Sensors and Actuators B 147 (2010) 765–774

Contents lists available at ScienceDirect

Sensors and Actuators B: Chemical

journal homepage: www.elsevier.com/locate/snb

Review

Hydrogel-based devices for biomedical applications

Kosmas Deligkaris ∗ , Tadele Shiferaw Tadele, Wouter Olthuis, Albert van den Berg
University of Twente, Department of Electrical Engineering, P.O. Box 217, 7500 AE Enschede, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: This review paper presents hydrogel-based devices for biomedical applications. The first part of the
Received 18 January 2010 paper gives a comprehensive, qualitative, theoretical overview of hydrogels’ synthesis and operation.
Received in revised form 25 March 2010 Crosslinking methods, operation principles and transduction mechanisms are discussed in this part. The
Accepted 26 March 2010
second part includes applications of hydrogel devices in specific fields of interest. Sensing, fluid control,
Available online 2 April 2010
drug delivery, nerve regeneration and other biomedical applications constitute the main focus of this
part. The aim of this paper is to briefly present recent advances of the field, without neglecting older
Keywords:
ones, and to discuss important or novel concepts of each.
Stimuli-responsive hydrogel
Chemical sensor © 2010 Elsevier B.V. All rights reserved.
Fluid control
Drug delivery
Nerve regeneration

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
2. Synthesis of hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
2.1. Physical crosslinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
2.2. Chemical crosslinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
3. Theoretical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
4. Operation principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
5. Transduction mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
5.1. Optical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
5.2. Conductometric and amperometric methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
5.3. Mechanical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
5.3.1. Microcantilevers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
5.3.2. Bending plate transducers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
6. Hydrogel applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
6.1. Sensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
6.1.1. pH sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
6.1.2. Additional chemical sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
6.2. Array networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
6.3. Fluid control and drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
6.4. Artificial muscles and nerve regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774

1. Introduction

∗ Corresponding author. Tel.: +31 611179743. Hydrogels are three-dimensional hydrophilic polymer net-
E-mail addresses: k.deligkaris@student.utwente.nl, kraig33@gmail.com works made up of water-soluble polymers, crosslinked to form a
(K. Deligkaris). water-insoluble hydrogel. They are able to swell and retain a sig-

0925-4005/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.snb.2010.03.083
766 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774
nificant portion of water when placed in an aqueous solution [1].
The amount of water in the polymer matrix is at least 20% [2]
and can reach values of 99% by weight [3]. Hydrogels containing
more than 95% water are termed superabsorbent and have high
biocompatibility due to their large degree of water retention and
their physiochemical similarity with the native extracellular matrix
both compositionally and mechanically [4]. In addition, they can be
made to be biodegradable. Hydrogels can be classified into different
groups based on their:
• physical structure: amorphous, semicrystalline, hydrogen-
bonded or supramolecular;
• electric charge: ionic (charged) or neutral;
• crosslink: physically or chemically crosslinked;
• responses to external effects: stimulus-sensitive and -insensitive
ones;
• origin: synthetic and natural.
Research on hydrogels started as early as in 1960s with a novel
paper on poly(2-hydroxyethyl methacrylate) by Wichterle and
Lim [5]. In 1968, it was successfully predicted that the net repul-
sion between a polymer network and a poor solvent can cause a
phase transition and a change in the swelling degree (and thus to
its volume) [6]. Other groups also reported a phase transition in
their experiments induced by changes in the environment [7,8].
Up to date hydrogels’ use has increased dramatically. Many dif-
ferent synthesis techniques have been presented [9–13]. Review
papers have been also published in this field [14–19] presenting
the theoretical background and applications in specific areas such
as molecular imprinting [15], micro-total analysis systems (␮TAS)
[17] and microsensors [19]. However, to our knowledge, there has
not been a recent review paper presenting a complete overview of
hydrogel biomedical applications. The purpose of this paper is to
give a thorough, qualitative overview of the field, while presenting
recent developments of hydrogel devices for biomedical applica-
tions and practical issues arising during synthesis, modeling or
use.
2. Synthesis of hydrogels
Hydrogels are formed by physical or chemical crosslinks of
homopolymers or copolymers, being appropriately used to give
the three-dimensional structures specific mechanical and chemical
characteristics. The crosslink can be formed by covalent [20,21] or
non-covalent interactions [22–24]. Covalently crosslinked hydro-
gels are also called chemical gels while non-covalent gels are
termed physical. The crosslink can take place after or at the same
time as the copolymerization [1]. Chemical hydrogels provide good
mechanical strength but suffer from side-effects [23]. Detailed
information about various physical and crosslinking methods has
been published by Hennink and van Nostrum [25].
2.1. Physical crosslinking
Physical gels are three-dimensional networks where the poly-
mer chains bond through non-covalent interactions. Junction zones
form when the separate polymer chains interact over a certain
length and not point to point (point crosslinks). One of the ways
to form physical crosslinking is hydrophobic interaction (Fig. 1a)
in which hydrophobic blocks are coupled to hydrophilic blocks
creating a polymer amphiphile. When temperature is increased
the hydrophobic blocks aggregate. The polymer concentration, the
hydrophobic’s block length and the chemical structure of the poly-
mer all affect the temperature in which the phase change takes
place [4].
Besides, polymers can also interact by charge interaction
(Fig. 1b) or by forming hydrogen bonds between them (Fig. 1c),
acting as a physical crosslink between the polymers. Charge inter-
action can occur between a polymer and a small molecule or
between two oppositely charged polymers [4]. Hydrogen and other
non-covalent bonds are much weaker than covalent ones.
2.2. Chemical crosslinking
When the bonds between the polymers are of covalent nature,
the crosslinking is of chemical character. Covalent interactions are
much stronger than non-covalent, providing excellent mechanical
stability. Chemical crosslinking methods include radical polymer-
ization, chemical reaction of complementary groups, high energy
irradiation and enzyme usage [25]. For chemical crosslinking, con-
trary to physical crosslinking, crosslinking agents are needed which
may react with other substances [23].
3. Theoretical studies
Theoretical study of hydrogel networks has the purpose of
revealing the structure and configuration of their chains and ana-
lyzing hydrogels’ kinetics by means of modeling. One of the most
well-known theoretical studies is the equilibrium swelling theory
[26]. Flory and Rehner developed the theory of the equilibrium
swelling of crosslinked polymer gels by modeling them as a Gaus-
sian distribution of polymer chains. In their analysis the swelling
of the polymer network was dependent on the elastic forces of the
polymer chains and the thermodynamic compatibility of the poly-
mer and water molecules. Thus, the free energy change of a neutral
hydrogel can be expressed as:
G = Gel + Gmix
where Gel represents the elastic retractive forces and Gmix the
thermodynamic compatibility of the polymer and the swelling
agent [27]. In case of ionic hydrogels, several additional factors have
to be taken in account such as degree of ionization, nature of the
counter ions and ionization equilibrium. As the ionic content of the
hydrogel increases, repulsive forces among the charges develop and
the hydrogel swells. When the charge density decreases the hydro-
gel shrinks. In addition to the thermodynamic equilibrium used
in neutral networks, chemical potential of the ions should also be
in equilibrium. Detailed information can be found in the original
paper and in various reference books [1,2]. When the assumption
of a Gaussian distribution is not adequate non-Gaussian models can
be used [28,29].
The equilibrium weight swelling ratio can be used to describe
the degree of swelling and can be measured by gravimetric tech-
niques (e.g. [30]). The hydrogel is immersed in distilled water until
it reaches its equilibrium state. It is then taken out and after wip-
ing out excess water it is being weighted. The equilibrium swelling
ratio of the hydrogel, SReq , can be calculated from measured values
as follows:
Ws
SReq =
Wd
where Ws is the weight of swollen hydrogel in equilibrium and Wd
is the initial dry weight of the hydrogel.
When a hydrogel swells according to a change in a stimulus, the
rate at which the hydrogel’s volume change takes place could be
more important than the equilibrium swelling ratio.
A widely used parameter describing hydrogel swelling is the
hydrogel’s characteristic time of swelling (), which is proportional
to the square of the characteristic length of the gel (L) and inversely
proportional to the diffusion coefficient of the gel network in the
 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774
Fig. 1. (a) Hydrophobic interactions drive in situ physical gelation, (b) in situ physical gelation driven by charge interactions, (c) physical gelation driven by hydrogen bonding
interactions, which can be disrupted by shear. Reprinted from [4] with permission from Elsevier.
solvent (D) as follows [31]:
L2
=
D temperature dependence the swelling increases with increasing
The characteristic length is the radius for spherical hydrogels
and the thickness for hydrogel sheets. The diffusion coefficient of
hydrogel networks is in the order of 10−7 cm2 /s [31,32]. A 1-mm-
thick gel slab with a diffusion coefficient of 10−7 cm2 /s takes over
an hour to reach 50% of the equilibrium swelling and more than 6 h
to reach 90% of equilibrium [33]. This slow swelling property can
been found useful in applications where a slow, steady response
is needed but the majority of hydrogels applications are in micro-
scaled systems.
4. Operation principles
The family of stimulus-sensitive hydrogels includes
pH-sensitive [34–66], temperature-sensitive hydrogels
[10,18,36,38,39,53,58–60,62,67–69] and hydrogels with mul-
tiple sensitivities [36,53,58,62]. Temperature- and pH-sensitive
hydrogels are very different in their physical behavior and
swelling mechanism. The following paragraphs discuss the pH-
and temperature-sensitive hydrogels independently.
pH-sensitive polymers are produced by adding acidic or basic
functional groups to the polymer backbone; these either accept or
release protons in response to appropriate pH and ionic strength
changes in aqueous media.
Neutral polymer gels show less swelling than polyelectrolyte
gels. The more ionized a hydrogel is, the more charges will exist,
increasing the electrostatic repulsion between the polymer chains.
The network is more hydrophilic then, and the swelling degree is
increased. The degree of ionization of these hydrogels depends on
the number of pendant acidic or basic groups in the hydrogel.
Hydrogels containing acidic groups become more ionized at
higher pH and basic hydrogels show more ionization at low pH.
Thus, acidic hydrogels tend to swell more as the pH of the surround-
ing solution increases while basic hydrogels exhibit the opposite
behavior.
767
Thermo-responsive gels go through a phase transition in
response to external temperature stimulus. The temperature
dependence can be positive [70] or negative [71,72]. With positive
temperature, while for negative it decreases. Polymers contain-
ing mostly hydrophilic groups are water-soluble, while polymers
containing mostly hydrophobic groups are water-insoluble. For
negative temperature sensitivity the polymers are soluble in water
at low temperatures due to their hydrophilic content, but they col-
lapse above a certain temperature due to increased hydrophobic
interactions and exhibit phase separation from the solution. This
temperature is termed the Lower Critical Solution Temperature
(LCST).
A common group of monomers, used in the synthesis of
temperature-sensitive hydrogels, are the N-alkyl acrylamides. A
well-known monomer from this group is N-isopropylacrylamide
(NIPAAm). This monomer has side chains which have favorable
interactions with water in the form of hydrogen bonds. The
efficiency of the hydrogen bonding process has negative tem-
perature dependence. At lower temperatures, hydrogen bonding
between hydrophilic segments of the polymer chain and the water
molecules dominates, leading to enhanced dissolution in water.
As the temperature increases, hydrophobic interactions among
hydrophobic segments become strengthened, while hydrogen
bonding becomes weaker. At higher temperatures the hydrogen
bond based crosslinks will break up causing a shrinking in the
hydrogel.
van der Linden et al. [73] have presented a new method for the
photolithographical deposition of temperature-sensitive hydro-
gels, while investigating many of the hydrogel’s characteristics. One
of them was the effect of the crosslinking density on its swelling
behavior. Their results (Fig. 2) indicate that the more the crosslink-
ing density the less the swelling.
5. Transduction mechanisms
Sensor transducers are components, which convert the non-
electrical changes of properties of the stimuli-responsive hydrogel
768 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774
Fig. 2. Swelling response for different crosslinking densities. Fabricated poly-
N-isopropylacrylamide (PNIPAAm) hydrogels clearly show negative temperature
dependence. A polyacrylamide hydrogel used as a reference was not temperature
sensitive. Reproduced from [73] by permission of the Royal Society of Chemistry.
into an electrical signal. Transducers can exploit the mechanical
work performed by hydrogels or observe alteration in hydrogel
properties such as density, volume and stiffness. Various trans-
duction methods have been presented up to date for measuring
hydrogel properties changes. These include optical, conductomet-
ric, amperometric and mechanical methods and are presented
below.
5.1. Optical methods
The optical methods for detecting the volume change of hydro-
gels have been widely explored with different techniques. Two
similar optical techniques are fluorescence resonance energy trans-
fer (FRET) [50] and non-radiative energy transfer (NRET) [74]. Both
techniques involve a donor fluorescent dye emitting a photon
which is consumed by another dye. Distance between the dyes,
and thus of the swelling, can be measured with these techniques.
Another optical method makes use of diffraction of light from a
hydrogel containing a crystalline colloidal array (CCA) [37,75,76].
The particles in the CCA are regularly spaced and cause the gel to
display Bragg diffraction dependent on the lattice spacing. When
the hydrogel changes volume, the spacing of the particles in the CCA
is changed, causing a shift in the wavelengths of Bragg diffraction.
5.2. Conductometric and amperometric methods
Conductometric methods employ the measurement of resis-
tance values which vary according to the measurand [35]. A thin
hydrogel layer was deposited on a planar interdigitated conduc-
tivity electrode array. The hydrogel changes volume in response to
pH changes leading to a corresponding increase or decrease in ion
mobility inside the hydrogel layer and a change in conductivity. A
common problem, loss of adhesion is acknowledged by the authors.
Lesho and Sheppard [77] examined the adhesion of polymer hydro-
gel films to oxidized silicon wafers and conductometric sensors.
Among the results were that adhesion was dependent on pH val-
ues while temperature effects were minimal. Another method of
detection is amperometric [78], in which measurement of the elec-
tric current after application of a potential difference between two
electrodes provides information regarding the measurand.
Fig. 3. (a) Microcantilevers, (b) bending plate transducer with a piezo-resistive ele-
ment, and (c) capacitive bending plate sensor. Reproduced from [19].
5.3. Mechanical methods
5.3.1. Microcantilevers
Microcantilevers can transduce changes of mass, temperature,
heat, or stress, into bending (static mode) or a change in resonance
frequency (dynamic mode). Hydrogel swelling leads to alteration
of surface stress, which in turn statically bends the microcantilever.
For dynamic mode, a change in the measurand alters the reso-
nant frequency which is measured after proper excitation of the
structure. This form of output is considered digital, since it can be
directly connected to digital circuits and is independent from ana-
log levels. This approach has many advantages when compared to
analog output (static mode). It minimizes errors from analog to dig-
ital conversion and the transduction sensitivity of such elements is
considered to be among the highest. The sensitivity of the resonant
sensor is of crucial importance in this case.
Dynamic modeling of a microcantilever can be complicated and
various simplifications such as linearity, absence of damping effects
and assumption of rigid supports may be needed [79]. Fig. 3a illus-
trates the operation principle in the static mode. A number of
publications using microcantilevers can be found in the literature
[41,42,47,80,81] while review papers have been published by Car-
rascosa et al. [82] and Lang et al. [83].
5.3.2. Bending plate transducers
These transducers usually include a piezo-resistive
Wheatstone-bridge and are commonly used as pressure sen-
sors [48,51,84]. The stimuli-sensitive hydrogel is placed in a fixed
volume between a stiff/rigid grate, which is permeable for the
stimulus, and the bending plate (Fig. 3b). When the hydrogel swells,
the plate deflects resulting in a change of the resistance of the
piezo-resistive bridge [19]. Device modeling can be accomplished
by means of finite element modeling (FEM). Trinh et al. presented a
hydrogel-based silicon piezo-resistive pH sensor [51]. The authors
state the need for modeling and optimization of the devices, which
was accomplished with ANSYS software. Membrane deflection,
membrane stress and voltage output results were computed and
measured with a good agreement between them although the
response time of the real structure was slower than the model
prediction. The authors give possible reasons for this such as
that gel extension was assumed to happen instantaneously and
time constants used for calculation were determined during free
swelling experiments and not inside a silicon chip cavity.
A capacitive bending plate sensor as shown in Fig. 3c has been
presented by Strong et al. [85]. The bending of the plate changes the
distance of the capacitor plates resulting in a change of its capaci-
tance which is inversely proportional to the distance between the
plates. This change in capacitance leads to a change in the resonance
frequency of a passive LC circuit.
6. Hydrogel applications
This part describes hydrogels’ applications from various
research groups and discusses their practical issues. Hydrogels that
 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774
Fig. 4. Equilibrium cantilever deflection as a function of pH around the polymer.
Reprinted with permission from [41], © 2002, American Institute of Physics.
can sense various external stimuli have been presented. The field
of sensing seems to attract most attention and therefore it is logical
to start with this theme. Other applications include drug deliv-
ery, fluid control, artificial muscles and nerve regeneration and are
discussed later.
6.1. Sensing
6.1.1. pH sensors
Bashir et al. [41] have presented one of the most sensitive
micromechanical pH sensors, having an ability to sense a change
of 5 × 10−5 pH by using an atomic force microscope for deflection
measurement. It is fabricated by coating a polymer network on
a cantilever. A change in pH leads to a change in surface stress
and expansion of the polymer, which in turn bends the cantilever.
Various simplifications were made since the actual model is quite
complicated. More specifically, the structure was modeled as a
composite beam with a constant modulus of elasticity and constant
polymer thickness. In reality, the modulus of elasticity decreases
while the polymer thickness increases with a pH increase. These
simplifications, as the authors acknowledge, may justify the small
differences between theoretical and experimental results as illus-
trated in Fig. 4.
A conductimetric pH microsensor is presented by Sheppard et
al. [35]. The sensor resistance changes as much as 45% per pH unit
at physiological pH values. Different conductivity-over-pH graphs
were produced for different copolymer compositions. The authors
found that the interfacial impedance between the gel and the elec-
trode plays a significant role in the total impedance and that the
loss of adhesion (Section 5.2) between the substrate and the gel
leads to a decrease in sensitivity.
A pH sensor based on a reversible, mass-changing pH-
responsive hydrogel is presented by Ruan et al. [43]. The authors
achieved increased sensitivity by increasing the fraction of the
acrylic acid in the poly(acrylic acid-co-isooctyl) acrylate copolymer.
Excellent adhesion was established by pre-coating the sensor with
a layer of polyurethane, and adding 1-(3-dimethylaminopropyl)-3
ethylcarbodiimide (EDC) into the hydrogel solution. The output of
the sensor is encoded in the frequency of the output signal.
More recently, Maruyama et al. [57] presented a different
approach in local pH sensing. Their patterned hydrogel film is made
of UV photosensitive resin. The output is a change in color (color
difference for red) of the hydrogel and is obtained by a CCD cam-
era. This form of output is one of the most easily recognizable for
humans, although small details may not be easily distinguished
with the human eye.
769
6.1.2. Additional chemical sensors
Hydrogels have been used for various sensing purposes either
directly or indirectly [45,49]. In direct methods the measurand
directly affects the output of the system. In indirect methods the
measurand affects an intermediate quantity, for example pH, which
in turn alters the output of the system. Many medically significant
sensors have been created including carbon dioxide sensors [45,49],
lactate sensors [86], sensors for rheochemical characterization of
solutions [87], oxygen sensors [56,88] and ion sensors [80,89].
One of the significant problems a designer of a hydrogel sensor
has to solve is the sensor’s selectivity. This problem is of out-
most importance in biomedical conditions where the environment
(human body) is not completely controlled (although its proper-
ties might be known) and invasive methods are preferred to be
avoided. Complications arise when, for example, an ion sensor pro-
duces non-zero output analogous to the concentration of a second
ion, or when it is affected by temperature.
Temperature sensitivity is acknowledged by Herber et al. [49],
where the authors acquire measurements in room temperature and
in the operational temperature during biomedical use. In this case
the increase of temperature has a positive effect in the response
time of the sensor. However, the output of the sensor was reduced
with increasing temperature for a constant concentration of the
measurand. Fortunately, the relationship was found to be linear,
making possible a compensation technique. In non-linear cases,
linearization methods are employed increasing the complexity and
cost of the final device.
The issue of other elements affecting the operation of the sensor
is explored on two typical papers of ion sensors using a micro-
cantilever [80,89]. In both papers the authors have examined the
influence of other ions in the sensors. The pH was held constant
during these experiments, so its effect on the sensor was minimal.
The conclusion was that, for the particular sensors, some ions have
minor effects while others had significant effects at large concen-
trations only.
6.2. Array networks
Recently presented papers describe exploitation of array tech-
niques for various purposes. One of these is the characterization
of liquid analytes [90]. A fluorimetric micro-spot array using a
non-specific recognition function is used for the analysis of liquid
samples. The array was composed of binary mixtures of various flu-
orescence dyes embedded in a hydrogel matrix. By visual extraction
of the changes in each spot and in the array as a whole, the method
seems to be effectively used as a recognition tool. The specific
array was composed of 32 individual spots (doubly redundant, for
reproducibility demonstration) and was prepared from single flu-
orescent dyes and binary mixtures. Image substraction techniques
were used to visualize the post pattern differences, assigned as the
fingerprint of the analyte liquid (Fig. 5).
An application of hydrogel arrays in cell biology research is
presented by Jongpaiboonkit et al. [91]. Due to the vast number
of parameters, cell behavior in a natural environment is difficult
to analyze. An adaptable, automated approach for 3D cell culture
within hydrogel arrays was proposed. As the authors conclude:
“our results indicate that the adaptable, array-based format
developed in this study may be useful as an enhanced through-
put platform for 3-D culture of a variety of cell types”.
Another fluorescent microarray sensor [56] is able to sense
dissolved oxygen and pH in a cell culture, with a response time
appropriate for its purpose. The output of the device is optical, while
the whole measurement technique is non-invasive. Other studies
include hydrogel-based protein arrays for analyte sensing [46] and
quantification of epidermal growth factor receptor (EGFR, a trans-
770 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774
Fig. 5. Operation principle of a hydrogel array used for characterization of liquid
analytes. (a) Reference image (dry array) and (b) image under pure methanol. Spot
pattern obtained after image subtraction (a-b) fluorescence diminished spot pattern.
(b-a) Fluorescence intensified spot pattern. Reprinted from [90] with permission
from Elsevier.
membrane protein, which if overexpressed could result in cancer)
activity in cell lysates [92].
6.3. Fluid control and drug delivery
Since the sensing of any measurand is accompanied by a volume
change of the hydrogel, they can be easily used as actuators or as a
combination of sensing–actuation mechanisms. Hydrogel elements
are soft materials and therefore, able to completely seal the fluid
pathway, minimizing leakage [93]. The most common approach
for controlling the fluid flow is by having the hydrogel swelling
in response to a stimulus and blocking the fluid’s pathway [94].
This approach is illustrated in Fig. 6. In Figs. 6a and c one hydrogel
sphere (with a stimulus-dependent state) is in a shrunken state,
allowing the fluid to pass either to the right or to the left (fluid flow
is represented by an arrow). In Fig. 6b both spheres are in a swelling
state, completely blocking the fluid’s pathway (indicated by an X).
Possible stimuli found in the literature are temperature [93], pH
[94,95] and glucose [95,96].
The suitability of hydrogels for drug delivery stems from the
fact that they are biocompatible and can be made to be biodegrad-
able. They do not pose any risk of rejection by the immune system
and when entering the human body they slowly degrade, releas-
ing the drug they carry. However, poorly soluble drugs are difficult
to entrap in the hydrogel matrix and Chen et al. [97] use a drug
entrapment strategy to increase the efficiency of such methods.
In cell microencapsulation techniques, cells are immobilized
within capsules [98]. Immobilization of therapeutically active
cells (drug-secreting) within a polymer matrix surrounded by a
semi-permeable membrane protects them from immune system
rejection [99] which makes use of immunosuppressants unneces-
sary. Orive et al. [100] were successful in designing biomimetic
cell-hydrogel capsules to promote even further the in vivo long-
Fig. 6. Operation of a fluid flow controller. The volume response of two different
hydrogels with respect to the pH of the surrounding fluid. Top, the fractional change
in diameter (fD ) of the hydrogels with respect to pH. Bottom, images showing a
device that directs (sorts) a fluid stream on the basis of its pH. The hydrogel gating
the right branch (circles on the top graph) expands in base and contracts in acid. The
hydrogel gating the left branch (squares on the top graph) behaves in the opposite
manner (expands in acid and contracts in base). At a pH of 7.8, the flow is directed
down the left branch. At a pH of 4.7, the flow is directed down the right branch. Both
hydrogels expand to shut off the flow when the pH is changed to 6.7. Scale bars,
300 mm. Reprinted by permission from Macmillan Publishers Ltd.: Nature [94], ©
2000.
term functionality of the enclosed cells and improve the mechanical
stability of the capsules which can be used in controlled drug deliv-
ery. This approach can also be used in other therapeutic methods
such as central nervous system (CNS) diseases and various patho-
logical problems.
Pachyman is a fungus polysaccharide, well-known in China
for its medical applications, harmless to the human body [101].
A biodegradable pachyman-based hydrogel has been devised for
controlled release of protein drugs with full preservation of the
protein’s stability and enzymatic activity [64]. The authors state
the possibilities of this technique for site-specific protein–drugs
delivery.
A transcutaneous vaccination system has been also studied
[102]. Benefits include the lack of need for specialized personnel,
lack of needles, lack of specialized facilities and others. The specific
vaccination system using hydrogels, successfully delivered anti-
genic proteins into the epidermal layer in quantities that exceeded
the theoretical expectations.
Reversing the fluid flow, a sampling mechanism, a micronee-
dle and a micro-glucose sensor constitute a so-called intelligent
mosquito being able to pump in and sense the glucose concentra-
tion of a solution [103]. The 90% response time was 30–40 s, typical
for such applications. This artificial “mosquito” is disposable and so,
it does not bear any fear of transmitting diseases from patient to
patient. Possible improvements include better geometrical design
and faster sampling mechanism.
6.4. Artificial muscles and nerve regeneration
Even from the 1989 researchers had realized the tremendous
capabilities of hydrogels to act as artificial muscles [104]. A more
detailed study of artificial muscles, acknowledging that the muscle
is both a system and a material has been recently done [105]. The
authors state advantages of polyacrylamide (PAAM) hydrogels for
such applications such as:
• Properties and materials similar to living tissue.
• Biocompatibility.
 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774 771

Fig. 7. Representative fluorescent images of agarose-treated and agarose/BDNF-treated spinal cords with NF-160 kDa stain. (A) An image of agarose-treated spinal cord
section at 10×. Scale bar = 50 ␮m. (B and C) Enlarged images (20×) of the white boxes in A. This shows that the axons stopped before entering the lesions and that they formed
bulbs; (D) agarose/BDNF-treated spinal cord at 10×; (E and F) enlarged images (20×) of the white boxes in (D). These images show that the axons did not bulb at the end as
the axons did in the agarose-treated spinal cords and the axons infiltrated the scaffold, thus crossing the interface. Reprinted from [115] with permission from Elsevier.

• Not biodegradable.
• Chemical manipulation of properties.
• Adjustable shape.
• Low-cost.
The main disadvantage of hydrogels, namely their slow response
time could not pass undetected however. This could mean that
hydrogel-based artificial muscles cannot be effectively used when
fast response is required, although to our knowledge there have not
been any detailed studies comparing the kinetics of real muscles
against artificial hydrogel muscles. Also, in contrary to some drug
delivery methods, when using hydrogels as artificial muscles they
should be made able to withstand the physiological environment
without degradation.
Hydrogels can be also used for nervous system repair. The cen-
tral nervous system (CNS) consists of the brain and the spinal
cord, while the peripheral nervous system (PNS) connects CNS to
the rest of the human body. The PNS can recover after damage
while the CNS has limited capacity of replacing damaged or lost
neurons, resulting in a permanent loss of function following an acci-
dent or disease. This difference has been attributed to the different
environment in PNS and CNS lesion sites. Main barriers to regener-
ation are the glial scar, which is composed from reactive astrocytes
and proteoglycans, degenerating myelin (myelin debris) and oligo-
dendrocytes [106,107]. Chondroitin sulfate proteoglycans are the
principal inhibitory component of glial scars but their effect can
be reduced or even eliminated with chondroitinase ABC (ChABC)
[108,109]. Besides the glial scar formation, CNS injury results in cell
death and pseudocyst formation further restricting regeneration.
By promoting nerve growth factors (substances promoting
nerve growth) and other therapeutic agents (such as ChABC)
researchers are focusing on changing the environmental conditions
in CNS lesion sites, and thus restoring nerve regeneration ability.
Hydrogels can be used in spinal cord injury repair [110–115] by
acting as scaffolds bridging the gap between lesions [110,112,115]
or by delivering neurotrophic factors [113,115], favoring regenera-
tion of neural connections. Syková et al. [111] found good adhesion
of HEMA hydrogels in the host tissue, bridging the whole spinal
cord lesion site. The same group noticed a smaller pseudocyst vol-
ume in hydrogels implanted 1 week after damage when compared
772 K. Deligkaris et al. / Sensors and Actuators B 147 (2010) 765–774
to immediate implantation. However, when a solid hydrogel is
implanted, the surgical procedure itself will cause damage. This
damage could be spared by using liquid hydrogels solidifying
inside the lesion site [110,114,115]. Jain et al. [115] investigated
an agarose scaffold, geling in situ and conformally filling an irreg-
ular spinal cord defect in adult rats. By embedding brain-derived
neurotrophic factor (BDNF) releasing microtubules in the scaffold,
neurite growth was successfully enhanced (Fig. 7).
7. Conclusions
This review briefly presented the basic principles of operation
and practical aspects of hydrogel devices in a wide variety of appli-
cations. They are able to convert chemical and electrical energy
into mechanical energy and therefore are considered to be chemo-
mechanical transducers.
Hydrogels are becoming widely applied into traditional fields
of science or medicine such as sensing and actuating. Their soft
nature makes them excellent candidates in applications where
dust particles would pose a threat or reduced the efficiency of
other structures. Besides, their biocompatibility and optional bio-
degradability further increases their vast possibilities. Examples
described in the present review include drug delivery and nerve
regeneration applications. One of the most significant disadvan-
tages is their slow response time, which makes them unsuitable
for large-scale applications or in situations where fast response is
required (e.g. when used as artificial muscles or sensors for fast-
changing parameters).
It is evident that the complexity of the devices and applications
is increasing while research in this field is mature enough to start
experimenting with advanced structures. As a result, it can be safely
predicted that hydrogel devices will continue to be highly involved
in biomedical research and applications in the future to come.
However, specific directions for research focus cannot be given.
Different applications demand hydrogels with different properties.
Examples include bio-degradability (drug delivery) or not (artificial
muscles), single or array elements, etc.
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Biographies
Kosmas Deligkaris was born in Thessaloniki, Greece, on March 25, 1983. He received
his BSc. In Electronic Engineering from the Alexander Technological Educational
Institute of Thessaloniki in 2008. He is currently pursuing his MSc Degree at the Uni-
versity of Twente, Enschede, The Netherlands, working in the Biomedical Systems
and Signals group. His research interests include neurotechnology, microsystems
and optimization algorithms.
Tadele Shiferaw Tadele completed his BSc in Electrical Engineering from Mekelle
University, Ethiopia in 2007. Currently, he is pursuing his MSc degree in Elec-
trical Engineering in the specialization of Measurement and Control systems
at the University of Twente, Enschede, The Netherlands. His research interests
include biomechatronics, structured agent-based control systems, intelligent con-
trol, robotics, and embedded systems.
Wouter Olthuis was born in Apeldoorn, the Netherlands, on October 23, 1960. He
received the MSc degree in electrical engineering from the University of Twente,
Enschede, The Netherlands in 1986 on the subject of thermally excited resonating
silicon membrane pressure sensors. In that year, he joined the Center for Micro-
Electronics, Enschede (CME) doing research on inorganic electret materials for
subminiature silicon microphones. In 1987 he started his Ph.D.-project and received
the Ph.D. degree from the Biomedical Engineering Division of the Faculty of Electri-
cal Engineering, University of Twente, in 1990. The subject of his dissertation was
the use of Iridium oxide in ISFET-based coulometric sensor–actuator devices. Since
1991 he has been working as an Assistant Professor in the Laboratory of Biosensors,
part of the MESA+ Research Institute, of the University of Twente and as such co-
supervising many projects on both physical and (bio)chemical sensors and sensor
systems for medical and environmental applications. Currently, he is Associate Pro-
fessor in the BIOS Lab-on-Chip group of the MESA+ Institute of Nanotechnology and
is as such responsible for the theme Electrochemical sensors and Sensor systems.
Since 2006 he is also the Director of the Educational Programme of Electrical Engi-
neering at the Faculty of Electrical Engineering, Mathematics and Computer Science
at the University of Twente.
Albert van den Berg received his Ph.D. at the University of Twente in 1988 on the
topic of chemically modified ISFETs. From 1988 to 1993 he worked in Neuchatel,
Switzerland, at the CSEM and the University (IMT) on miniaturized chemical sen-
sors. From 1993 until 1999 he was research director micro-total analysis systems
(␮TAS) at MESA, University of Twente, a topic that was extended to Miniaturized
Chemical Systems (MiCS) in 1999. In 1998 he was appointed as part-time professor
“Biochemical Analysis Systems”, and later in 2000 as full professor on Miniaturized
Systems for (Bio)Chemical Analysis in the faculty of Electrical Engineering, embed-
ded the MESA+ Institute for Nanotechnology. In 2002 he received the Simon Stevin
Master award from the Dutch Technical Science foundation (STW). In 2003 he was
appointed as captain of the Nanofluidics Flagship within the national nanotech-
nology program Nanoned. In 2005 he stayed for 6 months San Diego (USA) at the
La Jolla Institute for Allergy and Immunology (LIAI, group Green) during a sabbat-
ical leave, while he received an Advanced Research Grant from ERC in 2008. In
2009 he received the Spinoza prize, the most prestigious Dutch scientific award,
for his achievements in lab-on-a-chip research. His current research interests focus
on microanalysis systems and nanosensors, nanofluidics and single cells on chips,
with applications in health care and environment. Albert van den Berg is member
of the Royal Dutch Academy of Sciences (KNAW), the Dutch Health council, board
member of the Chemical and Biological Microsystems Society, member of the Dutch
chemical society (KNCV) and deputy chair of the journal Lab on a Chip. He has co-
authored over 180 papers (H = 33) and over 10 patents, and has been involved in >5
spin-off companies.