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Research area 04 - BIOLOGY AND LIFE SCIENCES, 04-202 - Proteomics; structure and functions of proteins

Keywordscompton microscopy, protein crystallography, detector development, GaAs sensor, X-ray, biological specimens

Annotation
The relevance of the project is defined by necessity of further improving of quality of biomedical research conducted using X-ray microscopy by reducing the dose load on the test object and improving the quality of the X-ray images. It is known that the strength of X-ray microscopy in conducting various biomedical researches is the possibility of visualizing relatively large objects, such as tissue sections and even small organs of model organisms such as a mouse. However, the large doses of X-rays necessary to obtain a three-dimensional image of biological samples with a high spatial resolution inevitably lead to damage to the sample under study and, thereby, to a significant limitation of the level of detail in the image. At present, high-resolution x-ray microscopy based on Rayleigh (coherent) scattering uses X-ray radiation with energy of up to 10 keV. At these energies, the main mechanism responsible for damaging the samples under study is absorption of significant part of X-ray energy by the object under study through photoelectric absorption. The same problem is characteristic for experiments protein crystallography (PX). Protein samples also can be irradiated by X-rays only for a limited time, after which they are irreversibly damaged. The scientific novelty of the project is the idea to use the effect of Compton (noncoherent) X-ray scattering to reduce the dose load on the test object and improve the spatial resolution of the resulting X-ray images. Compton scattering is characterized by the fact that only a small part of the X-ray energy is absorbed in the test object, which leads to a decrease in the rate of degradation of the investigated objects during the experiment. In addition, the Compton-based image will be characterized by a large number of events (i.e., a higher signal-to-noise ratio) for a fixed irradiation dose, compared to images obtained from the photoabsorption or coherent scattering effect. The dominance of the Compton scattering over photoelectric absorption and Rayleigh scattering, upon irradiation of biological objects, is achieved by increasing the X-ray energy up to 30 keV and higher. The increase of X-ray quanta energy determines the need for the development and manufacture of a specialized pixel detector based on large area gallium arsenide pixel sensors, which is one of the most important parts of the project. The project unites such fields of science as biomedicine, transmission and processing of a large amount of data. High-speed data transmission and multi-dimensional scanning of samples generate extremely large amounts of data, usually hundreds of GB per sample, which require improvements in the collection and processing of data for timely analysis and reconstruction of the image of the sample. Within framework of the project, the research will be carried out in the following directions: - development of mathematical methods for processing the recorded X-ray images to restore the structure of the test objects and the design of the specialized software; - development and production of specialized X-ray lenses (Multilayered Laue Lenses) operating in the energy range of about 30 keV; - optimization of the characteristics of HR GaAs material and manufacturing of large-area pixel sensors based on gallium arsenide compensated with chromium (HR GaAs), optimized for operation in the X-ray energy range of 30 keV and higher; - development and manufacturing of a multi-element pixel detector based on HR GaAs sensors; - development and manufacturing of a system for collecting and transmitting large amounts of data from a detector. - carrying out experiments using Compton X-ray microscopy of biological objects and analyzing the results. Thus, the project combines both fundamental research in the field of developing HR GaAs material and improving the methodology for reconstructing the structure of the test object, as well as exploratory studies of ways to optimally use all the information obtained in the multimodal X-ray imaging experiment in the field of X-ray microscopy of biological objects.

Expected results
The results of the project are: - mathematical methods and specialized software for X-ray images processing and reconstruction of structure of the test objects; - method of application of specialized X-ray lenses (Multilayered Laue lenses) operating with 30 keV X-ray quanta; - technologies of 4 inches chromium compensated gallium arsenide (HR GaAs) wafers and large area HR GaAs pixel sensors optimized for registration of 30 keV and higher energies X-ray quanta - prototype of a multielement pixel detector based on HR GaAs sensors, optimized for registration of 30 keV and higher energies X-ray quanta; - a high-speed system for collecting and transmitting a large amount of data from the detector. - the technique of conducting experiments using Compton X-ray microscopy of biological objects and analysis of experimental results. Upon completion of the project the optimized detector will constitute instrumentation that will be useful to other beam lines and synchrotrons. Improving the tools opens the door to scientific progress, which will ultimately benefit many areas, including technology, society and the economy. One possible scenario for this is the use of the Compton X-ray microscopy method for research in the field of: - development of X-ray equipment for obtaining and processing phase-contrast X-ray images using polychromatic X-ray radiation; - medicine by studying the structural changes in biological tissues that arise under the influence of various diseases; - pharmacology, in studying the structure of synthesized drugs based on high-molecular compounds, as well as the dynamics of interaction of these compounds with biological objects on cellular level; In this scenario, there is significance for both the scientific and the public spheres of society: - obtaining new knowledge, new technologies and devices, - development of new diagnostic methods; - production of new drugs, reducing the incidence of the population, increasing the efficiency of the economy.

Annotation of the results obtained in 2020
As a result of final stage of the project (stage 3), the following results were obtained: A comparative analysis of the dependence of the HR GaAs:Cr material and sensors characteristics on the growth technology (VGF and LEC) of the initial n-GaAs crystals is performed. It is experimentally shown: - the presence of large-scale (up to 500 microns in diameter) "bubble" type defects in LEC HR GaAs:Cr wafers is due to their presence in the original LEC n-GaAs; - VGF n-GaAs material is characterized by the absence of "bubbles" along the entire length of the crystal, as well as larger cells (up to 1-2 mm) of the dislocation grid compared to LEC n-GaAs; - post-growth annealing of LEC n-GaAs wafers significantly reduces the concentration of "bubble" defects in the corresponding LEC HR GaAs:Cr wafers, while the value of the mobility-lifetime product of non-equilibrium electrons reaches 0.0001 sq.cm/V; - post-growth annealing of VGF n-GaAs crystals makes it possible to produce a thermally stable "bubble free" VGF HR GaAs:Cr material with the mobility-lifetime product of non-equilibrium electrons of 0.00005 sq.cm/V. It is shown that the LEC technology provides manufacturing of HR GaAs:Cr material and sensors with higher characteristics compared to VGF technology. The technological groundwork was formed and prototypes of matrix HR GaAs:Cr sensors were made with a step of sensitive elements of 20 microns. The phase and component composition of local inhomogeneities in HR GaAs:Cr material is studied. It is stated that: - in the LEC HR GaAs:Cr material, both in the "bubble" area of the defect and in the defect-free area, the ratio of the Ga and As base elements corresponds to the stoichiometric ratio for GaAs; - the concentration of impurity atoms in LEC HR GaAs:Cr in the "bubble" region of defects is significantly less than 10^20 cm^-3; - in the first approximation, "bubble" defects in LEC HR GaAs:Cr can be represented by nested spheres: сentre, intermediate, and external, herewith the diameter of the external sphere can reach 1 mm; - within the "bubble" defect, the concentration of deep levels is distributed unevenly and can have both a maximum and a minimum in the centre of the "bubble" defect, which is due to different development stages of such defects. It is shown that main factors leading to the formation of local inhomogeneities of the "bubble" type in the LEC n-GaAs material are the stoichiometry of the components during crystal growth and the mode of post-growth annealing. The study of the deep levels of the HR GaAs:Cr material was carried out. A list of dominant deep levels in HR GaAs:Cr material is formulated and their influence on the characteristics of HR GaAs:Cr material and sensors is evaluated. A four-level model has been developed that includes deep and shallow acceptors and donors, which allows us to qualitatively and quantitatively evaluate and predict the characteristics of HR GaAs:Cr material and sensors based on it. It is established that the best qualitative and quantitative agreement of the calculated and experimental values of the lifetime of non-equilibrium charge carriers, Hall mobility, and resistivity of the HR GaAs:Cr material is achieved when using the concentration of EL2 centers in the range (1-3)×1015 cm-3, the Cr concentration equal to 1×10^17 cm^-3, and the concentration of thermoacceptors in the range (1-4)×10^16 cm^-3. It is shown that the dominant deep levels that determine the lifetime of non-equilibrium electrons and holes in LEC HR GaAs:Cr are ionized EL2+ centers and Cr-ions, respectively. It is established that HR GaAs:Cr sensors are characterized by a weak temperature dependence of the charge collection efficiency in the temperature range " + "10 C – " + " 50 C. The analysis of all project results was performed. It is shown that the performed research and the formed technological capacity allow manufacturing of the HR GaAs:Cr sensors with a dimension of 1536x512 pixels with a pixel pitch of 20 microns with 95 % transmission of quanta with an energy of more than 15 keV, providing effective registration and image formation of X-ray radiation with an energy of 15-80 keV. It is experimentally established that the use of matrix HR GaAs:Cr sensors as sensitive elements of a Compton X-ray microscope can produce images of biological objects with a spatial resolution of 100 nm when irradiated with 30-60 keV quanta and at a significantly lower dose compared to the systems in transmitted radiation. The results obtained at stage 3 (2020) of the project are presented at the IEEE 2020 international online conference (https://nssmic.ieee.org/2020/) and published in peer-reviewed journals: Journal of Instrumentation (Q1) - 2 articles; Pphysics and Technology of Semiconductors (Q3, 2020, volume 54, issue 6) – 1 article. The tasks of the stage and of the whole project, which are in the sphere of responsibility of the Russian contractor, have been solved in full.

Publications

1. A. Lozinskaya, M. C. Veale, I. Kolesnikova, V. Novikov, O. Tolbanov, A. Tyazhev, R. M. Wheater and A. Zarubin Influence of temperature on the energy resolution of sensors based on HR GaAs:Cr Journal of Instrumentation, - (year - 2021)

2. I. Chsherbakov, L. Shaimerdenova, A. Tyazhev, P. Chsherbakov, I. Kolesnikova, A. Lozinskaya, T. Mihaylov, A. Shemeryankina, M. Skakunov, O. Tolbanov, A. Zarubin Methods of charge-carrier mobility measurements in HR GaAs:Cr material Journal of Instrumentation, - (year - 2021)

3. V.M. Kalygina, A.V. Almaev, V.A. Novikov, Yu.S. Petrova Solar-blind UV detectors based on -Ga2O3 films Физика и техника полупроводников, том 54, вып. 6, стр.575-579 (year - 2020) https://doi.org/10.1134/S1063782620060093

Annotation of the results obtained in 2018
Technology has been developed for creating pixel contacts of matrix HR GaAs: Cr sensors with a pixel pitch of 55 μm. The technology allows creating of 25 microns diameter “openings” for under bump metallization (UBM). The technology can be used to produce HR GaAs: Cr pixel sensors based on 4 inches HR GaAs: Cr wafers. Technology of X-ray transparent backside contact of HR GaAs: Cr pixel sensors have been developed. The contact consists of thin VNi/Al layers with a total thickness of 1 μm. The contact is wire bondable and has good adhesion to the HR GaAs: Cr surface. The contact provides a transmission of at least 98% in the X-ray energy range from 10 keV and above. 4 inch HR GaAs: Cr wafers with a thickness of 550 μm and an average resistivity of 1.6 GOhm×cm with a non-uniform resistivity distribution of not more than 30% were manufactured. It has been established that at a resistivity value of 1.6 GOhm×cm and a Hall mobility of 2500 cm2 / (V ×), the value (µ ×) n reaches (1.8 - 2.0) × 10-4 cm2 / V. It is shown that with an average specific resistivity of 1.6 GOhm × cm and a distribution non-uniformity of no more than 30%, there is no correlation between the values of resistivity and (μ ×tau) n. Based on 4 inch HR GaAs: Cr wafers, pixel HR GaAs: Cr X-ray sensors with sizes of 256 × 256, 512 × 768 were produced and tested. It is shown that the characteristic form of the counting rate distribution over the sensor area is determined by the presence of a dislocation cells, originated with initial n-GaAs crystal growth technology. It is established that the dislocation grid is detected in transmitted near-infrared radiation with a wavelength of 900–930 nm. It is shown that flat field correction allows obtaining high-quality X-ray images by means of HR GaAs: Cr X-ray sensors. At the same time, on some sensors, local areas with sizes 200–800 μm were detected with a counting rate significantly different from the sensor average. The nature and causes of such areas are under investigations.

Publications

1. A.Lozinskaya, I. Chsherbakov, I. Kolesnikova, T. Mihaylov, V. Novikov, A. Shemeryankina, O. Tolbanov, A. Tyazhev and A. Zarubin Charge collection efficiency dependencies on temperature for GaAs:Cr X-ray sensors Journal of Instrumentation, - (year - 2018)

2. I. Chsherbakova, P. Chsherbakov, I. Kolesnikova, A. Lozinskaya, T. Mihaylov, V. Novikov, O. Tolbanov, A. Tyazhev and A. Zarubin The influence of contact material and its fabrication on X-ray HR-GaAs:Cr sensor noise characteristics Journal of Instrumentation, - (year - 2018)

3. V.M. Kalygina, T.Z. Lygdenova, V.A. Novikov, Yu. S. Petrova, A.V. Tsymbalov Структура и свойства пленок оксида галлия, полученных ВЧ магнетронным напылением Физика и техника полупроводников, - (year - 2019)

Annotation of the results obtained in 2019
As a result of the intermediate stage of the project (stage 2), the following results were obtained: - 12 HR GaAs:Cr wafers of detector material with a 4 inches diameter were manufactured with improved characteristics: resistivity of at least 1 GOhm × cm, resistivity inhomogeneity less than +/- 30%, product of mobility by lifetime for electron (mu × tau) not less than 0.0001 cm2 / V; - using improved pixel and backside contact technologies providing a “window” for UBM with a diameter of 25 um per pixel and backside contact with 95% transparency for X-ray with an energy of more than 15 keV, 4 matrix GaAs: Cr sensors with a dimension of 1536x512 pixels were manufactured; - The technology of saw cutting of sensors has been optimized, providing a reduction in the size of the defective edge region of the sensors of less than 50 microns; - Chromium compensation technology for n-GaAs wafers grown by VGF method was developed. It is shown that the technology allows obtaining of HR GaAs: Cr material with a resistivity of at least 1 GOhm × cm; - A non-contact technique has been developed to detect local optical heterogeneities in 4 inches diameter HR GaAs: Cr wafers by near-infrared mapping; - It was established experimentally correlation between the distributions of local optical inhomogeneity in HR GaAs: Cr wafers and the distribution of counting rate local inhomogeneity in the pixel sensors made from these wafers; - A non-contact methodology for measuring the photoconductivity distribution over the 4 inches diameter HR GaAs: Cr wafers was developed; - It was shown experimentally the existence of a correlation between mappings of photoconductivity of HR GaAs: Cr wafers and the charge collection efficiency distributions in sensors made from these wafers. The results obtained at stage 2 (2019) of the project are presented at the international conferences IWORID 2019 (Crete, Greece), 34 FCAL Workshop (Hamburg, Germany), HIZPAD Workshop 2019 (Didcot, United Kingdom) , III International Scientific Conference "Science of the Future" (Sochi, Russia) and published in peer-reviewed journals Journal of Instrumentation (2 articles) and Superlattices and Microstructures (1 article).

Publications

1. A.Lozinskaya, I. Chsherbakov, I. Kolesnikova, T. Mihaylov, V. Novikov, A. Shemeryankina, O. Tolbanov, A. Tyazhev, and A. Zarubin Detailed analysis of quasi-ohmic contacts to high resistive GaAs:Cr structures Journal of Instrumentation, - (year - 2019)

2. I. Chsherbakov, P. Chsherbakov, A. Lozinskaya, T. Mihaylov, V. Novikov, A. Shemeryankina, O. Tolbanov, A. Tyazhev, A. Zarubin, D. Beloplotov, V. Tarasenko Response of HR-GaAs:Cr sensors to subnanosecond X- and β-ray pulses Journal of Instrumentation, - (year - 2020)

3. Vera Kalygina, Aleksei Almaev, Yulianna Petrova, Evgeniy Chernikov Anomalous temperature dependence of the electrical conductivity of Metal/β-Ga2O3 /n-Si Superlattices and Microstructures, - (year - 2020)