Received: April Revised: April Accepted: April
Multi-functional magnetic hydrogel: Design strategies and
Fangli Gang1Le Jiang2,3Yi Xiao1Jiwen Zhang4Xiaodan Sun2,3
Department of Biology, Xinzhou Teachers University, Xinzhou, Shanxi , China
State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing ,
Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing
State Key Laboratory of Crop Stress Biology for Arid Areas and College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi
Fangli Gang, Department of Biology,
Xinzhou TeachersUniversity, Xinzhou,
Shanxi , China.
Xiaodan Sun, State Key Laboratory of New
Ceramics and Fine Processing, School
of Materials Science and Engineering,
Tsinghua University, Beijing ,
Natural Sciences Foundationof China,
Union Medical College Hospital Initiative
Scientific Research Program, Grant/Award
Number: ; Tsinghua Univer-
sity Initiative Scientific Research Program,
Hydrogel is one of the hottest biomaterials in recent years. Especially, magnetic
hydrogels (MHs) prepared by combining unique magnetic nanoparticles (MNPs)
with hydrogels have attracted wide attention due to their excellent biocom-
patibility, mechanical properties, absorbability and rich magnetic properties
(magnetocaloric, magnetic resonance imaging and intelligent response, etc.).
However, the current literature mainly focuses on the application of MHs,
without fully understanding the relationship between the design strategies
and applications of each function in MHs. This review highlights six major
functional properties of MHs, including mechanical properties, adsorption, mag-
netocaloric effect, magnetic resonance (MR) imaging, intelligent response and
biocompatibility. Principles and design strategies of each performance are thor-
oughly analyzed. Furthermore, the latest applications of MHs in biomedicine,
soft actuators, environmental protection, chemistry and engineering in recent
years are introduced from the perspective of each function. In the carefully
selected representative cases, the design strategies and application principle of
multi-functional MHs are detailed, respectively. The classical fabrication pro-
cessing of MHs is summarized. At last, we discuss the unmet needs and potential
future challenges in MHs development and highlight its emerging strategies.
adsorption, intelligent response, magnetic hydrogels, magnetic resonance imaging, magne-
tocaloric effect, multi-function
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© The Authors. Nano Select published by Wiley-VCH GmbH
Nano Select ;–. wileyonlinelibrary.com/journal/nano 1
Hydrogels are a highly swollen three-dimensional (D)
polymer networks synthesized by hydrophilic monomers,
which can be considered as polymer-reinforced water.
Hydrogels with unique physicochemical properties, such
as excellent softness, water content, biocompatibility,
bioactivity, etc., provide a strong candidate material for
many fields including biomedical and environmental
engineering.Various biomimetic hydrogels have been
developed to mimic natural hydration microenvironments
and successfully applied in tissue engineering and cancer
treatment.Hydrogels with specific microstructures
(anisotropic, tubular, etc.) have also been developed
to deliver drugs/cells and provide three-dimensional
biochemical microenvironments for supporting cell
growth.Despite great progress has been made, conven-
tional hydrogel systems still have some limitation. In par-
ticular, insufficient functionality severely limits its practi-
cal application potential in many fields. Therefore, it is a
hot research topic to endow hydrogels with functionality.
With the rapid development of permanent magnet
materials and electromagnetic technology, magnetic field
as an important physical field is widely used in scien-
tific research. The magnetic field can provide a feasible
and flexible strategy for inducing the functionality of
hydrogels. Thus, MHs composed of magnetic particles
O, etc.) and hydrogel matrix have attracted
more and more attention for their biocompatibility,
controllable structure, high adsorption and rich magnetic
properties (magnetocaloric, MR imaging and intelligent
response, etc.).For example, MNPs endow hydrogels
with remotely controllable characteristics, which can
be used in drug delivery,local hyperthermia,mag-
netic/thermal drive,tissue image enhancement,
adsorption, separation and purification,and so on. In
addition, stimulus-responsive MHs have broad application
prospects in soft robot.
As everyone knows, the versatility of materials will
enrich their potential in practical applications. In turn, dif-
ferent applications can also dictate the material desired
properties. Therefore, in this paper, from the design con-
cepts and application strategies of multi-functional MHs
(Figure ), we review the latest research progress on MHs.
Six main functional properties of MHs are highlighted:
mechanical properties, adsorption, magnetocaloric effects,
MR imaging, intelligent response and biocompatibility.
Focusing on its specific functions, the potential applica-
tions of MHs in biomedicine, environmental protection,
soft actuators, chemical catalysis and engineering are fur-
ther analyzed. Finally, the common preparation methods
of multi-functional MHs are systematically reviewed.
2 DESIGN STRATEGIES AND
APPLICATIONS FOR MULTIPLE
FUNCTIONALITIES OF MAGNETIC
MHs are generally formed by the interaction between
magnetic components (γ-FeO,Fe
O, etc.) and hydrogel
matrix through non-covalent or covalent bonds. This
combination simultaneously absorbs the advantages of
hydrogel (high water content, flexibility, etc.) and mag-
netic particles (smart response, etc.). There are differences
in raw material selection, design strategies and application
fields of MHs with specific performance. For example, in
most literatures, the composite MNPs in MHs are generally
spherical nanoparticles with a diameter of ∼ nm, and
some MNPs with significant magnetocaloric effect have a
ring shape.Biomedical MHs focuses on biocompatible
hydrogel matrix, while engineering application MHs uses
cheap and readily available materials. Therefore, it is of
great significance to study MHs from the six functions of
mechanical properties, adsorption, magnetocaloric effect,
magnetic resonance imaging, intelligent response and
In general, the good dispersity of MNPs in the matrix
is the fundamental factor in preparing high-performance
composite gels. However, most MNPs have a high specific
surface area and can easily agglomerate (Figure A). The
MHs obtained by simply compounding MNPs and hydro-
gel matrix often exhibits uneven network structure and
unstable properties. Notably, the introduction of function-
alized MNPs or special hydrogels components can effec-
tively solve these problems. Both of these aims to increase
the dispersity and crosslinking degree of the MNPs in the
hydrogels (Figure B,C). The difference is that the former
focuses on the modification of MNPs (FeO,MnFe
etc.), mainly including increasing functional groups (e.g.,
carboxylic groups),chemical loading,coating (e.g.,
tannic acid),etc. While the latter usually selects specific
hydrogel components with a large number of active func-
tional groups (carboxyl, hydroxyl, etc.), which can coor-
dinate with Fe ions and easily gelled. Polyacrylamide,
polyvinyl alcohol,hyaluronic acid,fibrin,and
nano-cellulose are commonly used MHs with high coor-
dination activity. The MHs obtained by these two methods
have uniform structure, stable performance and enhanced
mechanical properties. Under the action of long-range
magnetic field, functional MNPs exhibit remarkable intel-
ligent response (mobility), magnetocaloric effect and MR
imageability. The hydrogel matrix, as a structural and
mechanical support, is also affected by MNPs to produce
corresponding behaviors, including deformation, move-
ment, thermogenesis and MR imaging. By regulating the
GANG . 3
FIGURE 1 Schematic illustration of multifunctional MHs and their applications
FIGURE 2 Design strategies of MHs. Structure and properties of MHs prepared by A, MNPs +hydrogel, B, functionalized MNPs +
hydrogel and C, MNPs +special hydrogel
types or proportions of MNPs and hydrogel matrix to con-
trol multiple functions of MHs, so as to promote its fasci-
nating application prospects in different fields.
2.1 Mechanical properties
Mechanical property is a set of commonly used indexes,
which is the resistance to failure of materials under load
(such as tension, compression, torsion, impact, cyclic load,
etc.). Generally, the mechanical properties of hydrogels
mainly include strength, stiffness, toughness and fatigue
strength. For hydrogels, their mechanical properties deter-
mine their usage and service life.
At present, there are mainly four ways to improve
the mechanical properties of hydrogels: () the “sacri-
fice bond” is introduced to dissipate energy effectively,
thereby enhancing the mechanical properties of hydro-
gels. A variety of non-covalent interactions such as hydro-
gen bonding, complexation, supramolecular recognition
and hydrophobic association have been applied to pre-
pare high-strength hydrogel.The most representative
example is double network hydrogels. () The “pulley
effect” is used to reduce the internal stress in the crosslink-
ing network and greatly enhance the mechanical prop-
erties of the hydrogels. Topological hydrogel is a kind of
material with high strength by using O-shaped crosslink-
ing ring which can slide freely on the polymer chain
as a controllable crosslinking point.() the fracture
and reconstruction of some reversible non-covalent bonds
will also give hydrogels high-strength,while providing
certain recoverability and self-healing properties. () The
introduction of nanoparticles has been shown to signifi-
cantly alter hydrogel mechanical properties.This paper
focuses on MNPs composite hydrogel materials. On the
one hand, the rigid MNPs can not only improve the com-
pression modulus, storage modulus and thermal stability
of the composite hydrogel, but also adjust the water absorp-
tion, retention, saturation magnetization and pore size of
the MHs by changing its content. On the other hand, the
reversible interaction between MNPs and hydrogel compo-
nents can endow MHs with good self-healing, thermal sta-
bility, shear-thinning, and mechanical properties (rigidity
and viscoelasticity). Therefore, the design and application
of high-performance MHs with intrinsic magnetism have
received much attention from scientists.
High-strength MHs, as an important branch of
nanocomposite hydrogels, have important applica-
tions in biomedical and soft actuators.Biomaterials are
a promising strategy for repairing damaged or diseased
tissue. In general, in order to ensure the clinical safety of
biomaterials, rigorous in vitro biological evaluation must
be carried out in advance. In vitro simulation, hydrogels
can be used as mechanical support for cell growth and
differentiation. Unlike most in vitro cell culture D sub-
strates (petri dishes, porous plates), hydrogels provide a
D microenvironmental cell experience,better mim-
icking the in vivo biological environment. Up to now,
a variety of MHs have been used as multi-functional in
vitro culture platform to explore the effects of different
conditions (e.g., magnetic field and hyperthermia) on cell
function and morphology.Gu et al. reported a magnetic
polyacrylamide hydrogel with cell adhesion microarray
interface,which can effectively promote the formation
of multicellular spheroids. It is considered as a prevailing
tool to study the microenvironmental regulation of ther-
apeutic problems and tumor cell physiology. In addition,
as a polymer material most similar to biological tissue,
hydrogels can be used as scaffolds for tissue engineering
to repair or replace damaged tissues. As one of the three
key elements of tissue engineering, it is very important
for scaffolds to have excellent mechanical properties. In
particular, for osteochondral repair materials, excellent
compressive and anti-fatigue properties ensure that they
can withstand repeated mechanical stress without being
damaged, so as to steadily continue to exercise their
biological functions. However, it is still a great challenge
to develop MHs that match the mechanical properties of
normal tissues for repairing osteochondral defects in situ.
As a highly absorbent and high water-retaining material,
D network hydrogels have been widely applied in many
fields, such as food preservation, drought resistance in
arid areas. Moreover, hydrogels have a broad application
prospect in wastewater treatment by virtue of their high
adsorption capacity.Heavy metals (Pb, Cu, Cs, etc.),
organic compounds (pesticides, etc.) and dyes are all water
pollutants causing worldwide environmental problems.
These pollutants are non-biodegradable, carcinogenic and
highly toxic and should be removed from wastewater prior
to disposal. Compared with traditional hydrogels, MHs, as
an environment-friendly D nanomaterial with high phys-
ical strength, high adsorption rate and renewability, has
attracted increasing attention in wastewater treatment.
As shown in Table , the combination of magnetic addi-
tives (such as magnetite) and hydrogel matrix can simulta-
neously adsorb contaminants such as heavy metal ions and
dyes. Some MHs have a removal rate of more than .%.
Moreover, the optimized MHs has high-sensitivity, high-
selectivity, fast-adsorption and reusability.
The adsorption principle of MHs is shown in Figure A.
Porous hydrogels containing active functional groups
such as carboxyl, hydroxyl and amino groups can act as
GANG . 5
TABLE 1 Typical examples of magnetic hydrogels successfully applied in the removal of heavy metals, organic compounds, inorganic
salts and dyes
Magnetic additive Hydrogel matrix Contaminant RemarksaRef.
FeOModified gum tragacanth PbII,Cu
and congo red)
qmax values: . mg g−PbII,
. mg g−CuII,.mgg
crystal violet, . mg g−congo
Cs Excellent selectivity, high removal
Fluoride qmax =. ±. mg g−,the
adsorption capacity reaches % in
minutes, better fluoride
adsorption at low pH (.-.)
Ascorbic acid Au(CN)−qmax = mg g−, the spent hydrogel
could be easily collected using a
FeOnanoparticles Xylan/poly(acrylic acid) Methylene blue qmax =. mg g−, porous
Brilliant red X-B qmax =. mg g−, five cycles, pH
stability, adsorption kinetics could
be well-described by the
Weber–Morris model and the
homoge neous surface diffusion
FeOModified lignin Organic dyes and
Low-cost, suitable adsorption
capacities for removal dyes and
heavy metal ions, regenerating
from acid condition, reusability
high hydrophilicity, large adsorption
capacity, enrichment factors range
FeOnanoparticles Reduced graphene
simultaneous enrichment of different
types of insecticides, no matrix
effect, high sensitivity, ease of
Nano γ-FeOCationic hydrogel Aromatic
rapid sorption rate (% dye removal
within minutes), cycles, wide
pH adsorption range
Phosphate qmax =.±. mg P/g, wide pH
adsorption range, easily
regenerated, five cycles
γ-FeOAlginate Heat stable salts . g of composites giving the highest
removal of .% in minutes,
FeOnanoparticles Gluten/pectin Lake Urmia
% of the total heavy metal removal
rate, % of the total organic matter
Alginate Sulfide qmax =. mg g−, % removal,
easily regenerated with calcium
chloride solution, five cycles
a(n cycle refers to the adsorption/desorption cycle n times, and qmax refers to the maximum adsorption capacity).
FIGURE 3 A, Schematic diagram of removing contaminants from wastewater using MHs. B, MHs with different FeOcontents. C,
SEM images of different MHs. D, Adsorption kinetics of CrVIon the MHs adsorbent. Reprinted with permission.Copyright , Elsevier
adsorbents to remove contaminants through electrostatic,
ionic exchange or complexation with contaminants such
as heavy metal ions. More importantly, the incorporation
of MNPs can promote the separation, collection and reuse
of hydrogel adsorbents,and also have a positive effect
on the adsorption of MHs (Figure B-D).The main
results are as follows: () MNPs embedded in MHs can
increase the cross-linking degree and porosity of the sys-
tem, providing a channel for the entry, exit and adsorp-
tion of some substances. () When the amount of MNPs
is in a certain range, the adsorption amount of MHs is pos-
itively correlated with the amount of MNPs. The reason is
that with the increase of MNPs addition, the surface of the
hydrogel becomes rougher, which can increase the surface
area and adsorption capacity of MHs. However, once the
amount of MNPs exceeds a certain value, the saturation
absorptivity of MHs will decrease unexpectedly. This may
be attributed to the excessive coordination of the active
groups in the hydrogel system with MNPs, resulting in a
decrease in the number of free active groups and insuffi-
cient binding to pollutants.
The complete adsorption process of MHs is described
in Figure . First, the prepared MHs were added to the
treated wastewater, and the complete adsorption was guar-
anteed by shaken in an end-over-end manner. Then, under
the assistance of magnets, magnetic separation is carried
out on contaminants-loaded hydrogel. In this way, treated
water and renewable hydrogels are obtained. The reutiliza-
tion of MHs requires regeneration solution to desorb the
contaminants on the hydrogel, and then magnetic sepa-
ration to obtain reusable adsorption materials. The real-
ization of this process is attributed to the large surface
GANG . 7
FIGURE 4 The process flow chart of removing contaminants from wastewater using MHs
area, multiple adsorption (hydrogen bond, hydrophobic
interaction, etc.), suitable pore size distribution and para-
magnetism of MHs. Therefore, MHs can be considered
as a low-cost, efficient and recyclable adsorbent, and
have great attraction and broadly applicable in wastewater
Because magnetic separation methods can selectively
recover the desired proteins from biological fluids,
MHs materials have been extensively studied in protein
separation.For biomedical applications, especially
tissue engineering, the tendency of hydrogel to adsorb
protein in biological media should be considered as an
important characteristic. It has been demonstrated that
magnetic apatite nanoparticles introduced into poly(vinyl
alcohol) (PVA)/sodium alginate hydrogel could generate
magnetic response and enhance hydrogels.When pH
=., the maximum adsorption capacity of nano-beads
for bovine serum albumin was the highest, reaching
. mg⋅g−. In addition to the above applications, the
absorbability of MHs could also be used for enzyme
moisture transport,and so on.
2.3 Magnetocaloric effects
Magnetocaloric effect refers to the phenomenon that the
magnetic energy is transferred to the particles in the form
of heat when the ferromagnet or paramagnetism is placed
in the alternating magnetic field (AMF) and the mag-
netic direction is randomly transformed between paral-
lel and anti-parallel. This phenomenon can be used to
destroy morbid cells in organisms and control drug release.
As a common magnetocaloric agent, superparamagnetic
iron oxide (SPIOs) nanoparticles have obtained consider-
able development in tumor ablation. However, SPIOs have
shortcomings such as short residence time in vivo, lim-
ited timeliness, and many injections. Notably, the magnetic
particles were incorporated into hydrogels will greatly pro-
long the residence time in vivo. Not only that, hydro-
gel matrix with a D internal network microstructure,
high water content and biocompatibility, which are anal-
ogous with those of the natural tissue, plays a key role
in the application of MHs. On the one hand, hydrogel
matrix provides a microenvironment for magnetocaloric
therapy,effectively avoiding heat damage to normal tis-
sues, and provides adjustable D scaffolds for cell adhe-
sion, migration and differentiation.On the other hand,
injectable hydrogels with pores or microchannels are one
of the best candidates for local drug delivery.The mag-
netocaloric effect of MHs can be designed to sustain and
control the release of one or more combined therapeutic
drugs. Studies demonstrated that the anisotropic magnetic
coupling inside the gel is the main reason for the ther-
mogenesis of MHs. Moreover, compared with the disor-
dered MHs, the self-assembled oriented MHs has stronger
The practical application of MHs magnetocaloric effect
is mainly reflected in biomedicine, including tumor
treatment and tissue repair. Surgery is currently one of
the most common methods for solid tumor treatment.
However, wound infection and postoperative recurrence
are major challenges facing the surgical treatment of
solid tumors. Neoadjuvant and postoperative adjuvant
therapies play an important role in improving the prog-
nosis of patients. MHs have been applied to target tumors
by remote heating with an external magnetic field and
controlled release of anticancer drugs from hydrogels for
cancer therapy.Compared with photothermal therapy,
magnetocaloric therapy has unlimited tissue penetration
depth and is effective for deep-seated tumors such as
liver cancer and glioma. Moreover, an AMF-triggered
delivery system enables on-demand drug delivery with
more effective anticancer chemotherapy effects. However,
increasing the efficacy of ◦C therapeutic temperature
without resistance to induced thermal stress has been a
challenge. Therefore, Zhang et al. designed an injectable
magnetic hydrogel nano-enzyme (MHZ) utilizing the
inclusion interaction between α-cyclodextrin and PEGy-
lated nanoparticles.Employing this hydrogel could
FIGURE 5 Schematic diagram of enhanced tumor synergistic therapy by injectable MHZ.A, Synthetic procedure for MHZ. B, The
synergistic mechanism of MHZ on the generation of hyperthermia and ROS for cancer therapy. Reprinted with permission.[ ]Copyright
, American Chemical Society
improve the tumor oxidative stress level by generating
reactive oxygen species via nanozyme catalyzed reac-
tion based on hyperthermia (Figure ). Magnetic FeO
nanoparticles play a dual role of nanozymes and magnetic
heating simultaneously in the hydrogel system. On the one
hand, the magneto-heat generated after MHZ injection
into tumor tissue promoted FeOnanozymes to produce
more ⋅OH. On the other hand, ⋅OH further damages the
highly expressed protective heat shock protein in hyper-
thermia, thereby improving the efficacy of hyperthermia.
As such, this MHs exerts dual functions of catalytic
therapy and hyperthermia to synergistically treat tumors
and overcome the resistance of tumor cells to induced
thermal stress. This developed system offers a universal
platform for safer and precise synergistic therapy of solid
In the past decade, the combination of hyperthermia-
based physical therapy and biomaterials has exhibited
significant potential in tissue repair. In vitro cell experi-
ments have proved that mild thermal stimulation could
effectively promote osteochondral repair.Further
in vivo experiments are yet to be studied. In addition,
hyperthermia plays an important role in inhibiting local
inflammatory response, relieving pain and protecting joint
function.Therefore, hydrogels with magnetothermal
effect can be expected to have great application prospects
in the treatment of rheumatoid arthritis and osteoarthritis.
It is worth mentioning that the superior magnetocaloric
effect of MHs is conducive to develop discoloration
hydrogel,which may provide a new platform for color
display. This remarkable magnetochromatic property is
attributed to the superior magnetocaloric effect of D mag-
netic chain immobilized in a thermosensitive hydrogel.
Under an AMF, the magnetocaloric effect of aggregated
magnetic chains leads to hydrophilic–hydrophobic transi-
tion of the hydrogel, which reduces the inter-particle dis-
tance of the D magnetic chains and results in a blueshift
of the diffraction wavelength. Thus, the MHs also shows
the potential to monitor magnetic hyperthermia with sig-
nificant changes in its color and appearance.
2.4 MR imaging
Non-invasive imaging is a powerful tool that can provide
effective feedback for clinical diagnosis. MR imaging has
GANG . 9
become one of the most powerful detection methods in
contemporary clinical diagnosis due to its characteristics
such as safety, functional sequence diversity, good soft
tissue contrast and penetration depth. However, in prac-
tical application, the relaxation time of different tissues
or tumors overlaps with each other, which leads to the
diagnosis difficult. Therefore, the contrast agent began
to be studied in order to enhance the signal contrast and
improve the image resolution. Due to its biocompatibility
and superparamagnetism, FeO-based superparamag-
netic contrast agents are widely used in cancer detection,
drug delivery monitoring and stent implantation labeling.
Significantly, the incorporation of magnetic particles with
MR imaging into the hydrogel system will endow the gels a
good imaging capability.This non-invasive imaging of
materials could provide effective feedback for the real-time
degradation of biomaterials and the remodeling of new tis-
sues in vivo.Moreover, non-invasive monitoring meth-
ods help to reduce the number of experimental subjects.
The reason is that the experimental data can be obtained
repeatedly to avoid unnecessary sacrifice in histological
analysis at different time points. In addition, non-invasive
continuous observation will provide more effective infor-
mation, reduce individual differences, and contribute to
the clinical transformation of tissue engineering.
For the first time, Chen developed a functional, visu-
alizable superparamagnetic iron oxide (USPIO)-labeled
natural hydrogel system for semi-quantitative monitoring
the cartilage degradation process and elucidated the
regeneration of hyaline cartilage by multiparametric
MRI.USPIO particles with diameter of ∼. ±. nm
and a concentration less than µg Fe/mL had no effect
on chondrogenesis and cell proliferation of human bone
marrow mesenchymal stem cells (hBMSCs).In this
experiment, cellulose nanocrystal (CNC)/silk fibroin
(SF) blend hydrogel was selected as scaffold for tissue
engineering to promote cartilage regeneration. It has
a moderate degradation rate to coincide with cartilage
regeneration, which is essential to maintain the structural
integrity and mechanical properties of the joint. As shown
in Figure A, the USPIO-labeled CNC/SF hydrogel has an
interconnected network structure and uniform porosity.
Prussian blue staining exhibited that USPIO was evenly
distributed in the hydrogel matrix, and the material
showed no obvious cytotoxicity. This biocompatible
hydrogel with pore sizes ranging from to µm, are
effective in promoting cartilage formation.Next, MRI
characterization of the composite hydrogel was performed
with T-weighted imaging (TWI) sequence, indicating
that the signal contrast of the prepared hydrogel increased
with USPIO content. In vivo MR imaging further demon-
strated that the USPIO-labeled hydrogel had sufficient MR
contrast to monitor the degradation process (Figure D).
Therefore, this system may provide meaningful insights
for non-invasive monitoring and therapeutic efficacy of
implanted hydrogels in tissue engineering.
2.5 Intelligent response
Smart hydrogel is a kind of material that can perceive
small physical/chemical stimuli (such as temperature,
light, magnetism, pH) and make significant response
behaviors.Because of this intelligence, hydrogel has
a fascinating application prospect in tissue engineering,
drug-controlled release and soft actuators. Especially, as an
external stimulus of stimulus-responsive materials, mag-
netic field has the advantages of instant action, contactless
control and easy integration into electronic devices. There-
fore, the research and development of smart MHs has been
very active in recent years.
Over the past few decades, tissue engineering has been
successfully applied to the repair of various tissues (reti-
nas, ligaments, fats, blood vessels, etc.). With the potential
of hydrogel to construct microenvironment, the scaffolds
based on multi-functional MHs have attracted much atten-
tion due to their intelligence. On the one hand, under the
guidance of magnetic field, MHs can move directionally
or be induced into specific tissue-like microstructure,
providing a suitable growth environment for tissue recon-
struction. Schmidt proposed a novel magnetic templating
technology which can induce highly aligned D tubular
microstructures in naturally derived hydrogel scaffolds.
The scaffold was constructed by adding soluble magnetic
alginate particles (MAM) containing nano-iron oxide to
the hydrogel precursor solution. The diameter of MAM
is nm∼ µm, and a concentration of mg mL- of
MAM is the upper-limit allowing for optimal chain length
on the millimeter scale. Under an external magnetic field,
the gel forms an aligned columnar structure (Figure A).
The removal of MAM results in scaffolds with aligned
tubular microarchitectures that can facilitate cell remod-
eling in various applications. Moreover, the hydrogels
with electromagnetic effects can realize the above func-
tions, while constructing electric microenvironment under
external electrical stimulation to simulate directional tis-
sue, guide cell proliferation and tissue regeneration.
On the other hand, magnetic scaffolds can control
the biological behavior of cells through the magnetic
response between MNPs and magnetic field; thus, pro-
moting revascularization, cartilage/bone regeneration,
neuroregulation,and wound repair.Carlo et al.
described a D magnetic hyaluronic hydrogel that provides
non-invasive neuromodulation by magneto-mechanically
stimulating primary dorsal root ganglion (DRG) neu-
rons (Figure B).Mechanosensitive PIEZO channel is
10 GANG .
FIGURE 6 Non-invasive monitoring of hydrogel degradation by multiparametric MR imaging.A, In vitro SEM observation, MRI
characterization and Prussian blue staining of CNC/SF hydrogels incorporated USPIO. B, R and R* relaxometry rates and (C) cytotoxicity of
USPIO-labeled hydrogel. D, MRI analysis of the in vivo degradation of non-labeled and USPIO-labeled CNC/SF hydrogels in a rabbit cartilage
defect model. Reproduced with permission.Copyright , Ivyspring International Publisher
activated by magnetic particles embedded in the system
through membrane stretching. Mechanosensitive TRPV
channel is activated by magnetically induced deformation
of HA hydrogel. Under acute magneto-mechanical stimu-
lation, calcium influx in DRG neurons is induced through
TRPV and piezo channels, avoiding the step of exoge-
nous ion channel transfection.[ ]Under chronic magneto-
mechanical stimulation, is able to reduce piezo channel
expression, playing a role in chronic pain modulation. This
general strategy offers a way to achieve remote magnetic
modulation of different types of excitable cells through D
GANG . 11
FIGURE 7 A, Macroscopic view of crosslinked hydrogel, and
porous microarchitecture after removal of MAM.Copyright
, IOP Publishing Ltd. B, Mechanism of magneto-mechanical
stimulation of dorsal root ganglion neurons by magnetic hyaluronic
acid (HA) hydrogels.Copyright , WILEY-VCH Verlag GmbH
& Co. KGaA, Weinheim.
Another important application of smart soft material is
soft robot. The advent of soft robots has made great strides
in robotics, wearable devices and other areas by using
complete software systems that can safely interact with
any random surface while provide excellent mechanical
flexibility. The latest development in soft robotics have
benefited from advances in soft actuators and sensors that
enable robots to work mechanically unimpeded; thus,
expanding the range of robotic applications.Soft actu-
ator generally refers to a soft body that can reliably adapt
to any surface and cause various motions of the robot. Up
to now, many attempts have been made to fabricate soft
actuators sensitive to external stimuli.Especially, MHs
with flexibility and sensitivity to external magnetic fields
are expected to form a new research focus in the coming
era of soft robots.What is more, taking advantage of the
minimal invasions and the drive ability to use magnetic
fields of magnetic microrobots, therapeutic drugs can
be delivered to target areas.This controlled release
method can significantly reduce the dosage and minimize
the side effects on normal cells. Sukho park presented a
FIGURE 8 Schematic diagram of the treatment process using
retrievable biodegradable hydrogel microrobot for drug delivery.
Reproduced with permission.Copyright , Elsevier
novel hydrogel actuator (Figure ),which can deliver
anticancer drugs to cancer targets through a customized
near-infrared (NIR) and electromagnetic actuation (EMA)
integrated system, then retrieve problematic MNPs. First,
the microrobot reaches the predetermined lesion target
through the magnetic field of EMA. Next, after the NIR
irradiation, the hydrogel matrix was decomposed, drug
particles and MNPs were left in the target tissue. Finally,
with the assistance of EMA magnetic field, the disassem-
bled MNPs were recovered from the target region, and
the remaining anticancer drugs are continuously released
to generate therapeutic effects. This hydrogel actuator
can compensate for the inherent disadvantages of MNPs
(toxicity) by retrieval of MNPs, thereby maintaining the
advantages of electromagnetic drive (target characteristics
and drug delivery). In the future, developing a practical
drug delivery hydrogel robot is an attractive topic.
Biocompatibility refers to the degree of compatibility of
materials with human body after implantation, that is,
whether they will cause toxic effects on human tissues.
It mainly includes blood compatibility and histocom-
patibility. Blood compatibility refers to the ability of
materials to interact with blood directly without causing
coagulation, thrombosis, damaging blood composition
and function. Hydrogel directly contacting blood requires
good blood compatibility, such as hemostatic dressing.
Histocompatibility is the affinity between materials
and tissues without being eroded by tissues when they
come into contact with organs. Tissue engineering and
regenerative medicine research put more emphasis on the
12 GANG .
FIGURE 9 Cytocompatibility of magnetic nanocomposite hydrogels (MagGel).Fluorescence images of BMSCs adhesion and
morphology cultured on (a) MagGel and (b) gel. c-d, The endocytosis of magnetic nanoparticles by BMSCs. Black: magnetic nanoparticles;
Blue: nucleus; Green: F-actin; Red circle: magnetic nanoparticles outside of the BMSCs. Reproduced with permission.Copyright ,
American Chemical Society
histocompatibility and cytocompatibility of hydrogels.
Generally, strict biocompatibility evaluation is required
first to ensure the clinical safety of biomaterials. At
present, the biocompatibility evaluation of hydrogels is
mainly from the following aspects: cytotoxicity, hemolysis
test, acute systemic toxicity, subacute toxicity test, implant
test evaluation and so on.
In recent years, MHs find widespread applications in
biomedical fields due to their similar structure to native
extracellular matrix, hydrated environment, tunable prop-
erties (mechanical, biocompatibility) and unique active
response characteristics. Fibrin, chitosan, hyaluronic acid,
collagen and other natural biomaterials are the pre-
ferred raw materials for preparing medical MHs hydrogel
matrix.The reason is that they have excellent biocom-
patibility, low toxicity, enzyme degradation and degrada-
tion products are not easy to trigger immune response.
Some compounds are decomposed into small molecules
(water, carbon dioxide, etc.) that can be metabolized by
human body, such as polyglycolic acid. Therefore, these
compounds can also be widely used in the synthesis of bio-
compatible MHs. In addition, the concentration of MNPs
in most MHs is generally less than wt.%, but it has a pos-
itive effect on cells. Huang has proposed that the existence
of magnetic FeOnanoparticles can promote the growth
of stem cells and accelerate the cell cycle process.When
MNPs are incorporated into the scaffold, their magnetic
field effect may affect ion channels on cell membrane and
initiate changes in cytoskeleton structure.However, the
biosafety issues related to MNPs is the impact of MNPs
released from the degradation of implanted MHs. In gen-
eral, MNPs (∼ nm in diameter) selected for prepar-
ing MHs can be absorbed by the interaction with proteins
and cells. They can then distribute to different organs,
where they may stay in the same nanostructure or be
Liu and his colleagues created a magnetic hydro-
gel (MagGel) containing type II collagen, hyaluronic
acid and polyethylene glycol to provide a biomimetic,
bioactive and biodegradable platform for cartilage tissue
engineering.In cell experiments, MagGel has the high-
est average cell adhesion density, indicating its excellent
cytocompatibility. This is attributed to the synergistic
effect of hydrogel matrix and magnetic nanoparticles to
improve cytocompatibility,including adhesion and
growth. First, hydrogel mimics the extracellular matrix,
providing a favorable environment for cells. Second, the
interaction between magnetic nanoparticles and BMSCs
might promotes cell adhesion and growth. In addition,
BMSCs were observed to phagocytize magnetic nanopar-
ticles in cell culture without any effect on cell adhesion or
morphology (Figure ).The authors suggest that the
GANG . 13
FIGURE 10 Preparation technology of MHs. a, The blending method:the prepared MNPs was mixed with a hydrogel precursor
solution and crosslink hydrogels to embed the MNPs. b, In-situ precipitation method:MNPs was prepared by in-situ precipitation reaction
in polymer hydrogel network after cross-linking reaction. c, The grafting-onto method:MNPs and hydrogel systems are connected by
covalent or coordination bonds. Reprinted with permission.Copyright , WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ingested nanoparticles may eventually be decomposed by
lysosomes and excreted by exocytosis.
3FABRICATION PROCESSING OF
MHs are generally composed of polymer matrix and mag-
netic components embedded in the matrix (such as γ-
O). Up to now, various methods have been
developed to prepare MHs, including blending method, in-
situ precipitation method and grafting-onto method.
The blending method refers to simply mixing the pre-
prepared MNPs with hydrogel precursor solution, so that
MNPs is covered in hydrogels (Figure A).This is
the simplest and most commonly method for fabricating
MHs. However, the hydrogel obtained by simple blending
method usually has the defects of uneven distribution of
magnetic particles in colloids. This may result in unstable
properties (mechanical, magnetocaloric, MR imaging) of
the prepared MHs.
In the in-situ precipitation method,the hydrogel net-
work work as a chemical reactor, within which metal
ions react with precipitating agents (NaOH, NH⋅HO,
etc.) to generate MNPs (Figure B). For example, Ye
and Shen prepared a novel magnetic chitosan/polyvinyl
alcohol hydrogel beads (MCPHBs) by freeze-thaw method
combined with in-situ precipitation method.First, the
prepared PVA solution was mixed with CS solution, and
then Fe+and Fe+solutions were added. Then, the
mixed solution was added to the beaker containing ammo-
nium hydroxide to form MNPs. Finally, MHs beads were
obtained by repeated freezing and thawing. However, the
preparation of MHs by in-situ precipitation is often limited
by alkali-resistant hydrogel matrix.
Apparently, for both blending method and in-situ pre-
cipitation, there are no bonding interactions between
MNPs and hydrogel networks. Therefore, the stability of
MNPs dispersed in hydrogels cannot be guaranteed. The
generalized grafting-onto method,including modify-
ing or changing the structure and properties of MNPs,
can connect MNPs and hydrogel systems through cova-
lent or coordination bonds (Figure C). This direct cou-
pling allows MNPs to be stably and uniformly embedded
in the hydrogel. Recently, our group fabricated a magnetic
nano-FeOcomposite polyolefin-chitosan (AAD-CS-Fe)
double network hydrogel by grafting-onto method.A
large amount of Fe ions is exposed on the surface of nano-
FeOpre-etched by HCl, which can be cross-linked with
the active groups (carboxyl and hydroxyl) in the hydrogel
14 GANG .
system. In this way, magnetic AAD-CS-Fe hydrogel with
uniform structure and stable properties can be obtained.
4 CONCLUSION REMARKS
MHs are composed of magnetic components (such as γ-
FeO) and hydrogel matrix. The incorporation of MNPs
can enhance the initial performances (mechanical prop-
erties, adsorption, etc.) of the hydrogel, while providing
further magnetic properties (magnetocaloric, MR imag-
ing and intelligent response, etc.). In recent years, MHs
have attracted worldwide attention as a potential multi-
functional intelligent soft platform. This paper focuses
on six major functions of MHs, including mechanical
properties, adsorption, magnetocaloric effects, MR imag-
ing, intelligent response and biocompatibility. The design
strategies of various functions, as well as its application
prospects in biomedicine, soft actuators, environmental
protection, chemical catalysis and engineering in recent
years are reviewed. In addition, the classical fabrication
processing of MHs was introduced.
To further promote the development and practical appli-
cation of MHs, its future research focuses include the fol-
. At present, the magnetic component in MHs is mainly
confined to iron-containing nanoparticles. Further
exploration of other MNPs to enhance thermotherapy,
MRI contrast and intelligent response is of great signif-
icance for promoting the practical application of multi-
. MHs have important application prospects in biomedi-
cal fields, mainly including tissue engineering, because
of their unparalleled advantages such as in situ magne-
tocaloric therapy, magnetocaloric drive and MR imag-
ing. However, a lot of work remains to be done on the
long-term fate of implanting MHs to truly achieve clini-
cal application, such as metabolism and biodegradabil-
. The development of MHs in the future depends largely
on the synthesis of novel multi-functional hydrogels.
Combining magnetic stimulation with other stimuli,
such as light,electricity,temperature,pH,[ ]
and redox,MHs will become more intelligent and
This work was supported by the Natural Sciences Founda-
tion of China (); Natural Sciences Foundation of
China (No. ); Tsinghua University-Peking Union
Medical College Hospital Initiative Scientific Research
Program (grant number ); Tsinghua Univer-
sity Initiative Scientific Research Program [grant number
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Fangli Gang https://orcid.org/---
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Fangli Gang received her PhD
degree in chemical biology from
Northwest A&F University in
. Currently, she joined the
Biology department of Xinzhou
Teachers University. Her research
interests are mainly focused on
functional hydrogel materials and
their biomedical applications.
GANG . 17
Xiaodan Sun received her PhD
degree in engineering from
Tsinghua University under the
supervision of Prof. Hengde Li.
At present, she is an associate
researcher in the School of Mate-
rials of Tsinghua University.
Her current research is on the
nano biomaterials, osteochondral tissue engineering,
nerve tissue engineering, tumor diagnosis and treat-
How to cite this article: F. Gang, L. Jiang, Y.
Xiao, J. Zhang, X. Sun, Nano Select 2021,.