ICUS Weekly News Monitor 7-8-2016

  1. Journal of Ultrasound in Medicine,  Jul 1, 2016,  Role of Arrival Time Difference Between Lesions and Lung Tissue on Contrast-Enhanced Sonography in the Differential Diagnosis of Subpleural Pulmonary Lesions     Authors:  Jing Bai, MD,  et al
    2.  Journal of the American Society of Echocardiography,  Jul 1,  2016,  Safety and Efficacy of Cardiac Ultrasound Contrast in Children and Adolescents for Resting and Stress Echocardiography     Authors: Shelby Kutty, et al
    3.  ICI Meeting 2016,  Tel Aviv, Israel -- the International Conference for Innovations in Cardiovascular Systems (Heart, Brain and Peripheral Vessels) and High-Tech Life Science Industry
    Journal of Ultrasound in Medicine
    JUM July 1, 2016 vol. 35 no. 7 1523-1532
    Jul 1, 2016
    Role of Arrival Time Difference Between Lesions and Lung Tissue on Contrast-Enhanced Sonography in the Differential Diagnosis of Subpleural Pulmonary Lesions
    Authors:  Jing Bai, MD;  Wei Yang, MD; Song Wang, MD; Rui-Hong Guan, MD;  Hui Zhang, MD;  Jing-Jing Fu, MD; Wei Wu,, MD;  Kun Yan, MD
    Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Ultrasound, Peking University Cancer Hospital and Institute, Beijing, China
    Address correspondence to Wei Yang, MD, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Ultrasound, Peking University Cancer Hospital and Institute, 52 Fucheng Rd, Haidian District, 100142 Beijing, China.
    Objectives—The purpose of this study was to explore the diagnostic value of the arrival time difference between lesions and surrounding lung tissue on contrast-enhanced sonography of subpleural pulmonary lesions.
    Methods—A total of 110 patients with subpleural pulmonary lesions who underwent both conventional and contrast-enhanced sonography and had a definite diagnosis were enrolled. After contrast agent injection, the arrival times in the lesion, lung, and chest wall were recorded. The arrival time differences between various tissues were also calculated.
    Results—Statistical analysis showed a significant difference in the lesion arrival time, the arrival time difference between the lesion and lung, and the arrival time difference between the chest wall and lesion (all P < .001) for benign and malignant lesions. Receiver operating characteristic curve analysis revealed that the optimal diagnostic criterion was the arrival time difference between the lesion and lung, and that the best cutoff point was 2.5 seconds (later arrival signified malignancy). This new diagnostic criterion showed superior diagnostic accuracy (97.1%) compared to conventional diagnostic criteria.
    Conclusions—The individualized diagnostic method based on an arrival time comparison using contrast-enhanced sonography had high diagnostic accuracy (97.1%) with good feasibility and could provide useful diagnostic information for subpleural pulmonary lesions.
    Journal of the American Society of Echocardiography
    July 2016Volume 29, Issue 7, Pages 655–662
    Jul 1,  2016
    Safety and Efficacy of Cardiac Ultrasound Contrast in Children and Adolescents for Resting and Stress Echocardiography
    Authors: Shelby Kutty, MD, FASEcorrespondenceemail, Yunbin Xiao, MD, PhD, Joan Olson, RDCS, Feng Xie, MD, David A. Danford, MD, Christopher C. Erickson, MD, Thomas R. Porter, MD, FASE
    Small pilot studies of ultrasound contrast (UC) echocardiography in children have suggested that it is safe; therefore, larger scale evaluation of safety and efficacy in this population is of particular interest.
    This was a retrospective study (January 2005 to June 2014). Known intracardiac shunt was the only exclusion criterion. UC echocardiography was performed on commercially available ultrasound systems using Definity (3% infusion). When indicated, real-time myocardial contrast echocardiography was performed at rest and stress, with examination of myocardial contrast replenishment, plateau intensity, and wall motion. The primary outcome was short-term safety and efficacy (<24 hours).
    In all, 113 patients (55% male; mean age, 17.8 ± 3 years; age range, 5–21 years) underwent UC echocardiography for left ventricular opacification or stress wall motion and perfusion analysis. Diagnosis categories were congenital heart disease (30%), acquired heart disease (21%), and other (suspected cardiac complications of disease of other organ systems; 49%). Twelve patients (11%) with right ventricular systolic pressures > 40 mm Hg received UC without complications; four of these (33%) had the highest right ventricular–right atrial gradient recorded with ultrasound contrast–enhanced Doppler. Myocardial perfusion and/or UC echocardiography–detected wall motion abnormalities were seen in 13 patients (12%); four had confirmed correlations by angiography or magnetic resonance imaging. There were 13 instances of adverse events or reported symptoms during UC echocardiography. All symptoms and events were transient, all patients completed protocols, and there were no immediate sequelae.
    These data demonstrate the usefulness and safety of UC echocardiography in children and adolescents for a wide variety of indications. UC echocardiography provided myocardial perfusion and wall motion information important in clinical decision making.
    ICI Meeting 2016
    Organizing and Scientific Committee

ICI Meeting 2016, Tel Aviv, Israel – the International Conference for Innovations in Cardiovascular Systems (Heart, Brain and Peripheral Vessels) and High-Tech Life Science Industry will be taking place on December 4-6 2016 in Tel Aviv, Israel.  
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ICUS Weekly News Monitor 7-1-2016

1.  SpringerPlus,  Jun 30, 2016,  Hepatocellular adenoma: comparison between real-time contrast-enhanced ultrasound and dynamic computed tomography     Authors:  Wei Wang, et al
2.  NanoWerk,  Jun 30, 2016,  Graphene coated microbubbles as superior photoacoustic imaging contrast agent     By Michael Berger
DOI: 10.1186/s40064-016-2406-z
Wang, W et al. SpringerPlus (2016) 5: 951. doi:10.1186/s40064-016-2406-z
Jun 30, 2016
Hepatocellular adenoma: comparison between real-time contrast-enhanced ultrasound and dynamic computed tomography
Authors:  Wei Wang, Jin-Ya Liu, Zheng Yang, Yue-Feng Wang, Shun-Li Shen, Feng-Lian Yi, Yang Huang, Er-Jiao Xu, Xiao-Yan Xie, Ming-De Lu, Zhu Wang, Li-Da Chen
To investigate and compare the contrast-enhanced ultrasound (CEUS) features of histologically proven HCA with those of contrast-enhanced computed tomography (CECT).
Eighteen patients with proven hepatic adenoma by pathology were retrospectively selected from the CEUS database. Fourteen of them had undergone liver CECT exams. The basic features on unenhanced imaging and the enhancement level and specific features on contrast-enhanced imaging were retrospectively analyzed, and the differences between CEUS and CECT were compared.
All the HCAs showed hyper-enhancement in the arterial phase. During the portal and late phases, 12 HCAs (12/18, 66.7 %) on CEUS and 11 (11/14, 78.6 %) on CT showed washout. On CEUS, 10 (10/18, 55.5 %) showed centripetal filling in the arterial phase and persistent peripheral rim enhancement. Five of them (61.1 %, 11/18) showed delayed central washout in the portal or late phase. However, on CECT, 2 (14.3 %, 2/14) and 4 (28.6 %, 4/14) HCAs showed persistent enhancement of the peripheral rim and central non-enhancing hemorrhage areas, respectively.
Compared with dynamic CT, CEUS was superior at characterizing specific dynamic features. Considering that it is radiation-free, readily availability and easy to use, CEUS is suggested as the first line imaging tool to diagnose HCA.
Jun 30, 2016
Graphene coated microbubbles as superior photoacoustic imaging contrast agent
By Michael Berger
(Nanowerk Spotlight) Researchers have demonstrated that the coupling of pristine graphene sheets on practically any polymer surface can be accomplished in mild reaction conditions and in aqueous medium. The method leaves intact the 2D planar structure of graphene preserving its original features.
This novel hybrid construct enables in vivo photoacoustic signal enhancement and is a very promising step forward for an implementation of photoacoustic imaging (PAI), a powerful preclinical diagnostic tool.
Imaging and drug delivery based on miniaturized devices are keys in the future of personalized medicine. One of the main issues is the disease detection in the earliest stages. This increases the chance of success of any therapy. PAI is among the imaging methods with the highest resolution and this allows a less invasive way to detect tumors at very early stages. The targeting is key both for a localized diagnostic and to bring a drug focally to the diseased tissue.
The photoacoustic effect, discovered and studied by Bell more than 135 years ago (Nature, "Selenium and the Photophone"), occurs when light hits an absorber and the locally accumulated thermal energy is converted and dissipated in mechanical energy by the emission of ultrasound waves and detected by a transducer.
The light wavelength used in biomedical diagnostics is in the near infrared (NIR) spectral window, where light is less attenuated by the tissue (and water). Endogenous metabolites such as haemoglobin of red blood cells behave in this way.
"This effect is used in photoacoustic imaging (PAI) and it can be enhanced by exogenous devices as for example our hybrid assembly made by the stable coupling of pristine graphene with microbubbles," Gaio Paradossi, a professor in the Dipartimento di Scienze e Tecnologie Chimiche at Università di Roma Tor Vergata, explains to Nanowerk. "The efficiency in the enhancement of the photoacoustic signal makes such device an unprecedented multimodal contrast agent for ultrasound and PAI."
Paradossi and his team just reported in ACS Applied Materials & Interfaces ("Graphene Meets Microbubbles: A Superior Contrast Agent for Photoacoustic Imaging") a proof of concept, tested in vivo, where they fabricated a hybrid injectable device for use as an efficient and versatile photoacoustic contrast agent.
Schematics of the approach. (Reprinted with permission by American Chemical Society)
In their present work, the researchers present a technique to couple pristine graphene with polymer shelled microbubbles. The design is based on poly(vinyl alcohol) (PVA) polymer microbubbles, which are stably coupled to pristine graphene sheets through surfactant moieties covalently bound to the available functional groups on the microbubbles surface.
"At the center of our work is pristine graphene, the intact form of graphene," Paradossi points out. "Most of the applications reported in the literature highlights the use of graphene oxide (GO) or reduced graphene oxide (RGO). These forms of graphene, not directly obtained by graphite exfoliation, derive from chemical modifications of the 2D structure of graphene in very harsh conditions, which introduce kinks and irregularities in the carbonic material."
"Such modifications make GO and RGO more reactive and more processable than pristine graphene, but jeopardize the electrical, optical and mechanical properties of this material," he adds.
In their present work, the researchers present a technique to couple pristine graphene with polymer shelled microbubbles.
"Why polymer shelled microbubbles are such an exotic support for pristine graphene? Microbubbles are the best contrast agents for enhancing ultrasounds and it is a natural choice if ultrasound or photoacoustic imaging are the goals," says Paradossi. "Another important issue pointed out in our paper is the exceptional stability of the coupling to the polymer surface of the microbubbles is an asset for the biocompatibility of graphene."
This work contains several novel elements:
The use of pristine graphene leaves unchanged its relevant properties.
A general strategy for attaching pristine graphene to a large number of hydrophilic polymer surfaces in a stable way using mild conditions and aqueous media.
The assembly of a truly hybrid system where a hydrophobic moiety, i.e. graphene, is coupled with a hydrophilic moiety, i.e. the poly (vinyl alcohol) shelled microbubble, to obtain a novel multifunctional device implementing the potentialities of the photoacoustic imaging.
These results have been a by-product of the work presently carried out within the frame of the European project TheraGlio – Developing theranostics for Gliomas, where the goal is to develop a multimodal imaging system for Theranostics (therapy + diagnosis) of patients bearing malignant glioma, the most common primary brain tumour.
FESEM images of (a) G/PVA 2.5% (w/w), (b) G/PVA 5% (w/w), and (c) G/PVA 10% (w/w); insets, magnified graphene flakes on PVA microbubble shell of the selected zones. The arrows indicate graphene sheets. (Reprinted with permission by American Chemical Society)
The results also build on a method recently developed by Paradossi's group where graphene sheets were stably anchored to PVA hydrogels (The Journal of Physical Chemistry B, "Soft Confinement of Graphene in Hydrogel Matrixes"). This method consists of the ultrasound exfoliation of graphite assisted by a surfactant in aqueous medium followed by the tethering to the polyvinyl alcohol chemical hydrogels via the surfactant functional moieties.
Going forward, the team will address the biocompatibility of their graphene microbubbles; the ability to target pathological cells tissues; and ultrasound assisted drug delivery.
As for the biocompatibility, graphene is anchored to the surface of the PVA shelled microbubble in a stable way and loss of graphenic material was not monitored in physiological media. PVA, is already known as a biocompatible polymer and it was used for the fabrication of echogenic microbubbles with long shelf-life and good chemical versatility (see: Gaio Paradossi “Hydrogels Formed by Cross-linked Poly(vinyl alcohol)” in Polymeric Biomaterials: Structure and Function, Volume 1).
"However, for such hybrid system an increase of biocompatibility should be expected by surface pegylation," says Paradossi. "The chemical versatility of the shell can allow tumor tissues to be targeted by conjugating the peptide sequences as cyclic RGD or hyaluronic acid on the PVA microbubble surface. RGD is known to bind the receptor of αVβ3 integrins, a family of membrane proteins, which is over expressed by tumor cells."
"Analogously, grafting hyaluronic acid, a polysaccharide present in the extracellular matrix of mammals, on the PVA surface is a mean to address the graphene/microbubble device on the receptor of CD44, another membrane protein over expressed by tumor cells."
The microbubbles can also be converted to drug delivery systems by loading drugs directly on the surface by physisorption. Ultrasound can be used to excite the microbubbles – to 'shake' them – and release the drug molecules.
"More sophisticated methods are under study in our lab, consisting in tethering liposomes on the shell containing oligonucleotides cargo which can be transfected upon ultrasound irradiation," Paradossi notes.
In conclusion, anchoring graphene on PVA microbubble surfaces opens the way to leap from the use in small size animals functional imaging to a high resolution clinical diagnostic tool, by combining the appealing features of both PVA microbubble (as efficient ultrasound scatterer) and graphene (as strong NIR absorber with high thermal conductivity).
Copyright © Nanowerk

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.

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