Immanuel Kant Baltic Federal University

Materials for biomedical applications

Magnetic nanoparticles are becoming more and more attractive materials for the targeting, diagnostics and therapy (theranostic) of cancer diseases. Indeed, magnetic nanoparticles, suitably functionalized, are used for Magnetic Resonance Imaging (MRI) for early detection of cancer , enhancing the signal, for drug delivery and hyperthermia therapy. Optimization of the magnetic properties of nanoparticles in order to increase their local heating efficiency using the smallest possible amount of them is still a matter at issue. Magnetic and optical manipulation of cells for tissue repairing and reconstruction has been receiving a growing attraction in the last years. Mecanical stimulation of individual cancer cells, modifiying the cell plasticity and shape, till to their disruption reveals to be a promising alternative to the cancer therapy. In this context, the use of magnetoresistive biosensors able to detect and analyze with high sensitivity the signal from magnetic nanoparticles linked to biomolecules is also an essential issue.

1a) 3D-construction of cellular tissue using new Current Magnetic Tweezers (CMT)
(Alexander Omelijanchik; Team leader: Valeria Rodionova)

A new technique will be developed to manipulate individual cells by magnetic tweezers that allow particle and cell manipulation in three dimensions by means of the magnetic field generated by the electric currents flowing through the non-magnetic wires. The research is being carryied out by the groups led by Dr. Valeria Rodionova (Institute of Physics, IKBFU), Prof. Larisa Litvinova (Laboratory of Immunology and Cell Biotechnologies, IKBFU) and Prof. Igor Khlusov from Siberian State Medical University (Tomsk, Russia). The main goals are: a) to optimize the manipulation and to understand the effect of the magnetic field which is created by an electric current in the wires of the tweezer on the biological cells; b) to control of the position of magnetite nanoparticles (e.g. Fe3O4; prepared by the Institute of Structure of Matter of the National Research Council, in Rome). The dynamics of cell motion in a magnetic field is unique for each type of cells due to the different zeta-potentials of cell membranes for example. No theoretical prediction or description exists so far.

The main idea of this project is the construction of cellular and tissue structures for implantation of biological tissues in a living organism. This can be done through cultivation and building of cell structures in vitro with nanoparticles by CMT (Reference: New approaches in the design of magnetic tweezers–current magnetic tweezers, by V. Bessalova, N. Perov, V. Rodionova, J. Magn. Magn. Mat. 2016, 415, 66–71). The ultimate goal is to understand the influence of a magnetic field on cell dynamics, reproduction and functional activities for repairing malignous cell structures..

Cultivation of multipotentialmesenchymal stromal cell (MMSC) in the media with and without NPs for checking the process of cytotoxicity and accumulation in different concentration and different time of cultivation will be done. Cytotoxicity will be controlled by flow cytometry. The accumulation will be measured by magnetic method (VSM) and by fluorescence microscopy. Functional activities of cells will be monitored by a control of the supernatant. MMSC with and without NPs in the presence of a cuprum wire (0.2 mm) with DC (around 1A) and without current will be cultivated. Cytotoxicity and functional activities will be study in each step. Cell dynamics will be observed with an optical microscope at regular periods.

1b) Magnetic properties of magnetite Fe3O4 nanoparticles for biological applications

(Alexander Omelijanchik; Team leader: Valeria Rodionova)

Nanoparticles can be used in biomedicine such as MRI contrast enhancement, tissue repair, hyperthermia, drug delivery and cell separation. One of the most perspective directions in the treatment of cancer is a magneto-mechanical method of cell destruction and manipulation through nanoparticles, which has several advantages: a low-frequency magnetic field and a possible path to apoptosis. This is associated with many challenges: control of the monodisperse size, fluid stability, control of surfactants, choice of materials and others. Iron oxide nanoparticles are the only magnetic nanoparticles approved for clinical use (in particular, for diagnosis of cancer). Among the iron oxide species, magnetite nanoparticles (Fe3O4) have the most significant applications in biomedical research because of their low toxicity and biocompatibility to human tissue.

New protocols for the synthesis (bottom up and top-down approaches) and functionalization of nanoparticles will be developed and their magnetic properties will be optimized through the control of composition, size, shape, strongly affecting the magnetic anisotropy. Hybrid multifunctional particles will be used as building blocks to create 3D complex hybrid materials with tuned properties which “smartly” respond to external stimuli.

We investigated magnetic properties of magnetite NPs prepared using different methods with different size, shape, composition, surface area, coating and aggregation state by vibrating sample magnetometer at low temperatures.

In collaboration with Prof. Larisa Litvinova, head of Laboratory of Immunology and Cell Biotechnologies (IKBFU), and Prof. Igor Khlusov from Siberian State Medical University (Tomsk, Russia) we’ll study the effect of the magnetic field and nanoparticles on the biological cells. Cytotoxicity and dynamics of accumulation of iron oxide nanoparticles with the use of magnetic methods have been assessed in the example of two cell cultures.

Investigation of ferrofluids of magnetite Fe3O4 nanoparticles (~11 nm) were synthesized by co-precipitation method by Illés Erzsébet (Dept. of Theoretical and Condensed Matter Physics, Vinča Institute of Nuclear Sciences, Belgrade, Serbia) in water based solution with different pH-level. Investigation of magnetic interactions effect between nanoparticles using IRM/DCD, Henkel plot and activation volume methods has been carrying out in collaboration with Davide Peddis, Sara Laureti and Gapare Varvaro (Institute of Structure of Matter, Rome, Italy). Different types of samples will be investigated. Magnetization measurements down to low temperature will be performed on magnetite NPs prepared using different methods with different size, shape, composition, surface area, coating and aggregation state.

1) Magnetite Fe3O4 nanoparticles (~20nm) produced by method electric explosion of wire (EEW), in collaboration with Valentin Sedoy (Institute of High Current Electronics, Tomsk, Russian Federation), Igor Khlusov (Siberian State Medical University and Tomsk, Russian Federation).

2) Magnetite Fe3O4 nanoparticles (20-40nm) produced by laser ablation method. In collaboration with Victor Bagratashvili (Institute of Laser and Information Technology, Moscow, Russian Federation).

3) Fe3O4//SiO2//Ta2O5, Fe3O4//SiO2//Nb2O5, Fe3O4//SiO2//V2O5 and Fe3O4//SiO2 nanoparticles produced by gas-phase synthesis. In collaboration with Eugene Bogdanov (Institute of Chemistry & Biology IKBFU, Kaliningrad, Russian Federation).

1c) Giant Magnetoresistance biosensing platforms

(Oksana Koplak)

The programme deals with in vitro mapping of local magnetization in CoFeB/Ta/CoFeB trilayers contacting with protein–magnetic tag complexes.

The development of GMR (Giant Magnetoresistance) biosensing platforms is expected to have fruitful application perspectives in point-of-care clinical diagnostics, drug delivering, pharmaceutical industry, genomic and proteomic engineering. Rapidly developing technologies of nanosized objects (nanoparticles, nanotubes, and nanowires) as well as nanofabrication techniques (MEMS, microfluidics, and CMOS) gave rise to medical technologies. GMR platforms have been proposed and tested for biomedical applications biosensors. These platforms using magnets utilize the magnetic field created by magnetic particles tied to studied molecules in a biological systems. The main application of GMR sensors is recording of kinetics of protein–magnetic tag complexes binding to the antigen fixed on the sensor surface. Wide industry of nanoparticles used in hyperthermia, MRI, gene delivery cell separation requires corresponded nano- and micro sized sensors to control concentrations of the reagents and dynamics of processes. GMR sensors are already explored for multiplexed detection of cancer biomarkers, proteins, toxins, detection of hybridized DNA. The most researches are devoted to integrated response of GMR sensor to the significant amount of particles contributing to the detected magnetic field. Single magnetic nanoparticles and their ensembles cause locally inhomogeneous magnetization of the ferromagnetic CoFeBlayer. This circumstance dramatically changes the magnetization dynamics of the films and domain walls propagation as well as integrated output of GMR sensor. Local impact of the nanoparticles ensemble can oversaturated microsized area of the FeCoB films resulting in nonlinear output of the scheme, not proportional to the particles amount. The GMR sensor surface will be monitored during different stages of accumulation of protein–magnetic tag complexes binding to the antigen fixed on the sensor surface. Mapping of the sensor surface will allow us to distinguish the role of nucleation events, statistical distribution of the particles and effects on integrated GMR output.

Four stages of the the programme are foreseen:

1) Reference test of GMR platform. AFM attestation of the empty GMR platform and micomagnetic simulation of the clean surface of the films, recognizing domain walls and their propagation under magnetic field for different GMR as well as studying of integral magnetization and galvanic response of the GMR device.

2) Samples preparation. Series of the samples covered by proteins labelled by magnetic nanoparticles (FePt or similar) will be prepared. Different controlled concentrations of the magnetically labelled proteins will be used.

3) AFM scanning of the local magnetic field and corresponding magnetic and electrical responses of the CoFeB/Ta/CoFeB trilayers will be obtained for each concentration of the nanomagnets on the sensor surface. Analytical comparison of the magnetic domain distribution with nanomagnets distribution will be provided.

4) Micromagnetic simulation of the impact of the nanoparticles ensemble on magnetoresistance and surface magnetization of the CoFeB/Ta/CoFeB trilayers.

We are planning to use single crystalline CoFeB/Ta/CoFeB trilayers possessing GMR and being in our disposal. Preliminary magnetic attestation of the GMR trilayers planned in the frame of the project is already performed. Mapping of possible magnetization states of CoFeB/Ta/CoFeB trilayer in H-T phase diagram was done. Flop remagnetization of ferromagnetic CoFeB layers with perpendicular anisotropy is demonstrated. Exponential dynamics of the flop transition corresponding to single barrier depinning of the domain walls was revealed. The temperature dependent critical field of domain wall pinning as well as height of the potential barrier ΔE0 = 0.72 eV were determined.

Expected results of the project are:

1) Understanding of the interplay between domain walls statistical distribution and labeled bio- objects distribution on the GMR sensor surface.

2) Dependence of integral output of GMR circuit on homogeneity of the nanoparticles distribution.

3) Mapping of the different FeCoB states dependently on external magnetic field and nanoparticles concentration.

4) Practical recommendations for calibration of GMR sensor and measurements of absolute amount of magnetic nanoparticles.

1d) Magnetic-based Human Computer Interfaces

(Team leader: M.V. Patrushev)

Magnetic materials of biopotential registration, such as magnetomyography (MMG) and magnetoencephalography (MGE), generally have better spacial resolution, which makes them promising tools for both theoretical researches and creation of BCI and HCI.

MMG is a technique for mapping muscle activity by recording magnetic fields produced by electrical currents occurring naturally in the muscles. The measurement of magnetic fields from skeletal muscles may be useful, both clinically and in research for the following reasons:

Unlike the EMG, the magnetic detector sums the currents by a vector law and can also be at various distances from the skin in order to have different “views” of the muscle.

With the EMG the contact potentiais of both needle and surface electrodes are usually larger than any dc from the muscle and therefore mask and prevent its measurement. A magnetic detector, however, makes no contact with the skin and can detect muscle dc without any contact problems.

MEG is a functional neuroimaging technique for mapping brain activity by recording magnetic fields produced by electrical currents occurring naturally in the brain. Applications of MEG include basic research into perceptual and cognitive brain processes, determining the function of various parts of the brain, and neurofeedback. This can be applied in a clinical setting to find locations of abnormalities as well as in an experimental setting to simply measure brain activity.

For both MMG and MEG arrays of SQUIDs are currently the most common magnetometer, while the SERF (spin exchange relaxation-free) magnetometer is being investigated for future machines.