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

Sensors slip into the brain, then dissolve when the job is done

A team of neurosurgeons and engineers has developed wireless brain sensors that monitor intracranial pressure and temperature and then are absorbed by the body, negating the need for surgery to remove the devices.

Such implants, developed by scientists at Washington University School of Medicine in St. Louis and engineers at the University of Illinois at Urbana-Champaign, potentially could be used to monitor patients with traumatic brain injuries, but the researchers believe they can build similar absorbable sensors to monitor activity in organ systems throughout the body. Their findings are published online Jan. 18 in the journal Nature.

"Electronic devices and their biomedical applications are advancing rapidly," said co-first author Rory K. J. Murphy, MD, a neurosurgery resident at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "But a major hurdle has been that implants placed in the body often trigger an immune response, which can be problematic for patients. The benefit of these new devices is that they dissolve over time, so you don't have something in the body for a long time period, increasing the risk of infection, chronic inflammation and even erosion through the skin or the organ in which it's placed. Plus, using resorbable devices negates the need for surgery to retrieve them, which further lessens the risk of infection and further complications."

Murphy is most interested in monitoring pressure and temperature in the brains of patients with traumatic brain injury.

About 50,000 people die of such injuries annually in the United States. When patients with such injuries arrive in the hospital, doctors must be able to accurately measure intracranial pressure in the brain and inside the skull because an increase in pressure can lead to further brain injury, and there is no way to reliably estimate pressure levels from brain scans or clinical features in patients.

"However, the devices commonly used today are based on technology from the 1980s," Murphy explained. "They're large, they're unwieldy, and they have wires that connect to monitors in the intensive care unit. They give accurate readings, and they help, but there are ways to make them better."

Murphy collaborated with engineers in the laboratory of John A. Rogers, PhD, a professor of materials science and engineering at the University of Illinois, to build new sensors. The devices are made mainly of polylactic-co-glycolic acid (PLGA) and silicone, and they can transmit accurate pressure and temperature readings, as well as other information.

"With advanced materials and device designs, we demonstrated that it is possible to create electronic implants that offer high performance and clinically relevant operation in hardware that completely resorbs into the body after the relevant functions are no longer needed," Rogers said. "This type of bio-electric medicine has great potential in many areas of clinical care."

The researchers tested the sensors in baths of saline solution that caused them to dissolve after a few days. Next, they tested the devices in the brains of laboratory rats.

Having shown that the sensors are accurate and that they dissolve in the solution and in the brains of rats, the researchers now are planning to test the technology in patients.

"In terms of the major challenges involving size and scale, we've already crossed some key bridges," said co-senior author Wilson Z. Ray, MD, assistant professor of neurological and orthopaedic surgery at Washington University.

In patients with traumatic brain injuries, neurosurgeons attempt to decrease the pressure inside the skull using medications. If pressure cannot be reduced sufficiently, patients often undergo surgery. The new devices could be placed into the brain at multiple locations during such operations.

"The ultimate strategy is to have a device that you can place in the brain -- or in other organs in the body -- that is entirely implanted, intimately connected with the organ you want to monitor and can transmit signals wirelessly to provide information on the health of that organ, allowing doctors to intervene if necessary to prevent bigger problems," Murphy said. "And then after the critical period that you actually want to monitor, it will dissolve away and disappear."

Washington University School of Medicine

Nanotech weapon against chronic bacterial infections in hospitals

One of the scourges of infections in hospitals -- biofilms formed by bacteria that stick to each other on living tissue and medical instruments, making them harder to remove -- can be tricked into dispersing with the targeted application of nanoparticles and heat, researchers have found.

The University of New South Wales study, jointly led by Associate Professor Cyrille Boyer of the School of Chemical Engineering and deputy director of Australian Centre for NanoMedicine, appears in today's issue of Nature's open access journal Scientific Reports.

"Chronic biofilm-based infections are often extremely resistant to antibiotics and many other conventional antimicrobial agents, and have a high capacity to evade the body's immune system," said Boyer. "Our study points to a pathway for the non-toxic dispersal of biofilms in infected tissue, while also greatly improving the effect of antibiotic therapies." 

Biofilms have been linked to 80% of infections, forming on living tissues (eg. respiratory, gastrointestinal and urinary tracts, oral cavities, eyes, ears, wounds, heart and cervix) or dwelling in medical devices (eg. dialysis catheters, prosthetic implants and contact lenses).

The formation of biofilms is a growing and costly problem in hospitals, creating infections that are more difficult to treat -- leading to chronic inflammation, impaired wound healing, rapidly acquired antibiotic resistance and the spread of infectious embolisms in the bloodstream.

They also cause fouling and corrosion of wet surfaces, and the clogging of filtration membranes in sensitive equipment -- even posing a threat to public health by acting as reservoirs of pathogens in distribution systems for drinking water.

In general, bacteria have two life forms during growth and proliferation: planktonic, where bacteria exist as single, independent cells; or aggregated together in colonies as biofilms, where bacteria grow in a slime-like polymer matrix that protects them from the environment around them.

Acute infections mostly involve planktonic bacteria, which are usually treatable with antibiotics.

However, when bacteria have had enough time to form a biofilm -- within a human host or non-living material such as dialysis catheters -- an infection can often become untreatable and develop into a chronic state.

Although biofilms were first recognised in the 17th century, their importance was not realised until the 1990s, when it became clear that microbes exist in nature more often in colonies made up of lots of different microorganisms that adhere to surfaces through slime excreted by their inhabitants. Thus began a global race to understand biofilms, at a time when it was also realised they were responsible for the majority of chronic infections.

The discovery of how to dislodge biofilms by the UNSW team - jointly led by Dr Nicolas Barraud, formerly of UNSW and now at France's Institut Pasteur -- was made using the opportunistic human pathogen Pseudomonas aeruginosa. This is a model organism whose response to the technique the researchers believe will apply to most other bacteria.

When biofilms want to colonise a new site, they disperse into individual cells, reducing the protective action of the biofilm. It is this process the UNSW team sought to trigger, making the bacteria again susceptible to antimicrobial agents.

The UNSW team found that by injecting iron oxide nanoparticles into the biofilms, and using an applied magnetic field to heat them -- which induces local hyperthermia through raising the temperature by 5°C or more - the biofilms were triggered into dispersing.

They achieved this using iron oxide nanoparticles coated with polymers that help stabilise and maintain the nanoparticles in a dispersed state, making them an ideal non-toxic tool for treating biofilm infections.

"The use of these polymer-coated iron oxide nanoparticles to disperse biofilms may have broad applications across a range of clinical and industrial settings," said Boyer, who in October was named Physical Scientist of the Year in Australia's Prime Minister's Prizes for Science.

"Once dispersed, the bacteria are easier to deal with - creating the potential to remove recalcitrant, antimicrobial-tolerant biofilm infections."

University of New South Wales

Nanotechnology World Association

Scientists manipulate consciousness in rats

NIH-funded study may guide deep brain stimulation therapies used for neurological disorders

Scientists showed that they could alter brain activity of rats and either wake them up or put them in an unconscious state by changing the firing rates of neurons in the central thalamus, a region known to regulate arousal. The study, published ineLIFE, was partially funded by the National Institutes of Health.

"Our results suggest the central thalamus works like a radio dial that tunes the brain to different states of activity and arousal," said Jin Hyung Lee, Ph.D., assistant professor of neurology, neurosurgery and bioengineering at Stanford University, and a senior author of the study.

Located deep inside the brain the thalamus acts as a relay station sending neural signals from the body to the cortex. Damage to neurons in the central part of the thalamus may lead to problems with sleep, attention, and memory. Previous studies suggested that stimulation of thalamic neurons may awaken patients who have suffered a traumatic brain injury from minimally conscious states.

Dr. Lee's team flashed laser pulses onto light sensitive central thalamic neurons of sleeping rats, which caused the cells to fire. High frequency stimulation of 40 or 100 pulses per second woke the rats. In contrast, low frequency stimulation of 10 pulses per second sent the rats into a state reminiscent of absence seizures that caused them to stiffen and stare before returning to sleep.

"This study takes a big step towards understanding the brain circuitry that controls sleep and arousal," Yejun (Janet) He, Ph.D., program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS).

When the scientists used functional magnetic resonance imaging (fMRI) to scan brain activity, they saw that high and low frequency stimulation put the rats in completely different states of activity.

Cortical brain areas where activity was elevated during high frequency stimulation became inhibited with low frequency stimulation. Electrical recordings confirmed the results. Neurons in the somatosensory cortex fired more during high frequency stimulation of the central thalamus and less during low frequency stimulation.

"Dr. Lee's innovative work demonstrates the power of using imaging technologies to study the brain at work," said Guoying Liu, Ph.D., a program director at the NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB).

How can changing the firing rate of the same neurons in one region lead to different effects on the rest of the brain?

Further experiments suggested the different effects may be due to a unique firing pattern by inhibitory neurons in a neighboring brain region, the zona incerta, during low frequency stimulation. Cells in this brain region have been shown to send inhibitory signals to cells in the sensory cortex.

Electrical recordings showed that during low frequency stimulation of the central thalamus, zona incerta neurons fired in a spindle pattern that often occurs during sleep. In contrast, sleep spindles did not occur during high frequency stimulation. Moreover, when the scientists blocked the firing of the zona incerta neurons during low frequency stimulation of the central thalamus, the average activity of sensory cortex cells increased.

Although deep brain stimulation of the thalamus has shown promise as a treatment for traumatic brain injury, patients who have decreased levels of consciousness show slow progress through these treatments.

"We showed how the circuits of the brain can regulate arousal states," said Dr. Lee. "We hope to use this knowledge to develop better treatments for brain injuries and other neurological disorders."

National Institute of Neurological Disorders and Stroke

Nanotechnology World Association

A giant fullerene system inhibits the infection by an artificial Ebola virus

Different studies have demonstrated that the ebola virus infection process starts when the virus reaches the cellular DC-SIGN receptor to infect the dendritic cells (of the immune system). European researchers have designed a "giant" molecule formed by thirteen fullerenes covered by carbohydrates which, by blocking this receptor, are able to inhibit the cell infection by an artificial ebola virus model.

In this study, published in Nature Chemistry, researchers from the Universidad Complutense de Madrid/IMDEA-Nanociencia, the Instituto de Investigación Sanitaria Hospital 12 de Octubre (Madrid), and the Instituto de Investigaciones Químicas del CSIC-Universidad de Sevilla have collaborated, together with three european research groups (CNRS/Université de Strasbourg, France and Université de Namur, Belgium).

"Fullerenes are hollow cages exclusively formed by carbon atoms", explains Nazario Martín, Professor of Organic Chemistry in the UCM and main author of the study. In this work, scientists have employed C60 fullerene, which is formed by 60 carbon atoms and has the shape of a truncated icosahedron, which resembles a football ball.

These molecules decorated with specific carbohydrates (sugars) present affinity by the receptor used as an entry point to infect the cell and act blocking it, thus inhibiting the infection.

Researchers employed an artificial ebola virus by expressing one of its proteins, envelope protein GP1, responsible of its entry in the cells. In a model in vitro, this protein is covering a false virus, which is able of cell infection but not of replication.

"We have employed a cell model previously described in our lab which consists in a cell line of human lymphocytes expressing DC-SIGN receptor, which facilitates the entry of the virus in Dendritic Cells", points out Rafael Delgado, researcher of the Hospital 12 de Octubre, and other of the authors of the study.

By blocking this receptor and inhibiting the virus infection, the authors think that the dissemination of the virus would decrease and the immune response increase, but this idea has still to be developed with in vivo studies.

The biggest fullerene system in the lab

The system designed by the chemists, based on carbon nanostructures developed in the UCM, mimic the presentation of carbohydrates surrounding virus like ebola or VIH.

The team has achieved an unprecedented success in fullerene chemistry and dendritic growth: connecting in one synthetic step twelve fullerene units, each with ten sugars, to other central fullerene, creating a globular superstructure with 120 sugar moieties on its surface, "this is the fastest dendrimeric growth developed in a laboratory up to now" says Beatriz Illescas, Professor in the UCM and coauthor of the work.

According to scientists, the results highlight the potential of these giant molecules as antiviral agents. "This work open the door to the design and preparation of new systems to inhibit the pathogens infection in cases where the current therapies are not effective or are inexistent, as occurs with the ebola virus", clarifies Martín.

After these experiments on the cellular level, researchers will study the behavior of these systems in animal models, starting with mice. "We will study, on the one hand, the pharmacokinetics and, on the other, the antiviral activity in vivo" explains Javier Rojo, researcher of the Instituto de Investigaciones Químicas del CSIC and other of the authors of the study. Once the most effective compound has been identified, studies using the true ebola virus could be carried out.

Universidad Complutense de Madrid