Russian Foundation for Basic Research No. 20-57-7804 “Multifunctional Lung-on-Chip using acousto-electronic elements for studying viral diseases and repurposing antiviral drugs”
Head: PhD Anisimkin V.I.
The aim of the international interdisciplinary project is to model the Lung-on-Chip physiological microenvironment of the respiratory tract based on the Lab-on-Chip (LoC) concept and to study key functional parameters in real time using specialized sensors. The fundamental objective of the research was to study the processes of interaction of acoustic fields with biological objects in microfluidic devices of the “laboratory on a chip” type for biosensory applications. The applied objective of the project is to study the effect of potentially effective anti-SARS-COV-2 drugs on the barrier properties of epithelial cells immobilized in the microfluidic device under development.
To achieve this goal, the following works were performed: a microfluidic device combined with acoustic delay lines was developed and created; a microfluidic cell combined with a microelectrode structure was developed and created for conductometric studies of the effect of an electric field on the capillary flow of biological fluids in the presence of an acoustic field; methods for detecting and studying cellular objects in biological fluids using created microfluidic devices; The permeability, electrical resistance, and tight contacts of cellular barriers were studied; various drugs with a potential antiviral effect against SARS-COV-2 on the barrier properties of epithelial cells immobilized in the microfluidic device (Lung-op-Chip) under development were selected and investigated.
As a result of the work, together with the Italian team, microfluidic devices were developed, combined with acoustic delay lines and a microelectrode structure for conductometric measurements. Various topologies of microfluidic devices have been developed and a theoretical study of its effect on the characteristics of acoustic waves of various types has been conducted. Microelectrode structure templates for conductometric measurements in a microfluidic cell were obtained using the technology of the Italian team and promising drugs with potential antiviral effect to SARS-COV-2 were selected for use in further research within the framework of the project.
A study was conducted on the effect of an electric field on the capillary flow of biological fluids in the presence of an acoustic field. As a result, the characteristics of acoustic waves of various polarizations propagating on piezoelectric plates in contact with microfluidic cells were obtained, and it was proposed to use an antisymmetric Lamb wave in a 128YX lithium niobate plate to implement a combined microfluidic device. The possibility of increasing the concentration of the acoustic field of the piezoactive wave in the area of contact of the microfluidic channel with the piezoelectric plate is shown. It has been found that to increase the flow rate of liquid near the channel walls and reduce the hydrodynamic dispersion of the liquid in order to obtain a laminar flow with low hydrodynamic resistance, it is proposed to use a combination of hydrophobization and hydrophilization of the channel surface.
Methods of detection and investigation of cellular objects in biological fluids using created microfluidic devices have been developed. A combination of machine learning methods with anode voltammetry has been proposed to increase the analytical accuracy of the quantitative determination of heavy metal ions in cell culture media. The possibility of detecting the presence of biological objects both in liquid media and in hydrogels based on agarose of various concentrations using acousto-electronic delay lines is shown.
The permeability, electrical resistance (TEER), and dense contacts of cellular barriers of epithelial layers created by Italian and Russian teams were investigated. The transient transepithelial electrical resistance (TEER) of barrier-forming cells grown on porous membranes was studied based on the developed microfluidic device of the “Laboratory on a Chip” type. It has been shown that based on the developed technique and a microfluidic device of the “Laboratory on a chip” type, it is possible to monitor the composition of the electrolyte in real time, as well as monitor the functional state of the epithelial cell layer.
Drugs with a potential antiviral effect against SARS-COV-2 were selected and their effect on the barrier properties of epithelial cells immobilized in a microfluidic device (Lung-op-Chip) was investigated. Thus, promising drugs with a certain evidence base for their use in COVID-19 are riamilovir, favipiravir, clarimthromycin both independently and in combination with drugs for pathogenetic anti-inflammatory therapy of coronavirus infection (glucocorticosteroids, JAK kinase inhibitors, IL-6 and IL-6R blockers, low concentrations of alkylating compounds). It is important to investigate the effect of these drugs on cell cultures in concentrations achievable in the human body with sterile modeling of the inflammatory response characteristic of SARS-COV2 infection.
Models of the human respiratory lung on a chip have been developed and studied based on a biomimetic strategy that takes into account the integrated biological, mechanical structures and biochemical functions of a living lung. This is an urgent modern innovation area with important fundamental and applied significance, both for obtaining new knowledge about tissue and cellular physiology, as well as for medical and pharmaceutical practice. It has also been shown that to create microfluidic microarrays and further experiments with live cultures of alveolocytes and bronchial epithelium, it is necessary to use membranes based on MCE, a Flerov filter, porous ethylene and/or PTFE. Membranes based on bacterial cellulose and Al2O3 are not suitable for this purpose, as they are characterized by low adhesion, cytotoxicity and weak mechanical properties.
Publications:
- A. Smirnov, V. Anisimkin, E. Shamsutdinova, M.-A. Signore, L. Francioso, K. Zykov, V. Baklaushev,
I. Kuznetsova // Acoustic Waves in Piezoelectric Layered Structure for Selective Detection of
Liquid Viscosity // Sensors 2023, 23, 7329. https://doi.org/10.3390/s23177329 - I. Kuznetsova, I. Nedospasov, A. Smirnov, V. Anisimkin, D. Roshchupkin, M.-A. Signore, L.
Francioso, J. Kondoh, M. Serebrov, V. Kashin, V. Kolesov // The Peculiarities of the Acoustic
Waves of Zero-Order Focusing in Lithium Niobate Plate // Sensors 2021, 21, 4000.
https://doi.org/10.3390/s21124000 - Dmitry A. Skladnev, Vladimir V. Sorokin // Methods for Studying Parameters Biogenic Metal
Nanoparticles, Formed in situ // RENSIT: Radioelectronics. Nanosystems. Information
technologies | 2022 | Vol. 14 | No. 4 - S. Tarasov, Y. Plekhanova, V. Kashin, P. Gotovtsev, M.-A. Signore, L. Francioso, V. Kolesov, A.
Reshetilov // Gluconobacter Oxydans-Based MFC with PEDOT:PSS/Graphene/Nafion Bioanode
for Wastewater Treatment // Biosensors 2022, 12, 699. https://doi.org/10.3390/bios12090699 - F. Biscaglia, A. Caroppo, C. T. Prontera, E. Sciurti, M.- A. Signore, I. Kuznetsova, A. Leone, P. Siciliano, L.
Francioso // A Comparison between Different Machine Learning Approaches Combined with Anodic
Stripping Voltammetry for Copper Ions and pH Detection in Cell Culture Media // Chemosensors 2023,
11, 61. https://doi.org/10.3390/chemosensors11010061 - M.A. Signore, L. Velardi, C. De Pascali, I. Kuznetsova, L. Blasi, F. Biscaglia, F. Quaranta, P. Siciliano, L.
Francioso // Effect of silicon-based substrates and deposition type on sputtered AlN thin films: Physical
& chemical properties and suitability for piezoelectric device integration // Applied Surface Science 599
(2022) 154017