ICUS Weekly News Monitor 6-24-2016

1.  Chemical & Engineering News,  Jun 20, 2016,  Ultrasound implant safely opens blood-brain barrier in patients; New method could help anticancer drugs reach brain tumors
By Michael Torrice
2.  PLOS ONE,  Jun 20, 2016,  Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration     Authors: Donghee Park, et al
Chemical & Engineering News
Volume 94 Issue 25 | p. 6 | News of The Week
Issue Date: June 20, 2016 | Web Date: June 17, 2016
Jun 20, 2016
Ultrasound implant safely opens blood-brain barrier in patients
New method could help anticancer drugs reach brain tumors
By Michael Torrice
The cells lining blood vessels in the brain form tight, tough-to-penetrate junctions that prevent toxic molecules from slipping into the brain.
Unfortunately, this blood-brain barrier also blocks cancer drugs from reaching tumor cells in the brain, creating a significant drug-delivery problem.
Now, preliminary results from a Phase I/II clinical trial suggest that a small implant that emits ultrasound waves can safely open the blood-brain barrier in people, potentially allowing drugs in (Sci. Transl. Med. 2016, DOI: 10.1126/scitranslmed.aaf6086).
Scientists have previously tested ultrasound methods in animals and found that the techniques can aid drug delivery to the brain. These methods often rely on injecting microbubbles—typically fluorinated gases encapsulated in lipid spheres. The sound waves cause these bubbles to expand and compress. That mechanical energy helps loosen the junctions between endothelial cells lining blood vessels.
To translate such a treatment into people, the company CarThera, founded by Alexandre Carpentier, a neurosurgeon at Pitié-Salpêtrière Hospital, in Paris, developed SonoCloud, an 11.5-mm-diameter ultrasound transducer that surgeons can implant in a hole in patients’ skulls. Carpentier envisions a brain-cancer patient receiving such an implant after a tumor biopsy or a surgery to remove parts of a tumor.
In the new study, the team reported data from 15 glioblastoma patients who had received the implant. Before these patients were treated with the cancer drug carboplatin, they received a 2.5-minute ultrasound session.
By using magnetic resonance imaging to watch a gadolinium contrast agent enter the brain, the researchers found that these sessions opened the blood-brain barrier. And the patients didn’t experience adverse effects from the ultrasound—no signs of hemorrhaging, no complaints of pain, and no indications that speech or motor control was disrupted.
CarThera will start a Phase III trial in 2017 to assess how ultrasound treatments can improve chemotherapy for brain cancer patients. Also, Carpentier is interested in determining if the device can help treat Alzheimer’s disease. Some studies in animals suggest that ultrasound can clear out toxic protein plaques from the brain, in part, by temporarily opening the blood-brain barrier.
Nathan McDannold of Harvard Medical School says the clinical trial data are an impressive milestone for the ultrasound therapy field. He is working on similar methods that don’t rely on an implant and instead use an external array of 1,000 ultrasound transducers to focus on a target in the brain. So, he says, although the SonoCloud is more invasive, it is a simpler system.
Jun 20, 2016
Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration
Authors: Donghee Park, Gillsoo Song, Yongjun Jo, Jongho Won, Taeyoon Son, Ohrum Cha, Jinho Kim, Byungjo Jung, Hyunjin Park, Chul-Woo Kim, Jongbum Seo
Donghee Park, Chul-Woo Kim
Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea
Gillsoo Song, Jongho Won, Taeyoon Son, Ohrum Cha, Jinho Kim, Byungjo Jung, Jongbum Seo
Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea
Yongjun Jo
Gumi Electronics & Information Technology Research Institute, Gumi, Gyeongsangbuk-do, Republic of Korea
Hyunjin Park
School of Electronic Electrical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea
Correspondence:  This email address is being protected from spambots. You need JavaScript enabled to view it.
Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the concentration of microbubbles in case stable cavitation is predominant.

ICUS Weekly News Monitor 6-17-2016

  1. Ultraschall in Med 2016,  Jun 8, 2016,  A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA
    Ein Meilenstein: Zulassung von CEUS zur Leberdiagnostik an Erwachsenen und Kindern in den USA     Authors:  K. Seitz, D. Strobe
    2.  American Chemical Society,  Jun 1, 2016,  Enzyme-degradable hybrid polymer/silica microbubbles as ultrasound contrast agents       Authors:  Nadia H Tsao and Elizabeth Anne Howlett Hall
    3.  Journal of the American Society of Echocardiography,  June, 2016,  Detection of Carotid Atherosclerotic Plaque Neovascularization Using Contrast Enhanced Ultrasound: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies      Authors: Runqing Huang, PhD, et al
    4.  Echo Research and Practice,  Jun 1, 2016,  Echo your Work!
    Ultraschall in Med 2016
    37(03): 229-232
    DOI: 10.1055/s-0042-107411
    Jun 8, 2016
    A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA
    Ein Meilenstein: Zulassung von CEUS zur Leberdiagnostik an Erwachsenen und Kindern in den USA
    Authors:  K. Seitz, D. Strobe


The approval of microbubbles with the inert gas sulfur hexafluoride (SF6) and a palmitic acid shell (SonoVue®, Bracco Geneva, CH) for the diagnostic imaging of liver tumors in adults and children by the FDA in the United States represents a milestone for contrast-enhanced ultrasound (CEUS).

This warrants a look back at the history of the development of CEUS. The first publications based on echocardiographic observations of right ventricular contrast phenomena caused by tiny air bubbles following i. v. injection of indocyanine green appeared around 1970 [1] [2] [3]. A longer period of sporadic publications but no real progress then followed since, in contrast to X-ray methods, ultrasound works quite well without a contrast agent.

It is noteworthy that the foundations for further development were primarily laid in Europe. The development and approval (1991) of the contrast agent Echovist® by a German contrast manufacturer for echocardiography unsuitable for passing through lungcapillaries [4] [5] resulted in the first extracardiac indications, e. g. for detecting retrovesical reflux and tubal patency, in the mid-1980 s [6] [7] [8]. The sensitivity of color Doppler was not able to compensate for the lack of an ultrasound contrast agent compared to CT with its obligatory contrast administration.

Studies of SHU 508 – microbubbles of air moderately stabilized with galactose and palmitic acid – began in 1990 [9] [10] [11] [12] [13] [14] [15] and the contrast agent was then introduced in 1995 in Germany as Levovist®. The most important publications by Blomley, Cosgrove, Leen, and Albrecht are named here on a representative basis [16] [17] [18] [19] [20].

SHU 508 along with other US contrast agents provided impressive proof of the superiority of CEUS for the diagnosis of liver metastases. However, practical application remained complicated and required skill and technical know-how because of a lack of suitable software on US units [21] [22] [23] [24] [25]. The monograph regarding the use of contrast agent in the liver by Wermke and Gaßmann is impressive but unfortunately only available in German [26]. In addition to being applied in the heart and the liver, CEUS was first used in transcranial applications [27] and in vessels [28], the kidneys [29], and the breast [30]. Measurements at transit times were also of particular interest [31]. It was difficult to convince ultrasound device manufacturers of the need to adapt US units to US contrast agents and not vice versa.

The breakthrough came with low MI phase contrast inversion and the introduction of SonoVue® in many European countries in 2001. This more stable US contrast agent is easy to use and is becoming indispensable in diagnostic imaging of the liver [32] [33] [34] [35] [36] [37] [38] [39] [40]. Studies have shown its excellent tolerability [41] and diagnostic reliability comparable to that of MDCT and MRI in the liver [42] [43]. Today it would be unimaginable to diagnose liver tumors without CEUS [44]. This also applies to very small lesions [45] [46].

EFSUMB published the first CEUS guidelines in 2004 [47] which have since been reissued and divided into hepatic [48] and extrahepatic applications [49]. The first recommendations regarding quantitative assessment have also been published [50].

The increasing scientific interest in CEUS is evident based on the greater number of PubMed hits for Echovist®(ca. 130), Levovist® (ca. 500) and SonoVue® (ca. 1500) as well as on the fact that publications regarding CEUS comprise almost 20 % of UiM/EJU articles in the last 10 years. The number of CEUS articles in UiM/EJU continues to be high [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75].

In the clinical reality, CEUS has been able to become established alongside CT and MRI according to the saying “better is the enemy of good” [76] as the method of choice after B-mode ultrasound in the evaluation of liver tumor malignancy in Germany, where the technically challenging method is promoted. In the case of unclear CT and MRI findings, CEUS performed by an experienced examiner/clinician often provides the solution, particularly in the case of small lesions, and is the last resort before US-guided biopsy [45] [46]. However, there is a lack of competent CEUS examiners and Germany continues to be the world champion of X-ray examinations with no noticeable reverse trend. In almost every doctor’s office and hospital, ultrasound costs are by far not fully covered, resulting in an extremely high frequency of CT use with CT being available to everyone regardless of insurance status.

The USA is now in the starting position for CEUS. It will be exciting to see how the method will develop there. The FDA’s decision to approve sulfur hexafluoride (Lumason® = SonoVue®) should be considered against the background of the radiation exposure caused by CT examinations and the fact that MRI using gadolinium-containing contrast agents is no longer considered noninvasive because of nephrogenic systemic fibrosis (NSF) and the accumulation of the agent in the cerebrum. An essential point of the campaign regarding the avoidance of diagnostic radiation exposure triggered in the USA by the publications of Brenner et al. [77] [78] was that the agent was approved for use in the liver even for children [79] [80] – still off label in Europe – without additional comprehensive studies due to the available scientific results and the very low side effects profile of Lumason® (= SonoVue®). It is admittedly unclear why other indications (except the heart which has been approved since 2014) are excluded even though the microbubbles as a pure blood pool contrast agent can be diagnostically used in the entire vascular system and bed of all organs. To our knowledge, there is no such restriction on the approval of X-ray contrast agents.

Like echocardiography and emergency ultrasound, CEUS began in Europe but will probably only establish its final diagnostic value as a “reimport”.

This is a major opportunity to permanently define the role of Ultrasound as a highly valuable, patient-centered imaging method in the German health care system.

This may prompt some of our international readers to reflect upon the role of CEUS in their own countries.

American Chemical Society
DOI: 10.1021/acs.langmuir.6b01075
Jun 1, 2016
Enzyme-degradable hybrid polymer/silica microbubbles as ultrasound contrast agents
Authors:  Nadia H Tsao and Elizabeth Anne Howlett Hall
The fabrication of an enzyme-degradable polymer/silica hybrid microbubble is reported that produces an ultrasound contrast image. The polymer, a triethoxysilane end-capped polycaprolactone (SiPCL), is used to incorporate enzyme-degradable components into a silica microbubble synthesis, and to impart increased elasticity for enhanced acoustic responsiveness. Formulations of 75, 85 and 95 wt% SiPCL in the polymer feed, produced quite similar ratios of SiPCL and silica in the final bubble but different surface properties. The data suggest that different regions of the microbubbles were SiPCL-rich: the inner layer next to the polystyrene template core and the outer surface layer, thereby creating a sandwiched silica-rich layer of the bubble shell. Overall, the thickness of the microbubble shell was dependent on the starting TEOS concentration and the reaction time. Despite the layered structure, the microbubble could be efficiently degraded by lipase enzyme, but was stable without enzyme. The ultrasound contrast showed a general trend of increase in image intensity with SiPCL feed ratio, although the 95 wt% SiPCL bubbles did not produce a contrast image, probably due to bubble collapse. At higher normalized peak negative acoustic pressure (mechanical index, MI), a non-linear frequency response also emerges, characterized by the third harmonic at around 3f0, and increases with MI. The threshold MI transition from linear to non-linear response increased with decrease in SiPCL.
Journal of the American Society of Echocardiography
Volume 29, Issue 6, June 2016, Pages 491–502
June, 2016
Detection of Carotid Atherosclerotic Plaque Neovascularization Using Contrast Enhanced Ultrasound: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies
Authors: Runqing Huang, PhDa, d, Sahar S. Abdelmoneim, MB, BCha, Caroline A. Ball, MDb,
Lara F. Nhola, MDa, Ann M. Farrell, MLSc, Steven Feinstein, MDe, Sharon L. Mulvagh, MDa, ,
Intraplaque neovascularization is considered an important indicator of plaque vulnerability. Contrast-enhanced ultrasound (CEUS) of carotid arteries improves imaging of carotid intima-media thickness and permits real-time visualization of neovascularization of the atherosclerotic plaque. The authors conducted a systematic review and meta-analysis to evaluate the accuracy of CEUS-detected carotid atherosclerotic plaque.
A systematic search was performed to identify studies published in the MEDLINE, Embase, Scopus, and Web of Science databases from 2004 to June 2015. Studies evaluating the accuracy of quantitative analysis and qualitative analysis (visual interpretation) for the diagnosis of intraplaque neovascularization compared with histologic specimens and/or clinical diagnosis of symptomatic plaque were included. Parameters evaluated were plaque quantitative CEUS intensity and the visual grading of plaque CEUS. A random-effects meta-analysis was used to pool the likelihood ratios (LRs), diagnostic odds ratios, and summary receiver operating characteristic curves. Corresponding areas under the curves were calculated.
The literature search identified 203 studies, 20 of which were selected for systematic review; the final meta-analysis included seven studies. For qualitative CEUS, pooled sensitivity was 0.80 (95% CI, 0.72–0.87), pooled specificity was 0.83 (95% CI, 0.76–0.89), the pooled positive LR was 3.22 (95% CI, 1.67–6.18), the pooled negative LR was 0.24 (95% CI, 0.09–0.64), the pooled diagnostic odds ratio was 15.57 (95% CI, 4.94–49.03), and area under the curve was 0.894. For quantitative CEUS, pooled sensitivity was 0.77 (95% CI, 0.71–0.83), pooled specificity was 0.68 (95% CI, 0.62–0.73), the pooled positive LR was 2.34 (95% CI, 1.69–3.23), the pooled negative LR was 0.34 (95% CI, 0.25–0.47), the pooled diagnostic odds ratio was 7.06 (95% CI, 3.6–13.82), and area under the curve was 0.888.
CEUS is a promising noninvasive diagnostic modality for detecting intraplaque neovascularization. Standardization of quantitative analysis and visual grading classification is needed to increase reliability and reduce technical heterogeneity.
Echo Research and Practice
Jun 1, 2016
Echo your Work!
Echo Research and Practice is pleased to announce a new service for authors to aid them in increasing the impact of their published papers.
After publication of papers, many resources and tools are freely available to make them discoverable and citabl, and further increase impact. Whilst these tools are available to all, we understand that authors may not have the time to investigate all the available options, or have the specialist knowledge to use them to full advantage.
As such, the journal is offering authors a one-to-one session with a member of the Echo Research and Practice publishing team, to identify ways to quickly maximise the impact of published research.
Register interest now by emailing:  This email address is being protected from spambots. You need JavaScript enabled to view it. .

ICUS Weekly News Monitor 5-6-2016

1.  Dovepress,  May 2, 2016,  The advent of ultrafast ultrasound in vascular imaging: a review
By Mathieu Couade
2.  Reportlinker,  Apr 28, 2016,  Global Microbubbles/Ultrasound Contrast Agents Market Outlook: 2015-2021
May 2, 2016
The advent of ultrafast ultrasound in vascular imaging: a review
By Mathieu Couade
SuperSonic Imagine, Aix en Provence, France
In the last 10 years the advent of computational power and the availability of fully programmable research ultrasound imaging systems have allowed the emergence of ultrafast ultrasound imaging (<1000 frames per second), which has become a central research topic in the ultrasound community. Ultrafast ultrasound imaging relies deeply on the capability of massive parallel beamforming/processing of a single transmit ultrasound event insonifying a large field of view. This ultrafast acquisition capability opens up new tradeoffs in terms of processing and observations of transient rapid phenomena. Firstly, it can be used to improve conventional imaging modes such as B-mode, Doppler modes, Contrast Enhanced Ultrasound in terms of sensitivity, contrast, spatial, and/or temporal resolutions. It can also enrich conventional color flow imaging modes by providing quantitative and synchronous spectral information on the whole image. Secondly it can be used to capture transient phenomena that where unseen with conventional frame rates (<50 Hz) enabling completely novel imaging modes such as real time shear wave elastography (SWE), a technique for mapping quantitatively soft tissue elasticities, or ultrafast PWV, a technique for measuring locally the pulse wave velocity (PWV). In this review, we first introduce the theoretical basis of ultrafast imaging. We then present a state of the art of ultrafast ultrasound imaging in the specific field of arterial wall mechanical properties characterization.
Apr 28, 2016
Global Microbubbles/Ultrasound Contrast Agents Market Outlook: 2015-2021
(full report:
PRNewswire/ -- Microbubbles are composed of gas core stabilized by a shell of proteins, lipids, or polymers and have unique ability to respond to ultrasound, and thus are used as ultrasound contrast agents. The field of ultrasound contrast imaging has been literally bursting in the last decade. Incessant engineering advances in ultrasound technologies over the last decade have resulted in widespread usage of ultrasound for clinical applications.
The potential benefits of ultrasound such as low-cost, convenience, and real-time capability of ultrasound images has led to wide acceptance of this technology. When compared with other imaging modalities, the ultrasound molecular imaging has many advantages such as good temporal resolution, quantitative data, real-time practice, noninvasiveness, relatively inexpensive cost, and no ionizing radiation.
Microbubbles/ ultrasound contrast agents for medical imaging have been swiftly translated from exploratory research to clinical application. It helps to sharpen the image, improve the reliability of the scan and reduce the need for unnecessary downstream testing. In addition, microbubbles can be employed for diagnostic imaging and as a therapeutic tool. These are safe, convenient, completely radiation-free, versatile, and routinely used by physicians throughout the world to obtain a reliable ultrasound diagnosis.
The global microbubbles/ ultrasound contrast agents market is expected to grow at a CAGR of 28.7% to reach $797.5 million by 2021 from 2015. The research report on microbubbles market provides comprehensive analysis of the global market and helps in understanding the driving forces for the growth of this market. The report also provides analysis of major applications such as molecular imaging, gene therapy, drug delivery, and stem cell delivery with their application areas, trends, challenges, and opportunities in this market. In addition, the report analyzes the global microbubbles market by various disease areas such as renal disorder, cardiovascular, and neurology with their drivers, restraints, ongoing research, and future potential.
The market has been segmented by geography as North America, Europe, Asia-Pacific, and Rest of the World (RoW) with a detailed qualitative and quantitative analysis. North America is the major market in the global microbubble market and is expected to dominate this market during the forecast period followed by Europe, and Asia-Pacific.
Lantheus Medical Imaging with its DEFINITY ultrasound contrast imaging agent dominated the global microbubbles/ ultrasound contrast agents market in 2014. The other major players in the global microbubble market include Bracco Imaging S. p. A., Daiichi Sankyo Company, Limited, and GE Healthcare.
Source: Expert Interviews, Government Authorities, Related associations/Institutes, Related Research Publications, Government Publications, Company Press Releases, Company Annual Reports, Company Websites, Company Publications, SEC Filings, Meticulous Research Analysis.

ICUS Sponsors

ICUS gratefully acknowledges its 2017 sponsors:



Toshiba Medical logo resized





Contact ICUS

  • Address: 1900 K Street, N.W.
    Washington, DC 20006-1102, USA
  • Telephone: 202-408-6199

About ICUS

ICUS is the world’s only professional society exclusively devoted to contrast-enhanced ultrasound (CEUS) medical imaging technology.

Learn more...

You are here: Home ICUS Weekly News