Scientists at UCL have developed a new technique that uses microscopic magnetic particles to remotely activate brain cells; researchers say the discovery in rats could potentially lead to the development of a new class of non-invasive therapies for neurological disorders.
Microscopic magnetic particles, or micromagnets, are attached to astrocytes, and used as miniature mechanical switches that can turn “on” the cells when a strong magnet is placed near the head.
Co-author, Professor Alexander Gourine (UCL Centre for Cardiovascular and Metabolic Neuroscience) said: “Astrocytes are star-shaped cells found throughout the brain. They are strategically positioned between the brain blood vessels and nerve cells. These cells provide neurons with essential metabolic and structural support, modulate neuronal circuit activity and may also function as versatile surveyors of brain milieu, tuned to sense conditions of potential metabolic insufficiency.
Senior author, Professor Mark Lythgoe (UCL Centre for Advanced Biomedical Imaging) said: “Because astrocytes are sensitive to touch, decorating them with magnetic particles means you can give the cells a tiny prod from outside the body using a magnet, and as such, control their function. This ability to remotely control astrocytes provides a new tool for understanding their function and may have the potential to treat brain disorders.”
In developing MMS, scientists at UCL set out to create a more clinically relevant brain cell control technique. This contrasts with other existing research tools, such as optogenetics and chemogenetics, which require foreign genes to be inserted into the brain cells, typically with the help of a virus. This need for genetic modification has been a major obstacle to the clinical translation of the existing methods.
Lead researcher Dr. Yichao Yu (UCL Centre for Advanced Biomedical Imaging) said: “Our new technology uses magnetic particles and magnets to remotely and precisely control brain cell activity and, importantly, does this without introducing any device or foreign gene into the brain.
“Another advantage of using micromagnets is that they light up on an MRI scan so we can track their location and target very particular parts of the brain to get precise control of brain function.”
Professor Lythgoe, who received the Royal Society of Medicine Ellison–Cliffe Award 2021 for his “contribution of fundamental science to the advancement of medicine”, added: “We are very excited about this technology because of its clinical potential. In contrast to existing methods, MMS takes advantage of the remarkable sensitivity to touch of certain brain cells, therefore neither genetic modification nor device implantation is needed.
All conservative therapy methods can be grouped into three types according to the main approach used in them—chemical, biological/biochemical and physical [1]. Chemical methods are quite effective in many cases, but they are usually the most toxic and prone to inducing significant side effects. Biological and biochemical methods are more selective and are usually less toxic. The least toxic and safest methods are based on physiotherapy using magnetic fields (MF), but they are usually less effective, have insufficient physical background, and lack selectivity and locality.
Bionanotechnology opens new approaches that allow drastic increases in selectivity and simultaneous increases in the effects of localization up to the nanoscale and molecular levels [2,3,4,5,6,7], which also reduce the risk of organism intoxication. One of the advanced strategies is based upon functionalized magnetic nanoparticles (MNPs) that are controlled by an external alternating magnetic field (AMF) [8,9,10,11,12,13,14,15,16,17,18,19,20].
MNPs are already used to increase contrast in magnetic resonance imaging and in addressed drug delivery, including controlled drug release from the transport of nanoscale modules. Magnetic hyperthermia (MHT), which is a drugless therapy method that utilizes MNPs heated by AMF in the 100–800 kHz range, has already been developed for more than half a century [21,22,23,24,25,26,27,28,29,30,31,32]. The MNPs’ introduction to a living organism shifts the critical frequency by dividing the heating and non-heating AMF from the megahertz range to the kilohertz range. There are various combinations of MHT with thermally induced drug release from the transport of nanoscale modules [33,34,35,36,37,38,39,40].
It was reported in a number of papers that the stimulation of biomolecular systems through MHT produces more significant effects than the heating of the sample to the same macroscopic temperature in a water bath. For instance, in [38], the release rate of doxorubicin from micellar containers of 70 nm diameter, filled with magnetite MNPs coated with a hydrophobic oleylamine layer of 11 nm in diameter, was reported to be three times higher during MHT in a 330 kHz AMF than during heating to the same 45 °C temperature in a water bath. This suggests the presence of an additional factor, which, in our opinion, is related to nanomechanical magnetic activation (NMMA).
NMMA represents the other category of techniques that employ the nanoscale deformation of molecular structures by means of MNPs that are activated by non-heating low-frequency (LF) (f < 1 kHz) AMF, and these techniques have been developed during the last two decades [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. NMMA utilizes the sensitivity of tissue, cells, vesicles and micelles to applied forces and induced deformations [58,59,60,61,62].
The biochemical responses to the force applied to various molecular structures in living cells are the most studied, with apoptosis receiving particular attention [63,64,65]. This type of phenomena is generally referred to as mechanotransduction [66,67,68,69]. The use of mechanotransduction opens up a wide perspective in the development of new approaches and techniques in the treatment of oncological [53,70,71] and neurodegenerative diseases [72,73,74], as well as in regenerative medicine [41,58] and other biomedical fields [52,53,54,55]. “The dark side of the force” should also be mentioned. The impact of force could possibly stimulate tumor growth due to the transmission of force from more rigid malignant cells to surrounding healthy softer ones [75].
Over several decades of magnetobiological studies, a significant amount of contradictory information and erroneous conclusions about the nature of the recorded effects has been accumulated. We will briefly discuss the most important and the most frequently occurring problems in the identification of the possible mechanisms of the impact of MF on biological objects, including those containing MNPs.
There are some sources of evidence that weak MF can produce biophysical effects in living organisms, tissues and cells, and that, in some cases, this can occur even without any MNPs [76,77,78,79,80]. These effects are hard to predict because of unclear physical mechanisms of field action. Furthermore, the reported information concerning such effects is all too often controversial and incomplete insofar as it relates to experimental conditions and the construction of reproducible independent experiments. Insights regarding the general status of the scope of magnetobiology can be gained even by examining the titles of some papers published by prominent scientists: “Why magnetic and electromagnetic effects in biology are irreproducible and contradictory?”; “Are biochemical reactions affected by weak magnetic fields?” [81,82].
A separate, yet unresolved, problem is the plausibility of the impact of the Earth’s MF [83] with BEarth = 30–50 μT, and its fluctuations reaching 2–4 orders of magnitude lower intensity even during magnetic storms [84], on various components of the Earth biosphere. Summarizing the above, it can be argued that there is no evidence and there are no generally accepted judgments about the possible mechanisms—and simple plausibility—of the effect of a weak MF on biological objects.
The response of biological objects following the application of AMF depends upon a large set of spatial, temporal, amplitude and frequency characteristics of MF, including the field exposition mode, which can be continuous, intermittent or pulsed, as well as MNPs’ nature and composition, frequency windows of higher and lower sensitivity, electric and magnetic properties of the object itself, its individual peculiarities, geometry and prehistory, among other characteristics. This significantly increases the complexity of the problem.
All of these specifics distinguish the impact of vector AMF from the impacts of scalar thermodynamic parameters such as temperature, pressure, concentration, and so on. Unlike the AMF, the influence of the latter on biological objects is studied much more effectively at various scale levels, and is in good agreement with relatively simple common models and mechanisms.
Meanwhile, several magnetobiological effects are known with certainty and can be reproduced reliably. The most evident and straightforward ones, considering the underlying physical mechanism, are the induction heating of soft tissues caused by radio frequency (RF) AMF (typically 5–30 MHz in physiotherapy), and neuron stimulation caused by an eddy electric field generated by AMF pulses, with an intensity of ~1 T and a duration of ~1 ms, which is used in transcranial magnetic simulation in particular.
Many physicists question the ability of steady MF or LF non-heating AMF, with an intensity 0.1–1 T, to affect cells, tissues or living organisms, since it is hard to find a clear physical basis and molecular targets for such influence. Therefore, they consider the noticeable influence of the much weaker Earth MF (BEarth = 30–50 μT) to be even more unreasonable. The main objection is the lack of energy that MF could provide for any particles in the organism.
As long as magnetically ordered regions are extremely rare or even non-existent in warm-blooded organisms, MF interacts only with objects that have magnetic momentum in the order of Bohr magneton μB = 927.4·10−26 J/T, such as electrons, radicals, ions, atoms, etc. In any reasonable field with B~1 T their magnetic energy Um~μBB is well below thermal energy UT~kBTR, where TR ≈ 300 K is ambient temperature and kB = 1.380649·10−23 J/K is the Boltzmann constant. Magnetic fields with Um << UT are usually referred to as thermodynamically weak, which means that they cannot significantly affect the behavior of thermodynamic systems in equilibrium. This raises questions concerning the specific non-equilibrium processes in charge of the effect and appropriate targets that are susceptible to MFs that are so weak.
Despite the absence of commonly accepted answers to these questions, physicians, biologists, hygienists and work safety officers generally agree that hazards and risks related to the impact of AMF on the biosphere diminish with the lowering of the AMF frequency [84]. National and international guidelines and sanitary regulations [85,86,87,88] support the above relation: the lower the AMF frequency, the higher the maximal allowed field intensity both for citizens and for work staff who are maintaining electromagnetic equipment (Figure 1).
Failure to understand the mechanisms of magnetic sensitivity leads to a broken dependence of the maximum permissible MF intensity on its frequency. There is no reasonable substantiation of the breaks of the curve. Let us note that several certified medical technologies significantly exceed the limit, albeit for a short periods of time (Figure 1).
The AMF, when used in some medical technologies, particularly Magnetic Resonance Imaging (MRI) [89], exceeds even the empirical Brezovich threshold H·f = 4.85·108 Am−1s−1, defined as a point where a human starts to feel discomfort when the AMF is switched on [90]. Here, H = B/μ0 is the magnetic field strength and μ0 = 4π·10−7 H/m is the vacuum permeability. Both International Commission on Non-Ionizing Radiation Protection (ICNIRP) limits and the Brezovich threshold take into account damage from magnetically induced electric fields, but not the hazards from direct exposure to magnetic fields, since the latter are not sufficiently justified.
Magnetic field map with allowable intensity limits for a wide frequency range. Red broken lines indicate the maximum allowable fields according to the recommendation of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) [87]: the upper line corresponds to industrial conditions and the lower line corresponds to accommodation. The dashed line corresponds to Brezovich’s condition H·f = 4.85·108 Am−1s−1, which restricts the application of an AMF for medical purposes according to [90]. The green circle at the MF axis indicates the intensity of the Earth’s magnetic field. The techniques indicated by asterisks require the preliminary introduction of MNPs.
Meanwhile, it is an established fact that a reduction in MF intensity significantly below the Earth’s MF, known as a hypomagnetic condition, can, in many cases, result in verifiable changes in the functioning of biomolecular structures [91].
The authors of several comprehensive papers propose a number of mechanisms of weak MF that affect biological processes, which include the formation of short living radicals and radical reactions that take place far from thermodynamic equilibrium [92,93,94,95,96,97,98,99].
These and other related papers show that the kinetics and the yield of fast radical reactions can be affected by MF even if radical magnetic energy Um << UT. The mechanisms of MF that affect processes that encompass non-equilibrium paramagnetic centers were substantiated theoretically [92,93,94]. A short explanation is as follows: the spin subsystem in dynamic processes may have insufficient time for thermalization; therefore, it can be considered as isolated from the atomic-molecular one for a period of time that is determined by the relaxation time τT.
A weak MF could affect the spinning of paramagnetic particles during that time span, so that short living radical pairs can go from singlet to triplet state, thereby preventing its recombination. However, the kinetic restraints are quite strict for such spin-dependent reactions. The lifetime of such τL pairs should be higher than spin conversion time τC but lower than τT. It is unknown whether τC < τL < τT conditions could be satisfied for biochemical reactions in living objects; but, for simple radical reactions in model systems, this was already proven experimentally [97,98].
On the one hand, this uncertainty prevents the development of accurate models of biological processes in weak MFs and, consequently, reasonable and reliable methods of therapy; but, on the other hand, it requires monitoring of the traces of the possible impact of MFs on biological systems in each experiment, even with a sufficiently low MF intensity.
The above energy proportion can be changed drastically through the introduction of MNPs into the system. The interaction energy of MF with MNPs, with diameters ranging from several nanometers to several tens of nanometers, is thousands of times higher than with individual electrons, thus resolving the problem of kBT as long as Um >> UT.
Therefore, the magnetic energy becomes thermodynamically non-negligible and the only remaining question relates to the paths of further energy transfer into the biomolecular system. The above forms a foundation for methods of therapy that use MNPs, and it enables such methods to be advantageous compared to pure magnetic therapy.
There are at least two distinctly differing approaches to the conversion of this energy into biochemical effects. The first is its dissipation into the form of thermal energy, which takes place in magnetic hyperthermia at f = 100–800 kHz. The second utilizes magnetic forces more directly as local forces that induce deformation in biomolecules that are tethered or merely adjacent to MNPs rotating in non-heating low-frequency (f < 1 kHz) AMF. This approach is referred to as nanomechanical magnetic activation (NMMA).
Despite many attempts to provide theoretical and experimental evidence for heating localization in the volume of one cell (“intracellular hyperthermia”) [100,101], or even in the vesicle membrane [102], it was shown, both theoretically [52,54,103,104,105,106,107] and experimentally [108], that for the MNPs and MFs used in real applications, the heating cannot be localized in a region smaller than a few millimeters, and the individual MNP cannot be overheated more than by 10−6 °C relative to the environment.
The thermal energy generated inside the MNP and in the adjacent zone is very efficiently distributed over a large area. The thermal diffusivity of any biological material differs by several times, but not by more than an order of magnitude. Therefore, during a typical experiment with a duration of ~100 s, the thermal conductivity levels out the temperature gradients in an area much larger than the cell size.
In other words, adiabatic heating is possible only over a period of time that is 6–8 orders of magnitude less for a cell and 10–12 orders of magnitude less for the size scale of MNPs. To obtain a noticeable effect, one should accordingly increase the energy generation rate. An increase by many orders of magnitude in the MF intensity or the rate of energy dissipation of MNPs seems absolutely implausible, especially when taking into account all the limitations imposed by work with living organisms.
We believe that the local effects observed in [100,101,102] and some other similar works are due to the rotational-vibrational motions of MNPs in the AFM. In contrast to magnetic hyperthermia, NMMA acts on a region that is comparable in size to the diameter of MNP and may have molecular selectivity [52,54,55]. This forces us to focus further discussion on the features of the NMMA of biomolecular structures in the absence of their noticeable heating.
It is likely that the first application of the nanomechanical approach that used MNPs for the generation of force was implemented by future Nobel Prize winner F. Crick in 1950 to measure intracellular microviscosity [109]. In [110], the team from Lomonosov Moscow State University reported that the activity of the enzyme can be controlled by deformation of the biomolecule. Macromolecules (MM) of trypsin and chymotrypsin were immobilized on nylon fibers and other polymer matrices with covalent bonds.
Mechanical deformation of the matrix with immobilized MMs led to a decrease in the enzyme activity and an increase in its thermal stability at a deformation of about 0.05 nm, normalized to one enzyme MM. Later, this approach was developed into the field of mechanochemistry, which is associated with the immobilization of catalyst molecules on various soft materials and the control of their activity through macrodeformation of the material [56,111,112].
The first part of this mini review looks at the physical background, the second describes recent field results, and the third discusses the toxicity and other risks associated with this NMMA approach.
reference link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8470408/
More information: Yichao Yu et al, Remote and Selective Control of Astrocytes by Magnetomechanical Stimulation, Advanced Science (2021). DOI: 10.1002/advs.202104194
