France



Transcranial magnetic stimulation (TMS)&lt;sup&gt;1,2&lt;/sup&gt; is a widely available technology employing strong ( up to 4 T) pulsed (up to 300 Hz) magnetic fields for diagnostics of brain functions and treatment of various brain disorders. It is currently approved for clinical application in patients with drug-resistant depression&lt;sup&gt;2,3&lt;/sup&gt;, while a spectrum of new indications is emerging&lt;sup&gt;5-10&lt;/sup&gt;. The current paradigm of TMS biological effects implies magnetic induction of Eddy currents in the brain cortical neurons as the leading action mechanism. However, the effects of the TMS-like magnetic fields on non-neuronal cells and some artificial systems is almost unknown. Based on literature analysis&lt;sup&gt;4,11-24&lt;/sup&gt; and our pilot experimental data, we hypothesize, that the transcranial and extracranial repetitive magnetic stimulation employing pulsed magnetic fields (MFs) generated by TMS devices can have immunomodulatory effects, affect the growth of brain and extracranial malignant tumours and applied in drug delivery control to the cells.&lt;br/&gt;This motivated us to explore the effects of designed 18 regimes of patterned repetitive magnetic stimulation (PRMS) on tumor cells of brain (glioblastoma multiforme, GBM) and pancreatic (pancreatic ductal adenocarcinoma) cancers and on microglia (immune cells of the brain). We also tested the effect of PRMS on a drug release from polymer nanoparticles in aqueous environment. A standard TMS device “Magstim Rapid&lt;i&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/i&gt;” with Double 70mm Air Film Coil was applied to the cell cultures spatially configured to correspond to a peak MF of 0.6 T, 0.25-50 Hz frequency, with sessions of 300 or 600 pulses.&lt;br/&gt;PRMS selectively modulated the viability and functional polarisation of immune-stimulated microglia in a frequency/intensity-dependent manner (Figure 1) and affected the proliferation/viability of GBM astrocytes and pancreatic cancer cells (frequency- and pulse number-dependent up- and downregulation) (Figure 2). Finally, we show the triggering of the efficient drug release from biocompatible polymer nanoparticles by the 50 Hz/2 min PRMS mode.&lt;br/&gt;Our pioneering findings demonstrate the potential of PRMS performed with using of re-purposed TMS equipment for immunomodulation, cancer treatment, brain repair and regeneration.&lt;br/&gt;We thank Sydney Vital Translational Cancer Centre (for seed grant) and Medilink Australia (for providing the “Magstim”).

**References:**

1. Barker AT, et al.: Neurosurgery 1987, 20:100-9.&lt;br/&gt;2. Rossini PM, et al. U: Clinical neurophysiology 2015, 126:1071-107.&lt;br/&gt;3. Post A, Keck ME: Journal of Psychiatric Research 2001, 35:193-215.&lt;br/&gt;4. Funk RH, et al.: Prog Histochem Cytochem 2009, 43:177-264.&lt;br/&gt;5. Nardone R, et al.: Brain research bulletin 2020, 159:44-52.&lt;br/&gt;6. Gao F, et al.: J Neurosurg Sci 2017, 61:514-22.&lt;br/&gt;7. Rose DK, et al.: Stroke Res Treat 2014, 2014:305236.&lt;br/&gt;8. Jin Y, et al.: Pain Physician 2015, 18:E1029-46.&lt;br/&gt;9. Pérocheau D, et al.: Joint, bone, spine : revue du rhumatisme 2014, 81:22-6.&lt;br/&gt;10. Peng L, et al.: Medicine 2019, 98:e15572.&lt;br/&gt;11. Vazana U, et al.: J Neurosci 2016, 36:7727-39.&lt;br/&gt;12. Antov Y, et al.: Biophysical journal 2005, 88:2206-23.&lt;br/&gt;13. Shankayi Z, et al.: Electromagn Biol Med 2014, 33:154-8.&lt;br/&gt;14. Towhidi L, et al.: Radiol Oncol 2012, 46:119-25.&lt;br/&gt;15. Adey WR, Sheppard AR: in Mechanistic Approaches to Interactions of Electric and Electromagnetic Fields with Living Systems: Springer, 1987. pp. 365-87.&lt;br/&gt;16. Cullen CL, Young KM: Front Neural Circuits 2016, 10:26.&lt;br/&gt;17. Yamaguchi S, et al.: Bioelectromagnetics 2006, 27:64-72.&lt;br/&gt;18. Golovin YI, et al.: Journal of controlled release 2015, 219:43-60.&lt;br/&gt;19. Kim DH, et al.: Nat Mater 2010, 9:165-71.&lt;br/&gt;20. Master AM, et al.: Scientific reports 2016, 6:33560.&lt;br/&gt;21. Wong W, et al.: Scientific reports 2017, 7:10919.&lt;br/&gt;22. Maniotis N, et al.: Journal of Magnetism and Magnetic Materials 2019, 470:6-11.&lt;br/&gt;23. Pickard M, Chari D.: Nanomedicine 2010, 5:217-32.&lt;br/&gt;24. Pickard MR, Chari DM: Int J Mol Sci 2010, 11:967-81.

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/675949e68680cf21b88464bc22e3c533.jpg)
Figure 1. Effect of PRMS generated by a TMS device on viability of murine microglial BV-2 cells cultured in vitro. The  cells’ viability was evaluated by MTT assay in 24 h after performing magnetic treatment. Mean absorbance is directly proportional to the number of viable cells. The left bar represents absorbance in control (untreated group), and the next bars to the right represent the measurements in the cells’ cultures treated with different regimes of PRMS.

![](https://assets.underline.io/uploads/markdown_image/1/image/88bd8af725285a4c5a0ad3eb1f3c5956.jpg)
Figure 2. Effect of PRMS generated by a TMS device on viability of human pancreatic cancer cells (PANC-1) cultured in vitro. The  cells’ viability was evaluated by MTT assay in 24 h after performing magnetic treatment. Mean absorbance is directly proportional to the number of viable cells. The left bar represents absorbance in control (untreated group), and the next bars to the right represent the measurements in the cells cultures treated with different regimes of PRMS. Green dashed lines indicate the borders of CI&lt;sub&gt;95%&lt;/sub&gt; for mean absorbance in control (untreated group; the left bar).

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 Potential effects of TMS magnetic fields beyond the conventional neurostimulation

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Transcranial magnetic stimulation (TMS)1,2 is a widely available technology employing strong ( up to 4 T) pulsed (up to 300 Hz) magnetic fields for diagnostics of brain functions and treatment of various brain disorders. It is currently approved for clinical application in patients with drug-resistant depression2,3, while a spectrum of new indications is emerging5-10. The current paradigm of TMS biological effects implies magnetic induction of Eddy currents in the brain cortical neurons as the leading action mechanism. However, the effects of the TMS-like magnetic fields on non-neuronal cells and some artificial systems is almost unknown. Based on literature analysis4,11-24 and our pilot experimental data, we hypothesize, that the transcranial and extracranial repetitive magnetic stimulation employing pulsed magnetic fields (MFs) generated by TMS devices can have immunomodulatory effects, affect the growth of brain and extracranial malignant tumours and applied in drug delivery control to the cells. This motivated us to explore the effects of designed 18 regimes of patterned repetitive magnetic stimulation (PRMS) on tumor cells of brain (glioblastoma multiforme, GBM) and pancreatic (pancreatic ductal adenocarcinoma) cancers and on microglia (immune cells of the brain). We also tested the effect of PRMS on a drug release from polymer nanoparticles in aqueous environment. A standard TMS device “Magstim Rapid2” with Double 70mm Air Film Coil was applied to the cell cultures spatially configured to correspond to a peak MF of 0.6 T, 0.25-50 Hz frequency, with sessions of 300 or 600 pulses. PRMS selectively modulated the viability and functional polarisation of immune-stimulated microglia in a frequency/intensity-dependent manner (Figure 1) and affected the proliferation/viability of GBM astrocytes and pancreatic cancer cells (frequency- and pulse number-dependent up- and downregulation) (Figure 2). Finally, we show the triggering of the efficient drug release from biocompatible polymer nanoparticles by the 50 Hz/2 min PRMS mode. Our pioneering findings demonstrate the potential of PRMS performed with using of re-purposed TMS equipment for immunomodulation, cancer treatment, brain repair and regeneration. We thank Sydney Vital Translational Cancer Centre (for seed grant) and Medilink Australia (for providing the “Magstim”).

**References:**

1. Barker AT, et al.: Neurosurgery 1987, 20:100-9. 2. Rossini PM, et al. U: Clinical neurophysiology 2015, 126:1071-107. 3. Post A, Keck ME: Journal of Psychiatric Research 2001, 35:193-215. 4. Funk RH, et al.: Prog Histochem Cytochem 2009, 43:177-264. 5. Nardone R, et al.: Brain research bulletin 2020, 159:44-52. 6. Gao F, et al.: J Neurosurg Sci 2017, 61:514-22. 7. Rose DK, et al.: Stroke Res Treat 2014, 2014:305236. 8. Jin Y, et al.: Pain Physician 2015, 18:E1029-46. 9. Pérocheau D, et al.: Joint, bone, spine : revue du rhumatisme 2014, 81:22-6. 10. Peng L, et al.: Medicine 2019, 98:e15572. 11. Vazana U, et al.: J Neurosci 2016, 36:7727-39. 12. Antov Y, et al.: Biophysical journal 2005, 88:2206-23. 13. Shankayi Z, et al.: Electromagn Biol Med 2014, 33:154-8. 14. Towhidi L, et al.: Radiol Oncol 2012, 46:119-25. 15. Adey WR, Sheppard AR: in Mechanistic Approaches to Interactions of Electric and Electromagnetic Fields with Living Systems: Springer, 1987. pp. 365-87. 16. Cullen CL, Young KM: Front Neural Circuits 2016, 10:26. 17. Yamaguchi S, et al.: Bioelectromagnetics 2006, 27:64-72. 18. Golovin YI, et al.: Journal of controlled release 2015, 219:43-60. 19. Kim DH, et al.: Nat Mater 2010, 9:165-71. 20. Master AM, et al.: Scientific reports 2016, 6:33560. 21. Wong W, et al.: Scientific reports 2017, 7:10919. 22. Maniotis N, et al.: Journal of Magnetism and Magnetic Materials 2019, 470:6-11. 23. Pickard M, Chari D.: Nanomedicine 2010, 5:217-32. 24. Pickard MR, Chari DM: Int J Mol Sci 2010, 11:967-81.

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/675949e68680cf21b88464bc22e3c533.jpg)
Figure 1. Effect of PRMS generated by a TMS device on viability of murine microglial BV-2 cells cultured in vitro. The cells’ viability was evaluated by MTT assay in 24 h after performing magnetic treatment. Mean absorbance is directly proportional to the number of viable cells. The left bar represents absorbance in control (untreated group), and the next bars to the right represent the measurements in the cells’ cultures treated with different regimes of PRMS.

![](https://assets.underline.io/uploads/markdown_image/1/image/88bd8af725285a4c5a0ad3eb1f3c5956.jpg)
Figure 2. Effect of PRMS generated by a TMS device on viability of human pancreatic cancer cells (PANC-1) cultured in vitro. The cells’ viability was evaluated by MTT assay in 24 h after performing magnetic treatment. Mean absorbance is directly proportional to the number of viable cells. The left bar represents absorbance in control (untreated group), and the next bars to the right represent the measurements in the cells cultures treated with different regimes of PRMS. Green dashed lines indicate the borders of CI95% for mean absorbance in control (untreated group; the left bar).

technical paper

1. INTRODUCTION A variety of smart materials have been focused on a broad range of engineering applications. Among several kinds of smart materials, magnetorheological (MR) fluids inducing a reversible change in rheological behavior under an external magnetic field are suspensions of soft-magnetic particles randomly dispersed in a non-magnetic liquid medium [1]. MR fluids enable rapid switching and proper control between a liquid-like and a solid-like structure by controlling the magnetic field strength. Soft-magnetic carbonyl iron (CI) microspheres have been extensively studied as a major material in MR fluids due to their appropriate particle size and magnetic properties but possess a serious sedimentation problem due to their high particle density [2]. On the other hand, spinel ferrites can be a good alternative to CI particles because of their low density [3]. In particular, spinel zinc ferrite of super-paramagnetic behavior with high magnetic susceptibility, saturation magnetization, low coercivity, and low remanent magnetization is seen as a promising candidate for the use as a dispersed particle in MR fluids [4]. In this work, ZnFe2O4 particles were coated with polyindole (PIn), a conducting polymer with high thermal stability, redox activity, and stable degradation rate [5]. By combining an inorganic with a conductive polymer, the density was lowered, showing better sedimentation improvement. Furthermore, these particles can be also responsive under an applied electric field strength in addition to magnetic fields. 2. EXPERIMENT ZnFe2O4 nanoparticles were synthesized by a solvothermal method, and the PIn was followed to be coated as a shell onto the core ZnFe2O4 nanoparticles during oxidation polymerization. A proper amount of ferric chloride hexahydrate and zinc chloride were mixed in ethylene glycol solvent by magnetic stirring. Sodium acetate and polyethylene glycol 400 were slowly poured into the solution. The vigorously stirred mixture was placed in an autoclave and heated at 200 °C for 12 h. After that, the product was washed several times and dried to obtain particles. In the next step, ZnFe2O4 was coated by a polymerization process of indole monomer using ammonium persulfate as an initiator. The final particles were collected using an external magnet. For rheological analysis, a smart fluid responding to both magnetic and electric fields was prepared by dispersing the synthesized ZnFe2O4/PIn particles in silicone oil (100cSt, 5 vol%) under sufficient sonication. Morphology and chemical elements of the ZnFe2O4/PIn were examined by the field emission transmission electron microscope in combination with an energy-dispersive X-ray spectroscopy, respectively. Rheological properties of the MR fluid were measured using a rotational rheometer via either a parallel-plate geometry under the magnetic field or a concentric cylinder geometry under the electric field. 3. RESULT AND DISCUSSION Figure 1 shows the FE-TEM image and line scan profiles of core/shell structured ZnFe2O4/Pin particles. The main elements of ZnFe2O4 were found abundantly in the center of the particle, and C was confirmed as the main element on the outside of the particle. This result definitively demonstrates that the particles consist of ZnFe2O4 as the core material and PIn composed of C and N as the shell material. In addition, as the detection amount of the core elements increased gradually toward the center of the line drawn along the particle diameter for line scan, it was clearly revealed that the ZnFe2O4 core had a spherical morphology. Figure 2 shows the shear stress as a function of shear rate for ZnFe2O4/PIn based on MR fluid under various magnetic field strengths up to 239 kA/m. Without the magnetic field strength, shear stress of MR fluids increased in proportion to shear rate showing a Newtonian fluid-like behaviour, but as the magnetic field was applied, shear stress was relatively maintained within a certain shear rate range and displayed non-Newtonian fluid-like behaviour. When the magnetic field strength was increased, the interaction between magnetic particles was formed more strongly compared to the hydrodynamic force, resulting in a strong chain-like structure of the particles leading to an increase in yield stress. The solid lines in Figure 2 were fitted by Herschel-Bulkley model expressed as τ=τ0+KÝn to explain the rheological behaviour of non-Newtonian fluids [6]. In the given model, τ0 is the yield stress of materials, K is the consistency factor and n is the flow behaviour index. The n of pseudo-plastic materials is generally known to be between 0 and 1. [7]. The chain-like structure of ZnFe2O4/PIn particles formed by the magnetic field is destroyed as the shear rate increases, resulting in a shear thinning behaviour. In addition to steady shear test, dynamic test was also performed to examine dynamic moduli under a magnetic field strength. Rheological properties of this smart fluid under an applied electric field strength were further tested to confirm the dual characteristics of the synthesized ZnFe2O4/PIn particles.

**References:**

[1] J. S. Oh and S. B. Choi, J. King Saud Univ. Sci., 29, 390 (2017). [2] B. Sim, H. S. Chae and H. J. Choi, Express Polym. Lett., 9, 736 (2015). [3] G. Wang, Y. Ma and Y. Tong, J. Intell. Mater. Syst. Struct., 28, 2331 (2017). [4] Y. Xu, D. Sun and H. Hao, RSC Adv., 6, 98994 (2016). [5] I. H. Park, S. H. Kwon and H. J. Choi, J. Magn., 24, 155 (2019). [6] G. Mullineux, Appl. Math. Model., 32, 2538 (2008). [7] C. H. Jeon and B. R. Hodges, Nat. Hazards Earth Syst. Sci., 18, 303 (2018).

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/2c3c113e26171b2b321fc07d45e846b8.jpg)
Fig. 1 FE-TEM image of ZnFe2O4/PIn particle

![](https://assets.underline.io/uploads/markdown_image/1/image/43de2fa4ee266f281b0fd900148b2608.jpg)
Fig. 2 Shear stress curve of ZnFe2O4/PIn particle based MR fluid under various magnetic field strengths

 Fabrication of Polyindole Coated Zinc Ferrite Particles and Their Dual Rheological response under Magnetic and Electric Fields

1. INTRODUCTION While magnetorheological (MR) fluids consisting of soft-magnetic particles in non-magnetizable carrier fluid draw a huge attention with their active tune-ability under a magnetic field strength, electro/magnetorheolocial (E/MR) fluids prepared with conducting polymer and magnetic particle composite particles dispersed in a non-conducting carrier fluid exhibit a dual response under both magnetic and electric fields. The smart dual electro/magneto-responsive characteristics of fine tuning and the quick response make them appropriate candidates in wide engineering areas such as clutches, optical finishing systems, medical therapies, actuators, haptic master, micro-fluidic control which have been already adopted separately for either ER fluids or MR fluids [1]. Meanwhile, soft-magnetic carbonyl iron (CI) particles have been widely used in MR fluids, but possess several disadvantages such as their high density and low dispersion stability. Therefore, spinel ferrites with low density and sufficient magnetic behavior are also introduced as a new family of MR materials [2]. In this work, ZnFe2O4, a magnetic particle constituting the core, was synthesized in a spherical shape using the solvothermal method, and poly(diphenylamine) (PDPA), which has low density and suitable electrical conductivity, was coated through radical polymerization. ZnFe2O4/PDPA based MR fluid showed appropriate MR property due to the spinel structure of ZnFe2O4. Furthermore, it showed improved sedimentation stability because of the advantage of low density of particle [3]. 2. EXPERIMENT First of all, ZnFe2O4 was synthesized using the surfactant-assistant solvothermal method. 1.35g iron chloride hexahydrate (FeCl3.6H2O) (5mmol) and 0.34g Zinc chloride (ZnCl2) (2.5mmol) were added to 50ml of ethylene glycol, and agitation was performed using a magnetic bar. After stirring, sodium acetate of 3.6g (40mmol) as a weak base and polyethylene glycol 400 (1g) as a surfactant were slowly added to the prepared solution. After vigorously stirring the solution for about 1 h, it was transferred to a Teflon-lined stainless-steel autoclave, and the reacted at 200 for 12 h. After making the reactor to room temperature, black solid particles were obtained using magnets after several washing with ethanol and DI-water. Then, 0.75g ZnFe2O4 was added to a mixture of methanol and water 40ml/10ml, and then reaction was proceeded at 40 and 1ml of N-[(3-trimethoxysilyl)-propyl] aniline was added as a grafting agent, followed by stirring for 18 h. Modified ZnFe2O4 and diphenylamine (3mmol) were mixed with ethanol. Subsequently, HCl 1M 40ml was added and stirred at 5 for 30 min. Ammonium persulfate (4mmol) dissolved in 1M 10ml HCl was added to the solution, the reaction was carried out for 5 h, and the particles were obtained using a magnet and dried for 12h. 3. RESULT AND DISCUSSION TEM image of Fig. 1 for ZnFe2O4/PDPA particle synthesized shows that the size of synthesized material is about 300nm with its morphology of a core-shell structure. The thickness of the shell is about 14 nm, and by coating the polymer on the magnetic particle, the density of the particle is reduced, and the dispersion stability of its MR fluid can be improved. Figure 2 shows flow curve of MR fluid made by dispersing the synthesized core-shell particles in 100 cs silicone oil at 5 vol%. From the controlled shear rate test mode, the shear rate from 0.01s-1 to 200s-1 was applied, depending on the strength of the magnetic field up to 205kA/mm. In the absence of a magnetic field, the fluid behaves like a Newtonian fluid in which the shear stress increases lineary as the shear rate increases. This is because MR fluid behaves like a simple particle suspension following an Einstein equation behavior. On the other hand, when an external magnetic field is applied, the shear stress rises sharply and shows a certain specific yield. This behavior is due to the fact that the attractive force between magnetic particles becomes strong when a magnetic field is applied, and the particles form a chain-like structure in the fluid. As the strength of the magnetic field increases, the attractive force between particles also increases, so the shear stress value increases gradually [4]. To fit the curves representing non-Newtonian fluid properties of MR fluid, a solid line was drawn using the Herschel-Bulkley equation, which is expressed as τ=τ0+KÝn. Here, τ means shear stress and τ0 is the yield stress exhibited by the chain-like structure when a magnetic field is applied. The K value of the consisteny index refers to the viscosity of the fluid and n is the power law index [5]. As the solid lines fit well with the graph, it can be seen that Herschel-Bulkley equation interprets the behavior of MR fluid well over a wide shear rate range. In this work, we synthesized a core-shell structured magnetic particles and conducting polymer and confirmed MR properties such as yield stress and shear thinning under external magnetic field along with ER characteristics under an applied electric field.

**References:**

[1] M. T. Ramesan, Adv. Polym. Technol., 302, 21362 (2013) [2] G. S. Wang, Y. Y Ma, Yu Tong and J. Intell. Mater. Syst. Struct., 28, 2331 (2017) [3] J. H. Lee, H. J. Choi, Colloid Polym. Sci., 296, 1857 (2018) [4] Y. Z. Dong, H. J. Choi, IEEE Trans. Magn., 54, 4601004 (2018) [5] M. Zubieta, S. Eceolaza and M. J. Elejabarrieta, Smart Mater. Struct., 18, 095019 (2009)

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/05763e8056ec6cf88c5358ef8935fc89.jpg)
Fig 1. TEM image of core shell structure coated with PDPA on ZnFe2O4

![](https://assets.underline.io/uploads/markdown_image/1/image/754b14d10e8ee19da44d563737667334.jpg)
Fig 2. Flow curve of ZnFe2O4 coated with PDPA under the external magnetic field of ZnFe2O4 coated with PDPA

 Fabrication and shear response of conducting polymer coated zinc ferrite particles under magnetic/electric field

During the last decade, iron borate FeBO3 based crystals have been attracting an increased interest of scientific community, mainly for the following reasons: (i) these materials can be applied in modern technical devices, e.g. serving as sensitive instruments for measuring magnetic field, pressure, etc., or as monochromators for use with synchrotron radiation [1]; (ii) mixed iron gallium borate FexGa1-xBO3 crystals are quite suitable objects for studying properties of trigonal weak ferromagnets with zero orbital moment [2, 3]. We have recently shown that with decreasing iron contents the magnetic state of FexGa1-xBO3 crystals shows a gradual passage from easy-plane weak ferromagnet to diluted paramagnet, passing through magnetic clusters at intermediate iron contents [2]. Thus, by isomorphously substituting paramagnetic Fe3+ ions in iron borate, FeBO3, by diamagnetic Ga3+ ions one can synthetize a series of isostructural single crystals allowing not only fine-tuning their magnetic characteristics, thus creating new materials with sought-for properties, but also studying the nature of magnetic state, magnetocrystalline anisotropy, etc. [2, 3]. Such crystals can be synthesized using well-known flux growth technique [4]. However, obtaining high quality FexGa1-xBO3 crystals in wide range of substitutions, 0≤x≤1, has required many trials in order to find out optimal regimes for crystallization at different concentrations and a considerable improvement of the standard synthesis technique [1]. In this work, we have focused on microscopic characterization of certain magnetic properties of FexGa1-xBO3 borates by considering in detail intracrystalline interactions in these materials. The density of the magnetic energy for FexGa1-xBO3 crystals can be expressed as follows [5]: E=1/2 Em2+D (lxmy-lymx)+ 1/2 alz2+d (3lx2-ly2) lylz+e (lx4-14lx2ly2+ly4) (lx2-ly2) (1) where m and l are reduced ferromagnetic and antiferromagnetic vectors, D and E are the Dzyaloshinskii-Moriya and exchange constants, is the uniaxial anisotropy constant, and d and e are the basal anisotropy constants. Different mechanisms responsible for the magnetic properties have different dependences on the concentration of paramagnetic ions and temperature; therefore, experimental studies of the latter dependences and a subsequent modelling based on eq. (1) could, on the one hand, single out dominating mechanisms of the magnetic transitions observed and, on the other hand, get better insight in the nature of intracrystalline interactions in trigonal weak ferromagnets. Since the Dzyaloshinskii-Moriya and exchange constants characterize pair interactions between paramagnetic ions, we have assumed that the corresponding microscopic constants for a pair of Fe3+ ions in mixed crystals remain the same as those in unmixed crystal. Thus, we can express both constants for mixed iron-gallium borates through the macroscopic D and E constants for unmixed iron borate and obtain an analytical expression of the macroscopic constants for mixed crystals. We have put forward a computer code modelling the diamagnetically diluted crystal lattice by the Monte-Carlo technique [6] and implementing a summation, first, over the nearest-neighbouring Fe3+ for a reference Fe3+ ion and, next, over all sites occupied by Fe3+ ions. As a result, we have shown that the dependences of both D and E constants on x (at 0 K) follow a parabolic law. In calculating the magnetocrystalline anisotropy for FexGa1-xBO3 crystals one should take into account only crystal field and dipole-dipole contributions. Indeed, the 3d5 electronic configuration of Fe3+ has zero orbital moment; therefore, the exchange energy in a good approximation is isotropic [7]. Recently we have calculated the dipole-dipole interaction energy in the model of “extended dipoles” [8], having non-negligible dipole size. Unlike the point dipoles, the extended dipoles bring a non-zero dipole-dipole contribution to the basal magnetocrystalline anisotropy, and earlier we have evaluated it for unmixed iron borate [3]. In the model of extended dipoles, a calculation of the Ampérian current, i.e., a circular current loop of a radius R, results in two possible sizes of the magnetic dipole represented by a Fe3+ ion: R1 = 0.2189 and R2 = 0.0797 Å [3]. In this work, we have applied the model of extending dipoles to evaluating the dipole-dipole contributions to the magnetocrystalline anisotropy constants of mixed iron-gallium borates. To this purpose, we have put forward a computer code implementing the lattice-sum method [3] and modelling the diamagnetically diluted crystal lattice using the Monte Carlo technique in the same way as in calculating D and E constants, vide supra [6]. Resultantly, the dependences on x of the dipole-dipole contribution to the magnetocrystalline constants for FexGa1-xBO3 crystals have been obtained, see Figures 1 and 2. The dipole-dipole contributions to the basal anisotropy constants have been calculated at 0 K for different x using both possible effective dipole sizes, R1 and R2, determined for Fe3+ ions. This work was partially supported by the V.I. Vernadsky Crimean Federal University Development Program for 2015-2024 Grant no. VG04/2019; and by the RFBR projects Grants No. 19-32-90054 and 18-42-910008.

**References:**

1. E.S. Smirnova, N.I. Snegirev, I.S. Lyubutin et al., Acta Cryst., Vol. B76, p. 1100 (2020) 2. K. Seleznyova, M. Strugatsky, S. Yagupov et al., J. Appl. Phys., Vol. 125, p. 223905 (2019) 3. M. Strugatsky, K. Seleznyova, S. Yagupov et al., J. Magn. Magn. Mater., Vol. 442, p. 417 (2017) 4. S. Yagupov, M. Strugatsky, K. Seleznyova et al., Appl. Phys. A, Vol. 121, p. 179 (2015) 5. E.A. Turov and N.G. Guseinov, Soviet Physics JETP, Vol. 11, p. 955 (1960) 6. L. Devroye, Non-Uniform Random Variate Generation, Springer, 843 pp. (1986) 7. J. Kanamori, in: Magnetism, eds., G.T. Rado, H. Suhl, Acad. Press, Vol 1, pp. 127 (1963) 8. K. Seleznyova, M. Strugatsky and J. Kliava, Eur. J. Phys., Vol. 37, p. 025203 (2016)

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/c80785883160de382473c88ba885d8ea.jpg)
Fig.1 Dipole-dipole contribution to a vs. x in FexGa1-xBO3 crystals at 0 K.

![](https://assets.underline.io/uploads/markdown_image/1/image/530198f9d062fa644639968bd67c1f2b.jpg)
Fig.2 Dipole-dipole contributions to d (left) and e (right) vs. x in FexGa1-xBO3 crystals, calculated for two possible effective dipole sizes: R1 (dashed curves) and R2 (dash-dotted curves) at 0 K.

 Modelling of the Intracrystalline Interactions in Trigonal Weak Ferromagnets with Zero Orbital Moment

Magnetic Material for Electrical Vehicle Recent trends of magnetic mate- rial research about electrical motor drive system for electrical vehicle are shown in this lecture for magnetic material and electrical researcher and engineers. Motor drive system consists of electrical motor and power elec- tronics circuit, and magnetic material are used and an important role in both equipment. The purpose of the electrical motor is to make an electromag- netic torque to drive a vehicle based on Maxwell stress equations. The power electronics circuit such as inverter or DC-DC converter is an electrical power source in controlling the variable voltage and/or variable frequency based on a switching operation of power semiconductors [1]. Soft magnetic mate- rial is used in the stator core and the rotor core in the electrical motor, and permanent magnet is used in the field part of the motor. The electromagnetic torque is almost proportional to square of magnetic flux density. So higher magnetic flux density is required to obtain higher electromagnetic torque. Soft magnetic material is much useful to obtain a higher magnetic flux density in smaller electrical current, which is supplied by the power elec- tronics circuit. Magnetic Material for Motor Most of the electrical motor uses an electrical steel with a few % silicon due to high performance of magnetic characteristics with low price. Mechanical stress in manufacturing the motor core, magnetic non-linearity, and magnetic anisotropy, magnetic hysteresis, magnetic flux distribution base on grain shape and orientation, magnetic vector property of magnetic field and magnetic flux density, higher harmonics components derived from the slot shape of the stator core as well as the power electronics circuit base on the switching operation are main properties of the electrical steel to be discussed and researched. Mutual interaction between the power electronics circuit and the magnetic material or motor are often observed [2, 3]. To reduce the motor core loss, low iron loss magnetic materials such as amorphous and nano-crystal material are reported to be applied to the motor core [4, 5]. The details are shown in the presentation. Hard magnetic material is used in the field of the motor due to no electrical current supply and no slip ring. So most of electrical vehicle are driven by permanent magnetic synchronous motor, because the higher efficiency and the downsizing of the electrical motor can be realized. Due to almost the same electrical conductivity of the NdFeB permanent magnet as the stainless steel, the temperature of the permanent magnet increases and the demagnetization phenomena occur. To avoid it, rare earth problem generates such as Dy or so. Weakening field control scheme is used in the PM motor for the high speed rotation. So higher coercive force is required for the permanent magnet. Magnetic Material for Power Electronics In the electrical vehicle, variable speed operation is required to move from a starting point to a stopping point. So variable speed control is required for electrical motor. Variable voltage and variable frequency are required for the power source of the electrical PM motor, due to the electromotive force theory and the synchronous condition of the mechanical rotational speed and the magnetic rotation speed. The power electronics technology is possible to be realized by the switching operation of the power semiconductors. So the higher frequency operation can be realized by the high performance power semiconductor such as IGBT or GaN-FET or SiC-FET devices because it realizes the downsizing of the power electronics circuits. However, the bottle neck technology for the realization is a soft magnetic material in high frequency and high power operation. Nowadays, the hindrance for the reali- zation of power electronics technology might be said to be a high frequency magnetic material in a point of view of the downsizing, high efficiency and the low cost [6-8]. Ferrite is mainly used in the high frequency magnetic material up to 100 MHz or so. However, it has the low saturation magneti- zation such as 0.4 or 0.5 T, the thermal runaway phenomena of self-heating in high temperature, and the weakening of mechanical vibration which often occurs in automobile car. Metal material such as iron or steel is possible to solve the problems. Iron powder has good performance as the high satu- ration magnetization, no thermal runaway phenomena and no problem for the mechanical vibration. However, magnetic permeability is relative small due to the demagnetization in a small particle. So, as far as high frequency transformer which is quite useful for electrical circuit insulation, leakage magnetic flux may increase and then the low loss transformer might be diffi- cult. Thin plate shape of the steel or iron has no demagnetization phenomena, and then high magnetic permeability can be realized. Micro-meter order steel is trial manufactured by sputtering method, rolling or so [9]. The details will be shown in the presentation at that time.

**References:**

(1) Editor and author: Keisuke Fujisaki, “Magnetic Material for Motor Drive System - Fusion Technology of Electromagnetic Fields-”, Material Engineering, Springer-Nature, 2020. (2) N. Denis, M. Inoue, K. Fujisaki, H. Itabashi, T. Yano, “Iron Loss Reduction of Permanent Magnet Synchronous Motor by Use of Stator Core Made of Nanocrystalline Magnetic Material,” IEEE Transactions on Magnetics, Volume: 53, Issue: 11, 8110006, 2017. (3) S. Okamoto, N. Denis, M. Ieki, K. Fujisaki, “Core Loss Reduction of an Interior Permanent Magnet Synchronous Motor Using Amorphous Stator Core,” IEEE Transactions on Industry Applications, vol.52, no.3, pp.2261-2268, May/June 2016. (4) K. Fujisaki, S. Liu “Magnetic Hysteresis Curve Influenced by Power-Semiconductor Characteristics in PWM Inverter,” Journal of Applied Physics, Vol. 115, 17A321, 2014. (5) A. Yao, K. Tsukada, and K. Fujisaki, “Investigating Iron Loss Properties in an Amorphous Ring Excited by Inverters based on Silicon and Gallium Nitride,” IEEJ Journal of Industry Applications, Vol. 7, No. 4, p. 321-328, 2018. (6) J. W. Kolar, Future Challenges for Research and Teaching in Power Electronics, Presentation held at the 14th Int. Conf. Optimization of Electrical and Electronic Equipment (OPTIM 2014), Brasov, Romania, May 22-24, 2014. (7) Tim Heidel, “ARPA-E Initiatives in High Efficiency Power Conversion,” APEC Plenary Session Ft. Worth, TX, March 14, 2014. (8) J.S. Glaser, et. al. “A 900 W, 300V to 50 V dc-dc power converter with 30 MHz switching frequency,” In Proc. Twenty-Fourth Annual IEEE Applied Power Electronics Conf. and Exposition APEC 2009, pp. 1121-1128, 2009. (9) J. Tanase, E. Tsuchida, K. Fujisaki, “Magnetic characteristics of 1µm-thick pure iron sheets for power electronics circuits with GaN devices," IEEE Intermag2020, CW-02, 2020.

**Images:**

 Magnetics of Motor Drive System for Electrical Vehicle



Rare earth elements (REE) are crucial for many applications including clean energy, transportation, high-tech devices, medicine, advanced manufacturing and military. The most important usage of REE by value is the NdFeB permanent magnet. Rare earths recycling was always presented as a negligible amount (&lt;1%) and the low price of REO was blamed for that. On the other hand, China has been recycling REE from magnetic scrap for over a decade and the amounts are growing. What are the main drivers of REE recycling in China vs the main prohibitors of REE recycling outside of China? What are the advancements in REE recycling from permanent magnets outside of China? What are the main feeds that are recycled and how can one drive an increase of REE recycling in the future?

**References:**



**Images:**





 Rare Earth Magnet Recycling: The Missing Link in a Circular Economy

Magnetism plays an instrumental role in biomedical applications and healthcare, both from the perspectives of devices and techniques. In particular, Magnetic Resonance Imaging (MRI, [1]) addresses the magnetization induced on the patients’ constituent matter when subject to a magnetic field, and exploits the time-varying signal resulting from the contribution of the ubiquitous hydrogen nuclei spins for high quality spatial reconstructions. At present, MRI is the only available medical imaging technique known to deliver high resolution images of deep biological tissues in vivo and without harmful ionizing radiation. However, MRI does not come without its own limitations. In particular, it is much more efficient at detecting soft tissues and fluids than hard, solid samples. This is due to the weak, short-lived signals emitted by the latter, by cause of dipolar magnetic interactions between neighboring spins in the sample, which constitute a noisy environment that decoheres the quantum nature of the MR signal. The environment’s contribution averages out for soft tissues, but not so for solids, where nuclei are approximately fixed with respect to each other in the laboratory reference frame. This explains the scarcity of useful (with diagnostic value) MR images of dental tissues [2-4], the hardest in the human body. Furthermore, the MRI scanners employed so far use static magnetic field strengths ranging from 4 to 12 T, which makes them large and expensive. At around 1 M$ per Tesla [5], this precludes their penetration in dental clinics. In this symposium, devoted to evaluating the transition of biomagnetic research from laboratory to clinical environments, we present a new, inexpensive approach to MRI of combined hard and soft biological tissues, with a view on dental applications [6]. We will show 3D reconstructions of human teeth (Figures 1 and 2), as well as a rabbit head and a cow femur, all obtained at a field strength of only 260 mT. These images are, to the best of our knowledge, the first featuring soft and hard tissues simultaneously at sub-Tesla fields, and have been acquired in a home-made special-purpose MRI scanner designed with the goal of demonstrating dental imaging at low field settings. We also present two recently patented sequences for efficient encoding of spatial information and image reconstruction: VIEWS (Volumetric Image Encoding Without k-Space) and MASSIF (Magic Angle Spinning of Spatially Inhomogeneous Fields). These are key players in the roadmap we envision to shorten scan times from several hours, as in our first prototype, to a few minutes, as desired for clinical applications.

**References:**

[1] Haacke, E. Mark, et al. Magnetic resonance imaging: physical principles and sequence design. Vol. 82. New York:: Wiley-Liss, 1999. [2] Weiger, Markus, et al. "High-resolution ZTE imaging of human teeth." NMR in Biomedicine 25.10 (2012): 1144-1151. [3] Idiyatullin, Djaudat, et al. "Dental magnetic resonance imaging: making the invisible visible." Journal of endodontics 37.6 (2011): 745-752. [4] Mastrogiacomo, Simone, et al. "Magnetic Resonance Imaging of Hard Tissues and Hard Tissue Engineered Bio-substitutes." Molecular Imaging and Biology (2019): 1-17. [5] Sarracanie, Mathieu, et al. "Low-cost high-performance MRI." Scientific Reports 5 (2015): 15177. [6] Algarín, José Miguel, et al. "Simultaneous imaging of hard and soft biological tissues in a low-field dental MRI scanner." Scientific Reports 10 (2020): 21470.

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/6feb2d6202cc6897130f3a2a8eb5112c.jpg)
(a) Picture of the scanned rabbit head. (b) Picture of a rabbit skull. (c) Top: Single slices for 90 us dead time with PETRA; middle: the same slices for 1 ms dead time; bottom: difference between the above images.

![](https://assets.underline.io/uploads/markdown_image/1/image/1e40f4cf67c994af04ff3b7c6402f824.jpg)
(a) 2 dimensional slices of four human teeth embedded in a piece of pork ham (PETRA). (b) Photograph of the sample.

 Hard Tissue Magnetic Resonance Imaging with Fast Control of Intense Magnetic Fields

The median survival of glioblastoma, the main primitive brain tumor, 15 months. The progress of imaging, surgery, robotic, chemoradiotherapy, as well as last generation molecular biology and targeted therapy did not provide any curative strategies. Innovative therapies are warranted to increase our therapeutical efficacy. Magnetic nano and micro particles are widely studied for biomedical applications such as contrast agents for MRI, regenerative medicine, cell sorting, tissue engineering, protein purification, hyperthermia or magnetofection. For cancer therapy, Magnetic Particles (MP) offer new perspectives for untreated diseases such as glioblastoma. Indeed, new pharmacotherapies struggle to prove their efficacy while therapies based on physical effect, such as Tumor Treating Fields demonstrate promising results. An approach based on mechanical destruction of cancerous cells by low-frequency vibration of magnetic particles, that we call Treatment by Magneto-Mechanical Effect of Particles (TMMEP) has been studied for several years. Kim et al. first showed that they were able to reduce glioma cancer cells viability from 90% by applying a 20 Hz alternating field on cells incubated with permalloy microdisks. Master et al. put superparamagnetic iron oxide nanoparticles (SPIONs) on breast cancer cells and applied a 100 kA/m alternating magnetic field at 50 Hz for a total of 30 min, with 10 min on / 5 min off patterns. They demonstrated a reduction in cell viability up to 75%. Interestingly, they showed that healthy cells were less affected by the treatment because of different cell mechanical properties. A comparative study of cylindrical particles with different length and diameter was conducted by Wong et al. They showed that MP with smaller diameter have a better efficacy with about 75% of cell viability after application of a biaxial pulsed magnetic field thanks to 4 coils. In vivo study on an orthotopic model of glioblastoma was conducted by Cheng et al. In a preliminary approach, they injected cancerous cells mixed with disks microparticles in brain mice and showed a better survival of mice submitted to a daily exposition of a 1 T rotating magnetic field at 20 Hz for 1 h. In this work, we used permalloy microdisks submitted to a Rotating Magnetic Field (RMF) and optimized in in vitro assay the particle concentration, magnetic field amplitude, and duration of exposure. We demonstrate here a strong lethal effect of TMMEP in vitro. We conducted in vivo assay on an orthotopic model of glioblastoma on mice but could not demonstrate efficacy of the treatment. We explain this failure by a strong difference in cell mechanical properties between in vitro and in vivo assay. To face this difficulty, we propose an in vitro 3D model by the use of spheroids put in a gel which can then be treated as a tumor and enable to mimic particle injection and RMF exposure. We also developed a 3D gel model mimicking peri-tumoral invasion of glioblastoma cells. Similarly, to the spheroid model, no effect was observed on the tumor proliferating cell in the core of the tumor. Moreover, migrating cells outside the core were strongly altered in their migration by the mechanical stimulation. Indeed, the data in the literature that supported our approach to TMMEP are essentially in vitro experimental results and no evaluation of TMMEP had yet been performed on an in vitro 3D model. Only a few articles showed in vivo efficacy, but the only survival benefit has been obtained with particles injected at the same time as the cells. The use of spheroids and organoids for the study of cancer and its treatments is now booming. Taking into account the importance of mechanical properties in tumor development, this model, placed in between 2D cell culture and animal experiments, mimics the architecture and heterogeneity of the tumor microenvironment. Closer to the in vivo tumor environment, this technique enables to better optimize and test in vitro treatments before moving to the preclinical phase, thus reducing the number of animals used in medical research. Preclinical models have been also extensively questioned, poorly mimicking the human disease. We demonstrated that results obtained in 2D culture are not relevant for the in vivo situation. Similarly, classical animal models are also poorly relevant, harboring a few invasive cells in the peritumoral area that is the main driver for tumor relapse. The model developed in this study will be crucial to modelize potential effect of magnetic vibration. The anti-invasive properties of magnetic vibration discovered using this innovative model could be explained by the specificity of the cell cytoskeleton in the migrating machinery, potentially highly sensitive to mechanical impact. A new preclinical strategy is emerging using new models to detect potential therapeutical effect of nano-magnetic vibrations. Similarly, a new design of the clinical trials should be implemented using highly cognitive trials, multimodal imaging including mechanical imaging and in situ molecular and cellular analysis of the tumor after local delivery of magnetic particles and mechanical actuation. These new translational paradigms also warrant a rigorous ethical analysis.

**References:**

Cécile Naud, François Berger, Hélène Joisten et al. Cancer treatment by magneto-mechanical effect of particles, a review. Nanoscale Adv., 2020, 2, 3632. Jain KK. A Critical Overview of Targeted Therapies for Glioblastoma. Front Oncol. 2018;8(October):1–19. Kim D-H, Rozhkova EA, Ulasov I V, Bader SD, Rajh T, Lesniak MS, et al. Biofunctionalized magnetic-vortex microdiscs for targeted cancer-cell destruction. Nat Mater. 2010;9(2):165–71. Master AM, Williams PN, Pothayee N, Zhang R, Vishwasrao HM, Golovin YI, et al. Remote Actuation of Magnetic Nanoparticles for Cancer Cell Selective Treatment Through Cytoskeletal Disruption. Sci Rep. 2015;1(919):1–13. Zhang E, Kircher MF, Koch XM, Eliasson L, Goldberg SN, Renstrom E. Dynamic Magnetic Fields Remote-Control Apoptosis via Nanoparticle Rotation. ACS Nano. 2014;8(4):3192–201. Leulmi S, Chauchet X, Morcrette M, Ortiz G, Joisten H, Sabon P, et al. Triggering the apoptosis of targeted human renal cancer cells by the vibration of anisotropic magnetic particles attached to the cell membrane. Nanoscale. 2015;7(38):15904–14. Wong DW, Gan WL, Liu N, Lew WS. Magneto-Actuated cell apoptosis by biaxial pulsed magnetic field. Sci Rep . 2017;7(1):1–8. Cheng Y, Muroski ME, Petit DCMC, Mansell R, Vemulkar T, Morshed RA, et al. Rotating magnetic field induced oscillation of magnetic particles for in vivo mechanical destruction of malignant glioma. J Control Release. 2015 Feb;223:75–84. Mansell R, Vemulkar T, Petit DCMC, Cheng Y, Murphy J, Lesniak MS, et al. Magnetic particles with perpendicular anisotropy for mechanical cancer cell destruction. Sci Rep. 2017;7(1):1–7. Fong ELS, Harrington DA, Farach-Carson MC, Yu H. Heralding a New Paradigm in 3D Tumor Modeling. Biomaterials. 2016;108:197–213.

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/ba8b6c4eeab8d4b2dfb813ca3884c747.jpg)
Figure 1: Spheroid model for preclinical mechanical stimulation testing. 1) mechanical stimulation using Halbach cylinder 2) in situ local delivery of magnetic nanoparticles.

![](https://assets.underline.io/uploads/markdown_image/1/image/d0c76220555207e62848ace21d7b64c5.jpg)
Figure 2

 Nanoviber: magnetic nanovibrations for brain tumor therapy: the translational road also needs innovation

Transition metal elements play many essential roles in the normal functioning of the human brain. These elements are transported, stored, and used by a vast range of proteins and enzymes. In most examples they are bound as individual metal ions (such as cobalt in vitamin B12), but some mineralized forms (such as the iron oxide core in ferritin) are also present. Neurodegenerative disorders (an umbrella term encompassing many forms of dementia and movement disorders), exhibit complex pathological changes within the central nervous system and beyond. Among these changes, altered patterns of transition metal element storage and utilization are generally observed in neurodegenerative disorders, as reviewed by others (e.g. Mezzaroba 2019). Magnetism plays key roles both in distinguishing the post-mortem materials properties of transition metals in biology, and in the clinical detection of transition metals in brain tissues (Collingwood & Telling, 2016). To advance the field, it is necessary to be able to image and quantify these transition metal elements in the human brain with sensitivity and specificity. From an analytical perspective, these brain compartments are effectively dilute systems, and the abundance, distribution, and material properties of the respective metal elements in their local environments vary greatly between cell types, tissues, and brain regions, and this in turn has implications for detection. The earliest histochemistry studies of post-mortem tissue revealled the heterogeneity of elements throughout the brain architecture, for example with Perls staining for iron. The ways in which these metals are bound affects staining efficacy, and efforts have been made to quantify metal ion concentrations in brain tissue as a function of brain region and ageing (e.g. Hallgren & Sourander 1958). Imaging transition metals within the living human brain with sensitivity and specificity presents many challenges. Transcranial sonography has shown sensitivity to tissue iron concentration, and scope to apply Dual-Energy Computed Tomography to image the most abundant elements is being explored. The most widely recognised opportunity came with the advent of Magnetic Resonance Imaging (MRI), which created the opportunity for sensitive, if not specific, clinical imaging of iron in the human brain (Drayer 1986). Subsequent efforts to improve specificity have included i) Bartzokis’ approach with sequential MRI scans using two distinct (B0) magnetic fields, which enable measurement of the field-dependent transverse relaxation increase associated with ferritin-encapsulated iron oxide nanoparticles (e.g. Bartzokis 2000), and ii) Quantitative Susceptibility Mapping, a method utilizing phase images to determine magnetic susceptibility distributions within tissues to thereby infer chemical composition (e.g. Haacke 2015). Post-mortem analysis continues to play an important role in testing the relationships between the properties of transition metals in brain tissue, and the signals detected with clinically-applicable methods. Magnetometry methods enable the proportion of iron present as iron oxide to be distinguished and characterized, although historically this has been applied to bulk samples, so spatial distribution information has not been preserved. Opportunities for magnetic imaging continue to evolve, and recently we demonstrated the application of synchrotron X-ray Magnetic Circular Dichroism to image the magnetic properties of post-mortem tissue from Alzheimer’s disease patients at sub-micron spatial resolution (Everett 2018). Meanwhile, the relative distribution of transition metals can be measured with outstanding sensitivity and specificity using focused beam synchrotron X-ray fluorescence imaging, creating the opportunity to correlate these distributions with high resolution quantitative MRI (Finnegan 2019). These findings can in turn inform interpretation of clinical MRI data. In conclusion, current developments in both post-mortem and clinical imaging are supporting efforts to determine whether altered patterns of transition metals can be used as biomarkers, and to investigate the extent to which disease-associated changes in the regulation of transition metals may provide insight into the pathogenesis of neurodegenerative disorders.

**References:**

G. Bartzokis and T. Tishler, Cell Mol. Biol., Vol. 46, p.821 (2000) J. Collingwood and N. Telling, Iron Oxides: from Nature to Applications, Chap. 7, p143 (2016) B. Drayer, P. Burger, R. Darwin et. al., AJR Am. J. Roentgenol. Vol. 147, p.103 (1986) J. Everett, J. Collingwood, V. Tjendana-Tjhin et. al., Nanoscale, Vol. 10, p.11782 (2018) M. Finnegan, N. Visanji, I. Romero-Canelon et. al., J. Neurosci. Methods, Vol. 319, p.28 (2019) E. Haacke, S. Liu, S. Buch et. al., Magnetic Resonance Imaging, Vol. 33, p.1 (2015) B. Hallgren and P. Sourander, J. Neurochem. Vol. 3, p.41 (1958) L. Mezzaroba, D. Alfieri, A. Simão, and E. Reiche, Neurotoxicology, Vol. 74, p.230 (2019)

**Images:**

 Imaging and Quantifying Transition Metal Ion Distribution in the Human Brain for Early Detection and Diagnosis of Neurodegenerative Disorders

The power released by magnetic nanoparticles (MNPs) submitted to an alternating driving field in the typical frequency range used in therapeutic treatments based on magnetic hyperthermia is studied using a rate-equation approach in which MNPs are modelled as double-well systems with randomly distributed easy axes. Taking into account the temperature dependency of MNP magnetization and anisotropy, a detailed picture of their hysteretic properties and of the resulting heating efficiency. The temperature variation in a host medium is then studied by solving a simple, radial Fourier equation with two typical boundary conditions. The time evolution of the temperature increment of the medium turns out to be strongly affected by the non-monotonic temperature dependence of the power released by NPs (see Figure 1a); the direct consequences on the heating efficiency make the determination of the specific loss power (SLP) and the resulting maximum temperature from the initial slope of the heating curve misleading. An alternative, sounder method to measure the average power released by magnetic nanoparticles and the SLP is proposed [1]. Another way of optimizing the performance of MNPs as heat generators consists in applying non-harmonic driving-field waveforms, with notable advantages with respect to the effects of harmonic magnetizing fields of same frequency and amplitude [2]. This improvement is related to the presence of fast, quasi-adiabatic transformations where the occupancy numbers in the two potential wells are virtually frozen, resulting in largely off-equilibrium magnetization states and in hysteresis loops with a greater area. In particular, changes of the inclination of the trapezoidal waveform’s lateral sides are also shown to induce controlled changes in the specific loss power generated by the activated nanoparticles (Figure 1b). Specific issues typical of the therapeutic practice of hyperthermia, such as the need for fine tuning of the optimal treatment temperature in real time, the possibility of combining sequential treatments at different temperatures, the ability to substantially reduce the heating transient in a hyperthermia treatment are properly addressed and overcome by making use of versatile non-harmonic driving fields of trapezoidal shape [3]. In the light of our results, features, methods, advantages and dangers of MNP-assisted precision nanomedicine are assessed in a more accurate way, and the efficiency of magnetic hyperthermia treatments is improved.

**References:**

[1] G. Barrera, P. Allia, P. Tiberto, Nanoscale, 2020,12, 6360. [2] P. Allia, G. Barrera, P. Tiberto, Phys. Rev. Applied, 2019, 12, 034041. [3] G. Barrera, P. Allia, P. Tiberto, Nanoscale Advances, 2020, 2, 4652.

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/aceca2e127ef31688d27f6c19470c419.jpg)
(a) Left: Time evolution of the temperature increment. Right: released power by NPs as a fuction of temperature. (b) Temperature increment as a function of time for selected inclination of the trapezoidal waveform lateral sides.

 Heating efficiency of magnetic nanoparticles for magnetic hyperthermia: effects of temperature and driving-field waveform

In the last months, due to the COVID-19 pandemic, we have become familiar with the expression “rapid tests” referred to fast and easy-to-use bioanalytical devices to detect viral proteins or antibodies generated by the patient’s immune system in response to the infection. The same type of rapid tests is extremely interesting to detect cancer biomarkers for disease screening and early diagnosis. Besides the fast response, the optimal technology should be low-cost, easy to use, and portable. The rapid tests rely on the lateral flow immunoassay (LFIA) technique [1]. The LFIA substrate is a strip of nitrocellulose membrane along which the liquid sample containing the molecule of interest can flow by capillary action. Before this flow, the analyte is specifically tagged with fluorescent enzymes or particles to make it visible. Two lines of recognition molecules are immobilized across the strip: (i) the test line, formed by a molecule that captures the tagged molecule of interest, and (ii) the control line, at which the unbound tags are trapped. The LFIA technique is used for point-of-care detection of various biomarkers; the best known is the pregnancy hormone in the popular home pregnancy tests that we can buy in the pharmacy and use ourselves with no prescription. There are some limitations for LFIA expansion, mainly their sensitivity and limit of quantification, which are not sufficient for some biomedical applications. Despite their limitations, WHO highly encourages the research into their performance and utility for disease surveillance [2]. There are two crucial ways in which magnetism can contribute effectively to improve the performance of rapid diagnostic tests: magnetic nanotags and magnetic sensing. The use of magnetic particles to tag the biomolecule of interest can have several advantages compared to non-magnetic tags (used for optical detection): magnetic immuno-concentration, magnetic detection, and long-lasting signal. Once the biomolecule is tagged by magnetic particles, the magnetic pre-concentration or isolation of the target biomolecule can be achieved by a magnetic gradient that attracts them and allow their separation from the original medium. This is enormously advantageous to increase the sensitivity of any technique that is applied after it. We can then detect the particles through a magnetic sensor without interferences from the paper strip or the biological fluid. Finally, the magnetic signal coming from the particles in the test line perdures in time and is insensitive to the paper strip aging or staining [3]. We recently developed a bio-detection method based on LFIA using superparamagnetic labels combined with an inductive sensor for reading out their signal. We proved the viability of the technique for quantifying prostatic cancer biomarkers [3] and toxic biogenic amines [4] in the range of interest. In this work, we have developed a lateral flow immunoassay (LFIA) system to detect plasma-derived extracellular vesicles (EV). These small (micro- or nano-sized) membrane structures are released by cells to mediate intercellular communication. Given that they carry proteins and micro-RNA specific to their cell of origin, they are nowadays thoroughly studied as disease biomarkers. We used superparamagnetic iron oxide nanoparticles coated with a double layer of oleic acid [5] as reporter labels. They were conjugated to antibodies against proteins expressed in the EVs surface, specifically CD-63 and CD-147. The latter is in higher concentrations in patients with colorectal cancer [6]. We used different concentrations of EVs purified from human plasma to perform LFIA tests to calibrate the system. Fig. 1 shows some of the LFIA strips obtained for such calibration. Subsequently, the strips were analyzed by a commercial reflectance sensor and our magnetic inductive sensor. The results for the assays with CD63 are shown in Fig. 2. We can appreciate that the linear range extends to all the concentration range understudy for the magnetic sensor. The tendency to saturation that we observe with the optical reader is typical of the immunoassays and is caused by the available antibodies' occupation. Given that the reflectance signal comes only from the particles at the surface of the membrane, the saturation is achieved at lower concentrations than in the magnetic one, which comes from the whole volume. Besides this obvious advantage, the magnetic sensor provides better linearity (even taking a reduced linear range of concentration for the optical signal) and a lower limit of detection (three times smaller for CD63 and two times smaller for CD147). We must emphasize that the analyte has not been magnetically pre-concentrated for these measurements. Such a technique will be studied in an ongoing investigation to increase further the sensitivity of the magnetic LFIA aiming at a rapid, portable technology for liquid biopsy applied to colorectal cancer screening. Acknowledgements This work was supported by the Spanish Ministry of Economy and Competitiveness (grant MAT2017-84959-C2-1-R), the Principality of Asturias (IDI/2018/000185) and the Council of Gijón/IUTA (SV-20-GIJON-1-22).

**References:**

[1] C. Parolo, A. Sena-Torralba, J.F. Bergua, et al., Nat Protoc., Vol. 15(12), p.3788 (2020) [2] https://www.who.int/news-room/commentaries/detail/advice-on-the-use-of-point-of-care-immunodiagnostic-tests-for-covid-19 [3] D. Lago-Cachón, M. Oliveira-Rodríguez, M. Rivas, et al., IEEE Magn. Lett., Vol. 8, p. 1 (2017) [4] A. Moyano, M. Salvador, J. C. Martínez-García, et al., Anal. Bioanal. Chem, Vol. 411, p. 6615 (2019) [5] D. Bica, L. Vékás, M.V. Avdeev, et al., J. Magn. Magn. Vol. 311, p. 17 (2007). [6] Y. Yoshioka, N. Kosaka, Y. Konishi, et al., Nat. Commun. Vol. 5, p. 1 (2014)

**Images:**

![](https://assets.underline.io/uploads/markdown_image/1/image/f92db3f9ddab9742d7c6522ff6432089.jpg)
LFIA strips performed to test the concentration of human-plasma circulating EVs expressing CD63.

![](https://assets.underline.io/uploads/markdown_image/1/image/0b555f1683f3ae239395a4ececf06bc3.jpg)
Calibration of CD63 LFIAs using the magnetic (black) and optical (orange) readers.

Potential effects of TMS magnetic fields beyond the conventional neurostimulation

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Potential effects of TMS magnetic fields beyond the conventional neurostimulation

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