agents comprise of a suspension of small spheres of gas with a low solubility in blood (e.g., perfluorocarbon), typically ranging in size from below 1 to 8 µm in diameter. Unlike contrast agents used in other modalities, such as MRI and CT, the relatively large size of ultrasound contrast agents ensures that they remain strictly intravascular and act as red blood cell tracers . Due to the compressibility of their gas cores, microbubbles vibrate about their equilibrium radius in an ultrasound field and possess scattering cross-sections several orders of magnitude higher than a solid particle of the same size . The bubbles are stabilized by a thin bio-compatible encapsulation layer—typically a phospholipid monolayer, to offer a sufficient compromise between bubble vibration flexibility and resistance to dissolution in-vivo over timescales relevant for imaging, e.g., half-lives of minutes [10, 11].
Microbubble suspensions, typically on the order of
TABLE 1. Current clinical contrast agent microbubbles, their salient characteristics, and their approved uses.
In this review, we present an overview of this established yet evolving imaging modality. First, we present a brief summary of the fundamental physics of microbubble behaviors that are critical for the effectiveness of this approach, followed by an introduction to the main conventional pulse sequences that are designed to exploit these behaviors to generate bubble-specific images. Next, we discuss exciting advancements in the techniques and applications of ultrasound contrast imaging, including the development of emerging contrast agents, novel imaging and image analysis techniques, and the implementation of contrast ultrasound as a therapy monitoring technique. Note that this is not a comprehensive review, rather an overview of the critical work that has defined this modality and salient investigations into new and ground-breaking applications.
2 Ultrasound-Microbubble Interactions
A gas-filled microbubble vibrates when traversing through an acoustic beam, contracting and expanding about its equilibrium radius
FIGURE 1. Illustrative microbubble simulations depicting its resonant and nonlinear behaviour. (A) Radius versus time of an oscillating microbubble and (B) it is corresponding frequency content. Note the presence of subharmonic (0.5), ultraharmonic (1.5, 2.5, 3.5) and harmonic (2, 3) energy, as well as energy at the fundamental frequency band (1). (C) The presence of an encapsulating shell serves to increase the resonance frequency and dampen the vibrational amplitude of an otherwise identical microbubble. (D) Under large forcing conditions, microbubbles exhibit asymmetrical resonance, including a shift down in resonance frequency with increasing forcing amplitude. Note here the inherent skewing of the resonance response, typical of a strain-softening resonator.
Ultrasound-driven microbubble response is resonant in nature, and the resonance frequency is one of the important factors in agent design and optimization. Under low acoustic driving conditions, the nonlinear equation of motion Eq. 1 can be reduced to one of a harmonic oscillator with a linear resonance frequency
where an inverted relationship between resonance frequency and size can be observed.
The addition of an encapsulating shell has led to adjustments of Eq. 1, which incorporate the viscoelastic properties of the thin shell, i.e., shell stiffness and viscosity. While many models have been developed to capture various aspects of microbubble physics, under low-amplitude transmit pressure conditions they are all in agreement with experimental observations which confirm that the encapsulating layer serves to increase the resonance frequency and the vibration dampening of an otherwise identical bubble (Figure 1C). As driving amplitudes increase, microbubbles display nonlinear resonance phenomena, including strain-softening behavior resulting in asymmetric resonance curves shifting to lower resonance frequencies [44, 45] (see Figure 1D). While these nonlinear behaviors can be generated by unencapsulated gas bubbles , the surface rheology of the encapsulation material at megahertz oscillations plays a key role in amplifying these effects . As such, there have been extensive efforts to understand the underlying physics of encapsulated microbubble vibration dynamics, including asymmetric oscillations , nonlinear resonance , multiple scattering , and boundary effects .
3 Contrast Pulse Sequences
Nonlinear behavior of vibrating microbubbles is central to their effectiveness as an ultrasound contrast agent. These emissions provide a means to separate bubble signals within small vessels from those of the surrounding (approximately linear) tissue (Figure 2). Original methods of bubble detection consisted of harmonic imaging, whereby energy at the second harmonic (twice the driving frequency) was collected and filtered from the receive signal. Since microbubbles generate much larger second harmonic signal than tissue, this results in better signal-to-noise ratios than that from the fundamental energy. This approach however requires long-duration (narrowband) transmit pulses in order to ensure separation of the spectral components at
FIGURE 2. Microbubble-specific imaging sequences capture nonlinear signal from contrast agent while rejecting linear scattering tissue. (A) Schematic diagram depicting the pulse inversion technique. Two pulses that are 180° out of phase will result in tissue echoes that are similarly out of phase. However, this is not the case for microbubbles due to their nonlinear behavior. The summed echo results in near complete cancellation for linear tissue and significant signal from echoes generated from microbubbles. (B) B-mode and (C) contrast-specific imaging of an 8 mm vessel phantom highlights the increased vessel contrast due to microbubble-specific imaging. This was acquired with a Philips iU22 scanner using a C5-2 probe and Definity™ contrast agent.
3.1 Pulse Inversion
The generalized scattered signal from a scatterer
Note from the above equation that even-order terms create echoes at even harmonics (and DC), while the odd-order terms account for echoes at the fundamental frequency and odd-order harmonics. The pulse inversion multi-pulse sequence consists of sending in two transmit pulses that are 180° out of phase with each other (Figure 2A). Upon summation of the resulting echoes
While this technique suppresses fundamental signal, it still requires careful selection of transmit frequency to be able to sensitively detect even order harmonics with the given transducer.
3.2 Amplitude Modulation
In a similar attempt to preserve nonlinear contributions, amplitude modulation consists of transmitting a sequence of pulses that are scaled by a constant factor. Typically, the echoes received from
This results in a signal that partially retains all harmonics, including signal at the fundamental frequency; shown here to third order:
It is important to note here that the signal component within Eq. 8 at the driving frequency
Both PI and AM methods can be performed using three or more pulses, offering some advantages in tissue rejection at the cost of temporal resolution. The combination of these two approaches (PIAM, or CPS) retains similar levels of odd-order nonlinear energy as AM while preserving more even-order harmonics, albeit less than the PI technique alone.
4 Emerging Technologies
Contrast-enhanced ultrasound imaging is employed in many clinically approved and off-label applications worldwide. Cutting-edge advancements in this area are being made simultaneously on many fronts, including contrast agent synthesis, the design of novel pulse sequences and image processing techniques, device development, and on the development of remote monitoring for ultrasound therapeutics (Table 2).
TABLE 2. Summary of emerging ultrasound-microbubble based techniques. See text for references and further details.
4.1 Contrast Agents
Microbubbles are currently the only clinically approved ultrasound contrast agent. One of the strengths of these bubbles is that they remain intravascular due to their size, allowing for diagnostic measurements that would be otherwise difficult with diffusible tracers. However, there is a growing focus to extend the use of these ‘traditional’ ultrasound contrast agents towards other applications, including molecular-based imaging, imaging of the extravascular space, and as a dual imaging and therapeutic delivery platform.
4.1.1 Molecularly Targeted Microbubbles
Non-invasive imaging of pathophysiological events has recently been shown feasible with ultrasound due to the synthesis of functionalized microbubbles , i.e., microbubbles with one or more targeting moieties incorporated into the phospholipid encapsulation . Due to the strictly intravascular nature of microbubbles, target sites have aimed at processes that occur within the vasculature, such as inflammation , angiogenesis , and thrombus formation . This technique has shown significant pre-clinical promise, with agents synthesized to target key endothelial biomarkers involved in disease, e.g., ICAM-1 , VCAM-1 ,
Despite the relative success of the aforementioned bound bubble quantification techniques, only a small fraction the injected microbubbles bind to the activated endothelium, on the order 1–2% . A clever approach to increase the number of microbubbles that make direct contact with the endoluminal border is through the use of acoustic radiation force, originally postulated for such a purpose over two decades ago [72, 73]. Acoustic radiation forces, otherwise known as Bjerknes forces, are the forces imparted to a small object within an acoustic beam by the acoustic wave . In the context of ultrasound-stimulated microbubbles, the primary Bjerknes force magnitude
4.1.2 Sub-Micron Contrast Agents
Motivated by the enhanced-permeability and retention effect , whereby small nanometer sized particles locally extravasate from leaky blood vessels and accumulate in the perivascular space of solid tumors, there are numerous ultrasound-sensitive sub-micron agents currently under investigation. These mainly include phase-shift droplets , nanobubbles , gas vesicles , echogenic liposomes , and polymeric nanoparticles . Perhaps the most well-studied of these are volatile, phase-shift sub-micron droplets synthesized from perfluorocarbons (PFCs). As a liquid, droplets provide limited acoustic contrast and are generally not detectable with conventional ultrasound. However, under externally applied ultrasound conditions, these droplets can be acoustically vaporized into detectable, micrometer-sized bubbles approximately 5–10 times their precursor size . Droplet compositions generally consist of PFCs due to their low toxicity, low solubility and their boiling points near physiological temperatures , allowing the design of droplets in or near a superheated state. As these superheated droplets are thermodynamically unstable, they are stabilized through phospholipid encapsulation—reducing surface tension and inhibiting diffusion of the PFC into the surrounding medium. Indeed, droplets can be synthesized directly from pre-cursor microbubbles, e.g., commercially employed agents such as Definity™ [88, 89]. While the physics of acoustic droplet vaporization is still an active area of research, the process likely involves both intrinsic (e.g., PFC, encapsulation material) and extrinsic (e.g., sound and its propagation medium) factors. The vaporization threshold of individual droplets empirically exhibits a size-dependence, with larger, micron-sized droplets requiring lower pressures to vaporize [90–92]. Further, there is an increasing threshold with decreasing frequency —indeed these two factors make the vaporization of small, sub-micron droplets at clinically relevant frequencies a challenge. However, recent translational studies using pre-clinical and programmable array systems have shown the feasibility of in-vivo image-guided vaporization and extravascular imaging [94, 95], see Figure 3.
FIGURE 3. Estimated droplet extravasation signal is larger in tumor than in kidney. (A) Two successive vaporization sequences (Vaporization 1 and 2) separated by 30 s were transmitted to both the kidney (highly intravascular organ) and tumor xenograft (intravascular and extravascular components) in a mouse model, outlined in the dashed lines. The white arrowheads denote the lack of signal enhancement from the second vaporization pulse within the tumor, suggesting droplet extravasation. Scale bar is 5 mm. (B) Quantification of extravasation signal (p < 0.001). Reprinted by permission of Elsevier from Helfield et al Ultrasound and Medicine and Biology, 2020 , see the reference for more details.
As an alternative to phase-shift low-boiling point droplets, recent studies have begun to explore nanobubble contrast agent, typically on the order of several hundred nanometers in size . According to classical models (e.g., Eq. 1 and Eq. 3), nanobubbles are not expected to undergo significant vibrations and scattering at clinically relevant frequencies (e.g., 1–10 MHz). However, studies have demonstrated scattered emissions from nanobubbles at both low [97, 98] and high frequencies . The increased concentration of nanobubbles per unit volume may compensate for the weak scattering from an individual nanobubble, and bubble coalescence (multiple nanobubbles combining to form a microbubble) may also play a role in the observed signal. In addition to these aspects, recent surface modifications (surfactants, e.g., Pluronic) to nanobubble encapsulation layers has been suggested as a potential mechanism to further reduce surface tension and increase flexibility [96, 97]. Regardless of the mechanism, observations of intact nanobubbles in the extravascular space have very recently been documented [100, 101].
Recently, a new and exciting type of biologically-derived, sub-micron ultrasound contrast agent has been developed by harnessing gas vesicles (GVs) . These vesicles, which were originally identified within gas vacuoles of cyanobacteria, function natively to regulate cellular buoyancy for optimal exposure to light and nutrients . GVs are inert, hollow, gas-filled structures formed entirely from protein. The main consistent is a small protein (GVpA) arranged in a linear crystalline array along ribs that form the GV shell and conical caps. A second protein (GVpC) adheres to the outside of the ribs and stabilizes the structure. These vesicles are freely permeable to gases and liquid water is kept out due to surface tension at the hydrophobic inner surface. GVs have been found in many prokaryotes (e.g., bacteria and archaea), and extensive research has concluded that these GVs possess similar morphology and are constructed from a homologous protein. The size and shape of GVs is a function of the species that generate them, but they are typically cylindrical or spindle-liked shaped, with lengths ranging from 0.1 to 2 µm and widths between 45–200 nm . While similar in principle to other pre-formed sub-micron agents, GVs are rigid, non-spherical structures. In the pioneering work by Shapiro et al , purified GVs generated from Halobacterium salinarum (Halo) produced robust contrast using a pre-clinical scanner, including nonlinear harmonic content in-vitro and in mouse liver using an amplitude modulation pulse sequence (e.g., Eq. 7). Since then, many experimental and theoretical investigations have confirmed that GVs are able to elicit nonlinear signal and acoustically-mediated collapse in vitro and in-vivo [104, 105], which highlight the potential of GVs to serve as background-subtracted imaging agents. However, perhaps the greatest differentiator between GVs and traditional ultrasound contrast agents is their ability to be genetically modified. Indeed, the acoustic properties of GVs can be modified at the level of their constituent proteins , which enables the concept of environmentally-modulated nonlinear contrast signal (e.g., detecting the presence of specific proteases ). Further, recent work has demonstrated the capacity of GVs to act as an acoustic reporter gene in mammalian cells (e.g., an acoustic version of an optical reporter like green-fluorescent protein), whereby contrast signal can be correlated to genetic expression .
4.2 Super-Harmonic Imaging
As microbubble vibrations possess a rich resonant structure (Figure 1B), there have been recent developments towards generating contrast images using microbubble super-harmonic frequency components, defined as third-order harmonics and higher
4.3 Non-Invasive Pressure Estimation
Local blood pressure estimation provides valuable clinical information on the physiology of many organs, and can be employed in the diagnosis of disease in the heart and kidneys. Most current clinical techniques to assess blood pressure within non-limb vessels use catheter-based manometers, which is an invasive approach and introduces changes to the local blood circulation and thus the blood pressure. Perhaps one of the most impactful applications of non-invasive pressure estimation would be for the early detection of clinically significant portal vein hypertension, defined as an increase in the pressure gradient between the portal vein and hepatic veins exceeding 10 mmHg . As noted almost four decades ago , bubble response is a direct function of the ambient hydrostatic pressure and may, in principle, be used as a pressure sensor to detect fluctuations in local blood pressure. An increase in ambient pressure effectively compresses the microbubble, resulting in a shift upwards in resonance frequency. For a given transmit frequency, this will manifest itself in the amplitude of the resulting scattered echo. These original works performed on unshelled bubbles resulted in large uncertainties (as much as 30%, or 50 mmHg compared to reference standards ) due to the challenge of detecting the relatively small shift in resonance frequency (∼1 kHz shift from a change in 10 mmHg). While the rheological characteristics of phospholipid encapsulated microbubbles results in much larger resonant shifts (∼0.07–0.24 MHz per 10 mmHg ) that may be sufficiently detectable for clinical utility, major advances in this application of remote blood pressure estimation are derived from investigations into the modulation of subharmonic scattering. Based on earlier works on commercially available contrast microbubbles that indicate a decrease in subharmonic scattering with increasing hydrostatic pressure , subharmonic-aided pressure estimation efforts (referred to as SHAPE ) have met initial success in pre-clinical models [126, 127] and in clinical trials for portal hypertension  and intra-cardiac measurements .
4.4 Ultrasound Localization Microscopy
A flourishing research area within diagnostic ultrasound is the development, implementation and interpretation of ultrafast ultrasound imaging, in which up to 20 kHz frame rates (compared to 10–100 Hz using conventional scanners) can be achieved through advances in hardware and software. This concept is based off the transmission of an ultrasonic plane wave (i.e., unfocused beam), which avoids the time-consuming process of sequential scanning and beamforming conducted by traditional focused-mode imaging. The echoes from a single plane wave transmission are received by the transducer elements and subsequently processed and beamformed in parallel. While the use of a single, unfocused transmit beam results in poor image resolution, SNR can be markedly increased by transmitting multiple plane waves at different angles and compounding the coherent beamformed images. Despite this slight subsequent reduction in frame rate, this still results in a very fast acquisition relative to conventional focused beam, limited in principle only by the two-way speed of sound in tissue. Ultrafast plane wave imaging has opened an array of contrast and non-contrast ultrasound applications that take advantage of such increased temporal resolution, including ultrafast elastography , cardiac , and Doppler-based applications .
Perhaps the most disruptive technique derived from a microbubble-based application of this technology to date is ultrasound localization microscopy (ULM, see Figure 4) . As a super-resolution imaging technique, it has begun a paradigm shift in biomedical ultrasound imaging applications despite many previous investigations into methods to improve ultrasound imaging resolution. In standard imaging techniques, image resolution is bound by diffraction to the scale of the wavelength; for example, in a 6-MHz ultrasound imaging system (
FIGURE 4. (A) An example of ULM applied in a rat brain through a thinned, intact skull providing a resolution of 10 µm × 8 µm in depth and lateral direction, respectively. (B) In-plane velocity map from parts of the vessel from panel A. Scale bar runs from −14 mm/s (blue) to +14 mm/s (red). Reprinted from  with permission from the authors and Nature Publishing Group.
An ultrasonic version of super-resolution is achieved by replacing the fluorescent markers with microbubbles (which are sub-wavelength, individual acoustic sources), and the fast cameras with plane-wave, programmable ultrasound imaging systems. These programmable systems give access to the pre-beamformed time-domain data (RF data), whereby assuming a single source, the signal time delay
The general concept of acquiring a super-resolution imaging using ULM will next be outlined here. After injection of a dilute suspension of contrast agent, video acquisition of the location of interest, either using B-mode or contrast-specific sequences, can be taken using either conventional beam or fast-frame plane wave techniques. Since the resulting ULM image is constructed point by point, a sufficient quantity of microbubbles is required to reconstruct the vasculature, on the order of 1 million events  depending on the vessel density and field of view. Given the relatively slow blood velocities in the microvasculature, this often requires long image acquisition times and results in a vast amount of data for processing. Motion correction algorithms are next applied to minimize motion-related localization artefacts, which present a particular challenge due to these long scan times. Various techniques have been demonstrated within the context of the ULM workflow, including phase-correlation approaches between successive B-mode images, all of which result in corrections on the order of hundreds of micrometers for in-plane motion [143–145]. While out-of-plane motion correction is not possible using this 2D approach, 3D ULM techniques are currently being assessed . Following this, a microbubble-filtering processing step is introduced, which can include isolating nonlinear emissions [134, 141] as well as alternative image processing strategies including spatiotemporal-based filtering algorithms [135, 145, 147]. Microbubble localization is then performed by estimation of its centroid using either the raw RF data or the beamformed image. A critical challenge here is the reliable separation of one microbubble from another. The most direct way of localizing a single microbubble is to use a low concentration of contrast agent (e.g.,
While still in its infancy, ULM has already provided a new in-vivo approach to the study of tissue pathology, providing quantitative information on the density, tortuosity, and small modulations of flow patterns within the microvasculature at depth. The first clinical applications of this technology, using conventional focused beam acquisition, have been conducted on breast cancer , lower limb assessment  and liver imaging . While there are still limitations to this approach, including slow scan times, SNR, the use of plane-wave scanners not typical in clinics, large amounts of data storage and processing, and motion artefacts, significant advancements in all of these areas are currently ongoing.
4.5 Microbubble-Therapy Monitoring
It has long been recognized that ultrasound interactions with biological tissue induce bio-effects of both thermal and mechanical origin . On clinical diagnostic scanners, exposure levels are limited in order to avoid these effects . From a therapeutic standpoint, ultrasound-mediated bioeffects have been investigated as a desired endpoint: with effects ranging from tissue ablation , microvascular permeability , immunomodulation , and vascular occlusion . Recent works have highlighted that microbubble contrast agents, under specific acoustic conditions, can generate a wide spectrum of bioeffects [164–166] that contribute towards the treatment of many diseases. Due to their intravascular nature, a primary avenue of research in microbubble-mediated bioeffects is based on the spatially targeted and temporary enhancement of microvascular permeability, employed to promote local drug delivery to regions of disease. One such promising application is the local and transient opening of the blood-brain-barrier [167, 168] and blood-spinal cord barrier [169, 170] for targeted therapeutics into the central nervous system. This technology has recently entered clinical trials in patients with brain tumors [171–173], Alzheimer’s disease  and amyotrophic lateral sclerosis (ALS) .
Despite being met with initial success, widespread clinical adoption of microbubble-based therapeutics will require the continued development of online, real-time imaging strategies to guide and control treatments. While some of these applications employ MRI guidance, there is increasing interest in employing the acoustic scattering from the microbubbles themselves as an indicator of treatment outcome. Since the spectral echo characteristics can be indicative of the underlying microbubble vibrations , remote detection of these signals during treatment is under investigation as a robust and sensitive tool for therapy guidance. Many preclinical applications of targeted microbubble therapeutics, including cardiovascular disease [177, 178] and cancer , are performed as a dual imaging and therapeutic technique. Contrast enhanced ultrasound is applied and interleaved with a therapeutic pulse from either a separate ultrasound transducer  or incorporated by way of clinical  or custom-designed sequence. In this way, the presence of microbubbles within the anatomical site of interest can be visually confirmed before, during and after the treatment sequences. The acoustic emissions detected during microbubble-based therapies have been identified as potential markers for treatment outcome in applications including blood-brain barrier disruption [180, 181], and targeted therapeutic delivery . To this end, passive cavitation detectors are typically employed to measure raw acoustic data to extract quantitative metrics. Most of these methods to date utilize a single element passive transducer, which does not allow the bubble signal to be localized in space. Ongoing novel engineering of array transducers, combined with passive beamforming algorithms, are currently being designed to spatially map bubble activity and allow for confirmation that elicited bioeffects are localized to the target site [183, 184], see Figure 5. Above and beyond these correlative measures, efforts are underway to establish control feedback algorithms based on the measured bubble acoustic activity to promote safe levels of vibration and avoid more violent, disruptive bubble behaviour that leads to unwanted damage. These algorithms modulate the acoustic transmit parameters based off the real-time feedback from nonlinear microbubble emissions, including sub-harmonic energy [185, 186], harmonic energy [187, 188], or both .
FIGURE 5. Spatial correlation of ultrafast 3D microbubble cavitation with focused ultrasound (FUS) brain tissue damage in a rabbit model. Baseline
Ultrasound contrast imaging using microbubbles is a safe and reliable technique for many clinical practices, and its application base is expanding. The tremendous success of this imaging technology to date is courtesy of increased clinical awareness of the benefits of ultrasound, and the collaborative research endeavors between physicists, chemists, engineers, and clinicians on the investigation of microbubble behavior, signal processing techniques, contrast agent synthesis, and device development. In this review, we summarized the fundamentals of contrast agent microbubble vibration and how it is harnessed for routine contrast-imaging application. Specific pulse sequences are employed to extract bubble-specific acoustic signatures and suppress signal arising from the surrounding tissue to enable preferential imaging of the vasculature. We then presented an overview of emerging techniques and technologies associated with microbubble-based imaging, summarized in Table 2. These developments span new design efforts on acoustically-sensitive agents for disease-specific imaging, to new signal processing techniques to obtain highly resolved vascular images, to new interpretation techniques to extract biologically/physiologically relevant data from microbubble acoustic signatures. With the development of new ultrafast imaging technology and image processing techniques, along with increasing interest in targeted ultrasound therapeutic applications, there are still numerous emerging and exciting applications that remain to be explored.
HY and BH co-led the scientific discussion and writing for this paper. BH is the corresponding author.
This work is supported, in part, by the NSERC (RGPIN-2019-06969), the Fonds de recherche du Quebec—Nature et Technologies (2021-NC-282699), the Heart and Stroke Foundation of Canada (G-18-0022133), the Canada Research Chair program, and the Burroughs Wellcome Fund (1018212.03). BH holds a Career at the Scientific Interface award from the Burroughs Wellcome Fund (BWF-CASI).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: microbubbles, contrast enhanced ultrasound, imaging, nonlinear scattering, subharmonic, ultrasound localization microscopy, super resolution, harmonic
Citation: Yusefi H and Helfield B (2022) Ultrasound Contrast Imaging: Fundamentals and Emerging Technology. Front. Phys. 10:791145. doi: 10.3389/fphy.2022.791145
Received: 08 October 2021; Accepted: 26 January 2022;
Published: 17 February 2022.
Edited by:Federico Giove, Centro Fermi—Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, Italy
Reviewed by:Mehmet Burcin Unlu, Boğaziçi University, Turkey
Heikki Juhani Nieminen, Aalto University, Finland
Copyright © 2022 Yusefi and Helfield. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Brandon Helfield, email@example.com