Graphene patch could help patients manage diabetes

A wearable, graphene-based patch could one day maintain healthy blood glucose levels in people by measuring the sugar in sweat and then delivering the necessary dose of a diabetes drug through the skin (Nat. Nanotech. 2016, DOI:10.1038/nnano.2016.38).

The device takes scientists a step closer to the “coveted prize” in diabetes care: a noninvasive method to monitor and control blood glucose levels, writes Richard Guyof the University of Bath in a commentary about the new work.

Currently, most diabetic patients keep track of their blood glucose levels by pricking their fingers and testing a resulting droplet of blood. For people who must monitor their levels regularly, this can be a literal pain. “There are a lot of people who don’t like sticking things in their skin,” Guy says.

About 15 years ago, the Food & Drug Administration approved a noninvasive glucose-monitoring device called the GlucoWatch Biographer. Patients wore it on their wrists, and it extracted glucose from interstitial fluid in the skin using a small current. It didn’t catch on, in part because it wasn’t user friendly, Guy tells C&EN.

For the new patch, the researchers, led by Dae-Hyeong Kim of Seoul National University, decided to detect glucose in sweat because previous studies had shown that levels of the sugar in perspiration match those in blood. Other groups have also developed devices that can analyze biomolecules in sweat (C&EN, Feb. 1, 2016, page 11).

The new device uses layers of the fluoropolymer Nafion to absorb sweat and carry it toward the device’s sensors, which are built on modified graphene. The team doped the graphene with gold atoms and functionalized it with electrochemically active materials to enable reactions needed to detect glucose.

In the patch’s glucose sensors, the enzyme glucose oxidase reacts with the sugar and produces hydrogen peroxide, which, through an electrochemical reaction, extracts current from the doped graphene. This produces an electrical signal proportional to the amount of glucose present. The patch also contains pH and temperature sensors that help ensure that the glucose sensor’s signals accurately reflect the sugar’s concentration in sweat.

When two healthy volunteers wore the patch, the measured glucose levels—including spikes after meals—matched those from a commercial glucose meter. To monitor the levels, the patch sent its sensor signals to a device that analyzed them and then wirelessly relayed the data to a smartphone.

The drug delivery half of the patch consists of an array of 1-mm-tall polymer microneedles that pierce the skin. Each needle is made from a mixture of the diabetes drug metformin and a dissolvable polymer, polyvinyl pyrrolidone. And the needles are coated with a layer of tridecanoic acid. A gold and graphene mesh sits on top of the needle array and serves as a heater that can melt the coatings.

Once the tridecanoic acid melts, the needle dissolves in the skin and releases its drug payload.

When researchers applied just the drug-delivery component to the stomachs of diabetic mice, they could deliver enough metformin to lower the animal’s elevated blood glucose levels by more than 50% in 6 hours.

Guy thinks the sensor portion of the patch is closer to real-world use than the drug-delivery component. To make the drug-delivery system practical, he says, the researchers must make the microneedle array as small as possible. That means they must find a drug that’s effective at low doses.

As for the glucose-detection half of the device, Guy wonders how often a user would have to calibrate the sensors to ensure accurate readings.

Still, he calls the patch an impressive proof of concept.

University of Bath

Chip-based technology enables reliable direct detection of Ebola virus

This hybrid device integrates a microfluidic chip for sample preparation and an optofluidic chip for optical detection of individual molecules of viral RNA. (Photo by Joshua Parks)

A team led by researchers at UC Santa Cruz has developed chip-based technology for reliable detection of Ebola virus and other viral pathogens. The system uses direct optical detection of viral molecules and can be integrated into a simple, portable instrument for use in field situations where rapid, accurate detection of Ebola infections is needed to control outbreaks.

Laboratory tests using preparations of Ebola virus and other hemorrhagic fever viruses showed that the system has the sensitivity and specificity needed to provide a viable clinical assay. The team reported their results in a paper published September 25 in Nature Scientific Reports.

An outbreak of Ebola virus in West Africa has killed more than 11,000 people since 2014, with new cases occurring recently in Guinea and Sierra Leone. The current gold standard for Ebola virus detection relies on a method called polymerase chain reaction (PCR) to amplify the virus's genetic material for detection. Because PCR works on DNA molecules and Ebola is an RNA virus, the reverse transcriptase enzyme is used to make DNA copies of the viral RNA prior to PCR amplification and detection.

"Compared to our system, PCR detection is more complex and requires a laboratory setting," said senior author Holger Schmidt, the Kapany Professor of Optoelectronics at UC Santa Cruz. "We're detecting the nucleic acids directly, and we achieve a comparable limit of detection to PCR and excellent specificity."

Sensitivity and specificity

In laboratory tests, the system provided sensitive detection of Ebola virus while giving no positive counts in tests with two related viruses, Sudan virus and Marburg virus. Testing with different concentrations of Ebola virus demonstrated accurate quantification of the virus over six orders of magnitude. Adding a "preconcentration" step during sample processing on the microfluidic chip extended the limit of detection well beyond that achieved by other chip-based approaches, covering a range comparable to PCR analysis.

"The measurements were taken at clinical concentrations covering the entire range of what would be seen in an infected person," Schmidt said.

Schmidt's lab at UC Santa Cruz worked with researchers at Brigham Young University and UC Berkeley to develop the system. Virologists at Texas Biomedical Research Institute in San Antonio prepared the viral samples for testing.

The system combines two small chips, a microfluidic chip for sample preparation and an optofluidic chip for optical detection. For over a decade, Schmidt and his collaborators have been developing optofluidic chip technology for optical analysis of single molecules as they pass through a tiny fluid-filled channel on the chip. The microfluidic chip for sample processing can be integrated as a second layer next to or on top of the optofluidic chip.

Sample preparation

Schmidt's lab designed and built the microfluidic chip in collaboration with coauthor Richard Mathies at UC Berkeley who pioneered this technology. It is made of a silicon-based polymer, polydimethylsiloxane (PDMS), and has microvalves and fluidic channels to transport the sample between nodes for various sample preparation steps. The targeted molecules--in this case, Ebola virus RNA--are isolated by binding to a matching sequence of synthetic DNA (called an oligonucleotide) attached to magnetic microbeads. The microbeads are collected with a magnet, nontarget biomolecules are washed off, and the bound targets are then released by heating, labeled with fluorescent markers, and transferred to the optofluidic chip for optical detection.

Schmidt noted that the team has not yet been able to test the system starting with raw blood samples. That will require additional sample preparation steps, and it will also have to be done in a biosafety level 4 facility.

"We are now building a prototype to bring to the Texas facility so that we can start with a blood sample and do a complete front-to-back analysis," Schmidt said. "We are also working to use the same system for detecting less dangerous pathogens and do the complete analysis here at UC Santa Cruz."

The lead authors of the paper are postdoctoral researcher Hong Cai and graduate student Joshua Parks, both in Schmidt's lab at UC Santa Cruz. A team led by Aaron Hawkins at BYU fabricated the silicon-based optofluidic chips. Virologist Jean Patterson led the team at Texas Biomedical Research Institute that prepared viral samples for testing. This research was supported by the W. M. Keck Center for Nanoscale Optofluidics at UC Santa Cruz and grants from the National Institutes of Health and the National Science Foundation.

UC Santa Cruz

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Nanotechnology produces cheaper and portable measuring instruments

Researching, creating and applying nanoparticles go hand in hand in bionanotechnology. However, it is high time for a periodic table of nanoparticles. “Scientists working in bionanotechnology find themselves in the same position as the alchemists of the early Renaissance,” says Professor Aldrik Velders in his inaugural lecture as Professor of Bionanotechnology at Wageningen University on 17 September.

Let's start by correcting one misunderstanding: nanoparticles are not extremely small. In fact, they vary in size - from a couple of atoms to millions of atoms or thousands of molecules - and make up an intermediate form between loose molecules and relatively large grains. Proteins are also a type of nanoparticle. “In light of this, chemists see nanoparticles as actually being quite large,” explains Professor Velders in his inaugural speech entitled 'Much ado about nano'. “Nanoparticles form a whole new world, complete with its own peculiarities. With this in mind, it is important that all nanoparticles which form spontaneously or are formed by human intervention are properly catalogued. This is why we are working on technology which will allow us to catalogue them effectively, adopting an optical approach via absorption and fluorescence and using magnetic resonance spectroscopy such as the technology used in MRI scans. We also do not have a periodic table of nanoparticles like the one we have for all chemical elements. We currently only know a few classes of particles, and we have very few predictive values. We also have very little understanding of how nanoparticles behave in biological systems - this despite the fact that the basis of life is found within the interaction of molecules and that nanoparticles could hold a range of useful applications.”

Creating nanoparticles

 

Aside from carrying out pure research, Velders is also active in creating therapeutic and diagnostic nanoparticles. “We can create nanoparticles which change colour when they are in the vicinity of other molecules. We are currently working on this project together with Leiden University Medical Center. Amongst other things, we aim to create applications for robot-assisted surgery. It is also possible to make hard and soft nanoparticles, as well as to insert extra molecules into the soft nanoparticles. We are currently researching how we can insert metal complexes into a large nanoparticle, or a 'micelle’, which can then be implemented as a sort of Trojan horse. This technique can be used in the first instance for diagnostic purposes; later, it could be used to administer medication into a cell. To give you an idea of the scale of this: if an atom were a large as a football, the micelle would be as large as the Main Auditorium of the university, and the cell would be a city as large as Wageningen. Alongside this, we are studying the coming together and break up of nanoparticles under the influence of biomarkers in blood samples and other areas. Changes in light absorption or fluorescence indicate that somebody has a certain disease.”

A lab on a chip

 

Velders is also involved in researching how nanotechnology can be applied. This mostly involves the development of diagnostic sensors, as he explains. “By developing miniature instruments, we can produce cheaper and portable devices that can be used everywhere. We can create a lab on a chip. This is useful for analyses of ditchwater on the campus, for instance, or for monitoring malaria infections in the field in Sub-Saharan Africa.” A significant development in this respect is that Velders and his group are now able to create microchannels in small blocks that are made of polydimethylsiloxane (PDMS), a type of rubber. They use the same plastic as Lego bricks to do this. By creating a flow of substances - in some cases cooled, heated, and/or illuminated - through the small channels, you can trigger reactions in the PDMS blocks or carry out measurements without the need for large and expensive apparatus.

NMR antennae

 

“We are also in the process of developing very small NMR antennae. Using NMR, we can observe energy in the form of radio frequencies. These are specific to an element or atom, so this can also tell us how atoms will look later in the same molecule or nanoparticle. Every element has its own specific frequency. Our nanospools can listen to all frequencies simultaneously instead of just one, which is usually the case. Our nanospools are also a lot cheaper. A normal spool can easily cost ten thousand euros, whereas our most recently development antennae cost less than one euro.”

Finally, Velders will soon become involved with the catching and removing of antibiotic-resistant bacteria from the waste water of hospitals in order to prevent these bacteria from spreading. “We are developing technology that will allow us to attach these cells to nanoplates. We can convert expensive hospital technology to purify waste water; so from nanotechnology used in refined medicines to nanotechnology used in mud.”

Wageningen University

Nanotechnology World Association

MIPT Physicists Develop Ultrasensitive Nanomechanical Biosensor

Two young researchers working at the MIPT Laboratory of Nanooptics and Plasmonics, Dmitry Fedyanin and Yury Stebunov, have developed an ultracompact highly sensitive nanomechanical sensor for analyzing the chemical composition of substances and detecting biological objects, such as viral disease markers, which appear when the immune system responds to incurable or hard-to-cure diseases, including HIV, hepatitis, herpes, and many others. The sensor will enable doctors to identify tumor markers, whose presence in the body signals the emergence and growth of cancerous tumors.

The sensitivity of the new device is best characterized by one key feature: according to its developers, the sensor can track changes of just a few kilodaltons in the mass of a cantilever in real time. One Dalton is roughly the mass of a proton or neutron, and several thousand Daltons are the mass of individual proteins and DNA molecules. So the new optical sensor will allow for diagnosing diseases long before they can be detected by any other method, which will pave the way for a new-generation of diagnostics.

The device, described in an article published in the journal Scientific Reports, is an optical or, more precisely, optomechanical chip. “We’ve been following the progress made in the development of micro- and nanomechanical biosensors for quite a while now and can say that no one has been able to introduce a simple and scalable technology for parallel monitoring that would be ready to use outside a laboratory. So our goal was not only to achieve the high sensitivity of the sensor and make it compact, but also make it scalabile and compatibile with standard microelectronics technologies,” the researchers said.

Unlike similar devices, the new sensor has no complex junctions and can be produced through a standard CMOS process technology used in microelectronics. The sensor doesn’t have a single circuit, and its design is very simple. It consists of two parts: a photonic (or plasmonic) nanowave guide to control the optical signal, and a cantilever hanging over the waveguide.

A cantilever, or beam, is a long and thin strip of microscopic dimensions (5 micrometers long, 1 micrometer wide and 90 nanometers thick), connected tightly to a chip. To get an idea how it works, imagine you press one end of a ruler tightly to the edge of a table and allow the other end to hang freely in the air. If you touch the latter with your other hand and then take your hand away, the ruler will start making mechanical oscillations at a certain frequency. That’s how the cantilever works. The difference between the oscillations of the ruler and the cantilever is only the frequency, which depends on the materials and geometry: while the ruler oscillates at several tens of hertz, the frequency of the cantilever’s oscillations is measured in megahertz. In other words, it makes a few million oscillations per second!

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There are two optical signals going through the waveguide during oscillations: the first one sets the cantilever in motion, and the second one allows for reading the signal containing information about the movement. The inhomogeneous electromagnetic field of the control signal’s optical mode transmits a dipole moment to the cantilever, impacting the dipole at the same time so that the cantilever starts to oscillate. 

The sinusoidally modulated control signal makes the cantilever oscillate at an amplitude of up to 20 nanometers. The oscillations determine the parameters of the second signal, the output power of which depends on the cantilever’s position.

The highly localized optical modes of nanowave guides, which create a strong electric field intensity gradient, are key to inducing cantilever oscillations. Because the changes of the electromagnetic field in such systems are measured in tens of nanometers, researchers use the term “nanophotonics” – so the prefix “nano” is not used here just as a fad! Without the nanoscale waveguide and the cantilever, the chip simply wouldn’t work. Abig cantilever cannot be made to oscillate by freely propagating light, and the effects of chemical changes to its surface on the oscillation frequency would be less noticeable..

Cantilever oscillations make it possible to determine the chemical composition of the environment in which the chip is placed. That’s because the frequency of mechanical vibrations depends not only on the materials’ dimensions and properties, but also on the mass of the oscillatory system, which changes during a chemical reaction between the cantilever and the environment. By placing different reagents on the cantilever, researchers make it react with specific substances or even biological objects. If you place antibodies to certain viruses on the cantilever, it’ll capture the viral particles in the analyzed environment. Oscillations will occur at a lower or higher amplitude depending on the virus or the layer of chemically reactive substances on the cantilever, and the electromagnetic wave passing through the waveguide will be dispersed by the cantilever differently, which can be seen in the changes of the intensity of the readout signal.

Calculations done by the researchers showed that the new sensor will combine high sensitivity with a comparative ease of production and miniature dimensions, allowing it to be used in all portable devices, such as smartphones, wearable electronics, etc. One chip, several millimeters in size, will be able to accommodate several thousand such sensors, configured to detect different particles or molecules. The price, thanks to the simplicity of the design, will most likely depend on the number of sensors, being much more affordable than its competitors.

This work was financed by the Russian Ministry of Education and Science through state order # 16.19.2014 / K. 

Source: http://www.nanotechnologyworld.org/#!MIPT-Physicists-Develop-Ultrasensitive-Nanomechanical-Biosensor/c89r/55770f270cf293eac8071cb0