ICUS Weekly News Monitor 7-15-2016

1.  Ultraschall in Med 2016,  Jul 1, 2016,  Role of Contrast-Enhanced Ultrasound (CEUS) in Paediatric Practice: An EFSUMB Position Statement       Authors P. S. Sidhu, et al
2.  The Oregonian,  Jun 26, 2016,  OHSU-led study could help NASA's mission to Mars
By Lynne Terry
3.  National Space Biomedical Research Institute (NSBRI),  May 21, 2015,  NASA, NSBRI Select 24 Proposals to Support Crew Health of Astronauts on Deep Space Missions      Media Release
Ultraschall in Med 2016
Published online: 2016 Ultraschall in Med © Georg
Thieme Verlag KG Stuttgart ·New York · ISSN 0172-4614
Jul 1, 2016
Role of Contrast-Enhanced Ultrasound (CEUS) in Paediatric Practice: An EFSUMB Position Statement
Authors:   P. S. Sidhu1, V. Cantisani2, A. Deganello1, C. F. Dietrich3, C. Duran4, D. Franke5, Z. Harkanyi6,W. Kosiak7, V. Miele8, A. Ntoulia1, M. Piskunowicz9, M. E. Sellars1, O. H. Gilja10
Dr. Paul S. Sidhu
Radiology, King's College London, King's College Hospital
Denmark Hill, SE5 9RS London, UK
Tel.: ++ /44/2 03/2 99 41 64;  Fax: ++ 44/2 03/29 91 57
This email address is being protected from spambots. You need JavaScript enabled to view it.
The use of contrast-enhanced ultrasound (CEUS) in adults is well established in many different areas, with a number of current applications deemed “off-label”, but the use supported by clinical experience and evidence. Paediatric CEUS is also an “off-label” application until recently with approval specifically for assessment of focal liver lesions. Nevertheless there is mounting evidence of the usefulness of CEUS in children in many areas, primarily as an imaging technique that reduces exposure to radiation, iodinated contrast medium and the “patient-friendly” circumstances of ultrasonography. This position statement of the European Federation of Societies in Ultrasound and Medicine (EFSUMB) assesses the current status of CEUS applications in children and makes suggestions for further development of this technique.
The Oregonian
Jun 26, 2016
OHSU-led study could help NASA's mission to Mars
By Lynne Terry
Dr. Jonathan Lindner is head of imaging at the Knight Cardiovascular Institute at Oregon Health & Science University. For two decades, he's been looking for ways to identify the susceptibility for cardiovascular disease, in hopes of treating it at its inception.
Oregon cardiologists have hooked up with NASA to find better ways to screen astronauts who will take the next giant leap into space.
The National Aeronautics and Space Administration plans to send astronauts to an asteroid by 2025 and to Mars in the 2030s. But those missions will carry physical risks. In deep space, astronauts face being blasted with cosmic and solar radiation, threatening their cardiovascular systems.
The Oregon team, led by a cardiologist at Oregon Health & Science University, can't control the cosmos. But armed with a grant of nearly $1 million from the National Space Biomedical Research Institute, which works with NASA, they hope to uncover new ways to diagnose cardiovascular problems at an early stage to help astronauts and the rest of us.
"I will guarantee one thing and that is that this process is going to teach us a tremendous amount about how to treat people on Earth," said Dr. Jonathan Lindner, an OHSU cardiologist and lead investigator on the study. "To me, that's the big impact of this project."
Lindner's driving goal – one he's been pursuing for two decades – is to be able to thwart cardiovascular disease by identifying the disease early, when it's the most treatable. Right now, physicians are forced to scramble after symptoms, trying to slow progression of the disease and stem complications.
"There's not a cardiologist out there who has ever cured coronary disease," Lindner said. "We bypass it. We smush it. We stent it. We palliate it with medications. But nobody has ever cured anything."
Cardiologists know from studying the effects of radiation on Earth – from atomic bombs, radiation therapy and nuclear accidents – that it hurts the heart in multiple ways. It damages the muscle so it doesn't beat as well. It hurts the connective tissue, which becomes stiff. And it harms the lining of the blood vessels, which plays a key role in the build-up of plaque.
Atherosclerosis – the hardening of the arteries – can cause heart attacks, strokes and vascular disease.
While man-made radiation poses a risk on Earth, blasts from the sun do not. The planet's magnetic force defects them. But once astronauts leave low Earth orbit – where the International Space Station lives – they're bombarded by solar and cosmic radiation.
NASA can't build spacecraft to protect astronauts from all that radiation, Lindner said. The shielding would make the vessels too unwieldy.
And the threat from radiation can last a lifetime.
"The risk is not just around the time of being radiated," Lindner said. "It's lifelong."
His lab – and researchers at Oregon State University – will use advanced techniques to try to identify markers of cardiovascular disease beyond what's available now to use in the space program.
NASA chooses the fittest candidates who are in outstanding health. But they're picked long before they fly. As the years pass, their health changes, just like the rest of us.
"The reality is that cardiovascular disease is still a significant risk for any human being who's in their 40s, 50s or 60s," said Graham Scott, vice president and chief scientist of the National Space Biomedical Research Institute, which is partnered with NASA. "We would like to be able to detect at the earliest time possible if the cardiovascular status an astronaut is changing."
The idea would be to intervene early, with a drug, exercise regime or something else, to counteract that change.
Any new diagnostics that pass the necessary validation hurdles could even be used while astronauts are in flight or during the selection process.
The study will last two years and include 60 people between 35 and 55 who've undergone an advanced CT scan of the coronary blood vessels. Some might have a little plaque build-up. Others will have clear vessels. But no one admitted to the study will have severe blockage because those people would be excluded from the astronaut program.
Participants will undergo further testing. Researchers will use advanced imaging techniques developed at OHSU to check the health of their blood vessel linings. The endothelium, as its called, determines the susceptibility to developing plaque. It plays a key role in controlling inflammation and in the formation of blood clots.
Endothelial dysfunction is a harbinger of cardiovascular disease.
The final round of testing will involve blood tests. Scientists at OHSU and Oregon State University will analyze each person's blood, looking at their metabolism, genetics and the way their bodies handle lipids. These tests will reveal the "fingerprints" of how each person responds to their environment and offer clues about their susceptibility to disease.
Scientists will compare the tests, looking for connections. Any findings could lead to a new cardiovascular diagnostic test.
New tools will help NASA as it prepares to send men and women to Mars.
"Who are the people who are the most susceptible to atherosclerotic disease? That may help us determine candidacy for the astronaut program to Mars and for other deep space missions," Lindner said.
It could also help cardiologists – and patients -- here on Earth.
Once scientists figure out how heart disease starts, whether it's in response to radiation, a poor diet or inactivity, they'll have a key to preventing its progression and maybe even finding a cure.
National Space Biomedical Research Institute (NSBRI)
May 21, 2015
NASA, NSBRI Select 24 Proposals to Support Crew Health of Astronauts on Deep Space Missions
Media Release
NASA’s Human Research Program (HRP) and the National Space Biomedical Research Institute (NSBRI) will fund 24 proposals to help investigate questions about astronaut health and performance on future deep space exploration missions. The selected proposals will investigate the impact of the space environment on various aspects of astronaut health, including visual impairment, behavioral health, bone loss, cardiovascular alterations, human factors and performance, neurobehavioral and psychosocial factors, sensorimotor adaptation and the development and application of smart medical systems and technologies. All of the selected projects will contribute towards NASA’s future missions to Mars.
The selected studies represent how HRP and NSBRI work together to address the practical problems of spaceflight that impact astronaut health. HRP and NSBRI research provides knowledge and technologies that may improve human health and performance during space exploration. They also develop potential countermeasures for problems experienced during space travel. The organizations’ goals are to help astronauts complete their challenging missions successfully and preserve their long-term health. This applied research will be conducted in laboratory settings as well as ground-analog settings that mimic the spaceflight environment. Selected studies include one by Dr. Gary Strangman, Associate Professor at Massachusetts General Hospital in Boston, who will design, develop, and test a near infrared spectroscopy-electroencephalography system for sleep research in a realistic spaceflight analog environment. Dr. Valerie Meyers, a toxicologist at NASA’s Johnson Space Center in Houston, will examine the effects of carbon dioxide on cognitive performance in high-level decision-making in astronaut-like populations. Dr. Benjamin Levine, Professor in Internal Medicine at the University of Texas Southwestern Medical Center in Dallas, will assess the risk of atrial fibrillation in crewmembers participating in long-duration spaceflight missions.
The selected proposals are from 21 institutions in 11 states and will receive a total of about $12.9 million during a one- to three-year period. The 24 projects were selected from 178 proposals received in response to the research announcement entitled, “Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions.” Science and technology experts from academia and government reviewed the proposals. NASA will manage 17 of the projects and NSBRI will manage seven. Six of the investigators are new to HRP and NSBRI.
HRP quantifies crew health and performance risks during spaceflight and develops strategies that mission planners and system developers can use to monitor and mitigate the risks. These studies often lead to advancements in understanding and treating illnesses in patients on Earth.
NSBRI is a NASA-funded consortium of institutions studying health risks related to long-duration spaceflight. The Institute’s science, technology and career development projects take place at approximately 60 institutions across the United States.
Listed below is the complete list of the selected proposals, principal investigators and organizations:
NASA Awards
•             Dr. Dorrit Billman, San Jose State University Research Foundation, “Training for Generalizable Skills & Knowledge: Integrating Principles and Procedures”
•             Dr. Kim Binsted, University of Hawaii, “Using Analog Missions to Develop Effective Team Composition Strategies for Long Duration Space Exploration”
•             Dr. Mary Bouxsein, Beth Israel Deaconess Medical Center, “Vertebral Strength and Fracture Risk Following Long Duration Spaceflight”
•             Ms. Toni Clark, NASA Johnson Space Center, “Computational Modeling to Limit the Impact Displays and Indicator Lights Have on Habitable Volume Operational Lighting Constraints”
•             Dr. Noshir Contractor, Northwestern University, “CREWS: Crew Recommender for Effective Work in Space”
•             Prof. Leslie DeChurch, Georgia Institute of Technology, “SCALE: Shared Cognitive Architectures for Long-term Exploration”
•             Dr. Douglas Ebert, Wyle Laboratories, “Evaluation of an Impedance Threshold Device as a VIIP Countermeasure”
•             Dr. Edward Foegeding, North Carolina State University, “High-Protein And Polyphenol Bar Formulations: Utilizing Whey Protein-Polyphenol Ingredients”
•             Dr. Adam Gonzalez, State University Of New York, Stony Brook, “Asynchronous Techniques for the Delivery of Empirically Supported Psychotherapies”
•             Dr. Kritina Holden, Lockheed Martin, “Electronic Procedures for Crewed Missions Beyond Low Earth Orbit (LEO)”
•             Dr. Benjamin Levine, University of Texas Southwestern Medical Center at Dallas, “Integrated Cardiovascular (ICV) 2.0: Assessing the Risk for Atrial Fibrillation in Astronauts During Long Duration Spaceflight”
•             Dr. Steven Lockley, Brigham and Women’s Hospital, Harvard Medical School, “Lighting Protocols for Exploration – HERA Campaign”
•             Dr. Valerie Meyers, NASA Johnson Space Center, “Effects of Acute Exposures to Carbon Dioxide upon Cognitive Functions”
•             Dr. Greg Perlman, State University of New York, Stony Brook, “Personality and Biological Predictors of Resiliency to Chronic Stress among High-Achieving Adults”
•             Dr. Raphael Rose, University of California, Los Angeles, “Asynchronous Behavioral Health Treatment Techniques”
•             Dr. Jeffrey Ryder, Universities Space Research Association, “Sweat Rates During Continuous and Interval Aerobic Exercise: Implications for NASA Multipurpose Crew Vehicle (MPCV) Missions”
•             Dr. Richard Simpson, University of Houston, “The Impact of Modeled Microgravity and Prior Radiation Exposure on Cytomegalovirus Reactivation and Host Immune Evasion”
NSBRI Awards
•             Dr. Henry Donahue, Pennsylvania State University, “Somatic Mutations in Muscle and Bone Exposed to Simulated Space Radiation and Microgravity”
•             Dr. Robert Hienz, Johns Hopkins University, “Countermeasures for Neurobehavioral Vulnerabilities to Space Radiation”
•             Dr. Jonathan Lindner, Oregon Health & Science University, “Biomarker Assessment for Identifying Heightened Risk for Cardiovascular Complications During Long-duration Space Missions”
•             Dr. Brandon Macias, University Of California, San Diego, “Validation of a Cephalad Fluid Shift Countermeasure”
•             Ms. Debra Schreckenghost, TRACLabs, “Quantifying and Developing Countermeasures for the Effect of Fatigue-Related Stressors on Automation Use and Trust during Robotic Supervisory Control”
•             Dr. Gary Strangman, Massachusetts General Hospital, Harvard Medical School, “Sleep Electroencephalography and Near-Infrared Spectroscopy Measurements for Spaceflight and Analogs”
•             Dr. Gary Strangman, Massachusetts General Hospital, Harvard Medical School, “Testing Mechanical Countermeasures for Cephalad Fluid Shifts”
NSBRI Contact:
Graham B.I. Scott, Ph.D.
Vice President, Chief Scientist, & Institute Associate Director
National Space Biomedical Research Institute, (NSBRI)
This email address is being protected from spambots. You need JavaScript enabled to view it.
Tel: (713) 798-7227

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.  
To learn more, go to:

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).
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