[EN] Лаборатории

Contract number

075-15-2021-596

Time span of the project

2021-2023

Laboratory's website

since December 2022 Тимашев Петр Сергеевич

2021 - 2022 Liang Xing-Ji

As of 01.11.2022

Number of staff members

scientific publications

Objects of intellectual property

The Laboratory's work will be aimed at the development of personalised solutions in the field of regenerative medicine and nano-medicine, while the expected results will contribute significantly to the investigation of top priority problems of these areas in the coming years.

Name of the project: The development of smart nano-technologies for osteoarthritis treatment

Osteoarthritis (OA) is one of the most traumatic socially significant diseases that reduce the quality of life and lead to premature loss of working capacity. Apart from the traditional approaches to OA treatment (such as local and intra-articular administration of drugs and biomaterials), innovative treatment methods are also used that employ, for example, laser radiation or the injection of autologous cellular spheroids. However, these technologies require special conditions and the usage of additional competencies by medical personnel, which significantly impedes their large-scale introduction into practice. The main goal of the proposed project is the development of a smart nano- technology for OA treatment based on the use of matrix-bound vesicules (MBVs) and their functionalisation by magnetic nano-particles as activators of the anti-inflammatory phenotype of macro-phages and tissue remodelling thanks to the unique lipid profile of their membranes. In trauma care, magnetic physiotherapy is widely used, while its combined use with the developed nano-systems will allow for a more targeted impact on damaged tissues and immune cells. The unique and broad competencies of Professor Liang Xing-Jie in the field of formation of «smart» nano-systems for targeted delivery of biologically active substances and magnetic nanoparticles will allow to develop an original approach to efficient modification of MBVs and their control. We will additionally engage the groups lead by professor Stephen Badylak (University of Pittsburgh), a worldwide leader in the field of MBV research and professor Elizaveta Kon (Humanitas University), a worldwide leader in the field of innovative approaches in orthopaedics.

To achieve these goals, the following tasks have been set for the laboratory:

The development of an efficient method of amplification of accumulation and emission of MBVs;

The determination of the composition of MBVs, including the analysis of the lipid and protein profile, RNA sequencing;

The detection of molecular features of the interaction between MBVs and immune cells;

The development of an automated complex using a three-dimensional ultra-sound system and ultra-precise neural networks;

The modification of their surfaces to ensure targeted delivery to the damaged region of cartilaginous tissue and phenotype switching of immune cells;

The development of a method of their control by an external magnetic field;

The determination of the affinity of the developed nano-system, its safety and efficiency in an animal model (rats, rams/mini pigs).

Scientific results:

We have conducted work in the following domains:

Production, isolation and biobanking of MBVs.
MBVs as specific mediators of regulation of inflammation and stimulation of regeneration.
Modifying MBVs with magnetic nanoparticles (MNPs) and a method of controlling modified MBVs with an external magnetic field.
A unique expert-level computer-based analyzer based on artificial intelligence for the automated detection of hip joint pathology.

The developed methods of isolating multipotent mesenchymal stromal cells from various sources. Methods have been developed for stimulating the synthesis and accumulation of extracellular matrix by cells with the use of macromolecular crowding. A method has been designed for producing MBVs from monolayer cell cultures and cellular spheroids.

Our researchers have conduced a comparative analysis of MBV accumulation depending on the type of cells and the conditions of their cultivation. The peak diameter of MBVs isolated from various types of cells under various conditions of cultivation is 40-120 nm. A protocol has been developed for MBV biobanking without destroying their structure. It as been demonstrated that MBVs are stable and can be stored for at least 30 days at -80оС without a cryoprotectant while sustainably preserving their stricture and morphology.

We have studied the unique proteomic and transcriptomic profile of MBVs that ensures their functional activity in the regulation of intercellular communication, the modulation of regenerative processes and inflammatory reactions. Data has been collected on the the interaction of extracellular vesicles with cells and extracellular matrix, we reviewed the existing methods of modeling of these interactions, refined modifications of these models.

To develop a method of controlling modified MBVs by an external magnetic field, we conducted computations of noninvasive MNP registration using magnetic field detectors, we proposed the use of ultra-sensitive film nanostructured detectors of weak magnetic fields with a threshold resolution of ≤10 nT. We have established a connection between the magnetic properties of MNPs and their sizes, concentration and distribution, analyzed the dynamics of the residual magnetization of MNPs covered with a biocompatible shell. We found the optimal concentrations for modified MBVs in vivo using X-ray microtomography.

The Laboratory has developed biosensors to visualize nanovesicles as well as cellular and subcellular structures with the use of Raman microscopy, we also enhanced a new method of terahertz (THz) microscopy for the imaging of biological tissues with subwave spatial resolution that allows to overcome the Abbe diffraction limit.

For the early diagnostics, for forecsting the development of osteoarthritis and the assessment of the efficiency of therapy, we have created a unique computer-based expert-level analyzer based on artificial intelligence. The analyzer has two main variations: a cloud version reducing maintenance costs and the so-called stand-alone version that minimizes risks in case of poor Internet connection. Our researchers have created an extensive database of images the already contains 5000 MRI scans, developed and validated methods fo automated image segmentation. The computer model has demonstrated its stability with respect to MRI images obtained from devices made by various manufacturers that have various parameters. The developed service for marking up data on hip-joint osteoarthritis meets all the requirements for authorization and storing annotated data, it is a convenient and accessible tool for conducting large-scale research for the additional training of the existing models or the creation of new ones.

The computer model of automated hip joint pathology detection has provided an opportunity to analyze 200 real-life clinical cases already.

Implementation of research results:

We are currently developing a technology for personalized osteoarthritis treatment based on the use of a new type of biologically active regulators of inflammation and regeneration, which are secreted by MBV cells, and their functionalization with magnetic nanoparticles. A new method has been developed for producing specific mediators of regulation of inflammation and the stimulation of regeneration — MBVs from monolayer cell cultures and cellular spheroids. A method has been developed for controlling modified MBVs by an external magnetic field. Biosensors have been developed for visualizing nanovesicules, refined approaches to the imaging of biological tissues with high spatial resolution.

Education and retraining of personnel:

We have compiled and published the first handbook on regenerative medicine in Russia. Regenerative medicine: a handbook / Pyotr. V. Glybchenko, Yelena V. Zagaynova. – Moscow: GEOTAR-Media, 2023. – 456 p. - DOI:10/33029/9704-7535-5-REG-2023-1-456. ISBN 978-5-9704-7535-5.
Three education programs have been developed and implemented into the education process for First Moscow State Medical University (Sechenov University) students majoring in Pediatrics : 1) «Biodesign and personalized medicine. Module 1. Mammalian embryology»; 2) «Biodesign and personalized medicine. Module 3. General tissue engineering»; 3) «Biodesign and personalized medicine. Module 5. Foundations of assisted reproductive technologies».
We have developed and implemented into the education process the program «Synthetic biology and foundations of embryology» for First Moscow State Medical University (Sechenov University) master“s degree students majoring in Biology in the training direction «Synthetic biology and biodesign».
Using the Zoom online platform, two times a month we conduct seminars «Modern Advances in Biomedicine and Biophotonics».
Using the Zoom online platform, we organized and staged two annual international Russian-Chinese Symposium «Future Orthopedics: Nanotechnology and AI»).
In 2021, four members of the academic team completed additional training at the Russian Medical Academy for Continuing Professional Training of the Ministry of Health of Russia in the additional training program «Fundamental directions of general pathology and pathophysiology».
In 2022 five members of the academic team completed additional training: at Immanuel Kant Baltic Federal University in the additional training programs «Time management», «Adobe Illustrator. Part 2», «Adobe Illustrator. Part 1», «Adobe Photoshop. Part 1», «Adobe Photoshop. Part 2», «Autodesk 3ds Max», at the «Russian Medical Academy for Continuing Professional Training of the Ministry of Health of Russia» in the additional training programs «Current problems of modern biomedicine», at the Moscow School of Management «SKOLKOVO» in the additional training program «Basics of education ecosystem management».

Collaboration:

Humanitas University (Italy), University of Pittsburgh (USA), National Center for Nanoscience and Technology (China PR), Moscow State University, Privolzhsky Research Medical University of the Ministry of Health of Russia, Nizhniy Novgorod State University, N.N. Semenov Federal Research Center for Chemical Physics of the Russian Academy of Sciences, «Vympel-Communications» PJSC (Russia): joint research and publications.

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lychagin, a., cherepanov, v., lipina, m., tselisheva, e., yurku, k., yavlieva, h. roza, korkunov, a., vyazankin, i.

Prognostic role of affected side of the sacroiliac joint in pain recurrence after total hip arthroplasty with prior manual correction of iliosacral dislocation: prospective randomized clinical study //International Orthopaedics. – 2022. – Т. 46. – №. 3. – С. 541-548. https://doi.org/10.1007/s00264-021-05240-w

chailakhyan, r.k., kon, e., shekhter, a.b., ivannikov, s.v., telpukhov, v.i. grosheva, a.g., suslin, d.s., vorobieva, n.n., gerasimov, y.v., churbanov, s.n., kotova, s., fayzullin, a.l., lychagin, a.v., lipina, m.m., timashev, p.s.

Autologous bone marrow-derived mesenchymal stem cells provide complete regeneration in a rabbit model of the Achilles tendon bundle rupture //International Orthopaedics. – 2021. – Т. 45. – №. 12. – С. 3263-3276. https://doi.org/10.1007/s00264-021-05168-1

gerasimenko, a.y., kuksin, a.v., shaman, y.p., kitsyuk, e.p., fedorova, y.o., sysa, a.v., pavlov, a.a., glukhova, o.e.

Electrically Conductive Networks from Hybrids of Carbon Nanotubes and Graphene Created by Laser Radiation //Nanomaterials. – 2021. – Т. 11. – №. 8. – С. 1875. https://doi.org/10.3390/nano11081875

fayzullin, a., churbanov, s., ignatieva, n., zakharkina, o., tokarev, m., mudryak, d., khristidis, y., balyasin, m., kurkov, a., golubeva, e.n., aksenova, n.a., dyuzheva, t., timashev, p., guller, a., shekhter, a.

Local Delivery of Pirfenidone by PLA Implants Modifies Foreign Body Reaction and Prevents Fibrosis //Biomedicines. – 2021. – Т. 9. – №. 8. – С. 853. https://doi.org/10.3390/biomedicines9080853

wang, y., xia, b., huang, q., luo, t., zhang, y., timashev, p., guo, w., li, f., liang, x.-j.

Practicable Applications of Aggregation‐Induced Emission with Biomedical Perspective //Advanced Healthcare Materials. – 2021. – Т. 10. – №. 24. – С. 2100945. https://doi.org/10.1002/adhm.202100945

rabchinskii, m. k., sysoev, v. v., glukhova, o. e., brzhezinskaya, m., stolyarova, d. yu., varezhnikov, a. s., solomatin, m. a., barkov, p. v., kirilenko, d. a., pavlov, s. i., baidakova, m. v., shnitov, v. v., struchkov, n. s., nefedov, denis yu., antonenko, a. o., cai, p., liu, z., brunkov, p. n.

Guiding Graphene Derivatization for the On‐Chip Multisensor Arrays: From the Synthesis to the Theoretical Background //Advanced Materials Technologies. – 2022. – С. 2101250. https://doi.org/10.1002/admt.202101250

peshkova, m., lychagin, a., lipina, m., di matteo, b., anzillotti, g., ronzoni, f., kosheleva, n., shpichka, a., royuk, v., fomin, v., kalinsky, e., timashev, p., kon, e.

Gender-related aspects in osteoarthritis development and progression: a review //International Journal of Molecular Sciences. – 2022. – Т. 23. – №. 5. – С. 2767. https://doi.org/10.3390/ijms23052767

zurina, i. m., presniakova, v. s., butnaru, d. v., timashev, p. s., rochev, y. a., liang, x. j.

Towards clinical translation of the cell sheet engineering: Technological aspects //Smart Materials in Medicine. – 2022. https://doi.org/10.1016/j.smaim.2022.09.002

kosheleva, n. v., efremov, y. m., koteneva, p. i., ilina, i. v., zurina, i. m., bikmulina, p. y., shpichka, a.i., timashev, p. s.

Building a tissue: Mesenchymal and epithelial cell spheroids mechanical properties at micro-and nanoscale //Acta Biomaterialia. – 2022. https://doi.org/10.1016/j.actbio.2022.09.051.

markov, a., gerasimenko, a., boromangnaeva, a. k., shashova, s., iusupovskaia, e., kurilova, u., nikitina, v., suetina, i., mezentseva, m., savelyev, m., timashev, p., telyshev, d., liang, x. j.

Multilayered Organic Semiconductors for High Performance Optoelectronic Stimulation of Cells //Nano Research. – 2022. https://doi.org/10.1007/s12274-022-5130-8

Hosting organization	Field of studies	City	Invited researcher	Time span of the project
Laboratory for Laser Molecular Imaging and Machine Learning Tomsk State University - (TSU)	Medical technologies	Tomsk	Lednev Igor Konstantinovich Russia, USA	2021-2023
Laboratory for Biomedical Photoacoustics Saratov Chernyshevsky State University - (SGU)	Medical technologies	Saratov	Zharov Vladimir Pavlovich Russia	2018-2022
Scientific Laboratory for Optical Coherence Tomography Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation - (PRMU MOH Russia)	Medical technologies	Nizhniy Novgorod	Vitkin Ilya Alex Canada Gladkova Natalia Dorofeevna Russia	2013-2017

Hosting organization

Field of studies

City

Invited researcher

Time span of the project

Laboratory for Laser Molecular Imaging and Machine Learning

Tomsk State University - (TSU)

Medical technologies

Tomsk

Lednev Igor Konstantinovich

Russia, USA

2021-2023