Better than silicon

Graphene in medicine

Dmitry Kireev, Post-science

In 2010 , Andrey Geim and Konstantin Novoselov received the Nobel Prize for "pioneering experiments concerning two-dimensional graphene material." Since then, physicists and chemists around the world have begun to explore the properties of the new material and find new practical applications for them. Graphene is used to create electronic chips, sensors for gases, membranes for water purification. With the advent of graphene, a new stage in the development of medical technologies and bioelectronics began.

Graphene Properties

Graphene is a two–dimensional material, an allotropic modification of carbon. In the case of graphene, carbon atoms are arranged in a hexagonal structure and form a layer one atom thick – this is graphene.

It acquires such a structure due to sp2 hybridization. Four electrons are located on the outer shell of the carbon atom: during sp2 hybridization, three of them bond with neighboring atoms, and the fourth is in a state that forms energy zones. Therefore, due to sp2 hybridization, graphene has unique electrical properties and perfectly conducts electric current. Graphene also has impressive mechanical properties: it is flexible, thin and 97% transparent.

Theoretical work proves that graphene is very hard and resistant to mechanical stress. At the same time, if you put it on a substrate of soft material, it will take on its properties. These characteristics are useful in bioelectronics, in which scientists develop devices for use in living organisms. In this area, priority is given to soft materials that are more compatible with the tissues of the body. Silicon and hard metals, which are used in conventional electronics, are poorly suited for this. Since 2008, there have been works on graphene neurodevices and biosensors: scientists are exploring the possibilities of a new material and are already achieving tangible results in this area.

Neurodevices: reading the activity of neurons

Based on the unique properties of graphene, it is possible to make neurodevices that read the activity of neurons. The basic element of such devices is a graphene (ambipolar, field–effect) transistor through which current flows if voltage is applied. Bioelectronics developers make chips on which graphene transistors are placed on flexible substrates. Neuronal cells are grown on top of this chip. After about three weeks, when the cells grow sufficiently, they interact with each other and spontaneously excite, produce an impulse. On the surface of the cell, the charge changes – quickly and slightly, by tens of millivolts. This surface charge affects the conductivity of graphene due to the field effect, that is, the neuronal pulse changes the current throughout the transistor. Scientists read it and thereby see the activity of neurons. Neurodevices are dealt with at the Center for Microelectronics Research in At the University of Texas at Austin, as well as at the Institute of Bioelectronics at the Julich Research Center in Germany. The technology works in laboratory conditions, now scientists from The University of Texas is making devices that can be implanted in the brain. Several such devices have already been created by other research groups, they were able to test them in vivo on mice and rats.

In the future, this technology can be used for people. Neurodevices can make life easier for people with Parkinson's disease, who often face tremor, involuntary muscle contraction. To regulate seizures, patients are implanted with multielectrode arrays that deeply stimulate the brain with electrical impulses. When seizures occur, the patient presses a button on the mini-device, and several signals are sent through the electrode to the part of the brain that is responsible for the disease.

The problem with standard multielectrode arrays is that they are made of solid silicon. Implanting a silicon device in the brain is like trying to put a nail in a soft candy. The body reacts to silicon electronics as a foreign body. Glial cells form around such devices, with the help of which the brain tries to protect neurons and push out a foreign object. Therefore, stimulants are changed every 2-5 years. On the basis of graphene, it is possible to develop completely different devices – flexible, thin and soft. The cells test such a device, the protective reaction will not start. Then the devices can be changed much less often – every few decades.

Relief of Parkinson's disease is far from the only field of application of graphene neurodevices. They will be useful to researchers working with any neurodegenerative diseases. Most of them are still insufficiently studied: scientists lack data on how the human brain works. Now silicon devices are also used for such observations, so more efficient graphene devices will replace them in research tasks. 

Sensors: determination of biomarkers

Another application of graphene is the creation of sensors that detect biomarkers. In this way, it is possible to measure neuronal bioreceptors, DNA, immunoglobulin, biomarkers associated with cancer or cardiovascular diseases. This gives doctors new opportunities to diagnose diseases.

Biosensor devices also work on graphene transistors, but they are more complicated. Graphene is a carbon lattice in one plane. To make a biosensor, the molecule must interact with graphene. To do this, you need to build its two- or three–level functionalization - attach several chemical groups to graphene. To begin with, graphene is functionalized with pyrene, a chemical compound with the formula C ₁₆ H ₁₀, (cyclic polyaromatic hydrocarbon). This molecule can already be functionalized with others: for example, add glucose oxidase to it, and the result will be a biosensor for glucose. When glucose approaches glucose oxidase, these two elements will enter into a chemical reaction. It will provoke a change in the current in the graphene transistor, which scientists can observe and draw conclusions about the level of the biomarker in the body. A group of Korean researchers have built a glucose sensor into multifunctional contact lenses – they determine the glucose level based on the composition of the tear. In 2017, this technology was tested on rabbits. More recently, a Russian group has created graphene-based biosensors that allow measuring toxins, in particular ochratoxin A, which is considered one of the most dangerous. In the future, all these technologies will make it possible to more accurately diagnose diseases and track their course.

The myth of graphene toxicity

The question of the potential toxicity of graphene is inevitably raised at any conferences. Every time scientists have to explain that this is not quite true. Graphene can be produced in several ways. One of them is a simple stirring of graphite or carbon in water, which results in small particles with lateral dimensions of graphene less than one hundred nanometers. Graphene of this kind is really dangerous for cells: in the 2010s, researchers Akhavan and Gaderi published a paper that proved that small particles pass through the cell membrane and kill the cell.

Modern bioelectronics uses high-quality graphene grown by chemical deposition from the gas phase. It is a homogeneous layer of atoms over a very large area – up to 100 by 100 millimeters. Then the developers reduce it to about 100 by 100 micrometers and fix it on the substrate. In this case, it cannot show toxicity because it does not float among the cells. Moreover, there are several works in which scientists have grown cells on top of graphene on a substrate and on ordinary glass and compared the results. It turned out that cells grow much more actively on graphene. Graphene is a biocompatible material, because it is ordinary carbon.

Signal pre-amplification: the problem of data transmission at a distance

One of the disadvantages of graphene for electronics is the absence of a band gap, a range of values that electrons in a substance cannot possess. In graphene, electrons have arbitrary energy. It conducts current too well, so it is impossible to make a classical transistor based on it with positions 1 and 0, the presence and absence of current. A graphene transistor never closes: it simply conducts current either well or poorly. Because of this, it does not perform logical operations that classical silicon transistors can handle. This is a significant problem for modern graphene electronics.

The bioelectric potentials created by neuronal cells around the membrane are rather weak: from ten to two hundred microvolts, depending on the cell, the width of the gap between it and graphene, and other factors. It is almost impossible to transmit them over a distance of several meters without loss:  electromagnetic waves from other devices drown out a weak signal. It is impossible to build transistors based on graphene that will perform logical operations to amplify the signal. The optimal solution would be to use graphene for measurement and create additional transistors from other 2D materials. They will allow the signal to be pre-amplified from 10 microvolts to 10 millivolts, which can be carried out without loss for 10 kilometers. This is an important task for both conventional electronics and medical devices. Signal pre-amplification will make all technologies wireless and interact with devices through transistor systems.

Prospects of practical application of graphene

It is difficult to say when graphene bioelectronics will be widely used in practice. Scientists are testing neurodevices, biosensors and other research projects in the laboratory. In order to bring them to the level of medical use, it is necessary to develop the industry of production of graphene devices. From 10 to 100 devices are usually made for research. Medical practice requires a much larger scale: thousands and millions of such devices are needed. Now it seems that the prospect of practical application is still far beyond the horizon, but in 5-10 years it will be possible to say something more definite. Research groups are experimenting with graphene in different directions, using it to solve many problems. While it is difficult to single out promising approaches unambiguously, it takes time and investments that will help develop existing research.

About the author:
Dmitry Kireev – PhD in Microelectronics, The University of Texas at Austin.

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