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COMMUNICATIONKazunoriKataokaet al.pH-dependentpermeabilitychangeandreversiblestructuraltransitionofPEGylatedpolyioncomplexvesicles(PICsomes)inaqueousmedia

ISSN1744-683X

PAPERStefanHoworkaet al.SelectiveproteinandDNAadsorptiononPLL-PEGfilmsmodulatedbyionicstrength

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Stimuli-responsivehydrogelthinfilmsserveaversatileplatformforthefabricationofsmartresponsivesurfaces,cellculturesupports,autonomousdrugdeliverysystems,microfluidicdevicesandflowswitches,miniaturizedsensorswithvarioustransductionmechanisms,micro/nanoactuators,andmanyotherfunctionalsystems

Title: Stimuli-responsive hydrogel thin films

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Volume 5 | Number 3 | 7 February 2009 | Pages 481692

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Stimuli-responsive hydrogel thin films

Ihor Tokarev and Sergiy Minko*

Received 8th August 2008, Accepted 15th October 2008

First published as an Advance Article on the web 17th November 2008

DOI: 10.1039/b813827c

In this brief review we address a range of interesting applications and prospects of responsive hydrogel

thin films for the fabrication of smart responsive surfaces, membranes, sensors with various

transduction mechanisms, micro/nanoactuators, and capsules. We show that hydrogel thin films

compete with grafted polymers and demonstrate strong advantages for the fabrication of robust

multifunctional and multiresponsive surfaces. This article reviews recent publications on the synthesis

of responsive hydrogel thin films and hybrid films with entrapped nanoparticles and reagents by the

chemical crosslinking of reactive polymers, layer-by-layer deposition, and block-copolymer self-

assembly, as well as examining those publications to determine a ran

1 Introduction

and applications of responsive hydrogel thin films for sensors,

lation, and controlled release.

2004 from Technische Uni-

ergiy Minko is Egon Matijevic

haired Professor of Chemistry

t the Department of Chemistry

nd Biomolecular Science

Clarkson University, NY,

USA). Dr Minko received his

Department of Chemistry and Biomolecular Science, Clarkson University,

REVIEW www.rsc.org/softmatter | Soft Matter

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27CView OnlineIhor Tokarevversitat Dresden in Germany.

His research is in the fields of

nanostructured materials, self-

assembled and stimuli-respon-

sive polymer thin films, sensing

and actuating devices.

Sergiy Minko

DSc in Chemistry from the

National Academy of Sciences

of Ukraine in 1993. His research

is in the fields of thin polymer

films, polymer brushes, polymer

gels and membranes, colloidal

particles and self-assembly.gating devices, actuators, encapsu

Ihor Tokarev is a Research

Assistant Professor of Chem-

istry at Clarkson University in

Potsdam, NY. Dr Tokarev

received his PhD in Chemistry in

S

C

a

a

(

Potsdam, NY 13699, USA. E-mail: sminko@clarkson.eduPolymer hydrogels have been the focus of research for the past

several decades because of their range of important properties,

such as biocompatibility, responsive behavior (volumetric

changes) in changeable surrounding environments, ability to

store and immobilize reactive functional groups, chemicals or

cells, and low interfacial tension at the gel-aqueous solution

interface.112 The responsive behavior of hydrogels is of special

concern in this review. If the hydrogel is synthesized from stimuli-

responsive polymers, then changes in the surrounding aqueous

solution (for example, temperature, pH, salt concentration or

concentration of some chemicals) may cause conformation

transition of the polymer chains, which form strands between

crosslinking points in the polymer gel. The globule-to-coil tran-

sition of the strands is observed as volumetric changes of the gel

material, specifically in the swelling degree of the gel in the

solution. This change in swelling degree refers to changes of many

properties of the materials: refractive index, permeability, elastic

modulus, interfacial tension, adhesion, etc. The mechanism

required to change the physical properties of hydrogels uponThis journal is The Royal Society of Chemistry 2009ge of applications.

external stimuli has been explored for the tunable and switchable

transport of ions and molecules across the material, controlled

uptake and release of chemicals by bulk hydrogels, and various

kinds of sensors and actuators as discussed in this review.

Recent advances in nanotechnology have led to increased

interest in hydrogel thin films. The advantages of hydrogel thin

films have been explored for the fabrication of miniaturized

devices with fast response times. Hydrogel thin films have also

attracted interest as an approach to responsive surfaces and

interfaces, where they compete with grafted polymer layers. A

3D polymer network is much more stable at interfaces when

compared with polymer brushes, where polymer chains are

grafted to the surface via only one functional group while the

polymer network is linked to the surface by multiple anchoring

points. Unlike polymer brushes, the thin gel film can be trans-

ferred from the surface of one material to the surface of another

material or used as a free-standing film. The storage function of

the hydrogel thin films (their ability to accommodate various

nanoparticles, chemicals, dyes, enzymes, etc.) can be explored for

the substantial increase in the range of functional properties they

will demonstrate and external signals they will respond to.

In this review we analyze the recent results in synthesis, study,Soft Matter, 2009, 5, 511524 | 511

close to the pKa of the acidic groups. The introduction of

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2.1 Theory of swelling

When a polymer material is immersed in a good solvent, the free

energy of mixing in the form of osmotic pressure causes the

solvent to diffuse into the materials body. The solvent absorp-

tion continues until the complete dissolution of the polymer

occurs unless its chains are held together by chemical or physical

crosslinks, thus forming a 3D polymer network. In the cross-

linked polymer material, the solvent absorption leads to the

expansion (swelling) of the network. This swelling is possible due

to the elastic stretching of the polymer chain fragments (strands)

between the crosslinking points. This stretching of the chain

fragments (away from the Gaussian conformation) increases the

elastic retractive force of the entropic origin, which counteracts

the networks expansion. The balance of these two opposing

contributions governs the equilibrium volume of the polymer

network. The ratio of the swollen volume to the dry volume

determines the swelling degree of the polymer network. A

network imbibed with a solvent is called a gel. The equilibrium

swelling behavior of isotropic, neutral polymer gels is well

described by the Flory-Rehner theory, which is generally

a combination of the thermodynamic theory and the theory of

rubber elasticity.1315

When a polymer network is swollen in water, it is referred to as

a hydrogel. A polyelectrolyte (PE) gel is a special kind of

hydrogel. In the simplest case, the PE gel has ionizable groups of

only one sign (or their large excess). Such a gel may swell to

a significantly greater extent compared to neutral gels due to the

additional osmotic pressure arising from mobile counterions

trapped in the gel as well as the electrostatic repulsion of similarly

charged PE segments. The difference in mobile ion concentra-

tions inside the gel and in the outer solution is determined by the

Donnan equilibrium. For highly ionized PE gels, the osmotic

contribution of counterions to the swelling is dominating. The

corresponding osmotic term was included in the Flory-Rehner

theory16 and the theory proposed by Ricka and Tanaka17 to

describe the equilibrium swelling properties of a wide range of PE

gels. However, in many cases, these theories demonstrated strong

deviations from the experiment, indicating that the electrostatic

interactions in PE gels cannot be ignored. As a result, alternative

theories and models have evolved to account for the long-range

repulsive electrostatic interactions between the PE segments

(favoring swelling), attractive electrostatic interactions between

salt counterions and the charged polymer segments (favoring

shrinking), counterion condensation (leading to an inhomoge-

neous charge distribution and the formation of ion pairs), the

non-Gaussian conformation of charged polymer segments, and

other effects.1820

Stimuli-responsive hydrogels often exhibit sharp volume phase

transitions triggered by specific chemical or physical stimuli.

Such reversible transitions between the swollen and shrunken

phases are often referred to in the literature as swelling-shrinking

transitions. Hydrogels that demonstrate large-scale volumetric

changes in response to small levels of stimuli are obviously of the

most practical interest. The typical stimuli and mechanisms

of response are discussed below in Section 2.2. Fast kinetics of

swelling and shrinking is the prerequisite of most applications512 | Soft Matter, 2009, 5, 511524hydrophobic comonomers shifts the transition to higher pH

values. In contrast, an increase in the pH causes the deproto-

nation of the basic groups in a polycationic gel. At a certain point

this leads to the transition of the gel into a shrunken state.

The swelling degree of a weak PE gel can be altered by adding

salt to an aqueous solution. Theoretical descriptions of the salt-

induced volume phase transitions can be found in several

studies.2224 As an example, consider the case of a gel comprised

of a weak polyacid. At low ionic strength, protons are the major

counterions in the gel. They are trapped in the gel, maintaining

its electroneutrality. The degree of ionization of the gel is

controlled by the pKa of the acidic groups, the local pH, and ionic

strength. In fact, it is lower than the degree of ionization of the

corresponding acid in the bulk solution due to the lower local

pH. As the ionic strength increases, the protons exchange with

the salt ions from the surrounding solution. This causes a shift in

the chemical equilibrium accompanied by an increase in the

ionization degree of the acid groups and in the osmotic pressure

of the mobile counterions in the gel. As a result, at medium ionic

strengths, the gel undergoes additional swelling. The dilution ofof stimuli-responsive hydrogels. The volume phase transition is

a diffusion-limited process, which implies that at least one of the

dimensions of a hydrogel material must be decreased to such

a level that the transition occurs within a reasonable amount of

time (from the point of view of practical applications). Tanaka

and Fillmore have proposed a theory in which the swelling is

explained by the collective diffusion of a polymer network into

a solvent while the local motion of the network obeys a diffusion

equation.21 The theory predicts that the characteristic time of the

swelling transition is directly proportional to the square of the

linear size of the gel and inversely proportional to the diffusion

coefficient of the network (D). D is defined as a ratio of the

longitudinal bulk modulus of the network to the coefficient of

friction between the network and the solvent; it is of the order of

106108 cm2/s for common hydrogels. Simple calculations show

that a response time of less than 1 second is achieved for a gel in

which at least one of the dimensions is less than ten micrometres.

Therefore, we set this value as an arbitrary limit for the thickness

of stimuli-responsive hydrogel thin films selected for overview

from the literature.

2.2 Mechanisms of response

Volume phase transitions in hydrogels have been induced using

various physical and chemical stimuli. Typical examples of

physical stimuli are temperature and light. Chemical stimuli

include pH, ions, and molecules that interact specifically with

a polymer network (molecular recognition).

PE gels bearing weak acidic or basic (or both) pendant groups

demonstrate pH-induced volume phase transitions. For example,

the protonation of the ionized acidic groups of a polyanionic gel

upon lowering the pH of an aqueous solution causes a decrease in

the content of mobile counterions in the gel and in the strength of

electrostatic repulsions of PE chain segments. As the hydro-

phobic interactions arising from the hydrophobic backbone

begin to dominate, the swollen network shrinks into a compact

state. The volume phase transition occurs in a narrow pH rangeThis journal is The Royal Society of Chemistry 2009

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the degree of dissociation of the acidic groups in accordance with

Ostwalds dilution law, thus facilitating further swelling. On the

other hand, the increase in the concentration of the counterions

in the gel leads to the Debye screening of the electrostatic

interactions of the ionized acidic groups. Thus, at high ionic

strengths, the screening effects dominate and the gel starts

shrinking upon salt addition. Since the ionization degree is

independent of the pH in polymers bearing strong acidic/basic

groups, only the shrinking tendency is observed for the corre-

sponding gels. In addition to pH and ionic strength, the degree of

ionization can be tuned by light (isomerization of spiropyran

functional groups)25 or electrochemically (for functional groups

changing their charge state in a redox reaction).2629

In the case of neutral hydrogels, it has been demonstrated that

the swelling degree of an ultrathin hydrogel film immersed in an

electrolyte solution could be tuned by applying a voltage across

the film.30The film swelled or contracted depending on the voltage

polarity. The variations of the swelling degreewere rationalized by

the migration of mobile ions into or from the film with corre-

sponding changes in the osmotic pressure inside the film.

Temperature-responsive hydrogels are prepared from poly-

mers that exhibit the temperature-induced transition from the

state of preferential polymer-water interaction to the state of

preferential polymer-polymer interaction. The characteristic

temperature of the volume phase transition for the most studied,

specially tailored hydrogels is in the biologically relevant range of

temperatures (3040 C). Depending on the chemical structure ofthe polymer chains, some hydrogels shrink if the temperature

rises above a critical point, a lower critical solution temperature

(LCST), while others shrink if the temperature lowers below

a critical point, an upper critical solution temperature (UCST).

Poly(N-isopropylacrylamide) (PNIPAM), poly(vinyl methyl

ether) (PVME), poly(N-vinylcaprolactam) (PNVC), and

hydroxypropyl cellulose (HPC) are a few examples of hydrogels

exhibiting a LCST. For these hydrogels, water molecules form

hydrogen-bonds with the polar groups of the polymer network

below the critical temperature, causing its expansion. However,

the efficiency of the hydrogen-bonding decreases with the rise in

temperature and, above the critical temperature (LCST), the

hydrophobic interactions of the hydrophobic groups and back-

bone start dominating and the polymer network shrinks,

expelling water from the material. The LCST of temperature-

responsive hydrogels and their swelling behavior can be strongly

altered by incorporating weak acidic or basic comonomers into

the polymer network.

Hydrogels from polymers bearing acrylamide and acrylic acid

groups are examples of hydrogels exhibiting an UCST.31 These

groups form insoluble hydrogen-bond complexes which disso-

ciate above the critical temperature, thus triggering the transition

into the swollen state.

Certain hydrogels can be loaded with small molecules that are

known to produce specific interactions with active groups of

a polymer network. For example, the well-known property of

boronic acids to form a reversible covalent complex with cis-diols

was used to prepare hydrogels sensitive to glucose. In particular,

it has been demonstrated that glucose induces the volume phase

transition in hydrogels that contain acrylamidophenylboronic

acid comonomers.32,33This journal is The Royal Society of Chemistry 2009A copolymer bearing both phenylboronic acid and tertiary

amine groups forms a stable complex with poly(vinyl alcohol)

(PVA).35 The polymer-polymer complex involving the interac-

tions between the phenylboronic acid and hydroxyl groups of

PVA dissociates with the addition of glucose and forms a new

complex between the phenylboronic acid groups and the

hydroxyl groups of glucose. The amino groups stabilize the

complex formation through the charge transfer from nitrogen to

boron. As a result, thin films of the complex demonstrate changes

in their swelling degree in response to changes in the concen-

tration of glucose.

Some stimuli-responsive hydrogels exhibit hysteresis loops

between swelling and shrinking curves.3644 The hysteretic

behavior has been linked to the different kinetics of processes

occurring in the gel phase during swelling and shrinking transi-

tions, the existence of activation barriers for protonation/

deprotonation of ionizable groups, and the effects of confor-

mational memory. For example, the formation of intramolecular

and intermolecular hydrogen-bonds and the hydrophobic inter-

actions in a copolymer gel with PE fragments may suppress their

ionization. The mechanisms of hysteretic behavior of the

hydrogels are often poorly understood. Because hysteresis affects

the signal reproducibility and response time of hydrogel-based

chemical sensors, it has to be minimized if possible.39 On the

other hand, hysteretic behavior can be exploited for the creation

of threshold sensors and actuators.36

2.3 Effects of thin film confinement

If the swelling of isotropic bulk gel materials is uniform in all

directions, the swelling of surface-attached hydrogel thin films

and thin film patterns is highly anisotropic. Indeed, chemical

attachment of the network to a surface prohibits in-plane

(lateral) swelling, and the volumetric expansion of the network is

possible only in the direction normal to the substrate plane. It has

a strong impact on the swelling properties of the network. Thus,

the surface-attached polymer gels swell to a much lesser degree

than the bulk gels of the same crosslink density. For example,

bulk PNIPAM gels showed a 100-fold change in their total

volume compared to the 15-fold volume change for the 4 mm

thick surface-attached PNIPAM gel films.45

The swelling behavior of surface-attached poly

(dimethylacrylamide) (PDMAM) gel films was found to be inThe specificity of hydrogels toward target molecules can be

substantially increased by imprinting the molecules in a polymer

network. In particular, the imprinting refers to a process in which

the polymer network is synthesized in the presence of the target

molecules.3 The molecules are held in the highly crosslinked

network by interactions with the functional groups of the poly-

mer. Removing the molecules from the gel produces binding sites

(often referred as to molecular recognition sites, MRSs). These

sites make possible the subsequent rebinding of the target

molecules with high specificity.

Incorporation of enzymes in a hydrogel is an alternative route

for achieving specificity toward substances that are metabolized

by this enzyme.34 For example, glucose oxidase (GOx) can

catalyze oxidation of glucose, resulting in the formation of glu-

conic acid; the latter may induce the volume phase transition in

a weak PE hydrogel.Soft Matter, 2009, 5, 511524 | 513

either spin-coated onto a planar substrate or confined between

two planar substrates (one of them is non-sticky) using micro-

metre-thick spacers and polymerized in situ.45 Among the

free-radical polymerization techniques, a UV-initiated polymer-

ization technique has gained popularity because it allows

micro-patterning of films via a projection mask.55,56 Peppas and

attached (circles) and unconstrained bulk PDMAM (squares) networks.

Fig. 2 The transition temperature (a) and refractive index in the

collapsed state (b) of the surface-attached PNIPAM gel films are shown

as functions of the film thickness with different crosslinking densities; the

crosslinking degree of the PNIPAM gels increases in the following order:

squares, circles, and triangles. The arrow shows the refractive index of the

films in the swollen state. Reprinted with permission from ref. 49,

copyright (2003) American Chemical Society.

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particular, this theory, which was modified to describe one-

dimensional swelling, predicts that the linear extent of the

swelling scales with the density of crosslinks to the 1/3 power(as opposed to 3/5 for the bulk gel). Fig. 1 presents the overalldegree of swelling of the surface-attached and unconstrained

bulk PDMAM gels as a function of the degree of crosslinking.

Although the bulk gel undergoes much greater volumetric

changes than the surface-attached gel, the latter shows greater

linear expansion when considering the changes in one dimension

only.

The constraints for lateral swelling affected the transition

temperature of the surface-attached PNIPAM gel films, espe-

cially for those at high crosslinking density and for those con-

taining a high concentration of ionizable comonomers.45,4749 In

particular, the temperature of the volume phase transition star-

ted decreasing above some critical film thickness (Fig. 2a). The

presence of a substrate also limited the collapse of the thin gel

films at temperatures above the transition temperature (as

deduced from the dependence of the refractive index on the film

thickness, Fig. 2b).

A strong osmotic force in the lateral dimension puts a swollen

gel film under biaxial compressive stress. Such mechanical stress

can be large enough to overcome the adhesion forces and to

The X-axis denotes the molar concentration of 4-methacryloylox-

ybenzophenone (MaBP), a photocrosslinkable monomer, in the

PDMAM networks. Reprinted with permission from ref. 46, copyright

(2004) American Chemical Society.Fig. 1 Comparison of the overall degree of swelling between the surface-cause delamination of the film from a substrate.50,51 It may also

cause wrinkling of the free surface of the film. In particular, the

wrinkling was observed in 100 mm thick gel films52 and 150nm thick gel membranes.53,54

3 Synthesis of hydrogel thin films

Thin films of chemically crosslinked stimuli-responsive hydrogels

reported in the literature were prepared by the following

methods: (1) crosslinking copolymerization (adding multifunc-

tional comonomers), (2) crosslinking (co)polymers with reactive

groups, and (3) crosslinking with high-energy irradiation. Phys-

ically crosslinked films were prepared by (4) PE complexation

and (5) block-copolymer self-assembly.

In the first category, solvent-based free-radical polymerization

techniques are broadly used. A reaction mixture containing

monomers, a crosslinking agent, and a free-radical initiator is

514 | Soft Matter, 2009, 5, 511524coworkers used a mask aligner to precisely position hydrogel

patterns on a substrate surface.56 The photoinitiator is either

added to a reaction mixture or chemically immobilized on

a substrate. In the latter case, the growth of a film is initiated

from a surface, and the thickness can be controlled by varying the

exposure time.45 This method is also suitable for coating

substrates with complex geometry.57 Another free-radical poly-

merization technique is electrochemically-induced polymeriza-

tion. For example, the polymerization of PNIPAM hydrogel thin

films was initiated by electron transfer from a conducting

substrate to a redox-active initiator (potassium persulfate).58 In

another example, the hydrogel thin films of an m-acryl-

amidophenylboronic acid-acrylamide copolymer were grown by

Zn(II)-catalyzed electropolymerization.32 In both cases, the film

thickness was controlled by the electrolysis time. Recently,

a simple method for the generation of hydrogel films with

a thickness gradient has been reported.59 In this method, Zn(II)-

catalyzed electropolymerization of poly(acrylic acid) (PAA) was

This journal is The Royal Society of Chemistry 2009

microchannels.41 Hollow PE capsules were prepared by LbL

assembly on a surface of sacrificial colloidal particles.82,83 The

LbL assembly can be carried out in the presence of charged

analyte molecules to allow their imprinting in a film and selective

recognition.84

Weak PE can be assembled with a high percentage of segments

comprised of loops and tails by adsorbing under pH conditions

of incomplete charge. The resulting LbL films exhibit pH-

responsive swelling behavior. For example, poly(allylamine

hydrochloride)/poly(styrene sulfonate) (PAH/PSS) films were

rendered pH-sensitive by selecting appropriate assembly condi-

tions (pH).36 A strong excess of COO-groups can be built into

multilayers by using partially esterified PAA. As the assembly of

a multilayer is completed, the ester groups are hydrolyzed to

yield carboxyl groups.85

LbL films of water-soluble non-ionic polymers and PEs can

also be obtained via hydrogen-bonded self-assembly.86 For

example, the hydrogen-bonded LbL assembly was utilized to

produce temperature-responsive films.87,88

In highly acidic and basic solutions, LbL films become

unstable due to internal ionization, large swelling forces, and

partial dissociation of ionic bonds, resulting in film detachment,

decomposition, or phase separation.8992 In order to secure their

stability, the films are chemically attached to substrates and

internally crosslinked. For example, PE chains were functional-

ized with photoreactive groups (e.g., benzophenone) to enable

crosslinking with UV light.93,94 Condensation reactions (e.g.

carbodiimide chemistry) were used for crosslinking polymers

their size and the applied radiation dose. Reprinted with permission from

ref. 78, copyright (2006) Wiley-VCH.

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potential gradient applied to a resistive working electrode.

Plasma polymerization is an attractive one-step, solvent-free,

vapor-phase deposition technique used for producing highly

crosslinked hydrogel thin films (typically ranging from tens to

hundreds of nanometres thick) without the use of crosslink

agents (crosslinking occurs due to ion/electron bombardment of

the material during the deposition).6064 Film thickness is

conveniently controlled by polymerization time and plasma

power. The substrates are often surface modified with an adhe-

sion promoter (e.g., self-assembled monolayer or polymer brush)

to improve the stability of the films. Some monomers (e.g., N-

isopropylacrylamide) have to be heated to achieve an appro-

priate vapor pressure during plasma polymerization. Initiated

chemical vapor deposition (iCVD) is another solvent-free, one-

step technique suitable for the generation of uniform thin films of

crosslinked polymers.65

In the second and third categories, polymer crosslinking is

carried out after thin film deposition in the dry state. The

crosslinking of copolymers containing photoreactive pendent

groups or monomers (e.g., benzophenone or 4-cinnamoylphenyl

methacrylate) with UV irradiation is a popular approach.40,47,66

69 It is compatible with photolithography and is suitable for the

preparation of films with a wide range of thicknesses in the dry

state (from tens of nanometres to tens of micrometres).70,71

Photocrosslinkable films can also be obtained by mixing a poly-

mer with a photoinitiator.72 Alternatively, polymer thin films are

immobilized to the substrates surface and internally crosslinked

by plasma treatment.44,73

Thin films of a PVA/PAA miscible blend can be thermally

crosslinked via the esterification reaction to produce pH-sensitive

hydrogels.37,74 Furthermore, polymers containing tertiary amine

or pyridine groups can be crosslinked via the quaternization

reaction using bifunctional alkyl-halides (e.g., 1,4-diiodobutane).

Thin films from these polymers are usually crosslinked in the

vapor of a crosslinking agent.75 It also has been demonstrated

that the quaternized reaction between poly(2-vinyl pyridine)

(P2VP) and 1,4-diiodobutane in a solution led to the binding of

1,4-diiodobutane molecules to the nitrogen of the pyridine

groups, preferably by one end, hence converting P2VP into

a crosslinkable polymer. Spin-coated films were crosslinked by

annealing above the glass transition temperature of P2VP.53,76

High-energy irradiation (e.g., electron beam, g-rays, UV-light)

of a polymer causes random chain scission (radiolysis) and

recombination of the formed free-radicals, leading to the

formation of a crosslinked network. Crosslinking-agent-free

techniques based on electron beam7780 and UV irradiation81

were used to produce gel films (e.g., PNIPAM, PVME, HPC, and

poly(4-vinyl pyridine) (P4VP)) and patterns (Fig. 3) with a high

lateral resolution (100 nm). The degree of crosslinking ismainly controlled by the irradiation dose.

In the fourth category, thin films are mainly assembled by

multiple layer-by-layer (LbL) adsorption of oppositely charged

PE chains. The polymer films fabricated in this way are multi-

layered PE complexes.82 The main advantages of the LbL tech-

nique are in the fine control of a films structure and chemical

composition, and in the fact that LbL films can be assembled on

substrates of any shape and in confined environments. For

example, LbL deposition was used to modify the walls ofThis journal is The Royal Society of Chemistry 2009Fig. 3 (a) Scanning probe microscopy (SPM) image of irradiated stripes

(250 nm) at various doses, and (b) SPM image of irradiated squares with

lateral sizes ranging from 1.2 1.2 mm2 to 250 250 nm2 at variousradiation doses. (c) Three-dimensional plot of the SPM image of the

irradiated small squares representing the lateral resolution as well as the

pad height. (d) Pad heights of the submicrometre squares as a function ofSoft Matter, 2009, 5, 511524 | 515

(majority component) and a stimuli-sensitive polymer middle

block (minority component) leads to the formation of micro-

phase-segregated structures of hydrophobic polymer domains

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27CView Online(typically of spherical shape) embedded in amatrix of the stimuli-

sensitive polymer, where the hydrophobic domains serve as

physical crosslinks. For example, temperature-responsive thin

gel films of PS-b-PNIPAM-b-PS, where PS is polystyrene, were

prepared by spin-coating deposition on porous substrates.97 The

subsequent annealing of the films (showing spherical and gyroid

morphologies in the bulk) in the solvents vapor was carried out

to improve their microphase ordering.

Stimuli-responsive hybrid and composite hydrogel thin films

have been reported in several studies. The two-component hybrid

thin films with a dual response (temperature and pH) were

prepared by the grafting of a PNIPAM brush on top of a PAH/

PAA multilayer.98 Composite thin films that contain functional

nanoparticles were prepared using (1) an LbL approach where

PEs and the nanoparticles were co-assembled to formmultilayers

and (2) a PE gel matrix served as a reactor for the synthesis of

inorganic nanoparticles.

In the LbL approach, the nanoparticles function either as

stimuli-responsive inclusions or as crosslinks. For example, PE

chains served as linkers for assembling multilayers of tempera-

ture-responsive drug-impregnated PNIPAM-co-PAA microgel

particles (300 nm in size).99,100 In another example, goldnanoparticles and weak PE chains were co-assembled to form

pH-responsive composite LbL films.101 The incorporation of

monolayers of gold nanoparticles into LbL layers has been

demonstrated to make them extremely robust so that they can be

freely suspended over submillimetre openings.102,103

To demonstrate the second approach, we examined the

synthesis of gold nanoparticles inside the crosslinked P2VP thin

films.104 The films were pre-loaded with gold salt, and afterwards

the salt was reduced in the presence of citric acid. Gold nano-

particles were formed in the voids of the polymer network, and

they had an insignificant effect on the gels swelling properties. In

this example, the gold nanoparticles enabled the optical detection

of swelling transitions in the films.

4 Applications of stimuli-responsive polymerhydrogel films

4.1 Storage and regulation of mass-transport

Tunable ion-selective permeability (ion gating). Harris and

Bruening observed the pH-dependent ionic permeability of PAH/

PAA and PAH/PSS LbL multilayers.105 The tunable perme-

ability was attributed to the pH-dependent swelling of the

multilayers. The chemical crosslinking of the PAA/PAHcontaining carboxylic acids and amines.95 PAH/PAA LbL films

were also crosslinked via a heat-induced amidation reaction.85

Amphoteric PMAA hydrogel thin films were prepared by the

hydrogen-bonded assembly of poly(methacrylic acid) (PMAA)

and poly(N-vinylpyrrolidone) (PNVP), the crosslinking of

PMAA with carbodiimide and ethylenediamine, and the subse-

quent removal of PVPON.96

In the fifth category, self-assembly in amphiphilic triblock-

copolymers comprised of hydrophobic polymer end blocks516 | Soft Matter, 2009, 5, 511524multilayers allowed stabilization of the films, which otherwise

showed delamination at basic pH because of strong swelling.85

Reversible temperature-induced modulation of ion transport

across LbL multilayers assembled from ionically modified PNI-

PAM random copolymers (PAH-co-PNIPAM and PSS-co-

PNIPAM) has been demonstrated by Jaber and Schlenoff.106

Because of the high density of ionic crosslinks, the multilayers

showed very limited swelling with no delamination problem.

Highly stable ion-permselective membranes based on chemi-

cally crosslinked LbL multilayers and hydrogel thin films have

been reported by several groups. Akashi and coworkers have

demonstrated the switching on/off of ionic permeability of

crosslinked LbL multilayers (PAA-co-PNIPAM/PVAm, where

PVAm is poly(vinylamine hydrochloride)) below and above the

LCST of PNIPAM.95 Advincula and coworkers have reported

on pH-sensitive bipolar ion-permselective hydrogel films

prepared by LbL assembly and photo-crosslinking of benzo-

phenone-modified PAA and PAH.93 The ionization degree of the

groups in the multilayers was controlled by pH, thereby allowing

the switching on/off of ion transport for either cationic or anionic

species. Ion permselectivity occurs because the charges present in

the multilayer reject ions of the same sign and favor transport of

ions of the opposite sign. This approach was later extended to

films having the dual response.98 The films had a binary archi-

tecture, where a temperature-sensitive brush (PNIPAM) was

grafted atop a pH-sensitive LbL multilayer (PAH/PAA), thus

enabling a dual control mechanism for ionic permeability across

the films. pH-switchable permselective membranes from photo-

crosslinked LbL multilayers containing carboxylic acid and

imine groups have also been reported by Sun and coworkers.94

Aoyagi and coworkers prepared photo-crosslinked hydrogel

films of PNIPAM-co-poly(2-carboxyisopropylaclylamide) and

demonstrated that the ion transport across the films was strongly

affected by temperature and pH.68

Regulation of flow and permeability (chemical valves). A

responsive hydrogel material immobilized inside a microfluidic

channel can operate as a valve which opens and closes the

channel for a water flow. Smart hydrogel valves eliminate

the need for external power and external control and thus allow

the creation of autonomous lab-on-a-chip systems for

analytics. The hydrogel material can also be incorporated in

a MEMS-based microvalve to work as an actuator that deforms

an elastic diaphragm wall of a flow channel, thus altering its

cross-section.38,40 Such devices are suggested as components of

autonomous drug delivery systems. Since the size of a micro-

fluidic channel is typically larger than 100 mm, a hydrogel layer

has to be of the order of tens of micrometres thick in order to be

able to close the channel upon swelling. Hydrogel components

with even larger dimensions are needed to actuate mechanical

microvalves. Since hydrogels of this thickness are beyond the

scope of this review, we refer the interested reader to reviews on

this subject.107,108

An alternative approach for the pH-controlled switching of

the direction of an electroosmotic flow (EOF) in a microchannel

coated with a responsive ultrathin LbL multilayer was suggested

by Sui and Schlenoff.109 The reversal of the EOF direction was

attributed to pH-induced changes in the surface charge in

the multilayer (PSS/PDADMA + PDADMA-co-PAA, whereThis journal is The Royal Society of Chemistry 2009

PDADMA is poly(diallyldimethylammonium chloride)). Fine

control of the EOF has been demonstrated for these films by

varying the pH of solutions.

Porous inorganic and polymeric filtration membranes with

pore sizes ranging from 10 nm to a few micrometres can be

coated with responsive hydrogel thin layers to produce flow

valves and filters with size-selective permeability. Several groups

have explored this approach.110113 For example, PNIPAM

hydrogel layers were graft-polymerized on the surface of porous

polymer materials (inside pores and/or on the outer surfaces) to

produce composite membranes with temperature-controlled

permeability. The swelling and shrinking of the surface-attached

PNIPAM layers changed the effective pore size and hence altered

the flow rate or permeation rate for diffusional species. As

compared to stimuli-responsive polymer brushes, hydrogel layers

allowed for a much larger range of pore size changes and hence

a wider range of porous materials were suitable as substrates.

Chu et al. have reported chemical valves with the temperature

response opposite to that found in PNIPAM-based systems.31 To

achieve this behavior, they modified a porous nylon 6 membrane

with a layer of an interpenetrated polymer network (IPN)

composed of PAM and PAA (Fig. 4). The resulting gel exhibited

UCST behavior due to the temperature-induced dissociation of

the zipper-type H-bond complex between the polymers.

Rubner, Cohen, and coworkers have fabricated pH-controlled

valves from commercial track-etch membranes whose pores were

modified with PAH/PSS LbL multilayers.41 The valve showed

with relatively low molecular cutoff values (660 g/mol). Thepermeability of the membranes and their responsive properties

depended strongly on their morphology (spherical, cylindrical,

gyroid, and lamellar morphologies were studied).

Encapsulation and the triggered release of active substances.

The swelling properties of stimuli-responsive hydrogels can be

used for encapsulation and the triggered release of active

substances (e.g., drugs, fragrances, and flavor additives). In the

past two decades, bulk hydrogels and hydrogel microparticles

have been widely explored as potential responsive carrier mate-

rials.1,9,114,115 In recent years, numerous publications have

emerged in which hydrogel thin films were suggested for the same

purposes. In most studies, a hydrogel film forms a semipermeable

capsule which isolates water-soluble guest molecules (low

molecular weight or macromolecular) from their environment.

The permeability of the gel capsule for the molecules can be

regulated by an external stimulus (e.g., temperature, pH, ionic

strength, or light). A typical example of such a release system is

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permeability of high molecular weight poly(ethylene oxide)

(PEO) caused by pH-induced swelling and shrinking of the

multilayer. The swelling of the multilayer was found to be

Fig. 4 Schematic illustration of the temperature-responsive gating

membrane and the fabrication procedure: (a) porous membrane support;

(b) membrane support after plasma-graft polymerization of PAM; (c) the

subsequent synthesis of PAA results in the formation of PAM/PAA

hydrogel gate inside the membranes pores; (d) below the UCST the

membranes pores open as a result of the formation of an insoluble

hydrogen-bonded complex between PAM and PAAC; (e) above the

UCST the membranes pores close because of the complex dissociation

and swelling of the hydrogel. Reprinted with permission from ref. 31,

copyright (2005) Wiley-VCH.This journal is The Royal Society of Chemistry 2009hysteretic, meaning an open or closed state of the valve could be

attained at a single pH value.

An alternative approach to chemical valves based on macro-

porous hydrogel thin filmmembranes has been recently suggested

by our group.76 The 100 to 200 nm thick membranes (chemically

crosslinked P2VP) were prepared on a planar substrate and then

transferred onto 200 nm pore size polycarbonate track-etch

support membranes to form a pH-responsive skin layer (Fig. 5).

The pore size was altered (from wide open pores to completely

closed pores) by the expansion/shrinkage of the entire hydrogel

body of the membranes. This property was explored for

controlling the water transport through the membranes.

Temperature-responsive, self-assembled thin film hydrogel

membranes from PS-b-PNIPAM-b-PS triblock-copolymer

(Fig. 6a) have been reported by Ruokolainen and coworkers.97

The membranes were spin-cast directly on top of meso/macro-

porous polyacrylonitrile (PAN) support membranes (Fig. 6b).

The PS end blocks were the minor component and served as

physical crosslinks (see the fifth category in Section 3). The

membranes showed a switchable on-off permeability for poly(-

ethylene glycol) (PEG) below and above the LCST of PNIPAM

Fig. 5 (a) SPM images (7.5 7.5 mm2) of a P2VP gel membrane underwater of pH 5.5 (left) and 2 (right). (b) Schematic representation of the gel

membrane with the open (left) and closed (right) pores; the gel membrane

is deposited on the surface of a porous substrate.Soft Matter, 2009, 5, 511524 | 517

repeated many times. This encapsulation approach is of a limited

practical value because of the small capacity of thin films as

compared to bulk hydrogels. However, this approach has

scientific significance because it allows study of the processes of

the loading and release of guest molecules and nanoparticles in

responsive hydrogels, as well as the permeability of the hydrogels

for low molecular weight and macromolecular species using the

various techniques of thin film characterization (e.g., ellipsom-

etry, UV-vis and fluorescence spectroscopies, microgravimetric,

and electrochemical techniques).

Lyon and coworkers have demonstrated the temperature-

triggered pulsatile and the extended release of insulin99 and

doxorubicin100 from LbL films composed of alternating layers of

drug-impregnated crosslinked hydrogel nanoparticles (PNI-

PAM-co-PAA)/drug) and PAH (Fig. 7). The reversible stimuli-

controlled loading and release of guest molecules using hydrogel

films have been reported by several groups. For example, Hiller

and Rubner demonstrated that an anionic dye (as a model drug)

can be rapidly loaded (within minutes) into swollen PAH/PSS

LbL films (having an excess of free amine groups) at acidic pH

while it releases very slowly (on a time scale of weeks) from the

shrunken films (pH 611).36 This property of the films can be

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27CView OnlinePE LbL capsules with triggered release. The capsules are loaded

with desired substances by diffusion from concentrated solu-

tions. The diffusion is possible either through a swollen LbL shell

or through the nanoscopic holes in the shell. Afterwards, the

capsule shell is switched to the impermeable state by changing

environmental conditions or by chemical crosslinking, and the

loaded capsules are transferred to a medium of interest. The

release of the encapsulated substance is triggered by an appro-

priate stimulus. The triggered release of polyelectrolyte capsules

was reviewed by Sukhishvili82 and Smedt and coworkers.83 The

description of different types of hydrogel-based colloidal carriers

can be found in a review by Nayak and Lyon.115

A hydrogel film can also function as a container itself. An

active substance can be added to a hydrogel solution before the

film deposition, or it can even serve as a building block in the case

of LbL multilayers. As the film is prepared, the substance is held

(stored) in the deswollen hydrogel body. Alternatively, a hydro-

gel film can absorb the substance from the solution. When the

loading is complete, the hydrogel is caused to shrink by an

external stimulus. The stored substance can be released from the

film to a solution by applying the stimulus (trigger), which causes

the hydrogel to swell. The loading and release steps can be

utilized for the sustained release of drugs. The pH and ionic

strength dependent release of anionic dyes from chemically

Fig. 6 (a) Chemical structure of PS-b-NIPAM-b-PS triblock-copol-

ymer. On the right, a schematic illustration of the temperature-induced

conformation transition of a hydrogel having a self-assembled

morphology with spherical PS domains. These domains act as physical

crosslinks for the hydrogel, and as the temperature is raised above the

LCST the PNIPAM chains become hydrophobic and the gel collapses.

(b) Schematic view of the multilayer composite filter used for the

permeability studies. Reprinted with permission from ref. 97, Copyright

(2007) American Chemical Society.

518 | Soft Matter, 2009, 5, 511524crosslinked PNIPAM-co-PAA/PVAm LbL films was observed

by Akashi and coworkers.116 The reversible temperature-depen-

dent loading and release of a dye was documented for hydrogen-

bonded PNIPAM/PAA LbL films by Quinn and Caruso.87

Sukhishvili and coworkers fabricated PMAA hydrogel films with

pH-dependent polyampholytic swelling properties by the

hydrogen-bonded LbL assembly of PNVP and PMAA followed

by the crosslinking of PMAA with ethylenediamine as well as the

removal of PNVP. The pH-dependent loading and release of

dyes and macromolecules was demonstrated for these films.96

Fig. 7 Schematic representation of the LbL films composed of PAH and

temperature-responsive microgel particles (PNIPAM-co-PAA). The films

were loaded with doxorubicin (DX) by deswelling/swelling the film in

a buffered, pH 7.0 DX solution. DX was released from the films in pH 3.0

buffer by deswelling the film upon heating. Reprinted with permission

from ref. 100, copyright (2005) American Chemical Society.This journal is The Royal Society of Chemistry 2009

presence of the anionic nucleotide (adenosine monophosphate,

deformation of thin distortable membranes and microcanti-

levers.43,119,120

Commercial piezoresistive pressure sensor chips were used as

electromechanical transducers by Guenther and coworkers.38

The micrometres-thick hydrogel layers (PAA/PVA and PNI-

PAM) sensitive to pH and organic solvent concentration were

either deposited onto a distortable silicon membrane of the

sensor chip or placed in a cavity under the membrane. In the

latter case, the thickness of a hydrogel layer was determined by

the size of the cavity (250 mm). The swelling-induced deflection of

the membrane was converted into an electrical signal by pie-

zoresistive elements.

An ultrasensitive pH sensor based on micromachined canti-

levers has been reported by Peppas group.56,121 Patterned layers

of PMAA/poly(ethylene glycol) dimethacrylate were formed on

silicon wafers containing cantilevers by free-radical UV poly-

merization. pH-induced swelling/shrinking of a hydrogel

attached to one side of the cantilever created surface stress,

causing the cantilever to bend (Fig. 8). The use of an optical

laser-based reflection system (such as the one used in atomic

force microscopy) for monitoring of the cantilever bending

response resulted in a maximum deflection sensitivity of 1 nm/5105 DpH. The hydrogel coated microcantilevers were also

fabricated by other groups for sensing pH (PMAA-co-PAM,120

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27CView OnlineAMP) on a QCM resonator surface.84The subsequent removal of

AMP from the multilayer yielded the swollen hydrogel from the

cation-excess polyion complex. Rebinding of AMP neutralized

the complex, and thus the hydrogel shrank. The swelling-

shrinking of the hydrogel was sensed using a QCM resonator.

Transducers based on microelectromechanical systems

(MEMS). The swelling forces exerted by stimuli-sensitive

hydrogel thin layers are sufficient to cause the mechanical4.2 Chemical sensors based on hydrogel films

The stimuli-triggered volumetric transition in hydrogel layers

was explored for various sensors. The recent review by Richter

et al. describes hydrogel-based pH sensors.43 Here, we focus on

studies in which hydrogel thin films were used to sense temper-

ature, pH, and various kinds of analytes. Sensors are classified by

a scheme used to transduce analyte-induced chemical or physical

changes in a hydrogel into an electrical or optical signal.

Microgravimetric transducers. Several groups used mass-

sensitive quartz crystal microbalance (QCM) resonators coupled

with stimuli-responsive hydrogel coatings to monitor changes in

hydrogel swelling. Absorption and release of water by the

hydrogel are followed by changes in the surface load, which

results in a shift of the resonance frequency of a QCM resonator.

The response is typically nonlinear because both stiffness and

density of the hydrogel coating decrease upon swelling. Such

changes in the mechanical properties also cause damping of the

signal amplitude, which can be monitored in parallel with the

frequency. Richter et al. discussed physical aspects of the oper-

ation of hydrogel-based QCM sensors and their limitations.37

Their pH sensor, based on PVA/PAA hydrogel, showed high pH-

sensitivity but suffered from swelling hysteresis. The pH-sensitive

thin films of crosslinked P4VP prepared on QCM crystals have

been also reported by Ramstrom, Yan, and coworkers.81

Willners group used the QCM technique to study the selective

sensing of triazine herbicides,117 nucleotides, mono-

saccharides,118 and glucose,32 using hydrogels (electro-

polymerized acrylamide-methacrylic acid copolymers and

acrylamide-based copolymers containing boronic acid groups).

Herbicides were imprinted in the hydrogels to allow their selec-

tive detection. The boronic acid groups enabled the selective

binding of glucose. The combination of the boronic acid groups

and MRS provided the selective detection of nucleotides and

monosaccharides. The formation of negatively charged boronate

complexes with the analyte molecules was responsible for the

swelling of the hydrogel.32,118 In the case of herbicides, the density

of the MRS in the hydrogel was insufficient to provide a detect-

able surface load to the QCM surface. However, the binding was

found to be accompanied by the hydration of the MRS and

thereby it led to the additional swelling of the molecularly

imprinted hydrogel.117 Faradaic impedance spectroscopy, chro-

nopotentiometry, and surface plasmon resonance (SPR) spec-

troscopy were used as complementary techniques to monitor the

hydrogel swelling.32,118

Shinkai and coworkers prepared a nucleotide-sensitive

molecularly imprinted multilayer by carrying out the LbL depo-

sition of boronic acid containing polyanion and polycation in theThis journal is The Royal Society of Chemistry 2009where PAM is polyacrylamide, and polyelectrolytes with

amino groups122), Pb2+-ions (acrylamides containing benzo-18-

crown-6),123 CrO42-ions (polymers containing tetraalkylammo-

nium salt),124 and glucose (poly(methacrylamidophenylboronic

acid)-co-PAM120 and GOx/polycation LbL multilayers125).

Electronic transducers. Willner and coworkers deposited the

molecularly imprinted hydrogels (the same as hydrogels

described in the subsection on microgravimetric transducers) on

the gate surface of ion-sensitive field-effect transistors

Fig. 8 (a) Cross-sectional schematic of the cantilever/polymer gel

structure with the typical dimensions and (b) scanning electron micros-

copy (SEM) images of the cantilever/polymer gel structure in the dry

state. The cantilever is bent upwards and hence the tip region is out of

focus. Reprinted with permission from ref. 56, copyright (2002) American

Institute of Physics.Soft Matter, 2009, 5, 511524 | 519

Advincula et al. reported on the enhancement of an SPR signal

in pH-sensitive gold nanoparticle/PAH LbL multilayers.101 The

swelling/shrinking of these hybrid multilayers resulted in

a change in the spacing between individual Au nanoparticle

monolayers, which in turn strongly affected the propagation of

an SPR wave along the hybrid LbL film/metal substrate inter-

face. The introduction of an additional pH-sensitive LbL

multilayer (PAH/PSS) at the interface between the hybrid LbL

film and metal substrate was shown to further enhance the SPR

response towards pH changes. The enhanced SPR shifts were

rationalized by electromagnetic coupling between the individual

Au nanoparticle monolayers and the metal film of the SPR

detector.

A metallic thin film with a lithographically manufactured

periodic array of cylindrical nanoscopic wells (so-called plas-

monic crystal, Fig. 9a) is another promising sensing platform that

does not require a prism to excite the SPR by incident light. The

plasmonic crystal exhibits a complex, multi-peak transmission

spectrum in the visible and near-infrared regions. Mack et al.

immobilized a 500 nm thick pH-responsive hydrogel film(copolymer containing acrylic acid groups) on the surface of the

plasmonic crystal (Fig. 9b).131 They found that the pH-induced

swelling transitions occurring in the hydrogel film strongly

altered the positions and intensities of plasmon resonance peaks

in the spectra. Summing the absolute magnitudes of the differ-

ence spectra (as referenced to a spectrum acquired at a specific

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27CView Online(ISFETs).117,118 The ISFETs are field-effect transistors in which

the metal gate electrode is eliminated and the gate insulator is

directly exposed to an electrolyte solution (a reference electrode

is used to complete the circuit). In the case above, the gate

insulator with the surface-immobilized molecularly imprinted

hydrogel layer is exposed to the electrolyte solution containing

the analyte. The binding of the ionized/protonated analyte

molecules to the MRS leads to changes in the charge distribution

in the hydrogel and hence the potential on the gate. The drain-

source current is very sensitive to the gate potential and is used as

an output signal.

Optical transducers. The surface plasmon resonance (SPR)

technique has been widely used to monitor changes in the

thickness of polymer thin films and multilayers. The basics of this

technique and its applications for chemical and biochemical

sensing can be found in a recent review by Homola.126 Briefly,

SPR is a collective density oscillation of free electrons confined to

and propagating along a metal (typically silver or gold) surface.

This density oscillation is coupled with an electromagnetic

(evanescent) wave whose electric field is decaying exponentially

from the surface. The SPR can be excited on the surface of a thin

metal film deposited on the base of a prism (the Kretschmann

configuration) by monochromatic light incident at the prism-film

interface. The SPR is detected through a narrow minimum in

the reflection coefficient at a particular angle of incident light.

The angle at which the minimum occurs depends strongly on the

refractive index and the thickness of the dielectric layer deposited

on the metal surface. Because of the evanescent nature of SPR,

the probing depth of this technique is limited to layers of two to

three hundred nanometres in thickness.

Frank and coworkers used the SPR technique to study the

effects of temperature and hydrostatic pressure on the swelling

degree of 4 mm thick (dry state) PNIPAM hydrogel films. They

detected broadening of the volume phase transition region and

a shift in the transition temperature to higher values with an

increase in pressure. It has been demonstrated that the film

confinement has a significant effect on the transition temperature

and the swelling degree (see also Section 2.2).45

Willner and coworkers measured the kinetics of swelling and

shrinking of the glucose-sensitive hydrogel film (acrylamide

copolymer containing boronic acid groups) using the SPR

technique.32 They found that the film swelling upon addition of

glucose was rapid, whereas the shrinking as a result of the glucose

depletion was a slow process (tens of minutes), which indicated

strong interactions between the sugar molecules and the boronic

acid groups.

In several studies, hydrogel thin films were used as platforms

for immobilization of various bioreceptors for SPR monitoring

of biomolecular binding events, including DNA hybridization,

DNA-protein, protein-protein, and other receptor-ligand pair

associations.127130 The hydrogel films (usually carboxylated

dextran and ethylendiamine) enable better surface coverage and

adhesion of the receptor groups than is usually achieved when

they are directly immobilized on a metal surface. Being highly

hydrophilic, the hydrogel layers demonstrate low non-specific

adsorption of proteins on the detector surface. Furthermore,

protein bioreceptors are less prone to denaturation on hydrogel

substrates.129520 | Soft Matter, 2009, 5, 511524pH value) over all wavelengths yielded an integrated plasmonic

response that directly correlated with pH-dependent changes in

the properties of the hydrogel film (Fig. 9c and d).

The SPR can also be excited in noble metal nanoparticles by

exposing them to light of a specific wavelength. This phenom-

enon, known as localized surface plasmon resonance (LSPR), is

Fig. 9 Schematic representation of a plasmonic crystal before (a) and

after modification with a pH-responsive hydrogel layer (b). (c) Spectral

sensitivity map consisting of difference spectra from the hydrogel-

modified crystal referenced to t 0 s, after which the analyte solution wascycled between pH 7.86 and 1.44. (d) The integrated plasmonic response

corresponding to reversible changes in analyte solution from pH 7.86 to

1.44 (blue), 6.42 to 5.13 (red), and 5.76 to 5.66 (black). The smallest pH

change (0.10) is well differentiated from the stable background signal

(inset). Reprinted with permission from ref. 131, copyright (2007)

American Chemical Society.This journal is The Royal Society of Chemistry 2009

observed for surface immobilized nanoparticles (islands) and

colloidal dispersions. The LSPR leads to a pronounced extinc-

tion peak (or peaks) in a transmission UV-vis spectrum (also

referred to as a T-LSPR spectrum) that is noticeable even for

nanoparticle monolayers and sub-millimolar concentrations of

nanoparticle dispersions. The intensity and position of the peak

depend on the size and shape of nanoparticles, their size distri-

bution and spatial organization, shell thickness (for the core-shell

particles), and the dielectric constant of the surrounding

medium.132,133 If the metal nanoparticles are coupled with

a polymer, the stimuli-induced changes in the polymeric material

can be transformed into an optical signal. Although T-LSPR

spectroscopy was widely used for the registration of molecular

recognition events, it was only recently employed for sensing

stimuli-induced changes in polymeric materials. Lee and Perez-

Luna reported on the reversible aggregation of gold colloidal

nanoparticles linked to the surface-grafted carboxylated dextran

chains in solvents of different polarity and the associated changes

in the optical properties.134 The observed shifts in the position of

the plasmon resonance peak were assigned to changes in the

refractive index of the hydrogel and in the strength of electro-

magnetic inter-particle coupling.

An alternative T-LSPR sensing platform has been suggested135

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27CView Onlineby Fendler and coworkers. An ultrathin layer of cholesterol-

sensitive molecularly imprinted polymer (chemically crosslinked

P2VP) was prepared on gold islands and covered with a mono-

layer of colloidal gold nanoparticles. Swelling of this sandwich

layer upon binding of cholesterol molecules to the MRS altered

the strength of electromagnetic coupling between the islands and

nanoparticles, resulting in a strong shift of the peak position.

This approach was later extended to pH-sensitive P2VP gel

membranes (shown in Fig. 5).104 In this work, the membrane with

chemically reduced gold nanoparticles dispersed in the P2VP gel

was deposited on a substrate with gold islands (Fig. 10a). A

change in the distance between the gold nanoparticles and islands

Fig. 10 (a) Schematic illustration of an optical sensor utilizing localized

surface plasmon resonance excited in gold nanoparticles (NPs) and

islands and coupled via the pores of a pH-responsive P2VP gel

membrane. (b) UV-vis spectra of such an optical sensor acquired in water

of pH 5.5 (solid line) and 2 (dotted line), and (c) shifts of the absorption

maximum acquired from the UV-vis spectra as a function of pH.

Reprinted with permission from ref. 104, copyright (2008) Wiley-VCH.This journal is The Royal Society of Chemistry 2009enzymes) and acted as a tunable wavelength filter. The operation

principle was based on recording a reflection spectrum that was

sensitive to the swelling degree of the hydrogel.

Integrated optical sensor chips suitable for high-resolution pH

measurements have been fabricated by Kunz and coworkers.144

Compact dual-channel chirped grating coupler sensor chips were

coated with the 90 to 300 nm thick photopatterned films of pH-

responsive hydrogels (photocrosslinkable PHEMA copolymer

containing amino groups). The sensor detected changes in

a refractive index occurring upon swelling and shrinking of the

hydrogel. A resolution DpH < 1.1 104 (at pH 7.5) has beenreported.

4.3 Actuators

Cell-culture supports with the triggered release. A promising

application of responsive hydrogel thin films is related to tissue

engineering. The idea of controlling adhesion of mammalian cells

using substrates from thermoresponsive polymers dates back to

1990 when it was first reported by Okanos group.145 Since then,

several groups have studied different aspects of this process,

which has resulted in a large number of publications. Recent

reviews on the subject can be found in the papers of Kikuchi and

Okano146 and da Silva et al.147 In many studies, thermoresponsive

surfaces have been formed by 10 to 100 nm thick crosslinked

PNIPAM-based copolymer films.147 At temperatures above the

LCST, the cells adhere, spread, and proliferate on the relatively

hydrophobic PNIPAM surfaces the same way they do on the

traditional polystyrene tissue culture dishes. However, when the

temperature is lowered well below the LCST, all cultured cells

spontaneously detach due to the PNIPAM transition into the

hydrophilic state. Such temperature-responsive culture supports

have been demonstrated as useful in regenerative medicine and

tissue engineering applications. Specifically, sheets of cultured

cells along with their extracellular matrix are harvested from

the dishes and transplanted to tissue beds with minimal celldue to swelling-shrinking of the gel modulated the propagation

of plasmons on the island layer that led to a strong shift of the

UV-vis absorption peak (Fig. 10b,c).

Aussenegg and coworkers have proposed a reflectance optical

sensing principle namedmetal island coated swelling polymer over

mirror system or MICSPOMS, for short.72,136,137 The MIC-

SPOMS is an interference device in which gold particles and the

mirror act as an optical thin film resonance system with reflection

properties depending on the thickness of the hydrogel layer.

Changes in the thickness of the hydrogel layer were monitored by

the slope of the characteristic reflection minimum of the device.

Smooth, 100 nm thick layers of pH-responsive hydrogel(photocrosslinked PNVP) with immobilized enzymes were used

as biosensing elements.136

Lowe and coworkers have developed a range of hydrogel-

based holographic sensors for detecting bacterial spores,55

measuring pH,138 ionic strength,139 and the content of ethanol in

aqueous solutions,140 as well as the concentration of metal

ions,141,142 glucose,33 and metabolites of enzymatic reactions.143

Holographic diffraction gratings comprised of fringes of silver

particles were generated in 10 mm hydrogel films (mainlypoly(2-hydroxyethyl methacrylate) (PHEMA) copolymers con-

taining analyte-sensitive groups and, in one study, immobilizedSoft Matter, 2009, 5, 511524 | 521

Furthermore, the future research directions in the field of

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27CView OnlineLbL multilayers provide another versatile platform for tissue

engineering because the interaction between the multilayers and

cells can be tuned (from the viewpoint of adhesion, signaling, and

cytotoxicity) by changing the composition of the multilayers, by

micro-patterning, and by incorporating receptor and signaling

molecules and inorganic nanoparticles.151 Additionally, the

multilayers can be prepared easily on substrates of complex

geometry (e.g., 3D cell-culture scaffolds and tissues). The

potential of responsive LbL multilayers for creating cell-culture

substrates with the smart behavior is yet to be explored.

5 Conclusions and outlook

In this brief review, we have demonstrated the recent progress inloss.148 They can be micro-patterned to include cells of different

types and (Fig. 11) layered to create complex 3D tissue-like

structures .149,150

Fig. 11 Schematic representation of the methods for patterning cell co-cu

(a) The first cell type, hepatocytes, is seeded and cultured at 27 C, resultinggrafted islands showing a hydrophobic nature. (b) The second cell type, en

patterned co-cultures. (c) Decreasing the temperature to 20 C induces thesheet (right). Bar: 1 cm. Reprinted with permission from ref. 150, copyrigthe field of stimuli-responsive hydrogel thin films. Owing to their

unique ability to undergo large, reversible volumetric changes in

response to small amounts of external chemical and physical

stimuli, responsive hydrogels are promising materials for a broad

range of applications, from sensors to actuators. In particular,

the self-regulating properties of responsive hydrogels combined

with the energy of chemical reactions (no need for an external

power source) and a thin film structure makes them attractive for

miniaturized (bio)sensors, autonomous drug delivery systems,

microfluidic valves and flow switches, smart cell-culture

supports, regulation of the rate of electrochemical reactions, and

many other advanced applications. Many examples of such

applications can be found throughout this overview. Hydrogel

films are extremely versatile materials in terms of possible designs

(e.g., multilayers, membranes, and patterns), fabrication

methods (e.g., chemical crosslinking of reactive polymers, LbL

deposition, and block-copolymer self-assembly), and function-

alities that can be incorporated into them (e.g., functional

groups, active substances, inorganic nanoparticles, and

enzymes).152,153 They can be rendered multifunctional and mul-

tiresponsive without compromising their mechanical stability,

522 | Soft Matter, 2009, 5, 511524smart hydrogel films may include the development of coatings

for wound healing, drug delivery systems, lab-on-a-chip

systems, switchable antimicrobial and antifouling coatings,

coatings controlling (bio)catalytic activity, memory devices,

tunable/switchable optical coatings, rewritable microreliefs, and

deformable-upon-signal coatings.

Acknowledgements

The authors gratefully acknowledge the support of the US

ARMY via the grant W911NF-05-1-0339 and the Nationalwhich is secured by a 3D crosslinked network structure. The

potential of hydrogel thin films is not yet exploited and offers

virtually endless opportunities for the development of new,

exciting active materials and functional devices on their base.e and harvesting of co-cultured cell sheets using a dual patterned surface.

localization of hepatocytes onto PNIPAM-poly(n-butyl methacrylate) co-

helian cells, is seeded and cultured at 37 C, resulting in the generation ofchment of the co-cultured cell sheet. Harvested patterned co-cultured cellScience Foundation (NSF) via the grant DMR-0706209.

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