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Graphene underpins a new platform to selectively ID deadly strains of bacteria

Posted By Graphene Council, Friday, March 20, 2020
Using a single atom-thick sheet of graphene to track the electronic signals inherent in biological structures, a team led by Boston College researchers has developed a platform to selectively identify deadly strains of bacteria, an advance that could lead to more accurate targeting of infections with appropriate antibiotics, the team reported in the journal Biosensors and Bioelectronics.

The prototype demonstrates the first selective, rapid, and inexpensive electrical detection of the pathogenic bacterial species Staphylococcus aureus and antibiotic resistant Acinetobacter baumannii on a single platform, said Boston College Professor of Physics Kenneth Burch, a lead co-author of the paper.

The rapid increase in antibiotic resistant pathogenic bacteria has become a global threat, in large part because of the over prescription of antibiotics. This is driven largely by the lack of fast, cheap, scalable, and accurate diagnostics, according to co-author and Boston College Associate Professor of Biology Tim van Opijnen.

Particularly crucial is identifying the bacterial species and whether it is resistant to antibiotics, and to do so in a platform which can be easily operated at the majority of points of care. Currently such diagnostics are relatively slow - taking from hours to days - require extensive expertise, and very expensive equipment.

The BC researchers, working with colleagues from Boston University, developed a sensor, known as a graphene field effect transistor (G-FET), that can overcome critical shortcomings of prior detection efforts since it is a highly scalable platform that employs peptides, chains of multiple linked amino acids, which are inexpensive and easy-to-use chemical agents, according to co-author and BC Professor of Chemistry Jianmin Gao.

The team set out to show it could construct a device that can "rapidly detect the presence of specific bacterial strains and species, exploiting the large amount of electric charge on their surface and ability to capture them with synthetic peptides of our own design," said Burch.

The initiative built upon the earlier research of van Opijnen and Gao, who previously found peptides were highly selective, but at that time required expensive fluorescence microscopes for their detection. In addition to Burch, Gao, and van Opijnen, the lead co-authors of the paper included Boston University Assistant Professor of Chemistry Xi Ling.

The team modified existing peptides to allow them to attach to graphene, a single atomic layer of carbon. The peptides were designed to bind to specific bacteria, rejecting all others. In essence, the G-FET is able to monitor the electric charge on the graphene, while exposing it to various biological agents.

Due to the selectivity of the peptides, the researchers were able to pinpoint their attachment to the desired bacterial strain, the team reported in the article "Dielectrophoresis assisted rapid, selective and single cell detection of antibiotic resistant bacteria with G-FETs." By electrically monitoring the resistance and, ultimately, charge on the device, the presence of bacteria attached to graphene could be resolved, even for just a single cell.

To enable greater speed and high sensitivity, an electrical field was placed on the liquid to drive the bacteria to the device, again exploiting the charge on the bacteria, the team reported. This process, known as dielectrocphoresis, had never previously been applied to graphene-based sensors and could potentially open the door to dramatically improving efforts in that field to employ graphene for biosensing, the team reported.

"We were surprised how well the bacteria were electrically guided to the devices," said Burch. "We thought it would somewhat reduce the required time and needed concentration. Instead, it worked so well that the electric field was able to bring needed concentration of bacteria down by a factor of 1000, and reduce the time to detection to five minutes."

Tags:  Bioelectronics  Biossensor  Boston College  Graphene  Healthcare  Kenneth Burch  Tim van Opijnen 

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Jose A. Garrido’s vision: graphene bioelectronic eye implants

Posted By Graphene Council, Thursday, December 12, 2019
Jose A. Garrido is an ICREA Research Professor and leader of the Advanced Electronic Materials and Devices group at Graphene Flagship partner ICN2, in Barcelona. He is also the Deputy Leader of the Graphene Flagship's Biomedical Technologies Work Package, and he has a vision: a world in which doctors can cure diseases and disabilities using biomedical implants enabled by novel electronic materials like graphene.

His pioneering work on graphene-enabled retinal implants, which aim to provide artificial vision to patients with retinal degeneration, is internationally recognised – Garrido and his collaborators have recently been awarded a €1 million grant by the la Caixa Foundation to fund their research. He plans to use the money to enable an ambitious three-year project to design the next generation of retinal prostheses using graphene-based electrodes.

I spoke with Garrido at the Graphene Connect event in Barcelona, this November, and gained some fantastic insights into the work he's doing and his ideas for the future of medical bioelectronic devices.

What motivated you to start working on retinal implants?

In general, I'm very interested in merging electronics with biology to solve health problems. It started before trying to solve vision problems – in general, I've always been interested in how we could use electronics to help patients. But years ago, some people I was working with in France made me start thinking about the problem of blindness, and how it affects people. I thought that this would be a good bench test for our technologies, and a great platform for me to try to understand the challenges of restoring vision. I wanted to investigate how graphene electronics could solve these challenges.

Why use graphene?

Well, firstly, I started with other materials. Years ago, I was working with materials that are also chemically resistant, such as semiconductors like gallium nitride, and then I moved to diamond because it was stable as well. However, for each of these materials, we always had some sort of trouble! Either the flexibility was a problem, the material was not sensitive enough, or we couldn't inject sufficient charge. But when graphene came, everything changed. The fact is, we haven't found a reason not to work with graphene yet. It has a combination of properties that make it very attractive.

What makes graphene so good for biomedical devices?

Firstly, for this application, I believe the ability to integrate graphene with flexible technologies is the most important. You need to integrate it into a flexible substrate and do all the fabrication and microfabrication required to produce your device.

It also needs to be able to interface with the nervous system, to stimulate and to monitor electrical activity. In order to have a proper interface with the nervous system, you can't just have either recording or simulation. You need both to enable bidirectional communication. So far, graphene is very good at stimulating and recording nervous tissue. We can easily integrate it into flexible substrates, and it's a durable material when exposed to a harsh environment.

Could you explain to me how the retinal implants function in layman's terms?

We're trying to help patients who have degenerated photoreceptors. This happens in several neurodegenerative diseases such as retinitis pigmentosa or age-related macular degeneration. But this degeneration does not mean that the whole retina is degenerated. There are some parts of the retina that are still intact, and those are still connected to the optical nerve.

One solution is to have photoreceptors which stimulate the intact part of the retina, and then transfer that information through the optical nerve to the visual cortex.

We're taking a different approach. We don't use the photoreceptors – instead, we plan to implant an array of graphene-based electrodes on the retina. These electrodes mimic photoreceptor stimulation with an electrical impulse. It works like this: an image is captured with an external camera, then this information is sent wirelessly to the implant, received in the form of pulses applied to each of the electrodes on the implant. This effectively copies the function of the photoreceptors and should allow the patient to see a pixelated image.

What would you say are the challenges going forward?

When it comes to integrating graphene, we're at a pre-industrial level. But over the last four years, thanks to the Graphene Flagship, among other projects, we've gone from being research-orientated to actually applying that research. We have pre-industrial device prototypes, and we do fabrication in cleanrooms – the same cleanrooms we use for research. For me, I think that that integration and demonstration of the prototypes is not the challenge. The challenge is industrialisation.

How can we jump from what we do in a pre-industrial cleanroom to large-scale fabrication? Who is going to mass-produce these technologies? Right now, there's no one in Europe who can do this type of production on such a large scale, with the required levels of standardisation.

That's the main challenge for a lot of applications of graphene, and we're all suffering from the same problems. The Graphene Flagship have now realised this, and that's why they have launched the Standardisation and Validation services, and will soon launch the Experimental Pilot Line. This is a very important effort, but it will have to be matched by industry.

What ultimately led to you being awarded the grant?

Competition was very tough, I can tell you! They really valued the multidisciplinary team that we put together – it's really unique to have such a strong team with such different backgrounds, sharing the costs and responsibilities. Each of us was an expert in our field, and we just really wanted to work together. Experts in optical imaging were from ICFO, experts in electronics and ASIC design came from IFAE, clinicians were from the Barraquer Foundation, and the Paris Vision Institute provided experts in retina electrophysiology.

How are you going to use the €1 million grant?

We need to develop some understanding of the challenges. The challenges are not only at the interface with the tissue – there are challenges with the wireless transmission, with the design of the specialized chip controlling the whole system, and with the powering of the device. How do you power a device that small?

This grant is going to be crucial to bring together such a multidisciplinary team. A team that knows about optics, wireless transmission, neural interfaces, materials science and biology. Of course, we're going to divide the pie into many pieces. But we hope that when we put these pieces together, the project will be a great success.

Finally, where do you see graphene-enabled retinal implants in 10 years?

In 10 years, the project should be a commercial success! I think that in just three years, we should have demonstrated some of the hypotheses that we are proposing now. Without doubt, there's a huge amount of work to be done if we want to help patients to recover part of their lost vision, not to mention the promise of a complete recovery – but our technology will also lead to significant improvements in many other fields where medical neural implants are currently used, including brain surgery, epilepsy monitoring, and movement disorders such as Parkinson's disease.

Tags:  Bioelectronics  electronic materials  Graphene  Graphene Flagship  Healthcare  Jose A. Garrido 

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Using electronics to solve common biological problems

Posted By Graphene Council, Wednesday, December 4, 2019
Researchers from multiple disciplines are working together at KAUST to develop bioelectronics that can detect diseases, treat cancers and track marine animals; they may even discover the next generation of computing systems.

Cancer-killing magnets

Jurgen Kosel is an electrical engineer who loves to play with magnets. His research group has developed a technique to fabricate unique magnetic iron-oxide nanowires that can kill cancer cells1.

“Certain kinds of iron-based magnetic nanoparticles were approved many years ago by the U.S. Food and Drug Administration for use inside the human body. They are regularly used as contrast agents in magnetic resonance imaging and as nutritional supplements for people with iron deficiency,” says Kosel.

The magnetic nanoparticles currently in use are spherical in shape. Kosel and his team developed wire-shaped magnetic nanoparticles that can be rotated like a compass needle, creating a pore in cancer cell membranes that induces natural cell death. These cancer-killing nanowires can be made even more effective when coated with an anti-cancer drug or heated with a laser. They are "eaten" by cancer cells, and once released inside, they can wreak havoc.

Kosel has been working closely with cell biologist Jasmeen Merzaban, and more recently, with organic chemist Niveen Khashab to "functionalize" the surfaces of his magnetic nanowires to ensure the body’s immune system does not treat them as foreign. They are also working on preventing the wires from sticking together and on targeting cancer cells more specifically by coating them with antibodies that recognize specific antigens on their cell membranes.

Kosel has also worked with electrical engineer Muhammad Hussain to use magnets for improving the safety of cardiac catheters. They have developed a flexible magnetic sensor that is sensitive enough to detect the Earth’s magnetic field. When these sensors are placed on the tip of a cardiac catheter, for example, clinicians can detect its orientation inside blood vessels. This enables them to direct it where it is needed in order to insert a stent, for example, to relieve blockage in a heart artery. This reduces the need for prolonged doses of X-rays and contrast dyes during procedures like coronary angioplasty.

Disease detection

“Over the past 50 years, the 500-billion-dollar semiconductor industry has mainly focused on two applications: computing and communications,” says KAUST electrical engineer, Khaled Salama. “But this technology holds a lot of promise for other areas, including medical research, as people are living longer and needing more care. We need a paradigm shift to leverage some of the technologies we’ve developed for use in this area.”

Salama has developed a sensor that can detect "C-reactive proteins," a biomarker of cardiovascular disease2. He’s done this by functionalizing electrodes with nanomaterials and gold nanoparticles to improve their sensitivity. The electrodes give a signal that is proportional to the amount of C-reactive protein in a blood sample. His group developed a unique process that 3D prints the microfluidic channels that deliver samples to the sensor for biological detection.

Elsewhere at KAUST, Sahika Inal is developing a device that can make life easier for diabetics.

Inal comes from a textile manufacturing background, but her studies on the electrical properties of polymers, which are biocompatible, have led her down the route of bioelectronics. 

Her team has developed inkjet-printed, disposable, polymer-based sensors that can measure glucose levels in saliva3. “We inkjet-print conducting polymers. The biological ink contains the enzymes used for glucose sensing, an encapsulation layer that protects the enzymes, a layer that only allows glucose penetration and an insulating layer to protect the electronics,” she explains. “And then you have a paper-based sensor within a few minutes!”

Inal is also developing other biochemical sensors that can generate their own energy from compounds already present in the body to power implantable devices, such as cardiac pacemakers.

“To conduct impactful bioelectronics work, I need to be in an environment where there are biologists, the people who can give me feedback on what I develop,” says Inal.

Bio-inspired computers and animal tracking
Bioelectronics not only encompass electronic devices designed to solve biological problems, they are also electronic solutions inspired by biology.

Khaled Salama is interested in a relatively new type of bio-inspired device called a "memristor"4. These are electrical components inspired by the neural networks and synapses of the brain. Researchers hope they will lead to the next generation of computing systems and that they will be better equipped to very rapidly process huge amounts of data. Salama has developed an approach that improves their computational efficiency while reducing power consumption in these typically energy-intensive devices.

Sensing data in harsh marine environments can be particularly challenging, says Kosel. Researchers have often resorted to electronic tags placed on large marine animals to track their movements. They also use electronic sensors to conduct flow, salinity, pressure and temperature measurements in the sea. Smaller, lighter, less power-hungry tags are needed to resist corrosion, and withstand biofouling, a bacterial crust that forms on almost anything that stays in the sea for too long.

Kosel’s solution was to develop graphene sensors fabricated with a single-step laser-printing technique for marine applications. These laser-induced graphene sensors are resistant to corrosion and can survive high temperatures. They are very light and flexible, making them suitable for attaching to smaller marine animals. They also developed a technique5 that involves conducting high-frequency measurements that allow them to withstand the effects of an accumulating biofouling layer.

The group have started a conference, which will be held annually at KAUST. Last year, among the many esteemed attendees was George Malliaras, a Prince Philip Professor of Technology at the University of Cambridge. Malliaras praised the university for its world-class instrumentation, access to excellent collaborations within the campus and mechanisms to collaborate with people abroad. He says, "Taken together, these attributes have made KAUST very successful at addressing some of the most important problems that humanity faces today." 

Tags:  Bioelectronics  George Malliaras  Graphene  Healthcare  Jasmeen Merzaban  Jurgen Kosel  Khaled Salama  King Abdullah University of Science and Technology  Muhammad Hussain  nanoparticles  Niveen Khashab  Sahika Inal  semiconductor  University of Cambridge 

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