REVIEW

Magnetic Nanoparticles www.advhealthmat.de

Advances in Magnetic Nanoparticles for

Biomedical Applications
Vanessa Fernandes Cardoso, António Francesko, Clarisse Ribeiro, Manuel Bañobre-López,
Pedro Martins,* and Senentxu Lanceros-Mendez

1. Introduction
Magnetic nanoparticles (NPs) are emerging as an important class of biomed-
ical functional nanomaterials in areas such as hyperthermia, drug release, Nanoparticles (NPs) are particles having at
tissue engineering, theranostic, and lab-on-a-chip, due to their exclusive least one dimension in the nanometer size
range up to ≈100 nm.[1] Such nanoentities
chemical and physical properties. Although some works can be found
are categorized by high surface-area-to-
reviewing the main application of magnetic NPs in the area of biomedical volume ratio and are therefore particularly
engineering, recent and intense progress on magnetic nanoparticle research, strong, versatile, and reactive, when com-
from synthesis to surface functionalization strategies, demands for a work pared to the bulk state. These specific
that includes, summarizes, and debates current directions and ongoing properties offer new and interesting possi-
bilities of optimizing optical, mechanical,
advancements in this research field. Thus, the present work addresses the
and magnetic properties of NPs, among
structure, synthesis, properties, and the incorporation of magnetic NPs in others.[1,2]
nanocomposites, highlighting the most relevant effects of the synthesis on Particularly, magnetic NPs are of large
the magnetic and structural properties of the magnetic NPs and how these interest, having successfully demonstrated
effects limit their utilization in the biomedical area. Furthermore, this review their utility in a widespread range of appli-
next focuses on the application of magnetic NPs on the biomedical field. cations, namely magnetic fluids, magnetic
energy storage, catalysis, environmental
Finally, a discussion of the main challenges and an outlook of the future
remediation, magnetic inks, and magnetic
developments in the use of magnetic NPs for advanced biomedical applica- resonance imaging (MRI) (Figure 1).[3–7]
tions are critically provided. A large interest on those inorganic
nanomaterials with metal-based configu-
ration emerges once they can be simply
Dr. V. F. Cardoso, Dr. A. Francesko, Dr. C. Ribeiro, Dr. P. Martins manipulated using alternating current magnetic field and later
Centro de Física engaged in such numerous applications.[1] Progress in nano-
Universidade do Minho
technology and nanoparticle research field allows us to syn-
4710-057 Braga, Portugal
E-mail: pmartins@fisica.uminho.pt thesize magnetic NPs with precise morphology and to suitably
Dr. V. F. Cardoso modify particle surfaces, manipulating their characteristics for
MEMS—Microelectromechanical Systems Research Unit precise applications. For example, green chemistry methods
Universidade do Minho are already being used to synthesize magnetic dextran-coated-
4800-058 Guimarães, Portugal gadolinium nanoparticles at low temperature (up to 80 °C) for
Dr. C. Ribeiro biomedical applications on the whole body level, sparkling the
CEB—Centre of Biological Engineering
University of Minho kidneys, liver, spleen, tumor, and tumor angiogenesis without
Campus de Gualtar promoting toxicity (Figure 1).[6] Other extensive studies have
4710-057 Braga, Portugal been carried out, and protocols have been developed aiming the
Dr. M. Bañobre-López optimization of magnetic nanoparticle characteristics such as
INL—International Iberian Nanotechnology Laboratory composition, surface charge, shape, size and size distribution,
4715 Braga, Portugal
and magnetic properties.[8]
Prof. S. Lanceros-Mendez
With the latest evolution and demands of nano-biotech-
BCMaterials
Parque Científico y Tecnológico de Bizkaia nology, magnetic NPs are attracting increasing attention due to
48160 Derio, Spain their potential to improve conventional therapeutic procedures
Prof. S. Lanceros-Mendez and traditional clinical diagnostic, as well as to introduce novel
IKERBASQUE approaches in biomedicine and tissue engineering (TE).[2,9]
Basque Foundation for Science Magnetic NPs are typically classified into pure metals, metal
48013 Bilbao, Spain
oxides, and magnetic nanocomposites. The most popular mag-
The ORCID identification number(s) for the author(s) of this article
netic NPs in the biomedical field are Co, Fe, Ni, Ti, iron oxide,
can be found under https://doi.org/10.1002/adhm.201700845.
and some ferrites (BaFe12O19 and CoFe2O4). Among them, iron
DOI: 10.1002/adhm.201700845 oxide NPs (typically Fe2O3 or Fe3O4) are the most used due to

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their lower toxicity.[9] The key issues affecting the biocompati-

bility and toxicity of such materials are the characteristics of the Pedro Martins graduated in
component that is magnetically reactive, such as cobalt, iron, Physics and Chemistry in
nickel, samarium–cobalt, or neodymium–iron–boron, the size 2006 and received the Ph.D.
of the NPs, and their coating and core.[2] Knowing that mag- degree in Physics in 2012,
netic NPs can reveal novel phenomena, such as super-paramag- from the University of Minho,
netic behavior, high magnetic field irreversibility, and additional Braga, Portugal. He is now
anisotropic contributions,[2] the specific biomedical application a PostDoc researcher in the
is determined by the distinct magnetic properties. Such proper- University of Minho, Braga,
ties are, in turn, ruled by the type of magnetic nanoparticle, the Portugal and his work is
synthesis procedure, the interaction between NPs, and the focused on polymer-based
nano­­particles’ size, shape, and distribution. In this way, an magnetoelectric materials
appropriate synthesis procedure must be selected to achieve and electroactive polymers
specific and precise performance.[1] for advanced technological applications. He collaborates
From the different magnetic NPs that have been devel- with the Basque Country University, Spain; Wollongong
oped, the ones that exhibit fast change of magnetic state with University, Australia; and Cambridge University, UK, among
the application of an external magnetic field and no rema- others.
nence at room temperature (super-paramagnetism) are usually
desired.[5,10] Thus, these NPs must combine high magnetic sus-
Senentxu Lanceros-Mendez
ceptibility and loss of magnetization after removal of the mag-
was born in Bilbao, Spain.
netic field.[11]
He graduated in physics at
The appropriate functionalization of the magnetic NPs for
the University of the Basque
biomedical applications is ruled not only by their intrinsic
Country, Leioa, Spain. He
magnetic properties (magnetic saturation (Ms) and Curie
obtained his Ph.D. degree at
temperature (Tc)) but also by their biophysical properties (col-
the Institute of Physics of the
loidal stability, nontoxicity, specific absorption rate (SAR), and
Julius-Maximilians-Universität
biocompatibility) under pH conditions similar to the physio-
Würzburg, Germany. He
logical ones. To avoid magnetic NPs’ agglomeration, considera-
was a Research Scholar at
tions on the nanoparticle surface chemistry must be taken into
Montana State University,
account and should be stabilized by covering them with dif-
Bozeman, MT, USA and a
ferent types of materials, including inorganic and organic coat-
visiting scientist at The Pennsylvania State University, USA
ings.[1] Additionally, demands from the biomedicine require
and University of Potsdam, among others. He is Associate
magnetic NPs that are water stable at pH ≈ 7 and with salinity
Professor at the Physics Department of the University of
values close to the physiological ones. Such colloidal stability
Minho, Portugal (on leave), and from 2012 to 2014 he
will be dependent on NPs’ dimensions, surface chemistry, and
was also Associate Researcher at the INL—International
charge.[12] Other limitations or requirements strongly rely on
Iberian Nanotechnology Laboratory. Since 2016, he has
the use of the NPs, whether for in vitro or in vivo applications.
been Ikerbasque Professor at the BCMaterials, Basque
In the case of in vitro applications, the limitations are not as
Center for Materials, Applications, and Nanostructures,
restricted as in the in vivo case. For in vivo applications, the
Derio, Spain. His work is focused on the area of smart and
magnetic structures need to be covered with a biocompatible
functional materials for sensors and actuators, energy, and
polymer (if the nanoparticle is not biocompatible) after or
biomedical applications.
during the synthesis procedure to avoid toxicity, decrease the
risk of blood capillary obstruction, and prevent nanoparticle
aggregation.[5,9]
Due to their super-paramagnetism, some magnetic
NPs can be precisely collected in a desired location by an bridging sites for adjusting Trastuzumab, respectively, that
applied magnetic field, which is essential for target drug and represented a key paradigm development in cancer treatment
gene delivery,[9,13,14] allowing new therapeutic approaches and nanocarrier design in a preclinical application environ-
of merging multistage short-term magnetic control and ment (Figure 2).[14]
directing with enhanced mediated-ligand targeting in Furthermore, magnetic NPs are being developed for hyper-
recently developed nanodelivery systems.[14] A good example thermia and heat-activated drug release as a result of their
of such attractive capacity of super-paramagnetic NPs is the heating ability in high-frequency magnetic fields.[9,15]
synthesis of Trastuzumab-functionalized DOX-encapsulated Large efforts are being spent on the improvement of hyper-
magnetic nanocapsules (T-DOX-MNCs) through a simple thermia techniques for clinical uses. Advances in magnetic nano­­
double emulsion process reported by Chiang et al. The particle research contributed to the fast and, sometimes, dis-
authors have used synthesized antibody-targeted super-par- ruptive development of magnetic hyperthermia (MH), making
amagnetic iron oxide nanoparticles and poly(vinyl alcohol) this technique a promising tool for cancer treatment due to
(PVA)/poly (methacrylic acid), which include the capacity the possibility of targeting cancerous tissues. This approach
of magnetically targeting tumor localization and adequate leads to lower side effects than traditional radiotherapy and

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Figure 1.  Scheme of the synthesis of gadolinium-based NPs and their magnetic resonance imaging performance at the whole body level, tumor, and
tumor angiogenesis. Reproduced with permission.[6]
chemotherapy. Similarly, controlled drug release trough magnetic
NPs has an essential role in the future of personalized medi-
cine; once recent/ongoing clinical tests revealed substantial
reduction of such side effects (nausea/vomiting, fatigue, con-
stipation, and fever/chills).[16,17] The outstanding safety profiles
and appropriate magnetic properties of super-paramagnetic
iron oxide nanoparticles make them very good platforms for
the design of cancer treatments that have negligible side effects
and with the capacity to target cancers that cannot be obtained
by other types of nanostructures.[17]
Due to the synergic effect of magnetic NPs on cell’s differ-
entiation, proliferation and adhesion, one of the most popular
areas of investigation in the biomedical field is the development
of functional tissue engineering systems that can be triggered
by an external magnetic field.[18]
Regarding the use of magnetic NPs for theranostic, NPs
have the ability of providing in vivo real-time information,
drug administration, optimal dosage selection, and therapeutic
response monitoring, though there are still some missing
improvements in order to ensure successful clinical applica-
tions. As the capabilities and multifunctionality of magnetic
NPs for theranostic continue to growth, it is expected that this
research field will play a key role in the new era of personal-
ized medical care by allowing more efficient diagnostic and
therapeutic strategies.[19] In addition to this promising future,
encouraging results are already started to appear as the quan-
titative analysis performed by Peng et al.[20] which proves the
ability of multifunctional iron oxide nanoparticles modified
with YGRKKRRQRRR (TAT) peptide to obtain higher accumu-
lation in the nuclei, when compared to iron oxide nanoparti-
cles without modification (Figure 3). Furthermore, the TAT-
modified multifunctional iron oxide nanoparticles were found
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to be not only able to be used as agents for near-infrared (NIR)
fluorescence imaging but also for MRI. After in vivo studies,
the composite multifunctional nanoparticles were capable of
ablating tumor xenograft effectively with NIR laser exposure
and can be used in the future for cancer treatment studies.
Additionally and closely connected to the theranostics con-
cept, lab-on-a-chip (LOC) technologies are assumed as one of
the most relevant potential tools for in vitro medical analyses.
Nevertheless, the integration of truly multifaceted functions in
a very narrow space still remains challenging. NPs are an inno-
vative option, allowing noncontact manipulation of physical,
chemical, and biological samples.[21]
Despite some reviews that can be found on the applica-
tion of magnetic NPs in the biomedical area, recent progress
on magnetic NPs, from synthesis to surface functional strate-
gies and applications, demands for a comprehensive work that
includes, summarizes, and discusses current directions and
ongoing advances in this interesting and fast-growing research
field.
In this way, the first part of this review deals with the
structure, synthesis, and properties of magnetic NPs, as
well as their incorporation into nanocomposite systems. A
particular emphasis will be given to the most pertinent syn-
thesis effects on the structural and magnetic properties of the
magnetic NPs and how they limit their use in the biomedical
area. The second part will focus on the biofunctionalization
and technological application of such magnetic NPs in hyper-
thermia, drug release, tissue engineering, theranostic, and
lab-on-a-chip.
Finally, a brief summary and some future perspectives and
trends in the use of magnetic NPs for advanced biomedical
applications will be outlined.
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Figure 2.  Schematic representation of the functionality and synthesis of dual-targeting T-DOX- multifunctional magnetic nanocarriers and the influence
of modulating the trastuzumab density and respective use on intratumoral distribution. Reproduced with permission.[14]

2. Magnetic NPs
2.1. General Structure
NPs are submicrometer moieties made of organic or inorganic
materials and with unique characteristics compared to their
bulk counterparts. Besides their intrinsic nanoscale physical
phenomena, their often exhibit exceptional optical, electrical,
magnetic, and chemical properties, attracting vast attention in
many biotechnological areas,[22–24] such as magnetic resonance
imaging,[25,26] drug delivery systems,[27,28] hyperthermia[29,30]
and labeling and separation of cells[31,32] and proteins,[33,34]
among other biological entities.[35,36] Different kinds of NPs,
such as quantum dots,[37] carbon nanotubes,[38] gold NPs,[39]
silica NPs,[40] polymeric NPs,[41] and magnetic NPs (MNPs)[42]
have been designed and synthesized.
In particular, MNPs are a class of nanomaterials with the
potential to revolutionize the biomedical field due to their
multi­functional properties such as small size, high operational
surface areas, low sedimentation rates, and optimized tissular
diffusion, and because they can be manipulated under an
applied magnetic field. Such MNPs have been prepared using
different compositions and phases, involving pure metals such
as Fe, Co, Ti, and Ni; metal oxides such as Fe3O4 and γ-Fe2O3;
ferrites such as BaFe12O19, SrFe12O19, and MFe2O4 (M cor-
responds to Cu, Ni, Mn, Mg, among others); and metal alloys
such as CoPt and FePt.[9,43] Highly magnetic-responsive mate-
rials, such as Co and Ni, are toxic and are liable to oxidation,
which impedes their use in most of the biomedical applications.
On the other hand, iron oxide NPs, namely magnetite (Fe3O4)
and maghemite (γ-Fe2O3), are the most extensively studied and

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Figure 3.  Schematic illustration of iron oxide NPs-YGRKKRRQRRR-peptide- covalently conjugating trans-ferrin (IONP-TAT-Tf) synthesis and nuclear
targeted approach aiming operational cancer therapy. Reproduced with permission.[20]
applied ones in the biomedical field for their biocompatibility,
super-paramagnetic behavior, and chemical stability at room
temperature.[43] Magnetite shows a cubic symmetry with the
spinel structure (Figure 4a). The oxygen atoms are arranged in
a face-centered cubic (fcc) lattice, where the Fe2+ ions occupy
half of the octahedral sites and Fe3+are split evenly across the
remaining octahedral sites and tetrahedral sites. Maghemite
is the fully oxidized form of magnetite and shows an inverse
spinel structure with some cation deficiency (Figure 4b). Thus,
the structures of maghemite and magnetite are similar but
with vacancies, where Fe3+ ions are still occupying octahedral
and tetrahedral sites, but the vacancies of maghemite have a
preference for the octahedral sites. Specifically, one out of every
six octahedral sites in magnetite is vacant in maghemite struc-
ture.[44] Magnetite is sensitive to oxidation and usually trans-
forms to maghemite in the presence of oxygen. The oxidation
happens frequently from the migration of the positive ions
through the lattice framework. Under such an oxidation pro-
cedure, the cationic vacancies will be formed to maintain the
charge.[45]
Figure 4.  Crystalline structure and crystallographic data of the a) mag-
netite and b) maghemite (the black spheres are Fe2+, the green spheres
are Fe3+, and the red spheres are O2−). Adapted with permission.[44]
Copyright 2015, IOP Science.
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2.2. Magnetic Considerations
The property of super-paramagnetism is beneficial over fer-
romagnetism for several biomedical applications, as super-
paramagnetic NPs show a high magnetic moment and work
as a giant paramagnetic atom with a fast response to external
magnetic fields with insignificant coercivity and remanence at
room temperature.[46,47] Nevertheless, ferromagnetic NPs can
be super-paramagnetic when they show single domains, typi-
cally with sizes below 20 nm.[48] However, an inevitable issue
associated with particles in this size range is their intrinsic
instability and trend to aggregate in order to minimize the high
surface energy resulting from their large surface-to-volume
ratio.[49] Moreover, naked iron oxide NPs are chemically highly
active and easily oxidized in air, resulting, usually, in a loss of
magnetism and dispersity. Thus, for most of the applications,
proper surface modifications or coating—using, for example,
surfactants, polymers, silica, or carbon—are required to retain
the stability of the MNPs, especially in water at pH ≈ 7 and
physiological environment.[4] In almost all cases, the used shell
not only stabilizes and protects the MNPs from biodegradation
but can also confer biocompatibility or high surface area for fur-
ther functionalization with other NPs or ligands, depending on
the desired application, giving rise to complex coated and mul-
tiple functional surface engineered MNPs.[50] They can bind to
proteins, antibodies, enzymes, nucleotides, or drugs enabling
some exciting new approaches for bioseparation, biodetection,
and targeted drug delivery, and can be absorbed to an organ,
tissue, or tumor using an external magnetic field.[51,52] In addi-
tion, they can also respond resonantly to alternating magnetic
fields (AMFs) and function as a heater, offering a promising
therapeutic for use in hyperthermia.
2.3. Main Synthesis Methods
Several synthesis methods have been developed over the
years to obtain MNPs with controllable size, size distribu-
tion, shape, surface chemistry, magnetic characteristics, and
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reproducibility.[43] In fact, from a fundamental scientific point
of view, the synthesis of uniform-sized NPs with controllable
size, shape, and surface is very important in many biotechno-
logical fields and is generally challenging. Moreover, they must
be made of a nontoxic and non-immunogenic material and
when it comes to in vivo applications, MNPs should be small
enough to be stable in the biological circulation and to transit
via the capillary systems of tissues.[53] A short review of some
common procedures used for the synthesis of MNPs is sum-
marized in the following sections.
The coprecipitation technique is perhaps the mostly adopted,
simplest, and most efficient chemical pathway to synthesize
MNPs with an average diameter below 50 nm from aqueous
salt solutions.[54] Technically, the synthesis procedure is car-
ried out by a stoichiometric mixture of ferric and ferrous salts
in aqueous solution, followed by the addition of a base, e.g.,
NH4OH or NaOH to form MNPs, following a chemical reaction:
M2+ + 2Fe3+ + 8OH− → MFe2O4 + 4H2O, where M represents
Fe2+, Co2+, Cu2+, Zn2+, Mn2+, or Ni2+.[55] After the pioneering
work developed by Massart in 1981,[56] numerous investigations
have been performed not just to study and optimize the effects
of the synthesis parameters such as the nature and concentra-
tion of salts, pH and ionic strength of the medium, reaction
temperature, presence of oxygen, injection flux rates, but also
adapting the procedure itself [57–59] in order to control and tailor
the size, shape, morphology, magnetic behavior and composi-
tion of the MNPs.[11,60,61] In addition, surfactants or polymers
have been introduced in the reaction in order to control and
stabilize the surface of the MNPs to avoid NPs aggregation and
to increase biocompatibility.[60,62] Despite the successful produc-
tion of MNPs at high process yield and high magnetization,
MNPs with broad size distributions and irregular morphologies
are usually obtained by coprecipitation.[45]
High-temperature thermal decomposition appears as an
interesting alternative procedure to obtain monodispersed
NPs with high level of size control, shape, and high crystal-
linity. In this approach, organometallic precursors, such as
[Mn+(acetylacetonate)n] (M is Fe, Mn, Co, Ni, or Cr; and n corre­
sponds to 2 or 3; Mx(N-nitrosophenylhydroxylamine)x) or car-
boxyls (such as Fe(CO)5 or Fe(Cup)3) are decomposed inside
a nonpolar boiling solvent with the presence of a stabilizer
such as oleic acid, 1-octodecene, hexadecylamine, under high-
temperature conditions.[44,63,64] The stabilizer has the ability
to slow down the nucleation process, which may inhibit the
growth and favor the formation of MNPs with a spherical
shape and a size of <30 nm. Decomposition of precursors
with cationic metal centers leads directly to metal oxide NPs,
while organometallic precursors in which metal has zero
valence in their composition initially lead to the formation
of metal NPs, but when followed by oxidation they can lead
to high-quality monodispersed metal oxides.[65] Three main
factors control the size and shape of the obtained MNPs,
which include the decomposition temperature, the precursor/
capping agent ratio, and the duration of the reaction after
reaching the boiling point.[44,66] Despite the referred advan-
tages, thermal decomposition usually leads to complicated
processes at relatively high temperatures and to the produc-
tion of organic-soluble MNPs that may limit their applica-
bility in the biomedical field.
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Hydrothermal processes are used to synthesize MNPs in
aqueous media in reactors or autoclaves at high temperatures
(higher than 200 °C) and high pressure (higher than 2000 psi),
resulting in a rapid nucleation and fast growth of the newly
formed MNPs, which therefore lead to the formation of small-
sized MNPs.[67,68] Hydrolysis and oxidation is one main route
adopted for forming MNPs under hydrothermal synthesis, this
being the neutralization of mixed metal hydroxides other highly
used route.[11] After the completion of the reaction, the auto-
claves are cooled down to room temperature, and the MNPs are
washed with several solvents to eliminate impurity agents.[53,69]
However, Since the reaction undergoes in an automatic way,
it is challenging to understand the hydrothermal processes
through their mechanistic principles, which, in turn, is diffi-
cult for the development of a universal theoretical framework,
remarkable progresses have been achieved in the synthesis of
MNPs by hydrothermal techniques in order to better control
the MNP phases and morphologies by properly studying and
optimizing relevant experimental conditions such as tempera-
ture, reaction time, reactants concentration, stoichiometry, and
nature of the solvent, among others.[70] Moreover, adaptation
of the hydrothermal processes has been carried out to increase
the kinetics of crystallization by means of localized microwave
heating, resulting in a more convenient and fast reaction time
in comparison with conventional hydrothermal methods.[71,72]
Microemulsion is an alternative method used to synthesize
shape and size-controlled MNPs based on an isotropic and
thermodynamically stable systems composed by two immis-
cible phases: a polar phase—usually water—and a nonpolar
phase—commonly oil—in the presence of a surfactant.[73] The
surfactant molecules, which commonly include cetyltrimeth-
ylammonium bromide, bis(2-ethylhexyl) sulfosuccinate, poly-
vinylpyrrolidone (PVP), produce a monolayer at the water–oil
interface, with the hydrophobic tails of the surfactants dis-
solved in the oil phase and the hydrophilic head groups in the
aqueous phase.[44] In such a system, where the polar aqueous
phase could contain metal salts or/and other compounds, the
oil phase may be composed by a complex mixture of olefins
and hydrocarbons.[44] The two basic types of microemulsions
are based on oil droplets dispersed in a persistent water phase
(o/w) and water droplets dispersed in a persistent oil phase
(w/o).[74] Thus, the nanodroplets, employed as nanoreactors,
create an appropriate environment for controlled nucleation
and growing of MNPs.[65,75] The walls of the nanodroplets
made by the surfactant molecules act as cages for the growing
course, reducing the average size of the particles during the
collision and aggregation processes. Therefore, the size and
dynamic formation of the MNPs can be easily controlled by the
droplet size, initial concentration of reactants, and the nature
of surfactants.[76,77]
In addition to these popular methods, MNPs have been suc-
cessfully synthesized by means of other techniques including
chemical vapor deposition,[78,79] combustion,[80,81] carbon
arc,[82,83] electrochemical synthesis,[84,85] laser pyrolysis tech-
niques,[86,87] microbial synthesis[88,89] and in lab-on-a-chip sys-
tems,[90,91] among others. Representative published reviews
concerning existing synthesis routes to obtain MNPs along
with their physicochemical properties, toxicity, and biocompat-
ibility can be found in refs. [11,44,45,55]. The magnetization and
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coercive field of different representative magnetic nanoparticles
used in the biomedical field can be consulted in ref. [92].
2.4. Biofunctionalization
Besides the need to produce NPs with required size, shapes,
and monodispersity, for biomedical applications, it is of para-
mount importance that NPs are also biocompatible. Coating of
NPs is a strategy to prevent or reduce toxicity and undesired
toxic side effects.[93] Nevertheless, biofunctionalization of mag-
netic NPs is not only directed to improve the biocompatibility
with cells, but also to modify the cell interaction processes,
pharmacokinetics, and biodistribution of the NPs.[94,95] For
instance, the residence time of circulating iron oxide NPs can
be doubled by simple functionalization with “stealth” polymer,
polyethylene glycol (PEG), while at the same time, the particle
accumulation in different organs can be reduced.[96] The (bio)
functional layers that shell magnetic nanoparticle cores aim at
(i) protect the therapeutic and targeting agents during the circu-
lation in the body, (ii) improve their delivery efficiency, and (iii)
avoid undesired accumulation in important organs.
Surface of MNPs can be engineered to feature multifunc-
tionality combining, e.g., prevention, diagnosis, and treatment
of diseases. Intrinsic properties of MNPs allow for external
control and targeting the desired cells/tissues via the magnetic
core, which, at the same time might be also explored as an MRI
contrast agent. On the other hand, a biocompatible coating pro-
vides a therapeutic effect.[97] If a surface charge is imparted to
these nanostructures, it may further contribute to colloidal sta-
bility, circulation time, cellular uptake and/or nontoxicity. Most
unmodified MNPs show low stability and easily form aggre-
gates, which negatively affect the reactive surface area, bio-
availability, and toxicity.[98] Surface modifications are directed
to increase stability and provide functional groups for biocon-
jugation; however, this may also lead to a decrease in magnetic
response due to the coating thickness.[99] The most studied
surface coatings are polymer based, including dextran and its
derivatives,[100,101] PEG and PEG copolymers,[102] proteins,[103]
and antifouling polymers.[104] Dextran was the first extensively
investigated biopolymer to coat MRI-contrast MNPs, studied,
among others, in experimental animal models and in humans.
Similar to PEG, dextran enables long-circulating properties for
systemic delivery of iron oxide NPs with suitable accumulation
rates in tumors for MRI detection.[105] Long circulation is espe-
cially useful for nontargeted detection nanosystems, as proved
for dextran-coated super-paramagnetic iron oxide NPs used as
MRI contrasts for the detection of liver tumors or lymph node
metastases in humans.[106–108] Anti-biofouling surface modifica-
tions have been shown to best reduce nonspecific interactions
of magnetic NPs with serum proteins and macrophage uptake
during systemic delivery. Specially designed low-fouling PEG- or
polyethylene glycol (PEO)-copolymeric systems, besides biocom-
patibility and tumor-targeting ability, provide exceptionally long-
circulated times in vivo with significantly reduce nonspecific
binding to serum proteins and uptake by macrophages in the
liver and spleen.[104,109] Studies show that nanoparticle surface
charge plays also an important role in interaction with a wide
variety of biological molecules during circulation. Positively
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charged iron oxide NPs form aggregates easily and are more
likely to interact with usually negatively charged cell surfaces
and facilitate nanoparticle uptake by cells. Repeated systemic
administration of high-concentration positively charged NPs
may lead to enhanced nonspecific uptake into cells, causing
toxicity in normal tissues.[110,111] Neutral and negatively charged
NPs, on the other hand, are recommendable for the production
of targeted nanoparticle-imaging probes and drug carriers for
in vivo applications, especially in cases where long circulation
times through blood are required.[112] Finally, various proteins,
such as human serum albumin,[103] have also been tested for
nanoparticle coating to study cell labeling. Proteins are excellent
choice once, besides stabilization of magnetic NPs, they offer
availability for a wide variety of functional groups, for further
functionalization routes with drugs or other active agents. In
addition, proteins being natural polymers are easily cleared from
the body and dissociate in cells allowing agglomeration of mag-
netic NPs inside the target to enhanced MRI contrast effect.[113]
Toxicity remains the major concern for nanosystems in
biomedical applications, although in vivo studies on animals
repeatedly show minimal damage in the case of MNPs. In vitro
and in vivo studies raised initial concerns after discovering that
many NPs, including the magnetic ones, induce formation of
reactive oxygen species (ROS) after internalization into cells,
which results in the alteration of the levels of expression of
cell proliferative responsive genes.[114] Biocompatible coatings
reduce to different extents the toxicity following administra-
tions, as shown by in vivo studies on mice and monitoring the
no long-term toxicity in the major organs. Different response of
organs to exposure to NPs is due to their different biodistribu-
tion following administration. It has been also shown that non-
targeted super-paramagnetic iron oxide NPs accumulate mostly
in liver (86%) and spleen (6.2%), interestingly already within
1 h following intravenous injection. For a half-life of 3–4 d, it
is necessary to be cleared out from these organs, whereas the
incorporation of nanoparticles into hemoglobin of erythrocytes
raises more concerns.[115] Furthermore, studies of targeted mag-
netic NPs show a lack of apparent systemic toxicity even after
long-term subjection to administration (up to 3 months).[116]
These investigations encouraged safety, biodistribution, and
pharmacokinetic studies of approved magnetic NPs in human
patients. Super-paramagnetic iron oxide nanoparticle-based fer-
umoxytol, an Food and Drug Administration (FDA)-approved
agent for treatment of iron deficiency anemia,[117,118] was clini-
cally tested in over 2000 patients for MRI detection of lymph
node metastasis. The studies revealed safe doses for adminis-
tration (2.9 mg Fe per kg in humans), while it was previously
demonstrated that NPs with 30 nm in size were uptaken by
the macrophages in the spleen, liver, and lymph nodes.[119]
Magnetic-iron-based NPs thus will likely show lower safety con-
cerns than other nanomaterials for the translational develop-
ment of new theranostic agents for image-guided and targeted
cancer therapeutic approaches.[120]
The FDA- or Europe-approved MNP-based formulations are
paving the way for other similar formulations and different
biomedical applications. Careful formulation and considera-
tion of biofunctional components to the shell of the magnetic
cores allow for identification of the most suitable solutions
based on the expected performance of the multifunctional
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www.advancedsciencenews.com
NPs.[121] Targeted accumulation at the site of interest with
minimal losses during circulation is necessary to achieve pre-
cise diagnosis of diseases and eventually real-time monitoring
of the treatment efficacy, the cornerstone of the personalized
therapy concept, while using toxicity-free concentrations. The
multifunctional NPs should be further designed as carriers
to protect the therapeutics against cleavage in the body, i.e.,
premature degradation during the circulation.[122] However,
advances in the multifunctionality concept are the key to clin-
ical and market product approval. Overall, substantial research
efforts are being carried out to integrate nanoparticle systems
with multiple functionalities, resulting in relevant advances in
the field. However, obstacles such as nonspecific distribution
and inadequate accumulation of actives are still important chal-
lenges to overcome.
2.5. Nanocomposites
There is a significant scientific and technological interest on
developing nanocomposite materials based on the coordination
of magnetic inorganic components and organic compounds.
The implementation of inorganic components into the bulk
organic matrix without affecting their intrinsic properties can
provide high-performance novel materials for biomedical pur-
poses. Magnetic NPs typically suffer of low processability in
terms of shaping and adapting to a particular application.
Many organic compounds found in nature, such as polymers
and polyphenols, are more flexible components extracted or
produced at a low cost. They allow easy processing and can be
shaped into a wide variety of materials using traditional and
advanced processing methods. The integration of inorganic
NPs into an organic matrix would thus open new possibilities
for exploiting functionalities of both in a combined composite
material.
Techniques for materials assembled by supramolecular
coordination chemistry between polyphenols, found in many
plants and different metal species (e.g., metal ions), became
the matter of interest for numerous applications. On its basis,
this assembly is inspired from nature’s organic/inorganic com-
posites with high mechanical strength found in squid beaks
and mussel thread coatings. The recent interest led to the
development of thin films with advanced and dynamic proper-
ties. Importantly, this supramolecular self-assembly occurs in
one step and can serve for material development or coating
of various interfaces, including a range of planar, biological,
organic, and inorganic particle templates. Material develop-
ment is started by the polyphenol adsorption and controlled by
pH-dependent and multivalent coordination bonding.[123] More-
over, this self-assembly is achieved in aqueous medium within
minutes; thus, the technique is low cost, scalable and combined
with pH responsiveness of materials and negligible cytotoxicity,
and makes these materials very useful for technological bio-
medical applications.
Self-assembly via polyphenol coordination of a variety of
metal species indeed offers the possibility of fabricating supra-
molecular materials customized for desired properties,[124,125]
including stimuli-responsiveness. Such supramolecular
materials are currently investigated for drug delivery,[126–128]
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cytoprotection,[129,130] and imaging purposes.[126] The current
state-of-the-art indicates that although the process of metal–
phenolic coordination is thoroughly studied, the engineering
of functional materials using this coordination and simultane-
ously addressing different biofunctional requirements is still in
its infancy. As the properties of the assembled supramolecular
networks largely depend on the coordinated metal species,
the next challenge is to master the coordination in order to
tailor materials with desired functional properties.[131] How-
ever, developing bulk materials with combined mechanical and
functional properties remains a significant challenge. Excellent
trials are being carried out with the development of a class of
metallogels formed by direct gelation of tannic acid polyphenol
and different metal ions. These metallogels combine self-
healing properties with transparency, while various materials
can be added by in situ cogelation to increase the robustness
and flexibility required in a variety of chemical, biomedical, and
environmental applications.[132]
Perhaps the most straightforward approach to fabricate
bulk materials with the required characteristics is the direct
assembling of metal NPs with polyphenols, as both structural
and functional components. In the case of MNPs, their fea-
tures could be explored directly within the material. In addi-
tion to the intrinsic magnetic properties, these NPs can serve
as centers of multiple coordination and hence exhibit localized
increased functionality (Figure 5). Nevertheless, the excellent
performance of magnetic NPs in nanomaterial and biomedical
applications often relies on achieving the attachment of suit-
able polyphenolic ligands to the nanoparticle surface both in
sufficient numbers and with proper orientation.[133] The nature
of ligand binding does not only solely depend on the presence
of suitable functional groups, but also on relative positioning of
these groups within the ligand and dynamics of ligand exchange
on the nanoparticle surface. This is probably the reason why
the literature is still scarce on direct incorporation of magnetic
NPs into polymer-based coordinated materials, and this review
will briefly highlight the most representative findings in fabri-
cation of surface coatings and hydrogel nanocomposites.
A chitosan–polyphenol conjugate was synthesized by Zvarec
et al.[134] for the coordination of super-paramagnetic iron oxide
NPs in an organic/inorganic bio-nanocomposite. This hybrid
material mimics the interfacial chemistries of squid beaks
and mussel thread coating. The MNPs offered a significant
improvement in the functionality of the biomaterial conjugates,
whereas inorganic/organic interface was strengthened by coor-
dination bonding, resulting in a nanocomposite that able to
support challenging physiological pH conditions and exhibits
great thermal stability at high temperatures. The presence
of super-paramagnetic nanoparticles also made composites
stimuli-responsive.[134]
Another study that demonstrated a universal strategy for the
encapsulation of inorganic NPs, including iron oxide ones, into
distinct polymer phases was reported by Yabu et al.[135] These
NPs were independently encapsulated in two distinct mussel-
inspired amphiphilic copolymers. After inorganic–organic com-
posite, Janus particles were obtained through solvent evapo-
ration from the dispersion containing the nanoparticle and
the polymer. These hybrid particulates were found to rotate
extremely quickly in response to external magnetic fields. Such
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
Figure 5.  Strategy for coordination of magnetic NPs with biopolymer–polyphenol conjugates. Reproduced with permission.[134] Copyright 2013, RSC.
features can be potentially useful for many biomedical appli-
cations, including hyperthermia for cancer treatment and tar-
geting tumor sites.
A study that revealed insights into interactions between
polymer molecules and inorganic NPs in nanocomposite
mechanics and interfacial interaction dynamics was recently
published.[136] Iron oxide NPs were incorporated into a cat-
echol-modified polymer (PEG and PEGCOOH) network to
obtain hydrogels cross-linked via metal coordination bonds
at the nanoparticle surfaces (Figure 6). The supramolecular
cross-linking of the gels is thus achieved to provide solid-like,
yet reversible, hydrogel mechanics. This work highlighted the
relation between macroscale mechanics of nanocomposite
materials and nanoscale dynamics at the polymer–nanopar-
ticle interface. It was also demonstrated how magnetic NPs
can be incorporated into functional bulk materials (e.g., cross-
linked hydrogel networks). The foundation for future design
of stimuli-responsive smart materials with remotely controlled
mechanical and functional properties was also addressed.
3. Representative Biomedical Applications
3.1. Hyperthermia
3.1.1. Introduction and Traditional Approach
According to the “World Population Ageing 2015”[137] report by
the United Nations, every country in the world is facing growth
both in the number and in the proportion of older persons
in their already aged population. The most optimistic demo-
graphic trend estimations agree that population ageing—the
increasing percentage of older persons in the population—will
become one of the most relevant social transformations of our
century, with implications for nearly all sectors of society. As an
example, between 2015 and 2030, the number of people in the
world aged 60 years or over is projected to grow by 56%. One
of the most sensitive sectors that will mostly suffer this popula-
tion ageing will be undoubtedly the healthcare. Linked to this,
cancer is currently one of the leading causes of morbidity and
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mortality worldwide. According to the World Health Organiza-
tion,[63] despite increasing national expenditures for cancer care
(at least, in developed countries), the incidence of this ageing-
related disease is expected to rise by about 70% over the next
two decades. Therefore, innovative and targeted policies are of
urgent demand to tackle this threatening problem worldwide,
which is emphasized by the incessant increase of aged people.
In this scenario, nanotechnology is a powerful tool with the
expectation of revolutionizing the entire healthcare scene in the
future, especially in the fight against cancer. Currently, chemo-
therapy, radiotherapy, and surgery are the three clinically avail-
able therapies in cancer treatment. Alone or in combination
constitutes the existent toolbox to treat cancer patients in the
clinics. However, all of them have serious drawbacks mainly
related to the lack of specificity and harmful secondary effects.
As an adjuvant alternative, thermotherapy has been tradition-
ally used to kill tumor cells in two different ways: on the one
hand by hyperthermia, in which the temperature of a local
region or the whole body is increased up to 41–45 °C by ultra-
sounds, microwaves, or radiofrequency radiation;[138] on the
other hand, by thermal ablation, in which a temperature above
45 °C is applied to the diseased area of interest that destroys the
tissue.[139] Both methods are based on the more thermosensi-
tive character of the cancer cells compared to the healthy ones,
due to its high glycolytic activity and consequent lower pH.[140]
However, these conventional technologies resulted to be very
aggressive and suffer from low penetration depths and limited
targeting. Actually, targeted therapies remain a challenge in
cancer treatment and are the focus of nanotechnology in order
to improve the therapy efficiency and prognosis of disease.
An important step toward targeted and higher specific cancer
therapy has been given with MNP-mediated hyperthermia
(MH) which is already being used, for example, on the treat-
ment of mice’s tumors (Figure 7).[141]
MH takes the advantage of the magnetic properties of magnetic
NPs in a fluid to transform the electromagnetic energy (exter-
nally applied as an oscillating magnetic field) into heat.[142–145]
MH progressively consolidated itself as a promising alterna-
tive to fight cancer and currently constitutes one of the most
intense research areas of nanotechnology in the biomedical
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Figure 6.  a) Structures of polymers four-armed-PEG and mPEG-COOH. b) Schematic illustration of the preparation procedures of Fe3O4 nanoparticle
cross-linked hydrogel. Representative photos of samples at each stage, from left to right: Fe3O4 nanoparticle dry powder, stabilized Fe3O4 nanoparticle
in aqueous dispersion before gel assembly, the self-standing solid hydrogel obtained after assembly with four-armed-PEG, and magnetic attraction of
the resulting gel. Reproduced with permission.[136] Copyright 2016, ACS.

field.[146] The localization of MNPs in the tumor area allows for main drawback of the current methodologies used nowadays,
a localized heating that selectively kills the tumor cells while such as chemotherapy and radiotherapy, which show harmful
keeping healthy the normal cells. This approach overcomes the secondary effects derived from a lack of treatment specificity.[147]

Figure 7.  a) Tumor growth curves of ferromagnetic Fe1−xMnxO nanostructures magnetic hyperthermia. b) Mice weight in two groups (test and control).
c) Day 50 photographs of representative mice from test and control groups. Reproduced with permission.[141]

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Different physical mechanisms are involved in the absorp-
tion and transformation of the applied oscillating magnetic
energy into heat by the MNPs, which depend on the chemical
nature of the NPs and their physicochemical and colloidal prop-
erties, as well as on experimental parameters such as the fre-
quency and intensity of the magnetic field.[148–153] For example,
in metallic NPs, the main mechanism by which the NPs dis-
sipate the applied electromagnetic energy is by the generation
of eddy currents as a consequence of the law of induction,
which largely depends on the electric resistivity of the material.
In the case of MNPs (essentially metal transition oxides), the
main mechanism of heat generation is dominated by hysteresis
losses, which are strongly dependent on the particle size. Above
a certain diameter, the creation of magnetic multidomains is
energetically favorable in order to reduce the magnetocrystal-
line energy. These NPs are characterized by ferromagnetic
behaviors with open hysteresis loops that dominate the energy
dissipation process by reversal magnetization. However, as the
particle size decreases, the multidomain magnetic structure is
no longer energetically supported, and the NPs become single
domain, characterized by super-paramagnetic magnetic behav-
iors and closed hysteresis loops. Super-paramagnetic NPs are
the most demanded NPs in researched biomedical applications,
since magnetic interactions between NPs are minimized once
the magnetic field has been removed. In this particular case of
magnetic oxides with particle sizes below the single-to-multi-
domain limit, there are two mechanisms involved by which a
fluid of NPs efficiently transforms the electromagnetic energy
into heat: (i) Neél relaxation, based on the alignment of the
magnetic moment of the particle with the applied magnetic
field direction and their reorientation to the equilibrium posi-
tion under no magnetic field; (ii) Brownian relaxation, which is
based on the friction between the nanoparticle surface and the
solvent as a consequence of the torque forces generated in the
process of reversible orientation of the magnetic moment under
the magnetic field followed by the reorientation of the equilib-
rium position once the magnetic field has been removed, which
provokes the subsequent rotation of the nanoparticle in the
fluid.[148,154,155] Both Brownian and Neél fluctuations are catego-
rized by different magnetic relaxation times, which will regu-
late the heating output of the NPs for specific frequency and
intensity of the alternating magnetic field applied. They take
place in parallel, and the heating is driven by the one having
the shorter characteristic time.[156] SAR or specific loss power
represents normalized parameters that allow us to measure and
quantify the efficiency of a given material to transform the elec-
tromagnetic energy into heat at specific values of frequency and
amplitude of the alternating magnetic field.
The well-known Rosensweig equation[156] predicts the heat
loss of a magnetic hyperthermia test executed on a ferrofluid
will be dependent on (a) the magnetic field frequency and
strength, and (b) the physical properties of the ferrofluid such
as magnetic and hydrodynamic radius of the NPs and solvent
viscosity, particle size distribution, and the magnetic anisotropy
energy constant of the magnetic core. Experimentally, the SAR
(W g−1) is calculated according to the following equation
C ∆T
SAR = (1)
m ∆t designs and coatings have been developed with the aim of
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where C is the specific heat capacity of the medium (assumed
equal to that of water, Cwater = 4185 J L−1 K−1), m is the con-
centration of the transition metal of interest (g L−1) of the
magnetic material in solution, and ΔT/Δt is the slope of the ini-
tial linear section of the temperature versus time curve. Consid-
erable efforts have been devoted to maximize the SAR of a wide
range of NP compositions, since this would imply a lower dose
of NPs to be administered to the patient with the subsequent
lower risk experiencing harmful side effects directly derived
from the treatment in itself and from toxicity issues related to
the administered heat mediators. Although different nanoma-
terial compositions have been explored which show relatively
high SAR values, iron oxide NPs are so far the most accepted
nanostructures as heat mediators in magnetic hyperthermia at
both preclinical and clinical practice levels. They are biocompat-
ible and nontoxic, and show relatively high saturation magneti-
zation and zero residual magnetization in the absence of a mag-
netic field, and are easy to be surface-functionalized to improve
colloidal stability and therapeutic purposes.[157,158] However,
SAR values in iron oxides are far from optimal, and typically
vary from a few units of W g−1 up to several hundreds,[159–161]
which remains a major issue for their clinical use. Efforts have
been devoted in the last years to optimize the heating efficiency
of iron oxide NPs. Intrinsic structural and magnetic properties
have been deeply studied and correlated to the hyperthermia
performance of iron oxides.[162–164] On the one hand, key struc-
tural parameters such as high crystallinity and narrow particle
size distribution revealed to favor the energy losses.[165–167] On
the other hand, magnetic parameters such as saturation mag-
netization and magnetic anisotropy were found to largely affect
the heating properties of the nanomaterials under exposure of
an AMF.[142,153,168,169] Moreover, solvent properties such as vis-
cosity and specific heat capacity, as well as the colloidal prop-
erties of the NP dispersions, i.e., nanoparticle concentration,
resulted to be key in the optimization of the heating proper-
ties of the fluids.[170–172] The effect of magnetic dipolar inter-
actions has also been the focus of intense research in the last
years.[161,173] With the aim of better understanding the effect
of the magnetic NPs’ interaction in the heating properties of
the nanomaterials, Grillo et al. developed a magnetic nanocap-
sule with which evidenced the key role of the magnetic dipolar
interactions in the optimization of the SAR.[174] Additional theo-
retical and experimental studies have been performed which
showed nanoparticle aggregation and arrangement phenomena
to govern the heating properties of magnetic fluids.[168,175–179]
However, general conclusions about the general trend of the
nanoparticle aggregation remain unclear. The variation of one
or several of these factors is responsible for the wide ranged
SAR values observed among different laboratories, in addition
to the different results shown when the SAR is calculated by
using different approaches.[180,181] Also in the presence of dif-
ferent surfactant coatings, the nanoparticles were found to
largely affect the structural, magnetic, and hyperthermia prop-
erties of iron oxide NPs.[182] Chitosan, dextran, polyacrylic acid,
PEG, PVP, folic acid, and cysteine, among many others, were
some of the functional coating agents used for hyperthermia
applications of iron oxide NPs.[157,170,183–188] Recently, synthesis
procedures have been studied in depth,[189] and efficient NP
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www.advancedsciencenews.com
increasing the SAR of iron oxides as much as possible. Iron
oxide NPs with high shape and magnetic anisotropies, such
as nanowires (NWs),[190] nanocubes,[164] nanoflowers,[191] nano-
flakes,[192] and nano-octopods,[152,169] as well as multicore[161,176]
and core–shell nanostructures joining different material com-
positions and magnetic behaviors,[193,194] have showed the
highest SAR values reported so far. In spite of a lack of con-
sensus regarding the SAR trend as a function of some experi-
mental parameters, i.e., nanoparticle concentration in the
fluid and AMF magnitude, the maximum SAR values reached
already the 1–2 kW g−1. In an attempt to search new materials
with higher hyperthermia efficiency under an AMF field, other
nanomaterial compositions have been explored, Fe NPs, Co-,
Mn-, Ni- and Zn-ferrites (pure or doped), bimetallic FePt, FeNi,
FeCo, iron carbides such as FexCy, Fe@FexC, and combinations
of Fe with Au and Ag have been some of the materials investi-
gated for hyperthermia performance.[142,148,153,162,187,194–200] Even
magnetic nanomaterials with particle sizes above the single-to-
multidomain transition exhibiting ferromagnetic behavior have
been investigated.[188,201,202] However, too low SAR values and
serious toxicity concerns pointed out iron oxides as the mag-
netic NPs of excellence for hyperthermia applications.
The main application of magnetic fluid hyperthermia
appears in the biomedical field in anticancer therapy.[146,203]
The localized character of the temperature increase generated
by the heat mediators was quickly conceived as an opportu-
nity to selectively kill tumor cells and diminish the harmful
side effects derived from more conventional and aggressive
cancer treatments such as chemo- and radiotherapy. Many
studies have been designed to explore this methodology both
in vitro and in vivo that resulted in promising results; how-
ever, the limited efficacy observed in clinical trials seems to
determine its slow translation to the clinics. Magnetic hyper-
thermia is already included in the portfolio of treatments of
the national healthcare systems of some European countries
such as Germany and the Netherlands, and it appears as one
of the recommended treatments in the USA National Compre-
hensive Cancer Network guidelines for several types of cancer
diseases. NanoTherm treatment from MagForce is one of the
best known examples where magnetic hyperthermia is being
applied at clinical level for the treatment of glioblastoma with
successful results. Clinical trials have been extended to other
type of tumors, such as pancreatic, prostate, or esophageal.
Magnetic hyperthermia can be administered as a stand-alone
therapy or in combination with radiotherapy and chemo-
therapy. In this way, magnetic fluid hyperthermia showed the
most successful results, but it is worth mentioning that the
most successful results point to an increase of the life expec-
tancy up to about 8 months after diagnosis of primary tumor
in patients suffering glioblastoma.[96] This fact evidences the
promising but, so far limited, therapeutic efficacy of magnetic
hyperthermia to fight against cancer. Current limitations of
magnetic hyperthermia are associated with low SAR of heat
mediators, lack of tumor targeting, and impossibility to accu-
rately control the temperature in the treated area, which have
hindered the large implementation of the technique into the
clinics. Fine-tuning of NPs’ size, shape, and interparticle mag-
netic interaction, which determine the effective magnetic field
of anisotropy, are crucial to optimize the heating efficiency of
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a given material to be intrinsically used for magnetic hyper-
thermia applications. In particular, the last significant advances
to increase the SAR of iron oxide NPs were mainly based on
the fabrication of nanostructures with high magnetic anisot-
ropy (e.g., magnetite cubes,[164,204] rods,[205] and octopods[169])
and core–shell NPs that exploit the exchange and surface ani-
sotropy appearing when soft and hard magnetic materials are
join together in one single nanostructure.[193,206–208] However,
the challenge remains since high heating power in suspension
solutions may not transform into efficient heating in the cel-
lular environment,[209] where a drastic decrease in the SAR of
colloidal nanoparticle suspensions was observed when they got
into endosomes as a result of the cell internalization mecha-
nisms. Soukup et al.[210] demonstrated by in situ measure-
ments of magnetization relaxation that cellular internalization
can disable Brownian relaxation in live cells, which has impor-
tant repercussions for designing suitable NPs for intracellular
hyperthermia applications.
In the case of targeting, many small organic molecules and
biomolecules such as peptides and proteins have been used as
targeting moieties of functionalized iron oxide NPs for selective
accumulation of the nanoheaters in the tumor,[184–186,211] but
this remains a challenge for translational research, especially,
when the intended administration route of the heat probes is
systemic. On the other hand, the accurate control of the tem-
perature in the treated area is considered a major drawback
of magnetic fluid hyperthermia. Numerous efforts have been
devoted to this issue in recent years, and important advances
have been already achieved. In an initial stage, the research
was focused on demonstrating the higher temperature around
the NPs when an AMF was applied. Bañobre-López et al.[212]
and Rodrigues et al.[212] were pioneer in demonstrating the
local temperature increase around magnetic heat mediators
and their superior bactericide effect on food spoilage micro-
organisms in both planktonic and biofilm living states when
subjected to magnetic fluid hyperthermia, compared to the
situation in which the heat is traditionally and macroscopically
applied. This superior effect of magnetic hyperthermia com-
pared to other conventional methods of macroscopic heating
has been extended later on to eukaryotic and tumor cells.[213,214]
The localized thermal effect of magnetic hyperthermia was
also correlated with the gene expression of enhanced green
fluorescent protein (EGFP) in human lung adenocarcinoma
cells, expression that was found to be linked to the intracel-
lular temperature increase[215] due to the cell stress induced
to the cell even when this temperature increase was not mac-
roscopically observed. Parallel efforts were made with the
aim of accurately measuring the temperature value locally
reached around a magnetic nanoheater. Thus, Riedinger
et al.[216] designed a thermoresponsive linker that allowed us
to infer the temperature variation a few nanometers away from
the nanoparticle surface. And more recently, the development
of different designs incorporating magnetic and upconver-
sion NPs was exploited to provide a temperature measurement
through the temperature-dependent fluorescent properties,
but the lack of validation of the nanoprobes in vitro, the dif-
ficulty of the data interpretation due to the background fluores-
cent emission of living cells, together with the low penetration
depth applicability and the toxicity issues associated with the
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lanthanide elements, still make the accurate

measurement of the local temperature on
treated tumor site a major challenge in this
field.[217,218]
As a result of all the efforts devoted to
the optimization of MNPs to overcome the
aforementioned current limitations of MH,
numerous super-paramagnetic nanostruc-
tured systems have been established to
improve the effectiveness of heat therapy as a
treatment of cancer, mainly focused on intra-
cellular actuation. Doping of iron oxides with
transition metals[198] and coating agents with
different ligands such as antibodies, peptides,
small molecules, and carbohydrates[219,220]
have been used to increase the cell inter-
nalization of MNPs and the efficiency of
intracellular hyperthermia.[204] An extensive
literature reports on the use of super-para-
magnetic NPs in MH and the heating mech-
anisms involved, as well as on challenges and
Figure 8.  Scheme of application and mechanism of remote controlled drug delivery trough
promises of the technology.[16,221]
nanocomposite sol–gel materials. a) Injection of the gel. b) Application of the magnetic field
Beyond the local thermal therapy in which that causes heat and releases the trapped drug. c) Removal of the applied magnetic field that
a generated temperature increase can pro- leads to the temperature decrease (until the initial body temperature), entrapping the residual
duce on tumor site by the thermal activa- drug. d) Application of a magnetic field heats to upper transition, releasing residual drug.
tion of MNPs under a remote AMF (due to Reproduced with permission.[223]
more temperature sensitivity of cancer cells
compared to normal cells), the energy produced by the MNPs magnetic hyperthermia has provided innovative solutions is
in the presence of an AMF can be utilized in other therapeutic the development of biocompatible magnetic scaffolds for tissue
approaches, such as drug delivery, nanoscale energy delivery, regeneration. The incorporation of MNPs into natural and syn-
and combinational treatments. thetic matrices mimicking body tissues provided the final struc-
tures with heating properties when exposed to AMFs, which
were used either to deliver loaded drugs and grow factors or to
3.1.2. Hyperthermia through Drug Delivery induce magnetic gradients and mechanical effects that resulted
in an enhancement of the angiogenesis and cell proliferation in
Therapeutic capacity of magnetic hyperthermia has been the implanted regions. Magnetic hydroxyapatite (HA), gelatine,
greatly enhanced when exploited as an external thermal stimuli polycaprolactone, and silk are some of the natural materials uti-
generator in drug delivery. Here, we will highlight those macro- lized as hosts of MNPs for hyperthermia-induced bone tissue
and nanoscale systems containing MNPs in which a remotely engineering.[227–229]
applied AMF induces a thermal stimulus that is used to control On the other hand, a field of intense activity of nanotech-
the loading and delivery of therapeutic compounds previously nology, nowadays, in the fight against cancer is the develop-
incorporated into them. At the macroscale, a few recent exam- ment of organic–inorganic hybrid nanocomposites for diag-
ples of novel materials exist in which a remote AMF triggers nosis and therapy applications. Regarding therapy, magnetic
thermal transitions and morphological/structural changes that micro/nanohybrid self-assemblies have been found promising
result in the modulation of drug release. For example, ther- in hyperthermia-induced drug delivery, as they combine the
moresponsive magnetic hydrogels were developed by Campbell encapsulating properties and modified drug release together
et al.[222] who showed a fourfold enhancement of drug release. with the physicochemical properties of the inorganic coun-
Other magnetic thermoresponsive nanocomposites based terpart. Thus, a wide variety of magnetic organic–inorganic
on the combination of certain polymers, nanogels, or lipids, drug delivery hybrids have been developed which showed
together with iron oxide NPs, were developed in which thera- a modified cargo release under thermal stimuli induced by
peutic compounds (or drug models), such as lysozyme, sodium an AMF.[148,217,230–235] For example, Kim et al.[232] developed
fluorescein, ibuprofen (IBU), and nifedepin, were released by stimuli-responsive magnetic nanomicelles as multifunctional
the triggered thermal effect of a remote AMF (Figure 8).[223–226] heat and cargo delivery vehicles. Béalle et al.[236] also devel-
In most of the above examples, the burst of the drug release oped ultramagnetic liposomes with hyperthermia capability for
responds to structural phase transitions caused in the materials hyperthermia-induced drug delivery, and Katagiri et al.[237] opti-
as a consequence of the local heating induced by exposure to an mized hybrid liposomes constituted of thermosensitive block
AMF. In many cases, these phase transitions are even revers- copolymers, iron oxide MNPs, and phospholipids as ON–OFF
ible, and the thermoresponsive materials undergo several cycles switchable drug release activated by an AMF. In addition to
of responsive drug release. Other field of great activity in which magnetoliposomes, numerous magnetic hybrid architectures

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have been synthesized which are able to transform an applied
electromagnetic energy into a triggered thermal stimuli for con-
trolled drug delivery. Polymeric micelles (PMs), polymersomes,
polymeric nanocapsules, solid lipid NPs, among others, are
some of the hybrid nanoformulations which are able to simul-
taneously incorporate a significant amount of MNPs and bio-
active compounds, enabling an AMF-triggered cargo delivery.
Thus, Hu et al.[238] utilized a double emulsion technique to
develop composite nanocapsules based on a block copolymer
of poly(allyl alcohol) and polystyrene that were able to integrate
both hydrophobic and hydrophilic components along with
oleic-acid-coated MNPs, whereas Qu et al.[239] encapsulated both
camptothecin and hydrophobic MNPs into polymeric assem-
blies of an amphiphilic polymer that was thermosensitive. In
both systems, the cargo release significantly increased when
exposed to an AMF. Also, Almeida et al.[240] incorporated iron
oxide NPs and onco-A in triglyceride-based solid lipid NPs that
showed hyperthermia properties under an AMF. More recently,
Carregal-Romero et al.[234] proposed a system of microcapsules
prepared by layer-by-layer methodology in which the core was
loaded with dextran cascade blue, as a drug model, and mag-
netic nanocubes were placed at the shell of the structure. The
authors showed that after irradiation with AMF, the outer shell
was partially disrupted and the cargo was partially released.
Other recent example was reported by Griffete et al.[241] In this
study, magnetic NPs were used as individual cores with mole­
cularly imprinted polymers and doxo loaded by hydrogen bonds
in the binding sites. After AFM treatment, a significant amount
of the doxo was released, and in vitro studies with cancer cells
confirmed a reduction in the viability after AFM treatment.
3.1.3. Alternative Approaches
In parallel to the use of magnetic nanocomposites for AMF-
mediated drug delivery applications, alternative methods have
been explored based on the direct conjugation of a drug model
to the surface of MNPs.[242] Thus, a decade ago Derfus et al.[243]
conjugated a DNA strand to a dextran-coated iron oxide MNPs
and bound to this surface a fluorophore drug model. The
thermal activation of the MNPs under an AMF was enough
to melt the DNA strands and release the cargo model. More
recently, Nair et al.[244] validated the remote controlled drug
release of an anti-human immunodeficiency virus (anti-HIV)
component that was tethered to a magnetoelectric core–shell
structure, constituted of a cobalt ferrite core and a BaTiO3
shell, whereas very recently Meikle et al.[245] surface-conjugated
super-paramagnetic NPs with thermoresponsive poly(epsilon–
lysine) dendrons tethered with carboxybetaine for the mild
hyperthermia-controlled delivery of vascular endothelial growth
factor (VEGF). Other recent designs involve the organic func-
tionalization of iron oxide NPs with drug models through
linkers with thermosensitive bonds (i.e., Diels–Alder reaction—
maleimide and furan moieties—intramolecular lactamization,
and azo release[246]), which cleave the active ones once an AMF
is applied.[116,117] As an example, N′Guyen et al.[247] reported
super-paramagnetic iron oxides (SPIOs) stabilized with phos-
phonic ligands bearing alkyne and furan moieties. The nano-
conjugate offered the possibilities of functionalization through
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thermoreversible Diels–Alder and 1,3-dipolar cycloaddition. PEG
was chosen as a hydrophilic polymer to enhance colloidal
dispersability in water and maleimide-bearing rhodamine
B was employed as a model system for a drug. The authors
showed that rhodamine B was released from the NPs after
the application of AFM due to retro-Diels–Alder reaction. In
the same line, Saint-Cricq et al.[248] encapsulated a drug in a
mesoporous shell surrounding an SPIO nanoparticle. The pro-
posed drug delivery mechanism is based on the break of an
azo-containing PEG polymer, that after degradation expose the
porous, and consequently, releases the drug. The temperature
of the solution did not increase significantly; therefore, this
work highlights the local generation of very high temperatures
in the vicinity of SPIOs due to MH. All the aforementioned
examples of MNP-mediated drug delivery, both with covalent
and noncovalent drug conjugation approaches (see the review
from Ulbrich et al.[17] for further details), showed high promise
for cancer therapy. However, more studies are needed about
their interaction with other biomolecules, cells, and tissues.
As was already mentioned, MH can be applied as a stand-
alone methodology or in combination with radiotherapy or
chemotherapy. Nowadays, even when combined, all these meth-
odologies are provided separately. In the last years, important
efforts have been made to combine MH and chemotherapy by
using a single nanostructured nanoplatform, which will be able
to provide thermal cell killing and localized delivery of a chem-
otherapeutic drug. Kumar and Mohammad[148] reviewed the
magnetic nanomaterials used for hyperthermia-based therapy
and controlled drug delivery. Since then, important results have
been achieved related to the design of both magnetic cores
and nanocomposites aiming at achieving a joint thermo- and
chemo-therapy.[239,249–253] For example, Qu et al.[239] developed a
magnetoresponsive drug-loaded nanocarrier for efficient thermo-
chemotherapy achieved by combining highly efficient magnetic
hyperthermia with magnetothermally facilitated drug release,
which resulted in a synergy therapeutic effect. The operational
magnetothermal response leads to a high improvement of tumor
cell killing by an operating procedure involving heat shock pro-
tein overexpression and MH-facilitated cellular uptake. Last
trends regarding the use of MH in drug delivery applications
involve the conjugation of imaging and hyperthermia-derived
therapy in the same material architecture. Thus, Sanson et al.[250]
developed doxorubicin (DOX)-loaded magnetic polymersomes
as theranostic nanocarriers that combine contrast enhancement
MRI capability and dual thermo- and chemotherapy, whereas
Hayashi et al.[254] also developed theranostic NPs potentially suit-
able for MRI-guided thermo-chemotherapy by controlling the
particle clustering. On the other hand, Thorat et al.[252] devel-
oped self-regulating La0.7Sr0.3MnO3 nanoheaters functionalized
with an oleic acid–PEG PM structure, and loaded it with DOX,
which showed cancer cell killing up to 90% over apoptosis and
late necrosis pathway in MCF7 cells. In this line, Huang et al.[233]
have recently provided an overview on the last targeted and
image-guided approaches of MNPs in drug delivery, empha-
sizing the high importance of biomarker pointing for a more
personalized therapy and the single contrast-enhancing proper-
ties of theranostic MNPs in cancer therapy.
Beyond the uses of MH in drug delivery and its enhanced
therapeutic effect against cancer when it is in combination with
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chemotherapy, MH has also been utilized in combination with
photodynamic therapy. A. Espinosa et al.[255] designed a smart
nanoplatform based on dually loaded hybrid liposomes with
photosensitizers (in the bilayer) and MNPs (in the aqueous
core). After excitation with a laser, the generation of singlet
oxygen in combination with the heat induced by MH resulted
in complete cancer cell death in vitro and in solid tumor abla-
tion in an in vivo rodent model. In the same way, Kolosnjaj-tabi
et al.[256] developed multicore iron oxide NPs coated with a gold
branched shell with optimized magnetic and plasmonic prop-
erties, which allowed for a bimodal thermotherapy (magnetic
hyperthermia plus photothermal therapy) validated in vivo.
In addition to combinational treatment approaches involving
MH and chemotherapy, radiotherapy, and photodynamic therapy,
magnetic hyperthermia can also be applied in combination with
gene therapy.[242] Besides the development of responsive carriers
for the delivery of therapeutic molecules mediated by an AFM,
magnetic hyperthermia has been found to significantly enhance
the efficiency of nucleic acid delivery. Thus, Jiang et al.[235]
developed lipoid-coated iron oxide NPs for improved DNA and
small-interfering RNA (SiRNA) delivery induced by an AMF.
Combined thermal therapy via MNP-mediated hyperthermia
and gene therapy was found to provoke an enhanced toxicity
compared to gene treatment alone. As examples, Walther and
Stein[257] and Yin et al.[258] conjugated an amphipathic tail-
anchoring peptide and lethal-7a microRNA (miRNA) to MNPs,
respectively. In both cases, combined MH and gene therapy
showed additive effects than either treatment alone. Moreover,
MH has also been utilized as an immunotherapeutic treat-
ment[259] and as an ROS generator[260,261] with promising results.
Apart from biomedical applications, MNPs have also been incor-
porated into different polymeric matrices that show interesting
mechanical behaviors (i.e., shape memory effects) when sub-
jected to local heating under an applied AMF.[262]
As conclusion, the translation of MNP-mediated hyper-
thermia to the clinics has been hindered by the current limi-
tations found in in vivo experiments, mainly derived from the
lack of specificity and lower heating performance once the
MNPs get inside the cells. In this sense, increasing efforts have
been devoted to increase the specific absorption rate of MNPs
by studying different morphologies, structures, and designs.
The energy transfer at the nanoscale together with the intracel-
lular targeting at tumor site, avoiding nonspecific accumula-
tion of MNPs in other tissues, seems to be the most promising
approache to improve the efficiency of nanoscale thermal therapy
applications. Furthermore, combinational treatments combining
AMF-mediated hyperthermia with chemotherapy, radiotherapy,
gene therapy, immunotherapy, and photodynamic therapy have
shown enhanced toxicity and tumor growth inhibition compared
to either stand-alone treatment. Besides, magnetic hyperthermia
has been explored not only as a direct thermal therapy actuator,
but also as a thermal stimuli provider. In this regard, important
advances have been achieved in the field of drug delivery. Novel
architectures and nanoparticle designs have been synthesized
that allow for a combined thermal (magnetic)- and chemotherapy
by using dual-loaded magnetic platforms that able to encapsulate
both MNPs and bioactives (e.g., drug, RNA, and DNA). Thus, the
thermal energy generated is additionally used to induce the drug
delivery. In a step forward towards the treatment monitoring
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and personalized therapy, these MNPs-mediated thermo-chemo-
therapy approaches have been also exploited as theranostic nano-
structures, which additionally show image (i.e. MRI)-guided drug
delivery capabilities and allow for monitoring of patient response
to treatment. Despite the significant advances achieved, impor-
tant drawbacks related to the heating properties of MNPs, their
selective accumulation at tumor site, or cells and the monitoring
of the on-site temperature in vivo still remain. However, the
increasing number of in vivo assays and the promising results
obtained augur an increasing translational research with a great
impact on the treatment of several diseases.
3.2. Drug Release
Traditional application of medicines is impaired by limited
effectiveness, poor distribution in the body, and low selec-
tivity, the therapeutic delivery of drugs on the target placed
at the right time and with the right drug quantity being the
main problems in the treatment of numerous health disorders.
Those problems and disadvantages can be outdated by the use
of controlled drug delivery using MNPs.[263] As a result, the so-
called magnetic “smart” and “stimuli-responsive” systems are
being developed and optimized to deliver medicines at specific
sites or at precise times and rates within the body, according to
a magnetic stimulus that is externally applied.[264] In this way,
magnetically controlled drug delivery is one of the most prom-
ising and popular approaches for delivering the medicine to the
specified site, meeting two drug delivery milestones: reducing
the drugs’ side effects by accurately targeting to the desired
tissue/organ and the controlled release of the medicine to avoid
traditional underdoing cycle/overdosing problems.[263,265]
From all types of magnetic materials, namely ferrimagnetic
materials, paramagnetic, super-paramagnetic, antiferromag-
netic, ferromagnetic, and diamagnetic, the super-paramagnetic
ones are the most interesting ones to use in drug delivery due to
their ability to develop a magnetization in an external magnetic
field, losing their magnetic moment in the absence of an applied
external magnetic field.[263] In addition to that real-time tracking,
using established imaging techniques, surfaces of MNPs can be
coated with various polymers or surfactants that, in turn, are able
to interact with or bind pharmaceutically active materials.[266]
The most used MNPs on drug delivery systems are magnetite
(Fe3O4), maghemite (γ-Fe2O3), and cobalt ferrite (CoFe2O4).
Such MNPs doped with particular drugs have some application
problems such as stability and nontoxicity in the physiological,
not being easy to join high biocompatibility, magnetic satura-
tion and interactive functions on the magnetic nanoparticle
surface. As a solution, the polymer coating not only allows the
increase of the hydrophobicity of the nanoparticle, but also
offers a diversity of surface functional groups to bind drug
mole­­cules, increase stability, and inhibit agglomeration.[263]
Precise targeting approach depends on two aspects: first,
the magnetic NPs show magnetic attraction and second, the
coupling of high-affinity-modified ligands on the surface of
the MNP.[267]
After magnetic guidance, drug release can be initialized
not only by external stimuli such as a confined temperature
increase but also by internal ones such as a change in pH.
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Diverse approaches have been reported to attach a drug to
magnetic NPs; the medicine molecule can be loaded in stimuli-
responsive hydrogel/polymer frameworks,[268] encapsulated in
the polymer interspace of magnetic nanostructures,[269] linked
in magnetoliposomes,[270] or trapped to the activated surface of
MNPs.[266,271] Furthermore, drugs can be linked to the MNPs by
covalent connections that are susceptible to degradation as part
of the tissue metabolism.[266]
Any overview on magnetic drug delivery must start with the
merited credit of Paul Ehrlich (1854–1915), a German doctor
who worked in the fields of hematology, immunology, and anti-
microbial chemotherapy and proposed that if any molecule
could discriminatorily target a disease-causing entity, then a
drug for that entity could be accurately delivered sideways with
the mediator of selectivity.[272] Such a “magic bullet” could be
created to exterminate the selected organism exclusively. Later,
Paul Ehrlich won the 1908 Nobel Prize in Medicine for con-
tributions to the immunology research field and since then,
various strategies have been proposed to magnetically con-
trolled drug delivery, the first work concerning the magneti-
cally assisted drug delivery being developed by Widder et al. in
1978,[273] reporting a carrier system for the delivery of chemo-
therapeutic molecules to desired places. It was discovered that
the carrier, albumin/Fe3O4 microspheres can be in vivo accu-
mulated at a desired place with an external magnetic field. Adri-
amycin delivery was supported by the presence of a significant
content of the medicine at the site of the magnetic carrier local-
ization. This delivery system allowed us to concentrate in the
desired site the same Adriamycin dose that was usually accom-
plished by administration of 100-times higher dose of the drug.
In the 1980s, several reports were found developing this
strategy to deliver distinct drugs using magnetic microspheres
and microcapsules, namely mitomycin C (FM-MMC-mc) anti-
cancer drug,[274] the anthracycline antibiotic with antineoplastic
activity, doxorubicin hydrochloride,[275] and doxorubicin, a
chemotherapy medication used to treat cancer.[276]
In the following decades, Häfeli et al. developed magnetic
poly(lactic acid) (PLA) microspheres that include both mag-
netite and the β-emitter 90Y in vivo treatment of tumor cells.[277]
Despite those promising approaches, some tissues in the
human body are difficult to reach as drugs need to pass tight
tissues; only structures in the nanometer-sized range are able
to pass.[278] In this way, magnetic NPs were first used in animal
models by Lübbe et al.[279] This work is divided into two parts:
first, several contents of a magnetic fluid was tested in rats and
immunosuppressed nude mice with regard to tolerance and
efficacy studies; second, the same issues were evaluated after
administration of the ferrofluid with chemically bound epiru-
bicin (4′-epldoxorublcin). It was discovered that the ferrofluid
did not cause major laboratory abnormalities and there was no
LD50 and no intolerances with the epirubicin-bound ferrofluid.
Both forms of treatment led to complete tumor responses in an
experimental human kidney as well as in a xenotransplanted
colon carcinoma model. This pioneer work proved that mag-
netic nanomaterials are safe agents, which can be used in dif-
ferent ways for confined forms of disease treatment in combi-
nation with high-energy magnetic fields. After these preclinical
experiences, a clinical study was carried out with 14 patients
having advanced solid tumors.[279] Nine of these patients
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received two treatment sequences; three patients received one
sequence; and two patients received three sequences of mag-
netically controlled drug targeting that consisted of the infusion
of epirubicin in increasing doses (5–100 mg m−2) inserted into
a magnetic fluid. The tumors were treated with magnetic fields
for 1–2 h. In 2 of 14 patients, the same dose of epirubicin, not
inserted in the magnetic fluid, was systemically administrated
3 weeks after drug targeting, allowing intraindividual com-
parisons. It was reported that the magnetic material could be
effectively directed to the tumors in about 50% of the patients
without an increase of toxicity. It was concluded that improve-
ments were necessary to make this procedure more effective
and independent of patient origin or disease, leading to an
increase in the scientific activity of this research area.
Furthermore, a pilot study has used slices of tissue samples
of VX2 squamous carcinoma cells that were measured by mag-
netic relaxation, and the quantification of iron magnetic NPs on
the hind limb of New Zeeland white rabbits was determined by
using the original ferrofluid suspension as a reference. From
such distribution of the iron particles within the tissue sample,
the tumor was reconstructed, as highlighted by the higher vas-
cularization of regions with higher magnetite content than the
remaining tumor tissue. This study additionally revealed that the
microscopic histological methods and the integral method mag-
netorelaxometry can compete each other in an efficient way.[280]
Trying to comprehensively understand the performance of mag-
netic NPs in the blood stream, it was reported[281] that there are
three types of in vivo behaviors to magnetizable NPs (boundary-
layer formation, magnetic dominated, and velocity dominated)
exclusively identified by three essential nondimensional num-
bers (the Renkin, the mass Péclet, and the magnetic Richardson
numbers). When skin cells were added to this scenario, a new
interface was developed where magnetic NPs can build up,
adding, in this way, a qualitatively new behavior that requires a
fourth nondimensional number to map out its new effect.
More recently, smart material-based approaches allow us to
increase the efficiency of the traditional drug release magnetic
nanoparticle-based method, ensuring that a specific drug is
delivered with the right dosage, at the right time and in the right
place[282] using the so-called smart and stimuli-responsive method.
To achieve such smart drug delivery, smart polymer systems such
as pH-responsive polymers, temperature-responsive polymers,
and temperature/pH-dual-responsive polymers are being used
due to their biocompatible and fast responsive properties, nontox-
icity, biodegradability, effective payload, and release capability.[283]
The introduction of an external stimuli-sensitive element to the
active system that may change or trigger the drug release mecha-
nism is of great interest.[284] In this novel methodology, one of the
most promising strategies consists in using magnetic NPs that
are stimulated by means of an external magnetic field in poly-
meric composites.[285] In this context, it was reported[264] that the
fabrication, characterization, and study of the release kinetics of
IBU on a poly(l-lactic acid) (PLLA) membrane with inclusions of
a zeolite (Faujasite) and magnetostrictive Terfenol-D particles. It
was observed that the applied magnetic field modifies the release
kinetics of the polymeric membrane, leading to an increase of the
release rate by more than 30%. Additionally, the increase of the
magnetic field intensity from 100 to 200 mT promotes an increase
in the percentage of IBU released from 67% to 75%.
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Figure 9.  a) Schematic image of the biphasic ferrogel implant in mouse hindlimb. b,c) Cross-sectional images of biphasic ferrogels. Reproduced with
permission.[286]

A new biphasic ferrogel, containing iron oxide NPs (2–13 wt%),
capable of large deformations and the triggering of drug
release, was presented.[286] In this way, biphasic ferrogels
were subcutaneously, surgically, implanted in the hindlimb of
6-week-old mice (Figure 9).
Biphasic ferrogels demonstrated optimized mechanical
properties, enhanced porosity, and increased biocompatibility
as a result of their low iron oxide content. With their capability
to on-demand deliver drugs and cells, it is predictable that
such magnetic gels will gain wide values in the fields of drug
delivery, regenerative medicine, and tissue engineering.
By employing magnetic nanocomposites of temperature-
responsive hydrogels composed of N-isopropylacrylamide and
Fe3O4 NPs, the use of magnetic fields to trigger drug release on
demand has been discussed.[287] The application of the magnetic
field results in the heating of the nanocomposites leading to a
faster squeezing and collapse of large quantities of embedded
drug. When submitted to an AC magnetic field with a high
frequency, internalized hybrid polymer-based materials, with
doxorubicin and super-paramagnetic iron oxide NPs in their
composition, are capable of inducing cytotoxicity and increasing
intracellular drug release. A new approach that opened new
horizons in the improvement of smart delivery materials and
systems capable of releasing drugs upon demand and opti-
mizing the treatment control was presented in ref. [288]. It was
found that internalized hybrid polymer-based materials filled
with γ-Fe2O3 super-paramagnetic iron oxide NPs and doxoru-
bicin, when exposed to a high-frequency (750 kHz) magnetic
field (14 mT), were capable of increasing cytotoxicity to 18%
and activate intracellular drug release. Nevertheless, in clinical
tests the field intensity was decreased to 3–14 kA m−1 and the
field frequency was decreased to 100 kHz with the objective
to contain patient discomfort, which depends on the treated
region of the body.[289,290]
A multifunctional magnetic mesoporous Fe3O4/silica nano-
particle with both a successive dual-targeting (both active and
magnetic, Figure 10) ability and a controllably switched drug
release options was presented in ref. [291].

Figure 10. Schematic representation of doxorubicin (DOX)-loaded cross-linked magnetic mesoporous silica NPs MMSN-S2- poly(ethyleneimine)
(PEI)-PEG- phenylboronic acid (PBA) reservoirs being consecutively targeted to the tumor site through the magnetic targeting enhanced permeability
and retention effect and NanoEL, and the SA-positive HepG2 cells by the active-targeting, succeeding a fast drug release by GSH stimulus in the
cytoplasm. Reproduced with permission.[291]

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In vivo essays revealed that this magnetic nanoparticle can be
initially concentrated close to the tumor site under the applica-
tion of a magnetic field. After that, it can enter into tumor cells
by (poly(ethyleneglycol))-3-aminophenylboronic acid-mediated
endocytosis. In the end of the process, the chemically cross-
linked network on the surface of this magnetic structure is dis-
ordered as a response to the high concentration of glutathione
in cytoplasm, opening the mesopores and quickly releasing the
drugs, consequently, prompting apoptosis in cell.
Apart from the above-mentioned studies, there are some
limitations in the drug release based on MNPs, such as poor
tissue penetration and cell damage, which should be addressed
in the future. Additionally, as a suggestion for future investi-
gations, a new type of smart MNPs that are able to consecu-
tively release drugs and genes at precise time intervals and at
pre-established sites is needed. One way to meet this challenge
is to take advantage of physiological stimuli that are usual on
cancer cells and tumors such as lower pH to activate the drug
release.[292] Additionally, the possibility of associating control-
lable drug release with tumor targeting allows the design of
therapies with desirable pharmacodynamics and pharmacoki-
netics behaviors that will trigger the use of MNPs in clinical
personalized medicine.[17]
3.3. Tissue Engineering
Over the last decades, the use of MNPs has been increasingly
utilized in regenerative medicine and tissue engineering due
to the novel approaches that they offer and to their promising
potential. The magnetic particles have directly been incorpo-
rated into the cells or used to interact with cell membranes
but they have also been combined with biomaterials in order
to obtain new functionalities in the structural framework (scaf-
fold) that has been employed to support cells, namely for the
control of the cellular responses (Figure 11).
Several different methods exist to produce scaffolds for
tissue engineering. Most common are jetting methodologies
such as aerodynamically assisted jetting/ threading, pressure-
assisted/driven jetting/spinning, laser-guided writing, inkjet
printing, electrospray, and electrospinning.[294] Printing, elec-
trospray, and electrospinning are currently undergoing a wide-
spread revival of scientific investigation of chemical, physical,
and biological outputs, being able to produce structures more
similar in size to the natural extracellular matrix.[294,295]
MNP-based approaches and scaffold production methods
have been developed with the main objective to control cell
function. Cell functions are mainly controlled by bioactive
and growth factors and mechanic transduction pathways (for
example, by mechanical stress) that can influence and con-
trol the cell behavior by the conversion of mechanical stress
into intracellular biochemical cues.[296] The first use of MNPs
for intracellular labeling was reported in 1993; however, only
in 2000, they were applied to stem and progenitor cells.[297] It
should be noted that for the mechanic transduction studies, the
most commonly used magnetic particles are iron oxide parti-
cles because they are more easy to synthesize by coprecipita-
tion from iron salts.[298] This approach allows the remote con-
trol of the mechanic transduction pathway with spatial and/or
temporal precision in order to modulate the cell behavior,[296,298]
such as by cell stretching, micropost manipulation,[299,300] local-
ized stimulus at the single-cell level,[301] or cell receptors’ acti-
vation.[298] These techniques that can apply mechanical forces
directly to the cell or to the mechanoresponsive receptors of
individual cells are important for a wide variety of tissue engi-
neering applications, because they do not require the scaffold
deformation.[302] For example, micropost arrays composed of
cobalt nanowires and an array of elastomeric posts were used
as sensors for cellular traction forces to study the cell response
to the different applied forces. It was found that, when the
force was applied, these microposts enhanced the focal adhe-
sion recruitment and size at the local of the stimuli and not at
the nearby nonmagnetic posts.[299] In order to apply a confined
stimulation at the single-cell level, patterned MNP-dosed cells
in microengineered magnetic substrates have been used.[301]
Compared to the receptors’ activation, magnetic fields and
MNPs, all have been employed to control specific cell signaling
pathways by targeting specific cell surface receptors or sign-
aling proteins inside cells.[302,303]
In these days, tissue engineering is based on the cell cul-
ture onto 3D scaffolds in order to mimic their primitive
function. However, the construction of a scaffold or func-
tional organ that can mimic both complexity and precision
of the organ in vivo is difficult. This can be overcome by the
application of a mechanical stimulation based on a biomag-
netic approach (Figure 11c). Different strategies based on

Figure 11.  Magnetic actuation strategies for tissue engineering. a) Production of a cell sheet with magnetically prelabeled cells. Cell expansion of
magnetically labeled cells in a low adhesive cell culture Petri dish placed on top of a magnet yields an easily detachable cell sheet. b) Cell seeding
and invasion in a 3D porous scaffold with magnetically prelabeled cells. Placing a magnet underneath the tissue-engineered construct promotes cell
migration into the porous scaffold and homogeneous dispersion. c) Magnetically actuated scaffolds. The application of a magnetic field will potentially
induce a structural deformation in the scaffold and cells. Adapted with permission.[293] Copyright 2015, Elsevier.

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www.advancedsciencenews.com
Figure 12.  Representative images of the different effects on the cell behavior—mechanical and mechanoelectric—that can be applied through magne-
toelectric scaffolds. Reproduced with permission.[304] Copyright 2016, Elsevier.
biomagnetic biomaterial were developed, such as films,[304–306]
hydrogels,[307,308] fibers,[295,309,310] and 3D scaffolds.[311,312] The
combination of magnetic particles with polymeric biomaterials
has demonstrated large potential for disease treatment and
tissue repair, namely bone,[313,314] muscle,[315] nerve[316] and
cardiac tissue regeneration[317] with external magnetic stimula-
tion. In this way, the magnetically actuated scaffolds allow the
remote delivery of mechanical cell stimulation by the response
of the incorporated magnetic particles. For bone tissue engi-
neering, different kinds of magnetic scaffolds have been devel-
oped, and their evaluation, in vitro and in vivo, was performed.
Magnetic scaffold composed of MNPs and HA were developed
and used to study their influence on the cell behavior with and
without the application of an external magnetic field. Com-
posite scaffold, composed of PLA nanofibers, hydroxyapatite
NPs, and paramagnetic γ-Fe2O3 NPs, was prepared, and the
scaffold responds to the external static magnetic field. These
are implanted in rabbit defects and the results have shown
that NPs incorporated in the nanofibers enhanced bone
tissue formation and remodeling.[318] Other scaffolds with
hydroxyapatite and magnetic particles have been used and
have demonstrated that they can not only modulate cell adhe-
sion, proliferation, and differentiation, but also enhance bone
healing, showing promising results to be used for magnetic
controlling in orthopedic applications based on tissue engi-
neering.[9,319–321] Additionally, a high content of MNPs on the
magnetic scaffolds leads to a more noteworthy stimulation.
In the particular case of MNP-based bone scaffolds, the high
scientific interest results from the better capacity of magnetic
bone scaffolds to promote bone healing,[9] as proven by Hei-
dari et al.,[322] which applied chitosan/nanohydroxyapatite/
Cu–Zn alloy nanoparticle composite scaffolds on bone tissue
engineering. These scaffolds demonstrated improved anti-
bacterial effects and exhibited high potential for tissue engi-
neering in clinic environments. Another successful approach
on magnetic-based tissue engineering was reported by Peri-
yathambi et al.[323] By using goat blood as the starting mate-
rial, the authors prepared new magnetic fibrin and performed
Saos-2 cells’ viability assay and quantified alkaline phosphatase
levels to evaluate the magnetic fibrin nanoparticles. The MNPs
exhibited good biocompatibility allowing it to be used in bone
tissue engineering. Furthermore, adipose-derived regenerative
cell sheets were also produced with magnetite Fe3O4 MNPs
aiming to treat myocardial infarction. Previously, Ishii et al.[324]
have investigated the therapeutic potential of such MNPs. For
that, these NPs were first combined with liposomes to create
magnetic cationic liposomes (MCLs) with a positive surface
charge and later cultured on adipose-derived regenerative
cells. The special cell sheets were found to be a promising
and worthy regenerative strategy for the treatment of ischemic
heart disease.[9,323]
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Other magnetic nanocomposite scaffolds made of magnetic
particles and different kinds of polymers have been devel-
oped to study in vitro cell responses and in vivo tissue compat-
ibility, such as poly(caprolactone),[325,326] silk fibroin/chitosan,[327]
alginate,[328] poly(vinylidene fluoride) (PVDF),[304,329,330] PLLA,[331]
chitosan,[327,332] among others. Iron oxide was incorporated into a
3D-aligned structure of polycaprolactone fibers and starch. Then,
it was used to study the influence of an applied magnetic field on
the adipose stem cells’ differentiation, cultured on theses devel-
oped magnetic scaffolds.[326] The obtained results, on the dif-
ferent magnetic scaffolds, combined with magnetic stimuli have
shown their large potential for tissue engineering.
As a novel approach, magnetic particles have been used to
obtain a magnetoelectric scaffolds,[295,333,334] where these scaf-
folds, remotely triggered by an external magnetic field, can
provide electrical and mechanical stimulation to the cells.
Thus, it has been shown that magnetoelectric Terfenol-D/
poly(vinylidene fluoride-co-trifluoroethylene) multiferroic com-
posites can enhance the cell proliferation of MC3T3-E1 pre-
osteoblast.[304] In this way, magnetoelectric cell stimulation
represents an innovative and appropriate approach that allows
magnetic, mechanical, and electrical stimuli (Figure 12).
However, the use of artificial scaffolds in in vivo environ-
ments can become a problematic issue; once after their trans-
plantation, they can limit the cell migration into and from
the scaffold, and their degradation can induce an inflamma-
tion.[296,335] In this way, another approach includes the construc-
tion of 3D tissues without the use of scaffolds.
MCLs were extensively studied for tissue engineering appli-
cations once they provide the possibility of reconstructing a 3D
tissue without scaffolds, allowing also cell patterning.[336–338]
Basically, MLCs present a positive charge at the liposomal sur-
face that can interact with the negative charge of the cell sur-
face, being able to be used as carriers introducing magnetite
particles into the target cells, obtaining cells labeled with mag-
netite particles. So, in this way, these cells can be manipulated
by the use of a magnetic field (such as magnets or magnetic
bioreactors) for the construction in vitro of 3D tissues, mul-
tilayered cell sheet-like structures and tubular structures, as
well as to isolate target cells in culture systems for the isola-
tion and recovering of target cells.[293,339] This technique is
identified as magnetic-force-based tissue engineering (Mag-
TE, Figure 11a)[337] and has been used for different kinds of
TE applications, such as bone,[337,340] muscle,[341–344] skin,[345]
vascular,[346–348] cardiac,[349,350] and retinal[351] applications.
The definition of Mag-TE was proposed in 2008 by Mironov
et al. as “the bioinspired fabrication of more complex tissue
is performed using cells, cellular monolayers, and cell aggre-
gates labeled with MNPs.”[348,352] MCLs have been used for the
construction of 3D artificial skeletal muscle by the labeling of
myoblast cells applying a magnetic force.[341] This approach has
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received increasing attention for vascular tissue engineering
once it allows the construction of 3D vascular tubes.[346,348]
MCLs have also been employed to enrich and proliferate mes-
enchymal stem cells in vitro for clinical application.[353] Bone
marrow stromal cells were used to construct a cell sheet to be
transplanted into a bone defect, enhancing the formation of a
new bone.[354]
Other strategy is related to cell seeding in a 3D porous
scaffold for cell proliferation and differentiation to be later
implanted in the injury local. However, this approach presents
some unsolved challenges due to the depth and structure of the
3D scaffolds.[293] To overcome these problems, labeling cells
with magnetic particles can be used to be seeded into the scaf-
fold surface, as with the application of magnetic forces they can
be driven to invade the pores of the scaffold (Figure 11b). This
technique is named Mag-seeding and allows cell distribution
with great precision and resolution.
Finally, despite MNP-based scaffolds with the “core–shell”
structure, which have unique biological, physical, and chemical
properties such as nontoxicity and biocompatibility that make
them good candidates for tissue engineering applications, fur-
ther investigations into their diagnostic and therapeutic appli-
cations are necessary before considerations.[9]
3.4. Theragnosis
In the last two decades, there is a great interest for conceptu-
alizing and developing nanotechnology systems that are able
to diagnose and treat diseases such as cancer. Different from
traditional molecular contrast agents and therapeutics, the new
concept of cancer nanomedicine aims at integrated designs to
explore multiple functions in one system, including targeting
the site of interest, sensitive imaging, and therapy, the so-called
all-in-one system.[355] Multifunctional nanotechnology systems
are considered the next-generation materials in medicine that
would eventually enable premature detection of disease, simul-
taneous treatment, and monitoring of the response to the treat-
ment, and targeted therapy with low toxicity. The theranostics
paradigm was originally seen as a treatment strategy that joins
a targeted therapy with a diagnostic test. Nowadays, the thera-
nostic nanomedicine evolved into integrated nanotherapeutic
systems that are able to diagnose, deliver targeted drug therapy,
and monitor the reaction to therapy, all at the same time.
Lammers et al. highlighted the paramount importance of
imaging function within the nanotheranostic platforms for
three-level monitoring of therapy: (i) drug delivery, (ii) drug
release, and (iii) drug efficacy.[356] The optimization of this
three-level imaging and combination with the therapeutic func-
tion within a single nanoformulation aspire to provide real-
time feedback on drug kinetics, drug localization on target site,
and off-target accumulation (i.e., in healthy organs). Possibility
of monitoring real-time drug release and distribution opens
avenues for predicting the effectiveness of the therapy and opti-
mizing treatment outcomes—steps toward performing a real
personalized medicine that takes into account individual vari-
ability of response to treatments.[357]
Imaging of drug delivery refers to allowing easy, noninvasive,
and real-time pharmacokinetic and biodistributional analyses
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in order to improve drug targeting to pathological sites.[356]
Deep insight into the drug delivery process is a prerequisite for
predicting the therapeutic outcome of the used treatment. In
this way, the studies directed to real-time imaging of therapy
delivery may enable distinguishing between the carrier mate-
rials suitable for long circulation and systemic administration
of drugs, as well as those that more effectively accumulate in
targeted tissues, e.g., tumors.[358]
Not only it is important to predict the accumulation of
therapy at the target site, but it is also necessary to know if
the used drug is efficiently released. Many literature studies
are reporting only in vitro release kinetics in proof-of-concept
studies for developing novel therapeutics and carrier materials.
However, visualization and analysis of the release patterns
under physiologically relevant in vivo conditions is far more
complicated. The post-therapy analysis, for example, includes
cell lysis and release of drugs into suitable analysis buffers, the
procedures that can lead to destabilizing carriers and drugs,
resulting in ambiguous analysis outcomes. Enabling real-time
in vivo visualization of the drug release would overcome this
shortcoming. Therefore, theranostic nanoformulations also
aim at simultaneous loading of carriers with drugs and imaging
agents for real-time monitoring of drug release. Of particular
usefulness for such applications are contrast agents for MRI,
which emit different signals depending on the interaction
with surrounding environment, i.e., inside carriers and when
released at the targeted site. Noninvasive visualization of drug
release could be achieved through generation of an increased
MR signal in case of release of contrast agents versus the signal
of nonreleased agents. One of the systems that enabled non-
invasive visualization of drug release via increased MR signal
is based on temperature-sensitive carriers that, at temperatures
below the transition temperature, emitted signals that are com-
parable to nonsensitive carriers, but the signal substantially
increased upon heating to temperatures exceeding the transi-
tion ones.[359,360] Such a system also proved suitable for moni-
toring of doxorubicin release.[361]
A dual MR-contrast technique for monitoring drug release
from theranostic nanoformulations was introduced that relies
on synthetic polymer-based carriers loaded with 5-fluorouracil
(5-FU) as anticancer drug and two contrast agents: gadolinium–
diethylenetriaminepentacetate (Gd-DTPA) and super-paramag-
netic iron oxide NPs.[362] Immediately upon intravenous admin-
istration, a strong T2 contrast was found in the tumor area as a
result of the presence of iron oxide NPs, which remained unal-
tered for 2.5 h. In contrast, T1 contrast that corresponds to the
release of Gd-DTPA from these NPs was spotted only after 30
min upon administration and lasted less than T2 contrast (less
than 2.15 h). Assuming that 5-FU is released from iron oxide
NPs with the same kinetics as is Gd-DTPA, this system thus
allowed for simultaneous screening of both therapy delivery
and drug release. Despite all the advances in monitoring drug
release, in vivo screening is by far the most difficult task for
drug imaging, as it requires developing systems with increased
complexity.
Real-time imaging of drug efficacy requires somewhat less
complexity in the theranostics development. The theranostic
nanoformulations featuring this property are based on pre-
dicting and monitoring therapeutic responses for personalized
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therapy concepts. Also, imaging of drug efficacy is tightly
related to drug delivery, since both require precise informa-
tion with regard to target site accumulation. Nevertheless, the
rational predictions of therapeutic efficacy are only possible in
clinical trials. In a simplified concept, a trial should focus on
imaging a theranostic nanoformulation for prescreening the
patients in order to identify who have tumors permeable to
the used therapy and who have not, thereby predicting which
patients are likely to respond to the therapy. Good tumor accu-
mulation of a nanotheranostic would typically means a good
response to a therapy. A continuous subjection of patients to
imaging during receiving the therapy would allow visualiza-
tion of the therapy efficacy in real-time (e.g., tumor shrinking),
which is important information for deciding if the therapy
should be continued or not, and whether or not to adjust drug
doses. This is the main goal of theranostic nanomedicines for
tailor-made therapy on individual patients.[356]
Recently, magnetic NPs (e.g. iron oxide) have replaced tradi-
tional gadolinium contrast agents that are widely available as
commercial formulations, but commonly featuring poor body
clearance. Iron oxide NPs’ expansion as contrast agents is owed
to their high magnetic moment and very high resolution in
noninvasive monitoring of their distribution and accumulation
in soft tissues. Furthermore, magnetic NPs, if used in suitable
concentrations, offer additional hyperthermia effect and also
the possibility to be used as carriers themselves for entrapment
of various drugs.[363,364] They can also be externally controlled
(via magnetic field) for targeted delivery of these NPs, which
may, in addition, reduce toxicity risks (used in small concen-
trations) and offer enhanced treatment specificity.[365] Thus,
multifunctionality makes the magnetic NPs extremely attractive
for developing theranostic nanoformulations for personalized
nanomedicine.
Iron oxide NPs are unique in featuring all the above-men-
tioned functionalities and are perhaps the most promising
nanoplatforms for clinical applications, especially regarding
treatment of cancers (Figure 13). As a consequence, several
formulations based on iron oxide NPs received FDA/ European
approval for cancer imaging or are currently and the clinical
trial stages for therapy approval (Table 1). The approved formu-
lations are dominated by dextran-doped NPs, since dextran was
Figure 13.  Schematics of multifunctionality within theranostic magnetic NPs for tumor targeting, imaging (diagnosis) and therapy.
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the first (bio)polymer extensively investigated in experimental
animal models and in humans as an MRI contrast combined
with magnetic NPs. While these NPs provide high contrast
imaging, the heating efficiency of magnetic hyperthermia
is often low to effectively treat most advanced tumors using
toxicity-free concentrations. For providing only one function-
ality, some of these formulations have been discontinued or
their production is abandoned by the manufacturers. Instead,
new trend is the synthesis of hybrid inorganic magnetic nano-
constructs or combining magnetic NPs with traditional or
advanced therapeutics to achieve synergistic antitumor effects
via a variety of mechanisms.
An increase of MR contrast effects can be even achieved by
the substitution of one of the Fe ions in iron oxide NPs with
magnetic or nonmagnetic atoms replace the Fe ions.[366] For
example, the substitution of Fe ion with Zn2+ synthesizes Zn-
doped ferrite NPs of ≈15 nm with increased magnetization.[367]
An optimum Zn-to-Fe doping ratio to enhance the contrast
effect was found at Zn2+ of 0.4, which is six times higher than
that achieved by commercially available iron oxide formulation
Feridex. In another approach, the T1 and T2 contrast effects
were merged in a dual-mode contrast agent for providing
more accurate MRI and were better distinguished between
the normal and diseased areas.[58,368] Core–shell-type inorganic
NPs were fabricated with the fine layer of Gd-based T1 contrast
agent in the shell for direct contrast effects and the super-para-
magnetic T2 contrast material (MnFe2O4) of 15 nm in the core,
separated by SiO2. Using this hybrid structure, ambiguity of the
single mode contrast agent from different artifacts is effectively
eliminated, while self-confirmation of images is allowed and
leads to larger diagnostic accuracy.
Doxorubicin, as an FDA-approved agent, is by far the most
frequent anticancer drug loaded onto magnetic NPs, regardless
of the study positioning: from proof-of-concept to clinical trials.
A wide variety of cancers and tumors, including breast,[369]
lung,[370] and colon,[371] were investigated after subjection to
doxorubicin-loaded magnetic NPs, synthesized and function-
alized by many different methods. Doxorubicin is followed by
other anticancer drugs such as paclitaxel,[372] methotrexate,[373]
and epirubicin.[374] Despite achieving the great advances, espe-
cially when combined with targeted functions, and the fact
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1.  Some of the magnetic NPs clinically approved or in the phase of clinical trials.
Commercial name Formulation
Feridex Iron oxide coated with dextran
Combidex Ultrasmall iron oxide coated
with low Mw dextran
Resovist Iron oxide NPs coated with
carboxyldextran
Gastromark Silicone-coated iron oxide NPs
Feraheme Iron oxide coated with polyglucose
sorbitol carboxymethylether
Nanotherm Iron oxide NPs with aminosilane coating
that there exists the highest possibility that magnetic NPs will
be applied in future with some of these drugs in clinics, the
remaining issues for chemotherapeutics are the side effects
and resistance acquired by different tumors. The current inves-
tigation interests are therefore shifted to the combination of
magnetic NPs with advanced therapeutic options.
One of the most promising advanced solutions, as alterna-
tives to chemotherapies for cancer management, regards to
therapeutic DNA to correct a genetic defect or RNA interfer-
ence for gene silencing. For example, the use of siRNA mole­
cules are meant to specifically turn off the abnormal gene
expressions or genetic mutations in cancer cells. DNA and RNA
molecules alone are fairly ineffective due to their sensitivity in
complex physiological environments. Magnetic NPs are, thus,
increasingly investigated as carriers for gene delivery.[375] The
first prerequisite for magnetic NPs to be effective carriers is the
surface modification to allow the attachment of DNA or RNA
molecules. Some of the most popular ways employ cleavable
linkers (in the case of stimuli-responsive delivery) or utilization
of electrostatic interactions between the therapeutic molecule
and the surface of the nanoparticle. Alternatively, the active
molecules are incorporated into a degradable, in the tumor
environment, outer shell, which releases the incorporated mole­­
cule as it is broken down.
Conjugation of DNA with magnetic NPs is mostly achieved
via the NPs’ surface modification with polyethyleneimine (PEI),
especially with low-molecular-weight ones, as it shows strong
binding affinity and good protection of nucleic acids for trans-
fection purposes.[376] This approach is still in the investiga-
tion phase, but it results in more and more promising studies
toward clinical trials. For instance, super-paramagnetic NPs
with enhanced physiological stability can be achieved with
this method, combining targetable and convenient system for
delivering multiple genes into the desired cells or tissues.[377] A
stable and efficient coexpression of fluorescent proteins could
be achieved by magnetofection. An excellent study for delivery
of both DNA and siRNA was published by Jiang et al.[378] The
delivery system was based on iron oxide NPs of varying size
and cationic lipid-like materials, termed lipidoids. The study
shed the light on optimizing the diameter of magnetic NPs
for specific gene delivery. While siRNA molecules were intra-
cellularly delivered in similar extents by using different sized
NPs, spheres of 50–100 nm exhibited optimized DNA delivery.
Applied magnetic fields expressively increased the efficiency
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Application Status
MRI FDA approval, discontinued in 2008
MRI Approval in Europe, withdrawal in 2007
MRI Approval in Europe, production abandoned in
2009
MRI FDA approval, discontinued in 2012
Initially, iron-replacement therapy; FDA approval
Currently, MRI
Hyperthermia in solid tumors Clinical trial
of nucleic acid delivery (remote control of delivery), compared
to the commercially available agents. The study came to the
nearest to the multifunctional concept for the iron oxide nano-
particle gene delivery platform developed due to combining
magnetically guided targeting, and possibility of providing gene
therapy with MRI and magnetic hyperthermia.
The first study for in vivo imaging of siRNA delivery and
silencing in tumors considered probes for in vivo transmission
of siRNA and the synchronized imaging of its accumulation in
tumors by NIR optical imaging and high-resolution MRI.[379] The
probes comprised NIR dye/magnetic NPs/siRNA complexes to
enable the silencing and visualization of the process, providing
a reliable siRNA delivery and imaging approach that is impor-
tant for the development of cancer theranostic agents. In addi-
tion, the targeting of two separate tumor models was achieved
by modification of the nanoprobes with a membrane trans-
location peptide for intracellular delivery. This study encour-
aged other similar ones to use the all-in-one concept based on
magnetic NPs for simultaneous molecular imaging and siRNA
delivery.[380] The iron oxide nanoplatform was decorated with a
fluorescent dye, siRNA, and a Arg-Gly-Asp (RGD)-peptide tar-
geting moiety to enable macroscopic–microscopic dual imaging
of target cells and concurrent therapy. More recently, “stealth”
NPs, i.e., PEG-coated iron oxide NPs for miRNA delivery to
overcome drug resistance in gastric cancer cells by enforcing
miRNA expression in tumor cells are reported.[381] In this con-
text, miRNA delivery was combined with doxorubicin treatment
as a way to modulate the drug resistance and increase sensi-
tivity of tumor cells to doxorubicin therapy. Besides the invis-
ibility effect, PEG increased the biocompatibility of iron oxide
NPs, whereas miRNA was conjugated via electrostatic interac-
tions. The produced miR16/iron oxide NPs significantly sup-
pressed the tumor growth in a drug-resistant gastric cancer
mouse model allowing also in vivo imaging of the process.
Most recently, multifunctional iron oxide NPs were used to
deliver siRNA to downregulate the cell cycle-specific serine–
threonine-kinase, polo-like kinase-1 gene in pancreatic ductal
adenocarcinoma in animal models.[382] This advanced magnetic
nanoparticle-based system was further upgraded with a pancre-
atic-cancer-targeting ligand and a peptide for endosomal escape
peptide for specific tumor recognition and effective intracellular
delivery. Tumor growth ablation was directly visualized by MRI
as a demonstration of simultaneously achieving tumor-specific
gene therapy and monitoring of the tumor regression.
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3.5. Lab-on-Chip Applications
Since the advent of the original concept almost three decades
ago,[383] LOC technology is assumed to be one of the leading
and most promising research areas as a demand for achieving
affordable integrated ever-increasing automated miniatur-
ized healthcare systems providing monitoring, diagnosis, and
therapy.[384] The vision beyond the development of LOC plat-
forms is to integrate common laboratory functions into one
single chip within an area of only a few square centimeters with
the aptitude to identify toxins, biochemical products, or disease
symptoms, and allow biological screening essays or targeted
drug delivery.[385,386] Moreover, they demonstrated the poten-
tial and ability to be applied in a wide range of other techno-
logical applications beyond healthcare involving environmental
monitoring, food, agriculture, and biochemical research.[387,388]
LOC term is often indicated in the literature as an alternative
name for Micro Total Analysis Systems or even microfluidic
systems. An overview of the various operation units that can
integrate an LOC, including sample preparation, sample injec-
tion, sample manipulation, reaction, separation, and detection,
is presented in a series of relevant reviewed articles.[389–391]
LOC technologies provide numerous benefits over their mac-
roscopic conventional counterparts, including minute con-
sumption of the reagent and sample due to the miniaturized
microchannel dimensions and therefore producing reduced
amount of waste, relatively fast reaction time by the increased
surface-area-to-volume ratio for efficient mass transport, par-
allel operation for high-throughput analysis, and integration of
multifunctional units such as valves, pumps, mixers, actuators,
sensors, and detectors for in situ analysis.[318,392] Moreover, they
have the potential to be low cost, portable, and of simple and
practical handling. Microfluidic systems were originally fabri-
cated in silicon and glass, but as the field advanced, the focus
shifted to cheaper, simpler, and less consuming manufacturing
techniques involving polymer substrates, particularly polydi-
methylsiloxane (PDMS) and other distinct materials.[391,393]
More recently, paper emerges as a promising alternative flex-
ible and versatile material with unprecedented easy-to-use solu-
tion for low-cost and point-of-care devices that come from its
mechanical flexibility and strength, low cost, high availability,
and easy chemical functionalization. Its porous structure, com-
posed of a network of hydrophilic cellulose fibers, enables the
transport of fluids through capillary action, without the need
for external forces such as pumps.[394–396] The required func-
tion, degree of integration, and application are the main factors
to be considered when choosing a design and material, which
are closely related to materials’ properties and manufacturing
processes.[391] Moreover, biocompatibility, flexibility, optical
transparency, air permeability, thermal stability, electrical con-
ductivity, and nonspecific adsorption are physical features that
may set as the material choice.
Parallel to the boom of LOC, nanomaterials attracted large
attention in the scientific community and have been combined
with these platforms to improve the analytical performance
and overcome the frequent constraint inherent to miniaturiza-
tion in terms of sensitivity and selectivity, especially when con-
cerning the analysis of real samples.[397] This is mostly related
to their superior surface-to-volume area for further surface
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modification or functionalization compared to flat surfaces or
macroscaled particles. This modification can be performed in
order to modify a wide range of surface properties including
roughness, hydrophilicity, surface charge, surface energy, bio-
compatibility, reactivity, among others.[397] In particular, the
use of MNPs in LOC systems provides new possibilities of
capturing, transporting, labeling, and detecting entities in com-
plex aqueous systems, as they can be influenced and guided by
an external magnetic field by means of permanent magnet or
electromagnets, which is independent of any other biological,
microfluidic, or chemical procedures.[398] Furthermore, mag-
netic manipulation approaches do not harm or change the
sample that is imperative, particularly, in biomedical applica-
tions. The key to develop improved systems is the combination
of the proper affinity agents onto the surface of MNPs. Specially
hybrid MNPs consisting of ferromagnetic NPs of a few tens
to hundreds of nanometers in diameter embedded in a non-
magnetic matrix, such as polymer, silica, or quartz, have been
widely developed not only to stabilize NPs and avoid agglom-
eration due to van der Waals forces but also to enable further
functionalization to be used in a wide range of biotechnological
and biomedical applications, including magnetic separation,
immunoassays, drug delivery, and hyperthermia studies.[33,399]
These nano- and microsized particles with super-paramagnetic
behavior are frequently called magnetic beads due to their
spherical shapes and feature nonmagnetic behavior, unless
when exposed to a magnetic field. Moreover, they can come
with a wide range of sizes, physical and chemical properties,
and their surface functionalization can be tailored with bio-
logical and chemical ligands to accomplish specific bioanalyt-
ical tasks. Such beads can be usefully utilized as vehicle sub-
strates in bioassays, catalysis or even in vivo uses since they
can be easily recovered from a dispersion or as packed beds to
enhance interaction of reactive surfaces with fluids passing by
the microchannel of the microfluidic system.[400]
An important application of microfluidic technology that has
shown promising potential is the synthesis of nanomaterials,
including MNPs for a wide range of biotechnological applica-
tions, where critical stages such as nucleation, growth, and
reaction conditions can be modulated in order to control and
tailor morphology, size, size distribution, and reproducibility.
In fact, in contrast to conventional batch methods, precise con-
trol, rapid heat and mass transfer, high mixing efficiency, and
large reaction interfaces can be achieved in continuous-flow
microfluidic systems with online analysis. A PDMS T-junction
microfluidic system combined with an aluminum foil-based
UV light reflector was developed to controllably synthesize
magnetic (γ-Fe2O3) hydrogel microparticles in spherical and
nonspherical shapes. The MNPs were successfully encapsu-
lated in the hydrogel, providing the microparticles super-para-
magnetic properties that is required in most biotechnological
applications. Moreover, nonspherical particles have anisotropic
responses under an external magnetic field, offering features in
various fundamental studies and applications.[91] Hollow Fe/Ga-
based oxide nanospheres were also synthesized using a PDMS
microfluidic bioreactor comprising a micromixer, a microcon-
denser channel, microvalves, a microheater, and a microtem-
perature sensor. The developed NPs feature a diameter of about
157 ± 26 nm and saturated mass magnetization of 14.4 emu g−1
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at 300 K increasing to 18.8 emu g−1 at 5 K. The microfluidic
system may be a promising tool to produce hollow NPs for
drug delivery purposes.[401] A natural-rubber-based microfluidic
device was designed and fabricated for the synthesis of mag-
netic-decorated gold NPs (Fe3O4–AuNPs), which is a ferromag-
netic material with extraordinary potential for applications in
immunosensors, in photothermal ablation of tumor cells, and
as a contrast agent for imaging diagnosis. Monodispersed Fe3O4
NPs (10 nm) homogeneously decorated with uniform AuNPs
(4 nm), free of organic solvent and surfactants, were obtained.[402]
Biomimetic cell membrane-coated NPs were also obtained by
means of a PDMS microfluidic electroporation system. When
a mixture of Fe3O4 MNPs and red blood cell-membrane-derived
vesicles (RBC vesicles) flow through the electroporation zone,
applied electric pulses promote the entry of the MNPs into
the RBC vesicles. In vivo experiments of the resulting mate-
rials enhanced tumor MRI and photothermal therapy owing
to the superior magnetic and photothermal properties of the
MNP cores and the long blood circulation characteristics of
the RBC membrane shells.[403] Another interesting and dif-
ferent microfluidic system was designed for fabricating, in a
one-step continuous process, sophisticated alginate microfibers
(Figure 14a).[404] A fluid-focusing technique with two dimen-
sions, multi-inlets, and multijunctions was utilized to control
the unceasing laminar flow of alginate solutions without them
clogging the microchannels (Figure 14b). The diameter of the
microfibers (in the 177.4–364.3 µm range) is simply managed
by regulating the flow rate and channel size of the microflu-
idic system (Figure 1c–f). Diclofenac-loaded microfibers exhibit
a drug release profile characteristic of a proper and steady
release. Furthermore, the release kinetics of diclofenac could
be actively controlled by magnetic iron-oxide-loaded micro-
fibers, allowing for a rapid drug release by applying an external
magnetic field. The successful culture of glioblastoma multi-
form cells proved that the developed microfibers can provide a
good structural integrity and environment for cell culture and
tissue engineering applications that could be applied in drug
screening for targeting cancer cells.[404] Relevant reviews that
address nanomaterial synthesis in microfluidic systems can be
found in refs. [90,405–407].
Recent technological advances also provide new tools to
manipulate entities in micro/nanoliter volumes. In fact, the
capability of capturing and isolating biological entities at the
microscale level, combining LOC and MNP technologies, cre-
ates the potential for cost effective, portable, and disposable
point-of-care systems to monitor and detect various diseases.
In particular, the detection and isolation of circulating tumor
cells (CTCs) play a key role in the diagnosis and prognosis of
cancer, while the high capture efficiency and purity of CTCs are
difficult to reach simultaneously among the various conven-
tional isolation methods due to the small throughput, incapa-
bility to release captured cells, and dependence on expensive
instrumentation for enrichment or subsequent characteriza-
tion.[408] In an attempt to take a step forward to overcome the
aforementioned limitation, an inverted microchip integrating
silicon nanowires (SiNW) and multifunctional magnetic nano-
composites based on anti-EpCAM-Fe3O4@C6/Ce6@silane
(anti-epithelial cell adhesion molecule (EpCAM)) was designed
to enhanced capture efficiency and purity of CTCs.[408] The
system allows real-time detection and photodynamic therapy
of CTCs and showed improved capture purity of CTCs to 90%
and CTCs’ capture efficiencies of 90.3% and 82% in culture
medium and blood samples, respectively. A similar system
composed of anti-EpCAM conjugated with magnetic upcon-
version NPs was introduced into a microfluidic chip for spe-
cific recognition and detection of CTCs with enhanced CTC

Figure 14.  a) Photograph of the microfluidic chip: 1, inlets of center channels; 2 and 3, inlets of side channels; 4, cross junction; 5, outlet; 6, obser-
vation channel; 7, bottom layer disk; 8, screw orifices; 9, the scale bar of 11 cm. b) Schematic representation of the microfiber formation: 1, 2 wt%
CaCl2 solution; 2, deionized water; 3, alginate solution; 4, sunflower seed oil; 5, observation channel; 6, microfibers. The formation of microfibers: A,
photograph of the microfiber in the observation channel; B, photograph of the second cross junction; C, photograph of the first cross junction. c,e)
Microscopic images of microfibers stained with rhodamine B. d,f) Scanning electron microscopy images of microfibers. Adapted with permission.[404]
Copyright 2012, the authors, published under the terms of CC-BY license.

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www.advancedsciencenews.com
capture obtained by an integrated SiNW array that allows the
further convenient release of captured CTCs for analysis and
reculturing. The systems demonstrate good consistency in real
clinical samples for lung cancer patients.[409] A magnetic-force-
gradient-based microfluidic chip was also reported for simulta-
neously isolating CTCs in the sample and characterizes their
state with respect to EpCAM expression level. The systems
used Fe3O4 NPs functionalized with (3-glycidylox-ypropyl)tri-
methoxysilane for immobilization of EpCAm antibody on their
surface for the specific binding with CTCs. The system was able
to isolate 3 mL of the heterogeneous CTC sample in 1 h with
high isolating yield demonstrating its potential to shorten the
date to diagnose the cancer metastasis in clinic.[410] A different
approach through a microfluidic platform comprising three
different modules demonstrated high-throughput separation
of cancer cells from blood and on-chip organization of those
cells for streamlined analysis. While the first module employs
acoustic stranding waves to rapidly align cells, the second
module separates magnetically labeled cells from unlabeled
cells, offering purities beyond 85% for cells and 90% for binary
mixtures of synthetic particles. The last module integrates an
array of microwells with underlying micromagnets to capture
individual cells for on-chip analysis. The high capture efficiency
of 80% of magnetically labeled cells demonstrates the potential
of this system not just for the isolation and evaluation of rare
cancer cells, as it can be readily extended to address a variety
of applications across single cell biology and immunology.[411]
Extensive reviews of the latest advances in microfluidic rare cell
separation and processing can be found in refs. [412–415].
New techniques for HIV diagnosis and monitoring are also
needed to overcome the high cost, technically complex and
time-consuming conventional techniques to measure CD4+ cell
count such as flow cytometers, particularly when it comes to
developing countries. So far, several CD4+ cell counting tech-
niques have been implemented using microfluidic systems,
which require precise manipulation of blood on-chip[416] A
simple, rapid, and inexpensive CD4+ isolation and counting
device based on antimouse CD4 magnetic beads bed immu-
noassay was reported. CD4+ were successfully separated and
captured at a maximum capability of about 700 cell µL−1. The
system has the ability to avoid complex sample pretreatment
and the entire analysis time was significantly reduced to 15 min.
Though the separation of CD4+ from mouse was taken as a
model, it can also be used to separate and count human CD4+
with the antihuman CD4 magnetic beads, with the objective
to monitor HIV in resource-limited settings.[417] A dual-force
cellular separation strategy using centrifuge–magnetophoresis
was also developed and demonstrated separation efficiency
up to 92% for cells expressing CD4+ from whole blood. The
system uses a combination of super-paramagnetic Dynabeads
CD4 MNPs that specifically bind phenotypic markers on target
cells and centrifugal force to isolate magnetically specific cel-
lular phenotype.[418] Another system to isolate magnetically
tagged CD4+ cells directly from patient blood works by dual-
force CD4+ magnetophoresis, through which the interplay of
magnetic forces and flow controls the trajectory of target cells
depending on whether the cells binds to a magnetic bead. High
capture efficiency of about 93% was obtained from a back-
ground of nonmagnetic particles, and a linear relation between
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the amount of CD4+ cells in blood and the packing level
detected in the capture region was observed.[418] An interesting
review about the use of nano- and microfluidic technologies for
diagnosis of infectious diseases in developing countries can be
found in ref. [419].
Viral infectious diseases, such as severe acute respiratory
syndromes including norovirus and influenza, have been a
severe threat to human health worldwide, and therefore the
capability of rapidly detecting this kind of infections is a vital
need to be addressed in order to provide immediate and appro-
priate clinical treatment. A suction-type microfluidic system
using mAb-bound magnetic beads was developed for the rapid
and automatic immunological diagnosis of influenza infection.
The system comprises a control and optical detection module
to allow biosample incubation, purification, and optical analysis
automatically. Influenza concentration of 0.128 HAU with a
detection time of 30 min was obtained with the system.[420] A
more promising integrated microfluidic device with dynamic
mixing was later developed to perform the automatic detec-
tion of influenza infection using magnetic manganese fer-
rite (MnFe2O4) NPs with ≈100 nm diameter. This NP-based
immunoassay combined with layer-by-layer surface modi-
fication achieved a detection limit of influenza as low as
0.007 HAU within 20 min, showing promise for rapidly diagnosis
of infectious diseases. The fluorescence immunoassay signal
was increased by approximately twofold when compared with
commercial 4.5 µm magnetic beads due to the large surface-to-
volume ratio.[421]
Magnetic microfluidic arrangements were also established
for the diagnosis of malaria, which is a mosquito- transmitted
infectious illness that affects more than 3 billion people, ≈50%
of the total world’s population. An example is the system pre-
sented in Figure 15 that combines the use of microfluidic tech-
nology for the separation of infected red blood cells (iRBCs) and
the magnetic resonance relaxometry system for the label-free
and fast detection of malaria parasites. The iRBCs are separated
from the healthy red blood cells (hRBCs) through margination.
Moreover, it was shown that the existence of hemozoin crystal-
lites or natural paramagnetic malaria pigment in iRBCs serves
as a natural biomarker for malaria recognition, where the bulk
magnetic susceptibility of the iRBCs is considerably higher than
the hRBCs. This induces a substantial change in the transverse
relaxation rate. The microfluidic system demonstrates the capa-
bility of detecting ring stage parasites at parasitemia as low as
0.0005%. The approaches used are envisaged to provide a new
malaria diagnosis solution in the near future (Figure 15).[422]
Other microfluidic diagnosis systems were developed for the
detection and quantification of relevant biological entities. Glu-
cose and creatinine were successfully measured at (2–8) × 10−3
and (10−2–10) × 10−3 m, respectively, in a blood serum by means
of enzyme-coated magnetic beads immobilized on the surface
of an electrolyte–insulator–semiconductor sensor though an
external magnetic force on a microfluidic chip. The immobili-
zation method addresses the concern of long-term preservation
of enzymes in microchannels.[423] Another low-cost and effi-
cient microfluidic system was designed to quantify glucose by
packing enzyme modified MNPs as an enzyme microreactor.
The optimal linear ranges from 25 × 10−6 to 15 × 10−3 m with a
detection limit of 11 × 10−6 m and a reproducibility of 95.6%.[424]
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com www.advhealthmat.de

Figure 15.  Schematic representation of a) microfluidic microagitation device comprising two microfluidic components: a margination layer and a cover
layer. The margination layer consists of seven parallel margination channels. The yellow circles indicate the tubing ports’ locations. b) Zoom-in of the
inlet and filtration unit. The microstructures and pillars trap the coagulated blood and large debris to avoid channel blockage in the long and narrow
margination channels. c) Bifurcation outlet at the end of each margination channel. The hRBCs migrate to the axial axis of the microchannel and exit
via the middle outlet, while the stiffer iRBCs are directed to the sidewalls and exit via the side outlets. d) Complete microfluidic separation device with
one inlet, two outlets, and a margination channel. The insets show the schematic of the cross-sectional view of hRBC and iRBC distributions before
and after passing through the margination channel. The initially randomly distributed stiffer iRBCs are directed toward the sidewall, while the more
deformable hRBCs migrate toward the axial center of the microchannel. e) Bench top MRR system. The blood sample is centrifuged in a microcapillary
tube and loaded into MRR receiver coil placed inside a 0.5 T permanent magnet. The receiver coil is connected to a bench-top spectrometer for MRR
measurements. Adapted with permission.[422] Copyright 2015, the authors, published under the terms of CC-BY 4.0 license.

Another interesting microfluidic immunosensor was developed
for the electrochemical detection and quantification of immu-
noreactive trypsinogen (IRT) as marker for cystic fibrosis diag-
nosis. The system features two distinct approaches: the incor-
poration of MNPs into the central microfluidic channels and
performing as a bioaffinity scaffold for the immobilization of
the antibody against the immunoreactive trypsin (anti-IRT)
and the electrodeposition of copper NPs on a gold electrode.
Compared with the conventional enzyme-linked immuno-
sorbent assay (ELISA) analysis, the developed immunosensor
reduces the total assay time in less than 40 min.[425]
The detection and identification of bacteria is also crucial
in many fields of science and society. A automated microflu-
idic chip-based μ-Hall platform capable of measuring single,
magnetically tagged bacteria directly in clinical specimens was
developed (Figure 16).[426] Besides the minimal processing
and robust detection in different biological background,
the microfluidic system features high-throughput detection
(107 cells min−1) in a simple and automatic compact and self-
contained device. The system was successfully tested for the
detection of Gram-positive bacteria using vancomycin as the
targeting ligand. The overall detection limit of the system was
similar to that of the culture platform but the essay time was
50 times faster. Such results demonstrate the potential of this
powerful diagnosis tool for controlling infectious diseases and
promoting public health.
A different two-step microfluidic essay based on immuno-
extraction and enrichment in situ was developed to detect the
specific presence of Salmonella typhimurium from a complex
liquid sample based on a magnetic fluidize bed using Dyna-
beads anti-Salmonella. The system allows for a precise quanti-
fication of the initial bacteria coupled with a very high sensi-
tivity, after a few hours versus 2 d in conventional cell culture
platforms.[427] Helicobacter pylori is another relevant micro-
organism that affects around 10% of the world population
causing peptic ulcers and chronic gastritis. Noninvasive tests
that include serological tests and the urea breath test have been
pointed out as viable alternatives to invasive methods such
as endoscopy with biopsies for histology, culture, and rapid
urease test. Recently, a microfluidic magnetic immunosensor
coupled to a gold electrode for the fast and very sensitive quan-
tification of human serum immunoglobulin G (IgG) anti-
bodies to H. pylori was documented. The detection in serum
samples is performed using a noncompetitive immunoassay
based on the utilization of purified H. pylori antigens coupled
with 3-aminopropyl-modified magnetic microspheres. The
response obtained from the product reaction is directly pro-
portional to amount of IgG antibodies to H. pylori in serum
samples. The determined limits for electrochemical detection
and the ELISA procedure were 0.37 and 2.1 U mL−1, respec-
tively, and the within- and between-assay coefficients of varia-
tion were less than 5%. Moreover, the electrochemical detection

Adv. Healthcare Mater. 2018, 7, 1700845 1700845  (26 of 35) © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
Figure 16.  Design and implementation of the bacterial μHall sensor. a) A
photograph of the μHall device shows an array of μHall sensors incorpo-
rated onto a semiconductor substrate with PDMS microfluidics directly on
top. b) Eight μHall sensors, each measuring 8 µm × 8 µm were arranged
into an overlapping array across the fluidic channel. The dotted lines indi-
cate the width of the sample flow. c) The voltage signal (VH) was simulated
as a function of the vertical distance d between the center of a bacterium
and the surface of the Hall sensor. d) To enhance the μHall signal, a hydro-
dynamic focusing structure was used to bring individual pathogens close to
the μHall sensor. With hydrodynamic focusing, bacteria entering the chip
though the sample input port were pushed to the bottom of the channel
by the vertical sheath flow (flow rate, SV) and focused toward the center of
the channel by the lateral sheaths (flow rate, SL). The finite-element simu-
lation shows the focusing of bacteria to a region of ≈100 µm × 7.5 µm,
within a physical channel measuring 200 µm × 15 µm. The flow rates were
SV = 3S and SL = 8S, where S is the sample flow rate. e) A fluorescence
micrographic image of hydrodynamic focusing shows that focusing can
be controlled by varying the relative flow rates between the vertical and
lateral sheaths. F) With flow focusing, robust VH signals from individual
bacteria could be observed. The graph shows the VH of a single Staphylo-
coccus aureus passing over a μHall sensor. Reproduced with permission.[426]
was done within 1 min, and total essay time is 25 min. These
results proved the potential usefulness of the fabricated micro-
chip for the early assessment of IgG antibodies to H. pylori.[428]
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Another method to clearing bacteria and endotoxin from the
bloodstream, using MNPs modified with bis-Zn-dipicolylamine
(DPA), a synthetic ligand that binds to both Gram-positive and
Gram-negative bacteria, was developed in order to get a step
forward in bacterial sepsis, which is a serious clinical condition
that can lead to multiple organ malfunction and death despite
appropriate treatment with antibodies and fluid resuscitation.
A magnetic microfluidic system was designed to remove the
MNPs connected to Escherichia coli, a Gram-negative bacte-
rium usually involved in bacterial sepsis, from a bovine whole
blood resulting in almost 100% clearance.[429] Other magnetic
microfluidic systems have been reported in the literature for
the detection of relevant microorganisms, including Vibrio par-
ahaemolyticus,[430] Staphylococcus aureus,[431,432] Listeria monocy-
togenes,[433–435] among others.
This novel and exciting area of miniaturized applications of
magnetic beads with all their inherent benefits compared to
conventional counterparts offers many possibilities for future
development in an extensively wide range of biotechnological
fields, far beyond those previously exemplified, including tissue
engineering,[436,437] proteomics,[438–440] hyperthermia,[441,442]
and pharmacology,[404,443,444] among other biomedical
applications.[414,445–448]
4. Summary and Outlook
Magnetic NPs for advanced biomedical applications are an aus-
picious research field with huge and increasing interest. Rep-
resentative examples of the main obtained results in each area
of application have been summarized, indicating also the chal-
lenges that still remain to be overcome, such as the tendency to
aggregate or the poor magnetization of the smallest NPs used
in biomedical applications. Moreover, the selection of the proper
synthesis method is often among the most crucial aspects, as it
strongly determines nanoparticle’s characteristics and, therefore,
also their functionality. Thus, it is important to establish proper
large-scale synthesis protocols with accurate control of size and
shape of the different NPs, including their proper biofunction-
alization. Though iron oxides are relatively less toxic compared
with other semiconductor nanomaterials or transition metals,
concerns regarding toxicity still remain regarding Fe2O3-based
MNP composites.[449] Such an issue must be definitely solved in
the near future with clear and well-established procedures. Thus,
the specific characterizations of size, shape, dose, and content
of functional NPs should be classified in relation to their effi-
ciency in disease treatments. Although such NPs are very prom-
ising candidates for medicine and biology, they show a certain
degree of toxicity in both animals and humans. After some suc-
cessful tests in animals with promising results, drug delivery
through coating of MNPs is currently undergoing preliminary
human trials; nevertheless, it will take some time before them
be clinically available. Similarly, important steps must be given
in hyperthermia treatment. Despite such a procedure already
proven to be effective in animal trials (both at the regulatory
level and in the determination of specific materials and proce-
dures), it remains inaccessible to humans.[450] Theranostics and
tissue engineering applications show themselves as highly inter-
esting areas, in which strong research efforts must be devoted to
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
highlighting novel diagnosis and therapeutic strategies. Further-
more, microfluidic systems are one of the areas that is consist-
ently supporting the whole path of magnetic nanoparticle-based
biomedicine, offering proper solutions and reproducibility from
nanoparticle synthesis to diagnostics, passing through devel-
oping tests in cell culture, drug development, and theranostics,
among others.
The future applications and challenges in magnetic nanopar-
ticle-based biomedicine pass through the definitive clarification
of the toxicological aspects in nanoscale of NPs and nanosystems
both in in vivo and in vitro trials as well as the determination of
the long-term stability of the functionalized MNPs before they can
be widely introduced for their clinical use.[451] Further, interdisci-
plinary approaches are needed to guarantee that the experiments
performed in laboratory can more clearly match the estimated
conditions that would be faced in vivo, allowing proper steps
toward applications. Substantial contributions through mathemat-
ical modeling of more and smart complex systems, with the objec-
tive of understanding, more specifically, the complex interactions
and effects, will determine whether, in the final analysis, a given
biomedical approach can be successfully used.[450]
Thus, it has been shown that magnetic nanoparticle-based
materials and biomedical approaches represent a wide and
strong interdisciplinary research and application field. Impor-
tant advances have been achieved in the development of suit-
able MNPs and their functionalization. Interesting proofs-
of-concept in a large variety of biomedical areas have demon-
strated the full potential of this research area, representing an
important (re)evolution within the whole biomedical field.
Acknowledgements
V.F.C. and A.F. contributed equally to this work. The authors thank the
FCT—Fundação para a Ciência e Tecnologia—for financial support under
framework of the Strategic Funding UID/FIS/04650/2013, project PTDC/
EEI-SII/5582/2014 and project UID/EEA/04436/2013 by FEDER funds
through the COMPETE 2020—Programa Operacional Competitividade e
Internacionalização (POCI). Funds provided by FCT in the framework of
EuroNanoMed 2016 call, Project LungChek ENMed/0049/2016 are also
gratefully acknowledged. V.F.C., A.F., C.R., and P.M. also thank the FCT
for the grants SFRH/BPD/98109/2013, SFRH/BPD/104204/2014, SFRH/
BPD/90870/2012 and SFRH/BPD/96227/2013, respectively. Finally,
the authors acknowledge funding by the Spanish Ministry of Economy
and Competitiveness (MINECO) through the project MAT2016-76039-
C4-3-R (AEI/FEDER, UE) and from the Basque Government Industry
Department under the ELKARTEK program.
Conflict of Interest
The authors declare no conflict of interest.
Keywords
drug release, hyperthermia, lab-on-chip, magnetic nanoparticles, tissue
engineering
Received: July 14, 2017
Revised: September 28, 2017
Published online: December 27, 2017
Adv. Healthcare Mater. 2018, 7, 1700845 1700845  (28 of 35)
www.advhealthmat.de
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