2 s2.0 85122707226

Materials Today Bio 12 (2021) 100149
Contents lists available at ScienceDirect
Materials Today Bio

journal homepage: www.journals.elsevier.com/materials-today-bio
Magnetoelectric effect: principles and applications in biology and medicine–

a review
S. Kopyl a, **, R. Surmenev b, c, ***, M. Surmeneva b, c, Y. Fetisov d, A. Kholkin a, c, e, *
a
Department of Physics & CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, Portugal
b
Physical Materials Science and Composite Materials Centre, Research School of Chemistry & Applied Biomedical Sciences, National Research Tomsk Polytechnic
University, Tomsk, Russia
c
Piezo- and Magnetoelectric Materials Research & Development Centre, Research School of Chemistry & Applied Biomedical Sciences, National Research Tomsk
Polytechnic University, Tomsk, Russia
d
Research & Education Centre ‘Magnetoelectric Materials and Devices’, MIREA – Russian Technological University, Moscow, Russia
e
School of Natural Sciences and Mathematics, Ural Federal University, Ekaterinburg, Russia
A R T I C L E I N F O A B S T R A C T
Keywords: Magnetoelectric (ME) effect experimentally discovered about 60 years ago remains one of the promising research
Magnetoelectric effect fields with the main applications in microelectronics and sensors. However, its applications to biology and
Multiferroics medicine are still in their infancy. For the diagnosis and treatment of diseases at the intracellular level, it is
Piezoelectricity
necessary to develop a maximally non-invasive way of local stimulation of individual neurons, navigation, and
Brain stimulation
distribution of biomolecules in damaged cells with relatively high efficiency and adequate spatial and temporal
Tissue engineering
Drug delivery resolution. Recently developed ME materials (composites), which combine elastically coupled piezoelectric (PE)
Wireless power transfer and magnetostrictive (MS) phases, have been shown to yield very strong ME effects even at room temperature.
This makes them a promising toolbox for solving many problems of modern medicine. The main ME materials,
processing technologies, as well as most prospective biomedical applications will be overviewed, and modern
trends in using ME materials for future therapies, wireless power transfer, and optogenetics will be considered.
1. Introduction strong ME effects at room temperature [15,16], which is of particular

importance for biomedical applications of ME materials.
A class of multiferroic structures exhibiting magnetoelectric (ME) As is well known [17], the human body is an extremely complex en-
effect, which is a linear coupling between the applied magnetic field and gineering system of trillions of interconnected cells that has been opti-
generated electric voltage, has been attracted more and more research mized over many years of evolution. Intrinsic electric fields at the
attention over the last years [1–5]. The coupling between electric and subcellular level play an important (if not decisive!) role in these in-
magnetic properties in ME materials provides exceptional opportunities teractions, and this plethora of electrophysical effects determine funda-
to develop electric charges without any wire connections, which allows mental physiological mechanisms [18,19]. ME materials may enable cells
less-invasive integration into devices. Recent reviews [6–10] show to react remotely at nano- and microscales, thus opening up unprecedented
progress in the fundamental understanding, development, and charac- possibilities for biomedical applications. By controlling their own electric
terization of novel ME materials, as well as that these materials and fields that underlie cell-to-cell and cell-to-cell interactions, ME materials
structures are promising in microelectronics and related engineering are expected to play an important role in the development of imaging and
applications, for instance, as high-speed memories, compact ME antennas treatment methods that allow eliminating collateral damage and signifi-
[11,12], magnetoelectric sensors [13,14], etc. cantly improve the effectiveness of modern treatments [20–22].
Despite the fact that the ME effect was known for many decades, The use of ME materials in biology and medicine is still in its infancy,
scientists have only recently learned how to synthesize materials with so there are a few publications and no reviews. The recent introductory
* Corresponding author.
** Corresponding author.
*** Corresponding author.
E-mail addresses: svitlanakopyl@ua.pt (S. Kopyl), rsurmenev@mail.ru (R. Surmenev), kholkin@ua.pt (A. Kholkin).
https://doi.org/10.1016/j.mtbio.2021.100149
Received 18 August 2021; Received in revised form 5 October 2021; Accepted 8 October 2021
Available online 13 October 2021
2590-0064/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
S. Kopyl et al. Materials Today Bio 12 (2021) 100149
review [23] focuses only on the characterization of modern magnetic Much larger ME effects were found at room temperatures in artifi-
field sensors suitable for biomedical applications such as magneto- cially created composite materials containing ferromagnetic (FM) and
cardiography, magnetotomography, magnetomyography, magneto- piezoelectric (PE) phases. In such composites, ME effects arise as a result
neurography from a physical point of view and provides a brief overview of a combination ‘product-property’ of the magnetostriction of the FM
of recent studies in this field. Another review [24] considers the problems phase and piezoelectricity in the PE phase due to the mechanical
associated with the development and application of a new type of ‘smart’ coupling of the phases across the interfaces [31,32]. When the ME
medical materials based on ME composites, mainly for bone tissue composite is placed in an external magnetic field H, the FM phase is
regeneration, capable of creating additional stimuli that affect the deformed due to magnetostriction, this deformation is transferred to the
regeneration process. PE phase, and the piezoelectric effect results in the generation of an
In this work, we provide an extensive comprehensive overview of the electric field E (direct ME effect). While an electric field E is applied to the
principles of the ME effect, modern processing technologies, as well as composite, the converse piezoelectric effect results in a deformation of
current developments in their applications in biomedical research. We the PE phase, this deformation is transferred to the FM phase, and due to
discuss a number of applications in tissue engineering, brain stimulation, the inverse magnetostriction (Villari effect), the magnetic field B is
cancer treatment, and drug delivery. Magnetoelectric effect for wireless changed (converse ME effect).
power transfer and optogenetics will be considered, as well as current trends Fig. 2a–c schematically depicts the main types of two-phase ME
and prospects in the use of ME materials for future treatment methods. composites with connectivity types 0-0, 0–3, 1–3, and 2–2, respectively
[33]. The numbers indicate the number of coordinates along which
2. Principles of magnetoelectric effect: from single-phase deformation is transmitted in each of the phases, with the first number
materials to composites referring to the FM phase and the second to the PE phase. Particulate
composite (a) of 0–0 type is FM and PE particles embedded in a neutral
The magnetoelectric (ME) effect is defined as a change in the electric matrix. Composite (b) with the connectivity of the 0–3 type contains FM
polarization P of a substance under the influence of a magnetic field H particles located in a PE matrix. Composite (c) with the connectivity of
(direct effect) or a change in the magnetization M of a substance under 1–3 type is FM rods in a PE matrix. Particles and rods in 0–0, 0–3, and 1–3
the action of electric field E (converse effect) (see Fig. 1) [25]. ME effects composites can be distributed in the matrix both randomly or in a certain
are observed in multiferroic solids that simultaneously possess both the order. Composite (d) of 2–2 type is a planar heterostructure containing
ferromagnetic and ferroelectric ordering, as well as in other materials two or more alternating FM and PE layers. Additionally, it is worth
that acquire electric polarization under the action of a magnetic field. highlighting the core-shell nanocomposites (e), consisting of nano-
Generally, in multiferroic crystals, the polarization P and magneti- particles, the core of each is made of FM material, and the shell is made of
zation M are related to the electric E and magnetic H fields by the PE material [34,35]. The properties of ME composites can be engineered
following relations [26]: by selecting phase materials of the structure, phase volume ratio, and
changing the particle and sample sizes.
1 According to the ‘product-property’ concept, the magnitude of the
Pi ¼ PSi þ ε0 εij Ej þ αij Hj þ βijk Hj Hk þ γ ijk Hj Ek ::: (1a)
2 direct ME effect in the above-mentioned composites is qualitatively well
described by the formula
1
Mi ¼ MiS þ μ0 μij Hj þ αji Ej þ βijk Ej Hk þ γ ijk Ej Ek ::: (1b)
2 δE δE δS
αE ¼ A h q; (3)
δH δS δH
where PSi and MiS are the spontaneous polarization and magnetization,
respectively, ε0 and μ0 are the magnetic and electrical constants, εij and where A is the coefficient that depends only on the geometry of the
μij are the relative electrical permittivity and magnetic permeability of composite, and the dielectric characteristics of its phases, h(E) is the
the substance. The tensor αij determines the magnitude of the linear ME piezomodulus of the PE phase, qðHÞ ¼ ∂λ=∂HjH is the piezomagnetic
effect in the material, and the tensors βijk and γ ijk determine the magni- modulus of the FM phase, λ(H) is the dependence of the magnetostriction
tude of the nonlinear ME effects. of the FM material on the magnetic field. It follows from (3) that the
In practice, in order to eliminate the influence of the electrical con- characteristics of ME effects in composites can also be controlled using
ductivity of materials, ME effects are investigated in a dynamic mode by external H and E fields. Of great interest for applications are 2–2 type
applying an alternating magnetic or electric field to the samples. The layered structures containing alternating FM and PE layers, which are
magnitude of dynamic effects is characterized using ME coefficients: relatively easy to manufacture. In such composites, FM layers with high
conductivity and PE layers with low conductivity are spatially separated
δE u and retain their physical properties, which makes it possible to effec-
αE ¼ ¼ in V=ðOe cmÞ for the direct ME effect;
δH bδH (2a) tively polarize the PE layers.
It is worth adding that the stress coupling mechanism leads to an
increase of the ME effect in composites by a factor of Q ~102–103 due to a
δB δB sharp increase in deformations when the frequencies of the fields coin-
αB ¼ ¼ in G cm=V for the converse ME effect; (2b)
δE u=b cide with the frequency of the acoustic resonance of the sample [36].
Recently, a variety of composite materials with high ME conversion
where δE and δB are the amplitudes of the ac electric field and magnetic efficiency have been created. Fig. 3 shows the values of the ME
induction in the substance, caused by a change in the magnetic δH and
electric δE fields, respectively (parameters u and b are defined in Fig. 1).
The ME effect was first observed in 1960 in Cr2O3 single crystals [27,
28], where its magnitude at room temperature is αE 20 mV/(Oe cm). To
date, ME effects have been found in dozens of different single-phase
materials [29]. However, in ME crystals, the effects are small in magni-
tude αE ~1–20 mV/(Oe cm) and are observed (with rare exceptions, for
example, in Cr2O3, BiFeO3, Y3Fe5O12, SrCo2Ti2Fe8O19) at low tempera-
tures T ~ 4–20 K, or in high magnetic fields H ~ 10–50 kOe, which
complicates their practical use [30]. Fig. 1. Geometry of the direct (a) and converse (b) magnetoelectric effects. U is
the voltage appearing under the action of applied magnetic field H.
2
Fig. 2. Composite ME materials of various types of connectivity: (a) 0–0; (b) 0–3; (c) 1–3; (d) 2–2; (e) - core-shell nanocomposite. Highlighted in color: yellow -
dielectric matrix; orange - piezoelectric; blue - ferromagnet.
coefficient for some particulate composites and heterostructures in the of science and technology. The direct ME effect forms a basis for sensors
off-resonant and resonant excitation modes. of permanent and low-frequency alternating magnetic fields with a
It follows from (2) and Fig. 3 that to increase the ME effect in com- sensitivity of up to ~1011 T, operating at room temperature [21],
posites, one should use ferromagnets with a high piezomagnetic coeffi- solid-state inductors and transformers tuned by an electric field [1,38],
cient q (metals - Ni, Co, alloys - FeCo, FeGa, Metglas, Terfenol-D, ferrites energy harvesters, converting alternating-current (AC) magnetic fields
NFO, CFO) and piezoelectrics with a high piezoelectric modulus ratio to into direct-current (DC) voltage [39], etc. The converse ME effect is used
dielectric constant d/ε (ceramics of the PZT and PMN-PT types, LNO, in compact low-frequency antennas [1], electrically tunable resonators
BTO, AlN crystals). Flexible structures based on biocompatible polymeric and microwave filters [40], data storage elements switched by an electric
piezoelectrics of the PVDF type are promising for applications, too [2]. It field [41]. One of the most promising directions is the use of biocom-
is seen from Fig. 3 that for particulate composites, the magnitude of the patible ME materials in medicine [24,42,43].
ME coefficient αE is ~1–100 mV/(Oe cm) while for planar structures it is
about 1–50 V/(Oe cm) and increases to hundreds V/(Oe cm) at the fre- 3. Magnetoelectric composite materials
quencies of acoustic resonance.
The ability to mutually transform magnetic and electric fields makes Magnetoelectric (ME) composites allow either polarization in
it possible to use the ME effect in multiferroic materials in various fields response to an applied magnetic field or induce magnetization caused by
Fig. 3. Values of ME coefficients for: (a) particulate composites; (b) laminated heterostructures in off-resonance regime; (c) laminated heterostructures in resonance
regime. Adapted from Ref. [37].
3
an externally applied electric field, allowing ME effect at room temper- combined with a hydrogel matrix allowed mimicking the tissue’s hy-
ature [44], which is particularly important for biomedical applications of drated environment and simultaneously served as a support matrix [61].
ME composites. Moreover, the coupling between electric and magnetic Hybrid composites, which contain multiferroics, most frequently BiFeO3,
properties in ME composites provides exceptional opportunities to were reported for use in tissue engineering to significantly enhance cell
develop charges without any electrical connections, which allows viability and proliferation [62].
less-invasive integration into sensors, energy harvesters, wearable and A study of hybrid ME films of P(VDF-TrFE)/CoFe2O4 revealed that
implantable electrodes, etc. both proliferation and differentiation of the C2C12 myoblast cells are
Extensive overviews of electroactive, in particular piezoelectric ma- enhanced via the application of mechanical and/or electrical stimulation
terials and composites, are reported elsewhere [45]. Electroactive elec- with higher values of maturation index under mechano-electrical stimuli
trospun nanofibers are well-reviewed for various biomedical applications [51]. These composites allowed mechanical (13⋅103 μm/mm2) and
such as cardiac or nerve tissue regeneration, wound healing, skeletal electrical stimulation of cells (16.15 μV and 64 μV), in case of magnetic
muscle and bone regeneration, a therapeutic platform for drug delivery, and mechanical bioreactors, respectively.
biosensing, etc. [46]. Magnetic actuation of the ME composites provides A composite of P(VDF-TrFE)/CoFe2O4 has been reported as a new
electrical and mechanical stimuli to the neighboring cells [47]. Also magnetic field responsive bioactive coating to enhance cellular osteo-
important is that the ME composites enable, under the exposure of the genic differentiation. This composite allowed the authors to understand
external magnetic field, the remote stimulation of a specific tissue, e.g. the molecular mechanisms of osteogenic differentiation when magnetic
bone, nerve, etc [46,48]. responsive coating and static magnetic field are combined [64]. It was
Strain-induced ME effects have given rise to significant ME properties revealed that the most appropriate magnetic fields for cellular adhesion
in the various composites (polymer-based or hydrogel-based) that and proliferation are 2000 and 2600 Oe, respectively, which enable an
combine the piezoelectric and magnetostrictive phases such as poly- attractive remote-control approach to develop and design a new type of
vinylidene fluoride (PVDF) and metglas or Terfenol-D, respectively. The magnetic field responsive biomaterials for bone tissue engineering.
developed composites allow the increase of ME coefficients in the ma- The magnetic micro-environment achieved by the inclusion of 7.5 wt
terials of up to 370 V/(Oe cm) under an externally applied magnetic field % Fe3O4 nanoparticles in the PLLA/PGA scaffold significantly promoted
at room temperature [49], which is close to that of human body tem- cell differentiation over time [52,65]. The enhancement effect is due to
perature, thus making them prospective for a broad range of tissue en- the fact that magnetic nanoparticles embedded in scaffolds facilitate cell
gineering applications [44]. adhesion via activation of various signaling pathways with the extending
In general, the application of magnetic fields to stimulate cells and of culture time promoting cell differentiation [66]. More details on the
tissues is intensively studied in various tissue engineering applications results obtained on magnetic field simulation of magnetically responsive
[50–52]. As an example, magnetic poly(L-lactic) acid (PLLA) scaffolds materials and subsequent effects are presented in the following sections.
obtained via a freeze-drying approach containing Fe-doped hydroxyap- As already mentioned, the current state-of-the-art magnetoelectric
atite nanoparticles are also reported [50]. Silk fibroin magnetoactive composites contain high amounts of lead-based ferroelectrics, such as
nanocomposite films and membranes with cobalt ferrite (CoFe2O4) lead zirconate titanate (Pb [ZrxTi1-x]O3, PZT) and lead magnesium
nanoparticles have also been developed for dynamic bone tissue engi- niobate-lead titanate (Pb(Mg1/3Nb2/3)O3–PbTiO3, PMN-PT), endowing
neering strategies [53]. The application of electrically responsive scaf- them with excellent piezoelectric response [49]. However, over the last
folds can also be connected with nerve regeneration [54]. 15 years, a lot of studies have been done to decrease the amount of lead
ME materials in the form of core-shell nanoparticles have gained and other hazardous materials in commercial electronics and other
particular interest for various drug delivery systems allowing control via products, primarily due to health and environmental concerns. This has
external magnetic field over tissue regeneration processes, wireless motivated the search for lead-free materials with piezoelectric charac-
powering of miniature implantable devices without any harmful damage teristics similar to those of PZT and PMN-PT [67]. Furthermore, the
of tissues, allowing to avoid repeated surgeries and thus infection majority of ME transducers developed so far are laminates and compos-
apposition or even more complicated consequences [55,56], which are ites with different designs, such as 0–3, 1–3, and 2–2 [68]. In the case of
reviewed in detail in the following sections. ME composites, Metglas® is mostly used as a magnetostrictive layer [63].
Various ME composites were also reported in the form of laminates, Generally, amorphous metallic glass (e.g., Metglas® 2605SC (Fe81B13.5-
e.g. Terfenol-D/P(VDF-TrFE), Terfenol-D/PZT/PVDF, core-shell parti- Si3.5C2)) assumes the form of an amorphous ribbon [69], with no com-
cles, etc [47,57]. Usually, the piezoelectric phase in the ME composite is a parable alternatives having been reported thus far (Fig. 4). Metglas®
lead-containing ceramic such as PZT-5H [58]. A high generated output comprises magnetic grains with shiftable domain boundaries under an
voltage and significant value of deliverable power (~0.6 mW) were applied AC magnetic field, enabling the material to change its overall
achieved in the case of the composite Terfenol-D/Metglas/PZT-5H for shape. The resulting vibrations are transferred to the PZT, which de-
wireless powering of an embedded device for biomedical applications velops a voltage in response to the induced strain [63]. Therefore, a
[58]. Moreover, higher energy powers have been reported so far, e.g. thin-film laminate converts an externally applied low-frequency AC
power of ~10 mW is generated at an applied magnetic flux density of magnetic field into a voltage across the transducer via mechanical
318.9 μT in case of a laminated composite of two Galfenol and one PZT coupling between the magnetostrictive and piezoelectric phases.
layers [59]. Terfenol-D/P(VDF-TrFE) composites were found to provide Various ME composites have been developed, e.g., bilayer laminates
both mechanical and electrical stimuli to MC3T3-E1 preosteoblast cells [(Ba0.85 Ca0.15)(Zr0.1Ti0.9)O3 - CoFe2O4] (αME of ~615 mV/(Oe cm),
triggered by a remotely applied magnetic field. It was reported that the trilayer laminates (αME ~ 803 mV/(Oe cm) [70], and [Ba(Zr0.2Ti0.8)
proliferation of cells is enhanced up to ~25% when they are cultured O3-0.5(Ba0.7Ca0.3)TiO3]/CoFe2O4/[Ba(Zr0.2Ti0.8)O3- 0.5(Ba0.7Ca0.3)
under mechanical (up to 110 ppm) and electrical stimulation (up to TiO3] (αME ~ 740 mV/(Oe cm) [71]. Alternatives to magnetostrictive
0.115 mV). This demonstrated that ME cell stimulation via magnetic, Metglas-based materials with considerable ME properties have been re-
mechanical, and electrical cues is a perspective approach for various ported [72,73]. However, their energy harvesting performance is limited,
tissue engineering applications [47]. and can only be maximized under high-strength magnetic fields; thus,
Hydrogel-based ME microenvironments for tissue stimulation have they cannot achieve sufficient power transfer under safety levels and
been also reported [60]. Polymer-based ME materials demonstrated novel magnetostrictive materials which can overcome this problem are
suitable bioactivity to provide magnetically and mechanically activated highly demanded, which is one of the main objectives of the current
biophysical electrical stimuli capable of improving cellular processes research endeavors.
[61]. PLLA microspheres and magnetic microsphere nanocomposites Recently, a novel magnetostrictive material, Fe100-xGax compound,
composed of PLLA and magnetostrictive CoFe2O4 nanoparticles was discovered [69]. This alloy is more suitable for ME transducers
4
electroactive materials in neuronal wound healing environments can be

used to guide axons to grow along specific paths [86]. Other types of
tissues are also dependent on electric stimuli to help them to grow,
reconstruct, and regenerate. While the inclusion of electroactive mate-
rials can be used to guide osteoregeneration, neuronal differentiation,
and proliferation, there are many challenges associated with designing
materials that can apply electric fields in a minimally and/or noninvasive
manner.
Biochemical stimulation is the most frequently used strategy for cell
regeneration, while application of physical stimuli, including magnetic,
mechanical, or electrical fields, is a promising yet scarcely investigated
alternative approach up to now [87]. In addition, the fabrication of
materials with a potential control of their behavior in vitro and in vivo via
either externally applied magnetic field or intrinsic properties such as
Fig. 4. State-of-the-art in the field: (a) laminate structure and (b) operating piezoelectric or electroactive is in high demand [88].
principles of the PZT/Metglas ME transducer. A piezoelectric layer (pink) (Ni-
It has been reported that the bone should be exposed to mechanical
coated PZT) and a Metglas (magnetostrictive layer (blue)). © [2020] IEEE.
strain between 100 and 2000 microstrain with ~ strain 100 repetitions a
Reprinted, with permission, from Ref. [63].
day to achieve a balance in bone remodeling and healing [89]. By being
exposed to such mechanical stress, bone generates the charge density of
owing to its superior properties compared to the conventionally used ~7 1011 μC/cm2 (at 1 N/m2 of stress), resulting in a balance between
Metglas® 2605SC, such as lower Young’s modulus (65 against 160 GPa) bone resorption and a new bone formation [43,90]. During wound
and significantly higher magnetostriction constant (320 against healing, similar behavior of electrical signals was reported [91]. It has
~30 ppm) [69]. Typically, Fe–Ga alloys are magnetically soft, mechan- also been demonstrated that endogenous electrical fields affect both cell
ically robust, ductile with large [74] or giant [75] magnetostriction. In migration and wound healing. However, electrical stimuli influencing
general, magnetostriction in the rare-earth-free Fe–Ga alloys increases the natural tissue healing process may not exist at the defect site, i.e. at
with the increasing content of non-magnetic Ga, peaking in the meta- bone replacement and bone fracture. Therefore, the use of ex-situ elec-
stable (A2þD03) two-phase region [76]. The dependence of the magne- trical stimuli can potentially replace natural endogenous electrical
tostriction on the stoichiometry of Fe–Ga alloys has been extensively stimuli and thus restore/accelerate tissue healing [43]. Ex-situ electrical,
studied. In the case of Fe83Ga17, the λ100 magnetostriction coefficient can ultrasonic, and electromagnetic stimulation enables acceleration of bone
reach 0.02% [77]. In Fe81Ga19 alloys, an enhanced magnetostriction repair/healing. In particular, electrical stimulation is revealed to enhance
coefficient of λ100 ¼ 0.039% was measured [78]. Magnetostriction values bone healing through the changes in cell adhesion, alignment, prolifer-
of ~140–150 ppm were observed in a ~5 μm long section of a 150 nm ation, and migration to the defect site [43,92,93]. At a later stage, elec-
diameter Fe–Ga/Cu nanowire, which was the same as that found on the trically active smart biomaterials have served the purpose of generating
macroscale [79]. However, to date, little is known about the strain dis- electrical stimulation in situ [43,94]. Different approaches have been
tribution and magnetostriction both at the nanoscale/microscale due to used to alter cell behavior to accelerate bone healing via the design of the
the experimental challenges faced during characterization [80]. For polarized surfaces for bone replacements [43,95].
example, as the size of Fe–Ga alloys decreases to the nanoscale, shape Different ferroelectric and piezoelectric materials were used in tissue
anisotropy significantly hinders the actuation and sensing of the samples engineering applications such as polymers PLLA, PVDF, PVDF-TrFE,
[79]. Thus, to engineer magnetostrictive devices with high sensitivity poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV), poly-3-
and reliability, it is vital to understand the fundamental interactions hydroxybutyrate (PHB), ceramics (BaTiO3, BN, ZnO, BiFeO3, and hy-
between the lattice strain, dimensionality, and magnetic moment under droxyapatite) and composites thereof [45,48,96]. Several of them pro-
the influence of an external magnetic field. The materials with higher duce piezoelectric output in the range, which is very close to that of the
magnetostriction can be potentially suitable candidates for the higher endogenous potentials (0.15–1.2 V) naturally existing at the healing site
energy-scavenging performance of ME composites. of a wound. Piezoelectric nanocomposites combine relatively high
piezoelectric charge coefficients of a piezoceramic and flexibility of a
4. Biomedical application of magnetoelectric materials piezoelectric polymer matrix, thereby allowing regeneration of bone,
cartilage, and other tissues [45]. However, the effect of piezocharge
4.1. Piezoelectric materials in tissue engineering and/or piezoelectric potential on the regeneration process has not been
studied in sufficient detail so far [45].
The term biopiezoelectricity is used to describe piezoelectricity found PVDF and also its copolymers (e.g. P(VDF-TrFE), polyvinylidene
in biological systems. In addition, some of the hard tissues such as dentin, fluoride hexafluoropropylene, etc.) are the piezoelectric non-
bone, cementum, etc., and some soft tissues such as hair, tendon, muscle, biodegradable polymers most frequently used for tissue engineering ap-
cartilage, pineal gland, ligament, etc. reveal intrinsic piezoelectric effect plications due to intrinsic piezoelectricity [97]. In further, most of the
in the human body [81,82]. The piezoelectricity of bone was discovered studies describing cell response under dynamic stimulation used namely
for the first time by Fukada and Jasuda [83], which at a later stage was PVDF (also its copolymers) as a support for cell proliferation and
connected with the piezoelectric nature of collagen [84]. The piezo- differentiation.
electricity mainly originates from the liquid-crystalline or nanocrystal- Electrospinning is typically used to prepare various types of nano-
line structure of complex extracellular matrix (ECM) components such as fibrous composite scaffolds, e.g. PVDF/Fe3O4 [44] or PVDF with hybrid
keratin, elastin, glycosaminoglycans, collagen, and hydroxyapatite. It is nanofillers of graphene oxide/CoFe2O4 [98] and others [48,88].
known that there are circulating microcurrents in the human body, which Utilizing the piezoelectric effect requires applied alternating me-
determine the mechanisms of tissues regeneration and metabolic pro- chanical stimuli, which may have several of their own challenges. For
cesses. In Fig. 5, the most important tissues in the human body are listed, example, when ultrasound exposure is used as a stimulus, ultrasound
where electrical activity is observed. waves may be attenuated by the body tissues [99]. This means that ul-
Electric fields are pervasive in many biological processes. For trasound stimulation is limited in its efficiency to stimulate regions deep
example, in neuronal wound healing, neuronal cells experience a con- inside the body. Therefore, there is still a challenge to develop electro-
stant electric field of up to 140 mV/mm [48,85]. Thus, the inclusion of active materials that enable delivering electric fields to more remote
5
Fig. 5. Electrical activity in the human body. Adapted from Ref. [46] with permission from Elsevier. © 2021 Elsevier Ltd.
regions in the body. A short summary of the cellular responses to these translocation of dephosphorylated NF-AT into the cell nucleus and
composite materials is given in Fig. 6. cooperative binding with other transcription factors. The described
Piezoelectric BFOþ films with a thickness of about 10–20 nm were process regulates gene expression of specific signal proteins (bone
obtained on the surface of SrTiO3 implants (Fig. 6a). The results of PFM morphogenic proteins, growth factors (TGF-β)), which are important for
revealed that the films generated a constant, built-in electropositive field bone and cartilage formation [45].
of 75 mV, which enables a strong interaction with the electronegative The piezoelectric response of PVDF can be significantly increased via
bone potential (from 87 to 52 mV). As a result of such stimulation, a poling process [103]. This is a process that utilizes a high external
both bone healing and osseointegration of the coated implants in rat electrical field and allows aligning the molecular chains of the polymer
femoral defects were achieved (Fig. 6b). Possible mechanisms were to increase polarization proportional to the concentration of electro-
proposed that is BFOþ nanofilms promoted the adsorption of fibronectin active β-phase and/or γ-phase. As an example, poling procedure is
(isoelectric point 4.8–6.4) and also upregulated the expression of cad- described in Ref. 89. In addition, a poling approach may also affect
herin 16 (Cdh 16) (mediating intercellular adhesion), Cd44, Vcl, Itgb3, cellular response. The negatively poled β-PVDF samples with d33 ~ -
and Actb (mediating crosstalk between cells) and osteogenic genes (Spp1, 32 pC/N reveal a more pronounced ability to stimulate protein
Bmp2, and Wnt5a) via activation of the PI3K-AKT signaling pathway (Src, adsorption and osteogenic differentiation (ALP activity) of hASCs
Akt1, and Pten genes are responsible for bone formation, osteogenesis, compared with either unpoled samples or positively poled ones under
and remodeling). As a result of this stimulation, cortical-like bone dynamic conditions (frequency 1 Hz, maximum amplitude 1 mm)
deposition was triggered, accompanied by the osseointegration of the (Fig. 6d) [101]. In comparison with PVDF, P(VDF-TrFE) reveals a higher
coated implants. The alternative mechanism responsible for the obtained piezocharge coefficient, which can be further increased by annealing at
results can be the polarization of the piezoelectric materials due to body 135 C due to the increased amount of electroactive β-phase. As a result,
movements, which stimulated the adsorption of bioactive proteins fol- under dynamic compression (frequency 1 Hz, deformation 10%), sur-
lowed by apatite deposition from the ions of Ca2þ and PO3 4 [45]. face piezoelectric potential in the case of the annealed samples is
Exposure to physiological loads or mechanical vibrations/de- significantly increased as compared to as-spun P(VDF-TrFE) samples
formations at an implantation site results in the generation of electrical without annealing. The scaffolds revealed streaming potentials of
signals on the surface of piezoelectric material, which occur similarly to 61.1 1.5 μV and 25.2 2.5 μV, respectively. An increased piezo-
collagen fibrils in cartilage and bone matrix by the formation of the electric response of the P(VDF-TrFE) samples after annealing promoted
negative charges via dipole reorientation. The formed electrical signal osteogenic activity as compared to as-spun ones. In addition, the former
(Fig. 6c) subsequently triggers intricate cell signaling pathways, for samples expressed more pronounced levels of both osteogenic markers
example, by the opening of voltage-gated Ca2þ channels in cell mem- (osteocalcin, ALP, mineralization and upregulated osteogenic related
branes, which increases intracellular Ca2þ contents followed by activa- genes (Runx2 and ALP (early markers), OCN and OPN (late/mature
tion of the calmodulin/calcineurin pathway following bone markers), but downregulated collagen I (Col I) (immature fibro-
dephosphorylation of nuclear factor of activated cells (NF-AT), cartilage marker) at day 28. On the contrary, as-spun samples revealed
6
Fig. 6. The impact of a piezoelectric material or a thin film on cell behavior in vitro. (a) A schematic representation of fast osseointegration between electronegative
bone and electropositive implant; (b) Histological results revealing enhanced osseointegration with BFOþ (BiFeO3 films with downward polarization and positive
potential) coated SrTiO3 implants in comparison with uncoated or BFO (BiFeO3 films with upward-oriented polarization and negative potential) coated SrTiO3
implants (arrows in yellow: bone-material interfaces, NB: nascent bone, FT: fibrous tissue); (c) Schematic view of electric charge generation induced by mechanical
strain on piezoelectric material surface triggering the signaling pathways of the cells; (d) Alkaline phosphatase (ALP) activity at 15 day of static and dynamic culture of
human adipose stem cells (hASCs) on different PVDF films using either regular or osteogenic medium (*p 0.005); (e) The effect of ultrasound stimulation of SaOS-
2 cells seeded on P(VDF-TrFE) and hybrid P(VDF-TrFE)/BNNT films using a medium for differentiation (bright-field microscopy after staining with alizarin red) [45].
The images in Ref. [45] were adapted from as follows: (a,b) with the permission from Ref. [100] Wiley-VCH © 2017 WILEY-VCH Verlag GmbH & Co. KGaA,
Weinheim; (d) with the permission from Ref. [101] © 2014 Wiley Periodicals, Inc.; (e) with the permission from Ref. [102].
chondrogenic activity compared to annealed P(VDF-TrFE) ones. The increased until day 14, and thereafter the expression decreased. At the
as-electrospun materials stimulated the synthesis of GAGs, collagen same time, dynamic compression in the case of non-piezoelectric control
types II/I ratio, and upregulated expression of chondrogenic genes, e.g. has not revealed any significant response of the cells [104]. It was also
chondroadherin (late/mature hyaline cartilage marker), Sox9 (early reported that ultrasound stimulation of cast-annealed P(VDF-TrFE)/BN
chondrogenic transcription factor), collagen II and IX (late/mature hy- nanotube nanocomposite films, revealing 80% higher d31 piezocharge
aline cartilage and hypertrophic chondrocytes marker), downregulated coefficient, stimulated differentiation of SaOS-2 osteoblast-like cell as
expression of aggrecan (early hyaline cartilage marker) and Col I compared to the plain P(VDF-TrFE) films, developed surface potential in
(increased for the other). In addition, collagen II or IX expression the range of 20–60 mV (Fig. 6e) [105].
7
4.2. Magnetoactive and magnetoelectric materials for tissue engineering microspheres revealed a uniform diameter of ~440 μm. Fig. 7b presents
an image of the ordered hcp gelatin microspheres. A magnified image
It is well established that stimulation via magnetic field enables shows that the gelatin lattice is composed of well-connected micro-
activation of numerous sensitive receptors on the cell surface and also spheres with uniform void spaces. The fabricated ME inverse opal scaf-
related signaling pathways to promote cell activity [106,107]. In addi- folds obtained after removal of gelatin spheres with various
tion, the magnetic field that acts on the bone defect in a specifically magnifications are shown in Fig. 7c. It is clearly seen that the ME scaf-
tailored manner can enhance cell activity and thus increase the bone folds possess a uniform, well-ordered structure. Fig. 7d reveals a
healing rate. Besides, magnetic field stimulation can promote integration cross-sectional view of the scaffold with a well-defined, long-range or-
between scaffolds and host bone, increasing both Ca and newly formed dered interconnecting porous network with a uniform size. The fabri-
bone contents. Numerous sensitive receptors on the cell surface can also cated cobalt ferrite nanoparticles are cuboidal in shape with an average
be activated, thereby enhancing cell activity and promoting new bone size of ~12 nm. The core-shell cobalt ferrite@bismuth ferrite nano-
formation and fracture repair [52,108,109]. particles demonstrate an average size of 20 nm (Fig. 7e). The
The magnetoactive 3D porous scaffolds for the effective proliferation energy-dispersive X-ray mappings presented in Fig. 7f show a uniform
of osteoblasts in a biomimetic microenvironment were reported [87]. shell composed of iron, bismuth, and oxygen around the core of cobalt
The scaffolds are obtained through the development of nanocomposites ferrite. The EDX mappings of a typical ME scaffold are shown in Fig. 7g
comprised of a piezoelectric polymer PVDF and magnetostrictive and reveal that the ME nanoparticles are uniformly distributed in the
CoFe2O4 nanoparticles, using a solvent casting method guided by over- volume of the scaffold. MicroCT analysis of the cobalt ferrite@bismuth
lapping the structures of a nylon template with three different fiber ferrite/PLLA scaffolds revealed an overall porosity of ~86%. In its turn, a
diameter sizes (60, 80, and 120 μm), and thus, varied porosity. The cross-sectional MicroCT image of the same scaffold is shown in Fig. 7h
magnetoactive composites possess a structure, which is very similar to and also reveals a porous and well-ordered structure of the scaffold.
that of trabecular bone with pore size in the range from 5 to 20 μm owing The magnetic field (13 mT at the frequency of 1.1 kHz) resulted in
to the inherent process of crystallization of PVDF with the nanoparticles electric stimulation of human-derived MG63 osteoblast cell proliferation,
interconnected with larger pores, formed after removing the nylon which is a model for primary osteoblast cells, was studied on 3D scaffolds
templates [87]. A physically active microenvironment was prepared and 2D membranes. As a result, a 134% increase in cell proliferation was
through the bone-mimicking structure of the scaffolds combined with the obtained for stimulated 3D scaffolds compared with non-stimulated ones.
physical stimuli provided by a magnetic custom-made bioreactor on a An increase of 43% of stimulated 2D membranes was obtained compared
magnetoresponsive scaffold. In this study, a novel bioreactor based on with non-stimulated ones, which signifies the importance of 3D scaffolds
magnetic stimulation has been developed, allowing for advanced tissue to provide a suitable microenvironment to host the cells [113].
engineering strategies [110]. It can act as a valuable tool for mimicking in It was reported that cancellous bone is piezoelectric and reveals a 3D
vitro the human stimulations provided by the electrically active tissues interconnected porous structure, which is crucial to maintain its bio-
that are present in the body. The magnetic stimuli application (23 mT at a logical functions. Magnetoelectrically induced proliferation of
frequency of 0.3 Hz) to cells seeded on the ME leads to an increase in the MG63 cells cultured under the influence of alternating current (AC)
cell viability of almost 30% with respect to the cell culture under static magnetic fields was studied (Fig. 8a). Fig. 8b clearly shows a pronounced
conditions, which could mimic what occurs in the human body and for increase in cell proliferation seeded on ME scaffolds under exposure to a
the application in immobilized patients [110]. It could also be important magnetic field in comparison with the untreated scaffolds. The cell
for growing well-formed cellular tissues in vitro more effectively and viability of the 3D ME scaffolds exposed to a magnetic field increased by
rapidly, which could be further implanted in the human body without the 134% (p < 0.001), in comparison to the samples without treatment. This
material. In the case that magnetoactive materials are implanted in the result confirms the significant impact of ME effect-induced cell prolifer-
human body, it may provide a suitable platform to evaluate the remote ation on 3D porous scaffolds. Fig. 8c presents an SEM cross-section image
stimulation and thus for the effective growth and cell differentiation in of a 3D ME scaffold seeded with cells after exposure to a magnetic field.
immobilized patients. The top and the bottom of the scaffold, marked as red squares in this SEM
A novel approach for tissue engineering applications has been ach- image, are shown as magnified SEM images (Fig. 8d and e). On the top
ieved with ME composite biomaterials. As an example, ME Terfenol-D/ surface of the ME scaffold, the presence of many well-adherent cells
PVDF-TrFe composites promoted ~25% of MC3T3-E1 preosteoblast interacting and growing on the walls of the scaffold is observed (Fig. 8d).
cells proliferation when cultured under mechanical and electrical stim- The presence of many cells that successfully migrated within the scaffold
ulation remotely controlled via varying magnetic fields [111]. The sur- is revealed on SEM images obtained from the bottom region of the
face charge also stimulated enhanced cell proliferation for muscle scaffold. It can also be observed that the cells are well adherent and
regeneration [112]. However, the studies with piezoelectric biomaterials interacting with the curved walls of the scaffold. The results obtained
reporting the effect of dynamic conditions have been scarcely performed were further confirmed by confocal laser scanning microscopy (CLSM) of
[97]. the 3D ME scaffold (Fig. 8f and g) [113].
3D ME inverse opal scaffolds allowing the generation of localized Usually, the important stage prior to cell adhesion on the surface is
electric fields under external magnetic field exposure are presented in protein adsorption [114]. Thus, the success of any cellular tests in vitro
Fig. 7 [113]. The scaffolds are composed of biodegradable piezoelectric should take into account surface-protein interactions. Proteins expression
PLLA and hybrid ME nanoparticles (CoFe2O4@BiFeO3) and are designed of integrin α5β1-mediated FAK/ERK signaling pathway was studied to
to mimic porosity and piezoelectric properties of the native microenvi- understand the molecular mechanisms responsible for osteogenic dif-
ronment of cancellous bone. The protocol to prepare ME inverse opal ferentiation on poled CoFe2O4/P(VDF-TrFE) nanocomposite films under
scaffolds is presented in Fig. 7a, which includes fabrication and assembly the dynamic regulation of magnetic field [115]. The expression level of
of monodispersed gelatin microspheres into a hexagonally close-packed proteins, including α5, β1, p-FAK, and p-ERK is significantly upregulated
(hcp) lattice followed by thermal annealing to introduce necking be- on 2600/2600/0 at 4 days, compared with the 2000/2000/0 and
tween adjacent gelatin spheres. After that, a solution with the scaffolding 2600/2600/0 (Fig. 9A-F), which is attributed to a transformation from a
material composed of hybrid ME CoFe2O4@BiFeO3 core-shell nano- low-affinity binding state of α5β1-FN to a high-affinity binding state of
particles dispersed in a PLLA solution is infiltrated into the voids of the α5β1-FN strengthen integrin-mediated FAK/ERK signaling pathway,
gelatin lattice in vacuum conditions (Fig. 7a(i)). In the end, the obtained when the temporal dynamic regulation of magnetic field was performed
gelatin lattice is etched selectively by immersing the samples at 60 C in on poled nanocomposite film. A mechanism of recognition and
deionized water, which resulted in the fabrication of a ME scaffold with strengthening process between integrin FN and α5β1 is designed to
an ordered porous network (Fig. 7a(ii)). The prepared gelatin enhance osteogenic differentiation of cells based on integrin-mediated
8
Fig. 7. The fabrication scheme of ME inverse opal scaffolds and the results of ME nanoparticles and scaffolds properties. (a) Fabrication steps scheme dealing with the
assembly of the spheres of gelatin followed by (i) their infiltration with the solution of PLLA and ME nanoparticles and (ii) gelatin spheres removal to prepare 3D
porous ME scaffolds. SEM images of the assembled gelatin template (b) (a magnified image is shown as an inset). (c) SEM image of the top-view of a 3D ME scaffold (a
uniform porous structure is revealed in the inset). (d) SEM image of a ME scaffold cross-sectional view. (e) TEM image revealing many overlapped cobalt ferri-
te@bismuth ferrite nanoparticles. (f) high-angle annular dark-field detector (HAADF) scanning-transmission electron microscope (STEM) image of the overlapped
cobalt ferrite@bismuth ferrite nanoparticles and corresponding EDX maps for Fe, Co, and Bi, with the superimposed images of the hybrid core-shell cobalt ferri-
te@bismuth ferrite nanoparticles. (g) SEM image of the ME scaffold and the corresponding EDX maps obtained for Co, C, Fe, O, and Bi revealing a uniform distribution
of ME nanoparticles within the scaffold. (h) Cross-sectional reconstructed 3D micro-CT image of a scaffold with a porosity of 86% Reprinted with permission from
Ref. [113] © 2019 Elsevier Ltd.
FAK/ERK signaling pathway (Fig. 9G). preosteoblasts by means of the application of magnetic stimuli is revealed
Materials with a proper microenvironment providing mechanical and [66], which is attributed to both local magnetomechanical and ME
electrical cues to cells have been created mimicking the morphology and response of the scaffolds induced subsequent cellular mechano- and
physical environment of bone since it reveals piezoelectric nature and electro-transduction processes via the change of the magnetic field
allows generating electrical cues with mechanical stimulation, e.g., (Table 1) [87].
walking [88]. The ME composite materials can generate mechanical and Electrospun hybrids of PVDF/CoFe2O4/GO scaffolds were seeded
electrical cues indirectly upon the external magnetic field proving the with mesenchymal stem cells and then exposed for up to 21 days (8 h per
concept of remote stimulation of the immobilized patients [87]. For that day) to extremely low-frequency electromagnetic fields (1 mT, 50 Hz)
purpose, bioinspired magnetoactive 3D scaffolds for bone engineering produced by the home-made magnetic generator, which was placed in-
have been reported (Fig. 10). side the CO2 incubator [98]. The differentiation value increased with the
The obtained scaffolds are based on piezoelectric PVDF and magne- employment of bioreactor and was also reinforced after neural differ-
tostrictive CoFe2O4 nanoparticles. The improved proliferation of entiation media treatment. Thus, fabrication of ME scaffolds for neural
9
Fig. 8. Effect of magnetic stimulation of 3D

ME scaffolds seeded with cells. (a) A scheme
revealing the ME effect induced enhanced
cell proliferation on the prepared 3D scaf-
folds exposed to AC magnetic field. (b) A
comparison of cell viability assay of cell
proliferation on ME 3D scaffolds without and
with magnetic field stimulation (*p < 0.001).
(c) SEM image revealing the 3D ME scaffold
cross-section seeded with cells and subjected
to a magnetic field. A magnified image of the
(d) region 1 reveals the SEM image at the top
of the scaffold, where many interacting/
attached cells are seen. (e) An SEM image for
region 2, where there are many cells growing
on the inside wall of the scaffold, is seen. (f
and g) CLSM images of the 3D ME scaffolds
with MG63 cells after magnetic field expo-
sure. Phalloidin-stained f-actin in green and
Hoechst-stained nuclei in blue reveal
a uniformly grown layer of adherent
MG63 cells along the curved walls of the
scaffold [113]. Reprinted with permission
from Ref. [113] © 2019 Elsevier Ltd.
cell differentiation with no need for chemical differentiation media was individual nanofiber was studied [49]. It means that even magnetically
achieved. However, it should also be noted that no ME coupling was active materials with Fe-containing compounds studied mostly at the
discussed in detail in the study; thus, the physical mechanisms of the moment reveal the ME effect observed at the magnetic field up to
observed phenomena are not clear. 2000 Oe, which has not been given sufficient details so far. Thus, more
ME coupling was also revealed at the nanoscale in the case of elec- research should be done to derive the effect of magnetic field-induced
trospun nanofibrous PVDF/Fe3O4 (10 wt% of PVDF) scaffolds when an polarization due to magnetostriction of the magnetic phase. The
10
Fig. 9. Proteins expression of integrin-mediated FAK/ERK signaling pathway on the surface of 10% poled cobalt ferrite/P(VDF-TrFE) nanocomposite film. (A–F) The
relative expression levels of α5, β1, p-FAK, and p-ERK on the film with temporal dynamic regulation of magnetic field normalized to β-actin. (G) Schematic diagram of
cellular osteogenic differentiation on magnetically responsive cobalt ferrite/P(VDF-TrFE) nanocomposite film with temporal dynamic regulation of the magnetic field.
Reprinted with permission from Ref. [115]. Copyright © 2018, American Chemical Society.
Fig. 10. A scheme of a magneto-responsive nanocomposite and its effect on a cell under an external magnetic field exposure. Reprinted with permission from
Ref. [87]. Copyright © 2019, American Chemical Society.
11
Table 1
A summary of piezoelectric, magnetoactive, and ME composites and their potential for bone engineering. Redesigned based on the results reported elsewhere [43]. BT –
barium titanate (BaTiO3), PU – polyurethane, BM-MSCs – bone marrow mesenchymal stem cells.
Structure Composite Results Magnetic field ME coupling, Reference
Piezoelectric
Porous HA/BT Biocompatible, cell viability – – [116]
enhanced on HA composites with
up to 70% BT
BT/akermanite nano-bioceramic No cytotoxic effect – – [117]
Lithium Sodium Potassium Improved attachment and – – [118]
Niobate proliferation of osteoblasts
Fibre PVDF Excellent osteoblast cell spreading – – [119]
BT/PLLA Randomly oriented fibrous – – [120]
composite encouraged BM-MSCs
spreading/differentiation
ZnO/PU Promote in vitro fibroblasts cell – – [121]
adhesion, proliferation,
differentiation
Membrane BT/P(VDF-TrFE) Promote fast bone regeneration – – [122]
both in vitro and in vivo
Both enhanced in vitro – – [123]
osteoinductivity and in vivo bone
regeneration, used as
osteoinductive barrier membrane
3D printed BT Scaffold for bone tissue – – [124]
engineering
Enhance in vitro osteogenic – – [125]
differentiation
Magnetoactive
3D printed (selective laser PLLA/polyglycolic acid (PLLA/ Stimulated cell adhesion and Permanent 0.35 T – [52]
sintering) PGA) doped with Fe3O4 20 nm in viability, and enhanced
size proliferation rate and ALP activity
Significantly induced substantial
blood vessel tissue, fibrous tissue,
and new bone tissue formation at
2 months postimplantation in a
rabbit bone defect in vivo
Composite Bioactive glass incorporated with Enhance up to three times mouse 200 or 350 mT – [62]
BiFeO3 (2–15 wt%) preosteoblast MC3T3 cells
viability/proliferation exposed for
30 min/day
Magnetoelectric
Hydrogel-based scaffold CoFe2O4/Methacrylated Gellan Provide cell viability superior to 220 mT Δ|d33| 6 pC/N [60]
Gum (GGMA)/PVDF 80% in vitro
Film CoFe2O4/PVDF Mechanical (0.013 μm mm2) and 220 mT – [51]
electrical (16.15 μV and 64 μV,
magnetic and mechanical
bioreactor, respectively)
stimulation of C2C12 myoblast
cells
Composite Terfenol-D/P(VDF-TrFE) Enhanced MC3T3-E1 230 Oe (frequency 0.3 Hz) 0.115 mV [47,97,111]
preosteoblast cell proliferation up
to 25% while being cultured
under mechanical (up to 110 ppm)
and electrical stimulation
Scaffolds PVDF/CoFe2O4 Local magnetomechanical and ME 230-0 Oe 0.115 mV [87]
response induced subsequent
cellular mechano- and electro-
transduction processes
Composite membrane CoFe2O4/P(VDF-TrFE) (10 wt%) Enhanced BM-MSCs osteogenic 2300 Oe (DC) 54 mV [126]
differentiation, and also regulated
the osteoimmunomodulatory
environment to improve bone
regeneration
Film CoFe2O4/P(VDF-TrFE) (10 wt%) Synthetically programming the 0–3000 Oe ΔV93 mV [115]
preferred magnetic field of cell
adhesion and proliferation periods
during cell growth significantly
enhanced cellular osteogenic
differentiation
nanoscale ME effect is still to be demonstrated in the macroscale form of use the term ME effect in the case of a high-frequency magnetic field
electrospun nanofibrous samples, which typically have a porous, generating an electric current by charging conductors. Thus, a digital
randomly oriented nanofibrous structure. light processing (DLP) 3D printing method was used to prepare a
There are also a few results on ME composites, which composition biocompatible and stretchable nanocookie conduit (NC@conduit,
deviates from traditional ME structures containing both magnetostrictive NC@C) integrating features of mesoporous carbon sheets and protein
and piezoelectric phases. As an example, in the study [127], the authors permeable elastomers for the purpose to regenerate a peripheral nerve
12
Fig. 11. 4D Printing of stretchable NC@C with ME conversion capability for growth factors release and simulation of cells for neurite sprouting. (a) Composite bioink
consisting of 4-hydroxybutyl acrylate, urethanepolyethylene glycol-polypropylene glycol monomer, initiator, and NCs made through 3D printing for NC@C fabri-
cation. (b) NC@C under the treatment of a high-frequency magnetic field facilitated ME conversion for growth factor release and cell stimulation to induce neuron cell
differentiation. (c) Image of a 3D printed NC@C revealing elastic properties of the composite. (d) The stretchable properties of NC@C revealed. (e) SEM image of cells
adhered to the surface of NC@C. The surface roughness of the NCs improved cell attachment. (f) CLSM images of cells proliferating on NC@C with microchannels.
DAPI-stained nuclei (red) and phalloidin-stained F-actin (green). Copyright © 2020, reprinted from Ref. [127].
(Fig. 11) [127]. The authors reported that NCs with mesoporous silica on cell adhesion (Fig. 11e). In addition, through exquisite fabrication, the
the surface of the conduits provide ME conversion, protein adsorption, microchannels of NC conduits promoted cell alignment (Fig. 11f).
and thus cell stimulation. Electromagnetized carbon porous NCs under a For providing an understanding of the orientation and growth of re-
high-frequency magnetic field treatment facilitate ME conversion for the generated axons, the whole regenerated nerve from the proximal to the
release of growth factor and cell stimulation to induce neuron cell dif- distal section in the conduit was harvested and stained with DAPI and
ferentiation and proliferation in vitro and in vivo [127]. However, no ß–III–tubulin to reveal the cell nuclei and regenerated axons, respec-
details on the parameters of electromagnetic field were presented in the tively. Fig. 12 displays a large area of CLSM images of immunohis-
study. Fig. 11a reveals a bioink composed of mesoporous carbon layers tochemically stained sciatic nerve defects from different treatments one
on a graphene oxide sheet (sandwich NCs), and 4-hydroxybutyl acryl- month after implantation. It is seen that the autograft group had a thick
ate/urethanepolyethylene glycol-polypropylene glycol monomer was nerve, curled and random fiber-like morphologies of regenerated axons
placed in a 3D printer resin bath. Then, UV light possessing a channel were observed because the direct surgical suture led to the mismatch of
pattern in a ring was applied to cure the bioink to form a flexible com- axons. In addition, NGF-NC@C þ MF (MF – treated with magnetic field)
posite NC@C with internal channels through DLP 3D printing. Fig. 11b revealed a thicker nerve bundle compared with NGF-NC@C and NC@C,
shows that 3D printed NC@C loaded with a large payload of neuron indicating that the growth of a nerve was promoted by ME stimulation
growth factor (NFG) was implanted to implement its spatial distribution and NGF release (shown as an inset). In further, a small distribution of
for the promotion of axon outgrowth after a peripheral nerve was axon orientation was observed in the conduit groups, which confirmed
transected 10 mm from the bifurcation point of the sciatic nerve of the effective regeneration of the high-frequency magnetic field treatment
Sprague-Dawley rats. Upon receiving high-frequency magnetic field (i.e., ME stimulation-induced nerve differentiation mediated by NCs in
irradiation, the NFG encapsulated in NC@C revealed an excellent the conduit, and NGF release enhanced cell growth). In addition, judging
permeability and on-demand release enabling induction of the differen- from the limb muscle weights and functions, the nerve recovery effects in
tiation and proliferation of nerve cells in vivo while simultaneously sup- NGFNC@C þ MF were found to be excellent. A normal nerve was found
plying electromagnetic stimulation to cells. After the addition of NCs, the to exhibit a nerve conduction velocity (NCV) of 47.5 m/s and a com-
printed conduit and composite still revealed sufficient for successful pound muscle action potential (CMAP) of 46.2 mV. At 1 month after
application elastic and stretchable properties (Fig. 11c and d). The surgery, the NGF-NC@C þ MF group exhibited an NCV of 44.7 m/s and a
controllable roughness of the surface on a conduit by exposing NCs to 3D CMAP of 44.9 mV, which were both higher compared with those of the
printing was achieved, which is an advantageous physical stimulus for NGF-NC@C group.
13
Fig. 12. Immunohistochemistry images

of peripheral nerve regeneration. (a)
Sciatic nerve defects harvested from an
autograft, (b) NC@C, (c) NGF-NC@C,
and (d) NGF-NC@C þ MF (n ¼ 5). The
inserted images show the optical images,
and the bar charts show the orientation
analysis. Direct axonal outgrowth fol-
lowed the microchannels of the conduit.
Blue represents nuclei and green repre-
sents β–III–tubulin (axon). The orienta-
tion is from proximal to distal (n ¼ 5).
Copyright © 2020, reprinted from
Ref. [127].
In summary, despite the active research and results described in the severely limited in their capabilities. The DBS must make direct physical
section, there is still a gap in the knowledge regarding the control of contacts with the neural network and is therefore limited to a finite
proliferation and differentiation of cells, as well as tissue apposition to number of implants. TMS interacts only indirectly with electrical circuits,
ME scaffolds/implants via the ME effect. Most of the studies on electro- and therefore, has very low efficiency and poor spatial resolution. In
active materials were done using solely piezoelectric materials, which contrast, wireless ME-based stimulation can be performed locally, and
require deformation/loading to provide surface polarization [88,103, therefore, can be completely non-invasive (or only mildly invasive) while
128–131]. In all of these cases, the movement of a person resulting in the achieving unprecedently high efficacy. The idea of using ME nano-
mechanical deformation of a material/scaffold or mimicking this expo- particles for brain stimulation to recover the communication between
sure ultrasound, etc. was used. These exposures have got their pros and neurons in patients with PD was first discussed in a theoretical paper by
contras, making it necessary for new research in the field of novel ma- Yue et al. in 2012 [135]. A few years later, Guduru et al. [136] reported
terials development. In the case of ME composites, the surface charge can the first in vivo ME-mediated modulation of brain EEG activity of mice by
be controlled in a more precise way by the variation of an externally the external magnetic field via intravenous injection of core-shell
applied magnetic field, which can also be applied for immobilized pa- CoFe2O4–BaTiO3 ME nanoparticles. These studies demonstrate that
tients making them far more advantages in various tissue engineering wireless stimulation with ME nanoparticles is really possible. In their in
applications. vivo experiments, the authors administrated a relatively small dose of the
nanoparticles into the bloodstream intravenously through an injection of
4.3. Magnetoelectric effect for brain stimulation approximately 100 μg of ME materials in the tail of a mouse. The
nanoparticles were pulled into the brain across the blood-brain barrier
The potential of ME nanomaterials to provide wireless stimulation of (BBB) via the application of a magnetic field gradient of approximately
selective regions deep in the brain locally at the subneuronal level or 3000 Oe/cm. The significantly increased concentration of the nano-
vagus nerve stimulation cannot be underestimated [55,56,132]. This particles in the brain was confirmed through atomic and magnetic force
ability could open the door to definitive treatment for disabilities asso- microscopies (AFM and MFM), as well as through scanning electron
ciated with motor and sensory impairments and cure patients with Par- microscopy (SEM) imaging of brain slices post euthanasia. To demon-
kinson’s disease (PD) and some other neurodegenerative diseases. Both strate wirelessly controlled stimulation, electroencephalographic (EEG)
the central and peripheral nervous systems (CNS and PNS) are driven by signals from EEG implants in correlation with an applied AC magnetic
electric signals and thus may be represented as electric circuits. A field of 100 Oe strength at a frequency in a range up to 100 Hz were
neurodegenerative disease occurs when one or several electric sub- measured. Thus, magnetic stimulation of the brain using ME nano-
circuits have a defect or are completely broken. Local stimulation can particles requires a magnetic field intensity lower than that used for
help to repair such damaged subcircuits. It is noteworthy that typical TMS [137]. The unique properties of ME nanoparticles, such as
electric-field triggered stimulation is the basis for many modern stimu- small size (~30 nm) and the ME effect not displayed by any other
lation approaches like various forms of invasive direct-contact deep-- nanoparticles known to date, may provide significant improvements
brain stimulation (DBS) and low-efficacy transcranial magnetic according to currently used techniques in terms of efficiency, accuracy,
stimulation (TMS) techniques [133,134]. However, these approaches are and tissue penetration for non-invasive brain stimulation.
14
Fig. 13. (a) Illustration of a wireless electric stimulation with magnetoelectric nanoparticles via application of AC magnetic fields. Reprinted with permission from
Ref. [139]. (b) Schematic demonstrating of wireless deep brain stimulation in freely moving rodent model for Parkinson’s disease. Reprinted with permission from
Ref. [56] © 2020 Elsevier Inc.
Recently Nguyen et al. reported a non-invasive technique using core- other neurodegenerative diseases. For example, Singer et al. [56]
shell CoFe2O4–BaTiO3 ME nanoparticles to wirelessly stimulate cortical demonstrated that the wireless power method based on ME allows the
neuronal activity [138]. The nanoparticles have been injected into a use of magnetically powered miniature neural stimulators that operate at
vein. The authors showed by in vitro and in vivo fluorescent and clinically significant frequencies 100 Hz. Millimeter-scale (about
two-photon imaging techniques that ME nanoparticles can be drawn 7 mm) magnetoelectric device has been used for DBS using a unit
across the BBB and localized to a target cortical region without any attached to the skull and wired to the deep brain (Fig. 13b). These ME
apparent signs of neuroinflammation. Cortical activities in individual stimulators can provide therapeutic deep brain stimulation in a
neurons and in a large neural network in vivo were induced by acti- free-roaming rodent model for Parkinson’s disease.
vating ME nanoparticles with a weak external magnetic field Recently [55], a new study was published concerning wireless DBS in
(100–500 Oe) at a specific frequency. Under the influence of a relatively mice. For achieving wireless signal transmission to the insertion devices,
weak magnetic field, the core of ME nanoparticles of cobalt ferrite ME nanoelectrodes that couple magnetic and electric signals (Fig. 14A,B)
(CoFe2O4) undergoes non-zero deformation due to the magnetostrictive were used. ME nanoelectrodes were implanted into the subthalamic re-
effect. Due to the ME coupling, this deformation propagates through the gion by stereotaxic infusion and actuated using an external magnetic field
lattice-matched interface to the neighboring shell of barium titanate at nonresonant carrier frequencies and in freely moving mice (Fig. 14C).
(BaTiO3), which, in turn, creates a local electric field (on the order of Two-phase ME nanoparticles were prepared from magnetostrictive
1000 V/m) due to the piezoelectric effect. The concept of ME-based CoFe2O4 nanoparticles coated with a piezoelectric BaTiO3 by sol-gel
wirelessly controlled stimulation is shown schematically in Fig. 13a method (Fig. 14D-E). Magnetic stimulation of ME nanoparticles enables
[139] and can be briefly described as follows: an external magnetic field wireless modulation of neuronal activity in vitro and in vivo. Also re-
of very low intensity is directed to the brain and causes fluctuations in ported was the therapeutic potential of this technology through its ability
the electrical charge in the nanoparticles, which can interact with to modulate the activity of the motor cortex and non-motor thalamus, as
neurons and stimulate neural pathways: a low-intensity field generates well as to alter animal behavior.
AC signals at the same frequency as the activity of a healthy nerve It should be noted that, in order to perfectly recover any operation of
charge, and the vibration of a ME nanoparticle leads to the activation of the neural network with the help of ME nanoparticles, the individual ac-
neurons around it with the same frequency, that is, to their stimulation tion potentials should be triggered in any neural system at any time
non-invasively. instance on demand. The ME coefficient is critical for this, and its increase
The maximum effectiveness of wireless stimulation based on ME depends on improving the properties of materials. It was reported [1] that
nanoparticles is achieved when nanoparticles are located on the surface the coefficient ME coefficient above 1 V/(Oe cm) can be achieved. The ME
of the neuronal membrane. As known [139], at rest, a typical value of the coefficient can be increased through a dc field biasing [141,142], and the
membrane potential is approximately 70 mV, and increasing by ME effect strongly depends on the frequency [143–145]. In the case when
þ15 mV triggers the firing of an action potential. The type of neuron and both phases, magnetic and electric, resonate at the same frequency, the
the specific location on the membrane surface determine the value of the highest resonance will occur [146]. At the moment, most of these reso-
electric field required to reach this threshold. MEs on the membrane must nances in ME nanoparticles usually occur in the GHz range (e.g., from
be able to locally generate an electric field strong enough to overcome below 5 to over 10 GHz), while electromagnetic waves in this frequency
the potential threshold for the ignition of action potentials. The results of range are strongly attenuated due to absorption by water [147,148]. The
a back-of-the-envelope-type estimation [140] demonstrated that the integration of extremely sensitive nanotechnology with advanced signal
application of a magnetic field of 1000 Oe to a ME nanoparticle with an α processing technologies should solve this problem. It is very important that
of 100 mV/(Oe cm) would generate an electric field of 100 V/cm after treatment, ME nanoparticles can be removed from the brain through
(104 V/m), and that would be enough to trigger firing of an action po- the application of a magnetic field with a reverse gradient, as well as
tential by a single nanoparticle. ME nanoparticles provide highly efficient naturally. It has been shown on animal models that the nanoparticles are
stimulation when they act collectively and under the influence of peri- excreted within 2 months depending on their size [149] and also are
odic signals corresponding to periodic rhythms of brain waves. A rela- non-toxic [150] to the brain and other major organs, such as kidneys,
tively low-frequency periodic sequence of narrow pulses effectively lungs, liver, etc. Perhaps in the near future, some other types of biode-
stimulates the neural network at the local level [55,56], and may be gradable ME nanoparticles will be developed, possibly made of biocom-
useful for the treatment of depression, Parkinson’s disease, and some patible functionalized carbon materials.
15
Fig. 14. Material and magnetoelectric characterization of ME nanoparticles made from magnetostrictive and piezoelectric phases demonstrate wireless electric field
generation. Schematic demonstrating two-phase magnetoelectricity in materials made from magnetostrictive and piezoelectric materials that are strain-coupled (A).
Schematic demonstrating the rationale for using a large DC magnetic field overlaid with an AC field to generate optimal magnetoelectric output (B). Diagram of the
method of in vivo ME nanoparticles administration. ME nanoparticles are injected bilaterally into the subthalamic region of mice and are wirelessly stimulated using an
AC and DC magnetic field (C). Transmission electron microscope (TEM) (D) and TEM-electron energy loss spectroscopy (TEM-EELS) images (E) show ME nanoparticle
morphology and BaTiO3/CoFe2O4 phases (green and red, respectively), with quantitative elemental analysis measurement of the molar percentage of each material
(E). ME nanoparticles were analyzed via x-ray powder diffraction (XRD) to confirm the perovskite crystal structure of BaTiO3 (green) and the spinel crystal structure of
CoFe2O4 (red). Reprinted with permission from Ref. [55] © 2021.
4.4. Magnetoelectric effect for cancer treatment and drug delivery eliminate the HIV-1 virus hidden deep in the brain.
It is well known [18,19] that different cells, particularly their mem-
Cancer is one of the deadliest diseases in the world for now. Despite branes, could be distinguished through their electric properties such as
significant progress in finding a cure, fundamental questions remain membrane potential, dielectric permittivity, conductivity, etc. For
unresolved. Each successful therapy is not only limited to a few cancers example, the membrane potentials of cancer cells can be quite different
but also has relatively low specificity for target cancer cells; while cancer from those of their normal counterparts [153]. The membrane potential
cells can indeed be eradicated, many normal cells are sacrificed as defines the energy required to break through the membrane for entering
collateral damage. ME nanoparticles that could be externally controlled the cell. Electroporation is a well-established, highly specific process that
are very promising for cancer treatment due to high-specificity targeted is used to deliver biomolecules to cancer cells without affecting the
delivery and release of therapeutic drugs on demand. surrounding normal cells of the same type [154]. Relatively strong
As known [151], for the delivered drug to be bioactive, it is important electric fields (about 1000 V/cm) are used to electroporate cancer cells,
to release it off the carrier nanoparticles when they reach the target site. but such strong fields can also damage the surrounding normal tissue. In
The most important property of ME nanoparticles is the ability to release the case of using ME materials for the induction of electroporation, strong
the load in any place at any time on demand. ME nanoparticles can be fields are applied only in the local nanoscale region around the nano-
wirelessly controlled via the application of DC and AC magnetic fields. particles. That is why nanoparticle ME-induced electroporation, also
Using ME materials instead of single piezoelectric or magnetic nano- known as nanoelectroporation, does not cause any field-sensitive side
particles adds more flexibility and functionality to the drug delivery and effects. The ME-triggered nanoelectroporation was used for the first time
release process since both AC, DC magnetic, and ultrasonic activation can to deliver the well-known mitotic inhibitor paclitaxel into ovarian cancer
be used. Nair et al. showed [152] that, owing to the ME effect, the cells while sparing the surrounding normal ovarian cells. Such experi-
application of an AC magnetic field is equivalent to shaking the drug off ments were conducted both in vitro and in vivo. It was reported [155,156]
the nanoparticles. Therefore, the conjugation strength between the drug that drug-loaded ME nanoparticles showing relatively high specificity to
and the nanoparticles can be made adequately strong to ensure no drug is cancer cells can penetrate the cancer cell membrane while sparing the
released before the nanoparticles reach the target site. Only after the surrounding healthy cells, and then release the drug intracellularly via
nanoparticles with the drug are pulled across the BBB and reach the application of d. c. and a. c. magnetic fields, respectively. In vitro and in
target site in the brain, an AC magnetic field can be applied to trigger the vivo studies of ovarian cancer in mice carrying SKOV-3 human ovarian
desired high-efficacy release. The concept of the AC magnetic carcinoma xenografts have confirmed the hypothesis of a highly specific
field–controlled drug release across the BBB can be schematically rep- target delivery by drug-loaded ME nanoparticles [156].
resented as follows: (1) Intravenous (IV) injection of drug-loaded nano- The high specificity of nanoelectroporation was explained by the
particles, (2) the drug-loaded ME nanoparticles are pulled across the BBB substantial difference in the membrane potential between the two cell
via application of a DC magnetic field gradient (on the order of types. The membrane potentials of ovarian cancer and normal cells are on
3000 Oe/cm), (3) when, optionally through image guiding, ME nano- the order of 5 and 50 mV, respectively. In other words, the field
particles can be localized at the intended site, a relatively weak AC required to ‘penetrate’ normal cells must be ten times that of cancer cells.
magnetic field, with a strength of 100 Oe at a frequency of 100 Hz, is The physics behind nanoelectroporation was discussed in the paper by
applied to release the drug. Stimphil et al. [157]. The mode of SEM known as the energy-dispersive
In vitro BBB model was used to [152] that this ME nanoparticles spectroscopy (EDS) was used to directly measure the tissue specificity
concept could be used to deliver and release the well-known antiretro- for this approach and to detect the presence of ME materials with
viral therapy 30 -azido-30 -deoxythymidine-50 -triphosphate (AZTTP) to nanoscale precision [156]. The EDS-SEM imaging combines the
16
Fig. 15. Illustration of steps of the

concept of the field-controlled ME-based
nanoelectroporation to deliver drugs
specifically into cancer cells. (1) Drug-
loaded ME nanoparticles are adminis-
trated into the cellular microenviron-
ment of interest; (2) a DC magnetic field
above the threshold value for the
particular cancer cell line is applied to
induce the process of nano-
electroporation; and (3) the magnetic
field is turned off to trap the drug-loaded
nanoparticles inside the cancer cells.
Represented with permission from
Ref. [139].
advantages of the elemental compositional analysis on par with that by the tissue, thus limiting the level of power transmission. Furthermore,
mass spectroscopy and the high spatial resolution by SEM [149]. The tissue damage in humans can occur upon exposure to a boosted trans-
concept of ME-triggered nanoelectroporation used to deliver drugs spe- mitted power. Compared to wired or battery-powered implants, wire-
cifically into cancer cells via the application of a 100 Oe DC magnetic lessly powered battery-free neural stimulators have the potential to
field is schematically shown in Fig. 15. It is very important to maintain provide less invasive and longer-lasting interfaces for human nerves [63].
the DC field between the thresholds of nanoelectroporation for cancer The list of the most prominent power transfer methods employed by
and normal cells, respectively, to provide the required specificity. After implantable electronic devices found in the literature can be derived as
delivery of the loaded nanoparticles to cancer cells, a relatively weak AC follows: optical, electromagnetic, and ultrasound [160]. Electromagnetic
magnetic field, with a strength of 30 Oe at a frequency of 100 Hz, was methods, in their turn, are divided into near-field, mid-field, and
applied to release the drug on demand. far-field, inductive, and capacitive couplings, as well as ME ones, which is
Recently it was reported [158] that 30-nm ME nanoparticles which a relatively new ME wireless power transfer technology. Inductive
consist of the core–shell composition of CoFe2O4@BaTiO3 demonstrate coupling techniques seem to be the most advanced for powering im-
externally controlled high-efficacy binding with the hormone MIA690 plants; they utilize a pair of coils that must be physically close and
and targeted specificity to glioblastoma cells and on-demand release of well-aligned to allow for power transfer. Subsequently, the power
the peptide by application of DC and AC magnetic fields, respectively. transfer is dependent on the degree of the orientation, size, and distance
Notably, due to the fundamental nature of the approach, ME materials between the coils [162]. Ultimately, these dependencies make this form
can be used for intracellular delivery of any biomolecule, including of wireless power transfer most viable for implantable medical devices
nucleic acids, to enable genetic engineering or certain antitumor peptides (e.g., pacemakers [163]) where the depth of the implant is relatively
for the treatment of glioblastomas, as described in Stewart et al. [158]. shallow, and the alignment of the coils can be well controlled. Table 2
presents a list of pros and contras of the different wireless power transfer
4.5. Wireless power transfer approaches and ME antennas methods, and Fig. 16 proposes a graphical representation of the com-
parison between them.
Medical implants have become commonplace in biomedicine, owing to Mid-field and far-field electromagnetic wireless power transfer sys-
their multiple benefits; however, they demand certain levels of power (e.g., tems have also been widely used for power pacemakers [164,165],
~1–10 and ~10–100 μW for pacemakers and neurostimulators, respec- however, they can induce significant heating caused by radio frequency
tively). A fundamental challenge in developing miniature neural implants is wave absorption in the human body, which absorption can both
delivering sufficient power to the devices inside the body. Accordingly, reduce system efficiency and pose a health risk to users [59]. The
charging implants through wired power supplies presents severe draw- recoverable electromagnetic energy by radio frequency transmission or
backs, as lead wires increase the risks of infections, restrict device deploy- inductive coupling for micro-systems is usually low to enable a useful
ment, and affect subject mobility [159]. The most common method to power supply at a communication distance greater than 50 mm [58,166].
provide energy to an implanted electronic device is through a battery, as it is In its turn, ultrasound is proposed as an efficient approach to power and
portable, reliable, and convenient. Nevertheless, batteries are often bulky communicate with millimeter-scale implants deep inside tissues [167].
and make up for a large portion of the volume of the implanted electronic Application of ultrasound leads to a volume reduction of the size of
device [160]. Additionally, they need to be replaced periodically, which is a transducers/implants due to a shorter wavelength [168–170], which
significant economic and health burden, and the materials that compose maintains the ability to operate at moderate depths in tissue and perform
them are toxic, making leakage a serious health concern [160,161]. functions with moderate power requirements [171]. However, the
External recharging based on radio frequencies is attenuated through acoustic transmitter must be in direct contact with the skin, and the
Table 2
Summary of pros and cons of each wireless power transfer method according to the literature review [160]. IC – inductive coupling, CC – capacitive coupling, MF –
mid-field, FF – far-field, US – ultrasound, OW – optical, ME – magnetoelectric.
IC CC MF FF US OW ME
advantages Efficiency Small RX Well Delivered power Efficiency Small High depth TX High depth Small High efficiency Low absorption
established Efficiency RX practicality RX High Small RX
efficiency
limitations Low depth Misalignment Low depth Misalignment Efficiency Misalignment Low depth Misalignment
High RX area TX practicality High absorption Losses in Absorption in Early
TX practicality interfaces tissue development
Losses in bone TX practicality Efficiency
Misalignment
17
Fig. 16. Comparison of key parameters between wireless power transfer methods. © 2020 Elsevier B.V. Reprinted with permission from Ref. [160].
acoustic power transmission through the bone seems to be minimal due especially for implantable medical devices [59]. Body-area wireless
to a large acoustic impedance mismatch between soft tissues and bone, power transfer via high-frequency electric, magnetic, or electromagnetic
which results in the reflection of most of the acoustic energy. fields represents safety issues, such as heating, owing to the power
Unlike acoustic and inductively coupled systems, alignment is not as deposition in the human tissues. Therefore, the field strength and fre-
critical for radio frequency wireless power transfer systems because re- quency must be adjusted to provide safe operation in all cases. The In-
ceivers do not need to be tightly coupled to the transmitter. However, as ternational Commission on Non-Ionizing Radiation Protection (ICNIRP)
the size of receivers decreases, the operating frequency must increase to a and the Institute of Electrical and Electronics Engineers (IEEE) standards
level where tissue tends to absorb and attenuate the transmitted signal, are also applied. According to the ICNIRP regulation [178,179], the
which is not only inefficient, but it is potentially hazardous because of maximum SAR is set to be 2 W/kg per 10 g of tissue to stay within safety
associated tissue heating. A technology that could make efficient use of limit conditions. An example, according to the IEEE safety standards
low-frequency electromagnetic power transfer at a distance could be a [180–182], at 70 470 Hz, the highest allowable amplitude of the mag-
significant achievement for very small implantable systems [162]. The netic field that can be applied to humans is 0.205 mT. With the same
criteria, advantages, and limitations of the developed and most operating frequency and maximum magnetic field strength, the system
frequently used at the moment wireless power transfer technologies are under investigation is able to transfer up to 4.16 mW to a load resistance
reviewed in detail elsewhere [160]. (which is equivalent to 3.85 mW with 197.2 μT) [183]. This amount of
When delivering power to neural implants using a radio frequency power is sufficient to supply most of the biosensors. As an alternative
field, the carrier frequencies must be in the GHz range to match the example is that the IEEE standard for exposure to magnetic fields above
resonant wavelengths of small antennas [172], causing high electro- 3000 Hz is limited to 163 A/m [182]. ME films operate under
magnetic absorption in the body and violating safety limits, which will be low-frequency magnetic fields (100 kHz-1 MHz), enabling them to
discussed in detail in further. Near-field inductively powered devices penetrate the human body without substantial absorption, thus allevi-
primarily work at 13.56 MHz or higher, improving the quality factor of ating the safety limitations for power delivery [184]. For assessing the
the miniaturized receiver (RX) coil and its efficiency [173], also resulting safety of ME power transfer for deep-body implants, the specific ab-
in energy absorption by the body, and thus, requiring operation under sorption rate (SAR) must be determined [63]. A deeper understanding of
certain restrictions. Inductive coupling technology is sensitive to align- the safety concerns can be provided by taking into account Fig. 17 [185].
ment changes and inter-coil distance, resulting in excessive heat gener- Fig. 17a depicts the simulation model of a two-port communication
ation in tissues, damaging the metabolisms and immune system. In this system. Since the Tx antenna is placed close to the GM-CSF (gray
regard, both technologies raise efficiency and safety concerns. In addi- matter-cerebrospinal fluid) interface, the developed COMSOL model in-
tion, in vivo movements, which are regarded as internal energy sources, cludes all layers except the edema because it is very far from the Tx port.
yield low frequency and acceleration that are difficult to harvest [174]. Fig. 17b displays the simulated path loss between Tx and Rx antennas
Transducers based on acoustic energy via application of piezoelectric as a function of frequency. From Maxwell’s equation in a lossy media, one
materials or electromagnetic energy via application of inductive coupling should know that tissue absorption is directly proportional to the con-
between coils or radio frequency transmission between antennas are ductivity of the tissue and inversely proportional to its relative permit-
among the most studied solutions of the energy transmission techniques tivity. Thus, Fig. 17b reveals that the path loss increases with a higher
for micro-systems in the biomedical field [171,175]. The development of operational frequency. Fig. 17c shows the simulated path loss along with
a ME antenna indicated that for a given frequency, its wavelength could brain layers at different frequencies. It is shown that most of the loss
be five orders of magnitude shorter than the electromagnetic wavelength, occurs in the scalp and CSF layers due to their high conductivity to
thus enabling dramatic device miniaturization [176]. Furthermore, the permittivity ratio. In addition, the path loss is reduced with decreasing
typical operating frequency of ME systems is relatively low, in the range frequency. In addition, even in the GHz regime, the electromagnetic loss
of tens of kHz, which enables a higher permissible applied magnetic field is very small in the skull. This is a significant advantage of electromag-
than that of resonant inductive coupling wireless power transfer systems netic waves compared to ultrasound ones, in which the loss rate in the
[177]. skull is 22 dB/cm⋅MHz [186]. It implies that an acoustic-based
Low-frequency magnetic fields possess several key merits, including implantable device [167] such as operating at the frequency of 10 MHz
(i) strong penetration and low tissue absorption in a specific range of would have 110 dB loss in the skull alone. The results described above
parameters owing to low carrier frequencies; (ii) less sensitivity to clearly show that wireless implantable devices operating in the
changes in alignment (in comparison with inductive coupling); (iii) high low-frequency regime could be far more efficient than devices operating
output power and efficiency even with increasing miniaturization, due to in the high-frequency range because the former ones will face much less
the much smaller acoustic wavelength inside organic tissue (than that of tissue loss compared to the latter ones. Furthermore, a low tissue loss is
electromagnetic waves) which results in the decrease of the receivers’ especially important for passive implantable devices since there is little
size [59,63,160,162]. These characteristics make the ME generator a power available inside the body, and it is even more critical when
promising alternative to other wireless power transfer technologies, implanting a device into the brain because the implanted component
18
Fig. 17. (a) Finite element analysis simulation model of

brain layers. The external receiver antenna is on the
scalp, and the implanted device is close to the cerebro-
spinal fluid (CSF)-gray matter (GM) interface. (b) Path
loss between receiver (Rx) and transmitter (Tx) antennas,
where Rx is on the scalp outside the head and Tx is
implanted on the CSF-GM interface. Path loss increases
significantly with enhancing the operational frequency.
An inset reveals the brain structure and the position of Tx
and RX antennas. (c) Path loss along with brain layers at
different frequencies, where the layers are shown in the
background. Most of the loss occurs in the scalp and CSF
layers due to their low permittivity and high conductiv-
ity. Unlike acoustic waves, the loss of electromagnetic
waves in the skull is very small, which is an upper hand
for electromagnetic implantable devices. (Inset) Brain
layers along the path. © [2019] IEEE. Adapted with
permission from Ref. [185].
19
must be extremely small and batteries are not acceptable. Therefore, antenna with a size of 250 174 μm2 that can efficiently perform
implanted systems based on ME antennas could be a breakthrough in the wireless energy harvesting and sensing ultra-small magnetic fields, such
field of body implantable devices because these antennas are smaller as those arising from neural activities, is reported [187]. The ME antenna
than 200 μm in size and can work in 10 s or 100 s of MHz frequency reveals a wireless power transfer efficiency 1–2 orders of magnitude
range, while conventional inductive coils or antennas operating in a higher than any other reported so far miniaturized micro-coil, allowing
similar frequency range are more than a few centimeters in size [185]. An the wireless implantable medical devices to be compliant with the SAR
ultra-compact dual-band smart nanoelectromechanical systems ME limit and thus operating under safe radio frequency exposure. In
Fig. 18. (a) Conceptual diagram showing a wearable spinal cord neurostimulation system for pain relief, the implant is remotely powered via a magnetic field; (b)
Illustrations of the proposed neurostimulation implant. ME element contains a nickel-coated lead zirconate titanate (PZT), and a Metglas, a magnetostrictive layer. ©
[2020] IEEE. Adapted, with permission from Ref. [63].
20
addition, the magnetic sensing capability of the proposed smart ME an- Table 3
tenna, with a limit of detection of 300–500 pT at > 200 Hz, should allow A Comparison of the NanoNeuroRFID system design approach with some
the implantable medical devices to record neural magnetic fields from recently published wireless implantable devices. Re-designed based on [185].
the brain without requiring differential recording. Recording/ Size, mm mm Approach Reference
The ICNIRP and the IEEE standards were applied to the lumped ele- stimulation
ments models, which were then used to optimize device dimensions Micro electrodes 5 7.5 Electromagnetic [193]
within a volume of 2 mm3. An optimized ME device can produce (contact with
21.3 μW/mm3 and 31.3 μW/mm3 under the ICNIRP and IEEE standards, tissue)
Micro electrodes 55 Electromagnetic [194]
respectively, which are very attractive for a broad range of biomedical
(contact with
implants and wearable devices. tissue)
Encapsulated ME composites for the wirelessly powered brain Micro electrodes 3 6.5 Ultrasound [168]
implantable devices were reported [188]. Simulation results indicate that (contact with
a polymer encapsulant, rather than creating a substrate clamping effect, tissue)
Micro electrodes 31 Ultrasound (and [170]
increases the voltage output of the ME composite, which can be further (contact, E-field electromagnetic for
improved via a careful polymer selection. These attributes are modeled recording) intermediate transceiver)
using the finite element method with COMSOL Multiphysics software. A NanoNeuroRFID 11 Electromagnetic [185]
piezoelectric voltage of 3.77 V AC output at a magnetic field strength of
0.2 kOe was obtained. To the best of our knowledge, the highest ME
power densities reported in the literature is 175 mW/cm3 [58,189]. This stimulation covering 0.05–1.5 mA amplitude, 64–512 μs pulse width,
new technology can increase the power density and overpass the issues of and 0–0.2 kHz frequency ranges, making it appropriate for spinal cord
directionality present in the inductive transmission technique, and open stimulation for chronic pain treatment.
new prospects for wireless powering medical implants [99]. In general, the efficiency of the transferred power is dependent on the
When electromagnetic energy at 2 GHz and ultrasound energy at position of the transmitter relative to the receiver and the distance be-
2 MHz are compared, the former reveals lower attenuation through tissue tween them. In this context, a lot of research was done to provide
(1–2 dB/cm vs. 10–12 dB/cm [190]), a higher US Food and Drug direction-independent power transfer without significant losses due to
Administration (FDA) limit for power flux (7.2 mW/mm2 possible misorientations between a receiver and a transmitter. The per-
vs. 0.1 mW/mm2 [191]) and a smaller wavelength (0.75 mm vs. 25 mm) formance of the delivered to a resistive load power under uncertainties in
for more efficient coupling to small implants [169]. A key challenge in ME receiver position and orientation was studied [183]. In further, a
developing wireless millimeter-scale stimulators is wireless power and non-uniform applied magnetic field effect has also been considered. In
communication that provide well-controlled, therapeutically relevant the case of the studied experimental system, a maximum transferred
effects. A wireless, leadless, and battery-free implantable neural stimu- power of 4.91 mW was reached at a distance of 3 cm between the centers
lator (that is 1.7 mm3 in size) incorporating a piezoceramic transducer, of the ME transducer and the coil, in which the subsequent magnetic flux
an energy-storage capacitor, and an integrated circuit was reported density was 225.8 μT. When the distance was increased to 6 cm, the
[169]. generated power decreased to 1.97 mW. It was also revealed that the
Stemming from the low tissue absorption, low misalignment sensi- output power is proportional to the squared cosine of the misorientation
tivity, and high power transfer efficiency, the ME effect enables the safe angle, compared to the power reached at the zero-angle (nominal) po-
delivery of high power levels (a few mWs) at relatively low resonant sition. It was found that the delivered power is less sensitive to
frequencies (~ 0.25 MHz) to millimeter-sized implants deep inside the misalignment since the width of the receiver is relatively small in com-
body (3 cm in depth) (Fig. 18a) [56,63]. Although various wireless radio parison with the diameter of the transmit coil. In principle, the power
frequency-based neural implants exploiting electromagnetic, inductive generated at a specific load is a quadratic function of the effective
coupling, ultrasonic, and optical power transfer have been reported, magnetic field that is projected onto the operating direction of the ME
achieving safe and reliable wireless power transfer within the size and laminated composite (i.e., the longitudinal axis in this case) [183].
power constraints of neural and other types of implants is still chal- Despite the fact that αME has been widely used as a standard criterion
lenging [63]. The proposed device (Fig. 18b) features: (1) a miniature to determine the performance of a ME transducer, however, there is
physical dimension of 8.2 mm3 and 28 mg, (2) adaptive system control strong evidence that a higher αME does not always ensure higher opti-
and data transfer mechanisms robust under source amplitude variations, mum power delivered to the load. In general, many factors influence
(3) a 90% chip efficiency due to its low static power down to 23.7 μW, achievable power levels, including parameters and configurations of
and (4) the capability to perform fully programmable bi-phasic current magnetostrictive and piezoelectric phases. It was shown that the
Fig. 19. (a) Overview of the wireless implantable NanoNeuroRFID environment. (b) Architecture of the implantable NanoNeuroRFID with energy harvesting, clock
source, and radio frequency transmission capability. © [2019] IEEE. Adapted with permission from Ref. [185].
21
transduction factor between the mechanical and magnetic domains is 187].

also important for power optimization along with the mechanical- There are several non-invasive sensing methods that are clinically
electrical transduction because it defines and limits the maximum used which help to understand brain behavior, for example, magnetic
power available for transfer to a resistive load [59]. resonance imaging (MRI), functional MRI, and computer tomography
Two configurations of composite multiferroic structures were inves- [196]. However, controlled millisecond stimulation deep inside the brain
tigated as the transmitter and receiver to introduce the concept of bidi- at a cellular level to match the natural speed of neural spike patterns in
rectional strain-mediated multiferroic wireless energy transfer. the brain is very hard to achieve. Hence, to decipher the mechanisms in
Specifically, a stacked laminate tri-layer PZT/Terfenol-D/PZT was placed the neurobiological systems and dissect various neural diseases, scientists
at the center of a concentric PZT/Terfenol-D hollow cylinder [192]. The have tried exploring the cells using a variety of biologically engineered
first strain-mediated composite multiferroic wireless energy transfer techniques such as magnetic, electrical, genetic, chemical, optical,
configuration was tested by using ring composite as a transmitter and e infrared, and ultrasound stimulations [196]. Although many original
laminated plates as a receiver. In the second configuration, the laminate non-invasive approaches have been explored, the three most popular
plates were used as a transmitter, while the composite ring was a invasive techniques to access deep brain tissues at the cellular level are
receiver. The composite cylinders, in conjunction with laminated plates, electrical, optogenetic, and chemical stimulation, which are initiated
were successfully demonstrated as a novel technology of bi-directional through electric fields, photostimulation, and pharmacological de-
ME-based wireless energy transfer. A peak extracted power of liveries, respectively [196].
~0.1 mW was reported, which is sufficient to wirelessly power a multi- Optogenetics is a cutting-edge tool in neuroscience, which utilizes
tude of small electronic devices [192]. light-sensitive proteins and controlled illumination for neuromodulation
A novel wireless implantable device termed NanoNeuroRFID was also [197]. Optogenetics genetically inserts photosensitive ion channels into a
developed [185] (Fig. 19) with a novel multifunctional implantable neuron’s membrane and modulates the activity of neurons via blue light
design based on ME antennas. The device offers the following important [198,199], which reveals impressive spatial and temporal resolutions
advantages: (1) it operates in the low-frequency range of the electro- and cell-type specificity. However, the tissue-penetrating capability is
magnetic spectrum in which tissue loss is low, and at the same time its limited to a blue light, which usually makes the method invasive and
antenna size is in the μ-scale range; (2) its loss in the skull is small, unlike requires the implantation of a light. The main advantage of optogenetics
ultrasound approach which has a significant loss in bone structures; (3) it is the ability to demonstrate causal relationships by manipulating the
does not utilize contactelectrodes for recording action potential and is activity of specific neurons and observing behavioral phenotypes. An
entirely encapsulated with a biocompatible material such as parylene, optically powered and controlled wireless optogenetic system using
making it superior for long-time recording; (4) it is sub-mm in size and is near-infrared light for a high transmittance through live tissues was
suitable for large-scale (1000–10 000 devices) neural magnetic field shown [197]. In vivo optogenetic stimulations using this system-induced
transmissions with high temporal and spatial resolutions. The compari- whisker movement in channelrhodopsin-expressing freely moving mice,
son of NanoNeuroRFID system with the results on different wireless which confirmed that the photovoltaics-generated electrical power was
implantable devices is presented in Table 3. sufficient, and the remote controlling system was successful. To provide a
In spite of the described above advantages of ME composites and sophisticated optogenetic manipulation of neural circuits throughout the
transducers for wireless power transfer, we believe the potential benefits nervous system with limited disruption of the behavior of an animal,
of the ME effect have still not been studied in detail, which hinders the light-delivery systems beyond fiber optic tethering and bulky
possibility for further implanted devices miniaturization; thus, additional head-mounted wireless receivers are necessary.
research in the field is required. We believe that magnetic field pene- The near-field inductive coupling has been used to power optogenetic
trating through biological tissue without any harmful effect under the stimulators in freely moving mice, which is highly effective when the
range of the specific parameters enables further improvement of ME coils are at or near the surface of the skin [56,200]. However, a relatively
transducers and allows the increase of the transferred power, which is large cross-sectional area (70 mm2) of the receiving coil and sensitivity to
less sensitive to the angular alignment between a receiver and a coil curvature could limit its application in implants that are deep inside
transmitter. the body.
An easy-to-fabricate, implantable wireless optogenetic device was
4.6. Prospective use of ME composites in optogenetics reported in Ref. [172]. Its version (0.02 g, 10 mm3) is two orders of
magnitude lower than the alternative wireless optogenetic systems,
The human brain is one of the most sophisticated and complex or- which allows the implantation of the entire device subcutaneously. When
gans, which exist in nature [180]. Billions of neurons are burned per unit a radio frequency power source and a controller are used, this implant
of time to implement a broad range of objectives and tasks. A better generates sufficient light power for optogenetic stimulation with tissue
understanding of the brain activities and operation mechanisms will heating below 1 C. It is shown that untethered optogenetic control
enable for a human being a lot of functionalities in medicine such as throughout the nervous system (spinal cord, brain, and peripheral nerve
providing communication and interaction between the brain and com- endings) of behaving mice is thus possible, which allows for optogenetic
puter, advanced prosthesis systems, etc. The fundamental part of this experiments in animals behaving naturally with optogenetic manipula-
system understanding is the possibility to record the signals from the tion of both peripheral and central targets [172]. The micro-LED, with
brain with very high temporal and spatial resolutions [187]. emitted light power/input power ~19%, was efficient over the range of
At present, a lot of studies have been done in the field of brain-related light power densities suitable for optogenetic stimulation within the
research over the past several decades, and a variety of tethered and power density range 1–20 mW/mm2.
untethered devices have been proposed to modulate the activity of Remote regulation of optogenetic proteins by a magnetoluminescence
neurons. It has been a great challenge to obtain a high density distributed microdevice has been recently reported [201]. However, most of the
network of tethered (electrical, optical, etc.) devices due to intercon- frequently used microdevices utilize optical, acoustic, and magnetic
nection and wiring constraints related to them. Besides, tethered devices stimuli offer application-specific advantages for neural stimulation and
suffer from safety problems connected with biocompatibility and the recording, as depicted in Fig. 20 [202]. Although optical stimulation and
presence of conductive wires [172,187,195]. On the contrary, a wireless imaging approaches, such as infrared light [203], genetically encoded
approach enables overcoming these challenges. Sufficient progress has opsins [204], and calcium and voltage indicators [205] offer a superior
been recently achieved in the area of wireless neural interface devices. So spatial and temporal resolution, they are limited to penetration depths of
far, electromagnetic and ultrasound are two major approaches available <1 mm owing to tissue absorbance and scattering. Even three-photon
for implantable wireless communication and energy scavenging [185, excitation with a 1675 nm laser can only access brain structures not
22
Fig. 20. A schematic representation of tissue penetration by ultrasonic, optical, and magnetic stimuli. Electromagnetic waves in the visible and near-infrared optical
spectrum allow superior spatial and temporal resolution but limited penetration depth (~1–1.5 mm) [203,205]. Ultrasound allows accessing deeper brain regions
(>5 cm) with a spatial resolution that is inversely proportional to the wavelength, which, in turn, scales inversely with the penetration depth (in general for ul-
trasound, spatial resolution is > 1 mm3, and temporal precision is > 10 ms) [207]. Alternating magnetic fields with low frequencies (<1000 Hz) and high amplitudes
(0.1–2 T) inductively couple to the upper 0.1–1 cm of tissue [208]. Alternating magnetic fields with amplitudes of ~1–100 mT and frequencies in the low radio
frequency range 100–1000 kHz penetrate through tissue unaffected [177]. The temporal precision of neural activity is dependent on the used magnetic scheme [202].
deeper than 1.5 mm [202,206]. independent power source of conventional batteries [214,215]. How-
The genetically encoded cells rapidly and selectively respond to light, ever, the restricted lifetime (~60 months) of a battery may result in
enabling them to remedy various neurological diseases such as epileptic repeated replacements of the discharged battery every several years,
seizure, somnipathy, and Parkinsonism [209–211]. For optogenetic ap- which is a medically critical issue, especially for in vivo conditions [211,
plications, flexible microscale light-emitting diode (f-μLED) with high 216,217].
power efficiency, low heating, and thermal/humid/chemical stability An organic electrolytic photocapacitor (OEPC) to perform chronic
can be an excellent light stimulation tool for freely moving animals by peripheral nerve stimulation via transduction of tissue-penetrating deep-
achieving conformal attachment on the brain cortex surface with mini- red light into electrical signals has been developed to wirelessly modulate
mal invasion [212,213]. The optogenetic stimulation was demonstrated neural tissue [218]. The principle of the OEPC operation is based on
as a form of the implantable electronic system that contains an efficient charge generation by nanoscale organic semiconductors
Fig. 21. (a) Schematic view of experimental

procedures for energy-harvesting optogenetic
brain stimulation. (b) Implantation of f-μLED
array underneath the mouse skull for stimu-
lation of M1 (As a red light-activated chan-
nelrhodopsin variant, Chrimson was
expressed in the primary motor cortex). (c) i)
Video snapshot tracking the whisker move-
ments. The tracking point is shown as a yel-
low circle. ii) Relative whisker movements
via f-μLED stimulation with the operation of
MMTENG. (d) Confocal fluorescent images of
the mouse brain. The top is the expression of
Chrimson and the stimulation site in the
motor cortex, whereas the bottom is a
magnified image for the stimulated M1 site.
Red color signals indicate the expression of
tdTomato (a maker of Chrimson), and the
blue signals represent the DAPI (a maker of
neural cells). © 2020 Elsevier Ltd. Reprinted
with permission from Ref. [212].
23
containing nontoxic commercial pigments. The stimulation parameters Thus, the results revealed that the MMTENG device under a gentle magnetic
typically involve irradiation with pulses of 50–1000 μs with the length field is an efficient energy-harvesting device for the optogenetic f-μLED to
638 or 660 nm, which allows the actuation of the implant of ~1 cm define the functions of mammalian cortical areas. After the optogenetic
below the skin. A rat sciatic nerve model was implemented to benchmark neuromodulation on the mouse brain, a postmortem histological analysis
performance parameters of OEPCs first ex vivo and in vivo. The sustained was done to verify the expression of Chrimson in the M1 region. With the
ability to non-invasively mediate neurostimulation over 100 days was settlement of Chrimson into the M1 neurons, the movement of the mouse
revealed. Thus, OEPC device with an ultralow volume of 0.1 mm3 pro- whisker utilizing the in vivo f-μLED could be practical evidence of successful
vides a high-efficiency biocompatible approach to wireless optogenetic manipulation [221,222]. The top of Fig. 20d reveals a confocal
neuromodulation. fluorescent image of the cortex to investigate the Chrimson injection site,
Magnetic fields are able to penetrate the body tissues without any and an intensive fluorescent red color signal (normally generated by tdTo-
harmful effects which makes their use a perspective in the wireless de- mato; a maker of Chrimson) is seen at the stimulation site of M1. Since the
livery of different stimuli to deep targets [219]. Magnetic stimuli should autofluorescence backgrounds (fixative-generated fluorescence and fluo-
be imperceptible for many organisms, which is advantageous for small rescence of inherent tissue elements) of tdTomato overlapped on both the
animal behavioral experiments, where the subject’s ability to sense the neural cells and brain tissue, the nuclei of the M1 neurons were dyed using
application of a particular stimulus may compromise the obtained re- 40 6-diamidino-2-phenylindole (DAPI) to confirm whether the Chrimson
sults. In optogenetics, where visible light leaking from the waveguides or was expressed from neuronal cells [223,224]. If the DAPI (blue signal) and
scattered by the tissue may be seen peripherally by the subjects. One of Chrimson (red signal) appeared at the same points, it means that these lo-
the goals of magnetic neuromodulation strategies is to offer various cations are Chrimson-modified neurons. The bottom images of Fig. 21d
deep-brain stimulation means with a system that does not rely on a show magnified views of the stimulated M1 region. Even though the DAPI
physical connection to stimulation sites, which enables reduction of the and Chrimson signals are widely distributed in the observed area, several
deep-brain stimulation therapy invasiveness and tissue damage associ- red/blue superimposed signals (marked by white arrows) were discovered
ated with the implanted hardware [219]. on the ‘merged’ image, where successful optogenetic stimulation with the
A wireless magnetic resonance device for optogenetic applications in f-μLED array is demonstrated. In addition, identical brain morphology
an animal model was reported Ref. [220]. In the case of this remote-- confirmed the minimal damage to the frontal motor cortex after f-μLED
controlled wireless device, the electromagnetic field range (i.e., þ5 cm implantation through DAPI staining. These results indicate that the
and 5 cm of the outside coil) is larger than the range for the magnetic energy-scavenging brain photostimulator is a powerful tool for investi-
induction and radio frequency power sources, which allows controlling gating the neuro-muscular interactions and the ethological modulations of
animals’ behavior by the electromagnetic field effective range via pho- mammalians. The continuous optogenetic manipulation by using the
tostimulation. The developed wireless remote-controlled device with a wasted magnetic field, including home, hospital, factory, and infrastructure,
magnetic resonance technique can be used in many behavioral tasks in could be used as a novel therapeutic protocol to derive behavior change or
rats and mice. This novel technique serves as a helpful tool to modulate even treat life-threatening neurodiseases [211]. Thus, to the best of our
the neuronal activity of target neurons in specific brain areas for opto- knowledge, there has been no ME transducer for wireless power transfer to a
genetic experiments without adverse effects of high radio frequency. micro-LED for optogenetic stimulation of various brain activities; however,
A sophisticated optogenetic stimulating system by scavenging the the ME effect was successfully utilized in combination with other energy
wasted magnetic field of the home appliance was reported in Ref. 212. A scavenging approaches reported above and elsewhere [211].
flash-enhanced magneto-mechano-triboelectric nanogenerator
(MMTENG) allowed optogenetic neuromodulation by operating a flex- 5. Future challenges and conclusions
ible micro-light-emitting diode (f-μLED). An optogenetic stimulator
composed of MMTENG and f-μLED was implanted under a living mouse The development of effective methods to enhance bone healing,
skull without mechanical damage [211]. The flash-stamped MMTENG regeneration, and formation of strong bonding with artificial implants
effectively generated an open-circuit peak-to-peak voltage of 0.87 kV and has always been among the most important research areas [114,225,
a short-circuit current of 0.145 mA under a gentle alternating current 226]. Although interesting bone repair strategies have already been
magnetic field of 7 Oe. Maximum peak power of 8.1 mW was observed developed, elaboration of novel smart materials as artificial implants is
from the flash-induced harvester, which was 2.6 times higher than the still challenging because successful implantable materials for bone tissue
non-treated device. The MMTENG generated a rectified output voltage of engineering must meet a specific set of requirements such as bioactivity,
134 V by a 60 Hz stray magnetic field of the home appliance, enabling it biocompatibility, mechanical strength and endurance, microstructure
to operate the f-μLED continuously. The authors verified that the whisker and porosity, as well as other important functional properties such as a
movements of a living mouse were caused by the precise Chrimson quick reaction with its environment once being implanted.
activation in the light-emitted motor cortex. A schematic representation There exist various ME composites for tissue engineering applica-
of experimental procedures to scavenge energy for optogenetic brain tions, which have been developed and studied so far. As an example,
stimulation is presented in Fig. 21. hybrid scaffolds of PHBV and cobalt ferrite nanoparticles after the
Fig. 21a reveals an experimental illustration of the energy-harvesting degradation of the polymer due to the exposition of the CoFe2O4 revealed
optogenetic modulation using a living mouse, f-μLED array operated by suitability for magneto- and electroactive tissue engineering applications
the MMTENG, and a simplified neural pathway corresponding to the [96]. However, cytotoxic effects may occur when the magnetic cobalt
whisker movement. Fig. 21b presents an image of an anesthetized mouse ferrite nanoparticles needed for magnetoactive applications are released.
located on a stereotaxic fixture with the in-vivo f-μLED to stimulate the M1. Thus, the substitution of cobalt ferrite by biocompatible ferrites, such as
For triggering the whisker movement of the mouse, the f-μLED was powered Fe3O4 or toxic element-free ferrites, e.g. MnFe2O4, should be investi-
by the MMTENG with induction of a tiny AC magnetic field of 2.1 Oe at gated. In this case, non-toxic fillers being released will provide no po-
60 Hz, resulting in the energy-harvesting optogenetic system could produce tential cytotoxic effect on cells or tissues. In addition, Fe3O4
red LED light with ~10 ms duration by the rectified MMTENG output signal. nanoparticles are the only metal oxide nanoparticles approved by FDA
During the optogenetic stimulation, the vibration of the whisker was for clinical use [52]. Thus, a widespread application of ME nanoparticles
tracked utilizing video capture and image analysis (Fig. 21c–I, additional should face the challenge of FDA approval. Moreover, mechanical
video is provided in the original paper). Fig. 21c–ii presents the whisker properties of the ME composites can deteriorate, such as compressive
movement triggered via the optogenetic procedure for 2 s (120 frames), and strength and Young’s modulus, which are determined by the rigid
the tip position of the whisker was changed with an alternation during the enhancement effect of ME nanoparticles [52]. As a result, an optimiza-
recoding frames of a 1/60 s interval, which is compared to the control test. tion of the ME filler content in the composite should always be
24
accomplished. contributed to conceptualization, supervision, and funding acquisition.

Electroactive magnetically responsive materials which provide
controlled reactions with the host and degrade within the physiological
environment are still in development [43]. In addition, there are Declaration of competing interest
remaining challenges in the development of biocompatible composite
ME scaffolds for tissue regeneration. Because composite ME materials The authors declare that they have no known competing financial
exhibit both ME and magnetomechanical responses, it is a key to develop interests or personal relationships that could have appeared to influence
experiments that appropriately control and isolate these effects. Also, it is the work reported in this paper.
very important to develop methods to characterize ME materials and
scaffolds to determine the most appropriate surface potential that the Acknowledgments
cells experience to better understand the physiological response [48].
Despite a lot of research on the efficiency of ME composites to control This work was developed within the scope of the project CICECO-
over cell differentiation, the underlying mechanisms of cellular osteo- Aveiro Institute of Materials, refs. UIDB/50011/2020 and UIDP/50011/
genic differentiation caused by magnetization variation for different ME 2020, financed by national funds through the FCT/MCTES. Part of this
composites are still not clear and have to be studied in sufficient detail work was funded by national funds (OE), through FCT – Fundaç~ao para a
[64]. Ciência e a Tecnologia, I.P., in the scope of the framework contract
The properties of electroactive materials vary as a function of fre- foreseen in the numbers 4, 5, and 6 of the article 23, of the Decree-Law
quency, and many biological processes also occur at specific frequencies. 57/2016, of August 29, changed by Law 57/2017, of July 19. The
Thus, it is important to identify and validate testing conditions that most financial support from the Ministry of Science and Higher Education of
appropriately mimic physiological environment [48]. the Russian Federation is acknowledged (grant agreements #075-15-
ME composites provide a microenvironment for the precise control of 2021-588 from 1.06.2021).
bone regeneration in situ, which holds much promise for achieving effi-
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Materials Today Bio 12 (2021) 100149

Contents lists available at ScienceDirect

Materials Today Bio

Magnetoelectric effect: principles and applications in biology and medicine–

1. Introduction strong ME effects at room temperature [15,16], which is of particular

electroactive materials in neuronal wound healing environments can be

Fig. 8. Effect of magnetic stimulation of 3D

Fig. 12. Immunohistochemistry images

Fig. 15. Illustration of steps of the

Fig. 17. (a) Finite element analysis simulation model of

transduction factor between the mechanical and magnetic domains is 187].

Fig. 21. (a) Schematic view of experimental

accomplished. contributed to conceptualization, supervision, and funding acquisition.

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