Category Archives: medicine

Drink your spinach juice—illuminate your guts

Contrast agents used for magnetic resonance imaging, x-ray imaging, ultrasounds, and other imaging technologies are not always kind to the humans ingesting them. So, scientists at the University at Buffalo (also known as the State University of New York at Buffalo) have developed a veggie juice that does the job according to a July 11, 2016 news item on Nanowerk (Note: A link has been removed),

The pigment that gives spinach and other plants their verdant color may improve doctors’ ability to examine the human gastrointestinal tract.

That’s according to a study, published in the journal Advanced Materials (“Surfactant-Stripped Frozen Pheophytin Micelles for Multimodal Gut Imaging”), which describes how chlorophyll-based nanoparticles suspended in liquid are an effective imaging agent for the gut.

The University of Buffalo has provided an illustration of the work,

A new UB-led study suggests that chlorophyll-based nanoparticles are an effective imaging agent for the gut. The medical imaging drink, developed to diagnose and treat gastrointestinal illnesses, is made of concentrated chlorophyll, the pigment that makes spinach green. Photo illustration credit: University at Buffalo.

A new UB-led study suggests that chlorophyll-based nanoparticles are an effective imaging agent for the gut. The medical imaging drink, developed to diagnose and treat gastrointestinal illnesses, is made of concentrated chlorophyll, the pigment that makes spinach green. Photo illustration credit: University at Buffalo.

A July 11, 2016 University at Buffalo (UB) news release (also on EurekAlert) by Cory Nealon, which originated the news item, expands on the theme,

“Our work suggests that this spinach-like, nanoparticle juice can help doctors get a better look at what’s happening inside the stomach, intestines and other areas of the GI tract,” says Jonathan Lovell, PhD, assistant professor in the Department of Biomedical Engineering, a joint program between UB’s School of Engineering and Applied Sciences and the Jacobs School of Medicine and Biomedical Sciences at UB, and the study’s corresponding author.

To examine the gastrointestinal tract, doctors typically use X-rays, magnetic resonance imaging or ultrasounds, but these techniques are limited with respect to safety, accessibility and lack of adequate contrast, respectively.

Doctors also perform endoscopies, in which a tiny camera attached to a thin tube is inserted into the patient’s body. While effective, this procedure is challenging to perform in the small intestine, and it can cause infections, tears and pose other risks.

The new study, which builds upon Lovell’s previous medical imaging research, is a collaboration between researchers at UB and the University of Wisconsin-Madison. It focuses on Chlorophyll a, a pigment found in spinach and other green vegetables that is essential to photosynthesis.

In the laboratory, researchers removed magnesium from Chlorophyll a, a process which alters the pigment’s chemical structure to form another edible compound called pheophytin. Pheophytin plays an important role in photosynthesis, acting as a gatekeeper that allows electrons from sunlight to enter plants.

Next, they dissolved pheophytin in a solution of soapy substances known as surfactants. The researchers were then able to remove nearly all of the surfactants, leaving nearly pure pheophytin nanoparticles.

The drink, when tested in mice, provided imaging of the gut in three modes: photoacoustic imaging, fluorescence imaging and positron emission tomography (PET). (For PET, the researchers added to the drink Copper-64, an isotope of the metal that, in small amounts, is harmless to the human body.)

Additional studies are needed, but the drink has commercial potential because it:

·         Works in different imaging techniques.

·         Moves stably through the gut.

·         And is naturally consumed in the human diet already.

In lab tests, mice excreted 100 percent of the drink in photoacoustic and fluorescence imaging, and nearly 93 percent after the PET test.

“The veggie juice allows for techniques that are not commonly used today by doctors for imaging the gut like photoacoustic, PET, and fluorescence,” Lovell says. “And part of the appeal is the safety of the juice.”

Here’s a link to and a citation for the paper,

Surfactant-Stripped Frozen Pheophytin Micelles for Multimodal Gut Imaging by Yumiao Zhang, Depeng Wang, Shreya Goel, Boyang Sun, Upendra Chitgupi, Jumin Geng, Haiyan Sun, Todd E. Barnhart, Weibo Cai, Jun Xia, and Jonathan F. Lovell. Advanced Materials DOI: 10.1002/adma.201602373 Version of Record online: 11 JUL 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Nanotechnology-enabled electronic tattoo from Tel Aviv University (Israel)

This is the first stick-on, nanotechnology-enabled tattoo I’ve seen that’s designed for the face. From a July 11, 2016 news item on ScienceDaily,

A new temporary “electronic tattoo” developed by Tel Aviv University [TAU] that can measure the activity of muscle and nerve cells researchers is poised to revolutionize medicine, rehabilitation, and even business and marketing research.

A July 11, 2016 American Friends of Tel Aviv University news release (also on EurekAlert), which originated the news item, provides more detail (Note: Some formatting has been changed),

The tattoo consists of a carbon electrode, an adhesive surface that attaches to the skin, and a nanotechnology-based conductive polymer coating that enhances the electrode’s performance. It records a strong, steady signal for hours on end without irritating the skin.

The electrode, developed by Prof. Yael Hanein, head of TAU’s Center for Nanoscience and Nanotechnology, may improve the therapeutic restoration of damaged nerves and tissue — and may even lead to new insights into our emotional life.

Prof. Hanein’s research was published last month in Scientific Reports and presented at an international nanomedicine program held at TAU.

“Stick it on and forget about it”

One major application of the new electrode is the mapping of emotion by monitoring facial expressions through electric signals received from facial muscles. “The ability to identify and map people’s emotions has many potential uses,” said Prof. Hanein. “Advertisers, pollsters, media professionals, and others — all want to test people’s reactions to various products and situations. Today, with no accurate scientific tools available, they rely mostly on inevitably subjective questionnaires.

“Researchers worldwide are trying to develop methods for mapping emotions by analyzing facial expressions, mostly via photos and smart software,” Prof. Hanein continued. “But our skin electrode provides a more direct and convenient solution.”

The device was first developed as an alternative to electromyography, a test that assesses the health of muscles and nerve cells. It’s an uncomfortable and unpleasant medical procedure that requires patients to lie sedentary in the lab for hours on end. Often a needle is stuck into muscle tissue to record its electrical activity, or patients are swabbed with a cold, sticky gel and attached to unwieldy surface electrodes.

“Our tattoo permits patients to carry on with their daily routines, while the electrode monitors their muscle and nerve activity,” said Prof. Hanein. “The idea is: stick it on and forget about it.”

Applications for rehabilitation and more

According to Prof. Hanein, the new skin electrode has other important therapeutic applications. The tattoo will be used to monitor the muscle activity of patients with neurodegenerative diseases in a study at Tel Aviv Medical Center.

“But that’s not all,” said Prof. Hanein. “The physiological data measured in specific muscles may be used in the future to indicate the alertness of drivers on the road; patients in rehabilitation following stroke or brain injury may utilize the ‘tattoo’ to improve muscle control; and amputees may employ it to move artificial limbs with remaining muscles.”

As it often is, the funding sources prove to be interesting (from the news release),

The electrode is the product of a European Research Council (ERC) project and received support from the BSMT Consortium of Israel’s Ministry of Economy.

The involvement of the European Research Council underlines the very close relationship Israel has to the European Union even though it is not an official member.

Here’s a link to and a citation for the paper,

Temporary-tattoo for long-term high fidelity biopotential recordings by Lilach Bareket, Lilah Inzelberg, David Rand, Moshe David-Pur, David Rabinovich, Barak Brandes & Yael Hanein. Scientific Reports 6, Article number: 25727 (2016)  doi:10.1038/srep25727 Published online: 12 May 2016

This paper is open access.

Making ordinary microscopes image objects at the nanoscale

The researchers believe this technique for making ordinary microscopes capable of nanoscale imaging will make research into diseases easier, especially in developing countries. A July 20, 2016 news item on phys.org announces the new technique,

Research completed through a collaboration with University of Missouri [MU] engineers, biologists, and chemists could transform how scientists study molecules and cells at sub-microscopic (nanoscale) levels. Shubra Gangopadhyay, an electrical and computer engineer and her team at MU recently published studies outlining a new, relatively inexpensive imaging platform that enables single molecule imaging. This patented method highlights Gangopadhyay’s more than 30 years of nanoscale research that has proven invaluable in biological research and battling diseases.

This diagram shows the difference between regular and plasmonic gratings in terms of fluorescent intensity. Credit: Shubhra Gangopadhyay/Nanoscale.

This diagram shows the difference between regular and plasmonic gratings in terms of fluorescent intensity. Credit: Shubhra Gangopadhyay/Nanoscale.

A July 19, 2016 University of Missouri news release (also received via email), which originated the news item, explains further,

“Usually, scientists have to use very expensive microscopes to image at the sub-microscopic level,” said Gangopadhyay, the C.W. LaPierre Endowed Chair of electrical and computer engineering in the MU College of Engineering. “The techniques we’ve established help to produce enhanced imaging results with ordinary microscopes. The relatively low production cost for the platform also means it could be used to detect a wide variety of diseases, particularly in developing countries.”

The team’s custom platform uses an interaction between light and the surface of the metal grating to generate surface plasmon resonance (SPR), a rapidly developing imaging technique that enables super-resolution imaging down to 65 nanometers—a resolution normally reserved for electron microscopes. Using HD-DVD and Blu-Ray discs as starting templates, a repeating grating pattern is transferred onto the microscope slides where the specimen will be placed. Since the patterns originate from a widely used technology, the manufacturing process remains relatively inexpensive.

“In previous studies, we’ve used plasmonic gratings to detect cortisol and even tuberculosis,” Gangopadhyay said. “Additionally, the relatively low production cost for the platform also means it could be used to further detect a wide variety of diseases, particularly in developing countries. Eventually, we might even be able to use smartphones to detect disease in the field.”

Here’s a link to and a citation for the paper,

Plasmonic gratings with nano-protrusions made by glancing angle deposition for single-molecule super-resolution imaging by B. Chen, A. Wood, A. Pathak, J. Mathai, S. Bok, H. Zheng, S. Hamm, S. Basuray, S. Grant, K. Gangopadhyay, P. V. Cornish, and S. Gangopadhyay. Nanoscale, 2016,8, 12189-12201 DOI: 10.1039/C5NR09165A First published online 24 May 2016

This paper is behind a paywall.

ETA July 22, 2016: Dexter Johnson’s July 21, 2016 posting provides both a neat summary and added detail from an engineer’s perspective.

Inspiration from the sea for titanium implants (mussels) and adhesive panels for flexible sensors (octopuses/octopi/octopodes)

I have two sea-inspired news bits both of which concern adhesion.

Mussels and titanium implants

A July 8, 2016 news item on ScienceDaily features some mussel-inspired research from Japan into how to make better titanium implants,

Titanium is used medically in applications such as artificial joints and dental implants. While it is strong and is not harmful to tissues, the metal lacks some of the beneficial biological properties of natural tissues such as bones and natural teeth. Now, based on insights from mussels–which are able to attach themselves very tightly to even metallic surfaces due to special proteins found in their byssal threads–scientists from RIKEN have successfully attached a biologically active molecule to a titanium surface, paving the way for implants that can be more biologically beneficial.

A July 11, 2016 RIKEN press release (also on EurekAlert but dated July 8, 2016), which originated the news item, provides more information,

The work began from earlier discoveries that mussels can attach to smooth surfaces so effectively thanks to a protein, L-DOPA, which is known to be able to bind very strongly to smooth surfaces such as rocks, ceramics, or metals (…). Interestingly, the same protein functions in humans as a precursor to dopamine, and is used as a treatment for Parkinson’s disease.

According to Chen Zhang of the RIKEN Nano Medical Engineering Laboratory, the first author of the paper published in Angewandte Chemie, “We thought it would be interesting to try to use various techniques to attach a biologically active protein—in our case we chose insulin-like growth factor-1, a promoter of cell proliferation—to a titanium surface like those used in implants” (…).

Using a combination of recombinant DNA technology and treatment with tyrosinase, they were able to create a hybrid protein that contained active parts of both the growth factor and L-DOPA. Tests showed that the proteins were able to fold normally, and further experiments in cell cultures demonstrated that the IGF-1 was still functioning normally. Thanks to the incorporation of the L-DOPA, the team was able to confirm that the proteins bound strongly to the titanium surface, and remained attached even when the metal was washed with phosphate-buffered saline, a water-based solution. Zhang says, “This is similar to the powerful properties of mussel adhesive, which can remain fixed to metallic materials even underwater.”

According to Yoshihiro Ito, Team Leader of the Emergent Bioengineering Research Team of the RIKEN Center for Emergent Matter Science, “We are very excited by this finding, because the modification process is a universal one that could be used with other proteins. It could allow us to prepare new cell-growth enhancing materials, with potential applications in cell culture systems and regenerative medicine. And it is particularly interesting that this is an example of biomimetics, where nature can teach us new ways to do things. The mussel has given us insights that could be used to allow us to live healthier lives.”

The work was done by RIKEN researchers in collaboration with Professor Peibiao Zhang of the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, and Professor Yi Wang of the School of Pharmaceutical Sciences, Jilin University. The work was partially supported by the Japan Society for the Promotion of Science KAKENHI (Grant Number 15H01810 and 22220009), CAS-JSPS joint fund (GJHZ1519), and RIKEN MOST joint project.

Here’s a link to and a citation for the paper,

A Bioorthogonal Approach for the Preparation of a Titanium-Binding Insulin-like Growth-Factor-1 Derivative by using Tyrosinase by Chen Zhang, Hideyuki Miyatake, Yu Wang, Takehiko Inaba, Yi Wang, Peibiao Zhang, and Prof. Yoshihiro Ito. Angewandte Chemie International Edition DOI: 10.1002/anie.201603155 Version of Record online: 6 JUL 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Octopuses/octopi/octopodes and adhesive panels

Before launching into the science part of this news bit, here’s some grammar (from the Octopus Wikipedia entry; Note: Links have been removed),

The standard pluralized form of “octopus” in the English language is “octopuses” /ˈɒktəpʊsɪz/,[10] although the Ancient Greek plural “octopodes” /ɒkˈtɒpədiːz/, has also been used historically.[9] The alternative plural “octopi” — which misguidedly assumes it is a Latin “-us”-word — is considered grammatically incorrect.[11][12][13][14] It is nevertheless used enough to make it notable, and was formally acknowledged by the descriptivist Merriam-Webster 11th Collegiate Dictionary and Webster’s New World College Dictionary. The Oxford English Dictionary (2008 Draft Revision)[15] lists “octopuses”, “octopi”, and “octopodes”, in that order, labelling “octopodes” as rare and noting that “octopi” derives from the apprehension that octōpus comes from Latin.[16] In contrast, New Oxford American Dictionary (3rd Edition 2010) lists “octopuses” as the only acceptable pluralization, with a usage note indicating “octopodes” as being still occasionally used but “octopi” as being incorrect.[17]

Now the news. A July 12, 2016 news item on Nanowerk highlights some research into adhesives and octopuses,

With increased study of bio-adhesives, a significant effort has been made in search for novel adhesives that will combine reversibility, repeated usage, stronger bonds and faster bonding time, non-toxic, and more importantly be effective in wet and other extreme conditions.

A team of Korean scientists-made up of scientists from Korea Institute of Science and Technology (KIST) and UNIST has recently found a way to make building flexible pressure sensors easier–by mimicking the suction cups on octopus’s tentacles.

A July 5, 2016 UNIST (Ulsan National Institute of Science and Technology) press release, which originated the news item, provides more information,

According to the research team, “Although flexible pressure sensors might give future prosthetics and robots a better sense of touch, building them requires a lot of laborious transferring of nano- and microribbons of inorganic semiconductor materials onto polymer sheets.”

In search of an easier way to process this transfer printing, Prof. Hyunhyub Ko (School of Energy and Chemical Engineering, UNIST) and his colleagues turned to the octopus suction cups for inspiration.

An octopus uses its tentacles to move to a new location and uses suction cups underneath each tentacle to grab onto something. Each suction cup contains a cavity whose pressure is controlled by surrounding muscles. These can be made thinner or thicker on demand, increasing or decreasing air pressure inside the cup, allowing for sucking and releasing as desired.

By mimicking muscle actuation to control cavity-pressure-induced adhesion of octopus suckers, Prof. Ko and his team engineered octopus-inspired smart adhesive pads. They used the rubbery material polydimethylsiloxane (PDMS) to create an array of microscale suckers, which included pores that are coated with a thermally responsive polymer to create sucker-like walls.

The team discovered that the best way to replicate organic nature of muscle contractions would be through applied heat. Indeed, at room temperature, the walls of each pit sit in an ‘open’ state, but when the mat is heated to 32°C, the walls contract, creating suction, therby allowing the entire mate to adhere to a material (mimicking the suction function of an octopus). The adhesive strength also spiked from .32 kilopascals to 94 kilopascals at high temperature.

The team reports that the mat worked as envisioned—they made some indium gallium arsenide transistors that sat on a flexible substrate and also used it to move some nanomaterials to a different type of flexible material.

Prof. Ko and his team expect that their smart adhesive pads can be used as the substrate for wearable health sensors, such as Band-Aids or sensors that stick to the skin at normal body temperatures but fall off when rinsed under cold water.

Here’s a link to and a citation for the paper,

Octopus-Inspired Smart Adhesive Pads for Transfer Printing of Semiconducting Nanomembranes by Hochan Lee, Doo-Seung Um, Youngsu Lee, Seongdong Lim, Hyung-jun Kim,  and Hyunhyub Ko. Advanced Materials DOI: 10.1002/adma.201601407 Version of Record online: 20 JUN 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Getting one step closer to molecular robots

A July 5, 2016 news item on ScienceDaily announced research from Hokkaido University (Japan),

Scientists at Japan’s Hokkaido University have developed light-powered molecular motors that repetitively bend and unbend, bringing us closer to molecular robots.

A July 6, 2016 Hokkaido University press release (also on EurekAlert), which originated the news item, expands on the theme,

Researchers are working on mimicking cellular systems to develop molecular motors that can move or even deliver drugs to target tissues. Engineering such motors may ultimately lead to molecular robots that can execute more complex tasks. To this end, researchers must find ways to convert motion at the molecular level to motion at the macroscopic level. They also must find ways to cause chemical reactions to repeat autonomously and continuously.
Yoshiyuki Kageyama, Sadamu Takeda and colleagues at Hokkaido University’s Department of Chemistry have successfully created a chemical compound, or a crystalline assembly, which autonomously repeated flipping under blue light.

The team made crystals composed of an organic compound, called azobenzene, commonly used in dye manufacturing, and oleic acid, commonly found in cooking oil. Azobenzene molecules take two structurally different forms: cis and trans. They repetitively convert from one form to the other under blue right. The scientists tested if this would influence the structure of the azobenzene-oleic acid crystal, which contained unequal amounts of cis– and trans-azobenzene.

By applying blue light to the crystals in solution, the team observed, under a microscope, an oscillatory bending-unbending motion of the thin crystals, suggesting the existence of two stable structures, bent or unbent, depending on the cis/trans ratio. The frequency of the motion increased when the light intensity was increased. Some crystal complexes even exhibited ‘swimming-like’ motions in the water. Previously reported light-responsive materials have been limited in their ability to deform. The properties of the compounds in the Hokkaido University-developed crystals, however, allowed for a two-step switching mechanism, resulting in regular repetitive oscillations.

Schematic illustration of each step of the self-oscillatory motion. (Ikegami T. et. al., Angewandte Chemie International Edition, May 19, 2016)

Schematic illustration of each step of the self-oscillatory motion. (Ikegami T. et. al., Angewandte Chemie International Edition, May 19, 2016)

“The ability to self-organize rhythmic motions, such as the repetitive flipping motion we observed, is one of the fundamental characteristics of living organisms”, says Kageyama. “This mechanism can be used in the future to develop bio-inspired molecular motors and robots that will find applications in wide areas, including medicine”.

You can observe the flipping here in this video provided by Hokkaido University,

Here’s a link to and a citation for the paper,

Dissipative and Autonomous Square-Wave Self-Oscillation of a Macroscopic Hybrid Self-Assembly under Continuous Light Irradiation by Tomonori Ikegami, Dr. Yoshiyuki Kageyama, Kazuma Obara, and Prof. Sadamu Takeda. Angewandte Chemie International Edition Volume 55, Issue 29, pages 8239–8243, July 11, 2016 DOI: 10.1002/anie.201600218 Version of Record online: 19 MAY 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Using light to make gold crystal nanoparticles

Gold crystal nanoparticles? Courtesy: University of Florida

Gold crystal nanoparticles? Courtesy: University of Florida

A team from the University of Florida has used gold instead of silver in a process known as plasmon-driven synthesis. From a July 8, 2016 news item on phys.org,

A team of University of Florida researchers has figured out how gold can be used in crystals grown by light to create nanoparticles, a discovery that has major implications for industry and cancer treatment and could improve the function of pharmaceuticals, medical equipment and solar panels.

A July 6, 2016 University of Florida news release, which originated the news item, provides more detail,

Nanoparticles can be “grown” in crystal formations with special use of light, in a process called plasmon-driven synthesis. However, scientists have had limited control unless they used silver, but silver limits the uses for medical technology. The team is the first to successfully use gold, which works well within the human body, with this process.

“How does light actually play a role in the synthesis? [This knowledge] was not well developed,” said David Wei, an associate professor of chemistry who led the research team. “Gold was the model system to demonstrate this.”

Gold is highly desired for nanotechnology because it is malleable, does not react with oxygen and conducts heat well. Those properties make gold an ideal material for nanoparticles, especially those that will be placed in the body.

When polyvinylpyrrolidone, or PVP, a substance commonly found in pharmaceutical tablets, is used in the plasmon-driven synthesis, it enables scientists to better control the growth of crystals. In Wei’s research, PVP surprised the team by showing its potential to relay light-generated “hot” electrons to a gold surface to grow the crystals.

The research describes the first plasmonic synthesis strategy that can make high-yield gold nanoprisms. Even more exciting, the team has demonstrated that visible-range and low-power light can be used in the synthesis. Combined with nanoparticles being used in solar photovoltaic devices, this method can even harness solar energy for chemical synthesis, to make nanomaterials or for general applications in chemistry.

Wei has spent the last decade working in nanotechnology. He is intrigued by its applications in photochemistry and biomedicine, especially in targeted drug delivery and photothermal therapeutics, which is crucial to cancer treatment. His team includes collaborators from Pacific Northwest National Laboratory, where he has worked as a visiting scholar, and Brookhaven National Laboratory. In addition, the project has provided an educational opportunity for chemistry students: one high school student (through UF’s Student Science Training Program), two University scholars who also [sic] funded by the Howard Hughes Medical Institute, five graduate students and two postdocs.

Here’s a link to and a citation for the paper,

Polyvinylpyrrolidone-induced anisotropic growth of gold nanoprisms in plasmon-driven synthesis by Yueming Zhai, Joseph S. DuChene, Yi-Chung Wang, Jingjing Qiu, Aaron C. Johnston-Peck, Bo You, Wenxiao Guo, Benedetto DiCiaccio, Kun Qian, Evan W. Zhao, Frances Ooi, Dehong Hu, Dong Su, Eric A. Stach, Zihua Zhu, & Wei David Wei. Nature Materials (2016) doi:10.1038/nmat4683 Published online 04 July 2016

This paper is behind a paywall.

Viewing RNA (ribonucleic acid) more closely at the nanoscale with expansion microscopy (EXM) and off-the-shelf parts

A close cousin to DNA (deoxyribonucleic acid), RNA (ribonucleic acid) is a communicator according to a July 4, 2016 news item on ScienceDaily describing how a team at the Massachusetts Institute of Technology (MIT) managed to image RNA more precisely,

Cells contain thousands of messenger RNA molecules, which carry copies of DNA’s genetic instructions to the rest of the cell. MIT engineers have now developed a way to visualize these molecules in higher resolution than previously possible in intact tissues, allowing researchers to precisely map the location of RNA throughout cells.

Key to the new technique is expanding the tissue before imaging it. By making the sample physically larger, it can be imaged with very high resolution using ordinary microscopes commonly found in research labs.

“Now we can image RNA with great spatial precision, thanks to the expansion process, and we also can do it more easily in large intact tissues,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, a member of MIT’s Media Lab and McGovern Institute for Brain Research, and the senior author of a paper describing the technique in the July 4, 2016 issue of Nature Methods.

A July 4, 2016 MIT news release (also on EurekAlert), which originated the news item, explains why scientists want a better look at RNA and how the MIT team accomplished the task,

Studying the distribution of RNA inside cells could help scientists learn more about how cells control their gene expression and could also allow them to investigate diseases thought to be caused by failure of RNA to move to the correct location.

Boyden and colleagues first described the underlying technique, known as expansion microscopy (ExM), last year, when they used it to image proteins inside large samples of brain tissue. In a paper appearing in Nature Biotechnology on July 4, the MIT team has now presented a new version of the technology that employs off-the-shelf chemicals, making it easier for researchers to use.

MIT graduate students Fei Chen and Asmamaw Wassie are the lead authors of the Nature Methods paper, and Chen and graduate student Paul Tillberg are the lead authors of the Nature Biotechnology paper.

A simpler process

The original expansion microscopy technique is based on embedding tissue samples in a polymer that swells when water is added. This tissue enlargement allows researchers to obtain images with a resolution of around 70 nanometers, which was previously possible only with very specialized and expensive microscopes. However, that method posed some challenges because it requires generating a complicated chemical tag consisting of an antibody that targets a specific protein, linked to both a fluorescent dye and a chemical anchor that attaches the whole complex to a highly absorbent polymer known as polyacrylate. Once the targets are labeled, the researchers break down the proteins that hold the tissue sample together, allowing it to expand uniformly as the polyacrylate gel swells.

In their new studies, to eliminate the need for custom-designed labels, the researchers used a different molecule to anchor the targets to the gel before digestion. This molecule, which the researchers dubbed AcX, is commercially available and therefore makes the process much simpler.

AcX can be modified to anchor either proteins or RNA to the gel. In the Nature Biotechnology study, the researchers used it to anchor proteins, and they also showed that the technique works on tissue that has been previously labeled with either fluorescent antibodies or proteins such as green fluorescent protein (GFP).

“This lets you use completely off-the-shelf parts, which means that it can integrate very easily into existing workflows,” Tillberg says. “We think that it’s going to lower the barrier significantly for people to use the technique compared to the original ExM.”

Using this approach, it takes about an hour to scan a piece of tissue 500 by 500 by 200 microns, using a light sheet fluorescence microscope. The researchers showed that this technique works for many types of tissues, including brain, pancreas, lung, and spleen.

Imaging RNA

In the Nature Methods paper, the researchers used the same kind of anchoring molecule but modified it to target RNA instead. All of the RNAs in the sample are anchored to the gel, so they stay in their original locations throughout the digestion and expansion process.

After the tissue is expanded, the researchers label specific RNA molecules using a process known as fluorescence in situ hybridization (FISH), which was originally developed in the early 1980s and is widely used. This allows researchers to visualize the location of specific RNA molecules at high resolution, in three dimensions, in large tissue samples.

This enhanced spatial precision could allow scientists to explore many questions about how RNA contributes to cellular function. For example, a longstanding question in neuroscience is how neurons rapidly change the strength of their connections to store new memories or skills. One hypothesis is that RNA molecules encoding proteins necessary for plasticity are stored in cell compartments close to the synapses, poised to be translated into proteins when needed.

With the new system, it should be possible to determine exactly which RNA molecules are located near the synapses, waiting to be translated.

“People have found hundreds of these locally translated RNAs, but it’s hard to know where exactly they are and what they’re doing,” Chen says. “This technique would be useful to study that.”

Boyden’s lab is also interested in using this technology to trace the connections between neurons and to classify different subtypes of neurons based on which genes they are expressing.

There’s a brief (30 secs.), silent video illustrating the work (something about a ‘Brainbow Hippocampus’) made available by MIT,


Here’s a link to and a citation for the paper,

Nanoscale imaging of RNA with expansion microscopy by Fei Chen, Asmamaw T Wassie, Allison J Cote, Anubhav Sinha, Shahar Alon, Shoh Asano, Evan R Daugharthy, Jae-Byum Chang, Adam Marblestone, George M Church, Arjun Raj, & Edward S Boyden.     Nature Methods (2016)  doi:10.1038/nmeth.3899 Published online 04 July 2016

This paper is behind a paywall.

Artificial pancreas in 2018?

According to Dr. Roman Hovorka and Dr. Hood Thabit of the University of Cambridge, UK, there will be an artificial pancreas assuming issues such as cybersecurity are resolved. From a June 30, 2016 Diabetologia press release on EurekAlert,

The artificial pancreas — a device which monitors blood glucose in patients with type 1 diabetes and then automatically adjusts levels of insulin entering the body — is likely to be available by 2018, conclude authors of a paper in Diabetologia (the journal of the European Association for the Study of Diabetes). Issues such as speed of action of the forms of insulin used, reliability, convenience and accuracy of glucose monitors plus cybersecurity to protect devices from hacking, are among the issues that are being addressed.

The press release describes the current technology available for diabetes type 1 patients and alternatives other than an artificial pancreas,

Currently available technology allows insulin pumps to deliver insulin to people with diabetes after taking a reading or readings from glucose meters, but these two components are separate. It is the joining together of both parts into a ‘closed loop’ that makes an artificial pancreas, explain authors Dr Roman Hovorka and Dr Hood Thabit of the University of Cambridge, UK. “In trials to date, users have been positive about how use of an artificial pancreas gives them ‘time off’ or a ‘holiday’ from their diabetes management, since the system is managing their blood sugar effectively without the need for constant monitoring by the user,” they say.

One part of the clinical need for the artificial pancreas is the variability of insulin requirements between and within individuals — on one day a person could use one third of their normal requirements, and on another 3 times what they normally would. This is dependent on the individual, their diet, their physical activity and other factors. The combination of all these factors together places a burden on people with type 1 diabetes to constantly monitor their glucose levels, to ensure they don’t end up with too much blood sugar (hyperglycaemic) or more commonly, too little (hypoglycaemic). Both of these complications can cause significant damage to blood vessels and nerve endings, making complications such as cardiovascular problems more likely.

There are alternatives to the artificial pancreas, with improvements in technology in both whole pancreas transplantation and also transplants of just the beta cells from the pancreas which produce insulin. However, recipients of these transplants require drugs to supress their immune systems just as in other organ transplants. In the case of whole pancreas transplantation, major surgery is required; and in beta cell islet transplantation, the body’s immune system can still attack the transplanted cells and kill off a large proportion of them (80% in some cases). The artificial pancreas of course avoids the need for major surgery and immunosuppressant drugs.

Researchers are working to solve one of the major problems with an artificial pancreas according to the press release,

Researchers globally continue to work on a number of challenges faced by artificial pancreas technology. One such challenge is that even fast-acting insulin analogues do not reach their peak levels in the bloodstream until 0.5 to 2 hours after injection, with their effects lasting 3 to 5 hours. So this may not be fast enough for effective control in, for example, conditions of vigorous exercise. Use of the even faster acting ‘insulin aspart’ analogue may remove part of this problem, as could use of other forms of insulin such as inhaled insulin. Work also continues to improve the software in closed loop systems to make it as accurate as possible in blood sugar management.

The press release also provides a brief outline of some of the studies being run on one artificial pancreas or another, offers an abbreviated timeline for when the medical device may be found on the market, and notes specific cybersecurity issues,

A number of clinical studies have been completed using the artificial pancreas in its various forms, in various settings such as diabetes camps for children, and real life home testing. Many of these trials have shown as good or better glucose control than existing technologies (with success defined by time spent in a target range of ideal blood glucose concentrations and reduced risk of hypoglycaemia). A number of other studies are ongoing. The authors say: “Prolonged 6- to 24-month multinational closed-loop clinical trials and pivotal studies are underway or in preparation including adults and children. As closed loop devices may be vulnerable to cybersecurity threats such as interference with wireless protocols and unauthorised data retrieval, implementation of secure communications protocols is a must.”

The actual timeline to availability of the artificial pancreas, as with other medical devices, encompasses regulatory approvals with reassuring attitudes of regulatory agencies such as the US Food and Drug Administration (FDA), which is currently reviewing one proposed artificial pancreas with approval possibly as soon as 2017. And a recent review by the UK National Institute of Health Research (NIHR) reported that automated closed-loop systems may be expected to appear in the (European) market by the end of 2018. The authors say: “This timeline will largely be dependent upon regulatory approvals and ensuring that infrastructures and support are in place for healthcare professionals providing clinical care. Structured education will need to continue to augment efficacy and safety.”

The authors say: “Cost-effectiveness of closed-loop is to be determined to support access and reimbursement. In addition to conventional endpoints such as blood sugar control, quality of life is to be included to assess burden of disease management and hypoglycaemia. Future research may include finding out which sub-populations may benefit most from using an artificial pancreas. Research is underway to evaluate these closed-loop systems in the very young, in pregnant women with type 1 diabetes, and in hospital in-patients who are suffering episodes of hyperglycaemia.”

They conclude: “Significant milestones moving the artificial pancreas from laboratory to free-living unsupervised home settings have been achieved in the past decade. Through inter-disciplinary collaboration, teams worldwide have accelerated progress and real-world closed-loop applications have been demonstrated. Given the challenges of beta-cell transplantation, closed-loop technologies are, with continuing innovation potential, destined to provide a viable alternative for existing insulin pump therapy and multiple daily insulin injections.”

Here’s a link to and a citation for the paper,

Coming of age: the artificial pancreas for type 1 diabetes by Hood Thabit, Roman Hovorka. Diabetologia (2016). doi:10.1007/s00125-016-4022-4 First Online: 30 June 2016

This is an open access paper.

Wireless, wearable carbon nanotube-based gas sensors for soldiers

Researchers at MIT (Massachusetts Institute of Technology) are hoping to make wireless, toxic gas detectors the size of badges. From a June 30, 2016 news item on Nanowerk,

MIT researchers have developed low-cost chemical sensors, made from chemically altered carbon nanotubes, that enable smartphones or other wireless devices to detect trace amounts of toxic gases.

Using the sensors, the researchers hope to design lightweight, inexpensive radio-frequency identification (RFID) badges to be used for personal safety and security. Such badges could be worn by soldiers on the battlefield to rapidly detect the presence of chemical weapons — such as nerve gas or choking agents — and by people who work around hazardous chemicals prone to leakage.

A June 30, 2016 MIT news release (also on EurekAlert), which originated the news item, describes the technology further,

“Soldiers have all this extra equipment that ends up weighing way too much and they can’t sustain it,” says Timothy Swager, the John D. MacArthur Professor of Chemistry and lead author on a paper describing the sensors that was published in the Journal of the American Chemical Society. “We have something that would weigh less than a credit card. And [soldiers] already have wireless technologies with them, so it’s something that can be readily integrated into a soldier’s uniform that can give them a protective capacity.”

The sensor is a circuit loaded with carbon nanotubes, which are normally highly conductive but have been wrapped in an insulating material that keeps them in a highly resistive state. When exposed to certain toxic gases, the insulating material breaks apart, and the nanotubes become significantly more conductive. This sends a signal that’s readable by a smartphone with near-field communication (NFC) technology, which allows devices to transmit data over short distances.

The sensors are sensitive enough to detect less than 10 parts per million of target toxic gases in about five seconds. “We are matching what you could do with benchtop laboratory equipment, such as gas chromatographs and spectrometers, that is far more expensive and requires skilled operators to use,” Swager says.

Moreover, the sensors each cost about a nickel to make; roughly 4 million can be made from about 1 gram of the carbon nanotube materials. “You really can’t make anything cheaper,” Swager says. “That’s a way of getting distributed sensing into many people’s hands.”

The paper’s other co-authors are from Swager’s lab: Shinsuke Ishihara, a postdoc who is also a member of the International Center for Materials Nanoarchitectonics at the National Institute for Materials Science, in Japan; and PhD students Joseph Azzarelli and Markrete Krikorian.

Wrapping nanotubes

In recent years, Swager’s lab has developed other inexpensive, wireless sensors, called chemiresistors, that have detected spoiled meat and the ripeness of fruit, among other things [go to the end of this post for links to previous posts about Swager’s work]. All are designed similarly, with carbon nanotubes that are chemically modified, so their ability to carry an electric current changes when exposed to a target chemical.

This time, the researchers designed sensors highly sensitive to “electrophilic,” or electron-loving, chemical substances, which are often toxic and used for chemical weapons.

To do so, they created a new type of metallo-supramolecular polymer, a material made of metals binding to polymer chains. The polymer acts as an insulation, wrapping around each of the sensor’s tens of thousands of single-walled carbon nanotubes, separating them and keeping them highly resistant to electricity. But electrophilic substances trigger the polymer to disassemble, allowing the carbon nanotubes to once again come together, which leads to an increase in conductivity.

In their study, the researchers drop-cast the nanotube/polymer material onto gold electrodes, and exposed the electrodes to diethyl chlorophosphate, a skin irritant and reactive simulant of nerve gas. Using a device that measures electric current, they observed a 2,000 percent increase in electrical conductivity after five seconds of exposure. Similar conductivity increases were observed for trace amounts of numerous other electrophilic substances, such as thionyl chloride (SOCl2), a reactive simulant in choking agents. Conductivity was significantly lower in response to common volatile organic compounds, and exposure to most nontarget chemicals actually increased resistivity.

Creating the polymer was a delicate balancing act but critical to the design, Swager says. As a polymer, the material needs to hold the carbon nanotubes apart. But as it disassembles, its individual monomers need to interact more weakly, letting the nanotubes regroup. “We hit this sweet spot where it only works when it’s all hooked together,” Swager says.

Resistance is readable

To build their wireless system, the researchers created an NFC tag that turns on when its electrical resistance dips below a certain threshold.

Smartphones send out short pulses of electromagnetic fields that resonate with an NFC tag at radio frequency, inducing an electric current, which relays information to the phone. But smartphones can’t resonate with tags that have a resistance higher than 1 ohm.

The researchers applied their nanotube/polymer material to the NFC tag’s antenna. When exposed to 10 parts per million of SOCl2 for five seconds, the material’s resistance dropped to the point that the smartphone could ping the tag. Basically, it’s an “on/off indicator” to determine if toxic gas is present, Swager says.

According to the researchers, such a wireless system could be used to detect leaks in Li-SOCl2 (lithium thionyl chloride) batteries, which are used in medical instruments, fire alarms, and military systems.

The next step, Swager says, is to test the sensors on live chemical agents, outside of the lab, which are more dispersed and harder to detect, especially at trace levels. In the future, there’s also hope for developing a mobile app that could make more sophisticated measurements of the signal strength of an NFC tag: Differences in the signal will mean higher or lower concentrations of a toxic gas. “But creating new cell phone apps is a little beyond us right now,” Swager says. “We’re chemists.”

Here’s a link to and a citation for the paper,

Ultratrace Detection of Toxic Chemicals: Triggered Disassembly of Supramolecular Nanotube Wrappers by Shinsuke Ishihara, Joseph M. Azzarelli, Markrete Krikorian, and Timothy M. Swager. J. Am. Chem. Soc., Article ASAP DOI: 10.1021/jacs.6b03869 Publication Date (Web): June 23, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

Here are links to other posts about Swager’s work featured here previously:

Carbon nanotubes sense spoiled food (April 23, 2015 post)

Smart suits for US soldiers—an update of sorts from the Lawrence Livermore National Laboratory (Feb. 25, 2014 post)

Come, see my etchings … they detect poison gases (Oct. 9, 2012 post)

Soldiers sniff overripe fruit (May 1, 2012 post)