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Oglat\" } ], \"publisher\": { \"@type\": \"Organization\", \"name\": \"F1000Research\", \"logo\": { \"@type\": \"ImageObject\", \"url\": \"https://f1000research.com/img/AMP/F1000Research_image.png\", \"height\": 480, \"width\": 60 } }, \"image\": { \"@type\": \"ImageObject\", \"url\": \"https://f1000research.com/img/AMP/F1000Research_image.png\", \"height\": 1200, \"width\": 150 }, \"description\": \"Efforts have been made over the last five decades to create effective ultrasonic contrast media (UCM) for cardiac and noncardiac applications. The initial UCM was established in the 1980s, following publications from the 1960s that detailed the discovery of ultrasonic contrast enhancement using small gaseous bubbles in echocardiographic examinations. An optimal contrast agent for echography should possess the following characteristics: non-toxicity, suitability for intravenous injection, ability to traverse pulmonary, cardiac, and capillary circulations, and stability for recirculation. Definity, Optison, Sonazoid, and SonoVue are examples of current commercial contrast media. These contrast media have shown potential for various clinical reasons, both on-label and off-label. Several possible UCMs have been developed or are in progress. Advancements in comprehending the physical, chemical, and biological characteristics of microbubbles have significantly improved the visualization of tumor blood vessels, the identification of areas with reduced blood supply, and the enhanced detection of narrowed blood vessels. Innovative advances are expected to enhance future applications such as ultrasonic molecular imaging and therapeutic utilization of microbubbles.\" } { \"@context\": \"http://schema.org\", \"@type\": \"BreadcrumbList\", \"itemListElement\": [ { \"@type\": \"ListItem\", \"position\": \"1\", \"item\": { \"@id\": \"https://f1000research.com/\", \"name\": \"Home\" } }, { \"@type\": \"ListItem\", \"position\": \"2\", \"item\": { \"@id\": \"https://f1000research.com/browse/articles\", \"name\": \"Browse\" } }, { \"@type\": \"ListItem\", \"position\": \"3\", \"item\": { \"@id\": \"https://f1000research.com/articles/12-1444/v3\", \"name\": \"A review of ultrasound contrast media\" } } ] } Home Browse A review of ultrasound contrast media ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Oglat AA. A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.12688/f1000research.140131.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Revised A review of ultrasound contrast media [version 3; peer review: 2 approved] Ammar A. Oglat https://orcid.org/0000-0002-7907-6889 Ammar A. Oglat https://orcid.org/0000-0002-7907-6889 PUBLISHED 04 Jun 2024 Author details Author details Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, Zarqa Governorate, 13133, Jordan Ammar A. Oglat Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Efforts have been made over the last five decades to create effective ultrasonic contrast media (UCM) for cardiac and noncardiac applications. The initial UCM was established in the 1980s, following publications from the 1960s that detailed the discovery of ultrasonic contrast enhancement using small gaseous bubbles in echocardiographic examinations. An optimal contrast agent for echography should possess the following characteristics: non-toxicity, suitability for intravenous injection, ability to traverse pulmonary, cardiac, and capillary circulations, and stability for recirculation. Definity, Optison, Sonazoid, and SonoVue are examples of current commercial contrast media. These contrast media have shown potential for various clinical reasons, both on-label and off-label. Several possible UCMs have been developed or are in progress. Advancements in comprehending the physical, chemical, and biological characteristics of microbubbles have significantly improved the visualization of tumor blood vessels, the identification of areas with reduced blood supply, and the enhanced detection of narrowed blood vessels. Innovative advances are expected to enhance future applications such as ultrasonic molecular imaging and therapeutic utilization of microbubbles. READ ALL READ LESS Keywords contrast agents for ultrasound, Microbubbles, echocardiographic, M-mode Corresponding Author(s) Ammar A. Oglat ( [email protected] ) Close Corresponding author: Ammar A. Oglat Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Oglat AA. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Oglat AA. A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.12688/f1000research.140131.3 ) First published: 07 Nov 2023, 12 :1444 ( https://doi.org/10.12688/f1000research.140131.1 ) Latest published: 04 Jun 2024, 12 :1444 ( https://doi.org/10.12688/f1000research.140131.3 ) Revised Amendments from Version 2 1. The grammatical and typo errors in all manuscript sections are corrected. 2. The conclusion is rephrased in a good Scientific way. 1. The grammatical and typo errors in all manuscript sections are corrected. 2. The conclusion is rephrased in a good Scientific way. See the author's detailed response to the review by Hamad Yahia Abu Mhanna See the author's detailed response to the review by Haytham Alewaidat READ REVIEWER RESPONSES Introduction In obstetrics, cardiology, and radiology, ultrasound imaging is a common clinical tool for the morphological examination of soft tissues. 1 – 7 As an ultrasonic wave—a longitudinal wave—travels through the body, tissue surfaces with various acoustic characteristics, such as speed of sound and density, produce reflections. The same transmitting transducer captures these scattered impulses and uses them to create an image. However, because to the size and characteristics of red blood cells, the intrinsic scattering from the blood pool is often several orders of magnitude lower than tissue at standard diagnostic frequencies (1–9 MHz). As a result, blood appears black on typical ultrasound images, making it difficult to determine the properties of blood flow. Doppler techniques can be used to measure blood velocity in bigger veins by comparing the relative motion of red blood cells to the surrounding tissue. 8 , 9 This technique is frequently used in clinical settings ( e.g. , obstetrics, 10 assessment of peripheral artery disease, 11 cardiology 12 ). However, this method has drawbacks when applied to areas with poor blood flow, significant tissue motion, and/or low hematocrit percentage. 13 – 15 Ultrasound imaging’s diagnostic applications have significantly expanded during the past few decades. The advancement of UCM has resulted in the presentation of valuable physiological and pathological information, as well as the accessibility of perfusion imaging for cardiac or tumor tissue in routine clinical decision-making. 16 , 17 The early 1960s saw the first reports of the ultrasonic contrast effect was studies by Joyner. Further research revealed the existence of UCM made of saline, indocyanine green, hydrogen peroxide, dextrose, and renografin. 16 , 18 UCM comprise of a suspension of small spheres of gas with a poor solubility in blood ( e.g. , perfluorocarbon), often ranging in size from below 10 μm in diameter. The relatively large size of UCMs guarantees that they remain strictly intravascular and function as red blood cell tracers, in contrast to contrast media employed in other modalities like (magnetic resonance imaging) MRI and computer tomography (CT). 19 Around 1980, achieving stability long enough for the UCM to reach the correct heart was one of the primary objectives in creating efficient UCMs. Left heart contrast was not possible until the 1990s because lung capillaries are effective filters. In 1995, contrast-enhancing substances with enhanced blood pool enhancement capabilities first surfaced. The next goal was to create bubbles that would allow for real-time imaging. In order to achieve this, air was substituted with weakly soluble gases, such as perfluorocarbons, which increased bubble endurance and allowed the development of software algorithms that could effectively distinguish UCM from tissue signals. 20 – 23 Microbubbles vibrate about their equilibrium radius in an ultrasonic field due to the compressibility of their gas cores, and they have scattering cross-sections that are many orders of magnitude higher than a solid particle of the same size. 16 , 24 , 25 A thin biocompatible encapsulation layer, often a phospholipid monolayer, stabilizes the bubbles by striking a balance between their ability to vibrate freely and their resistance to dissolving in-vivo during timeframes important for imaging, like half-lives of minutes. 26 , 27 Contrast echocardiography has a virtually limitless potential. Contrast echocardiography is currently the subject of extensive interest and research, as this review demonstrates. The creation of novel contrast-producing chemicals is arguably the most intriguing component of this research. It will be fascinating to watch how these different agents grow. Ideally, one or more of these novel agents will be able to cross the capillaries, allowing for peripheral venous injection-based visualization of the left side of the heart. Emerging technique Over the world, contrast-enhanced ultrasound imaging is used in numerous medical and off-label applications. On multiple fronts, including the creation of novel pulse sequences and image processing techniques, the development of devices, and the creation of remote monitoring for ultrasonic therapies, this field is seeing cutting-edge breakthroughs at the same time. Contrast media The only UCM that has received clinical approval is microbubbles. These bubbles have the advantage of remaining intravascular because of their size, making it possible to perform diagnostic tests that would be challenging with diffusible tracers. The use of these “conventional” UCM is being expanded, though, to include molecular-based imaging, imaging of the extravascular space, and as a platform for both imaging and therapeutic administration. 28 – 32 Creation of the “optimal” UCM Extensive study was done beginning in 1980 to establish contrast echocardiography as a recognized diagnostic method. 33 Ophir and Parker (1989) provided a summary of UCM’s application in medical imaging. 34 Free gas bubbles, encapsulated gas bubbles, colloidal suspensions, emulsions, and aqueous solutions were the five categories of agents that were categorized according to their physical characteristics. Producing the “perfect” contrast media that would satisfy the following requirements was still a major difficulty in those days. Such as, distribution of the substance inside the myocardial or heart chambers, which is indicative of regional blood flow; agent’s capacity to endure after an intravenous infusion during an imaging test; containing microbubbles with a diameter of less than 8 mm (smaller than red blood cells), allowing passage via the pulmonary system and the body’s smallest capillaries; good safety profile, physiological inert; and strong, regulated, and echogenic acoustic interaction. Synthesis of functionalized microbubbles In 1984 (Feinstein et al. 1984), cavitation was used to create microbubbles after inserting the tip of a sonicator horn into a solution of human serum albumin. 17 This solved the problem of creating stable encapsulated microbubbles that could survive passage through the heart and the pulmonary capillary network. After a peripheral venous injection, these microbubbles could be seen in the left heart. Due to the creation of functionalized microbubbles, 35 or microbubbles with one or more targeted moieties inserted into the phospholipid encapsulation, 36 non-invasive imaging of pathophysiological events has recently been demonstrated to be viable with ultrasound. Target sites have focused on internal vasculature processes such inflammation, 37 angiogenesis, 38 and thrombus formation 39 since microbubbles are purely intravascular. See Table 1 . Table 1. Lists the most popular microbubble-based intravenous UCM at various stages of development. 40 Trademark name Manufacturer Formulations Bisphere Point Biomedical Albumin/air Echogen Sonus Pharmaceuticals Surfactant Echovist Schering AG Galactose/air Optison Amersham Health Inc. Protein-type A/perfluoropropane The development of the first microbubbles that met the majority of the requirements for an intravenous UCM also sparked intense research by doctors, scientists, and the makers of ultrasound equipment to explain the physical phenomena and apply what they learned to therapeutic settings. There were several technologies looked at to stabilize the microbubbles. For the purpose of lowering surface tension and stabilizing the gas core against quick dissolution, thin shells consisting of protein, polymer, or phospholipids were utilized. Unfortunately, due to the high solubility of air in water, the first-generation agents still had poor stability and relatively short circulation times. By substituting perfluorinated gases with low solubility in water, such as sulphur hexafluoride, perfluoropropane, or perfluorobutane for air during circulation, persistence during circulation was dramatically improved, resulting in sufficient persistence of the agent in the blood circulation for clinical use. 41 There are many ultrasound-sensitive sub-micron agents currently being researched. This research is motivated by the enhanced-permeability and retention effect, 42 whereby small nanometer sized particles locally extravasate from leaky blood vessels and accumulate in the perivascular space of solid tumors. Phase-shift droplets, 43 nanobubbles, 44 gas vesicles, 45 echogenic liposomes, 46 and polymeric nanoparticles 47 are a few of the more common examples. Although research into the physics of acoustic droplet vaporization is still ongoing, it is most probable that both intrinsic and external elements play a role in the process. Ultrasound imaging techniques using UCM Vibrating microbubbles’ nonlinear nature is essential to their efficiency as an ultrasonic contrast agent. These emissions allow for the separation of bubble signals from the surrounding (about linear) tissue from those within tiny vessels. Thus, certain microbubble imaging modes were created concurrently with the advancements in UCM and as a result of a better knowledge of non-linear microbubble behavior; these are now used in the majority of clinical ultrasound systems. 48 – 50 The first methods of bubble identification were harmonic imaging, which involved gathering and filtering energy from the receive signal at the second harmonic, which is twice the driving frequency. Because the second harmonic signal produced by microbubbles is substantially greater than the second harmonic signal produced by tissue, it has a higher signal-to-noise ratio than the fundamental energy. The success of low mechanical index (MI) (0.1) contrast-specific imaging, which is primarily employed for real-time perfusion and intra-cavitary measurements, is particularly explained by the non-linear shell behavior. Furthermore, a number of diagnostic imaging procedures and/or quantification strategies are founded on the distinct and extremely sensitive attribute of microbubble destruction. 51 See Figure 1 . Figure 1. Microbubble-specific imaging sequences capture the nonlinear signal from the contrast agent while excluding tissue with linear scattering. Pulse inversion diagram (A). Two 180-degree pulses produce tissue echoes that are out of phase. Microbubbles are nonlinear; hence, this is not true. Microbubbles produce a strong echo, while linear tissue almost totally cancels it off. B-mode and contrast-specific imaging of an 8-mm artery phantom exhibit microbubble-specific imaging's improved vascular contrast. The Philips iU22 scanner, C5-2 probe, and DefinityTM contrast medium were used to record this. This source provides this number. Microbubble-specific imaging sequences exclude linear scattering tissue and capture a nonlinear contrast agent signal. Yusefi, H., & Helfield, B. (2022), https://www.frontiersin.org/files/Articles/791145/fphy-10-791145-HTML/image_m/fphy-10-791145-g002.jpg , CC BY 4.0. 28 In other words, the reflection pattern from the bubble to the ultrasound signal is significantly altered by UCM. They start by greatly boosting the backscattered signal. 23 UCM resonate linearly in response to acoustic pressure. Acoustic pressure increases cause nonlinear vibrational patterns to manifest. 52 Only at higher mechanical indices (MI) do tissues create harmonic resonances, making it easy to distinguish between the signal’s tissue or UCM origin. Multiples of the natural frequencies are received using filter devices, allowing for some background (non-UCM) signal reduction. Microbubbles are disrupted by high pressure levels, which results in strong signals and signals with various properties. M-mode echocardiograms using UCM Understanding the interaction between ultrasonic waves and gaseous microbubbles was made much easier by using the process utilized to explain the set of echoes first discovered on M-mode echocardiograms. The strong compressibility of the gas core appears to be particularly significant since it produces frequency-dependent volume pulsations with a clear maximum at the resonance frequency, which is inversely proportional to the size of the microbubbles. 24 , 53 However, In the following circumstances, UCM is advised by cardiologic guidelines: if the left ventricular (LV) cavum does not have two continuous segments, If the original spectrum signals are insufficient, to enhance Doppler evaluations, when periodic evaluation of the ejection fraction is necessary given the reduced variability caused by UCM, and in the case of Takotsubo myopathy, left ventricular (LV) aneurysms, and intracavitary thrombi. 52 , 54 , 55 Microbubbles-based color Doppler ultrasound Acoustic color Doppler is an imaging method that overlays color-coded maps of tissue velocity on grey-scale images of tissue anatomy. It combines anatomical information acquired from ultrasonic pulse-echo techniques with velocity information derived from ultrasonic Doppler techniques. The technique is most frequently used to visualize blood flow through the heart, arteries, and veins, but it can also be used to visualize the movements of solid tissues like the walls of the heart. vectors. Almost all commercial ultrasound equipment now provides color Doppler imaging, which has been proven to be very useful in determining blood flow in a variety of clinical circumstances. Although the technique for getting velocity information is quite similar to the technique for getting anatomical information, there are a number of reasons why it is technically more difficult. It also has a few flaws, the biggest of which is that, in conventional systems, the velocities measured and subsequently displayed are the components of the flow velocity directly towards or away from the transducer, whereas the method’s ideal output would provide data on the magnitude and direction of the three-dimensional flow vectors. 56 – 61 In conjunction with color or power Doppler, stimulated acoustic emission is employed in high mechanical index (MI) imaging. A high MI ultrasound impulse is used to deflate the microbubbles, and the signal that is received is a complicated mixture of ultrasound waves that causes a Doppler shift. 62 It is especially helpful when a UCM with tissue specificity, is in its late stages. 20 Color Doppler imaging has been shown that despite the poor spatial resolution, real-time imaging was possible due to the tiny size of the picture window. 63 Recently, the use of ultrasound color Doppler has been shown to monitor bubbles during ultrasound therapy. An active ultrasound imaging method called color Doppler uses the phase shifts between the echoes of imaging pulses to measure velocities. In the aforementioned investigation, an increase in the color Doppler signal was connected with the formation of cavitation bubbles on their own under a high-pressure ultrasonic beam. The rise was utilized to evaluate tissue fractionation and was related to the mobility of the surrounding tissue brought on by cavitation within the focused location. Although this method is helpful for high-pressure therapy, it does not reveal how net bubbles flow through the field. 64 , 65 Modern commercial UCM All currently marketed UCM are made up of an inert gas enclosed in a shell. The gas determines solubility and most of the acoustic qualities of the bubbles, while the shell mostly affects the viscoelastic properties, such as stability and durability. 66 Perfluorocarbon bubbles, which range in size almost 10 m and are real blood pool agents, allow transit through the pulmonary vascular system, which is necessary for entry to the systemic circulation. 52 Soft shell materials have better nonlinear oscillations and are made of phospholipids or other surfactants. 67 There are also protein-shelled microbubbles that contain an albumin shell around perfluoropropane gas. Conclusion Contrast agent microbubble vibration basics and its applications in common contrast-imaging are outlined in this paper. Over the span of the last fifty years, UCM imaging has made substantial progress. Previously, the primary clinical emphasis was on echocardiography, while myocardial perfusion was considered the ultimate goal and an attractive market for contrast echo. The primary purpose of echocardiography was to enhance the visibility of the LV by making it more opaque, hence improving the clarity of the LV endocardial border. UCM imaging is a safe and effective method for many clinical applications, and its use is growing. Due to increased clinical awareness of ultrasound’s advantages as well as collaborative research projects between physicists, chemists, engineers, and clinicians on the study of microbubble behavior, signal processing methods, contrast agent synthesis, and device development, this imaging technology has achieved tremendous success to date. Data availability Underlying data No data are associated with this article. References 1. Oglat AA, et al. : A review of medical doppler ultrasonography of blood flow in general and especially in common carotid artery. J Med Ultrasound. 2018; 26 (1): 3–13. PubMed Abstract | Publisher Full Text | Free Full Text 2. Oglat AA, et al. : A new scatter particle and mixture fluid for preparing blood mimicking fluid for wall-less flow phantom. J Med Ultrasound. 2018; 26 (3): 134–142. PubMed Abstract | Publisher Full Text | Free Full Text 3. Ammar AO, et al. : Characterization and construction of a robust and elastic wall-less flow phantom for high pressure flow rate using Doppler ultrasound applications. Nat Eng Sci. 2018; 3 (3): 359–377. Publisher Full Text 4. Oglat AA, et al. : Artifacts in diagnostic ultrasonography. Los Angeles, CA: SAGE Publications Sage CA; 2020. 5. Shalbi SM, et al. : A brief review for common doppler ultrasound flow phantoms. J Med Ultrasound. 2020; 28 (3): 138–142. PubMed Abstract | Publisher Full Text 6. Dakok KK, et al. : A review of carotid artery phantoms for doppler ultrasound applications. J Med Ultrasound. 2021; 29 (3): 157–166. PubMed Abstract | Publisher Full Text 7. Athamnah SI, et al. : Diagnostice breast elastography estimation from doppler imaging using central difference (CD) and least-squares (LS) algorithms. Biomedical Signal Processing and Control. 2021; 68 : 102667. Publisher Full Text 8. Oglat AA, Dheyab MA: Performance evaluation of ultrasonic imaging system (Part I). J Med Ultrasound. 2021; 29 (4): 258–263. PubMed Abstract | Publisher Full Text | Free Full Text 9. Oglat AAJB: Performance Evaluation of an Ultrasonic Imaging System Using Tissue-Mimicking Phantoms for Quality Assurance. Biomimetics. 2022; 7 (3): 130. PubMed Abstract | Publisher Full Text | Free Full Text 10. Mone F, et al. : The clinical application of Doppler ultrasound in obstetrics. Obstet Gynaecol. 2015; 17 (1): 13–19. Publisher Full Text 11. Grant EG, et al. : Carotid artery stenosis: gray-scale and Doppler US diagnosis—Society of Radiologists in Ultrasound Consensus Conference. Radiology. 2003; 229 (2): 340–346. PubMed Abstract | Publisher Full Text 12. Quiñones MA, et al. : Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr. 2002; 15 (2): 167–184. PubMed Abstract | Publisher Full Text 13. Cobbold RS: Foundations of biomedical ultrasound. Oxford University Press; 2006. 14. Jensen JA: Estimation of blood velocities using ultrasound: a signal processing approach. Cambridge University Press; 1996. 15. Szabo TL: Diagnostic ultrasound imaging: inside out. Academic Press; 2004. 16. Gramiak R, Shah PM: Echocardiography of the aortic root. Investig Radiol. 1968; 3 (5): 356–366. Publisher Full Text 17. Feinstein SB, et al. : Microbubble dynamics visualized in the intact capillary circulation. J Am Coll Cardiol. 1984; 4 (3): 595–600. PubMed Abstract | Publisher Full Text 18. Forsberg F, et al. : Effect of filling gases on the backscatter from contrast microbubbles: theory and in vivo measurements. Ultrasound Med Biol. 1999; 25 (8): 1203–1211. Publisher Full Text 19. Becher H, Burns PN: Handbook of contrast echocardiography: Left ventricular function and myocardial perfusion. Springer Science & Business Media; 2012. 20. Cosgrove D: Ultrasound contrast agents: an overview. Eur J Radiol. 2006; 60 (3): 324–330. Publisher Full Text 21. Goldberg BB, et al. : Ultrasound contrast agents: a review. Ultrasound Med Biol. 1994; 20 (4): 319–333. Publisher Full Text 22. Ignee A, et al. : Ultrasound contrast agents. Endosc Ultrasound. 2016; 5 (6): 355–362. PubMed Abstract | Publisher Full Text | Free Full Text 23. Calliada F, et al. : Ultrasound contrast agents: basic principles. Eur J Radiol. 1998; 27 : S157–S160. Publisher Full Text 24. Medwin HJU: Counting bubbles acoustically: a review. Ultrasonics. 1977; 15 (1): 7–13. Publisher Full Text 25. Covella M, et al. : Echocardiographic aortic root dilatation in hypertensive patients: a systematic review and meta-analysis. J Hypertens. 2014; 32 (10): 1928–1935. Publisher Full Text 26. Unger EC, et al. : Therapeutic applications of lipid-coated microbubbles. Adv Drug Deliv Rev. 2004; 56 (9): 1291–1314. PubMed Abstract | Publisher Full Text 27. Garg S, Thomas A, Borden M: The Effect of Lipid Monolayer In-Plane Rigidity on. Vivo; 2013. 28. Yusefi H, Helfield B: Ultrasound contrast imaging: Fundamentals and emerging technology. Front Phys. 2022; 10 : 100. Publisher Full Text 29. Frinking PJ, et al. : Ultrasound contrast imaging: current and new potential methods. Ultrasound Med Biol. 2000; 26 (6): 965–975. PubMed Abstract | Publisher Full Text 30. Averkiou M, et al. : Ultrasound contrast imaging research. Ultrasound Q. 2003; 19 (1): 27–37. Publisher Full Text 31. Correas J-M, et al. : Ultrasound contrast agents: properties, principles of action, tolerance, and artifacts. Eur Radiol. 2001; 11 : 1316–1328. PubMed Abstract | Publisher Full Text 32. Sofuni A, et al. : Differential diagnosis of pancreatic tumors using ultrasound contrast imaging. J Gastroenterol. 2005; 40 : 518–525. Publisher Full Text 33. Senior R, et al. : Clinical practice of contrast echocardiography: recommendation by the European Association of Cardiovascular Imaging (EACVI) 2017. Eur Heart J Cardiovasc Imaging. 2017; 18 (11): 1205–1205af. PubMed Abstract | Publisher Full Text 34. Ophir J, Parker KJ: Contrast agents in diagnostic ultrasound. Ultrasound Med Biol. 1989; 15 (4): 319–333. Publisher Full Text 35. Lindner JR: Microbubbles in medical imaging: current applications and future directions. Nat Rev Drug Discov. 2004; 3 (6): 527–533. PubMed Abstract | Publisher Full Text 36. Langeveld SA, Meijlink B, Kooiman K: Phospholipid-coated targeted microbubbles for ultrasound molecular imaging and therapy. Curr Opin Chem Biol. 2021; 63 : 171–179. PubMed Abstract | Publisher Full Text 37. Wang Y, et al. : Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial: one-year outcomes. Circulation. 2015; 132 (1): 40–46. Publisher Full Text 38. Willmann JK, et al. : Targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with contrast microbubbles conjugated to integrin-binding knottin peptides. J Nucl Med. 2010; 51 (3): 433–440. PubMed Abstract | Publisher Full Text | Free Full Text 39. Hamilton AJ, et al. : Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol. 2004; 43 (3): 453–460. PubMed Abstract | Publisher Full Text 40. Frinking P, et al. : Three decades of ultrasound contrast agents: a review of the past, present and future improvements. Ultrasound Med Biol. 2020; 46 (4): 892–908. PubMed Abstract | Publisher Full Text 41. Schneider M, et al. : BR1: a new ultrasonographic contrast agent based on sulfur hexafluoride-filled microbubbles. Investig Radiol. 1995; 30 (8): 451–457. PubMed Abstract | Publisher Full Text 42. Matsumura Y, Maeda H: A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986; 46 (12_Part_1): 6387–6392. 43. Sheeran PS, Dayton PA: Phase-change contrast agents for imaging and therapy. Curr Pharm Des. 2012; 18 (15): 2152–2165. PubMed Abstract | Publisher Full Text | Free Full Text 44. Helfield B, Zou Y, Matsuura N: Acoustically-stimulated nanobubbles: opportunities in medical ultrasound imaging and therapy. Front Phys. 2021; 9 : 654374. Publisher Full Text 45. Shapiro MG, et al. : Biogenic gas nanostructures as ultrasonic molecular reporters. Nat Nanotechnol. 2014; 9 (4): 311–316. PubMed Abstract | Publisher Full Text | Free Full Text 46. Kopechek JA, et al. : Acoustic characterization of echogenic liposomes: Frequency-dependent attenuation and backscatter. J Acoust Soc Am. 2011; 130 (5): 3472–3481. Publisher Full Text 47. Kwan JJ, et al. : Ultrasound-propelled nanocups for drug delivery. Small. 2015; 11 (39): 5305–5314. PubMed Abstract | Publisher Full Text | Free Full Text 48. Burns PJCR: Harmonic imaging: principles and preliminary results. Clin Radiol. 1996; 51 : 50–55. 49. Wei K, et al. : Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation. 1998; 97 (5): 473–483. PubMed Abstract | Publisher Full Text 50. Averkiou MA, et al. : Imaging methods for ultrasound contrast agents. Ultrasound Med Biol. 2020; 46 (3): 498–517. Publisher Full Text 51. Albrecht T, et al. : Improved detection of hepatic metastases with pulse-inversion US during the liver-specific phase of SHU 508A: multicenter study. Radiology. 2003; 227 (2): 361–370. PubMed Abstract | Publisher Full Text 52. Appis AW, et al. : Update on the safety and efficacy of commercial ultrasound contrast agents in cardiac applications. Echo Res Pract. 2015; 2 (2): R55–R62. PubMed Abstract | Publisher Full Text | Free Full Text 53. Hu Y-Z, et al. : Ultrasound microbubble contrast agents: application to therapy for peripheral vascular disease. Adv Ther. 2009; 26 : 425–434. PubMed Abstract | Publisher Full Text 54. Albrecht T, et al. : Comparison of bolus and infusion of the ultrasound contrast media levovist for color doppler ultrasound of renal arteries. Rofo. 2000; 172 (10): 824–829. PubMed Abstract | Publisher Full Text 55. Porter TR, et al. : Guidelines for the cardiac sonographer in the performance of contrast echocardiography: a focused update from the American Society of Echocardiography. J Am Soc Echocardiogr. 2014; 27 (8): 797–810. PubMed Abstract | Publisher Full Text 56. Arning C, et al. : Revision of DEGUM ultrasound criteria for grading internal carotid artery stenoses and transfer to NASCET measurement. Ultraschall Med. 2010; 31 (3): 251–257. Publisher Full Text 57. Udesen J, et al. : Examples of in vivo blood vector velocity estimation. Ultrasound Med Biol. 2007; 33 (4): 541–548. PubMed Abstract | Publisher Full Text 58. Thalhammer C, et al. : Colour-coded duplex sonography after renal transplantation. Ultraschall Med. 2007; 28 (1): 6–27. quiz 25. Publisher Full Text 59. Parikh S, Shah R, Kapoor P: Portal vein thrombosis. Am J Med. 2010; 123 (2): 111–119. Publisher Full Text 60. Baik SKJLI: Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review. Liver Int. 2010; 30 (10): 1403–1413. Publisher Full Text 61. Whittingham TA: Medical diagnostic applications and sources. Prog Biophys Mol Biol. 2007; 93 (1-3): 84–110. Publisher Full Text 62. Albrecht T, et al. : Stimulated acoustic emissions with the ultrasound contrast medium levovist: a clinically useful contrast effect with liver-specific properties. Rofo. 2000; 172 (1): 61–67. PubMed Abstract | Publisher Full Text 63. Dietrich CF, et al. : Improved differentiation of pancreatic tumors using contrast-enhanced endoscopic ultrasound. Clin Gastroenterol Hepatol. 2008; 6 (5): 590–597.e1. Publisher Full Text 64. Zhang X, et al. : Real-time feedback of histotripsy thrombolysis using bubble-induced color Doppler. Ultrasound Med Biol. 2015; 41 (5): 1386–1401. PubMed Abstract | Publisher Full Text | Free Full Text 65. Evans DH, Jensen JA, Nielsen MB: Ultrasonic colour Doppler imaging. Interface Focus. 2011; 1 (4): 490–502. PubMed Abstract | Publisher Full Text | Free Full Text 66. Paefgen V, Doleschel D, Kiessling F: Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery. Front Pharmacol. 2015; 6 : 197. Publisher Full Text 67. Leong-Poi H, et al. : Influence of microbubble shell properties on ultrasound signal: Implications for low-power perfusion imaging. J Am Soc Echocardiogr. 2002; 15 (10): 1269–1276. PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 07 Nov 2023 ADD YOUR COMMENT Comment Author details Author details Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, Zarqa Governorate, 13133, Jordan Ammar A. Oglat Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 04 Jun 2024, 12:1444 https://doi.org/10.12688/f1000research.140131.3 version 2 Revised Published: 11 Mar 2024, 12:1444 https://doi.org/10.12688/f1000research.140131.2 version 1 Published: 07 Nov 2023, 12:1444 https://doi.org/10.12688/f1000research.140131.1 Copyright © 2024 Oglat AA. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Oglat AA. A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.12688/f1000research.140131.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 11 Mar 2024 Revised Views 0 Cite How to cite this report: Alewaidat H. Reviewer Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.163423.r254669 ) The direct URL for this report is: https://f1000research.com/articles/12-1444/v2#referee-response-254669 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 May 2024 Haytham Alewaidat , Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan Approved VIEWS 0 https://doi.org/10.5256/f1000research.163423.r254669 This review shows An ideal contrast medium for echography should be nontoxic, capable of being injected intravenously, able to travel through pulmonary, cardiac, and capillary circulations, and stable for recirculation The comments are below: The author mentioned each detail ... Continue reading READ ALL This review shows An ideal contrast medium for echography should be nontoxic, capable of being injected intravenously, able to travel through pulmonary, cardiac, and capillary circulations, and stable for recirculation The comments are below: The author mentioned each detail about the contrast media used in ultrasound, such as the composition, applications, stability, currently commercially available ultrasound contrast agents, and ultrasound contrast agent imaging. Examples of current commercial contrast media include Definity, Optison, Sonazoid, and SonoVue, which have demonstrated potential for various clinical purposes, both on- and off-label. Please check the grammatical and typo errors in all manuscript sections. The contents of this review reflects an excellent scientific subject. Please note that the conclusion part requires a small correction. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Medical Imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Alewaidat H. Reviewer Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.163423.r254669 ) The direct URL for this report is: https://f1000research.com/articles/12-1444/v2#referee-response-254669 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Jun 2024 Ammar A. Oglat , Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, 13133, Jordan 10 Jun 2024 Author Response Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to ... Continue reading Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: Please check the grammatical and typo errors in all manuscript sections. Answer: Esteemed reviewer, Thank you for your helpful comments. Noted and done. The contents of this review reflects an excellent scientific subject. Answer: Thank you for your valuable scientific comments. Please note that the conclusion part requires a small correction. Answer: Noted and done. A major correction of conclusion part is done. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: Please check the grammatical and typo errors in all manuscript sections. Answer: Esteemed reviewer, Thank you for your helpful comments. Noted and done. The contents of this review reflects an excellent scientific subject. Answer: Thank you for your valuable scientific comments. Please note that the conclusion part requires a small correction. Answer: Noted and done. A major correction of conclusion part is done. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Competing Interests: competing interests : None Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Jun 2024 Ammar A. Oglat , Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, 13133, Jordan 10 Jun 2024 Author Response Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to ... Continue reading Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: Please check the grammatical and typo errors in all manuscript sections. Answer: Esteemed reviewer, Thank you for your helpful comments. Noted and done. The contents of this review reflects an excellent scientific subject. Answer: Thank you for your valuable scientific comments. Please note that the conclusion part requires a small correction. Answer: Noted and done. A major correction of conclusion part is done. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: Please check the grammatical and typo errors in all manuscript sections. Answer: Esteemed reviewer, Thank you for your helpful comments. Noted and done. The contents of this review reflects an excellent scientific subject. Answer: Thank you for your valuable scientific comments. Please note that the conclusion part requires a small correction. Answer: Noted and done. A major correction of conclusion part is done. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Competing Interests: competing interests : None Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Abu Mhanna HY. Reviewer Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.163423.r254568 ) The direct URL for this report is: https://f1000research.com/articles/12-1444/v2#referee-response-254568 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 27 Mar 2024 Hamad Yahia Abu Mhanna , Universiti Sains Malaysia, Minden Heights, Pulau Pinang, Malaysia Approved VIEWS 0 https://doi.org/10.5256/f1000research.163423.r254568 I agree with ... Continue reading READ ALL I agree with all modifications made by the authors Competing Interests: No competing interests were disclosed. Reviewer Expertise: Medical Imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Abu Mhanna HY. Reviewer Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.163423.r254568 ) The direct URL for this report is: https://f1000research.com/articles/12-1444/v2#referee-response-254568 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 07 Nov 2023 Views 0 Cite How to cite this report: Abu Mhanna HY. Reviewer Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.153460.r248551 ) The direct URL for this report is: https://f1000research.com/articles/12-1444/v1#referee-response-248551 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 05 Mar 2024 Hamad Yahia Abu Mhanna , Universiti Sains Malaysia, Minden Heights, Pulau Pinang, Malaysia Approved VIEWS 0 https://doi.org/10.5256/f1000research.153460.r248551 Minor comments: The title is accurately representing the content of the article. Kindly make the contribution of this review clearer in the abstract section. In the abstract section, please rephrase ... Continue reading READ ALL Minor comments: The title is accurately representing the content of the article. Kindly make the contribution of this review clearer in the abstract section. In the abstract section, please rephrase most of the sentences using academic language. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Some of grammatical errors in the conclusion section need correction. Number of references is enough for this manuscript. Good Make sure that all sentences are linked together and all values in this study are true. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Medical Imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Abu Mhanna HY. Reviewer Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.153460.r248551 ) The direct URL for this report is: https://f1000research.com/articles/12-1444/v1#referee-response-248551 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 04 Apr 2024 Ammar A. Oglat , Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, 13133, Jordan 04 Apr 2024 Author Response Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to ... Continue reading Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: The title is accurately representing the content of the article. Answer: Esteemed reviewer, Thank you for your helpful comments. Yes, I tried to make the title comprehensive to cover all the manuscript content. Kindly make the contribution of this review clearer in the abstract section. Answer: The mentioned comment is corrected. The whole abstract is modified and the contribution of this review is simplify and clarify. In the abstract section, please rephrase most of the sentences using academic language. Answer: The abstract section is modified and rephrased to be in a good scientific manner. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. Answer: Noted and done. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Answer: Yes. The caption is modified and shortened. Some of grammatical errors in the conclusion section need correction. Answer: Ok. Noted and the conclusion is edited. Number of references is enough for this manuscript. Good Answer: Thank you very much for your valuable comments and scientific support. Make sure that all sentences are linked together and all values in this study are true. Answer: I made a double check if all values in the manuscript again and there is no any error or mistake. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: The title is accurately representing the content of the article. Answer: Esteemed reviewer, Thank you for your helpful comments. Yes, I tried to make the title comprehensive to cover all the manuscript content. Kindly make the contribution of this review clearer in the abstract section. Answer: The mentioned comment is corrected. The whole abstract is modified and the contribution of this review is simplify and clarify. In the abstract section, please rephrase most of the sentences using academic language. Answer: The abstract section is modified and rephrased to be in a good scientific manner. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. Answer: Noted and done. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Answer: Yes. The caption is modified and shortened. Some of grammatical errors in the conclusion section need correction. Answer: Ok. Noted and the conclusion is edited. Number of references is enough for this manuscript. Good Answer: Thank you very much for your valuable comments and scientific support. Make sure that all sentences are linked together and all values in this study are true. Answer: I made a double check if all values in the manuscript again and there is no any error or mistake. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Competing Interests: There is no conflict of interest Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 04 Apr 2024 Ammar A. Oglat , Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, 13133, Jordan 04 Apr 2024 Author Response Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to ... Continue reading Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: The title is accurately representing the content of the article. Answer: Esteemed reviewer, Thank you for your helpful comments. Yes, I tried to make the title comprehensive to cover all the manuscript content. Kindly make the contribution of this review clearer in the abstract section. Answer: The mentioned comment is corrected. The whole abstract is modified and the contribution of this review is simplify and clarify. In the abstract section, please rephrase most of the sentences using academic language. Answer: The abstract section is modified and rephrased to be in a good scientific manner. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. Answer: Noted and done. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Answer: Yes. The caption is modified and shortened. Some of grammatical errors in the conclusion section need correction. Answer: Ok. Noted and the conclusion is edited. Number of references is enough for this manuscript. Good Answer: Thank you very much for your valuable comments and scientific support. Make sure that all sentences are linked together and all values in this study are true. Answer: I made a double check if all values in the manuscript again and there is no any error or mistake. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: The title is accurately representing the content of the article. Answer: Esteemed reviewer, Thank you for your helpful comments. Yes, I tried to make the title comprehensive to cover all the manuscript content. Kindly make the contribution of this review clearer in the abstract section. Answer: The mentioned comment is corrected. The whole abstract is modified and the contribution of this review is simplify and clarify. In the abstract section, please rephrase most of the sentences using academic language. Answer: The abstract section is modified and rephrased to be in a good scientific manner. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. Answer: Noted and done. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Answer: Yes. The caption is modified and shortened. Some of grammatical errors in the conclusion section need correction. Answer: Ok. Noted and the conclusion is edited. Number of references is enough for this manuscript. Good Answer: Thank you very much for your valuable comments and scientific support. Make sure that all sentences are linked together and all values in this study are true. Answer: I made a double check if all values in the manuscript again and there is no any error or mistake. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate Competing Interests: There is no conflict of interest Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 07 Nov 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 3 (revision) 04 Jun 24 Version 2 (revision) 11 Mar 24 read read Version 1 07 Nov 23 read Hamad Yahia Abu Mhanna , Universiti Sains Malaysia, Minden Heights, Malaysia Haytham Alewaidat , Jordan University of Science and Technology, Irbid, Jordan Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Alewaidat H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 May 2024 | for Version 2 Haytham Alewaidat , Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan 0 Views copyright © 2024 Alewaidat H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This review shows An ideal contrast medium for echography should be nontoxic, capable of being injected intravenously, able to travel through pulmonary, cardiac, and capillary circulations, and stable for recirculation The comments are below: The author mentioned each detail about the contrast media used in ultrasound, such as the composition, applications, stability, currently commercially available ultrasound contrast agents, and ultrasound contrast agent imaging. Examples of current commercial contrast media include Definity, Optison, Sonazoid, and SonoVue, which have demonstrated potential for various clinical purposes, both on- and off-label. Please check the grammatical and typo errors in all manuscript sections. The contents of this review reflects an excellent scientific subject. Please note that the conclusion part requires a small correction. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Medical Imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 10 Jun 2024 Ammar A. Oglat, Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, 13133, Jordan Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: Please check the grammatical and typo errors in all manuscript sections. Answer: Esteemed reviewer, Thank you for your helpful comments. Noted and done. The contents of this review reflects an excellent scientific subject. Answer: Thank you for your valuable scientific comments. Please note that the conclusion part requires a small correction. Answer: Noted and done. A major correction of conclusion part is done. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate View more View less Competing Interests competing interests : None reply Respond Report a concern Alewaidat H. Peer Review Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.163423.r254669) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1444/v2#referee-response-254669 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Abu Mhanna H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 27 Mar 2024 | for Version 2 Hamad Yahia Abu Mhanna , Universiti Sains Malaysia, Minden Heights, Pulau Pinang, Malaysia 0 Views copyright © 2024 Abu Mhanna H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I agree with all modifications made by the authors Competing Interests No competing interests were disclosed. Reviewer Expertise Medical Imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Abu Mhanna HY. Peer Review Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.163423.r254568) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1444/v2#referee-response-254568 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Abu Mhanna H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 05 Mar 2024 | for Version 1 Hamad Yahia Abu Mhanna , Universiti Sains Malaysia, Minden Heights, Pulau Pinang, Malaysia 0 Views copyright © 2024 Abu Mhanna H. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Minor comments: The title is accurately representing the content of the article. Kindly make the contribution of this review clearer in the abstract section. In the abstract section, please rephrase most of the sentences using academic language. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Some of grammatical errors in the conclusion section need correction. Number of references is enough for this manuscript. Good Make sure that all sentences are linked together and all values in this study are true. Is the topic of the review discussed comprehensively in the context of the current literature? Yes Are all factual statements correct and adequately supported by citations? Yes Is the review written in accessible language? Yes Are the conclusions drawn appropriate in the context of the current research literature? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Medical Imaging I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 04 Apr 2024 Ammar A. Oglat, Department of Medical Imaging, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan., The Hashemite University, Az-Zarqa, 13133, Jordan Responses to Reviewer’s Comments Title: A review of ultrasound contrast media Dear Editor-in-Chief, The author sincerely appreciates the reviewers’ technical comments and the useful suggestions offered to us to revise our manuscript. My response to reviewers’ comments point by point are listed hereafter. Comments from Reviewer #1: The title is accurately representing the content of the article. Answer: Esteemed reviewer, Thank you for your helpful comments. Yes, I tried to make the title comprehensive to cover all the manuscript content. Kindly make the contribution of this review clearer in the abstract section. Answer: The mentioned comment is corrected. The whole abstract is modified and the contribution of this review is simplify and clarify. In the abstract section, please rephrase most of the sentences using academic language. Answer: The abstract section is modified and rephrased to be in a good scientific manner. The introduction part is written in a thorough and complete manner. However, in the second paragraph, this is a run on sentence and hard to follow. “Throughout the past few decades, ultrasound imaging’s diagnostic uses have greatly increased. The development of UCM has led to the provision of new useful physiologic and pathologic data, and the availability of perfusion imaging of cardiac or tumor tissue for everyday clinical decision-making.” Recommend breaking it up for clarity. Answer: Noted and done. The caption of Figure (1) is too long and make the reader confused. Please rewrite it again in a brief way. Answer: Yes. The caption is modified and shortened. Some of grammatical errors in the conclusion section need correction. Answer: Ok. Noted and the conclusion is edited. Number of references is enough for this manuscript. Good Answer: Thank you very much for your valuable comments and scientific support. Make sure that all sentences are linked together and all values in this study are true. Answer: I made a double check if all values in the manuscript again and there is no any error or mistake. Dear Respected reviewer. Thank you very much for your valuable comments which enhance the manuscript with scientific information. Appreciate View more View less Competing Interests There is no conflict of interest reply Respond Report a concern Abu Mhanna HY. Peer Review Report For: A review of ultrasound contrast media [version 3; peer review: 2 approved] . F1000Research 2024, 12 :1444 ( https://doi.org/10.5256/f1000research.153460.r248551) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1444/v1#referee-response-248551 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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