Translation. Region: Russian Federation –
Source: Novosibirsk State University –
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A terahertz nanoantenna sensor for detecting the biomarker L-2-hydroxyglutarate was created by researchers at the Laboratory for Functional Diagnostics of Low-Dimensional Structures for Nanoelectronics at the Analytical and Technological Research Center "High Technologies and Nanostructured Materials." Faculty of Physics Novosibirsk State University. L-2-hydroxyglutarate and its enantiomer (the "mirror image" of the substance molecule), D-2 hydroxyglutarate, are formed as a result of specific changes in cellular metabolism in various types of cancer. As the pathological process progresses, the level of biomarkers in the body increases, and they accumulate in affected organs and tissues, as well as in the blood of cancer patients. Early detection of this biomarker and determination of its concentration in the body are crucial for developing a treatment strategy and assessing the effectiveness of cancer therapy. The sensor developers presented the results of their study in the article "Terahertz nanoantenna sensor for detecting the biomarker L-2-hydroxyglutarate: design optimization and testing" (“Terahertz nanoantenna sensor for detection of biomarker L‑2‑Hydroxyglutarate, design optimization and testing”), published in the journal Optical and Quantum Electronics.
— L-2-hydroxyglutarate plays an important role in many physiological processes and is considered as a biomarker for various types of cancer. An increase in its level occurs in malignant tumors of the brain, pancreas, kidneys and other organs. To correctly diagnose and predict the course of the disease, it is necessary to know what the concentration of L-2-hydroxyglutarate is in the patient’s organs and tissues. For these purposes, gas and liquid chromatography methods are currently used in combination with mass spectrometry to determine the level of this biomarker in blood serum and cerebrospinal fluid. These methods require complex sample preparation and expensive equipment. There are other diagnostic methods aimed at detecting changes in blood composition, but they require a long time and, as a rule, they are performed strictly according to medical indications. Some diseases develop covertly for a long time, so their timely detection is difficult. For example, glioma, a tumor that affects the glial cells of the brain or spinal cord, often does not make itself felt until a certain point, often appearing in late stages, when therapy is either ineffective or completely impossible. Therefore, we have attempted to develop optical systems capable of performing rapid diagnostics by detecting excess concentrations of L-2-hydroxyglutarate and D-2 hydroxyglutarate, as well as changes in their ratio. Our development can make it possible to detect oncological diseases in the early stages and, therefore, begin treatment in a timely manner,” said Nazar Nikolaev, Candidate of Technical Sciences, senior researcher at the Laboratory of Functional Diagnostics of Low-Dimensional Structures for Nanoelectronics, ATIC FF NSU, as well as the head of the Terahertz Photonics Laboratories at the Institute of Automation and Energy SB RAS.
A team of six scientists from NSU, the Institute of Automation and Electrometry SB RAS, and the A.V. Rzhanov Institute of Semiconductor Physics SB RAS collaborated on the development of new optical sensors. They drew on the research of their colleagues in China, who conducted spectroscopy of the biomarkers L-2-hydroxyglutarate and D-2 hydroxyglutarate and found that the spectra of these isomers in the far-infrared (terahertz) range differ. The L-isomer has a characteristic absorption peak near 1.337 THz, while the D-isomer has a peak near 1.695 THz. Based on these data, the laboratory's researchers developed a new type of optical sensor based on terahertz nanoantennas for detecting L-2-hydroxyglutarate in biological samples.
The device is an array of gold nanoantennas on a silicon substrate. NSU scientists performed electrodynamic calculations of the sensor structure and optimized the geometric parameters to excite plasmon resonance at the required frequency for this biomarker – 1.337 THz. The sensor was fabricated using nanolithography at the Institute of Semiconductor Physics SB RAS and characterized using scanning electron microscopy. Spectral measurements and testing of the sensor were conducted at the Spectroscopy and Optics Shared Use Center of the Institute of Automation SB RAS. Its specific sensitivity to the L-2-hydroxyglutarate biomarker was confirmed experimentally using pulsed terahertz spectroscopy. By monitoring the resonance behavior in the sensor's transmission spectrum with increasing L-2-hydroxyglutarate concentration, the researchers determined the sensor's sensitivity. The study identified the device's shortcomings and proposed a solution to improve its sensitivity and biomarker level detection accuracy.
The nanoantenna itself is a simple dipole resonator. With a length close to half the wavelength, it effectively interacts with the electromagnetic wave, whose energy is concentrated at the antenna ends. In our case, the antenna length is approximately 40 µm. The prefix "nano" means that we moved the antennas end-to-end and created the smallest possible gap between them. This gap is approximately 100 nanometers. The University team was tasked with optimizing the antenna dimensions to increase the field strength at a frequency of 1.337 THz in the nanogap. As the field strength increases, so does the sensor sensitivity. The sensor design itself was not new, but the engineering task of optimizing it for the terahertz frequency range was our first. After testing, we identified key ways to increase the sensitivity of this class of sensors, related to further increasing the signal-to-noise ratio and increasing the spectral resolution of the entire sensor system, for example, by applying an antireflective coating to the back of the sensor or increasing the thickness of its substrate, explained Nazar Nikolaev.
Scientists claim that in a similar way it is possible to make a sensor for detecting the biomarker D-2 hydroxyglutarate, which has a resonance frequency of about 1.695 THz, and, combining it with one already developed for the biomarker L-2-hydroxyglutarate, obtain a universal device that works to detect the amount of both isomers. However, in the process of working on these devices, they identified a number of shortcomings of the technical approach using nanoantennas. The plasmon surface resonance interacting with the biomarker molecule is an absorption resonance: interacting with an electromagnetic wave, the nanoantenna absorbs energy, and a dip is formed in the corresponding region of the spectrum. To assess the concentration of a biomarker, it is necessary to study changes in the characteristics of a given dip: amplitude, frequency shift. And a problem arises: due to the absorption of energy in this area, the signal-to-noise ratio decreases. Therefore, strong noise does not allow one to reliably determine the presence and concentration of a small amount of a substance. It became obvious that such a design as nanoantennas is not the optimal technical solution. Scientists have proposed another approach to solving the problem, based on an inverse structure, i.e. instead of thin metal strips (antennas) there are slits. The metal surface of the sensor must be solid, in which nano-sized slits are cut. This structure must have an inverse spectrum – not energy absorption at the operating frequency, but maximum transmission at a given frequency and suppression of other frequencies. Then the optimal signal amplitude and high signal-to-noise ratio will be achieved, which will improve the diagnostic accuracy. Now scientists have to translate the results of their research into a new device. They have already begun to develop a new sensor that will not have the shortcomings identified in the nanoantenna sensor. Work on it is expected to be completed this year.
We anticipate that the new sensor will produce more reliable results and lower measurement noise. If this is confirmed, we will be able to move on to testing not model solutions of the substance, as in the previous stage of research, but blood serum, which is a complex biological fluid. This will allow us to test our sensor for detecting the L-2-hydroxyglutarate biomarker under conditions close to real-world conditions. Potentially, if successful, our device could be used in clinical diagnostics. However, to test the sensor and detect this biomarker, we currently use expensive systems with a wide spectral range. Only specialized specialists with the skills to configure and process data can operate such laboratory equipment. However, since real-world practice requires only resonant frequency analysis, the entire diagnostic system can be simplified by transferring it to a more accessible single-frequency radiation source. With further development of the appropriate software, this diagnostic equipment could be used by medical professionals without the need for specialized physicists. However, even if our new sensor proves effective, it will require several years of engineering and design work, as well as the device's certification process, said Nazar Nikolaev.
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