Research Article

Received: 19 February 2010

Revised: 30 April 2010

Accepted: 21 May 2010

Published online in Wiley Online Library: 14 October 2010

(wileyonlinelibrary.com) DOI 10.1002/pi.2929

Multi-responsive hydrogels based on

N-isopropylacrylamide and sodium alginate
Raluca P Dumitriu,a Geoffrey R Mitchellb and Cornelia Vasilea
Abstract
Hydrogels consisting of sodium alginate and N-isopropylacrylamide covalently crosslinked with N,N -methylenebisacrylamide
were prepared. The mixed-interpenetrated networks obtained were characterized using elemental analysis, Fourier transform
infrared and Raman spectroscopy, swelling measurements and environmental scanning electron microscopy. The thermo- and
pH-responsive properties of these hydrogels were evidenced by their swelling behaviour, which depended also on the amount
of crosslinking agent and hydrogel composition.
c 2010 Society of Chemical Industry


Keywords: hydrogels; alginate; N-isopropylacrylamide; stimuli-responsive; swelling

INTRODUCTION

222

Stimuli-responsive hydrogels are capable of undergoing marked

volume changes (volume phase transition) in response to small
variations in the external conditions, such as temperature,1 3
pH,4 6 solvent composition,7,8 ionic strength,9 11 presence of
biological molecules12,13 and in some cases the application of a
small electric field14,15 or light irradiation.16,17 Such smart materials
have a great potential for applications in high-performance areas
like biotechnology, medicine or pharmacy for biosensors, bioseparators and bioreactors, in tissue engineering or in controlled
drug delivery systems responding to environmental stimuli by
swelling/deswelling they modify drug release rates.18 21 This wide
range of applications is due to their excellent biocompatibility,
tunable chemical and three-dimensional physical structure, high
swelling capacity, good mechanical properties and physical similarity to living tissue.22,23 Among smart materials, pH- or/and
temperature-responsive polymeric hydrogels have been extensively studied in the biomedical field because these two factors
can be easily controlled and they are applicable in vitro and in vivo
conditions.
Volume phase/solgel transitions have been widely studied
since the first observation of gel collapse by Tanaka,24 which
demonstrated that small changes in the external conditions
could bring about marked changes in the state of a gel.
Recent research has focused on developing new polymeric
matrices for biomedical applications, which are biodegradable
and also multi-stimuli-responsive, by associating a biopolymer
with a thermo-sensitive macromolecule.25 28 Polysaccharides are
promising candidates to obtain hydrogel, film, membrane or
microcapsule carriers of biologically active agents due to their
lack of toxicity towards living organisms, their biocompatibility
and their biodegradability in contact with biological fluids.
Many hydrogels with superabsorbent properties have been
obtained from cellulose derivatives,29,30 dextran,28,31 guar gum,3,4
hyaluronic acid,32,33 chitosan27,34,35 and alginate.6,36,37
Alginate, a natural polysaccharide derived from brown seaweeds (Phaeophyceae), is a polyanionic linear copolymer com-

Polym Int 2011; 60: 222233

posed of 1,4-linked -D-mannuronate (M) and -L-guluronate

(G) residues arranged in a blockwise fashion as homopolymer
blocks (MM, GG) or alternating blocks of M and G with different M/G
ratios,38 which is frequently used in medical applications including
wound dressings, scaffolds and pharmaceutical formulations.39,40
Having one carboxyl group in each M or G unit, alginate is
a negatively charged polyelectrolyte at neutral or basic pH.
Alginate gels have been shown to be pH-sensitive and biocompatible, with a relatively low cost, having wide applicability as
biomaterials.41,42 These hydrogels are obtained mainly by ionic
or covalent crosslinking. It is well known that alginate can form
gel beads by cooperative binding of multivalent cations (usually
Ca2+ ) which interact with the carboxylate groups on the polymer
chain and induce intermolecular crosslinking.43 These beads can
be used for encapsulation of bioactive agents like cells, enzymes,
proteins and vaccines.44 Recent studies have reported the preparation of poly(N-isopropylacrylamide) (PNIPAAm)/alginate gels as
semi-interpenetrating polymer networks and comb-type graft hydrogels, based on the cation-mediated crosslinking of alginate
with Ca2+ ions.45 50
PNIPAAm is one of the most widely studied thermo-sensitive
polymers, exhibiting a reversible temperature-sensitive phase
transition in aqueous solutions at a lower critical solution
temperature (LCST) of ca 32 C.51 Below this LCST, PNIPAAm is
water-soluble and hydrophilic, existing in a coil conformation;
above this LCST, PNIPAAm undergoes a sharp coil-to-globule
transition, forming hydrophobic associations. Stimuli-responsive
interpenetrating polymer network (IPN) hydrogels based on

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Correspondence to: Raluca P Dumitriu, Petru Poni Institute of Macromolecular

Chemistry, Physical Chemistry of Polymers Department, 41A Gr. Ghica Voda
Alley, 700487 Iasi, Romania. E-mail: rdumi@icmpp.ro

a Petru Poni Institute of Macromolecular Chemistry, Physical Chemistry of

Polymers Department, 41A Gr. Ghica Voda Alley, 700487 Iasi, Romania
b Centre for Advanced Microscopy and Polymer Science Centre, University of
Reading, Whiteknights, Reading RG6 6AF, UK

c 2010 Society of Chemical Industry

Multi-responsive hydrogels based on NIPAAm/sodium alginate

PNIPAAm were developed especially as drug delivery systems,
because they swell below and collapse above the LCST in an
aqueous environment, modulating the release of various drugs
in response to temperature changes, by adding a hydrophilic
component or a hydrophobic one.1
A few studies have been dedicated to various approaches
to obtain alginate microcapsules or macroscopic hydrogels by
covalently crosslinking alginate, rather than ionic crosslinking as
discussed above. Formation of an acetal-linked network through
an acid-catalysed acetalization reaction of alginate hydroxyls with
bifunctional glutaraldehyde52,53 and also the covalent crosslinking
of carboxylic acid groups of alginate with poly(ethylene glycol)
diamines having various molecular weights54 have been reported.
This paper deals with the synthesis and characterization of new
covalently crosslinked poly(N-isopropylacrylamide)/alginate (PNIPAAm/Alg) mixed-IPN hydrogels. The chemical structures of the
synthesized hydrogels were determined using elemental analysis
and Fourier transform infrared (FTIR) and Raman spectroscopy.
The multi-responsive properties of the hydrogels were investigated using swelling measurements at various temperatures and
pH values. Their morphological aspects at various degrees of relative humidity (RH) were studied using environmental scanning
electron microscopy (ESEM).

EXPERIMENTAL
Materials
The monomer N-isopropylacrylamide (NIPAAm) was used as
received (97%) from Aldrich. The alginic acid (Alg) from brown
algae (Macrocystis pyrifera kelp) used in the experiments, with a
weight-average molecular weight Mw of 48 000186 000 g mol1 ,
was purchased from Fluka (Switzerland). It is a straight-chain,
hydrophilic, colloidal, polyuronic acid composed primarily of
anhydro--D-mannuronic acid residues with 1 4 linkage.
The crosslinking agent N,N -methylenebisacrylamide (BIS; Fluka),
initiator potassium persulfate (KPS; Merck) and accelerator
N,N,N ,N -tetramethylethylenediamine (TEMED; Fluka) were all
used as received. Aqueous media with various pH values were
prepared using suitable solutions of hydrochloric acid, potassium
dihydrogen phosphate and sodium hydroxide. Twice-distilled
water was used for both synthesis reactions and the preparation of
buffer solutions. All other reagents used were of analytical grade.

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A NIPAAm aqueous solution containing also KPS was mixed with

a solution of sodium alginate obtained by dissolving the necessary
amount of alginic acid in 0.5 mol L1 NaOH. BIS was then added to
this mixture. Final concentrations of BIS with respect to NIPAAm
of 2.0 wt% (2 BIS), 3.0 wt% (3 BIS), 4.0 wt% (4 BIS), 5.0 wt% (5
BIS), 6.0 wt% (6 BIS) and 7.0 wt% (7 BIS) were used. Finally, TEMED
was added. The mixture obtained was vigorously stirred and then
the final solution was left undisturbed for a while to remove
the trapped air bubbles. The crosslinking reaction took place at
25 C, gel formation being observed in about 2 h. The gel samples
obtained were stored for about 4 days for stabilization and to
reach equilibrium, and then were washed repeatedly with twicedistilled water to remove residual monomer or non-crosslinked
compound. Samples were washed during 3 days, with the water
changed many times each day, and the presence of extracted
residues verified spectroscopically until their full removal.
The PNIPAAm/Alg gels obtained were then lyophilized using a
freeze-drying system (LABCONCO FreeZone) to obtain dehydrated
porous aerogels. The reaction yield was about 65% for almost all
experiments. (PNIPAAm/Alg hydrogels with various NIPAAm to
alginate percentage weight ratios were prepared, namely 100/0,
99/1, 95/5, 90/10, 85/15, 80/20 and 75/25. Any greater amounts
of alginate hindered the hydrogel formation reaction. The gels
were insoluble in solvents in which the components were soluble
(water, ethanol), resisting repeated washing and keeping their
shape.
Appearance of hydrogels
It was observed that the aspect and colour varied depending
on the composition and crosslinking density of the hydrogels:
the gels with small amounts of alginate in their composition
were transparent and clear, while those with a higher quantity
of alginate were white and opaque (Fig. 1(b)). With increasing BIS
content the samples also became opaque (Fig. 1(a)). After removal
from vials the hydrogels kept their form (Fig. 1(c)).
Chemical structure of hydrogels
To confirm the successful synthesis of the PNIPAAm/Alg mixedIPN hydrogels we investigated their chemical structure. The
percentage of nitrogen in samples was evaluated using elemental
analysis with the Kjeldahl method.
FTIR spectra were recorded by means of a PerkinElmer FTIR
spectrometer. Dried samples of various compositions were ground
into powder form and the powder was then mixed with KBr and
compressed into tablets. The spectra were recorded between 500
and 4000 cm1 .
Raman spectra were recorded with a Renishaw Ramascope
system equipped with an argon laser operating at a wavelength
of 633 nm and coupled to a confocal Leica microscope. The laser
beam was focused first by a 50 objective on a silicon plate
for calibration. Freeze-dried hydrogel samples were wrapped in
aluminium foil and their Raman spectra, recorded in the range
5004000 cm1 , were analysed using spectroscopic software
(GRAMS 32).
Swelling measurements
The swelling behaviour of the PNIPAAm/Alg hydrogels was
determined by immersing dried samples to swell in twice-distilled
water or in buffer solutions of a certain pH, at various temperatures.
At specific time intervals, the samples were removed from the
swelling medium, excess droplets were gently and quickly wiped

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223

Preparation of PNIPAAm/Alg stimuli-responsive mixed-IPN

hydrogels
The objective of the work reported was to obtain multi-responsive
(temperature- and pH-sensitive) hydrogels containing PNIPAAm
and sodium alginate as polymeric matrices with potential
application in controlled/sustained drug delivery using a novel
method for preparation, namely by crosslinking of alginate in
a manner different from that using Ca2+ ions. Considering
the synthesis procedure described by Krusic and Filipovic55 for
obtaining copolymer hydrogels of NIPAAm and itaconic acid
by radical crosslinking copolymerization at 25 C (where the
monomers were dissolved in water with a KPS and TEMED redox
couple) and also the synthesis of carboxymethylcellulose/sodium
alginate hydrogels by crosslinking with BIS,36 we assumed that
alginate might be covalently crosslinked with NIPAAm using
BIS. Therefore, by combining the methods described above we
obtained new PNIPAAm/Alg gels as a result of two simultaneous,
coupled reactions of radical copolymerization and covalent
crosslinking.

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(a)

RP Dumitriu, GR Mitchell, C Vasile

Table 1. Elemental analysis results for PNIPAAm/Alg hydrogels with

various compositions and amounts of BIS
PNIPAAm/Alg with
4.0 wt% BIS
NIPAAm (wt%)

Alg (wt%)

99
95
90
85
80
75
75/25 NIPAAm/Alg
BIS (wt%)
2
3
4
5
6
7

(b)

1
5
10
15
20
25

N, experimental
(wt%)

NIPAAm in hydrogel,
calculated (wt%)

11.71
11.04
10.77
10.2
9.67
7.8

99
93.36
91.05
86.2
81.8
65.94

7.22
7.5
7.8
7.67
7.86
7.98

RESULTS AND DISCUSSION

(c)

Figure 1. Photographs of (a) 75/25 NIPAAm/Alg hydrogel samples with

various amounts of BIS as indicated; (b) 99/1, 90/10 and 75/25 NIPAAm/Alg
hydrogel samples with the same amount of BIS (4.0 wt%); (c) final aspect
of hydrogels.

with filter paper and the progress of the swelling process was
monitored gravimetrically. The degree of swelling (QS ) of the
samples was calculated using the following expression:
QS =

WS WD
100%
WD

where WS is the weight of the swollen test sample at time t of the

process and WD is the weight of the dried test sample.
Dynamic swelling of the PNIPAAm/Alg hydrogels prepared with
various weight ratios and with various degrees of crosslinking was
studied in the 2045 C temperature range and at various pH
values (pH = 2, 2.2, 3, 3.5, 4, 5, 5.5, 6 and 7.2). The pulsatile swelling
behaviour was also studied by immersing dried gel samples in
water alternately at 25 and at 45 C.

224

Morphological assessment
ESEM studies were performed with a FEI Quanta 600 FEG ESEM
instrument, allowing us to observe the morphology of the gels as
the water content changed. The measurements were performed
at various values of RH in the range 0 to 100%.

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Synthesis and characterization

The synthesis of the three-dimensional networks composed of
sodium alginate and PNIPAAm is shown schematically in Fig. 2. The
NIPAAm polymerization reaction (initiated by KPS and accelerated
by TEMED) and its crosslinking with BIS take place simultaneously
with the covalent crosslinking with sodium alginate. Alginate
is covalently connected to PNIPAAm chains through BIS, which
also crosslinks PNIPAAm chains. Pourjavadi et al.36 showed that
ammonium persulfate in our case KPS can also act as a free
radical initiator for sodium alginate crosslinking. The sulfate anion
radical from KPS abstracts hydrogen from the hydroxyl groups
of the polysaccharide to form corresponding alkoxy radicals on
the alginate backbone, which can act as active centres capable of
initiating free radical reactions with BIS to form the hydrogel. Selfcrosslinking of the alkoxy free radicals onto polysaccharide chains
can also produce hydrogel.36 The self-crosslinked alginate chains
may be entrapped in a PNIPAAm network crosslinked with BIS
and may have some unreacted carboxyl groups available, which
are responsible for the pH-sensitive behaviour of the gels. Some
hydrogen bonds are also possible between the carboxyl groups of
alginate and the amide groups of PNIPAAm.
These systems are obtained based on covalent crosslinking at
the hydroxyl groups of alginate, leaving the carboxyl groups
available. Functional groups are still present in the network
because not all groups of alginate participate in crosslinking
reactions. Thus the samples show not only thermo-responsive but
also pH-responsive behaviour, which is very important in drug
delivery applications.
The nitrogen content in the PNIPAAm/Alg hydrogels, determined using elemental analysis, is given in Table 1. It can be
observed that the nitrogen content decreases in line with decreasing NIPAAm content, while in the samples prepared with the same
feed ratio but using various amounts of crosslinking agent, the nitrogen content is broadly constant, showing a slight dependence
on BIS concentration.

c 2010 Society of Chemical Industry

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Multi-responsive hydrogels based on NIPAAm/sodium alginate

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Figure 2. Schematic representation of the reaction for the formation of PNIPAAm/Alg three-dimensional mixed-IPN.

Figure 3. FTIR spectra of (a) Alg, (b) 75/25 NIPAAm/Alg, (c) 80/20 NIPAAm/Alg, (d) 90/10 NIPAAm/Alg and (e) NIPAAm monomer.

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225

From comparative analysis of the FTIR and Raman spectra (Figs 3

and 4) and band assignments (Table 2), the successful synthesis of
PNIPAAm/Alg copolymerized hydrogels is confirmed.

Characteristic absorption bands of alginate appear in the FTIR

spectra (Fig. 3) at 3430 cm1 (s, broad band) corresponding to the
stretching vibration OH of hydroxyl groups, and at 1632 cm1
(s, asymmetric COO ) and at 1418 cm1 (m, symmetric COO )
corresponding to the stretching vibration C=O of carboxylic
groups. The band at 1032 cm1 (s, broad band) is due to the
CO stretching of alcoholic groups. The FTIR spectra of NIPAAm
shows characteristic peaks located at ca 3290 cm1 (s, double
peak) corresponding to the stretching vibration C H of CH
bonds, at 1660 cm1 (s, amide I; mainly due to the C=O stretching
vibration) and 1550 cm1 (s, amide II; mainly due to CNH
bending vibration), at 1618 cm1 (s, C=C), 1411 cm1 (m, CH2 )
and also the double peaks at 1307 and 1327 cm1 (w) attributed
to the isopropyl group. The spectra of the hydrogel samples with
various NIPAAm/Alg weight ratios in the composition are different
from those of the two components over the entire wavenumber
range.
The successful crosslinking to obtain PNIPAAm/Alg hydrogels
is also suggested by the presence of some characteristic bands
of both NIPAAm and Alg in the FTIR spectra of the hydrogels
and modification of other bands. Moreover most of the bands are
wider, demonstrating an advanced crosslinking, and some bands
are shifted to higher wavenumbers in the 27004000 cm1 region
and also in the 8001900 cm1 fingerprint region, indicating
interactions between the components. In all the FTIR spectra of
the PNIPAAm/Alg hydrogel samples (Figs 3(b)(d)), the strong
vibration band attributed to the hydroxyl groups of alginate
is shifted from 3430 to 34383442 cm1 (s), while the strong

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RP Dumitriu, GR Mitchell, C Vasile

bound to amide NH groups (C=O HN). The sharp band
at 1550 cm1 (s, amide II, NH) in the NIPAAm spectrum becomes
a larger and lower intensity but distinct band, which appears
at ca 1548 cm1 (m) in the spectra of the hydrogels and can
be attributed also to the presence of NIPAAm and BIS. The
results of Raman spectroscopy are in agreement with those of
FTIR spectroscopy, showing the presence of amide I vibration
band at 1650.91652.4 cm1 corresponding to C O stretch of
carboxylic acids and amide II band at 1567.41567.6 cm1 , mainly
due to the NH vibration from NIPAAm and BIS. In the FTIR
spectra, the characteristic double bands at 1307 and 1327 cm1
(w) corresponding to the isopropyl group of NIPAAm are shifted
to ca 1369 and ca 1388 cm1 , respectively, while the bands
at 1618 (s) and 1411 cm1 (m) disappear because NIPAAm is
polymerized to PNIPAAm during the crosslinking reaction. The
bands characteristic of the isopropyl group can also be identified
in the Raman spectra through the bands at 1372.9 and 830 cm1 ,
corresponding to amide III vibration (CN) coupled with CH3
bending mode (Table 2).56 58
The results from elemental analysis and FTIR and Raman
spectroscopy together suggest that PNIPAAm and alginate are
well mixed and definitely form hydrogel networks.

Figure 4. Raman spectra of (a) 100/0 NIPAAm/Alg, (b) 99/1 NIPAAm/Alg

and (c) 75/25 NIPAAm/Alg.

226

broad band at 1032 cm1 (CO stretching of alcoholic groups)

has a considerably lower intensity and is shifted to 1038 cm1 in
the spectra of the 75/25 NIPAAm/Alg sample and disappears
in the case of the other compositions, probably due to the
covalent interactions between the components facilitated by
the BIS crosslinking agent. Therefore the covalent crosslinking
is advanced for all compositions, but in the 75/25 NIPAAm/Alg
sample some alcoholic groups from alginate may still be unreacted
and free.
The Raman spectra of 100/0 NIPAAm/Alg and 99/1 NIPAAm/Alg
are noted to be quite similar and the spectrum of 75/25 NIPAAm/Alg presents some modifications, which can be attributed
to the higher alginate content of the sample. The bands of the
Raman spectra (Fig. 4) of these three samples with different compositions are assigned according to literature data (Table 2).56 58 A
band with three maxima at 2980, 2929 and 2881 cm1 is present in
the 100/0 NIPAAm/Alg and 99/1 NIPAAm/Alg Raman spectra and
disappears in the 75/25 NIPAAm/Alg spectrum, being replaced
by two maxima at 2943.6 and 2862 cm1 , which can be assigned
to the CH stretching bands (n-alkanes). Also, a band located
between 1456.2 and 1456.6 cm1 for the compositions studied
can be attributed to CH2 bending vibration.
The absorption bands at 1460 cm1 (m) and 16251638 cm1
(s) in the FTIR spectra of all PNIPAAm/Alg hydrogels, which are
shifted with respect to those of the components, can be assigned
to the overlapped vibration bands of the stretching vibration of
carboxylate groups from alginate (1632 and 1418 cm1 ) with
the amide I bands from NIPAAm (1660 cm1 ), probably due
to the interaction through hydrogen bonding: C=O groups

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Swelling behaviour of hydrogels

The response of the PNIPAAm/Alg hydrogels to temperature
and pH was studied using swelling measurements. The preliminary swelling investigations performed show that the hydrogels
obtained show behaviour close to that of the PNIPAAm homopolymer, with some new characteristics, which are due to the
interaction between the components and the presence of alginate. The alginate sequences contribute to the sensitivity of the
hydrogels to environmental pH changes, while PNIPAAm, as a
temperature-sensitive polymer, imparts thermo-responsivity.
In our previous studies the swelling kinetics of the PNIPAAm/Alg
gels was investigated59 and a dual sensitivity to temperature and
pH was observed, which was dependent on composition. This
behaviour provides a potential use as drug delivery carriers for
ketoprofen and vanillin.60 The dual sensitivity of the swelling
behaviour of these gels was first observed based on the Qeq values
recorded at various temperatures and pH values for the 75/25
NIPAAm/Alg sample.61
In the work reported in the present paper, a detailed study
of the swelling behaviour of PNIPAAm/Alg hydrogels of various
compositions and various amounts of crosslinking agent was
performed, for a wide range of temperature and pH, allowing us a
better understanding of the swelling/shrinking kinetics in view of
application of these hydrogels as smart matrices for drug release.
Influence of amount of crosslinking agent and composition
Water uptake measurements allowed us to determine the
influence of the amount of crosslinking agent and of the
composition on the swelling behaviour of the PNIPAAm/Alg
hydrogels. The swelling kinetic curves at pH = 5.5 are shown in
Figs 5 and 6 and the values of the equilibrium degree of swelling
of the hydrogels are given in Table 3.
The water uptake capacity of the samples is clearly influenced
by the crosslinking agent content (BIS), with specific variation with
time (Fig. 5). In the first 200 min the samples having a lower BIS
concentration (2 BIS and 3 BIS) present a slower swelling, with
smaller QS values than samples with higher BIS concentration (5
BIS and 7 BIS). The swelling behaviour is completely different after

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Table 2. Assignments of FTIR and Raman spectra vibration bands for components and PNIPAAm/Alg hydrogels with various compositions
PNIPAAm/Alg hydrogels
Alginate
FTIR
(cm1 )

NIPAAm
FTIR
(cm1 )

Band
assignment

3430, s, broad
band

Band
assignment

Band
assignment

FTIR (cm1 )
34383442, s,
broad band;
shifted

OH groups
3290, s, sharp,
double
peak

Raman (cm1 )

OH groups

CH bonds

2980, 2929, 2881

(3 max.)
COO ,
1660, s
asymmetric

1632, s

1550, s, sharp
peak
1618, s
1411, m
COO ,
symmetric

1418, m

1307, 1327, w
(double
peaks)

1032, s, broad
band

Amide I (C=O) 16251638, s

Amide II
(CNH
bending)
C C
CH2 =

Isopropyl
group

CO
stretching
of alcoholic
groups

1650.91652.4

CH stretching
bands/nalkanes
Amide I (C=O)

1567.41567.6

Amide II (NH)

COO , symmetric 1456.21456.6

CH2 bending
vibration
Amide III (CN)
coupled
isopropyl
group
vibrations

Overlapped
carboxylate
amide I bands
amide II, NH

1548, m, large
peak
Disappeared
Disappeared
1460, m
1369, 1388, w;
shifted

Isopropyl group

1038, w; shifted
(75/25);
disappeared

CO, alcoholic
groups

4000

1372.9 and 830

4000

3500

3500

3000

3000

2500

2500
QS (%)

QS (%)

Band
assignment

2000
2 BIS
3 BIS
5 BIS
7 BIS

1500
1000
500

2000
1500
100/0 NIPAAm/Alg
99/1 NIPAAm/Alg
90/10 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg

1000
500
0

-500

100

200

1300

1400

1500

-100

Polym Int 2011; 60: 222233

1400

1500

1600

Figure 6. Swelling kinetic measurements of PNIPAAm/Alg samples with

various compositions, at pH = 5.5 and 20 C.

electrostatic repulsive forces between the charged sites (COO )

also contribute to an increase in swelling. As a result the network
expands, with a fast increase of QS , followed by a slower and
less significant increase until reaching equilibrium, due to high
polymer chain density, which hinders further expansion of the
network by absorption of additional water. These networks (i.e.
5 BIS, 7 BIS) are more compact and covalent crosslinking is more

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227

24 h, when samples 2 BIS and 3 BIS reach an equilibrium swelling

state with a marked increase of QS . For the hydrogel samples
with greater amount of crosslinking agent (5 BIS and 7 BIS) the
water is absorbed faster at the beginning of the swelling process
because the water molecules interact first with the most polar
hydrophilic groups on the polymer backbone62 (COO groups of
alginate and probably those of crosslinker fragments). In addition,

100 200 1300

Time (min)

Time (min)
Figure 5. Swelling kinetic measurements of 90/10 NIPAAm/Alg samples
with various amounts of crosslinking agent, at pH = 5.5 and 20 C.

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RP Dumitriu, GR Mitchell, C Vasile

4000

Table 3. Maximum degree of swelling at pH = 5.5 of PNIPAAm/Alg

hydrogels with various compositions and the same amount of BIS (4.0
wt%) and of 90/10 NIPAAm/Alg with various amounts of crosslinking
agent, at various temperatures

3500
3000

Qmax = (m m0 )/m0 100 (%)

100/0 NIPAAm/Alg
99/1 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
85/15 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg
90/10 NIPAAm/Alg
2 BIS
3 BIS
4 BIS
5 BIS
6 BIS
7 BIS

2133
2385
2436
3199
2800
3363
3634

1553
1650
1682
1976
2453
2682
2979

1148
1196
1328
1362
1491
1597
1817

242
204
294
569
532
423
843

132
134
143
212
232
390
485

2001
2251
2293
2987
2568
2973
3149

Qeq (%)

Sample

2500

Qmax
20 C 30 C 33 C 35 C 40 C (2040 C)

100/0 NIPAAm/Alg
99/1 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
85/15 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg

2000
1500
1000
500
0
20

25

30

35

40

Temperature (C)
3390
2879
3199
2754
2676
2542

2027
1801
1976
1649
1667
1653

1495
1242
1362
1096
1257
1163

1156
1020
569
687
839
762

218
170
212
174
226
205

3172
2709
2987
2580
2450
2337

advanced in their case, and thus water cannot penetrate easily by

osmotic forces. In the case of the samples with lower crosslinking
density (2 BIS, 3 BIS) water uptake is slower at the beginning of the
process because few interactions with water occur, due to a smaller
number of polar hydrogen bonding hydrophilic groups, while at
the later stage the network is able to absorb a large amount
of additional water through osmotic forces, due to the porous
surface with large cavities, resulting in a marked increase of QS
until equilibrium swelling is reached, accompanied by expansion
of the three-dimensional network. The degree of swelling values
measured at equilibrium decrease with increasing BIS content
due to the advanced covalent crosslinking, which increases the
density and compactness of the hydrogel networks and hinders
further expansion of the three-dimensional networks through
water sorption.
Swelling kinetic measurements performed on samples with
various compositions allow us to observe that the swelling
capacity increases with an increase of Alg content in the samples
(Fig. 6). From Fig. 6 it can be observed that the swelling curve
of the 99/1 NIPAAm/Alg sample is rather different from those of
samples with a higher Alg content, as it exhibits smaller values
of QS , which are much closer to those observed for the 100/0
NIPAAm/Alg sample. The swelling kinetic measurements show
that the hydrophilic character of alginate definitely influences
the water uptake capacity of the hydrogel samples, especially
when equilibrium is established. Therefore the maximum swelling
determined at equilibrium increases with increasing Alg content
in the samples (Table 3). This feature can be attributed to the
increased number of free carboxylic acid groups in ionized Alg,
which can break hydrogen bonding and generate electrostatic
repulsion among Alg macromolecules attracting more water into
the hydrogel, which results in a higher swelling ratio.

228

Temperature- and pH-dependent swelling behaviour

The dual temperature- and pH-responsive behaviour of the
PNIPAAm/Alg gels, depending on their composition, was also
evident from swelling measurements performed under various

wileyonlinelibrary.com/journal/pi

Figure 7. Maximum degree of swelling versus temperature for hydrogels

with various compositions.

conditions. The thermo- and pH-responsive properties of the

PNIPAAm/Alg hydrogels were studied in the temperature range
2040 C and at various pH values, i.e. acidic media (pH = 2.2) and
alkaline media (pH = 7.2).
The thermo-responsive behaviour was investigated by measurements performed at temperatures below the LCST of PNIPAAm
(32 C), characterized by a relaxed network, and also above this
value, when hydrophobic interaction and chain collapse occurring
in PNIPAAm macromolecules determine a fast shrinking of the
gels. This behaviour is reversible. The dependence of the equilibrium degree of swelling on temperature for samples with various
compositions shows clearly a rapid decrease of the degree of
swelling as the temperature varies around the LCST (Fig. 7).
Traditionally, in terms of change of degree of swelling, the phase
separation temperature or LCST is regarded as the temperature at
which the change of degree of swelling versus temperature change
(dQ/dT) decreases dramatically, because of the phase separation.
The volume phase transition temperature of PNIPAAm/Alg gels
has been evaluated from these curves using a Boltzmann function.
The hydrophobic character of PNIPAAm above the LCST is
counteracted by the presence of hydrophilic alginate chains.
Therefore the transition temperature Ttr determined from Qeq T
curves of the hydrogels exhibits a linear increase with increasing
Alg content in a narrow interval, taking values between 31.8 and
32.8 C.61 The modification of Ttr is not very significant due to the
mixing ratio in favour of PNIPAAm.
The maximum degrees of swelling for hydrogels with various
compositions and amounts of crosslinking agent at various temperatures, for a time interval of 24 h, are presented in Table 3. It
is noticed that the Qmax values decrease with increasing temperature for all samples. The presence of alginate in the composition
leads to increased Qmax values. Qmax decreases significantly with
increasing BIS content, especially at temperatures below the LCST,
the smallest modification being observed at 40 C (Table 3), where
the values are close whatever the BIS content. Comparing Qmax
for 100/0 NIPAAm/Alg with that for 75/25 NIPAAm/Alg at all
studied temperatures, the values are 1.7 times higher for 75/25
NIPAAm/Alg at temperature lower than the LCST and 3 and 4
times higher at 35 and 40 C, respectively. The lowest increase is
at temperatures close to the LCST, 33 C, when the increase is only
1.5 times.

c 2010 Society of Chemical Industry

Polym Int 2011; 60: 222233

Multi-responsive hydrogels based on NIPAAm/sodium alginate

www.soci.org

(a) 2400

100/0 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
85/15 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg

2000

700

1600

600

T = 37C
pH = 2.2

500

1200
100/0 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg

800
T = 25C
pH = 2.2

400

QS (%)

QS (%)

(a) 800

400
300
200
100

0
0

40

80

120

160

200

240

Time (min)

40

80

120

(b) 2400

200

240

100/0 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
85/15 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg

2000
(b) 500

T = 37C
pH = 7.2

1600
400

1200
800
T = 25C
pH = 7.2

400

300

100/0 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg

QS (%)

QS (%)

160

Time (min)

200

100

40

80

120

160

200

240

Time (min)

Figure 8. Swelling kinetic measurements of PNIPAAm/Alg samples with

various compositions, in buffer solutions of (a) pH = 2.2 and (b) pH = 7.2,
at 25 C.

Polym Int 2011; 60: 222233

40

80

120

160

200

Time (min)
Figure 9. Swelling kinetic measurements of PNIPAAm/Alg samples with
various compositions, in buffer solutions of (a) pH = 2.2 and (b) pH = 7.2,
at 37 C.

The swelling process is very fast in acidic media for 80/20 and
75/25 NIPAAm/Alg hydrogels, compared with the slower swelling
behaviour at pH = 5.5 up to the equilibrium swollen state in
about 24 h. This fast initial swelling at pH = 2.2 can be attributed
to the COO groups of alginate present in great numbers in these
two samples. The COO groups are rapidly hydrated in the first
few minutes resulting in the sudden increase in QS , and then are
protonated at acidic pH; thus the main anionanion repulsive
forces are eliminated while continued swelling due to osmotic
forces is retarded because at this pH the hydrophilic alginate takes
a collapsed form making the network less permeable despite
the porosity, as has been found for other systems containing
alginate.62,63 The effect of pH on the swelling capacity observed
at pH = 7.2 may be more pronounced than carboxyl group
protonation and decreased alginate solubility at acidic pH for
some compositions, probably due to the smaller amount of
alginate in samples (up to 25%), thus decreasing slightly the
swelling capacity.
The influence of the BIS content on the swelling behaviour is
marginal with change in pH.

c 2010 Society of Chemical Industry

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229

The pH-sensitive behaviour of the PNIPAAm/Alg hydrogels was

investigated by immersing gel samples in buffer solutions with
acidic (2.2) and alkaline (7.2) pH, at 25 and at 37 C.
At 25 C and pH = 2.2 a clearly different behaviour of the samples
with higher alginate content (20 and 25%) is noticed. These
hydrogels exhibit fast and significant swelling in the first minutes
followed by a slower and less significant increase until reaching
equilibrium, while samples with lower alginate content present
a constant gradual swelling. The 75/25 NIPAAm/Alg hydrogel
reaches equilibrium swelling in only 40 min and 80/20 NIPAAm/Alg
in 160 min (Fig. 8(a)). At pH = 7.2 all samples reach equilibrium
values in about 40 min, the highest QS values belonging also to the
samples with greater alginate content (Fig. 8(b)). The influence of
pH on PNIPAAm swelling behaviour can be appreciated from the
data given in Table 4. At 25 C it is evident that there is an influence
of pH on swelling behaviour, while at higher temperature there is
hardly any influence of pH for samples with high NIPAAm content.
At 37 C, above the LCST of PNIPAAm, the samples present
significantly lower QS , with fast swelling in the first minutes,
followed by the expulsion of some of the absorbed water due to
the collapse of PNIPAAm chains and then equilibrium values are
established at both pH values (Figs 9(a) and (b)). Only the samples
with higher alginate content exhibit a gradual increase at pH =
7.2, up to 40 min before equilibrium.

www.soci.org

RP Dumitriu, GR Mitchell, C Vasile

800

Table 4. Maximum degree of swelling in buffer solutions of pH =

2.2 and 7.2 for PNIPAAm/Alg hydrogels with various compositions and
the same amount of BIS (4.0 wt%) and for 90/10 NIPAAm/Alg hydrogel
with various amounts of crosslinking agent, at 25 and 37 C

T = 37C
600

Sample
100/0 NIPAAm/Alg
99/1 NIPAAm/Alg
95/5 NIPAAm/Alg
90/10 NIPAAm/Alg
85/15 NIPAAm/Alg
80/20 NIPAAm/Alg
75/25 NIPAAm/Alg
90/10 NIPAAm/Alg
2 BIS
3 BIS
4 BIS
5 BIS
6 BIS
7 BIS

37 C

pH = 2.2

pH = 7.2

pH = 2.2

pH = 7.2

1397
1360
1440
1647
1850
2137
2185

1042
998
987
1197
1449
1697
2350

138
131
136
196
242
328
486

137
182
146
178
177
268
340

500
400
300
200
100
0
1

pH
191
185
196
179
167
164

168
176
178
157
175
169

230

The hydrogel samples containing a higher quantity of alginate

(75/25 and 80/20 NIPAAm/Alg) show a quite similar swelling
behaviour at both temperatures studied and a higher swelling
capacity at both temperatures and pH values studied compared
with the other samples, with much higher QS values at 25 C
(Table 4). The maximum degrees of swelling reached at 25 C are
much higher than at 37 C for both pH values. Comparing the Qmax
value of 100/0 NIPAAm/Alg with that of 75/25 NIPAAm/Alg at the
studied temperatures and pH, there are larger differences in acid
pH at 37 C. At pH = 2.2 the values are 1.5 times higher for 75/25
NIPAAm/Alg at 25 C and 3.5 times higher at 37 C, while at pH =
7.2 they are 2 times higher at 25 C and 2.5 times higher at 37 C.
The results of the swelling measurements show the versatility of
the behaviour of the samples and their dual-responsive properties.
To test in more detail the PNIPAAm/Alg gel sample behaviour
according to pH changes, swelling measurements were also
performed at 37 C in 0.1 mol L1 NaCl solutions of pH adjusted
to 2, 3, 3.5, 4, 5 and 6 (Fig. 10). We chose 0.1 mol L1 NaCl solution
for the study, considering that this solution concentration will
have only a reduced influence of the ionic strength, taking into
consideration the experimental data obtained by Lee and coworkers.47 The 75/25 NIPAAm/Alg sample was selected for this
study due to its higher swelling capacity compared with the
other compositions. The dependence of the maximum degree
of swelling on the pH in NaCl shows variations in the swelling
capacity with increased values at pH 3 and 3.5 (482 and 552%,
respectively) compared with the other pH values studied, with
maximum at pH = 3.5 (Fig. 10). This particular behaviour is due
mainly to the presence of alginate in the composition, because
at 37 C PNIPAAm chains are in a collapsed form. The increase
in the swelling capacity from pH = 2.2 up to 3.5, followed by a
decrease at higher pH, is related to the pKa values of the guluronic
and mannuronic acid residues from alginate of 3.38 and 3.65,
respectively, as reported in the literature.64
At pH = 3.5, the carboxyl groups of alginate, partially ionized,
determine an increased swelling due to greater electrostatic

wileyonlinelibrary.com/journal/pi

Qmax (%)

Qmax = (m m0 )/m0 100 (%)

25 C

Sample 75/25 NIPAAm/Alg

700

Figure 10. Equilibrium degree of swelling versus pH for 75/25 NIPAAm/Alg

sample, at 37 C in NaCl solutions of various pH.
(a)

(b)

Figure 11. Pulsatile temperature-dependent swelling behaviour of (a)

75/25 NIPAAm/Alg hydrogels with various BIS contents and (b) various
compositions with the same BIS content (4.0 wt%) in response to
temperature changes between 25 and 45 C, at pH = 5.5.

c 2010 Society of Chemical Industry

Polym Int 2011; 60: 222233

Multi-responsive hydrogels based on NIPAAm/sodium alginate

(a)

www.soci.org

(b)

(c)

(b)

(c)

(A)
(a)

(B)
Figure 12. ESEM images for (A) 99/1 NIPAAm/Alg with 4.0 wt% BIS at (a) 20% RH, (b) 50% RH and (c) 100% RH (500) and (B) 75/25 NIPAAm/Alg with 2.0
wt% BIS at (a) 20% RH, (b) 50% RH and (c) 100% RH (1000).

Polym Int 2011; 60: 222233

Pulsatile swellingdeswelling measurements

The rapid swellingdeswelling behaviour observed for the
PNIPAAm/Alg hydrogels allows us to investigate the repeatability
of the swelling process.
The pulsatile swelling behaviour of the hydrogels was investigated by immersing gel samples alternately in water for 1 h at
25 C and at 45 C, and measuring the degree of swelling. The
75/25 NIPAAm/Alg hydrogel with various BIS contents and also
samples with various compositions were investigated (Fig. 11). It
is observed that all samples exhibit fast and marked changes of
QS , the samples with lower BIS content (2 BIS) and greatest Alg
content having higher QS values during all swellingdeswelling
cycles. The swelling process is repeatable, in accordance with the
temperature changes.
The particular swelling behaviour of the samples in both acidic
and alkaline media and also at various temperatures can be
attributed to their free chain mobility and large porous surface
area, which allow water molecules to transfer easily in and out
of the matrix.60
Hydrogel morphology
Morphological studies performed using ESEM show a relaxed
network at high RH, which explains the swelling profiles. Images
were obtained at various degrees of RH, at 10 C.
The morphological study of the samples performed using ESEM
reveals a porous honeycomb structure, which expands as the
hydrogels swell as RH increases (Fig. 12). There are distinctive
differences between samples prepared with various compositions
(Fig. 13) and various amounts of crosslinking agent (Fig. 14). The
images from these in situ swelling experiments show that the
dimensions of the cavities increase at higher RH for all samples.
The larger pores and in some cases the breakage of the cavity walls
make the structures more accessible to water vapour sorption.
Thus, the morphology of the samples changes with increasing RH
from a compact, dense structure to an expanded one. Samples
with higher alginate content (25%) have larger cavities with porous
walls, which favour water diffusion in the hydrogels, explaining
their enhanced swelling capacity.

c 2010 Society of Chemical Industry

wileyonlinelibrary.com/journal/pi

231

repulsive forces. At lower pH (<3.5) the electrostatic repulsion

between the carboxyl groups is suppressed due to their gradual
protonation, and thus the degree of swelling is smaller. At pH = 2.2
alginate is generally reported to be in a collapsed (shrunk) form,63
having lower solubility. Cao et al.65 showed that the alginate
molecules may form hydrophilichydrophobic aggregates in
aqueous solution depending on the pH of the medium. They
postulated this pH dependence of aggregation as a signature
for self-assembly caused by the partial protonation of dissociated
carboxyl groups in the alginate main chain. At low pH, e.g. pH =
2.2, carboxyl groups on the alginate chains may form enhanced
intermolecular hydrogen bonds, thus possible entanglements
emerge and association structures are formed,66,67 thus explaining
the lower degree of swelling. Carboxylic acid groups in alginate
and ammonium ions in PNIPAAm coexist in the pH range from
2 to 3.5 and thus the degree of swelling increases. Some of
the carboxylic acid groups in alginate become carboxylate ions
(COO ) at pH > 3.38 (pKa of guluronic acid),64 but the number
of ammonium ions of PNIPAAm exceeds that of carboxylate ions,
resulting in an increase of the degree of swelling up to pH = 3.5.47
At pH higher than the pKa of guluronic and mannuronic acid
residues from alginate, the carboxylic groups should be almost
completely ionized and the electrostatic repulsion forces should
lead to a continued increasing swelling,46 but due to interchain
bonding possible between carboxylate ions (COO ) in alginate and
ammonium ions in PNIPAAm, the swelling capacity decreases.47
The decrease of the swelling capacity at pH > 3.5 can also be
attributed to the presence of a greater amount of additional
cations (Na+ counterions from NaCl solution, adjusted with a
small amount of 1 mol L1 NaOH), which may shield the charge of
the carboxylate anions and prevent efficient repulsion due to an
enhanced screening effect.36
The pH-sensitive swelling of the PNIPAAm/Alg hydrogels is less
dramatic and sometimes slower than the temperature-sensitive
response due to the lower alginate content than PNIPAAm in
the network and also due to the possible formation of interchain
bonds, which might limit the chain mobility to a certain extent.

www.soci.org

RP Dumitriu, GR Mitchell, C Vasile

(a)

(b)

(c)

(d)

Figure 13. ESEM images of PNIPAAm/Alg hydrogels with various compositions and 4.0 wt% BIS obtained at RH = 50%: (a) 100/0 NIPAAm/Alg, (b) 99/1
NIPAAm/Alg, (c) 90/10 NIPAAm/Alg; (d) 75/25 NIPAAm/Alg (500).

(a)

(b)

(c)

Figure 14. ESEM images of 75/25 NIPAAm/Alg hydrogels with various amounts of BIS obtained at RH = 50%: (a) 2 BIS, (b) 5 BIS; (c) 7 BIS (500).

CONCLUSIONS

232

New mixed-interpenetrated hydrogel networks based on NIPAAm

and alginic acid/sodium alginate were obtained by simultaneous
copolymerization and covalent crosslinking with BIS. The hydrogel
network formation with various NIPPAAm/Alg compositions
and crosslinking agent (BIS) concentrations was assessed using
elemental analysis and FTIR and Raman spectroscopy. The
swelling measurements performed enabled us to ascertain that
the PNIPAAm/Alg hydrogel networks possess dual thermo- and
pH-responsive properties dependent on the composition and
degree of crosslinking. It has been established that the water
sorption capacity increases with the alginate content due to
its hydrophilicity and decreases with the crosslinking agent
concentration because the networks become more compact. The
swelling capacity decreases with increasing temperature above
the LCST of PNIPAAm, due to the collapse of PNIPAAm chains
and the hydrophobicity that is induced. PNIPAAm/Alg hydrogel
samples showed differences in behaviour at acidic and alkaline pH,
influenced especially by the amount of alginate in the composition.
The degree of swelling measured at various pH values showed a

wileyonlinelibrary.com/journal/pi

maximum at pH = 3.5, related to the pKa values corresponding to

guluronic and mannuronic acid residues from alginate.
The hydrogel morphology changes with increasing RH from
a compact, dense structure to an expanded one, depending on
composition and amount of BIS.
The sudden and sharp swellingdeswelling behaviour at various
temperatures and pH makes these systems suitable for use in
pulsatile (onoff swelling) drug delivery systems.

ACKNOWLEDGEMENTS
The authors gratefully acknowledge the financial support of
the Romanian ANCS through the national research projects IDEI
17/2007, NOSITEC 41-017/2007 and TD 506/2007 and also funding
from COST P12 Action Structuring of Polymers.

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