Acoustic angiography

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A specific branch of contrast-enhanced ultrasound, acoustic angiography is a minimally invasive and non-ionizing medical imaging technique used to visualize vasculature. [1] Acoustic angiography was first developed by the Dayton Laboratory at North Carolina State University [1] and provides a safe, portable, and inexpensive alternative to the most common methods of angiography such as Magnetic Resonance Angiography and Computed Tomography Angiography. Although ultrasound does not traditionally exhibit the high resolution of MRI or CT, high-frequency ultrasound (HFU) achieves relatively high resolution by sacrificing some penetration depth. [2] HFU typically uses waves between 20 and 100 MHz and achieves resolution of 16-80μm at depths of 3-12mm. [2] Although HFU has exhibited adequate resolution to monitor things like tumor growth in the skin layers, [2] on its own it lacks the depth and contrast necessary for imaging blood vessels. [3] Acoustic angiography overcomes the weaknesses of HFU by combining contrast-enhanced ultrasound with the use of a dual-element ultrasound transducer to achieve high resolution visualization of blood vessels at relatively deep penetration levels.

Contents

Acoustic angiography is performed by first injecting specially designed microbubbles with a low resonant frequency into the vessels. Next, a low-frequency transducer element with good depth penetration is used to send ultrasound waves into the sample at the resonant frequency of the microbubbles. [3] This will generate a response from the microbubbles consisting of subharmonic, fundamental, and super-harmonic frequencies, as well as a response from the surrounding tissue consisting of only the fundamental and second-harmonic frequencies. [1] Finally, a high-frequency transducer with high resolution is used to measure the super-harmonic frequencies, effectively removing any background signal from the microbubble signal, and allowing the vessels to be visualized [3]

Background

Angiography, or the examination of blood vessels, is essential in many areas of research and clinical practice. In particular, angiography is needed to monitor angiogenesis, which is the growth and development of new blood vessels. Angiogenesis is an essential process which is most often observed in organ growth in fetuses and children, the development of the placenta in adults, and wound healing. [4] However, excessive angiogenesis has been observed in dozens of disorders, including diabetes, endometriosis, autoimmune disease, and asthma. [4] Angiography has been used in the research, diagnosis, and treatment of many of these disorders. Perhaps the most important application of angiography for monitoring angiogenesis is in tumor growth. Tumors can exist for months or even years in a non-angiogeneic stage of development and only begin rapid growth once the angiogenic phenotype is expressed. [5] Thus, angiogenesis has become a target for certain cancer therapies. Some therapies aim to promote organized development of blood vessels in tumor regions, which allows for more homogenous and effective distribution of chemotherapy. [6] Other methods aim to block the start or progression of angiogenesis altogether. [7] In both cases, angiography is essential for measuring the growth, recession, or shape of blood vessels in-vivo over time during these treatments and related research [7]

Currently, the most common techniques used for angiography are X-ray CT and MRI. However, many other methods are used for performing angiography in special circumstances, such as the use of optical coherence tomography for performing angiography during retinal exams. [8] MRI angiography provides the highest resolution of the current angiographic methods [7] and can often be performed without the use of contrast agents by modifying the pulse sequence to visualize aspects of the vessels such as blood flow. [9] On the other hand, x-ray CT angiography requires the use of a contrast agent, but still maintains relatively high resolution. [10] Despite the high quality images produced by both of these techniques, there remain significant drawbacks. Both are relatively slow and require expensive equipment, while x-ray CT also exposes patients to potentially harmful ionizing radiation. Thus, there is still a need for an inexpensive, portable, and safe candidate for angiography. Acoustic angiography is able to fill this need. By using microbubbles as a contrast agent and a dual-element transducer for signal identification, acoustic angiography achieves depth, vessel contrast, and resolution not possible with other ultrasound techniques.

Ultrasound contrast agents

Ultrasound contrast agents are particles used in ultrasound scans to improve image contrast. The first reported use of an ultrasound contrast agent was by Dr. Raymond Gramiak and Pravin Shah in 1968, when they injected saline into the aortic root of the heart and observed increased contrast. [11] They hypothesized that the increase in contrast was a result of "mini bubbles produced by the rapid injection rate or possibly included in the contrast medium". Although most ultrasound contrast agents take the form of microbubbles, other types exist, such as perfluorocarbon nanoparticles or echogenic liposomes. [12]

Components

Microbubble contrast agents generally have three main components: [13]

  1. Inner Gas: The gas inside the microbubble is generally air or a perfluorocarbon.
  2. Lipid Shell: This shell serves to enclose the gas within it and is always made of lipids due to their hydrophobic property
  3. Ligands: In the case of actively targeted microbubbles, ligands are attached to the outer surface of the lipid shell. These ligands are specific to membrane receptors in the body, and can be used to target certain physiological processes (such as inflammation) or organs. In the case of passively targeted microbubbles, no ligands are attached to the outer shell, and instead the microbubbles rely on factors such as surface charge in order to adhere to the endothelium. [12]

Mechanism of contrast

Microbubbles work as contrast agents in ultrasound for two main reasons: The large difference in acoustic impedance between body tissues and the microbubbles and their quality of having a resonant frequency generally under 10 MHz. Due to the larger mismatch in acoustic impedances, the microbubbles are near-perfect reflectors of ultrasound waves in the body. This allows them to be point-sources of acoustic waves. Furthermore, at their resonant frequency, the microbubbles have a relatively large-magnitude broadband frequency response, which is picked up by the ultrasound transducer.

Microbubble signal identification

In classical contrast-enhanced ultrasound, many methods exist for separating signal reflected by the microbubbles and signal reflected by surrounding body tissues. Most of these methods utilize the subharmonic and super harmonic response of the microbubbles, as well as the microbubbles nonlinear response to ultrasound waves, as opposed to body tissues linear response to ultrasound waves. Some of the more common filtering methods are listed below.

With the creation of a dual-element transducer, these filtering methods are no longer critical. This is what distinguishes acoustic angiography from the more generic contrast-enhanced ultrasound. An element centered at a low frequency serves to excite the microbubbles at their resonant frequency, while an element centered at a high frequency receives the super harmonic response of the microbubbles. [14] Since the tissue is excited by the low frequency input and does not produce a high frequency response, the only response received by the dual-element transducer is that originating from the microbubbles. Thus, little to no signal processing is necessary to remove tissue signal from the acquired data.

Because the inner element is receive only while the outer element is transmit only, special materials can be chosen to optimize the efficiency and sensitivity of this process. Lead Zirconate Titanate (PZT) works well as a material choice for the transmitting element because it has a high transmitting constant (d = 300 x 10^-12 m/V) while Polyvinylidene Fluoride (PVDF) works well as a material for the receiving element because it has a high receiving constant (g = 14 x 10^-2 Vm/N). Generally, PVDF is not a good choice for an ultrasound transducer because it has a relatively poor transmitting constant, however, since acoustic angiography separates the transmitting and receiving elements, this is no longer an issue.

Image formation

Data acquisition

Wobbler vs Linear Sweep Mechanical Scanning Configurations Wobbler vs Linear Scanning Configurations.png
Wobbler vs Linear Sweep Mechanical Scanning Configurations

As acoustic angiography uses a dual-element ultrasonic transducer in the format of a focused ultrasound probe, it is not feasible to form an array of transducers as can be done in other forms of ultrasound imagining. Thus acoustic angiography images are formed by combining multiple a-mode [15] images where each a-mode is a one-dimensional image identifying the acoustic boundaries along a vector originating at the transducer.

In order to form two or three dimensional images, the position and angle of the transducer and the resulting a-mode image must be mechanically manipulated. Two common configurations used to acquire these a-mode images include the wobbler configuration and mechanical sweep configuration.

In the wobbler configuration, the probe is rotated back and forth about a central axis in one plane so that the a-scans are radially oriented and the field of view, or region that is able to be imaged, is a cone. This allows for very quick acquisition of a-scans, but has nonhomogeneous resolution as the distance between each point on neighboring a-scans increases with depth.

In the linear sweep configuration, the ultrasound probe is mechanically moved, either by an external mechanism or hand, in a direction orthogonal to the direction of the a-scan. This configuration allows relatively consistent resolution as a function of depth as each point on neighboring a-scans is equidistant.

Once data has been collected as described above, it can be processed to form a variety of image types including projections and volumetric reconstruction.

Projection

Projection images in ultrasound are similar in concept to projection radiography. However, instead of projecting the degree of absorbance of X-ray photons along a given path, projection images in ultrasound generally project the mismatch of acoustic impedance and the location along a given boundary in tissue.

Maximum amplitude projection

The maximum amplitude projection or the maximum intensity projection is an image processing technique used to project three dimensional data onto a two dimensional image. This is a valuable tool as it allows the complex data to be formed into more readily understandable images that include the perception of depth.

In many forms of ultrasound imaging and photoacoustic imaging, the maximum amplitude of the signal along a given a-scan is used as the value for a pixel associated with that a-scan. As acoustic wave experience distance-dependent acoustic attenuation, the amplitude of a given signal along a given a-scan also encodes the distance to the object that generated that signal.

This simple image reconstruction technique allows for easily formed and interpretable projection images formed from acoustic signals.

Volumetric renderings

Volumetric renderings convert volumetric data into projection images. Most methods use data acquired in lower dimensions to generate voxels, volumetric pixels, that can form 3D images when combined. [16]

Volumetric reconstruction

Volume reconstruction techniques are used to convert multiple 1D or 2D images into 3D volumes. Common volume reconstruction techniques include pixel-nearest-neighbors, voxel-nearest-neighbors, distance-weighted voxels, and function based methods used to statistically infer the value of a given voxel. [17]

Applications

As acoustic angiography is currently under development, this specific branch of contrast-enhanced ultrasound is not currently used in clinical settings. The majority of the previous work using acoustic angiography has studied angiogenesis in animal models for research purposes.

Though the FDA has only approved contrast-enhanced ultrasound use in one clinical application in the United States, [1] echocardiography, the broader technique has been used throughout Europe and Asia to great success in a variety of clinical applications. To learn more, see the current applications of contrast enhanced ultrasound. [18]

Currently investigated clinical uses

The only use of acoustic angiography that has been investigated in clinical settings to date studied angiogenesis in the peripheral vasculature of human breast tissue. [12] This study investigated if acoustic angiography could be used to reduce the need for biopsy of breast tissue when diagnosing if lesions in breast tissue were cancerous or not.

Using acoustic angiography, the authors collected and reconstructed the 3D volumes associated with vasculature surrounding lesions in the breast. These reconstructed volumes were then analyzed for vascular density and tortuosity. This information is useful for diagnosis as it has been shown that when these two factors increase in the vasculature surrounding a lesion, there is an increased risk that the lesion is cancerous. [12]

Related Research Articles

<span class="mw-page-title-main">Ultrasound</span> Sound waves with frequencies above the human hearing range

Ultrasound is sound with frequencies greater than 20 kilohertz. This frequency is the approximate upper audible limit of human hearing in healthy young adults. The physical principles of acoustic waves apply to any frequency range, including ultrasound. Ultrasonic devices operate with frequencies from 20 kHz up to several gigahertz.

<span class="mw-page-title-main">Medical ultrasound</span> Diagnostic and therapeutic technique

Medical ultrasound includes diagnostic techniques using ultrasound, as well as therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal body structures such as tendons, muscles, joints, blood vessels, and internal organs, to measure some characteristics or to generate an informative audible sound. The usage of ultrasound to produce visual images for medicine is called medical ultrasonography or simply sonography, or echography. The practice of examining pregnant women using ultrasound is called obstetric ultrasonography, and was an early development of clinical ultrasonography. The machine used is called an ultrasound machine, a sonograph or an echograph. The visual image formed using this technique is called an ultrasonogram, a sonogram or an echogram.

<span class="mw-page-title-main">Photoacoustic imaging</span> Imaging using the photoacoustic effect

Photoacoustic imaging or optoacoustic imaging is a biomedical imaging modality based on the photoacoustic effect. Non-ionizing laser pulses are delivered into biological tissues and part of the energy will be absorbed and converted into heat, leading to transient thermoelastic expansion and thus wideband ultrasonic emission. The generated ultrasonic waves are detected by ultrasonic transducers and then analyzed to produce images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission, which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast. 2D or 3D images of the targeted areas can then be formed.

<span class="mw-page-title-main">Transcranial Doppler</span>

Transcranial Doppler (TCD) and transcranial color Doppler (TCCD) are types of Doppler ultrasonography that measure the velocity of blood flow through the brain's blood vessels by measuring the echoes of ultrasound waves moving transcranially. These modes of medical imaging conduct a spectral analysis of the acoustic signals they receive and can therefore be classified as methods of active acoustocerebrography. They are used as tests to help diagnose emboli, stenosis, vasospasm from a subarachnoid hemorrhage, and other problems. These relatively quick and inexpensive tests are growing in popularity. The tests are effective for detecting sickle cell disease, ischemic cerebrovascular disease, subarachnoid hemorrhage, arteriovenous malformations, and cerebral circulatory arrest. The tests are possibly useful for perioperative monitoring and meningeal infection. The equipment used for these tests is becoming increasingly portable, making it possible for a clinician to travel to a hospital, to a doctor's office, or to a nursing home for both inpatient and outpatient studies. The tests are often used in conjunction with other tests such as MRI, MRA, carotid duplex ultrasound and CT scans. The tests are also used for research in cognitive neuroscience.

<span class="mw-page-title-main">Contrast-enhanced ultrasound</span> Medical imaging technique

Contrast-enhanced ultrasound (CEUS) is the application of ultrasound contrast medium to traditional medical sonography. Ultrasound contrast agents rely on the different ways in which sound waves are reflected from interfaces between substances. This may be the surface of a small air bubble or a more complex structure. Commercially available contrast media are gas-filled microbubbles that are administered intravenously to the systemic circulation. Microbubbles have a high degree of echogenicity. There is a great difference in echogenicity between the gas in the microbubbles and the soft tissue surroundings of the body. Thus, ultrasonic imaging using microbubble contrast agents enhances the ultrasound backscatter, (reflection) of the ultrasound waves, to produce a sonogram with increased contrast due to the high echogenicity difference. Contrast-enhanced ultrasound can be used to image blood perfusion in organs, measure blood flow rate in the heart and other organs, and for other applications.

<span class="mw-page-title-main">Focused ultrasound</span> Non-invasive therapeutic technique

High-intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that uses non-ionizing ultrasonic waves to heat or ablate tissue. HIFU can be used to increase the flow of blood or lymph or to destroy tissue, such as tumors, via thermal and mechanical mechanisms. Given the prevalence and relatively low cost of ultrasound generation mechanisms, the premise of HIFU is that it is expected to be a non-invasive and low-cost therapy that can at least outperform care in the operating room.

<span class="mw-page-title-main">Scanning acoustic microscope</span>

A scanning acoustic microscope (SAM) is a device which uses focused sound to investigate, measure, or image an object. It is commonly used in failure analysis and non-destructive evaluation. It also has applications in biological and medical research. The semiconductor industry has found the SAM useful in detecting voids, cracks, and delaminations within microelectronic packages.

Acoustic microscopy is microscopy that employs very high or ultra high frequency ultrasound. Acoustic microscopes operate non-destructively and penetrate most solid materials to make visible images of internal features, including defects such as cracks, delaminations and voids.

<span class="mw-page-title-main">Thermoacoustic imaging</span>

Thermoacoustic imaging was originally proposed by Theodore Bowen in 1981 as a strategy for studying the absorption properties of human tissue using virtually any kind of electromagnetic radiation. But Alexander Graham Bell first reported the physical principle upon which thermoacoustic imaging is based a century earlier. He observed that audible sound could be created by illuminating an intermittent beam of sunlight onto a rubber sheet. Shortly after Bowen's work was published, other researchers proposed methodology for thermoacoustic imaging using microwaves. In 1994 researchers used an infrared laser to produce the first thermoacoustic images of near-infrared optical absorption in a tissue-mimicking phantom, albeit in two dimensions (2D). In 1995 other researchers formulated a general reconstruction algorithm by which 2D thermoacoustic images could be computed from their "projections," i.e. thermoacoustic computed tomography (TCT). By 1998 researchers at Indiana University Medical Center extended TCT to 3D and employed pulsed microwaves to produce the first fully three-dimensional (3D) thermoacoustic images of biologic tissue [an excised lamb kidney ]. The following year they created the first fully 3D thermoacoustic images of cancer in the human breast, again using pulsed microwaves. Since that time, thermoacoustic imaging has gained widespread popularity in research institutions worldwide. As of 2008, three companies were developing commercial thermoacoustic imaging systems – Seno Medical, Endra, Inc. and OptoSonics, Inc.

The photoacoustic Doppler effect is a type of Doppler effect that occurs when an intensity modulated light wave induces a photoacoustic wave on moving particles with a specific frequency. The observed frequency shift is a good indicator of the velocity of the illuminated moving particles. A potential biomedical application is measuring blood flow.

Microbubbles are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, medicine, life science, and food technology. The composition of the bubble shell and filling material determine important design features such as buoyancy, crush strength, thermal conductivity, and acoustic properties.

Preclinical imaging is the visualization of living animals for research purposes, such as drug development. Imaging modalities have long been crucial to the researcher in observing changes, either at the organ, tissue, cell, or molecular level, in animals responding to physiological or environmental changes. Imaging modalities that are non-invasive and in vivo have become especially important to study animal models longitudinally. Broadly speaking, these imaging systems can be categorized into primarily morphological/anatomical and primarily molecular imaging techniques. Techniques such as high-frequency micro-ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) are usually used for anatomical imaging, while optical imaging, positron emission tomography (PET), and single photon emission computed tomography (SPECT) are usually used for molecular visualizations.

<span class="mw-page-title-main">Doppler ultrasonography</span> Ultrasound imaging of the movement of tissues and body fluids using the Doppler effect

Doppler ultrasonography is medical ultrasonography that employs the Doppler effect to perform imaging of the movement of tissues and body fluids, and their relative velocity to the probe. By calculating the frequency shift of a particular sample volume, for example, flow in an artery or a jet of blood flow over a heart valve, its speed and direction can be determined and visualized.

Super-resolution photoacoustic imaging is a set of techniques used to enhance spatial resolution in photoacoustic imaging. Specifically, these techniques primarily break the optical diffraction limit of the photoacoustic imaging system. It can be achieved in a variety of mechanisms, such as blind structured illumination, multi-speckle illumination, or photo-imprint photoacoustic microscopy in Figure 1.

<span class="mw-page-title-main">Photoacoustic microscopy</span>

Photoacoustic microscopy is an imaging method based on the photoacoustic effect and is a subset of photoacoustic tomography. Photoacoustic microscopy takes advantage of the local temperature rise that occurs as a result of light absorption in tissue. Using a nanosecond pulsed laser beam, tissues undergo thermoelastic expansion, resulting in the release of a wide-band acoustic wave that can be detected using a high-frequency ultrasound transducer. Since ultrasonic scattering in tissue is weaker than optical scattering, photoacoustic microscopy is capable of achieving high-resolution images at greater depths than conventional microscopy methods. Furthermore, photoacoustic microscopy is especially useful in the field of biomedical imaging due to its scalability. By adjusting the optical and acoustic foci, lateral resolution may be optimized for the desired imaging depth.

<span class="mw-page-title-main">Functional ultrasound imaging</span>

Functional ultrasound imaging (fUS) is a medical ultrasound imaging technique of detecting or measuring changes in neural activities or metabolism, for example, the loci of brain activity, typically through measuring blood flow or hemodynamic changes. The method can be seen as an extension of Doppler imaging.

Deep learning in photoacoustic imaging

Deep learning in photoacoustic imaging combines the hybrid imaging modality of photoacoustic imaging (PA) with the rapidly evolving field of deep learning. Photoacoustic imaging is based on the photoacoustic effect, in which optical absorption causes a rise in temperature, which causes a subsequent rise in pressure via thermo-elastic expansion. This pressure rise propagates through the tissue and is sensed via ultrasonic transducers. Due to the proportionality between the optical absorption, the rise in temperature, and the rise in pressure, the ultrasound pressure wave signal can be used to quantify the original optical energy deposition within the tissue.

Ultrasound-switchable fluorescence (USF) imaging is a deep optics imaging technique. In last few decades, fluorescence microscopy has been highly developed to image biological samples and live tissues. However, due to light scattering, fluorescence microscopy is limited to shallow tissues. Since fluorescence is characterized by high contrast, high sensitivity, and low cost which is crucial to investigate deep tissue information, developing fluorescence imaging technique with high depth-to-resolution ratio would be promising.. Recently, ultrasound-switchable fluorescence imaging has been developed to achieve high signal-to-noise ratio (SNR) and high spatial resolution imaging without sacrificing image depth.

Focused-ultrasound-mediated diagnostics or FUS-mediated diagnostics are an area of clinical diagnostic tools that use ultrasound to detect diseases and cancers. Although ultrasound has been used for imaging in various settings, focused-ultrasound refers to the detection of specific cells and biomarkers under flow combining ultrasound with lasers, microbubbles, and imaging techniques. Current diagnostic techniques for detecting tumors and diseases using biopsies often include invasive procedures and require improved accuracy, especially in cases such as glioblastoma and melanoma. The field of FUS-mediated diagnostics targeting cells and biomarkers is being investigated for overcoming these limitations.

Ultrasound Localization Microscopy (ULM) is an advanced ultrasound imaging technique. By localizing microbubbles, ULM overcomes the physical limit of diffraction, achieving sub-wavelength level resolution and qualifying as a super-resolution technique.

References

  1. 1 2 3 4 Gessner, Ryan C.; Frederick, C. Brandon; Foster, F. Stuart; Dayton, Paul A. (2013). "Acoustic Angiography: A New Imaging Modality for Assessing Microvasculature Architecture". International Journal of Biomedical Imaging. 2013: 936593. doi: 10.1155/2013/936593 . ISSN   1687-4188. PMC   3730364 . PMID   23997762.
  2. 1 2 3 Bezugly, A. (2015).High frequency ultrasound study of skin tumors in dermatological and aesthetic practice. Medical Ultrasonography, 17(4). https://doi.org/10.11152/mu.2013.2066.174.hfy
  3. 1 2 3 Shelton, S. E., Lindsey, B. D., Tsuruta, J. K., Foster, F. S., & Dayton, P. A. (2016). Molecular Acoustic Angiography: A New Technique for High-resolution Superharmonic Ultrasound Molecular Imaging. Ultrasound in Medicine & Biology, 42(3), 769-781. https://doi.org/10.1016/j.ultrasmedbio.2015.10.015
  4. 1 2 Carmeliet, P. (2005). Angiogenesis in life, disease and medicine. Nature, 438(7070), 932-936. https://doi.org/10.1038/nature04478
  5. ↑ Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine, 1(1), 27-30. https://doi.org/10.1038/nm0195-27
  6. ↑ Maj, E., Papiernik, D., & Wietrzyk, J. (2016). Antiangiogenic cancer treatment: The great discovery and greater complexity (Review). International Journal of Oncology, 49(5), 1773-1784. https://doi.org/10.3892/ijo.2016.3709
  7. 1 2 3 Ungersma, S. E., Pacheco, G., Ho, C., Yee, S. F., Ross, J., Van Bruggen, N., Peale, F. V., Ross, S., & Carano, R. A. D. (2010). Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis. Magnetic Resonance in Medicine, 63(6), 1637-1647. https://doi.org/10.1002/mrm.22442
  8. ↑ Kashani, A. H., Chen, C.-L., Gahm, J. K., Zheng, F., Richter, G. M., Rosenfeld, P. J., Shi, Y., & Wang, R. K. (2017). Optical coherence tomography angiography: A comprehensive review of current methods and clinical applications. Progress in Retinal and Eye Research, 60, 66-100. https://doi.org/10.1016/j.preteyeres.2017.07.002
  9. ↑ Park, C.-A., Kang, C.-K., Kim, Y.-B., & Cho, Z.-H. (2018). Advances in MR angiography with 7T MRI: From microvascular imaging to functional angiography. NeuroImage, 168, 269-278. https://doi.org/https://doi.org/10.1016/j.neuroimage.2017.01.019
  10. ↑ Kumamaru, K. K., Hoppel, B. E., Mather, R. T., & Rybicki, F. J. (2010). CT Angiography: Current Technology and Clinical Use. Radiologic Clinics of North America, 48(2), 213-235. https://doi.org/10.1016/j.rcl.2010.02.006
  11. ↑ Gramiak, Raymond; Shah, Pravin M. (1968). "Echocardiography of the Aortic Root". Investigative Radiology. 3 (5): 356–366. doi:10.1097/00004424-196809000-00011. ISSN   0020-9996. PMID   5688346.
  12. 1 2 3 4 5 Dayton, Paul, A. (2007). "Molecular ultrasound imaging using microbubble contrast agents". Frontiers in Bioscience. 12 (12): 5124–5142. doi: 10.2741/2553 . ISSN   1093-9946. PMID   17569635.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ↑ Unnikrishnan, Sunil; Klibanov, Alexander L. (2012). "Microbubbles as Ultrasound Contrast Agents for Molecular Imaging: Preparation and Application". American Journal of Roentgenology. 199 (2): 292–299. doi:10.2214/ajr.12.8826. ISSN   0361-803X. PMID   22826389.
  14. ↑ Czernuszewicz, Tomasz J.; Papadopoulou, Virginie; Rojas, Juan D.; Rajamahendiran, Rajalekha M.; Perdomo, Jonathan; Butler, James; Harlacher, Max; O'Connell, Graeme; Zukić, Dženan; Aylward, Stephen R.; Dayton, Paul A. (2018). "A new preclinical ultrasound platform for widefield 3D imaging of rodents". Review of Scientific Instruments. 89 (7): 075107. Bibcode:2018RScI...89g5107C. doi:10.1063/1.5026430. ISSN   0034-6748. PMC   6045495 . PMID   30068108.
  15. ↑ "VetFolio". www.vetfolio.com. Retrieved 2021-12-04.
  16. ↑ Nelson, T.R.; Elvins, T.T. (November 1993). "Visualization of 3D ultrasound data". IEEE Computer Graphics and Applications. 13 (6): 50–57. doi:10.1109/38.252557. ISSN   0272-1716. S2CID   9026058.
  17. ↑ Mohamed, Farhan; Siang, Chan Vei (2019-04-27). A Survey on 3D Ultrasound Reconstruction Techniques. IntechOpen. doi:10.5772/intechopen.81628. ISBN   978-1-78984-018-6. S2CID   164345254.
  18. ↑ Dietrich, Christoph F.; Nolsøe, Christian Pállson; Barr, Richard G.; Berzigotti, Annalisa; Burns, Peter N; Cantisani, Vito; Chammas, Maria Cristina; Chaubal, Nitin; Choi, Byung Ihn; Clevert, Dirk-André; Cui, Xinwu (October 2020). "Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2020 – WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS". Ultraschall in der Medizin - European Journal of Ultrasound (in German). 41 (5): 562–585. doi: 10.1055/a-1177-0530 . ISSN   0172-4614. PMID   32707595. S2CID   225464369.
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