ICUS Weekly News Monitor 12-4-2015

1.  EurekAlert/AAAS,  Dec 2, 2015,  Popping microbubbles help focus light inside the body
California Institute of Technology     Credit: Haowen Ruan, et al
2.  BBC News,  Nov 26, 2015,  Ultrasound captures rat brain in microscopic 3D     By Jonathan Webb Science reporter, BBC News
3.  Dovepress,  Nov 25, 2015,  Ultrasound-mediated oncolytic virus delivery and uptake for increased therapeutic efficacy: state of art     Authors:  Nande R, et al
Dec 2, 2015
Popping microbubbles help focus light inside the body
California Institute of Technology
Credit: Haowen Ruan, Mooseok Jang, and Changhuei Yang/Caltech
A new technique developed at Caltech that uses gas-filled microbubbles for focusing light inside tissue could one day provide doctors with a minimally invasive way of destroying tumors with lasers, and lead to improved diagnostic medical imaging.
The primary challenge with focusing light inside the body is that biological tissue is optically opaque. Unlike transparent glass, the cells and proteins that make up tissue scatter and absorb light. "Our tissues behave very much like dense fog as far as light is concerned," says Changhuei Yang, professor of electrical engineering, bioengineering, and medical engineering. "Just like we cannot focus a car's headlight through fog, scientists have always had difficulty focusing light through tissues."
To get around this problem, Yang and his team turned to microbubbles, commonly used in medicine to enhance contrast in ultrasound imaging.
The gas-filled microbubbles are encapsulated by thin protein shells and have an acoustic refractive index--a property that affects how sound waves propagate through a medium--different from that of living tissue. As a result, they respond differently to sound waves. "You can use ultrasound to make microbubbles rapidly contract and expand, and this vibration helps distinguish them from surrounding tissue because it causes them to reflect sound waves more effectively than biological tissue," says Haowen Ruan, a postdoctoral scholar in Yang's lab.
In addition, the optical refractive index of microbubbles is not the same as that of biological tissue. The optical refractive index is a measure of how much light rays bend when transitioning from one medium (a liquid, for example) to another (a gas).
Yang, Ruan, and graduate student Mooseok Jang developed a novel technique called time-reversed ultrasound microbubble encoded (TRUME) optical focusing that utilizes the mismatch between the acoustic and optical refractive indexes of microbubbles and tissue to focus light inside the body. First, microbubbles injected into tissue are ruptured with ultrasound waves. By measuring the difference in light transmission before and after such an event, the Caltech researchers can modify the wavefront of a laser beam so that it is focuses on the original locations of the microbubbles. The result, Yang explains, "is as if you're searching for someone in a dark field, and suddenly the person lets off a flare. For a brief moment, the person is illuminated and you can home in on their location."
In a new study, published online November 24, 2015, in the journal Nature Communications, the team showed that their TRUME technique could be used as an effective "guidestar" to focus laser beams on specific locations in a biological tissue. A single, well-placed microbubble was enough to successfully focus the laser; multiple popping bubbles located within the general vicinity of a target functioned as a map for the light.
"Each popping event serves as a road map for the twisting light trajectories through the tissue," Yang says. "We can use that road map to shape light in such a way that it will converge where the bubbles burst."
If TRUME is shown to work effectively inside living tissue--without, for example, any negative effects from the bursting microbubbles--it could enable a range of research and medical applications. For example, by combining the microbubbles with an antibody probe engineered to seek out biomarkers associated with cancer, doctors could target and then destroy tumors deep inside the body or detect malignant growths much sooner.
"Ultrasound and X-ray techniques can only detect cancer after it forms a mass," Yang says. "But with optical focusing, you could catch cancerous cells while they are undergoing biochemical changes but before they undergo morphological changes."
The technique could take the place of other of diagnostic screening methods. For instance, it could be used to measure the concentrations of a protein called bilirubin in infants to determine their risk for jaundice. "Currently, this procedure requires a blood draw, but with TRUME, we could shine a light into an infant's body and look for the unique absorption signature of the bilirubin molecule," Ruan says.
In combination with existing techniques that allow scientists to activate individual neurons in lab animals using light, TRUME could help neuroscientists better understand how the brain works. "Currently, neuroscientists are confined to superficial layers of the brain," Yang says. "But our method of optical focusing could allow for a minimally invasive way of probing deeper regions of the brain."
The paper is entitled "Optical focusing inside scattering media with time-reversed ultrasound microbubble encoded (TRUME) light."
BBC News
Nov 26, 2015
Ultrasound captures rat brain in microscopic 3D
By Jonathan Webb Science reporter, BBC News
From the section Science & Environment
ultrasound image of blood vessels in rat cortex
In this image, the direction of blood flow is colour-coded red and blue, while brightness indicates how fast it is moving
Scientists in France have developed an ultrasound technique that can rapidly build up a 3D view of a network of blood vessels, in microscopic detail.
They used it to scan the blood vessels throughout the brain of a live rat.
Within a few years, the researchers say their system could reach the clinic and help with cancer and stroke diagnosis.
For the procedure, published in Nature, the rat was injected with millions of very tiny bubbles, which reflect sound waves much better than blood vessels.
"Ultrasound propagates easily in water - or in our organs, because almost 90% of our soft tissue is water," explained the study's senior author, Mickael Tanter, from the Institut Langevin in Paris.
"But as soon as it hits a very small microbubble of gas, there's a big reflection. It's a very good scatterer of ultrasound."
This is what makes these bubbles, which are already used for some scans in humans, a "contrast agent" for ultrasound.
Spot the difference
But the key to getting a sharp, super-resolution image - unlike conventional ultrasound, which is limited to capturing objects at millimetre scales - was to scan at a very high frame-rate.
Instead of spending a long time acquiring a single, beautifully detailed image, the team snapped more than 500 coarse images every second and then compared them. The system they have built is able to compile those thousands of images and create a single, high-resolution view by looking at the differences between them - caused as the bubbles move around.
"We found a way to separate these bubbles by using ultrafast imaging," Prof Tanter told the BBC.
"If you take ultrafast images of the bubble cloud, and then you take one and you subtract the previous one, you see all the bubbles individually, time after time."
In two-and-a-half minutes he and his colleagues acquired enough images (75,000 to be precise) to compile a 3D view of the rat's brain with pixels just 10 micrometres (0.01mm) in size.
"It makes a very, very nice map of the brain vasculature... even down to 2cm deep. You can see the whole brain, with microscopic resolution," Prof Tanter said.
ultrasound image of blood vessels in whole rat brain
The technique imaged blood vessels up to 2cm deep in the rat's brain
Within a few years, he added, the system could be used by doctors. The team is already beginning clinical experiments - beginning with liver scans.
Mengxing Tang, a biomedical engineer at Imperial College London, agreed that the technique has a lot of promise and described the new study as "very commendable".
With colleagues from King's College London, Dr Tang is also working on super-resolution ultrasound. He said that between his team and Prof Tanter's, plus a third group working in Germany, hopes are high for relatively rapid progress.
"The significant step in this study is to take the technology and to further improve it, and to demonstrate that it can be done in 3D," Dr Tang told BBC News.
"This technique is highly translatable, so I would imagine that with the right resources and support, it could go into the clinic in the next few years."
Published 25 November 2015 Volume 2015:4 Pages 193—205
Nov 25, 2015
Ultrasound-mediated oncolytic virus delivery and uptake for increased therapeutic efficacy: state of art
Authors:  Nande R, Howard CM, Claudio PP
Rounak Nande,1 Candace M Howard,2 Pier Paolo Claudio,3,4
1Department of Biochemistry and Microbiology, Marshall University School of Medicine, Huntington, WV, 2Department of Radiology, University of Mississippi Medical Center, Jackson, MS, 3Department of BioMolecular Sciences and National Center for Natural Products Research, School of Pharmacy, University of Mississippi, MS, 4Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS, USA
Abstract: The field of ultrasound (US) has changed significantly from medical imaging and diagnosis to treatment strategies. US contrast agents or microbubbles (MB) are currently being used as potential carriers for chemodrugs, small molecules, nucleic acids, small interfering ribonucleic acid, proteins, adenoviruses, and oncolytic viruses. Oncolytic viruses can selectively replicate within and destroy a cancer cell, thus making them a powerful therapeutic in treating late-stage or metastatic cancer. These viruses have been shown to have robust activity in clinical trials when injected directly into tumor nodules. However limitations in oncolytic virus’ effectiveness and its delivery approach have warranted exploration of ultrasound-mediated delivery. Gene therapy bearing adenoviruses or oncolytic viruses can be coupled with MBs and injected intravenously. Following application of US energy to the target region, the MBs cavitate, and the resulting shock wave enhances drug, gene, or adenovirus uptake. Though the underlying mechanism is yet to be fully understood, there is evidence to suggest that mechanical pore formation of cellular membranes allows for the temporary uptake of drugs. This delivery method circumvents the limitations due to stimulation of the immune system that prevented intravenous administration of viruses. This review provides insight into this intriguing new frontier on the delivery of oncolytic viruses to tumor sites.

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