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HOME > No.31, Nov. 2022 > Feature Story : Enabling disease diagnosis and viral detection with ultra-sensitive microsensors

Enabling disease diagnosis and viral detection with ultra-sensitive microsensors

Kazuhiro Takahashi

Kazuhiro Takahashi

Professor Kazuhiro Takahashi is working on the development of ultra-compact biosensors that can be used to diagnose diseases, and more. What makes these sensors special is the use of optical interference to measure mechanical changes that occur when the substance to be measured is absorbed onto a suspended thin film on a microchip. The sensors will enable cancer screening, virus detection, and other functions to be performed by the compact device with a high level of sensitivity as well as with ease. In addition, Professor Takahashi is seeking to apply this mechanism to the development of devices that can detect virus particles in the air.

Interview and report by Madoka Tainaka

Microchips play a useful role in biomarker testing and beyond

MEMS-based biosensors fabricated at the LSI factory of Toyohashi University of Technology.
MEMS-based biosensors fabricated at the LSI factory of Toyohashi University of Technology.

In recent years, disease-specific proteins (biomarkers) in the blood, such as prostate-specific antigen (PSA) and carcinoembryonic antigen (CEA), have been measured during medical checkups and other health exams to help screen for diseases. Since biomarkers can be measured from a tiny amount of blood, they are an extremely useful indicator linked to early diagnosis and treatment of diseases. Until now, however, it has been necessary to examine each individual biomarker using bulky equipment, such as biochemical analyzers, and testing can only be conducted at certain facilities. By detecting biomarkers with a microchip, and using a smartphone to carry out the analysis, Professor Takahashi hopes to enable users to manage their health at home and elsewhere, at an affordable price.

"We already know about various kinds of disease-specific biomarkers, and research has identified specific proteins involved in serious cases of COVID-19. If we were able to test for these at home or in a rest home, using our smartphones, it would be possible to provide priority treatment to patients who have higher values. Since our sensors not only examine blood, but also saliva, urine, and exhaled breath, I think they can be applied in a wide range of areas, such as health care and prevention of infectious diseases."

Professor Takahashi and his team are developing a semiconductor microchip that will unlock the potential of such a visionary device. Above the chip sits a thin film, engineered to adsorb only the molecule that needs to be measured (modified chemically to adsorb only a specific substance, such as a receptor), and the device detects the mechanical change that occurs when the target molecule is adsorbed onto the film. The point is to form the film so that it floats above the substrate of the semiconductor.

"In other words, there is a tiny gap of less than one micrometer between the semiconductor and the film. Now, for a polymer film that adsorbs a biomarker, the thickness of the film will be about 100 nanometers. When molecules attach to this film, since each molecule is electrically charged, the molecules repel each other, and the film naturally expands into a dome shape. In other words, the film deforms due to the stress caused by the adsorption of molecules. To facilitate this deformation, the film must be as thin as possible, and there needs to be a gap between the semiconductor and the film. Then, by measuring the degree of deformation, you can determine how much of the target molecule has been adsorbed."

Enhanced sensitivity through sensing with optical interference

Professor Takahashi is also working on the detection of virus and gas molecules, which are even smaller than biomarkers. What they are measuring here is the mass of the molecule.

"To measure the molecular mass, voltage is applied to make the film vibrate. The frequency of vibration depends on the molecular mass: When molecules such as viruses attach to the surface of the film, the mass increases, and the vibration frequency falls. By measuring this frequency, we can observe how much of the molecule has been absorbed. So in both cases we are utilizing the functionality of micro-electromechanical systems (MEMS), but we are doing so in two different ways: In one we observe the deformation of the film due to intermolecular force, and in the other we actively apply a voltage to make the film vibrate and observe the change in frequency," explains Professor Takahashi.

Motion of a MEMS sensor associated with molecular adsorption (60x speed). The interaction of adsorbed molecules deforms the freestanding membrane, resulting in a change of optical interference.

So how do the sensors detect the film deformation or changes in the vibration? They use the principal of optical interference. The idea is to measure an optical phenomenon called "Fabry–Pérot interference", which occurs when a film is illuminated by a monochromatic light source, such as a red laser. What makes this research unique is the use of optical interference to detect biosensors.

"Here too, the gap between the semiconductor and the film is critical. Because the wavelengths at which the beams of light reinforce each other change depending on the thickness of the gap between the semiconductor and the film—the same principle as Newton’s rings, which we studied in high school physics. In other words, as molecules are adsorbed and the film expands, increasing the thickness of the gap, the colors produced when the light is applied change. This light intensity (change in color) is detected using a semiconductor—a complementary metal oxide semiconductor (CMOS)—image sensor."

With CMOS image sensors, which are also used in smartphone cameras, if a different film is prepared for each pixel, a 10-megapixel CMOS sensor, for example, can in principle detect 10 million different substances. This means that it would also be possible to view the types of molecules adsorbed onto each film (pixel) as an image.

"The conventional method used for biosensing is to observe reactions in a solution, but since this new method allows you to observe molecules in the air it is also well suited to downsizing and integration. What’s more, the measurements can be done at a level of sensitivity more than two orders of magnitude higher than other methods," says Professor Takahashi.

He will now work toward commercializing the technology in partnership with industry.

Detection of viruses in the air

What Professor Takahashi is focusing on right now, however, is the development of an innovative sensor that can detect COVID-19 particles in the air.

"PCR testing is designed to show if the subject is infected. Since the reaction is examined in a solution, it takes time for the result to come through. But what we really need right now is 'on-the-spot' infection control. So, we’ve developed a sensor that can visualize virus particles in the air. The sensor, which tests for the presence of the virus in exhaled breath, could be used to check whether people are infected upon entering a facility or boarding an airplane, or for screening of high-risk contacts. With sensors installed at different locations, it would be possible to visualize viral hotspots and use the information to create hazard maps. So, the technology can be used to visualize risk."

This sensor adopts the same principle as the one introduced above, the main difference being that it uses an ultra-thin film with a single atomic layer. The film is only 0.34 nanometers thick. The reason for using such a thin film is that if the mass of the film is closer to that of the molecule to be adsorbed, a larger reaction—a higher level of sensitivity–can be achieved. The research team has already created a chip, in which graphene film (a sheet of carbon atoms) floats freely from the semiconductor substrate, which is more sensitive than a conventional silicon-based MEMS sensor.

(Left)Schematic image of receptor-modified freestanding graphene. (Right)Photograph of a freestanding atomic layer graphene film.
(Left) Schematic image of receptor-modified freestanding graphene.
(Right) Photograph of a freestanding atomic layer graphene film.

"When a single virus particle—which weighs 100 attograms, or about 10-16 grams—attaches to the film, this alone causes the frequency of vibration to fall by as much as 100 kilohertz. This means that, in principle, the sensor can detect a single virus particle. But making something this small not easy. In particular, when modifying the antibody molecule on the graphene we need to perform the process in a solution; but even just adding it to a solution causes it to break. To solve this problem, we enhanced the strength of the graphene structure by making innovative changes to the structure of the graphene, successfully modifying the antibody molecule."

"In fact, this sensor was originally developed to detect influenza viruses. In the future, we hope to be able to test for COVID-19 and influenza simultaneously," adds Professor Takahashi.

This is exactly the kind of technology we need today; we look forward to its speedy rollout.

Reporter's Note

Professor Takahashi explains how in high school he was fascinated by rockets and space development. As a university student, he stepped unexpectedly from the macro to the micro world.

"It was while I was researching optical switches at graduate school that I learned that Toyohashi University of Technology had a fully-fledged LSI factory, and I resolved to do research there one day," recalls Professor Takahashi. All the sensors introduced in this article were developed at the university.

Furthermore, Toyohashi University of Technology has just been selected for the Ministry of Education, Culture, Sports, Science and Technology’s Initiative to Establish Next-generation Novel Integrated Circuits Centers (X-NICS). We hope that the research of Professor Takahashi and his team will spark a series of breakthroughs, helping drive the revival of Japan’s semiconductor industry.

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Researcher Profile

Kazuhiro Takahashi

Kazuhiro Takahashi

Kazuhiro Takahashi received PhD degree in 2008 from The University of Tokyo, Tokyo, Japan. He started his career at Institute of Industrial Science, The University of Tokyo as a postdoc researcher. Since he started his career at Toyohashi University of Technology as an assistant professor in 2009, had been involved in the development of CMOS-MEMS sensors and actuators for optical and biological applications. He is currently a professor at Electronics-Inspired Interdisciplinary Research Institute (EIIRIS).

Reporter Profile

Madoka Tainaka

Madoka Tainaka
Editor and writer. Former committee member on the Ministry of Education, Culture, Sports, Science and Technology Council for Science and Technology, Information Science Technology Committee and editor at NII Today, a publication from the National Institute of Informatics. She interviews researchers at universities and businesses, produces content for executives, and also plans, edits, and writes books.