Magnetite in Human Brain? - People can sense Earth’s magnetic field, brain waves suggest

I'm sure some folks can sense the charge field as well...?
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People can sense Earth’s magnetic field, brain waves suggest
A new study hints that humans have magnetoreception abilities, similar to some other animals
Earth magnetic field

ANIMAL MAGNETISM  Like birds, bacteria and other creatures with an ability known as magnetoreception, humans can sense Earth’s magnetic field (illustrated), a new study suggests.

By Maria Temming

MARCH 18, 2019 AT 1:05 PM

A new analysis of people’s brain waves when surrounded by different magnetic fields suggests that people have a “sixth sense” for magnetism.

Birds, fish and some other creatures can sense Earth’s magnetic field and use it for navigation (SN: 6/14/14, p. 10). Scientists have long wondered whether humans, too, boast this kind of magnetoreception. Now, by exposing people to an Earth-strength magnetic field pointed in different directions in the lab, researchers from the United States and Japan have discovered distinct brain wave patterns that occur in response to rotating the field in a certain way.

These findings, reported in a study published online March 18 in eNeuro, offer evidence that people do subconsciously respond to Earth’s magnetic field — although it’s not yet clear exactly why or how our brains use this information.

“The first impression when I read the [study] was like, ‘Wow, I cannot believe it!’” says Can Xie, a biophysicist at Peking University in Beijing. Previous tests of human magnetoreception have yielded inconclusive results. This new evidence “is one step forward for the magnetoreception field and probably a big step for the human magnetic sense,” he says. “I do hope we can see replications and further investigations in the near future.”

During the experiment, 26 participants each sat with their eyes closed in a dark, quiet chamber lined with electrical coils. These coils manipulated the magnetic field inside the chamber such that it remained the same strength as Earth’s natural field but could be pointed in any direction. Participants wore an EEG cap that recorded the electrical activity of their brains while the surrounding magnetic field rotated in various directions.

This setup simulated the effect of someone turning in different directions in Earth’s natural, unchanging field without requiring a participant to actually move. (Complete stillness prevented motor-control thoughts from tainting brain waves due to the magnetic field.) The researchers compared these EEG readouts with those from control trials where the magnetic field inside the chamber didn’t move.

Joseph Kirschvink, a neurobiologist and geophysicist at Caltech, and colleagues studied alpha waves to determine whether the brain reacts to changes in magnetic field direction. Alpha waves generally dominate EEG readings while a person is sitting idle but fade when someone receives sensory input, like a sound or touch.

Sure enough, changes in the magnetic field triggered changes in people’s alpha waves. Specifically, when the magnetic field pointed toward the floor in front of a participant facing north — the direction that Earth’s magnetic field points in the Northern Hemisphere — swiveling the field counterclockwise from northeast to northwest triggered an average 25 percent dip in the amplitude of alpha waves. That change was about three times as strong as natural alpha wave fluctuations seen in control trials.


ROTATION REACTION When downward-pointing magnetic fields were rotated counterclockwise, from northeast to northwest, researchers saw a significant dip in participants’ alpha brain waves (left). Alpha waves are similarly dampened when someone receives sensory input like a sound or smell. This response was not seen when downward fields rotated clockwise (center) or were held steady (right).
Curiously, people’s brains showed no responses to a rotating magnetic field pointed toward the ceiling — the direction of Earth’s field in the Southern Hemisphere. Four participants were retested weeks or months later and showed the same responses.

“It’s kind of intriguing to think that we have a sense of which we’re not consciously aware,” says Peter Hore, a chemist at the University of Oxford who has studied birds’ internal compasses. But “extraordinary claims need extraordinary proof, and in this case, that includes being able to reproduce it in a different lab.”


Questions raised
If these findings are replicable, they pose several questions — such as why people seem to respond to downward- but not upward-pointing fields. Kirschvink and colleagues think they have an answer: “The brain is taking [magnetic] data, pulling it out and only using it if it makes sense,” Kirschvink says.

Participants in this study, who all hailed from the Northern Hemisphere, should perceive downward-pointing magnetic fields as natural, whereas upward fields would constitute an anomaly, the researchers argue. Magnetoreceptive animals are known to shut off their internal compasses when encountering weird fields, such as those caused by lightning, which might lead the animals astray. Northern-born humans may similarly take their magnetic sense “offline” when faced with strange, upward-pointing fields.

This explanation “seems plausible,” Hore says, but would need to be tested in an experiment with participants from the Southern Hemisphere.

The brain’s attention to counterclockwise but not clockwise rotations “is something surprising that we don’t really have a good explanation for,” says coauthor Connie Wang, who studies magnetoperception at Caltech. Some people may respond to clockwise rotations, just like some people are left-handed rather than right-handed, or clockwise rotations generate brain activity not captured in the alpha wave signal, she says.

Even accounting for which magnetic changes the brain picks up, researchers still don’t know what our minds might use that information for, Kirschvink says. Another lingering mystery is how, exactly, our brains detect Earth’s magnetic field. According to the researchers, the brain wave patterns uncovered in this study may be explained by sensory cells containing a magnetic mineral called magnetite, which has been found in magnetoreceptive trout as well as in the human brain (SN: 8/11/12, p. 13). Future experiments could confirm or eliminate that possibility.

More at Link including Video:
https://www.sciencenews.org/article/people-can-sense-earth-magnetic-field-brain-waves-suggest

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Research ArticleNew Research, Sensory and Motor Systems
Transduction of the Geomagnetic Field as Evidenced from alpha-Band Activity in the Human Brain
Connie X. Wang, Isaac A. Hilburn, Daw-An Wu, Yuki Mizuhara, Christopher P. Cousté, Jacob N. H. Abrahams, Sam E. Bernstein, Ayumu Matani, Shinsuke Shimojo and Joseph L. Kirschvink
eNeuro 18 March 2019, 6 (2) ENEURO.0483-18.2019; DOI: https://doi.org/10.1523/ENEURO.0483-18.2019

More at link:
https://www.eneuro.org/content/6/2/ENEURO.0483-18.2019

Abstract

Magnetoreception, the perception of the geomagnetic field, is a sensory modality well-established across all major groups of vertebrates and some invertebrates, but its presence in humans has been tested rarely, yielding inconclusive results. We report here a strong, specific human brain response to ecologically-relevant rotations of Earth-strength magnetic fields. Following geomagnetic stimulation, a drop in amplitude of electroencephalography (EEG) alpha-oscillations (8–13 Hz) occurred in a repeatable manner. Termed alpha-event-related desynchronization (alpha-ERD), such a response has been associated previously with sensory and cognitive processing of external stimuli including vision, auditory and somatosensory cues. Alpha-ERD in response to the geomagnetic field was triggered only by horizontal rotations when the static vertical magnetic field was directed downwards, as it is in the Northern Hemisphere; no brain responses were elicited by the same horizontal rotations when the static vertical component was directed upwards. This implicates a biological response tuned to the ecology of the local human population, rather than a generic physical effect. Biophysical tests showed that the neural response was sensitive to static components of the magnetic field. This rules out all forms of electrical induction (including artifacts from the electrodes) which are determined solely on dynamic components of the field. The neural response was also sensitive to the polarity of the magnetic field. This rules out free-radical “quantum compass” mechanisms like the cryptochrome hypothesis, which can detect only axial alignment. Ferromagnetism remains a viable biophysical mechanism for sensory transduction and provides a basis to start the behavioral exploration of human magnetoreception.

alpha-ERDbiogenic magnetitebiophysicsEEGmagnetoreceptionquantum compass

Significance Statement

Although many migrating and homing animals are sensitive to Earth’s magnetic field, most humans are not consciously aware of the geomagnetic stimuli that we encounter in everyday life. Either we have lost a shared, ancestral magnetosensory system, or the system lacks a conscious component with detectable neural activity but no apparent perceptual awareness by us. We found two classes of ecologically-relevant rotations of Earth-strength magnetic fields that produce strong, specific and repeatable effects on human brainwave activity in the electroencephalography (EEG) alpha-band (8–13 Hz); EEG discriminates in response to different geomagnetic field stimuli. Biophysical tests rule out all except the presence of a ferromagnetic transduction element, such as biologically-precipitated crystals of magnetite (Fe3O4).

Introduction

Magnetoreception is a well-known sensory modality in bacteria (Frankel and Blakemore, 1980), protozoans (Bazylinski et al., 2000) and a variety of animals (Wiltschko and Wiltschko, 1995a; Walker et al., 2002; Johnsen and Lohmann, 2008), but whether humans have this ancient sensory system has never been conclusively established. Behavioral results suggesting that geomagnetic fields influence human orientation during displacement experiments (Baker, 1980, 1982, 1987) were not replicated (Gould and Able, 1981; Able and Gergits, 1985; Westby and Partridge, 1986). Attempts to detect human brain responses using electroencephalography (EEG) were limited by the computational methods that were used (Sastre et al., 2002). Twenty to 30 years after these previous flurries of research, the question of human magnetoreception remains unanswered.

In the meantime, there have been major advances in our understanding of animal geomagnetic sensory systems. An ever-expanding list of experiments on magnetically-sensitive organisms has revealed physiologically-relevant stimuli as well as environmental factors that may interfere with magnetosensory processing (Wiltschko and Wiltschko, 1995a; Lohmann et al., 2001; Walker et al., 2002). Animal findings provide a potential feature space for exploring human magnetoreception, the physical parameters and coordinate frames to be manipulated in human testing (Wiltschko, 1972; Kirschvink et al., 1997). In animals, geomagnetic navigation is thought to involve both a compass and map response (Kramer, 1953). The compass response simply uses the geomagnetic field as an indicator to orient the animal relative to the local magnetic north/south direction (Wiltschko and Wiltschko, 1995a; Lohmann et al., 2001). The magnetic map is a more complex response involving various components of field intensity and direction; direction is further subdivided into inclination (vertical angle from the horizontal plane; the North-seeking vector of the geomagnetic field dips downwards in the Northern Hemisphere) and declination (clockwise angle of the horizontal component from Geographic North, as in a man-made compass). Notably, magnetosensory responses tend to shut down altogether in the presence of anomalies (e.g., sunspot activity or local geomagnetic irregularities) that cause the local magnetic field to deviate significantly from typical ambient values (Wiltschko, 1972; Martin and Lindauer, 1977), an adaptation that is thought to guard against navigational errors. These results indicate that geomagnetic cues are subject to complex neural processing, as in most other sensory systems.

Physiologic studies have flagged the ophthalmic branch of the trigeminal system (and equivalents) in fish (Walker et al., 1997), birds (Semm and Beason, 1990; Beason and Semm, 1996; Mora et al., 2004; Elbers et al., 2017), and rodents (Wegner et al., 2006) as a conduit of magnetic sensory information to the brain. In humans, the trigeminal system includes many autonomic, visceral, and proprioceptive functions that lie outside conscious awareness (Saper, 2002; Fillmore and Seifert, 2015). For example, the ophthalmic branch contains parasympathetic nerve fibers and carries signals of extraocular proprioception, which do not reach conscious awareness (Liu, 2005).

If the physiologic components of a magnetosensory system have been passed from animals to humans, then their function may be either subconscious or only weakly available to conscious perception. Behavioral experiments could be easily confounded by cognitive factors such as attention, memory and volition, making the results weak or difficult to replicate at the group or individual levels. Since brain activity underlies all behavior, we chose a more direct electrophysiological approach to test for the transduction of geomagnetic fields in humans.

Materials and Methods

Part 1: summary and design logic

Experimental equipment setup

We constructed an isolated, radio frequency-shielded chamber wrapped with three nested sets of orthogonal square coils, using the four-coil design of Merritt et al. (1983) for high central field uniformity (Fig. 1; further details in Fig. 2 and Materials and Methods, Part 2: details for replication and validation). Each coil contained two matched sets of windings to allow operation in active or sham mode. In active mode, currents in paired windings were parallel, leading to summation of generated magnetic fields. In sham mode, currents ran antiparallel, yielding no measurable external field, but with similar ohmic heating and magnetomechanical effects as in active mode (Kirschvink, 1992b). Active and sham modes were toggled by manual switches in the distant control room, leaving computer and amplifier settings unchanged. Coils were housed within an acoustically-attenuated, grounded Faraday cage with aluminum panels forming the walls, floor and ceiling. Participants sat upright in a wooden chair on a platform electrically isolated from the coil system with their heads positioned near the center of the uniform field region. The magnetic field inside the experimental chamber was monitored by a three-axis Applied Physics Systems 520A fluxgate magnetometer. EEG was continuously recorded from 64 electrodes using a BioSemi ActiveTwo system with electrode positions coded in the International 10-20 System (e.g., Fz, CPz, etc.). Inside the cage, the battery-powered digital conversion unit relayed data over a non-conductive, optical fiber cable to a remote-control room, ∼20 m away, where all power supplies, computers and monitoring equipment were located.



Magnetic field rotations used in these experiments. In the first ∼100 ms of each experimental trial, the magnetic field vector was either: (1) rotated from the first preset orientation to the second (SWEEP), (2) rotated from the second preset orientation to the first (also SWEEP), or (3) left unchanged (FIXED). In all experimental trials, the field intensity was held constant at the ambient lab value (∼35 μT). For declination rotations, the horizontal rotation angle was +90° or –90°. For inclination rotations, the vertical rotation angle was either +120°/–120°, or +150°/–150°, depending on the particular inclination rotation experiment. A, Inclination rotations between ±60° and ±75°. The magnetic field vector rotates from downwards to upwards (Inc.UP.N, red) and vice versa (Inc.DN.N, blue), with declination steady at North (0°). B, Declination rotations used in main assay (solid arrows) and vector opposite rotations used to test the quantum compass hypothesis (dashed arrows). In the main assay, the magnetic field rotated between NE (45°) and NW (315°) with inclination held downwards (+60° or +75°) as in the Northern Hemisphere (DecDn.CW.N and DecDn.CCW.N); vector opposites with upwards inclination (−60° or −75°) and declination rotations between SE (135°) and SW (225°) are shown with dashed arrows (DecUp.CW.S and DecUp.CCW.S). C, Identical declination rotations, with static but opposite vertical components, used to test the electrical induction hypothesis. The magnetic field was shifted in the Northerly direction between NE (45°) and NW (315°) with inclination held downwards (+75°, DecDn.CW.N and DecDn.CCW.N) or upwards (−75°, DecUp.CW.S and DecUp.CCW.S). The two dotted vertical lines indicate that the rotations started at the same declination values. In both B, C, counterclockwise rotations (viewed from above) are shown in red, clockwise in blue.

Conclusion

Our results indicate that at least some modern humans transduce changes in Earth-strength magnetic fields into an active neural response. We hope that this study provides a road-map for future studies aiming to replicate and extend research into human magnetoreception. Given the known presence of highly-evolved geomagnetic navigation systems in species across the animal kingdom, it is perhaps not surprising that we might retain at least some functioning neural components especially given the nomadic hunter/gatherer lifestyle of our not-too-distant ancestors. The full extent of this inheritance remains to be discovered.

Also: https://info.tmsi.com/blog/types-of-brain-waves

April 28 2022 | Blog

What Are the Different Types of Brain Waves?
Explaining the characteristics of alpha, beta, theta, and delta waves seen on EEG

What are brain waves?

Throughout daily tasks, your brain is firing with neuronal activity. The neurons can fire randomly or in a synchronized manner. These synchronized, rhythmic electrical pulses from communicating neurons are called neural oscillations, or brain waves. For these signals to be detected from the cerebral surface, a large number of neurons must be synchronously active.1 When the signals’ amplitude is high enough, they can be detected from the cerebral surface with electroencephalography (EEG). There are different categories of brain waves, which are characterized by their differences in frequency and amplitude. The four main brain waves that are recognized are: alpha, beta, theta, and delta waves. These waves can be seen in Figure 1.

Types of Brain Waves-5

Figure 1: Types of Brain Waves (Picture source for alpha, beta, theta, and delta)


What are the characteristics of alpha waves?

Alpha waves have a frequency of 8-12 Hz. They can be seen in states when a subject is awake, relaxed, and resting. These waves are seen most intensely in the occipital region (visual cortex) when a subject has their eyes closed. The synchronization is caused by blocking visual input to occipital areas. In addition to the occipital region, these waves can also be recorded from the parietal and frontal scalp regions.1

They are waves with high amplitudes (voltage 20-200 µV) and are therefore easy to distinguish in the EEG. Modern research suggests multiple, distinct mechanisms that are responsible for producing alpha waves, such as thalamocortical loops, rhythmically firing pyramidal cells, and local interneurons.2 Alpha waves disappear when the subject is asleep. When the subject is awake and the attention is directed to some specific type of mental activity, the alpha waves are replaced by asynchronous waves of higher frequency but lower amplitude.1

What are the characteristics of beta waves?

Beta waves typically occur at a frequency of 14-30 Hz. These waves are small and faster and can be seen in states of intellectual activity, focus, and alertness. Beta waves can be separated into two subgroups: beta I and beta II. They are most prominent in the parietal and frontal regions of the scalp, as this is where the abovementioned mental tasks take place. Beta waves are less easy to identify in EEG compared to the other types of brain waves, as they do not have a regular signature waveform. Studies have shown that beta waves are involved in somatosensory processing and motor control.3

What are the characteristics of theta waves?
Theta waves have a frequency of 4-7 Hz. They can be seen in states of daydreaming or light sleep. These waves can be seen in the parietal and temporal regions. They are more pronounced in children or adolescents and less prominent in adults. Functionally, they have been linked to coordinating the process of memory storage.4 Moreover, they are associated with inhibition of elicited responses.5

What are the characteristics of delta waves?
Delta waves have a frequency of 0.5-3 Hz. These waves have a low frequency and relatively high amplitude. They can mainly be seen in states of deep sleep. Delta waves only occur within the cortex, independent of activities in the lower regions of the brain.1 Delta waves during sleep are thought to play a role in transferring learning and long-term memory storage. Lastly, delta waves intensify (higher amplitude) and occur more often when a subject is sleep-deprived before going to sleep.1

Conclusion
In summary, brain waves originate from the summed synchronized synaptic activity of cortical neurons. They can be categorized into alpha, beta, theta, and delta waves based on their frequency and amplitude. These brain waves provide insights into brain activity. Since the first discovery of the alpha waves by Berger, many studies have shown a close link between perceptual, cognitive, motor, and emotional processes and the type of oscillations in the EEG.6

Some interesting finds on Harmine-Harmaline with Magnetite:
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Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy

Zhao, T., Zheng, S.S., Zhang, B.F., Li, Y.Y., Bligh, S.W.A., Wang, C.-H. and Wang, Z. 2012. Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy. Food Chemistry. 134 (2), pp. 1096-1105.

https://doi.org/10.1016/j.foodchem.2012.03.024

TITLE Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy

AUTHORS Zhao, T., Zheng, S.S., Zhang, B.F., Li, Y.Y., Bligh, S.W.A., Wang, C.-H. and Wang, Z.

ABSTRACT

The β-carboline alkaloids, harmaline and harmine, are present in hallucinogenic plants Ayahuasca and Peganum harmala, and in a variety of foods. In order to establish the metabolic pathway and bioactivities of endogenous and xenobiotic bioactive β-carbolines, high-performance liquid chromatography, coupled with mass spectrometry, was used to identify these metabolites in human liver microsomes (HLMs) in vitro and in rat urine and bile samples after oral administration of the alkaloids. Three metabolites of harmaline and two of harmine were found in the HLMs. Nine metabolites for harmaline and seven metabolites for harmine, from the rat urine and bile samples, were identified. Among them, four in vivo metabolites were isolated and fully characterised by NMR analysis. For the first time, harmaline is shown transforming to harmine by oxidative dehydrogenation in rat. Five metabolic pathways were therefore proposed, namely, oxidative dehydrogenation, 7-O-demethylation, hydroxylation, O-glucuronide conjugation and O-sulphate conjugation.

JOURNAL Food Chemistry
JOURNAL CITATION 134 (2), pp. 1096-1105
ISSN 0308-8146
YEAR Sep 2012
PUBLISHER Elsevier
DIGITAL OBJECT IDENTIFIER (DOI) https://doi.org/10.1016/j.foodchem.2012.03.024

Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopyZhao, T., Zheng, S.S., Zhang, B.F., Li, Y.Y., Bligh, S.W.A., Wang, C.-H. and Wang, Z. 2012. Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy. Food Chemistry. 134 (2), pp. 1096-1105. https://doi.org/10.1016/j.foodchem.2012.03.024
TITLE Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy
AUTHORS Zhao, T., Zheng, S.S., Zhang, B.F., Li, Y.Y., Bligh, S.W.A., Wang, C.-H. and Wang, Z.
ABSTRACT
The β-carboline alkaloids, harmaline and harmine, are present in hallucinogenic plants Ayahuasca and Peganum harmala, and in a variety of foods. In order to establish the metabolic pathway and bioactivities of endogenous and xenobiotic bioactive β-carbolines, high-performance liquid chromatography, coupled with mass spectrometry, was used to identify these metabolites in human liver microsomes (HLMs) in vitro and in rat urine and bile samples after oral administration of the alkaloids. Three metabolites of harmaline and two of harmine were found in the HLMs. Nine metabolites for harmaline and seven metabolites for harmine, from the rat urine and bile samples, were identified. Among them, four in vivo metabolites were isolated and fully characterised by NMR analysis. For the first time, harmaline is shown transforming to harmine by oxidative dehydrogenation in rat. Five metabolic pathways were therefore proposed, namely, oxidative dehydrogenation, 7-O-demethylation, hydroxylation, O-glucuronide conjugation and O-sulphate conjugation.

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Factors Affecting the Analytical Performance of Magnetic Molecularly Imprinted Polymers

by Nur Masyithah Zamruddin 1,2,Herman Herman 2,Laode Rijai 2 andAliya Nur Hasanah 1,3,*ORCID
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Padjadjaran University, Jl. Raya Bandung Sumedang KM 21, Sumedang 45363, Indonesia
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mulawarman University, Gunung Kelua 75119, Indonesia
Drug Development Study Centre, Faculty of Pharmacy, Padjadjaran University, Jl. Raya Bandung Sumedang KM 21, Sumedang 45363, Indonesia
*

Author to whom correspondence should be addressed.
Polymers 2022, 14(15), 3008; https://doi.org/10.3390/polym14153008
Received: 15 June 2022 / Revised: 16 July 2022 / Accepted: 19 July 2022 / Published: 25 July 2022
(This article belongs to the Special Issue Molecularly Imprinted Polymer (MIP) Materials for Separation, Purification and Sensing)

Abstract

During the last few years, separation techniques using molecular imprinting polymers (MIPs) have been developed, making certain improvements using magnetic properties. Compared to MIP, Magnetic molecularly imprinted polymers (MMIPs) have high selectivity in sample pre-treatment and allow for fast and easy isolation of the target analyte. Its magnetic properties and good extraction performance depend on the MMIP synthesis step, which consists of 4 steps, namely magnetite manufacture, magnetic coating using modified components, polymerization and template desorption. This review discusses the factors that will affect the performance of MMIP as a selective sorbent at each stage. MMIP, using Fe3O4 as a magnetite core, showed strong superparamagnetism; it was prepared using the co-precipitation method using FeCl3·6H2O and FeCl2·H2O to obtain high magnetic properties, using NH4OH solution added for higher crystallinity. In magnetite synthesis, the use of a higher temperature and reaction time will result in a larger nanoparticle size and high magnetization saturation, while a higher pH value will result in a smaller particle size. In the modification step, the use of high amounts of oleic acid results in smaller nanoparticles; furthermore, determining the correct molar ratio between FeCl3 and the shielding agent will also result in smaller particles. The next factor is that the proper ratio of functional monomer, cross-linker and solvent will improve printing efficiency. Thus, it will produce MMIP with high selectivity in sample pre-treatment.
Keywords: magnetic molecularly imprinted polymer (MMIP); factors affecting MMIP; components of MMIP; magnetic separation technology

Graphical Abstract

1. Introduction
Imprinting technology provides the basis for molecular recognition to design coordinated, specific, selectively identified sites within synthetic polymer systems. Molecular imprinted technology (MIT) is seen as an effective and efficient approach to achieve molecular recognition functions [1,2] and is a method for producing synthetic materials such as artificial receptors (molecularly imprinted polymers, MIPs), which are obtained by generating a memory of the printed molecule in the form of the size, shape and functional group of the imprint molecule [3,4]. The most widely used methods in the manufacture of MIPs are free radical polymerisation (FRP) methods, namely bulk polymerisation, suspension polymerisation, emulsion or precipitation polymerisation, and the sol-gel method [5]. However, MIPs prepared by the common FRP method have several disadvantages, such as slow mass transfer, irregular shape, imperfect removal of the template molecule, poor site accessibility and/or heterogeneous distribution of the binding sites [6]. Efforts were made to overcome these problems by implanting a magnet during the manufacture of the MIP and performing magnetic separation [7].

Magnetic separation technology, in which polymers are prepared using MIP fabrication on the surface of a magnetic substrate, has been widely used in recent years for separation and extraction applications [8,9,10,11], such as in the field of drug analysis in biological fluids [12,13,14,15,16,17], analysis of compounds in the environment [9,10,11,18,19,20,21,22], analysis of compounds in food [8,23,24,25] and analysis of compounds in plants and other naturally occurring products [26,27,28,29]. Magnetic molecular imprinted solid phase extraction (MMI-SPE) is a new solid phase extraction (SPE) procedure based on the use of magnetic sorbents [8,16]. Magnetic molecularly imprinted polymers (MMIPs) have the advantages of fast and effective binding to the target analyte, spherical shaped sorbents that exhibit magnetic properties, highly selective binding to target imprinted molecules and analogues, easy isolation from samples using magnets via external filtering or centrifugation steps, shorter pre-treatment times, reversible and controlled flocculation, and easy separation of polymers from the sample matrix using external magnets [9,30,31].
Several MMIP technologies have been successfully applied to several compounds: MMIPs based on surface MIT have been used for the extraction of norfloxacin in water samples, with an absorption capacity of 82.7% for non-imprinted polymer (NIP) and 91.1% for MMIP [3]; a MMIP has also been synthesised on the surface of chitosan-Fe3O4 by precipitation polymerisation for the extraction of tricyclazole from rice and water samples, with a binding capacity of 45,454.55 g/g compared to 26,315.79 g/g for the NIP [31]; and a MMIP has been synthesised and modified using oleic acid as a surfactant for the extraction of chloramphenicol from honey samples, showed the value of the dissociation constant of 329.9 lmol/L and the maximum binding capacity of 17.1 lmol/g, compared to magnetic non-imprinted polymer (MNIP) with values of dissociation constant 217.2 mol/L and maximum binding capacity 8.8 mol/g [8].

MMIP preparation begins with the preparation of a magnetic core, commonly called magnetite, using a co-precipitation technique between ferric chloride (FeCl2·H2O) or ferrous sulphate (FeSO4·7H2O) and iron(III) chloride hexahydrate (FeCl3·6H2O), which can be achieved under basic conditions of 80–100 °C [14]. After the magnetite is formed, its surface is modified, either by silanisation or by adding a surfactant such as ethylene glycol or oleic acid, enhancing the amphoteric properties of the magnetite surface and improving its interaction with polar solutions. The modified magnetite is then polymerized using a template, functional polymer or cross-linker. The final step in the manufacture of MMIP is the desorption of the template molecules from the polymer. Combining magnetic separation with molecular imprinting would be ideal, providing a powerful analytical tool for use in separation [32].

The type of magnetic particle used affects the yield of the magnetic core particles created. [13], and temperature, reaction time [33], initial concentration of ferric chloride (FeCl3) [34], pH value and surfactants [35] will also influence the magnetic core that results. After synthesis of the magnetic core, the core-shell is usually modified, and the components used will influence the size of the final particles [33]; oleic acid is used more widely as it results in smaller nanoparticles (NPs) [36]. At the polymerisation stage, the selection of the polymerisation component and the ratio have to considered [17,37,38]. The amount of MMIP, extraction time, washing and eluent conditions affect the results of template extraction which is the final stage in making MMIP with good performance [8].

There have been MMIP review articles discussing the synthesis and application of MIPs, recent configurations and progressive use of magnetically imprinted polymers for drug analysis [13], and the design and characterization, toxicity and biocompatibility of magnetic nanoparticles (MNPs) [39]. There have also been reviews on magnetic molecularly imprinted electrochemical sensors [40], magnetic solids in analytical chemistry [41] and updates on the use of MMIPs in the separation of active compounds [27]. However, there are no review articles that specifically address the factors affecting the performance of MMIPs in an effort to produce the desired shape and performance of MMIP.Hence, this review will discuss the factors relating to the production of MMIPs with good analytical performance.

2. Synthesis of MMIP

Magnetic nanoparticles expressing a unique surface effect with super-magnetism properties, easy modification by functional groups, non-toxic properties, and availability in abundant quantities are able to assist in synthesizing on a large scale an efficient recycling process for efficient water purification processes. Magnetic properties can be obtained by VSM studies analyzing hysteresis loops (MH) which shows values for saturation magnetization (Ms), remanent magnetization (Mr), and coervicity (HC). Iron oxide nanoparticles have an Ms value of more than 1 emu/g, indicating that the material has good magnetic separation ability. However, magnetic nanoparticles have a strong tendency to oxidize on contact with air and exhibit Fe3O4 leaching, limiting their applicability in water. To overcome this deficiency, materials such as silica oxide (SiO2) and MIP are used to modify the MNP. Magnetic molecular imprinted polymers (MIPs) consist of magnetic materials and non-magnetic polymers with the combined effect of their properties namely, selective recognition and magnetic separation [42].

In magnetic separation, Fe3O4 nanoparticles are encapsulated or coated as iron and iron salts by co-precipitation wherein a magnetic material added to a suspension containing a template. Modified components such as PEG, SiO2 are able to prevent flocculation of Fe3O4 nanoparticles. The most common and simplest fabrication technique is bulk polymerization in which the reaction takes place in a small amount of solvent to precipitate as an imprinted polymer. However, during polymerization, the components form agglomerates and reach irregular sizes which can damage the binding sites. Therefore, MIPs are subjected to post-treatment processes including, crushing, milling, and sieving to avoid this agglomeration. However, this rigorous process demands a long reaction time which provides only 30–40% of polymer recovery. In addition, to compare the selectivity against the targeted template, a non-imprinted magnetic preparation (MNIP) was carried out by following all process steps but without adding template molecules. MNIP also exhibits a strong but nonspecific binding capacity due to the interaction between the template and the polymer [42].
Compared to conventional MIPs, MMIPs exhibit many superior characteristics involving fast and effective binding to the target analyte, and a shorter pre-treatment time [7]. The sorbent does not need to be packed into an SPE cartridge as in traditional SPE, and phase separation can be easily produced by applying an external magnetic field [8]. The MMIP is made using a combination of magnets and MIP [43]. The general MMIP preparation steps using Fe3O4 can be seen in Figure 1.

Polymers 14 03008 g001 550Figure 1. The general steps in the preparation of magnetic molecularly imprinted polymer.

2.1. Magnetic Core-Shell Synthesis

Magnetic solids have two main applications in analytical chemistry, namely, the purification or separation of chemical samples (especially magnetic-SPE) and the use of biosensors or sensors, applications that are currently gaining popularity. Magnetic particles were initially applied to separate biological species and have been applied for decades to improve the separation of chemical species with various properties. An important aspect of magnetic particles is the method used for their synthesis, as their composition determines their compatibility and suitability for a particular application. Fe, Ni and Co are three well-known ferromagnetic metal elements in the periodic table. There are various magnetic materials involving metals, metal oxides, metal alloys and ferrites that are based on simple ferromagnetic elements [13]. Several types of magnetic materials are used in sample preparation, including nickel [44], Hematite iron (III) oxide (γ-Fe2O3) used in several MMIP synthesis [45,46,47]. In Can et al.’s [48] study, namely the comparative of nanosized iron oxide particles, magnetite (Fe3O4), maghemite (γ-Fe2O3) and hematite (α-Fe2O3), using ferromagnetic resonance showed a Fe3O4 particle size of 23.0 ± 0.6 nm, maghemite (γ-Fe2O3) 25.5 ± 0.5 nm and hematite (α-Fe2O3) 54 ± 5, indicating that the particle size of γ-Fe2O3 is smaller than α-Fe2O3 and the value of magnetization saturation (MS) using VSM is Fe3O4 12.4 emu/g, γ-Fe2O3 9.1 emu/g and α-Fe2O3 1.3 emu/g indicates a value MS γ-Fe2O3 is bigger than α-Fe2O3 Fe3O4 [19,49,50] and nickel (II) oxide (NiO) [51]. However, the most commonly used magnetic material is Fe3O4 because of its easy fabrication, low toxicity and, most importantly, its abundant hydroxyl surface, which allows for further modification processes to be easily carried out [52]. Fe3O4 NPs can be easily synthesised by co-precipitation [52,53,54] and can also be prepared using the solvothermal method [26,55]. Fe3O4 NPs are usually coated with oleic acid before being further modified, to produce a better dispersion [49].

A summary of the MMIP method using Fe, Ni and Co magnetic particles can be seen in Table 1.
2.1.1. Fe3O4

Fe3O4 is an easily prepared substrate with low toxicity, good biocompatibility, fast magnetic susceptibility and high surface area, and is the most commonly used support [7]. Magnetite Fe3O4 was prepared by the co-precipitation method, from a mixture of 0.01 mol FeCl2·4H2O and 0.02 mol FeCl3·6H2O dissolved in 100 mL water. The mixture was stirred vigorously and cleaned with nitrogen gas, then a solution of sodium hydroxide [8,56] or ammonia (NH4OH) [57] was added. After one hour, the magnet was isolated from the solvent using an external magnet and washed several times with water [8,56].

Several studies involve the MMIP polymerisation process using Fe3O4 as the magnetic core. In the study by Ali Zulfikar et al. [56], a poly vinyl chloride (PVC) MMIP sample solution was successfully synthesised for the selective separation of di(2-ethylhexyl)phthalate (DEHP) using Fe3O4 as the magnetic core. A magnetisation saturation (MS) value of 39.92 emu/g was produced using a vibrating sample magnetometer (VSM), indicating that the MMIP is superparamagnetic (SPM), and the resulting MMIP was better than the MNIP, with an imprinting factor (IF) value of 3.37, a maximum adsorption capacity value of 17.21 mg/g and a recovery percentage of around 91.03–99.68%.

In the study by Chen et al. [25], Fe3O4@SiO2–MPS was used as a sorbent in the magnetic SPE of resveratrol in wine (where MPS is 3-(trimethoxysilyl) propyl methacrylate). The MMIP showed a high MS capability of 53.14 emu/g, leading to fast separation, a high adsorption capacity capability for resveratrol and contained homogeneous binding sites. The recovery of spiked samples ranged from 79.3% to 90.6%, with a limit of detection (LOD) of 4.42 ng/mL. In the study by Fu et al. [58], Fe3O4 cyclodextrin material (Fe3O4-CD) was used for the rapid and specific adsorption of zearalenone. The results of the test of the magnetic properties of Fe3O4 NPs showed SPM properties; the coercivity and residual magnetic field strength were close to zero, and the saturation magnetic field strength was 99.68 emu/g for Fe3O4, 42.81 emu/g for the MMIP and 38.10 emu/g for the MMIP–CD. In real sample testing, the limit of quantification (LOQ) and LOD were 0.1 ng/kg and 0.3 ng/kg, respectively.
In the study by Habibi et al. [59], the highly lipophilic drug buprenorphine was analysed in human urine samples using an Fe3O4 magnetite core surrounded by polyamidoamine and buprenorphine as a template. The magnetic properties results using a VSM showed supermagnetic properties, and the MS of Fe3O4-oleic acid and MMIP nanoparticles (MMIPNP) were 55.75 and 59.04 emu/g, respectively. The relative recovery was 97.4–100.3%, and the LOD and LOQ were 0.21 and 0.71 ng/mL, respectively. The extraction of herbicide chloroacetamide from environmental water samples was carried out using the amphiphilic MMIP method with Fe3O4 microspheres [9]. Under optimized conditions, good linearity (0.1–200 g/L) and good precision (relative standard deviation (RSD) < 7%) were demonstrated, with a low detection limit (0.03–0.06 g/L), and recovery ranged from 82.1% to 102.9%.

Tadalafil analysis on the surface of MNPs was carried out by Li et al. using Fe3O4@SiO2 [16]. VSM analysis showed MS values of 61 and 42 emu/g for Fe3O4@SiO2 and MIP-coated MIP, respectively, and a recovery value in the range of 87.36 to 90.93%, with RSD < 6.55%. Purification of alkaloid isomers (theobromine and theophylline) from green tea using magnetic solid phase extraction (MSPE) with Fe3O4 as the core [60] showed the practical recovery of theobromine and theophylline in green tea was 92.27% and 87.51%, respectively.

The MMIP polymer synthesised by SPE for the efficient separation of racemic tryptophan (Trp) in aqueous media used Fe3O4 (Fe3O4@MIPs). The magnetic properties of Fe3O4-NH2 and Fe3O4@MIPs were measured by VSM and showed a MS of 75 and 69 emu/g, respectively, indicating a high level of superparamagnetism. The respective maximum adsorption capacity values for L-Trp and D-Trp were 17.2 ± 0.34 mg/g and 7.2 ± 0.19 mg/g, and good selectivity to L-Trp was observed, with an IF of 5.6 [10]. Another MMIP was synthesised by Qin et al. for the adsorption of sulphonamides using a surface imprinting technology with Fe3O4-chitosan (Fe3O4-CS) as a template for a mixture of sulphamethazine (SMZ) and sulphamethoxazole (SMX) molecules [61]. The magnetic property test showed the presence of symmetry at the origin and coercivity, and a resonance was zero. The MS values were 69.94, 20.84 and 3.91 emu/g, indicating SPM properties. Maximum adsorption (Q) capacity values were Q (SMX) = 4.32 mg/g and Q (SMZ) = 4.13 mg/g, and recovery and RSD were from 85.02 to 102, respectively, 98% and from 2.77 to 6.47%.

The development of methods in the synthesis of magnetite Fe3O4 has been carried out. Recent research conducted by Ferrone et al. [62] carried out the simple synthesis of Fe3O4@-activated carbon from wastepaper for dispersive magnetic solid-phase extraction of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in human plasma. The wastepaper showed an excellent capacity to absorb the iron oxide by forming a colloidal solution simply due to cellulose, which entrapped iron in its fibrous structure. The SEM images show the morphology of the samples after grinding, all of which appeared very similar, made of large particles (tens of microns) heterogeneously distributed. The XRD patterns showed a lower crystallinity of the Fe3O4 phase, this could be due to the sluggish kinetics of the formation of magnetite, considering that the iron precursor was likely entrapped in the cellulose fibers and less exposed to the nitrogen atmosphere. The method developed herein proved to be fast and accurate.

https://www.mdpi.com/2073-4360/14/15/3008

Sadegh, N.; Asfaram, A.; Javadian, H.; Haddadi, H.; Sharifpour, E. Ultrasound-Assisted Solid Phase Microextraction-HPLC Method Based on Fe3O4@SiO2-NH2-Molecularly Imprinted Polymer Magnetic Nano-Sorbent for Rapid and Efficient Extraction of Harmaline from Peganum Harmala Extract. J. Chromatogr. B 2021, 1171, 122640. [Google Scholar] [CrossRef] [PubMed]
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