2018 Book PolymerGels
2018 Book PolymerGels
2018 Book PolymerGels
Polymer Gels
Science and Fundamentals
Gels Horizons: From Science to Smart
Materials
Series editor
Vijay Kumar Thakur, School of Aerospace, Transport and Manufacturing,
Cranfield University, Cranfield, Bedfordshire, UK
This series aims at providing a comprehensive collection of works on the recent
advances and developments in the domain of Gels, particularly as applied to the
various research fields of sciences and engineering disciplines. It covers a broad
range of topics related to Gels ranging from Polymer Gels, Protein Gels,
Self-Healing Gels, Colloidal Gels, Composites/Nanocomposites Gels, Organogels,
Aerogels, Metallogels & Hydrogels to Micro/Nano gels. The series provides timely
and detailed information on advanced synthesis methods, characterization and their
application in a broad range of interrelated fields such as chemistry, physics,
polymer science & engineering, biomedical & biochemical engineering, chemical
engineering, molecular biology, mechanical engineering and materials science &
engineering.
This Series accepts both edited and authored works, including textbooks,
monographs, reference works, and professional books. The books in this series will
provide a deep insight into the state-of-art of Gels and serve researchers and
professionals, practitioners, and students alike.
Editors
Polymer Gels
Science and Fundamentals
123
Editors
Vijay Kumar Thakur Manju Kumari Thakur
Faculty in Manufacturing, Enhanced Division of Chemistry
Composites and Structures Centre, Government Degree College Bhoranj,
School of Aerospace, Transport Himachal Pradesh University
and Manufacturing Shimla, Himachal Pradesh
Cranfield University India
Cranfield
UK
This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Preface
A gel is described as a soft, solid- or liquid-like unique condensed material that has
a three-dimensional network composed of several components such as long poly-
mers, species of small molecules and a large amount of solvent. These 3D network
condensed materials usually form through chemical, physical or supramolecular
crosslinking. The weight and size of gels are more like a liquid, but they are treated
like a solid. Two important characteristics of gels are phase state and their rheo-
logical properties. On the other hand, a polymer is defined a large molecule
(macromolecules) composed of repeating structural units that comprise of multiple
assemblies of simple structural units. In gels, the polymer network can be physi-
cally or chemically crosslinked. In case of physical gels, the network formation
occurs due to various weak interactions, like the entanglement of the polymer
chains, hydrogen bonds or van der Waals interactions. Such structures are usually
not permanent and they dissolve over the time when immersed in their solvents.
However, the polymer chains can also be crosslinked through chemical reactions,
leading to strong covalent bonds. The chemically crosslinked network is much
more stable and cannot be dissolved without the degradation of the polymer.
Therefore, chemical gels are usually preferable in the majority of the application
fields. Polymer gels comprise a great variety of different polymeric components that
present innumerable industrial applications. Polymers can be naturally produced
(some time referred as bio-based polymers), in which case the most representative
group is polysaccharides. Natural polymers' demand is expected to grow 7.1%
every year. Moreover, their low toxicity and excellent biodegradability have also
attracted researchers to pay attention towards the widespread application of natural
polymers. Polymer obtained from natural sources such as chitosan, alginate, dex-
tran, starch, pectin, cellulose and lignin has shown excellent potential for
biomedical and other applications in the form of microsphere, nanoparticles,
crosslinked hydrogels, beads, membranes and granules. On the other hand, a wide
variety of synthetic polymers capable of forming gels present different industrial
applications, such as polyacrylamide and polyvinyl alcohol-based gels. Both syn-
thetic and natural polymer-based gels find applications from health sciences such as
v
vi Preface
agents for controlled drug delivery, sustained drug delivery, targeted drug delivery
and various other types of novel drug delivery systems to water purification.
Polymer gels due to their several unique characteristics have become an indis-
pensable part of new advanced and smart materials in the twenty-first century for
numerous applications including but not limited to biological, biomedical, elec-
tronic and environmental. Keeping in mind the immense advantages of polymer
gel-based materials, this volume of the series is solely focused on the science and
fundamental of polymer gels. It provides a comprehensive collection of works on
the recent advances and developments in science and fundamentals of both syn-
thetic and natural polymer-based gels particularly as applied to the various research
fields of sciences and engineering disciplines. Some of the important topics include
but not limited to: polysaccharide-based gels and their fundamentals;
stimuli-responsive polymer gels; polymer gels applied to enzyme and cell immo-
bilization; chitosan-based gels for cancer therapy; natural polymeric and gelling
agents; radiation dosimetry—a different prospective of polymer gel; polymeric gels
as vehicles for enhanced drug delivery across skin; transport in and through gel;
graphene oxide—polymer gels; polymer gel nanocomposites; and functional gels to
name a few.
In editing and organising this volume Polymer Gels: Science and Fundamentals
of the book series Gels Horizons: From Science to Smart Materials, we have made
our best efforts to cover the growing field of polymer gels and related technologies.
It reflects the recent theoretical advances and experimental results and opens new
avenues for researchers as well as readers working in the fields of polymer and
functional materials. In addition, several critical issues and suggestions for future
work are comprehensively discussed in this book with the hope that the book will
provide a deep insight into the state of the art of Polymer Gels. We express our
sincere thanks to all the authors, who have contributed their extensive experience
through their work for the success of this book. We would also like to thank Swati
Meherishi and the rest of the team at Springer for invaluable help in the organi-
sation of the editing process.
vii
viii Contents
ix
x About the Editors
1 Introduction
Organic polymers, next to minerals, belong to the most widespread materials on the
earth. From the 20s of the twentieth century, when the era of synthetic polymers
was born, these materials have been introduced into each area of human life
replacing traditional feedstock (e.g., metals, alloys, glass, ceramics, or wood) due to
relatively low cost, low weight, anti-corrosion properties, easy forming and pro-
cessing, etc. On the other hand, some unrewarding properties of polymers preclude
them from many applications. To improve mechanical and rheological properties, to
enhance thermal stability as well as to reduce permeability and production costs,
polymers are often filled with various inorganic particles (Sinha Ray and Okamoto
2003; Okada and Usuki 2006; Kotal and Bhowmick 2015). Multiphasic solid
HO
O HO HO
OH HO
O O
O OH O OH O OH O HO
OH O O
HO HO OH
O O O OH OH OH
OH
OH O OH O OH n
OH Cellulose
OH OH OH OH
Starch
O SO
3
- OH
O O
OH OH NH2 O O
OH O
O
OH O Polysaccharides OH OH
O
Kappa-carrageenan
NH2 OH
n
OH
Chitosan OH O HO
O
OH O
O O
OH O HO
O O
HO OH O
O
OH
O O
OH
OH
Alginate
OH
O
2 Clay Materials
The layered minerals incorporated into polymers, even at small amounts (1–5 wt%),
play a crucial role in the formation of desirable structures of polymeric or composite
materials, acting not only as fillers, but also as crosslinking agents and stabilizers
(Haraguchi 2007a; Sinha Ray and Okamoto 2003; Haraguchi and Takehisa 2002).
Being highly dispersed within polymer, they enhance its thermal stability, perme-
ability, biodegradability, biocompatibility, rheological, and mechanical properties
(Oliveira et al. 2014; Haraguchi 2011a; Nistor et al. 2013). Moreover, in the case
of hydrophilic polymers, forming hydrogels, the addition of layered aluminosili-
cates can significantly improve adsorption properties in relation to metal cations
(Natkański et al. 2012, 2013b; Güçlü et al. 2010; Kundakci et al. 2011), dyes (Yi
and Zhang 2008; Zhang et al. 2013; Bhattacharyya and Ray 2014), and drugs
(Nistor et al. 2013; Kevadiya et al. 2011; Dadkhah et al. 2014), as well as swelling
ability in polar solvents (Kamoun and Menzel 2012; Li et al. 2009a; Nair et al.
2007). These features depend on the clay type (the charge of layer), its form (e.g.,
organophilized, acid activated), concentration and dispersion degree in the polymer
matrix.
The units building layered aluminosilicates are tetrahedral and octahedral sheets
(sublayers) composed of [SiO4]4− tetrahedrons or [AlO6]9− octahedrons, respec-
tively. The sheets are parallelly arranged to each other and connected to each other
by common oxygen atoms located in one layer (package) (Brindley and Brown
1980; Schulze 2005; Brigatti et al. 2006). The tetrahedral and octahedral sheets can
4 P. Kuśtrowski et al.
be grouped into two-sublayer (1:1 type) or three-sublayer packages (2:1 type), that
are separated by a interlayer space (so-called gallery), which most often contains
metal cations (mainly alkali and alkaline earth metal) and/or water molecules or
remains empty (Brindley and Brown 1980; Schulze 2005; Brigatti et al. 2006;
Murray 2007b). The presence of hydrated cations in the gallery is closely related to
the net layer charge, that is generated by isomorphic substitution of cations in
tetrahedral (e.g., Si4+ by Al3+) and/or octahedral (e.g., Al3+ by Mg2+) positions.
Depending on the occupation of sites in the octahedral sheet by metal cations,
dioctahedral (gibbsitic, gibbsite-like) or trioctahedral (brucitic, brucite-like) type of
clays are distinguished. In the dioctahedral clays, one site is vacant and two others
are occupied by Me3+, while in the trioctahedral minerals all sites of brucite-like
layer are filled by Me2+ cations (Brigatti et al. 2006; Guggenheim et al. 2006).
In 2006, the international organization AIPEA (Association Internationale pour
l’Etude des Argil), clustering scientists and institutions dealing with the clay
minerals, proposed an actual classification of layered aluminosilicates (Table 1)
(Guggenheim et al. 2006). The layered aluminosilicates were classified in terms of
various arrangement of octahedral and tetrahedral sheets, types of octahedral sub-
layer (e.g., trioctahedral, dioctahedral, di,trioctahedral), types of interactions
between adjacent layers, as well as a layer charge attributed to the structure unit (x).
In the literature, the hydrogel-clay materials synthesized based on various types
of clay minerals (e.g., montmorillonite, hectorite (laponite), saponite, kaolinite,
Table 1 (continued)
Layer type Groups of minerals Interlayer Type of Examples of
(tetrahedral: (x is the net layer material octahedral species
octahedral) charge) sublayer
Vermiculite Hydrated Trioctahedral Trioctahedral
exchangeable vermiculite
cations Dioctahedral Dioctahedral
(x 0.6–0.9) vermiculite
True (flexible) mica Non-hydrated Trioctahedral Phlogopite,
monovalent annie, lepidolite
cations Dioctahedral Muscovite,
(x 0.85– celadonite,
1.0) paragonite
Interlayer-deficient Non-hydrated Trioctahedral Illite, glauconite,
mica monovalent or brammalite
divalent Dioctahedral Wonesite
cations (x < 0.6)
(x 0.6–
0.85)
Brittle mica Non-hydrated Trioctahedral Clintonite, bityit,
divalent anandite
cations Dioctahedral Margarite,
(x 1.8–2.0) chernykhite
2:1:1 Chlorite Hydroxide Trioctahedral Clinochlore,
sheet chamosite, nimite
(x = variable) Dioctahedral Donbassite
Di, Cookeite, sudoite
trioctahedral
Tri, None
dioctahedral
1:1 Regularly Variable Trioctahedral Corrensite,
interstratified kulkeite,
hydrobiotite
Dioctahedral Rectorite,
tosudite,
brinrobertsite
1:1, 2:1 Trioctahedral Dozyite
halloysite, attapulgite, illite, and vermiculite) are described. Most of them occur
naturally as components of rocks (e.g., kaolinite in the kaolin rock, montmorillonite
and small amount of hectorite in the bentonite minerals), however they can be also
synthesized.
The minerals from serpentine-kaolin (1:1) group belong to less often used clays
in the synthesis of hydrogel-clay (nano)composites. The general crystal structure of
the 1:1 minerals is shown in Fig. 2. In the serpentine-kaolin family of clay minerals,
the single layer with a thickness of about 0.7 nm, consists of one tetrahedral and
one octahedral sheet, joined each other by common oxygen anions. The unit cell
6 P. Kuśtrowski et al.
includes six octahedral sites and four tetrahedral sites (Brindley and Brown 1980;
Brigatti et al. 2006; Murray 2007b). The [SiO4]4− tetrahedrons are connected into
rings of hexagonal symmetry, however in the real crystal, the orientation of tetra-
hedral units is disturbed and they are turned toward each other, giving the ditrigonal
(pseudo-hexagonal) arrangement. A part of Si4+ cations may be isomorphically
substituted by cations with lower valence (e.g., Al3+ or Fe3+) (Wang and Siu 2006).
The second, gibbsite sheet, contains metal cations (Al3+, Fe3+, Mg2+) in the central
position of octahedrons, which are coordinated with O2− and OH− ions, located in
the corners of the polyhedron. The clay layers interact with each other via van der
Waals forces and hydrogen bonds formed between O2− anions in the tetrahedral
layer and the octahedral hydroxyl groups and/or water molecules (e.g., in hal-
loysite) (Murray 2007b; Wang and Siu 2006). In the group of 1:1 phyllosilicates,
the octahedral sites in the metal–oxygen sheet are entirely or nearly completely
filled with Me2+ or Me3+ cations. In the case of dioctahedral clays of this group
(e.g., kaolinite, halloysite), the substitution of central Al3+ ions by other cations
(e.g., Mg2+, Fe3+, Cr3+, or Ti4+) almost does not occur. The total charge of layer,
resulting mainly from the substitutions in the tetrahedral sheet is close to zero
(Brigatti et al. 2006; Wang and Siu 2006). On the other hand, in the minerals from
the serpentine group (trioctahedral), the octahedral sites are fully occupied by
cations Mg2+ (most commonly), Fe2+, Fe3+, and/or Mn2+ (rarely) (Murray 2007b).
The layered structure of clay is stable only when a very large number of layers is
overlaid and in some cases can form tubes (e.g., halloysite) (Schulze 2005; Murray
2007b). The most known member of the 1:1 clay minerals, used is the
hydrogel-clay (nano)composites synthesis, is kaolinite. Due to the absence of
interlayer cations, kaolinite does not exhibit a natural ability to swelling. However,
1 Polymer Hydrogel-Clay (Nano)Composites 7
corners, sharing oxyanions. In most cases (except for the minerals from talc–
pyrophyllite group), the layers are negatively charged, that is a result of isomorphic
substitution of Al3+ cations for Si4+ ions in the tetrahedral sheet and substitutions
occurring in the octahedral sublayer (Brindley and Brown 1980; Brigatti et al. 2006;
Murray 2007b; Kloprogge 1998). Excluding the minerals from the talc–pyrophyl-
lite and chlorite groups, the aluminosilicates of 2:1 type contain metal cations in the
interlayer spaces, which counterbalance the negative charge of the layer and play a
role in a stabilization of the layered structure. The d(001)-spacing for these materials
is equal to ca. 0.96 nm and includes both the thickness of the layer and interlayer
space (Brigatti et al. 2006; Murray 2007b).
Regarding the structure, chlorites belong the most distinctive layered minerals of
2:1 type. In this group of clays, the interlayer spaces contain an additional single
positively charged octahedral sheet, linked with the 2:1 layer by hydrogen bonds.
The thickness of such formed chlorite package (described as 2:1:1) is about 1.4 nm
(Schulze 2005; Brigatti et al. 2006). Due to the wide range of substitutions in both
tetrahedral and octahedral sublayers, the charge of basal structure unit, as well as
the composition of chlorites are variable. The tetrahedral sheets contain mainly Si4+
and Al3+, while the octahedral sites are occupied most frequently by Al3+, Mg2+,
Fe2+, and Fe3+. However, the presence of other cations, such as Cr3+, Mn3+, Ni2+,
V3+, Cu2+, Zn2+, and Li+, is also possible (Schulze 2005; Brigatti et al. 2006;
Murray 2007b).
The characteristic feature of the 2:1 clay minerals belonging to talc–pyrophyllite
family is a neutral charge of layers, that results from only limited substitutions of
Si4+ for Al3+ and minor amounts of Fe2+, Fe3+, Mg2+, or Ti4+ (Schulze 2005;
1 Polymer Hydrogel-Clay (Nano)Composites 9
Guggenheim et al. 2006). Although, the interlayer spaces do not contain cations
and/or water molecules, the layered structure of clay is stable due to the presence of
van der Waals forces. The weak interactions between the layers cause a very low
hardness of crystals (1-2 according to Mohs scale) (Schulze 2005; Murray 2007b;
Guggenheim et al. 2006).
In the family of mica minerals, the clay gallery is filled with non-hydrated metal
mono- and/or divalent cations (e.g., K+, Na+, Ca2+). Depending on the type of
interlayer cations, true micas ( 50% monovalent cations), brittle ( 50% divalent
cations), and interlayer-deficient micas (mono- and divalent cations at various
amounts) can be distinguished. The overall net layer charge, equal to approx. −1.0
(in true micas) or −2.0 (for brittle micas), is a result of a substitution of Si4+ by Al3+
(or Fe3+) cations in the tetrahedral layers (Murray 2007b; Guggenheim et al. 2006;
Rieder et al. 1998). The exception is the interlayer-deficient micas, in which the
charge is within the range from −0.6 to −0.85. A strong interaction between the
strongly negatively charged clay layers and cations located between them main-
taining the layered structure in micas, as well as a lack of hydration shell around the
interlayer ions cause a non-expandable character of layers, that is a distinctive
feature of this group of aluminosilicates. The d(001)-spacing of these materials is
usually approx. 1 nm and depends only on the type of cations present in the clay
gallery (Schulze 2005). Similarly to other above mentioned layered minerals, micas
can be classified as di- and trioctahedral types. In the case of dioctahedral type, the
internal sheet is occupied by trivalent ions (e.g., Al3+, Fe3+), whereas in the tri-
octahedral micas, these positions may be filled by Mg2+, Fe2+, Mn2+, or Li+
(Schulze 2005; Guggenheim et al. 2006). Due to the specific layered structure, the
mica minerals are characterized by a lamellar crystal shape and an excellent
cleavage parallel to the basal plane. They also reveal high dielectric resistance, high
thermal stability, resistance to fire and chemical agents, whereby are widely used in
industry (Brigatti et al. 2006; Murray 2007b; Rieder et al. 1998).
The vermiculite group concentrates minerals also characterized by relatively
high negative net charge (in the range from −0.6 to −0.9), however containing
hydrated, exchangeable interlayer cations (Schulze 2005; Murray 2007b;
Guggenheim et al. 2006). In contrast to the smectites, interlayer ions are regularly
arranged (ordered) at specific positions in relation to oxygen anions of tetrahedral
layers, resulting in “permanent” value of d(001)-spacing of ca. 1.4 nm (Schulze
2005; Murray 2007b). The negative charge of clay surface is generated mainly by
the substitutions in the tetrahedral sheet (e.g., Si4+ by Al3+). Trioctahedral vermi-
culites usually contain Mg2+ cations in the metal–oxygen layer, that may be partly
replaced by Fe2+, Ni2+, Fe3+, Al3+, while in the interlayer spaces hydrated Ca2+ and
Mg2+ cations are located (Brindley and Brown 1980; Schulze 2005; Kloprogge
et al. 1999). In the dioctahedral vermiculites, the internal sheet is mostly occupied
by aluminum cations, which are also present in the interlayer spaces. Due to high
thermal insulation properties, they are used as additives for concrete and refractory
elements. Moreover, due to the ion-exchange abilities, vermiculites are tested as
sorbent materials (Brigatti et al. 2006; Murray 2007b; Kloprogge et al. 1999).
10 P. Kuśtrowski et al.
Smectites are the most popular family of clay minerals, used in many fields of
science and technology. Among the best-known materials of this group, mont-
morillonite, saponite, and hectorite (laponite) should be highlighted. The reason of
wide range of application of these minerals is their specific layered structure,
characterized by the presence of hydrated cations in the interlayer spaces. The
general chemical formulas of the main smectite representatives are shown in
Table 2 (Kloprogge 1998). In the layered aluminosilicates of this group, the sub-
stitutions are present both in the tetrahedral and octahedral sublayers. The iso-
morphic substitution in the tetrahedral sheets involves mainly the replacement of
Si4+ by Al3+ (Fe3+), while Al3+ cations in the octahedral sublayer can be exchanged
by mono-, di-, and/or trivalent cations (Li+, Mg2+, Fe2+, Ni2+, Zn2+, and Fe3+)
(Brindley and Brown 1980; Schulze 2005; Brigatti et al. 2006; Murray 2007b;
Guggenheim et al. 2006). Due to the nature of the octahedral sheet, di- and
trioctahedral-type smectites can be distinguished (cf. Table 1). Trioctahedral
smectites (e.g., saponite, hectorite), being rather rare silicates and usually appearing
as soil-forming minerals, are most often synthesized. In this case, the structure of
octahedral sheet is similar to that of talc. In saponite, the octahedral sites are usually
occupied by magnesium cations, while in hectorite a part of Mg2+ ions is substi-
tuted by Li+ (Brindley and Brown 1980; Schulze 2005; Kloprogge et al. 1999).
Dioctahedral smectites (e.g., montmorillonite, beidellite, and nontronite), being
main constituents of sedimentary rocks (clays) (e.g., bentonite), belong to the most
common group of the 2:1 type minerals. The low, negative charge of the surface (in
the range from −0.2 to −0.6) is a result of the partial substitution of Al3+ by Mg2+
cations in the octahedral sublayer (e.g., in montmorillonite) or substitution of Si4+
by Al3+ ions in the tetrahedral sheet (e.g., in beidellite). In the octahedral layer,
small amounts of iron and other metal cations may be present (Schulze 2005;
Brigatti et al. 2006; Murray 2007b). In the smectites, the negative charge of the
layers is compensated by hydrated cations of alkali and alkaline earth metals (Na+,
K+, Li+, Ca2+, and Mg2+) located on the outer surface of the layers and in the
interlayer spaces. The small content of interlayer ions causes a weak interaction
between clay layers, which results in high cation-exchange capacity (Brigatti et al.
2006; Murray 2007b; Kloprogge 1998). Therefore, the originally occurring inter-
layer cations can be relatively easily replaced by other cations (e.g., Sr2+, Ba2+,
H3O+, or NH4+) or larger positively charged molecules, such as metal oligomers,
surfactants, monomers, or polymer chains (Sinha Ray and Okamoto 2003;
Kloprogge 1998; Lagaly et al. 2007; Murray 2007a). Moreover, due to the specific
structure, smectites reveal an excellent ability to swelling in polar solvents, which
Table 2 General chemical Montmorillonite Mnn þ x=n ½Al4x Mgx ½Si8 O20 ðOHÞ4 mH2 O
formulas of the best known
smectite minerals Beidellite Mnn þ x=n ½Al4 ½Si8x Alx O20 ðOHÞ4 mH2 O
Nontronite Mnn þ x=n ½Fe4 ½Si8x Alx O20 ðOHÞ4 mH2 O
Saponite Mnn þ x=n ½Mg6 ½Si8x Alx O20 ðOHÞ4 mH2 O
(F-)hectorite Mnn þ x=n ½Mg6x Lix ½Si8 O20 ðOH; FÞ4 mH2 O
1 Polymer Hydrogel-Clay (Nano)Composites 11
both. The presence of functional hydrophilic pendant groups causes that hydrogels
show water swelling. Furthermore, the crosslinked structure makes hydrogels
insoluble in water. Depending on the nature of functional groups, the polymeric
chains of hydrogels may be polycations, polyanions, polyampholytes, polybetaines,
or may be nonionic.
The chemically crosslinked hydrogels are prepared by two different methods:
(i) three-dimensional free-radical polymerization of water-soluble monomers in the
presence of multifunctional monomer (crosslinker), (ii) chemical crosslinking of
water-soluble polymers by a reaction between functional groups of polymers and
bifunctional crosslinking agent. Copolymerization of the water-soluble vinyl
monomers and multifunctional monomers (crosslinkers) is a preferable route of
hydrogels synthesis in three-dimensional free-radical polymerization (TFRP)
(Thakur and Thakur 2014a, b, 2015). The commercially available monomers used
as crosslinkers are shown in Fig. 5.
Using this method, interpenetrating (IPN) and semi-interpenetrating (sIPN)
hydrogel networks are synthesized (Shivashankar and Mandal 2012; Dinu et al.
2011). The polymerization can be carried out in solution, suspension/
inverse-suspension, emulsion/inverse-emulsion, or as bulk polymerization (Odian
1991; Choudhary 2009; Hussain et al. 2012). The solution polymerization is used
for the synthesis of large amounts of the hydrogel. The process is most frequently
proceeded in water, but a variety of polar solvents can be applied. Moreover, they
can be exchanged for water in the hydration step. The polymerization is usually
initiated by the presence of free-radical initiators [such as 2,2-azo-isobutyronitrile
effective exfoliation of clays in water, but also sonication is often applied at this
stage. The appropriate radical polymerization is usually carried out at ambient
temperature for 24–72 h in an inert atmosphere and does not require stirring, which
makes the method relatively simple. However, not all of the vinyl monomers can
form (nano)composites in the presence of exfoliated clay in such a simple way,
because the effective stabilization of clay dispersion by the monomer molecules is
required to prepare hydrogels crosslinked by the clay platelets. The nonionic vinyl
monomers having amide groups such as acrylamide, N-isopropylacrylamide, and N,
N-dimethylacrylamide effectively stabilize clay platelets in aqueous media as a
result of mild interaction between the ionic clay and the dipolar molecules, and so
largely prevent the gel formation of clay itself. The ionic monomers, such as acrylic
acid, form strong hydrogen bonds with hydroxyl and silane groups present on the
clay surface, and consequently, inhomogeneous hydrogel-clay aggregates are
formed. Thus, obtaining the homogeneous initial reaction solution by simple
mixing of the solution of acrylic acid and clay dispersion is impossible (Song et al.
2008).
Contrary to other ionic monomers, 2-acrylamido-2-methylpropanesulfonic acid
(AMPS), which is a commonly used vinyl monomer for the synthesis of conven-
tional hydrogels, can successfully avoid the aggregation and gelation of laponite
even in the presence of acrylic acid. The stabilization of clay suspension by AMPS
is the result of synergistic interaction of acrylamido and sulfonic acid groups with
the laponite platelets (Chen et al. 2013; Du et al. 2014).
The chemical redox systems (e.g., APS or KPS) in combination with TMEDA
are used to initiate the process as well as UV irradiation in the presence of pho-
toinitiators (Haraguchi and Takada 2010).
The mechanism of hydrogel-clay (nano)composite formation is determined by
specific interactions between clay platelets and monomer as well as initiator
molecules. Haraguchi et al. revealed that in the polymerization of N-iso-
propylacrylamide initialized by the KPS/TMEDA system, the ionic groups of ini-
tiator more intensively interact with the clay platelets by strong ionic interactions
than the polar monomer molecules, and therefore, on the surface of clay platelet
centers of radical polymerization are located. Hence, the formed polymer chains are
grafted on the clay surface (Haraguchi et al. 2005).
All layered silicates in their pristine state are of good water swellability and
obtaining homogeneously dispersed clay platelets in aqueous media does not cause
any problem at low clay concentrations. Nevertheless, the clay suspensions are
characterized by high viscosity, which makes the polymerization extremely diffi-
cult. Due to this fact, the clay concentration in the initial reaction solution usually
does not exceed 6 wt%. At high concentrations of nonmodified clays, the prepa-
ration of aqueous dispersion is hard, even under strong agitation. The commercially
modified clay (laponite), which is mixed with the sodium salt of pyrophosphate as
an inorganic modifying agent, is much easier dispersible in water and gives less
viscous solutions (Liu et al. 2007). Another way to the lower viscosity of initial
reaction solution is an addition of poly(ethylene glycol) to suspension, which easily
adsorbs on the clay platelets and acts as a dispersing agent (Hu et al. 2010).
1 Polymer Hydrogel-Clay (Nano)Composites 17
Fig. 8 SEM (a) and TEM (b) images of poly(acrylic acid)-montmorillonite nanocomposite
The interaction between the hydrogel and clay surface are very often studied by
Fourier transform infrared spectroscopy (FTIR). The negative charge of clay sur-
face (electronegative oxygen), as well as the presence of hydroxyl groups, results in
the interaction with functional groups of the polymer by van der Waals forces or
hydrogen bonds (Xiang et al. 2006). For instance, the interaction of hydroxyl
groups of clay mineral with carboxylic groups of poly(acrylic acid) is identified in
the FTIR spectrum as a shift of band attributed to C=O groups toward lower
wavenumbers in relation to unmodified polymer (Fig. 9a), while the absorption
band attributed to the Si–O bond is shifted toward lower frequencies
(1007 cm−1 ! 1037 cm−1) (Janovák et al. 2008). Similar effects are found during
the formation of hydrogen bonds between N–H groups of poly(acrylamide) and
hydroxyl groups of halloysite (Fig. 9b) (Liu et al. 2012b).
In the case of adsorption studies of dyes or heavy metal cations on hydrogel-clay
composites, the FTIR technique is applied to determine the type of complex, which
forms between hydrogel functional groups and adsorbed species, and thus indirectly
to study the adsorption mechanism (Nakamoto 1986).
Furthermore, certain effects accompanying the presence of clay particles in the
hydrogel matrix may be studied by means of Raman spectroscopy. Namely, based
on the analysis of wavenumber shifts of the band attributed to the CH3 stretching
vibrations, the hydration degree of the polymer chains in the aqueous solution in the
function of clay content can be estimated (Lian et al. 2015).
The changes of thermal and swelling properties of the polymer after the intro-
duction of small amounts of clay filler are examined with the use of thermal
methods, namely thermogravimetry analysis (TGA) and differential scanning
calorimetry (DSC). Basically, the TGA technique is used to determine the clay
content in the composite, as well as the decomposition mechanism of polymer
part. However, in order to study the thermal decomposition process precisely, an
additional analysis of gaseous products (evolved during the sample heating) by
1 Polymer Hydrogel-Clay (Nano)Composites 21
(a) (b)
Si-O stretching C=O Si-O stretching
C=O vibrations stretching vibrations
stretching
Kubelka Munk [a.u.]
Kubelka-Munk [a.u.]
PAA
PAAm
MT-PAA
MT-PAAm
MT MT
4000 3500 3000 2500 2000 1500 1000 4000 3500 3000 2500 2000 1500 1000
-1 -1
Wavenumber [cm ] Wavenumber [cm ]
Fig. 9 Interactions between functional groups of montmorillonite (MT) and hydrogels (poly
(acrylic acid)—PAA (a) and poly(acrylamide)—PAAm (b)) observed in FTIR spectra
of the polymer chains. This effect observed for many (nano)composites can be
explained by the restriction of movement of hydrogel chains in the presence of
well-dispersed clay nanoparticles (Wang and Chen 2012; Mansoori and Salemi
2015; Kamoun and Menzel 2012; Nair et al. 2007).
It was observed that no linear correlation between the clay content and the
mechanical properties of the formed (nano)composite exists. The highest strength
of the composite is usually achieved at the critical concentration of clay, and a
further increase in its loading leads to the formation of disordered organic–inor-
ganic network and does not improve the expected properties (Lungu et al. 2012;
Haraguchi 2008). Nevertheless, at the high clay contents, a steep increase in initial
modulus can be found due to the appearance of rigid structures involving clay–clay
interactions, similar to house-of-card or nematic-like structures (Haraguchi 2011b).
The mechanical properties of hydrogel-clay (nano)composites depend also
strongly on many other factors such as a type of clay and polymer, their initial
functionalization and modification, a clay dispersion, and a synthesis method. The
post-synthesis treatment of (nano)composite materials can have also a crucial
influence on their mechanical strength. For example, drying procedure can result in
additional crosslinking by irreversible rearrangement of polymer-clay system pro-
ceeding at more concentrated state. On the other hand, a lower water content in the
(nano)composite promotes its plastic-like deformations (Haraguchi and Li 2009).
The details of mechanical and rheological properties determined for the
(nano)composites containing various more common synthetic hydrogels as well as
clays can be found in the scientific papers listed in Table 3, which summarizes
other properties of the studied materials as well.
loss modulus
Laponite Tensile strength, stress Water absorbency, Transparency Thermal analysis, Can et al. (2007), Li et al. (2008,
(hectorite) relaxation, elongation at swelling rate, water DSC analysis 2009a, b), Okay and Oppermann
break, shear modulus, diffusion (2007), Xiong et al. (2008), Zhu et al.
tensile modulus, storage (2006)
modulus, loss modulus
Montmorillonite Compressive strength, Water absorbency, Thermal analysis, HelvacIoǧlu et al. (2011), Ibraeva et al.
(bentonite) tensile strength, Young swelling rate DSC analysis (2015), Pereira et al. (2015), Salimi
modulus, elongation at et al. (2014)
break, storage modulus,
loss modulus
Sepiolite Water absorbency, Ekici et al. (2006)
swelling rate, water
diffusion
(continued)
25
Table 3 (continued)
26
The rate of swelling (e(t)) is usually well described by the Voigt model (Eq. 2),
which consists of two parameters—spring parameter (corresponding to the resis-
tance to expansion of the polymer network—r0/E) and dashpot parameter (corre-
sponding to the resistance to permeation—s0) (Santiago et al. 2006):
r0 ðt0 tÞ
eðtÞ ¼ 1 e s0 ð2Þ
E
It was found that the values of s0 become rather independent of the external
solution, whereas the values of r0/E decrease with an increase in ionic strength. It
means that the water absorbency in the saline solutions is slower than in deionized
water mainly due to (i) the osmotic pressure difference between the hydrogel
composite and the saline solution, and (ii) possible complexation. The effect of salt
is more distinct if the salt contains multivalent ions (Zhang et al. 2014b, c; Li et al.
2007) and is used at a higher concentration (Xu et al. 2007a). At the elevated saline
solution concentration, the solute ions migrate to the (nano)composite structure
shielding a part of charged functionalities (e.g., carboxylic) located in the hydrogel
bulk (Zhang et al. 2005a). Furthermore, Zheng et al. (2007) demonstrated that the
water absorbency of vermiculite-filled poly(acrylic acid) was also affected by the
kind of anions and was the highest in a trivalent anion (PO43−) salt solution.
The initial water uptake process of hydrogel-clay (nano)composites corresponds
to the diffusion of water molecules into the structure, which can be analyzed using a
simple power law equation (Eq. 3):
Mt
¼ ktn ð3Þ
Me
where Mt and Me are the weight of the swollen (nano)composite at time t and
equilibrium swollen state. The constant n is often used to determine the swelling
mechanism. In the case of disk-shaped samples, if n 0.5 swelling proceeds by
the Fickian diffusion (the swelling process is controlled by solvent diffusion). For
n 1 swelling is limited by the relaxation of hydrogel chains. Finally, if
0.5 < n < 1 non-Fickian diffusion is prominent and is meant as the synergistic
effect of solvent diffusion and polymer chains relaxation (Kaşgӧz and Durmus
2008; Yi and Zhang 2007; Boruah et al. 2015). The analysis of various systems
indicates that the physical and chemical interactions between the water molecules
and the (nano)composite lead to diffusion of H2O toward the inside dry material. At
the beginning, the water molecules react with more exposed polar moieties located
on the surface of hydrogel and dispersed clay platelets, initializing the hydration
process. The macromolecular rearrangement of the hydrogel is subsequently con-
tinued resulting in the accommodation of absorbed H2O (Guilherme et al. 2010).
Such mechanism was confirmed by the swelling measurements combined with the
elasticity tests, which showed that the effective crosslink density (me) of hydrogel
first decreased, but then increased with increasing time of swelling (Can et al.
2007).
32 P. Kuśtrowski et al.
The swelling rate depends strongly on size of particles and their porosity. For the
large grains, more void is available to absorb water, but the quick absorption
requires rather smaller particles. This effect was demonstrated for poly
(acrylamide-co-itaconic acid)-laponite (nano)composite crosslinked by different
amounts of N-methylene-bis-acrylamide resulting in the average particle size
ranging from 0.12 to 4.6 lm and consequently a prolonged swelling time from 30
to 300 min, respectively (Wan et al. 2015a, b). Nevertheless, the (nano)composite
particles cannot be too fine, because the adverse gel blocking effect occurs (Kabiri
et al. 2011). The porosity of hydrogel-clay (nano)composites can be improved by
using of various porogens (such as acetone or sodium dicarbonate) during the
synthesis. The kind of clay filler and its modification are also important factors
influencing the swelling capacity and swelling rate (Swain et al. 2013; Zhang et al.
2014c).
6.1 Adsorption
ðC0 Ct ÞV
qt ¼ ð4Þ
m
ln ðqe qt Þ ¼ ln qe k1 t ð5Þ
t 1 t
¼ þ ð6Þ
qt k2 q2e qe
qt ¼ k3 t0:5 þ A ð7Þ
where qe is an amount adsorbed at equilibrium, k1, k2, k3, are rate constants for
pseudo-first-order, pseudo-second-order and intra-particle diffusion, A is the
thickness of boundary layer.
Furthermore, the adsorption equilibrium concentrations of the solution are fitted
by different isotherms including the most appropriate Langmuir (Eq. 8) and
Freundlich models (Eq. 9),
qm kL Ce
qe ¼ ð8Þ
1 þ kL C e
qe ¼ kF Ce1=n ð9Þ
6.1.1 Dyes
Dyes have been commonly used from ancient times for coloring textiles and pro-
duction of paints and pigments. They have been recognized as dangerous organic
pollutants, which escape conventional wastewater treatment processes and persist in
the environment being highly stable during treatment with light, temperature, or
various chemicals. Bioaccumulation of dyes causes chemical and biological
changes in the aquatic system resulting in environmental damage and human dis-
ease. Therefore, new, effective technologies for the purification of water from
redundant dyes have been still developed. Beside some known techniques (such as
coagulation-flocculation, aerobic or anaerobic treatment, electrochemical treatment,
membrane filtration), cheap, simple, and efficient adsorption process seems to be a
reasonable way to achieve this target (Mahdavinia et al. 2012; Mahdavinia and
Asgari 2013; Hosseinzadeh et al. 2015; Dalaran et al. 2009, 2011; Wan Ngah et al.
2011). Usually, activated carbons are applied as solid adsorbents, but this role can
be also played by other materials including polymer-clay (nano)composites (Tan
et al. 2015; Mahdavinia et al. 2013). Especially, the hydrogel-clay
1 Polymer Hydrogel-Clay (Nano)Composites 35
3C H CH3 3C H
N
H + -
N Cl
3C H
O
-
Cl
CH3
3C H + CH3 NH
N N
O
CH3 CH3 CH3
CH3
- -
Cl Cl
+ +
(H3C) 2N S N(CH 3)2 2N H S NH2
N N
Ogawa 2013; Kaplan and Kasgoz 2011; Marandi et al. 2015; Haraguchi and Li
2010; Ekici et al. 2006; Yi and Zhang 2008; Mahdavinia et al. 2012, 2013;
Mahdavinia and Asgari 2013; Shirsath et al. 2015) and poly(acrylic acid)-based (co)
polymers (Li et al. 2008; Shirsath et al. 2011, 2013; Dalaran et al. 2011; Zhang
et al. 2006; Bhattacharyya and Ray 2014; Shi et al. 2013; El-Sigeny et al. 2014) as a
hydrogel part.
The adsorption capacity of crystal violet was examined for (nano)composites
containing poly(acrylic acid-co-N-vinyl-2-pyrrolodine)-laponite (Zhang et al.
2006), poly(acrylic acid)-FeCo-bentonite (Shirsath et al. 2011),
kappa-carrageenan-g-alginate-g-poly(acrylamide)-montmorillonite (Mahdavinia
et al. 2013), poly(acrylamide)-g-carrageenan-laponite (Mahdavinia et al. 2012),
poly(N-isopropylacrylamide) crosslinked by lithium magnesium silicate hydrate
(Zhang et al. 2014a), kappa-carrageenan-g-poly(acrylamide)-sepiolite (Mahdavinia
and Asgari 2013), kappa-carrageenan-g-poly(vinyl alcohol)-montmorillonite
(Hosseinzadeh et al. 2015), poly(acrylamide)-laponite (Li et al. 2008), poly(acry-
lamide)-kaolin (Shirsath et al. 2015), poly(acrylamide-co-itaconic acid)-laponite
(Marandi et al. 2015). The kinetics of adsorption of crystal violet on the presented
materials was well described by the pseudo-second-order model. Moreover, the
Langmuir model was found as the best one for the description of equilibrium
adsorption of this dye (Zhang et al. 2006; Shirsath et al. 2011; Mahdavinia et al.
2012, 2013; Hosseinzadeh et al. 2015; Mahdavinia and Asgari 2013). Basing on the
Langmuir isotherm, the maximum dye adsorption capacity of about 151 mg/g was
achieved for kappa-carrageenan-g-poly(vinyl alcohol)-montmorillonite
(Hosseinzadeh et al. 2015). Calculations of thermodynamic parameters confirmed
the spontaneity, feasibility and endothermic nature of the adsorption process
(Shirsath et al. 2011; Hosseinzadeh et al. 2015).
The adsorption capacity of crystal violet strongly influenced the adsorbent
composition (especially the clay loading) and content, pH, and temperature used
during the adsorption process, as well as the initial concentration of dye solution
(Hosseinzadeh et al. 2015). More dye was adsorbed by the materials containing
higher amounts of clay due to enhanced negative charge density related mainly to
the negative clay surface (Zhang et al. 2006; Mahdavinia et al. 2012, 2013;
Hosseinzadeh et al. 2015; Mahdavinia and Asgari 2013; Shirsath et al. 2011;
Dalaran et al. 2011; Zhang et al. 2014a). For example, the incorporation of nonionic
poly(acrylamide) into the laponite clay gave a material characterized by the pres-
ence of high amount of ionizable groups, which exhibited the dye adsorption
corresponding to type S adsorption isotherms in the Giles classification (Li et al.
2008). Such isotherm type is typical of the so-called cooperative adsorption pro-
moted by increasing adsorbate concentration. It should, therefore, be assumed that a
part of the surface was covered by multilayers of adsorbed dye, whereas its
monolayer was still incomplete on remaining fragments of the surface. On the other
hand, the rate of dye removal increased with raising clay loading in the (nano)-
composite. The partition coefficient (Kd) is defined as (Eq. 10), which is as follows:
1 Polymer Hydrogel-Clay (Nano)Composites 37
ðC0 Ce Þ
Kd ¼ ð10Þ
Ce
molecules and the methine and methyl groups on the composite, as well as
(iii) dipole–dipole and dipole-induced dipole interactions between the dye mole-
cules and the hydrogel chains.
In the open literature, some examples of adsorption process of other cationic
dyes can be also identified, including Safranine T (ST) on poly(acrylamide)-poly
(sodium methacrylate)-kappa-carrageenan-montmorillonite and starch-g-poly
(acrylic acid)-montmorillonite (Karadaǧ et al. 2014; Al et al. 2008), brilliant cre-
syl blue on poly(acrylamide-co-itaconic acid)-montmorillonite (Kaplan and Kasgoz
2011), Basic Blue 12 (BB-12) Basic Blue 9 (BB-9), and Basic Violet 1 (BV-1) on
poly(acrylamide)-laponite (hectorite) (Li et al. 2009b; Ekici et al. 2006), Brilliant
Green on poly(acrylic acid)-kaolin (Shirsath et al 2013), Janus Green B on poly
(acrylamide-co-zinc acrylate)-g-xanthan gum-sepiolite (Karadağ et al. 2015), as
well as Acid Green B and Maxilon C.I. Basic on poly(styrene-co-acrylic acid)-
organophilic montmorillonite (El-Sigeny et al. 2014).
In some exceptional cases, the adsorption of dyes containing negatively charged
functional groups (e.g., indigo carmine (Dalaran et al. 2009, 2011) and congo red
(Bhattacharyya and Ray 2014) presented in Fig. 11) on hydrogel-clay (nano)-
composites was also examined. Both poly(acrylic acid-co-2-(N,N-dimethylamino)
ethyl methacrylate)-montmorillonite (Dalaran et al. 2011) and poly(2-(N,N-dime-
thylamino)ethyl methacrylate-co-2-acrylamido-2-methylpropane sulfonic acid-co-
2-hydroxyethyl methacrylate)-montmorillonite (Dalaran et al. 2009) with enhanced
mechanical properties showed a high adsorption performance in the elimination of
indigo carmine (up to 320 mg/g). On the other hand, (nano)composites synthesized
from crosslinked poly(acrylic acid), poly(ethylene glycol) and a bentonite nanofiller
appeared to be efficient adsorbents of congo red (Bhattacharyya and Ray 2014). The
ionization and polarization of various functional groups of hydrogel and filler
(such as amide, hydroxyl, or carboxylic ones) changed with pH. The abrupt
O H
+ -
Na O3 S N
Indigo carmine
N - +
SO3 Na
H O
+
2N H Na
-
N O3 S
N
Congo red
N
-
SO3 Na+ N
NH2
Heavy metals (e.g., Pb, Cr, Cd, Hg, As, Ni, Cu, and Zn) are pollutants discharged
from industrial, domestic, and agricultural wastewater that can enter the drinking
water system through groundwater. These components are non-biodegradable and
accumulate in the natural ecosystem with a harmful influence on the human health
(toxic effects on various systems and organs, including nervous system, cardio-
vascular system, or kidneys) (Ihsanullah et al. 2016; Zhao et al. 2016; Fu and Wang
2011). In spite of a few disadvantages (related mainly to production of waste
products and low selectivity), adsorption, being relatively simple, cheap, and highly
effective, is considered as a powerful method used for the removal of heavy metal
cations (Zhang et al. 2006; Ihsanullah et al. 2016; Zhao et al. 2016; Beisebekov
et al. 2014). Various activated carbons, biomaterials, metal oxides, and zeolite, as
well as natural and modified clays, are applied adsorbents of heavy metal cations,
which can operate in a wide pH range and be easily recovered/regenerated after the
adsorption process.
A possible application of hydrogel-clay (nano)composites in adsorption of metal
cations was preliminarily verified using Fe3+ as a model ion (Natkański et al. 2013a,
b). The studied (nano)composites contained montmorillonite (20–50 wt%) dis-
persed in matrix of poly(acrylamide), poly(acrylic acid), poly(sodium acrylate),
poly(ammonium acrylate), or poly(acrylamide-co-sodium acrylate) copolymers. For
the poly(acrylic acid)-based (nano)composites, an increase in the hydrogel content
had a positive effect on the adsorption capacity of Fe3+ ions, which were removed
from a solution by ion exchange with protons of carboxyl groups. The adsorption
kinetic was well described by the model of pseudo-second order (Natkański et al.
2013b). The adsorption properties of hydrogel-clay (nano)composites is strongly
influenced by chemical content and distribution of polymer part. This issue was
deeply recognized for the (nano)composites containing poly(acrylic acid) and its
salts (sodium and ammonium). During the synthesis, poly(ammonium acrylate) was
preferentially deposited on the external surface of clay particles, and therefore
exhibited the superior adsorption capacity of Fe3+ cations. It was shown that the
Langmuir model better described the adsorption on the poly(acrylic acid)-con-
taining material, whereas the Freundlich model was more adequate for the
description of process occurring on the polyacrylate-based samples, suggesting
unspecific adsorption of Fe3+ ions in the composite structure (Natkański et al.
2012). In the case of materials based on poly(acrylamide-co-sodium acrylate)
copolymers, higher adsorption capacities were observed for those containing free
1 Polymer Hydrogel-Clay (Nano)Composites 41
Fig. 12 Model (a) and TEM images (b) of structure of metal–oxide particles-pillared
montmorillonite after elimination of hydrogel template
composite at constant pH (from 2.0 to 4.0) and temperature (30 °C). The interca-
lation of hydrogel into the gallery of montmorillonite followed by the Fe3+
adsorption resulted in the layer disordering (Fig. 12a) which was preserved after
calcination at 600 °C. High dispersion of a-Fe2O3 nanoparticles was confirmed by
TEM images (Fig. 12b). The presented synthesis strategy was used by Rokicińska
et al. (2016) to obtain the Co3O4 containing catalysts for the total oxidation of
volatile organic compounds. The highest dispersion and Co loading were achieved
for the poly(acrylic acid)-montmorillonite (nano)composite modified by adsorption
of Co2+ cations at pH = 6–8. For these materials, the highest conversions in the
toluene combustion were observed. The catalytic activity was additionally corre-
lated to the reducibility of active phase suggesting that the process undergoes
according to the Mars–van Krevelen mechanism.
Hydrogels filled with selected clays have good potential to be used as functional
soft materials in biological applications, because of their excellent mechanical and
rheological properties, high water content, and good biocompatibility. Based upon
properties such as swelling, film-forming ability, bioadhesion, and cell capture
capacity, the hydrogel-clay (nano)composites have been considered as platforms to
construct new forms of drug release systems with highly specific dosage and an
improvement of technological and biopharmaceutical properties (Tu et al. 2013;
Rodrigues et al. 2013; Pongjanyakul and Puttipipatkhachorn 2007). The
hydrogel-clay (nano)composites were sometimes used as tablet-coating materials
for modifying drug release from tablets, which present good stability towards
enzymatic degradation in simulated intestinal fluid (Khunawattanakul et al. 2011).
However, a majority of studies was concerned on the active role of these com-
posites in a drug storage and its subsequent delivery. It was found that the drug
1 Polymer Hydrogel-Clay (Nano)Composites 43
release largely depends on the clay content, its dispersion in the polymer matrix, the
presence of intercalated agents, the charge of drug, the interaction between the gel
and the drug, and ionic strength of the medium. The swelling capacity is also the
crucial parameter influencing the drug release from the composite structure. As
revealed for poly(N-2-vinyl pyrrolidone) (PVP) hydrogels containing chitosan and
laponite (Oliveira et al. 2014), the minor release of glucantime was presented by the
PVP/chitosan/clay (nano)composite, which was associated to the crosslinking
between PVP and chitosan, compared to the more loosely bonded clay-free
hydrogel. Similarly, the release of sulfamethoxazole and diclofenac sodium from
polyester-polyol-acrylate-bentonite (nano)composites was controlled by the physi-
cal or chemical crosslinking density (Thatiparti et al. 2010). Chemically crosslinked
hydrogels degraded due to hydrolysis or enzymatic digestion, and the rate of
polymer degradation decided mostly on the drug delivery from these systems.
The stimuli-responsive materials containing pH-sensitive hydrogels, exhibiting
phase transitions (i.e., volume change) in response to changes in pH, have been
very often studied. Such systems could allow to deliver desired drugs introduced
into a human body directly to the small and large intestines (pH = 5–8), while
avoiding release in the stomach (pH = 1–3), because of hydrogels containing
ionizable weakly acidic groups swell in the acidic medium of stomach much lesser
than in the basic medium of intestines, resulting in the release of loaded drug
mainly in the latter (Dadkhah et al. 2014).
Wang et al. (2009) studied pH-sensitive (nano)composites containing
chitosan-g-poly(acrylic acid), attapulgite and sodium alginate as diclofenac sodium
delivery matrices crosslinked by Ca2+ owing to the ionic gelation of sodium algi-
nate. It was shown that at pH = 6.8 the drug release was slower than at pH = 7.4,
and additionally decreased with an increase in the attapulgite content. The drug
release mechanism based on the swelling-controlled mode was proposed. At low
pH and in the presence of attapulgite and sodium alginate crosslinked by Ca2+, a
longer path for diclofenac sodium to migrate from the composite structure promoted
the prolongation of its release time. The entrapment efficiency of hydrogel mate-
rials, especially under basic conditions, can be improved by the intercalation of
drug molecules between the positively charged layers of clay, used as an inorganic
filler. This effect was revealed for alginate modified with montmorillonite inter-
calated with bovine serum albumin (Kaygusuz and Erim 2013), procainamide
hydrochloride (Kevadiya et al. 2010) or lidocaine hydrochloride (Kevadiya et al.
2011), magnesium aluminum silicate intercalated with complexes of propranolol
HCl (Pongjanyakul and Rongthong 2010), and chitosan crosslinked with sodium
tripolyphosphate containing montmorillonite pillared with ofloxacin (Hua et al.
2010). The mechanism of drug release can be studied based on the kinetic exponent
(n) calculated from the Ritger and Peppas model (Ritger and Peppas 1987)
describing the process kinetics as follows:
44 P. Kuśtrowski et al.
F ¼ kp t n ð11Þ
where F is the fraction of drug released at time t, kp—the rate constant and n—the
release exponent. For spherical matrices (such as alginate beads), n 0.43 indi-
cates a Fickian diffusion, 0.43 n 0.85—a non-Fickian transport (involving
both Fickian diffusion and polymer chain relaxation), whereas n 0.85—a
zero-order release mechanism (swelling or erosion controlled). It was shown that
the introduction of bovine serum albumin-intercalated montmorillonite into alginate
gel resulted in the decrease of the n value from 1.05 to 0.60–0.63 showing the
change in the release mechanism from the surface erosion to the swelling/erosion
combined with diffusion (Kaygusuz and Erim 2013).
Another mechanism of drug release from hydrogel-clay (nano)composites is
based on thermally induced volume phase transition phenomenon characteristic of
ionic temperature-sensitive hydrogels. Such polymers, for example, poly(N-iso-
propylacrylamide), exhibit critical gel transition temperature which defines changes
in their swelling capacity. Below this point, the functional groups of hydrogel form
strong hydrogen bonds with water molecules. When critical gel transition tem-
perature is reached, the hydrophobic force of the gel increases, it collapses, and the
bound water together with entrapped substances are released from the gel. The
destruction of the hydrogel structure was clearly evidenced by a sudden drop in
generalized diffusion coefficient (Ka) determined from the following Eq. 12
describing 2D anomalous diffusion (Stempfle et al. 2014):
6.3 Biomedicine
6.4 Others
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Chapter 2
An Overview on Polymer Gels Applied
to Enzyme and Cell Immobilization
1 Introduction
Polymer gels comprise a great variety of different polymeric compounds that pre-
sent innumerable industrial applications. Polymers can be naturally produced, in
which case the most representative group is polysaccharides (Thakur and Thakur
2014a, b). This includes alginate, chitosan, and agar-agar. Some polysaccharides
form gels through ionic gelation in the presence of ions like calcium (Ca2+), such as
alginate or pectin, while other gels solidify in high temperatures. In addition to
polysaccharides, lignin based hydrogels have recently been studied and reviewed
(Thakur and Thakur 2015). On the other hand, a wide variety of synthetic polymers
capable of forming gels presents different industrial applications, such as poly-
acrylamide and polyvinyl alcohol.
An extremely important use of polymer gels is for biocatalyst immobilization,
fixing in place microbial enzymes or cells (Lahiri 2015; Wilkowska et al. 2015). In
the latter case, the cells can be entrapped and used for biotransformation or they can
be used for the production of enzymes with industrial interest (Kamble and Banoth
2013; Hemachander et al. 2001). Immobilization of biocatalysts takes place via the
fixation of the protein or cells to a support medium through any of various means
including adsorption, covalent bonding, or entrapment inside a polymeric matrix.
The last technique is the main focus of this review, as several polymer gels can be
used for enzyme or cell entrapment and is a method in which activity loss is low
when compared to other techniques.
Enzyme or cell immobilization allows the reuse of the biocatalyst and reduces
cost if the catalytic activity is maintained. Furthermore, the enzyme immobilization
process is able to allow for an improvement in the stability of the enzyme (Milessi
et al. 2015). Lastly, both the advantages and disadvantages of immobilizing
enzymes as well as comparing this to microbial cells will be discussed.
In this chapter, various aspects of polymer gels applied to enzyme and cell
immobilization will be discussed. Initially, polymer gels used for biocatalyst
immobilization will be introduced, followed by a more detailed discussion on
enzyme immobilization. Afterwards, the results of cell entrapment in gels will be
reported.
network. Typically, entrapment techniques utilize any of several natural and syn-
thetic supports for efficient immobilization. The use of natural polymers such as
chitosan, chitin, alginate, and many others have been applied as important matrices
for immobilization (Table 1) (Hsuanyu 2004; Taylor et al. 2010; Zajkoska et al.
2013). Natural polymeric materials used in entrapment processes demonstrate
important characteristics, such as their ability to be gathered from many sources,
ease of modification, and lack of pollutants. Furthermore, they have a range of
functional groups and good biocompatible properties such as being non-toxic and
inert to organisms that are often necessary for applications in the pharmaceutical
and food industries (Zhang et al. 2013).
In other science sectors, synthetic polymeric matrices are also efficiently applied
for the immobilization of cells and enzymes. Synthetic polymers present several
advantages: good mechanical rigidity, high specific surface area, easy alteration of
their surface characteristics, and their potential for providing specific functional
groups that match the individual needs of each bioprocess. Other advantages offered
by synthetic polymers are that they can be synthesized in larger amounts more
easily than most natural polymers, and do not suffer batch-to-batch variations like
natural polymers (Zhang et al. 2013; De Vos et al. 2014). In general, polyvinyl
alcohol, polyacrylamide, and polyacrylonitrile are often the most suitable synthetic
matrices for gel immobilization (Table 1).
A wide variety of ionic hydrogels are used as supports for cell and enzyme
entrapment. Normally, ionic hydrogels used in immobilization are alginate, cellu-
lose, chitosan, chitin, pectin, and pectate. Ionic hydrogels contain ionizable groups
in their structures such as amino groups, carboxylates, sulfates, and hydroxyls that
possess varying degrees of affinity with water molecules. In addition, several
anionic polymers are also utilized with their own benefits and drawbacks.
Alginate is a natural anionic biomaterial formed by b-D-mannuronic acid and a-
L-glucuronic acid chains. The L-glucuronic acid content present in the alginate’s
structure has great importance on its mechanical rigidity and can influence the
stability of the gels in the presence of anti-gelling ions and calcium ion sequesters.
Structurally, alginates rich in glucuronic acid exhibit high porosity and low
shrinkage capacity during gel formation and do not swell when dried. In contrast,
alginates showing higher mannuronic acid levels make the gels softer and more
elastic (Thu et al. 1996). Alginate gels can be constructed by an ionic network in the
presence of cations such as Ca2+ or other multivalent counterions (Orive et al.
2006).
Cellulose is a natural, semi-crystalline polysaccharide that is very abundant on
earth, typically composed of 1,4-linked b-D-glucopyranosyl chains. Cellulose is a
very useful matrix for enzyme immobilization due to its low cost and commercial
availability both in fibrous and granular forms. However, this support is accom-
panied by some drawbacks, such as susceptibility to hydrolysis by microbial
enzymes (cellulases) and low particle size, which impairs their use in rapid
high-pressure applications (Hsuanyu 2004; Agbor et al. 2011).
Chitosan is a polymer obtained from deacetylated chitin chains, and is the
second most abundant support compound that can obtained from nature after cel-
lulose. It is a natural product, non-toxic, biocompatible, biodegradable, and inex-
pensive, making it very important, both economically and environmentally.
Chitosan is a polymer that has a molecular structure similar to cellulose, only
differing in a few specific functional groups. The main difference between these
biopolymers is the presence of amino groups (−NH2) in the chitosan structure.
Chitosan is recognized for its solubility in dilute acid media, forming a polymer
with cationic characteristics due to the protonation of the amino group, generating
an ammonium (−NH3+) ion, which gives special properties to this biomaterial
(Berger et al. 2004; Mendes et al. 2011).
Carrageenans are described as a family of linear, sulfated polysaccharides and are
isolated from certain species of red seaweed. These polysaccharides are inexpensive
and possess distinct, flexible helical structures that give them the capacity to form a
variety of distinct gels. The formation of carrageenan gels can be carried out either
by cooling or by interacting with an aqueous solution containing cations (i.e. K+,
2 An Overview on Polymer Gels Applied … 67
Cu2+, Fe3+, Mg2+, NH4+, Ca2+, and Mn2+), amine-containing compounds, and\or
water-miscible organic solvents (Van De Velde et al. 2002; Zajkoska et al. 2013).
Pectins are one of the main water-soluble structural polysaccharides present in
plant cell walls. Structurally, pectins are formed by biopolymers of 1,4-a-D-galac-
turonic acid partially linked by methyl esterification. The process of pectin gelation
is carried out by connection between the divalent cations and polygalacturonate
structure. The gelling reaction is depicted using the egg-box model where the
divalent cations form non-covalent interpolymer associations with clusters of two or
sometimes four adjacent polygalacturonate structures (Braccini and Pérez 2001;
Müller-Maatsch et al. 2016).
Gelatin consists of proteins and peptides derived from the partial hydrolysis of
collagen extracted from skin and bones. The proteins found in gelatin are applicable
in various sectors in the food industry due to their physical properties, such as a
melting point similar to physiological temperatures. The gelatin-based immobi-
lization process has already been developed for the immobilization of different cells
and enzymes. The gelation process of gelatin can occur reversibly with temperature;
however, when solutions are cooled to 30–35 °C, more efficient immobilization
occurs. However, some techniques have been described as achieving an irreversible
gelation process, for example, using cross-linking compounds (Tanriseven and
Doǧan 2002; Yang and Ou 2005; Górecka and Jastrzębska 2011).
Agar and agarose are polysaccharides used as entrapment supports for cells and
enzymes. Agar is an inert polymer composed of two principal components: agarose
and agaropectin. Agarose is a heteropolysaccharide with neutral properties that has
a strong ability for gelation. Agar and agarose are both advantageous in their price,
availability, acid tolerance, and low reactivity with other biomolecules (Duckworth
and Yaphe 1971). However, their use is limited by their low melting points
(Zajkoska et al. 2013).
Among synthetic gels, polyacrylamide was the first matrix used for cell immobi-
lization and is currently the most used matrix for enzyme entrapment. The poly-
acrylamide matrix has the advantage of being nonionic and the properties of
immobilized enzymes are only minimally altered when in its gel matrix. However,
the initiator of the polymerization process, dimethylaminopropionitrile, is highly
toxic and requires great care (Hsuanyu 2004).
An alternative is polyvinyl alcohol (PVA), a non-toxic thermoplastic polymer,
and is biodegradable, water-soluble, and biocompatible. Polyvinyl alcohol is
commercially obtained from polyvinyl acetate, in which the vinyl acetate is
68 G. P. Borin et al.
Polymer gels, whether natural or synthetic, can be used for entrapment by utilizing
the porous matrix of the gel. In this context, biocatalyst immobilization is rising as a
useful and robust technology to facilitate and improve many bioconversion pro-
cesses based on whole cells or enzymes. Among the many advantages of this
technology are the following: (i) increase of the robustness of the biocatalyst,
(ii) possibility of reuse, (iii) improvement of the product yield, and (iv) reduction or
even elimination of hazardous and toxic substances from the process (Zajkoska
et al. 2013; Kras et al. 2016).
According to IUPAC (1997), biocatalyst immobilization is the fixation of a cell
or its derivatives (e.g. organelles and proteins) into or onto a support to increase
their stability and prolong their use. In other words, the immobilized structure may
be inside or alongside a support depending on the desired purpose and type of
immobilization method applied. Likewise, the cells and their derivatives may be
retained by a membrane (Kras et al. 2016). In choosing the best method of
immobilization, four criteria must be considered: (1) the substrates that will be used
for biotransformation or production and the type of biocatalyst used (enzyme or
whole-cell); (2) the equipment to be used for the biocatalysis reaction; (3) the
downstream-process technology necessary for the purification of the product(s); and
(4) how to avoid the release of compounds toxic to humans or the environment
(Bianchini et al. 2015).
In this section, different studies on enzyme immobilization using various poly-
mer gels are discussed.
For a more efficient and feasible process, the immobilization conditions using
calcium alginate must be optimized. Alginate concentration is a very important
parameter, since higher concentrations of sodium alginate may result in a decrease
2 An Overview on Polymer Gels Applied … 69
of pore size which can limit the ability of compounds to reach the enzymes (Kumar
et al. 2009). Another important parameter is CaCl2 concentration, since high con-
centrations of this compound can modify the pH of the system and affect enzyme
activity (Rehman et al. 2014).
It is possible that some of an enzyme’s characteristics can suffer alterations after
immobilization in gels, such as an increase of the optimum temperature of its
reaction (likely due to physical limitations of enzymes within the interior of the
gel). This results in a higher activation energy needed for the substrate to easily
diffuse into the beads and bind to the biocatalyst (Kara et al. 2006). In addition,
thermal stability of a confined protein can be altered compared to the free form,
often likely due to the restriction in conformational changes allowed, directly
caused by the support matrix (Shah et al. 2008).
Abdulla and Ravindra (2013) described the immobilization of a microbial lipase
using glutaraldehyde and gel confinement into a hybrid matrix of equal amounts of
j-carrageenan and alginate. The immobilization of the lipase improved certain
properties of the enzyme, including its thermal stability and hydrolysis perfor-
mance. The immobilized enzyme showed an activity yield of 89.26%, and main-
tained 84.02% of its activity after being stored at 4 °C for 14 days. And
subsequently, after being run for 10 cycles, it was still possible to observe 75.54%
of enzymatic activity. As for the evaluation of the influence of immobilization on
the enzyme properties, both enzyme preparations were characterized, showing that
Vmax values remained approximately similar, while Km values changed consider-
ably between the free and immobilized lipase.
Awad et al. (2015) studied the immobilization of phytase from Penicillium
purpurogenum GE1 on grafted alginate/carrageenan beads. The authors observed
maximum loading capacity after 20 h at the enzyme: acetate buffer dilution ratio of
1:2. Some properties of the confined enzyme were different from those observed in
the free form. The optimal temperature and pH of the immobilized preparation were
greater than the soluble one. The immobilized biocatalyst was more stable in higher
temperatures (50 °C for 1 h) and acidic pH conditions (pH 4 for 45 min). In
addition, the immobilization allowed 100% activity retention when the enzyme was
incubated at 4 °C for 3 months, while the free form preparation completely lost
activity after 4 weeks when incubated at the same temperature. Regarding the
reusability of the immobilized enzyme, the gel beads containing the enzyme
maintained 100% activity for more than 12 repeated batch reutilizations.
The immobilization of a pectinase from Bacillus licheniformis KIBGE-IB21 into
calcium alginate has been studied by Rehman et al. (2014). These enzymes are
particularly important since they catalyze the hydrolysis of pectin and are indus-
trially applied such as in the clarification of fruit juices. The authors optimized the
concentration of calcium chloride and sodium alginate, 0.2 M and 3.0%, respec-
tively. The immobilized enzyme showed increased optimal reaction time for the
degradation of pectin, showing an increased optimal activity. In addition, the
entrapped enzyme showed increased thermal stability.
In another experiment, a commercial a-amylase (Diastase) was entrapped in
calcium alginate beads. The best conditions for immobilization were 4% (wt/v)
70 G. P. Borin et al.
sodium alginate, 1 M calcium chloride, and 2 h of curing time and as a result, 85%
of immobilization yield was obtained. Immobilized enzymes showed a higher Km
than the free enzyme, indicating that the substrate affinity of a-amylase was
decreased after immobilization (Lahiri 2015).
Non-natural polymers have also been studied for enzyme immobilization. These
matrices allow the obtention of particles with good mechanical and chemical sta-
bility and appear to be promising alternatives to natural polymers to overcome the
disadvantages of some polysaccharides (Lozinsky et al. 2003; Schlieker and Vorlop
2006).
A commercial invertase was immobilized in a system composed of polyacry-
lamide and gelatin (Emregul 2006). The authors observed that the Km values were
166 and 86 mM for immobilized and free enzymes, respectively. All immobilized
preparations were successfully utilized twenty times within 60 days approximately,
still showing good activity.
Fernandes et al. (2009) studied the immobilization of an inulinase with invertase
activity in particles composed of PVA. After immobilization, the enzyme showed a
broadened optimal pH towards lower values, as well as good mechanical stability of
the particles when the temperature was above 55 °C. The authors observed a
1.8-fold increase in Km, probably due to diffusion limitations. In addition, a 10%
decrease in the reaction yield was observed at a reaction temperature of 50 °C, after
20 repeated, consecutive batches.
72 G. P. Borin et al.
Some studies have been carried out to understand the physiological and mor-
phological changes that cells may undergo when they are immobilized (Omar et al.
1992; Niu et al. 2013). Due to various physical characteristics of supports, the
choice of polymer may also influence cell productivity, seemingly even differing
across microorganisms (Bisht et al. 2013; Chandorkar et al. 2014). Further building
upon that data, attempts to attain the optimal conditions for a particular product’s
production or bioconversion (Chen et al. 2012) as well as studies focusing on the
development of new polymer gels with different characteristics (Niu et al. 2013)
were also carried out.
period (Covizzi et al. 2007). In addition, immobilized cells can work in a higher
concentration than free cells, which increases fermentation speed and throughput,
guarantees the synthesis of the metabolites, and protects the living cells from
environmental stress factors that might arise from the process such as pH changes,
high concentrations of the end-products, or phenols and other toxic compounds
(Bisht et al. 2013; Martins et al. 2013; Vilela et al. 2013; Lin et al. 2015).
Still, the major advantage of cell immobilization, often cited in literature, is that
they are easily recovered and can be reused for many cycles, remaining nearly just
as effective as in the first use for a long period (Pradella 2001). Additionally,
continuous systems can be operated above the usual µmax (maximum specific
growth rate) observed for free cells. In this sense, Chandorkar et al. (2014) observed
that lipase production by A. niger entrapped in sodium alginate remained almost the
same after 4 cycles, whereas Bisht et al. (2013) described the maintenance of lipase
activity by Pseudomonas aeruginosa for 7 cycles in a bioreactor. In another study
(Duarte et al. 2013), S. cerevisiae cells were evaluated for ethanol production
through the fermentation of glucose and sucrose after immobilization using two
different substrates, calcium alginate and calcium alginate covered with chitosan. In
both cases, the immobilized cells could withstand 8 fermentation cycles of 10 h
each, with no observed contamination.
In contrast with the easier whole-cell recovery, enzyme immobilization is an
expensive technology due to the enzyme recovery and purification steps that are
required to obtain the desired products from the fermentation broth. Furthermore,
there may be losses during the enzyme purification process, as well as catalytic
activity reduction (Sührer et al. 2015). Conversely, some disadvantages of
whole-cell immobilization must be considered, namely: (1) it can generate unde-
sired byproducts and/or toxic metabolites which might damage the cell biocatalyst;
(2) possibility of cell leakage from the carrier; and (3) alteration in the physiology
and growth kinetics of the cells (Hattori and Furusaka 1959; Mattiasson and
Hahn-Hägerdal 1982; Robles-Medina et al. 2009; Martins et al. 2013; Sührer et al.
2015). Mattiasson and Hahn-Hägerdal (1982) discussed that many studies had
demonstrated that immobilized cells have alterations in metabolism in comparison
to the same free cells. According to these authors, while in some cases growth rates
might be reduced, specific metabolites can become highly produced, of which
industrial processes take advantage. They propose that the microenvironment of
entrapped cells might be responsible for such changes, more specifically due to a
decreased water activity and/or oxygen deficiency. Vilela et al. (2013) also discuss
that the interior of the polymer beads, having a limited access to the substrate, does
not promote cellular growth. The authors point to other studies that suggest it is the
microenvironment inside the gelatinous bead—and not the polymer itself—that
causes changes in the entrapped microbial cell physiology.
The advances in the understanding of the metabolism and physiology of
microorganisms and cells and the development of new matrices allowed the use of
cell immobilization for various applications, predominantly the production of
ethanol, biodiesel and alcohols, organic acids, antibiotics and enzymes; aroma
formation; the bioremediation of waste residues; and biosensors. Some of these
2 An Overview on Polymer Gels Applied … 75
practical applications are described below, concretely showing the vast potential of
this technology.
Biodiesel fuel (BDF) is composed of fatty acid alkyl esters or methyl esters
(MEs) derived from vegetable oil or animal fats and may be produced from any of three
different reactions: (i) pyrolysis (or cracking), (ii) microemulsion, or (iii) transesteri-
fication. The first two options are considered too expensive for industrialization and
yield low-quality biodiesel. The transesterification (i.e. acidolysis, alcoholysis, or
interesterification, depending on the acyl group acceptor) is the most common reaction
used to produce biodiesel (Robles-Medina et al. 2009). It consists of a reaction between
triglycerides (TAGs) from an oil or fat along with an alcyl-acceptor, such as alcohols
like methanol and ethanol. As products of this reaction, methyl esters (MEs or bio-
diesel) and glycerol (via alcoholysis) can be formed, as well as another triacylglycerol
(via interesterification) (Fig. 2) (Huang et al. 2012).
Transesterification can be catalyzed by acids such as sulfuric acid (H2SO4) or
phosphoric acid (H3PO4), bases such as potassium hydroxide (KOH) or sodium
hydroxide (NaOH), enzymatically, or through lipases attached to the surface of
immobilized cells or overexpressed in the intracellular environment (Fig. 2)
(Fukuda et al. 2008; Robles-Medina et al. 2009). An alkaline biocatalyst is the most
used process worldwide for transesterification catalysis, contributing to almost
100% of the biodiesel production process as of 2008 (Demirbas 2008;
Robles-Medina et al. 2009).
Fig. 2 Example of transesterification reactions (alcoholysis) and types of catalysts used for
biodiesel production
76 G. P. Borin et al.
Facing the need to discover another low-cost and more environmentally friendly
way to produce biodiesel than by an alkaline biocatalyst or enzymatic process, cell
immobilization recently appeared as an attractive substitute due its aforementioned
advantages. The first project with this type of technology aimed at BDF production
was described by Ban et al. (2001). In this work, the 1,3-specific fungal lipase
(ROL) of Rhizopus oryzae cells was immobilized within biomass support particles
(BSPs). They were then used for the catalysis of the transesterification reactions and
ME production. Interestingly, ME content reached 90% yield, the same percentage
obtained by extracellular lipases (Ban et al. 2001), and these results supported
further research regarding cell immobilization as a good alternative to produce
biodiesel.
Since then, many other studies have been conducted to discover the most
appropriate culture conditions and microorganisms for whole-cell immobilization
systems and to attain the same—or higher—levels of biodiesel production obtained
through the enzymatic process. Table 2 shows a small bibliographic survey with
some promising studies of biodiesel production.
Table 2 Whole-cell immobilization of microorganisms, culture conditions, and biodiesel yield
(ME %)
Microorganism Support Carbon Oil Alcohol ME** References
source (%)
R. oryzae BSP* Olive oil Soybean Methanol 90 Ban et al. (2001,
and oil 2002), Hama et al.
glucose (2007), Hama
et al. (2015)
R. oryzae BSP* Fatty Soybean Methanol 80 Hama et al. (2004)
acids oil
R. oryzae BSP* Olive oil Jatropha Different 89 Tamalampudi
or oil alcohols et al. (2008)
glucose
R. oryzae BSP* Soybean Soybean Methanol 70 Li et al. (2007a)
oil oil
R. oryzae BSP* Soybean Rapeseed Methanol 72 Li et al. (2007b)
oil oil
R. oryzae BSP* Soybean Oleic acid Methanol 90 Li et al. (2008)
oil
R. oryzae BSP* Olive oil Soybean Methanol 73 Chen and Lin
oil (2010)
R. oryzae Sodium Olive oil Jatropha Methanol 80.5 Ganesan et al.
alginate oil (2011)
A. niger BSP* Olive oil Palm oil Methanol 87 Xiao et al. (2010)
S. cerevisiae – Glucose Soybean Methanol 71 Matsumoto et al.
(intracellular oil (2001)
ROL)
S. cerevisiae – Glucose Soybean Methanol 78 Matsumoto et al.
(cell surface oil (2002)
ROL)
2 An Overview on Polymer Gels Applied … 77
Hama et al. (2007) studied the methanolysis of soybean oils for the production of
biodiesel using R. oryzae biomass immobilized in polyurethane foam. The repeated
methanolysis reaction was carried out in a 20-L air-lift bioreactor (also named
packed-bed reactor (PBR) system) for 20 batch cycles and a ME content of 65–80%
was reached and maintained during the entire process. In addition, when methanol
(four molar equivalents to oil) was added in the first cycle, 90% of the ME con-
version was achieved. The disadvantages observed in the PBR system, however,
included cellular exfoliation when the reaction flow rate was high (near 55 L/h) and
a decrease in the conversion rate at a flow of 5 L/h because of the inefficiency of the
mixture inside the reactor (Hama et al. 2007). One of the reasonable explanations
for exfoliation is the shear stress at high flow rates that damages the cells and causes
loss of lipase activity (Hama et al. 2007; Andrade 2012).
Ban et al. (2001; 2002) investigated the immobilization of R. oryzae, the effects
of pretreatments on the cell biomass, the effect of water on the transesterification
reaction, and also studied vegetable oils used for biodiesel production. The
researchers found that in the presence of 15% water, methanolysis increased up to
90%, a conversion rate similar to that reached with extracellular lipases. They used
a discontinuous mode process and after six cycles, the biocatalyst cells retained a
yield of 70-80% of ME.
Comparing the enzymatic transesterification of fungal lipases with cell immo-
bilization, the latter is still disadvantageous because it does not attain the high ME
mixture content and has a lower reaction rate than the former. However, the results
observed so far point to a hopeful future, where cell immobilization can be as
efficient as free enzymes, overcoming the current major bottlenecks and increasing
economic viability.
Immobilized cells are showing great potential for the production of enzymes,
particularly those of industrial interest. There are already a myriad of examples in
published literature. Siddiqui et al. (2016) used A. niger cells immobilized by
entrapment in calcium-alginate beads for the production of native cellulolytic
enzymes, achieving up to 0.37 IU/mL of enzymatic activity on glucose after 48 h
of incubation. In comparison, the same A. niger free cells took twice the time to
obtain enzymatic activity close to this value. Bacterial cells immobilized in calcium
alginate beads were also successfully employed by Darah et al. (2015) for poly-
galacturonase production. Entrapped Enterobacter aerogenes NBO2 cells produced
23.48 U/mL of the enzyme, while 18.54 U/mL were obtained using the free cells. In
these two studies, there is a clear observation that, given the appropriate opti-
mization, cell immobilization can significantly enhance enzyme production.
78 G. P. Borin et al.
bacteria is responsible for both reactions. However, the sludge needs additional
organic compounds, such as acetic acid, glucose, or methanol, because the organic
molecules existing in the wastewater are not sufficient for bacterial growth and
proliferation, the addition of which increases wastewater treatment costs. Hence,
there are some disadvantages in the conventional process that can be overcome by
bacterial cell immobilization (Kras et al. 2016).
One example of this is the LentiKats® technology developed, patented, and
improved in recent years by a group from the Czech Republic. The last update of
this technology initiative consisted of two tanks: the first one is filled with
immobilized bacteria of nitrifiers N. europaea and N. winogradskyi, while the
second has immobilized denitrifiers P. denitrificans and P. fluorescens. These
strains are immobilized on a porous hydrogel matrix made of polyvinyl alcohol
(PVA), being non-toxic and non-biodegradable. The manufacturer states that this
technology can treat waste residues containing 800 mg/L of N–NH4+ or 1000 mg/L
of N–NO3− with an efficiency of 98% (Cechovská et al. 2009; Bousková 2010).
Several different waste sources have been treated with LentiKats®, from industrial
wastewater to groundwater from uranium mining sites (Kras et al. 2016).
LentiKats® still remains an expensive investment for wastewater treatment, but it
can be used for other applications, like ethanol production, bioconversion of malic
to lactic acid present in apple juices, and even could potentially be used for xylitol
production from sugarcane bagasse (lignocellulosic residue, abundant in Brazil).
Thus, despite being costly, this technology may be a good long-term alternative for
various applications.
Another application for whole-cell immobilization is the bioremediation of
organophosphates (OPs). These neurotoxic compounds are found in pesticides and
insecticides and their removal or decomposition is currently done by chemical
treatment, incineration, or deposition in landfills. It is of paramount importance that
these OPs be detoxified and converted in new, non-harmful compounds in order to
not damage the environment and human health (Kim et al. 2014).
Organophosphorus hydrolases (OPHs) are enzymes produced by soil microorgan-
isms and are able to degrade the OPs. Many attempts have been made to improve
OP degradation efficiency by immobilizing these metalloenzymes in different
supports (Kim et al. 2014); however whole-cell immobilization has also attracted
attention because of its many advantages already cited, including higher enzyme
stability and lower cost.
Bacteria and yeasts have been used as OP degradation biocatalysts, such as
E. coli, Moraxella sp., Pseudomonas putida, Stenotrophomonas sp., and Y.
lipolytica. Their OPHs were attached on the cell surface through fusion systems
(like lipoproteinand outer membrane protein A, Lpp-OmpA system; protein InaV
from Pseudomonas syringae; GPI-based; or Flo1p-based) or were located inside the
periplasm. Different enzymatic activities were found against each class of OP
(paraoxon, parathion, diazinon, fenitrothion) and the whole-cell immobilization
stability lasted up to weeks (Kim et al. 2014).
Besides the ability to detoxify OPs, whole-cell immobilization also can be
applied to construct biosensors to detect different compounds such as heavy metals
80 G. P. Borin et al.
(Shing et al. 2013), pesticides (Anu Prathap et al. 2012), sugar (Kitova et al. 2010),
urea (Jha et al. 2009), lactate (Smutok et al. 2007), and even carry out quorum
sensing related to N-acylhomoserine lactones (Struss et al. 2010). Notably, a
cell-based system was developed by Grosh et al. (2008) to measure the levels of
cytokines in the sera of cancer patients. For this, a cellulose triacetate
(CTA) membrane of an ion-selective electrode was used to immobilize human
umbilical vein endothelial cells (HUVEC). The electrode was exposed to the serum
of healthy and cancer patients and after one hour, it was possible to note differences
between cytokine (b-FGF, HGF, TNF-a, etc.) levels of the two patient groups and
to correctly correlate the response of the biosensor with the stage of cancer (Ghosh
et al. 2008). Despite promising results, the hype created from the use of biosensors
for medical applications remains in the numerous research reports instead of
transitioning to the commercialization of practical biosensors. In addition to the
initial studies, it would be more than reasonable to expect the development of new
biosensor technologies (D’Orazio 2011).
As described in this chapter, polymer gels show tremendous potential for the
immobilization of industrially relevant enzymes, such as lipases, amylases, and
xylanases. In general, it can be expected that enzyme immobilization results in
increased enzyme stability, reaction efficiency, and reusability. All of these factors
are involved in the cost reduction of enzyme-related industrial processes. To
achieve the best results, the enzyme immobilization must be individually optimized,
using simple and low-cost supports and processes.
In addition, depending on the conditions and goal, whole-cell immobilization
appears to be an effective and less expensive strategy, while remaining just as
efficient as other methods. Different types of cells can be immobilized in several
matrices for biocatalytic reactions. Their applicability ranges from environmental
issues, like heavy metal and pesticide contamination of the soil, to more industrial
and clinical uses, like complex chemical production and biosensors for medical
tests.
Despite many efforts to better understand and optimize whole-cell immobiliza-
tion, including better understanding cell physiology and metabolism, selecting the
type of matrix, dealing with inhibitory compounds released during biocatalysis
steps, and optimizing cell growth conditions, a lot has yet to be done to best benefit
from this technology and promote more efficient applications in all fields. Genetic
improvement of microorganisms, development of new materials for support, and
perfecting growth conditions are just some of the details that deserve more attention
to translate the preliminary results into industrial reality.
2 An Overview on Polymer Gels Applied … 81
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Chapter 3
Hemicellulose-Based Hydrogels
and Their Potential Application
Abstract The hydrogels obtained from renewable resources have aroused great
interests because they are nontoxic, economical, biodegradable, and biocompatible.
Hemicellulose is the second most abundant polysaccharides after cellulose in lig-
nocellulosic biomass. In recent years, hemicellulose-based hydrogels as biomate-
rials have received ever-increasing attention and they have a wide range of the
promising applications in drug delivery and release, waste treatment, dye adsorp-
tion, and tissue engineering because of their peculiar physicochemical properties.
This paper described the structure of hemicellulose in plant and its
physical-chemical prosperities, and summarized the type of hemicellulose-based
hydrogels and their potential application, which provide useful information for the
utilization of hemicellulose polymers.
Keywords Hemicellulose Structure Physical-chemical prosperities
Hydrogels preparation Application
1 Introduction
2 Hemicellulose
Table 1 The main types of polysaccharides of hemicellulose (Buranov and Mazza 2010; Sun et al. 2004a, 2005)
Polysaccharide Biological units Amounta Units DPb
origin Backbone Side chains Linkages
Arabinogalactan Softwoods 5–35 b-D-Galp b-D-Galp b-(1 ! 6) 100–600
a-L-Araf a-(1 ! 3)
b-L-Arap b-(1 ! 3)
Xyloglucan Hardwoods, softwoods, and grasses 2–25 b-D-Glcp b-D-Xylp b-(1 ! 4)
b-D-Xylp b-D-Galp a-(1 ! 3)
a-L-Araf b-(1 ! 2)
a-L-Fucp a-(1 ! 2)
Acetyl a-(1 ! 6)
Galactoglucomannan Softwoods 10–25 b-D-Manp b-D-Galp a-(1 ! 6) 40–100
b-D-Glcp Acetyl
Glucomannan Hardwoods 2–5 b-D-Manp 40–70
b-D-Glcp
Glucuronoxylan Hardwoods 15–30 b-DXylp 4-OMe-a-D-GlcpA Acetyl a-(1 ! 2) 100–200
Arabinoglucuronoxylan Grasses 5–10 b-D-Xylp 4-OMe-a-D-GlcpA a-(1 ! 2) 50–185
And softwoods a-Laraf a-(1 ! 3)
Glucuronoarabinoxylans Grasses 0.15–30 b-D-Xylp a-LAraf a-(1 ! 2)
4-OMe-a-D-GlcpA a-(1 ! 3)
Acetyl
Homoxylans Algae 2–15 b-D-Xylpc b-(1 ! 3)
b-DXylpc Grasses b-D-Glcp b-(1 ! 4)
b-(1 ! 3, 1 ! 4)-glucan
a
%, dry biomass. bDegree of polymerization. cMay also present b-(1 ! 3) linkages on the backbone
W. Kong et al.
3 Hemicellulose-Based Hydrogels and Their Potential Application 91
Arabinoglucuronoxylan Softwoods
Arabinoxylan Gramineae
Others Homoxylan OH O
O HO
O O O
HO HO O
O
OH n>1 OH
W. Kong et al.
3 Hemicellulose-Based Hydrogels and Their Potential Application 93
products have caused wide public concern over the recent years (Ebringerová et al.
2005; Oliveira et al. 2010). More importantly, the biological activity is one of the
most important features of hemicellulose for the promising application in medicine
and biology fields. Some studies have reported that xylan-type hemicellulose has
unique physiological properties (inhibiting cell mutation) and some functions
(anti-inflammatory, detoxification and anticancer) (Oliveira et al. 2010).
Additionally, xylan-type hemicellulose is digested little in the stomach and intestine
of the body, but can be degraded by anaerobic bacteria in the colon (Ebringerová
and Heinze 2000; Sinha and Kumria 2001; Sinha et al. 2004; Yang et al. 2002).
Those striking features of xylan-type hemicellulose have greatly broadened the
application of xylan in medicinal materials and biological engineering.
There are large amounts of active hydroxyl groups on the main chain and side
chain of hemicellulose, which offers the chance of the chemical or enzymatic
modification. The chemical modification endows hemicellulose with specific
properties depending on the functional groups, the substitution pattern, and the
degree of substitution. There are many hemicellulose derivatives that have been
synthesized including carboxymethyl hemicellulose (Gulati et al. 2014; Peng et al.
2010a; Petzold et al. 2005), cationic hemicellulose (Kong et al. 2014; Petzold et al.
2005; Ren et al. 2008a, 2011, 2007b, 2006; Schwikal and Heinze 2007; Schwikal
et al. 2005), acetylated hemicellulose (Fang et al. 2000; Ren et al. 2007a), lau-
roylated hemicellulose (Ren et al. 2008b), oleoylated hemicellulose (Sun et al.
2004b), R-caprolactone-grafted hemicellulose (Zhang et al. 2014a, b), etc. Those
hemicellulose derivatives with different functional groups can be used to prepare
functional polymers (Petzold et al. 2006; Ren et al. 2007a, b 2008a, b; Schwikal
et al. 2005) and materials (Hansen and Plackett 2008; Hartman et al. 2006; Liu et al.
2001) to expand the application of hemicellulose. Among them, hemicellulose and
hemicellulose derivatives based hydrogels containing environmental
multi-responsive sensitivity to temperature, pH, salt, light, etc., have aroused broad
interests due to the special physical and chemical properties such as biodegrad-
ability and biocompatibility (Gao et al. 2015a; Bhattarai et al. 2010).
control group, which showed that the incorporation of xylan or GMAX in hydro-
gels could improve the biocompatibility of hydrogels. Hydrogels based on the
acetylated galactoglucomannan (AcGGM) were prepared and their properties in
drug release were studied (Voepel et al. 2009, 2010; Edlund and Albertsson 2008;
Liu et al. 2004; Roos et al. 2008). It was found that ACGGM-based hydrogels had
the great performance for the drug release. In addition, hemicellulose-based
hydrogels were also prepared as novel bioadsorbents for the removal of heavy metal
ions and dye from the wastewater. For example, xylan-type hemicellulose-based
hydrogel was synthesized by the graft copolymerization of acrylic acid (AA) and
xylan for adsorption of Cd2+, Pd2+ , and Zn2+ from aqueous solutions (Peng et al.
2012b). The maximum adsorption capacities of Cd2+, Pd2+, and Zn2+ were 495,
859, and 274 mg/g, respectively. The xylan/poly(acrylic acid) magnetic
nanocomposite hydrogel adsorbent was synthesized from wheat straw xylan and
Fe3O4 nanoparticles, and its adsorption property was studied on the methylene blue
removal and the maximum adsorption capacity was estimated to be 438.60 mg/g
(Sun et al. 2015c). Therefore, hemicellulose and hemicellulose derivatives based
hydrogels have a promising application in drug release, water absorption and
storage, metal ion absorption and dye absorption, etc. (Gabrielii and Gatenholm
1998; Xu et al. 2007). The preparation methods and the applications of hemicel-
lulose and hemicellulose derivatives based hydrogels will be described in detail in
the following sections.
N-alkyl acrylamide
N,N-alkyl acrylamide
(continued)
W. Kong et al.
Table 3 (continued)
Properties Structure Name
2-Diethylaminoethyl methacrylate
Vinylethylbenzene (DVB)
O
O O Ethyldiol methacrylate (EGDMA)
O
97
98 W. Kong et al.
Jens Voepel et al. (2010) designed AcGGM-based hydrogels and studied its
release properties of different model drugs (Voepel et al. 2010). The synthesis route
consists of the following three steps: (1) the carbonyldiimidazole activation of
primary hydroxylated vinylic molecules such as acrylates, vinyl alcohols, and vinyl
ethers (2) the covalent coupling of the alkenyl precursors to the polysaccharide
backbone hydroxyls (3) the radical cross-linking of pendant vinyl functionalities
affording a hydrophilic network (Fig. 6). The results showed that the properties of
hydrogels are affected by the different functionalization strategies.
100 W. Kong et al.
Over the past few decades, interpenetrating polymer networks (IPNs) showed high
potential in the biomedical fields applications, such as drug delivery. IPNs have
promoted the development of bioengineering tissues, such as cartilage scaffolds,
tissues, and bone substitutes greatly (Rokhade et al. 2007). IPNs comprise two or
more networks which cannot be separated unless chemical bonds are broken
because they are interlaced on a molecular scale but not covalently bonded to each
other. Semi-IPNs are different from IPNs due to the compositions linear or bran-
ched polymers can be separated from the compositions polymer networks without
the breakages of chemical bonds (Chikh et al. 2011). Semi-IPNs are considered as
popular sensitive polymers with great mechanical strength, various sensitivity, and
easy fabrication of devices (Zhao et al. 2006). Natural polysaccharide and its
derivatives, such as hemicellulose, chitosan, sodium alginate and cellulose, which
are biocompatible and biodegradable, could be used as linear macromolecule
forming half interpenetrating networks. Moreover, their functional groups could
respond to the environmental stimuli, and have been widely used in preparing
biomedical materials. The formation of semi- and full interpenetrating hydrogels is
shown Fig. 7.
Karaaslan et al. (2010, 2012) designed novel pH-responsive semi-IPN hydrogels
to utilize hemicellulose and chitosan, which were synthesized with glutaraldehyde
as the cross-linker. Swelling abilities have improved with the increase of hemi-
cellulose content and mainly consisted of H-bonded bound water. Covalent
cross-linkings rather than crystallites introduced through hemicellulose were the
main factor that would influence the mechanical stability of hydrogels. In addition,
konjac glucomannan-based (KGM) semi-IPNs hydrogels were synthesized by using
3 Hemicellulose-Based Hydrogels and Their Potential Application 101
poly (aspartic acid) and KGM using trisodium trimetaphosphate as the cross-linker
(Liu et al. 2010). These results indicated that these two semi-IPN hydrogels are
suitable to be used as the polymeric carrier for designated site-specific drug delivery
in the intestine. Zhang et al. (2012) prepared a pH-responsive semi-interpenetrating
polymer network (semi-IPN) hydrogels based on methylacrylic acid (MAA) and
Konjac glucomannan (KGM) reacted with different concentrations of initiator
potassium persulfate (KPS) in the presence of N,N-methylene-bis-acrylamide
(MBA) as the cross-linker through free radical polymerization. Moreover, a novel
semi-IPNs were prepared by copolymerizing konjac glucomannan (KGM) and poly
(ethylene glycol diacrylate) (PEGDA) with poly (N-vinyl pyrrolidinone) (PNVP)
using 2-hydroxy-2-methyl-propiophenone (HMPP) as an initiator under UV curing
(Fig. 8). And the study indicated that the KGM hydrogel could benefit wound
healing (Shahbuddin et al. 2014).
Fig. 8 Schematic representation of the formation of (i) cross-linking with liner KGM initiated by
Ce (iv), (ii) semi-IPN of P(NVP-co-PEGDA) initiated by HMPP with uncrosslinked KGM and
(iii) grafted conetwork of KGM and P (NVP-co-PEGDA) by Ce (iv) and HMPP (Shahbuddin et al.
2014)
type hydrogel is synthesized due to the polyelectrolyte polyvalent ionic bonds with
opposite charges and timeliness (Fig. 10). But with opposite charges of two kinds
of polyelectrolyte interaction to form the physical cross-linking system are called
electrolysis compounds (Fig. 10).
For cross-linking hydrogels, entanglement among molecules, hydrophobic
interaction between molecules and ionic bond areas could facilitate the formation of
cluster structure, thus causing an irregular structure in hydrogels (Kweon and Noh
2001). Meanwhile, free chain end and link can also lead to instantaneous network
defects. The ionic cross-linking with polyvalent counter ion is a simple way to form
physical cross-linking hydrogels. However, such ions could exchange with soluble
ions in body fluids, inevitably, resulting in loss of performance compared with the
3 Hemicellulose-Based Hydrogels and Their Potential Application 103
removed, the pores were retained with the increasing of temperature. This indicated
that these hydrogels had a large number of hydroxyl bonds and that hydrogen-bonded
network structures still kept a highly stable state at low temperatures.
CH3
H H
( C C ) ( H2C C C C )
H2 ( C C ) H2
C O H2 C O C O
C O
NH NH O
N
CH CH CH2CH2CH2CH3
CH2CH3 CH2CH3
H3C CH3 H 3C CH3
Table 5 Groups used for prepare pH-sensitive hydrogels (Peng et al. 2011)
Anionic groups −COO−
−OPO3−
Cationic groups −NH3+
−NRH2+
−NR2H+
−NR3+
106 W. Kong et al.
The swelling and shrinkage of pH-sensitive hydrogels are closely associated with
the value of pH (Falamarzian and Varshosaz 1998; Gao et al. 2015a). Generally
speaking, the networks of pH-responsive hydrogels containing a lot of acidic and
alkaline groups such as carboxyl, sulfonic groups, and amino tend to decomposed
or protonated (Zhao et al. 2006). Dissociation of these groups is easily affected by
the pH value of the environment, which could damage the inner related hydrogen
bonds of hydrogels, with the decrease of cross-linkings, resulting in a swelling of
hydrogels. This kind of polymer with large amounts of ionization group is called
the polyelectrolyte. Ionic strength, pH value, and the type of the counter ion could
affect the swelling behavior of polyelectrolyte hydrogels due to the electrostatic
repulsion like charges (Zhao et al. 2014a). The stimulus–response behaviors indi-
cated that the hydrogel could be easily controlled by changing solvent pH and
solvent type. The responsiveness of polyelectrolyte gel can be adjusted by
copolymerization with neutralization monomer. Moreover, the introduction of
2-hydroxyethyl methyl methacrylate, methyl methacrylate (MMA) and maleic
3 Hemicellulose-Based Hydrogels and Their Potential Application 107
anhydride can change the hydrophilicity of polymer (Sun et al. 2013), which can be
used to adjust the responsiveness of hydrogels.
Sun et al. (2013) designed a novel pH-sensitive and biodegradable
hemicellulose-based hydrogel which was prepared by grafting AAc into hemicel-
lulose. The swelling ratio data showed apparent transitions at physiological pH.
Fig. 17 The synthesis mechanism for xylan/PAAC semi-IPN magnetic hydrogel (Sun et al.
2015b)
have been alternative absorbent materials for water pretreatment as well as other
chemical adsorbents (Ayoub et al. 2013; Peng et al. 2012b; Sun et al. 2015a; Zhang
et al. 2014a). Recent years, hemicellulse possessing the unique physiological
properties have been widely reported and extensively studied among the fields of
medical science (Barbat et al. 2008; Noaman et al. 2008; Oliveira et al. 2010),
including histological scaffolds for tissue engineering, biosensors, immunization
barriers for the cells encapsulation, and controlled drug delivery systems owing to
their special properties (Dai et al. 2015; Gao et al. 2015a; Lee and Mooney 2001;
Lin and Metters 2006; Qiu and Park, 2012; Sefton et al. 2000). Moreover, hemi-
cellulose with a number of charged groups has attracted great attention to be
conductive materials for application in biosensors, electronic devices, and tissue
engineering fields (Guimard et al. 2007; Guo et al. 2013; Zhao et al. 2014c).
Nowadays, the increasing environmental issues have aroused global concern. One
of most serious problems is water pollution by heavy metal ions derived from
industrial wastes, mainly textile factories and metal workshops (Peng et al. 2012b).
The heavy metal ions, such as cadmium, plumbum, zinc, nickel, and chromium,
have brought serious threat to the human beings, living life organisms, and eco-
logical resources worldwide, causing various heavy diseases and damage of natural
environment (Ayoub et al. 2013; O’Connell et al. 2008; Wan Ngah and Hanafiah
2008). Different from organic wastes, heavy metals ions were difficult to remove
and could be accumulated in the environment and living body. Furthermore, heavy
metal ions exhibit toxic impact even at very low dosages. Recently, biodegradable
hydrogels as adsorbent materials for removing heavy ions have been paid extensive
attention instead of conventional methods from aqueous solutions including
chemical precipitation, ion exchanges, chemical oxidation/reduction, electrodialy-
sis, reverse osmosis, and ultrafiltration because hydrogels with a three-dimensional
polymer network as adsorbents which have big porous structure, multifunctional
groups, and high internal specific surface area (Zheng and Wang 2009).
Biodegradable polysaccharides based hydrogels have apparent advantages, such as
higher efficiency, high hydrophilicity, lower costs, minimization of chemical or
biological sludge, flexibility, simplicity of design, good reusability, and good
biodegradability (Ahluwalia and Goyal 2005; Crini and Badot 2008; Li and Bai
2006). The swelling abilities of polysaccharides-based hydrogels in water and their
solutes adsorption could be controlled by their cross-linking density and chemical
compositions (Ferrari et al. 2014).
Hemicellulose is a suitable resource to prepare bioadsorbents for removing metal
ions and has been attracted important attention (Ayoub et al. 2013; Dax et al. 2014;
Peng et al. 2012b; Sun et al. 2015a; Zhong et al. 2013). Peng et al. (2012b) prepared
xylan-rich hemicellulose-based hydrogels as bioadsorbent by grafting copolymer-
ization of AA and hemicellulose for the application of heavy metal ions (Pd2+,
3 Hemicellulose-Based Hydrogels and Their Potential Application 113
Cd2+, and Zn2+) adsorption from aqueous solutions. AA was the most common
hydrophilic monomer in adsorbent hydrogels because it is the simplest unsaturated
carboxylic acid and has pH sensitivity. The adsorption kinetics study demonstrated
that the optimum adsorption values of Pd2+, Zn2+, and Cd2+ were 859, 274, and
495 mg/g, respectively. More importantly, xylan-rich hemicellulose-grafting-AA
hydrogels also showed highly efficient reusability and metal ion recovery efficiency.
After plenty of repeated adsorption/desorption cycles, there were no noticeable loss
of adsorption capacity emerging. Similarly, but to a less extent, a hydrogel for
adsorbing Cu2+ and Ni2+ was prepared by cross-linking of arabinoxylan and AA
(Zhong et al. 2013). Table 6 shows the comparison of adsorption values of metal
ions (Pb2+, Cd2+, Zn2+, Cu2+) of different adsorbents. Hemicellulose-based
hydrogels had the excellent adsorption capacities.
Superabsorbent hydrogels based on xylan and inorganic clay montmorillonite
(MMT) were prepared by Zhang et al. (2014a). The hydrogels had very high
swelling ratio due to the addition of hydrophilic AA and
2-acrylamido-2-methylpropanesulfonic acid (AMPS) as well as MMT with good
absorption property. Furthermore, the increment of MMT content could increase the
compression strength of hydrogels. The swelling ratio of the porous xylan-based
hydrogels in the cationic salt solutions (LiCl, CaCl2, and FeCl3) followed the order:
Li+ > Ca2+ > Fe3+. Poly(amidoamine)/hemicellulose-based hydrogels were pre-
pared from O-acetylated galactoglucomannan-rich plant and displayed a remarkable
adsorption capacities for Cu2+, Cd2+, Pb2+, Zn2+, Ni2+, Co2+, and CrO42− (Ferrari
et al. 2014). In their study, two different polyacrylamide-based oligomers were
synthesized and polysaccharide networks were formed by chemically radical
grafting copolymerization. Generally, the order of adsorption affinity toward Me2+
was Cu2+ > Co2+ > Zn2+ Ni2+ > Pb2+ > Cd2+. All obtained hydrogels were had
great potential as adsorbent materials. Dax et al. (2014) investigated GMA-modified
O-acetyl galactoglucomannan-based hydrogels and their application for removing
arsenic and chromium ions. The results revealed that hydrogels had a high surface
area and were evaluated to have a great capacity to remove arsenic and chromate
ions at different pH aqueous solutions. To separate the adsorbent simply and
quickly from the solution system, additives such as Fe3O4 nanoparticles were
introduced and separated by an external magnetic field (Sun et al. 2015c). The
xylan/poly(acrylic acid) magnetic (Fe3O4 nanoparticles) nanocomposite hydrogel
adsorbent for methylene blue removal from aqueous medium was prepared from
wheat straw xylan by Sun et al. (2015c). Results showed that the optimal condition
for methylene blue adsorption was at pH 8, adsorbent dosage was 3 g/L and a
beginning concentration was 400 mg/L, and the final removal rate reached more
than 90%. The addition of Fe3O4 nanoparticles could enhance the cyclic utilization
of the xylan-based adsorbent. The adsorption isotherm of methylene blue was
consistent with the Langmuir model. The hemicellulose-based adsorbent hydrogel
materials will provide potential choice for water pretreatment and heavy metal
removal.
The major challenges in developing medical materials (e.g., drug delivery carriers,
human tissues scaffold) were found to require suitable biomaterials and convenient
preparation methods that would ensure excellent durability, nontoxicity, and bio-
compatibility (Reis et al. 2006). There is increasing interest in cooperating
multi-sensitive monomers with natural polysaccharides as hydrogel materials for
medical application. So many relevant researches on biopolymers (e.g., chitosan,
cellulose, dextran, starch, and pullulan) based hydrogels have been reported in the
past decades (Bhattarai et al. 2010; Bostan et al. 2013; Fundueanu et al. 2008; Gao
et al. 2015b; Hebeish et al. 2014; Li et al. 2012; Wang and Chen 2016; Zhang et al.
2004). However, hemicellulose-based intelligent hydrogels including temperature,
pH, salt, light-sensitive hydrogel materials showed excellent application prospects
in biomedical fields because xylan had unique physiological characteristics such as
biocompatibility, anticancer effect and inhibiting growth rate of tumors, etc. (Barbat
et al. 2008; Oliveira et al. 2010; Whistler et al. 1976). These unique and competitive
advantages aroused broad interest among researchers in studying hemicellulose-
based hydrogels which could be applied in the fields of drug-controlled delivery,
immunity of the human body, and tissue engineering.
Xylan isolated from corn cobs was proved to be an appropriate additive in the
pharmaceutical and immune fields (Hromadkova et al. 1999; Oliveira et al. 2010).
Moreover, hemicellulose is proved to be stable in the human stomach and intestine
(Oliveira et al. 2010). Therefore, hemicellulose and hemicellulose derivatives based
hydrogels had promising application as sustained controlled release carriers in the
3 Hemicellulose-Based Hydrogels and Their Potential Application 115
human digestive system (Ebringerová et al. 2002). Moreover, compared with other
polysaccharides such as cellulose, starch, and chitosan, hemicellulose has relatively
high solubility due to their low molecular weight and high substitution degree of
side chain (Chimphango et al. 2012). Hence, hemicellulose could be easily dis-
solved in common solvents such as alkaline solution, DMF/LiCl, dimethyl sul-
foxide (DMSO), and ionic liquid, which provide more chance for modification of
hemicellulose with active hydroxyl groups (Peng et al. 2012b). Hemicellulose
derivatives were also investigated to increase the reactivity of preparing hydrogels
and overcome the shortcomings of hemicellulose, such as brittleness and relatively
poor forming ability (Gabrielii et al. 2000; Gao et al. 2015a). Peng et al. (2012a)
introduced methacryloyl groups (from GMA) onto hemicellulose by the transes-
terification reaction in the DMSO medium. Cao et al. (2014) prepared photosen-
sitive hydrogels by the radical copolymerization of GMA-modified hemicellulose
using 4-[(4-acryloyloxyphenyl)azo] benzoic acid (AOPAB), the resulting hydrogels
showed multi-sensitive behaviors to pH, water/ethanol solutions and light. Vitamin
B12 (VB12) was chosen as drug model to determine its in vitro release performance
under UV irradiation at 37 °C. The maximum cumulative release rates of the
hydrogel in pH 2.2 and 7.4 solutions were 78.2 and 89.3%, respectively. Besides,
the cumulative VB12 release of hemicellulose-based hydrogels under UV irradiation
was higher than that without UV irradiation, which had a potential application in
the light on-off drug delivery field. Temperature-sensitive hemicellulose-based
hydrogels were prepared by grafting maleic anhydride (MA) to hemicellulose and
then photocrosslinking with NIPAm in LiCl/DMF solvent to prepare the hydrogels
(Yang et al. 2011). Maleic anhydride modified hemicellulose (Hce-MA) based
hydrogels had well-defined honeycomb-like structure and temperature sensitivity.
The LCST of hydrogels ranged approximately between 28 and 32 °C and increased
with the increasing Hce-MA content due to the hydrophilicity of Hce-MA. The
induced temperature-sensitive properties were induced by the balance of
hydrophilic/hydrophobic in the hydrogels system induced sensitive hydrogels (Pan
and Sano 2005). The Hce-MA-based hydrogels could be as drug controlled carriers
in the further studies. The attributes of the raw materials and preparation methods
are the main influence factors of the functionalities of hydrogels for using as
encapsulation matrix. Hydrogels applied for controlled release delivery systems had
the demandings of protecting the functionalities of the encapsulated agents
(Coviello et al. 2007). Xylans are considered to possess excellent gelation for
preparing hydrogels which could be used as coating materials for controlled release
of bioactive agents (Chimphango et al. 2012). The oat spelt xylan hydrogels were
prepared by recombinant-L-arabinofuranosidase (AbfB). The horseradish peroxi-
dase (HRP) as bioactive agent was encapsulated in situ and was released actively
for a period of 180 min. It was noticeable that the drug delivery behaviors of HRP
were based on the sequence of addition during the preparation of hydrogels. The
results revealed modification of xylan-based hydrogels as biodegradable encapsu-
lation matrices were suitable for encapsulating bioactive agents to reach slow or
targeted release. AcGGM-based hydrogels were prepared using APS and Na2S2O5
by radical polymerization (Voepel et al. 2009). The drug release behaviors of
116 W. Kong et al.
Fig. 18 Drug release performance of acetylsalicylic acid and theophylline loaded hydrogels as
functions of pH at 37 °C (Sun et al. 2013)
3 Hemicellulose-Based Hydrogels and Their Potential Application 117
80
Cell viability (%)
60
40
20
0
Ctrl 24h 72h
118 W. Kong et al.
(Kuzmenko et al. 2014). Tyramine (TA) side groups were cross-linked with xylan
chains. Xylan-TA conjugate was formed using horseradish peroxidase (HRP) and
H2O2. The results showed that a 3D hydrogel network was formed in about 20 s at
room temperature, which is the best result achieved for any hemicellulose-based
hydrogel so far. The hydrogels had excellent swelling properties and maintained
mechanical integrity for more than 2 months. Mesenchymal stem cells were able to
differentiate into adipocytes inside the hydrogels. It was concluded that xylan had a
promising precursor for in situ forming hydrogels and could be assessed further for
tissue engineering.
diodes, and biomedical devices (Guarino et al. 2013; Heeger 2001). Furthermore,
the CPs-based materials can improve the biodegradability and biocompatibility of
products, especially in biomedical fields like scaffold. The CPs can also facilitate to
increase the solubility in most solvents (Wang et al. 1996).
Electrically conductive O-acetylgalactoglucomannan based hydrogels and con-
ductive aniline tetramer were prepared using a robust pathway by Zhao et al.
(2014a). Combining electrically conductive aniline tetramer with degradable,
hydrophilic, and nontoxic hemicellulose is a potential choice to surmount the
deficiencies of conventional high molecular weight conductive polymers, such as
poor polymerization and solubility, the absence of reaction sites, and low
hydrophilicity (Guimard et al. 2007; Guo et al. 2013). When the aniline tetramer
content increased from 10 to 40% (w/w), the swelling ratio (SR) decreased from
548 to 228% while simultaneously conductivities of hydrogels changed from
2.93 10−8 to 1.12 10−6 S/cm. The conductivities of the hydrogels increased
with increasing aniline tetramer content. Thus, adjusting the amount of aniline
tetramer could change the conductivities of hydrogels, which could be applied in
biosensor field. Subsequently, Zhao et al. (2014b) synthesized conductive
hemicellulose-based hydrogels by one-step reaction. These hydrogels were pre-
pared by reacting O-acetyl-galactoglucomannan with epichlorohydrin in the exis-
tence of aniline pentamer via a facile and green approach in water. The results
showed the thermostability of hydrogels was increased due to aniline pentamer.
Besides, equilibrium swelling ratios (SReq) of hydrogels varied from 13.7 to 11.4
and could be controlled by cross-linker concentration. The SReq decreased from 9.6
to 6.0 by changing the aniline tetramer content from 10 to 40% (w/w). While
conductivity of hemicellulose-based hydrogels changed from 9.05 10−9 to
1.58 10−6 S/cm which increased by three orders of magnitude. The excellent
swelling and conductive properties impart hydrogels with broaden application
prospects. Hemicellulose-based hydrogels with controllable swelling behavior and
conductivity show promising application in biomedical aspects, especially in
biosensors, electronic equipments, and histological engineering fields.
5 Conclusion
Acknowledgements This work was supported by grants from National Natural Science
Foundation of China (No. 21406080).
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Chapter 4
Updates on Stimuli-Responsive
Polymers: Synthesis Approaches
and Features
Recently, an important evolution has been made in the field of hydrogels and their
applications as biomaterials (Thakur and Thakur 2014a, b, 2015). The use of
hydrogels in biomedical applications was limited due to both the toxicity and the
physiological impacts of crosslinkers used during hydrogel formation. Biomaterials
designing and synthesis require merging of the well knowledge of both polymer
chemistry and biological processes (Trache et al. 2017; Corobea et al. 2016; Voicu
et al. 2016; Miculescu et al. 2016). Hydrogel materials can be synthesized using
various polymers either naturally derived or synthetic ones, where polymer chains
are held together using different physical or chemical crosslinking agents. The
developed hydrogel matrices have high capacity to carry pharmaceutical agents in
their architecture and thus they are considered to be good candidates for the syn-
thesis of biomaterials for controlled drug release and tissue regeneration applica-
tions. Although hydrogel matrices have many advantages, they still possess several
limitations to be converted into clinical products. In this section, a historical
overview of development of more sophisticated smart hydrogels using simple
polymeric networks will be highlighted.
Hydrogels are three-dimensional polymer networks capable of retaining a sig-
nificant amount of water in their swollen state due to the presence of many
hydrophilic functional moieties within their structures such as –OH, –CONH−,
–CONH2, –COOH, and –SO3H. Hydrogels could be classified into three categories
according to the nature of the building polymers: (a) natural, (b) synthetic, or
(c) hybrid of both (Peppas and Khare 1993). Hydrogels can be crosslinked through
(a) chemical covalent bonds, (b) physical non-covalent interactions, or (c) a com-
bination of both interactions. The balance between forces within the hydrogel
structure arises from water sorption including capillary property, osmotic forces or
hydration, and the forces exerted by the crosslinked polymer chains retaining
polymer matrix and resisting its expansion (Roorda et al. 1986).
In 1960s, Wichterle and Lim successfully applied hydrogels as contact lenses
(Wichterle and Lim 1960). Later on, hydrogels have been commonly used as
controlled drug delivery systems to enable both localized and sustained releases of
drugs. In 1984, the Journal of Controlled Release has been launched to play a
fundamental role in publishing the state-of-the-art of research work and review
articles focusing on drug delivery using hydrogel matrices.
In this section, a presentation of the major progress in hydrogel research over the
last 50 years, starting from relatively simple and chemically crosslinked networks
in the 1960s to today’s smart hydrogel matrices, would be described in details as
illustrated in Fig. 1.
4 Updates on Stimuli-Responsive Polymers: Synthesis Approaches … 131
In 1894, hydrogel as term was first used in literature to describe crosslinked net-
works made of swellable polymeric chains (VanBemmelen 1894). Afterward, in
1960, a landmark paper about the fabrication of soft contact lenses using poly
(2-hydroxyethyl methacrylate) pHEMA hydrogels was the first to report hydrogels
as water-swollen crosslinked macromolecular networks (Wichterle and Lim 1960).
Following that discovery, many scientific literature articles were reported focusing
on the preparation of relatively simple and chemically crosslinked synthetic poly-
mers networks to be used as hydrogels in ophthalmic and drug delivery applications.
The two main strategies used for hydrogels preparation are either polymerization of
monomers in the presence of a crosslinking agent or direct crosslinking of already
abundant hydrophilic polymers. The famous first-generation hydrogels were
pHEMA, poly(vinyl alcohol) (PVA), and poly(ethylene glycol) (PEG).
Katchalsky research in the period between 1950s and 1960s opened a new era of the
concept of transforming chemical energy into mechanical response (Kuhn et al.
132 I. M. El-Sherbiny et al.
1950; Steinberg et al. 1966). Starting the 1970s, the simple networks of hydrogels
shifted to new materials with the capability to respond to external environmental
conditions such as pH, temperature, etc. (Kopecek 2009). The external environ-
mental stimuli can be used to induce specific response like gel formation or con-
trolled drug release.
Temperature-sensitive hydrogels are the most famous environmentally respon-
sive hydrogels. The significant features that create the crosslinkages are hydrogen
bonding, physical entanglements, and hydrophobic interactions. In situ formation of
hydrogels (Sol–Gels) is an important example of formation of the
temperature-sensitive hydrogels. Simply, the sol–gels are polymer solutions con-
verting from solutions to gels after injection in specific tissues or organs
(Ruel-Gariépy and Leroux 2004; Ward and Georgiou 2011). The main advantage of
the in situ formation of hydrogels is that it does not need any surgical procedures to
be applied. Biological components can be simply incorporated within the polymeric
network and then flow easily in the body leading to proper shape fitting to the
surrounding tissue. The most extensively investigated hydrogels in this generation
are poly(ethylene glycol)-polyester block copolymers, poly(N-isopropylacrylamide)
(pNIPAAm), and polyN-(2-hydroxypropylacrylamide) (PHPMAm).
The second most used type of the in situ formed hydrogels is the pH-sensitive
one. It has the advantages of responding to various pH values in the different parts of
the human body. It contains either acidic or basic functional groups that can be
ionized at low or high pH, respectively (Gupta et al. 2002; Qiu and Park 2012). Last
member of second-generation hydrogels is biomolecule-sensitive hydrogel that
could respond to different concentrations of biomolecules like hormones, glucose,
etc. (Miyata et al. 2002). All of the second-generation sensitive hydrogels are mainly
utilized for the synthesis of controlled delivery systems for drugs and therapeutics.
In the 1990s, other physical interactions were used as crosslinkers that led to the
improvement of degradation, thermal, and mechanical properties of hydrogels.
These interactions used for the in situ hydrogel formation. The third-generation
hydrogels include stereocomplexation, inclusion complex formation, metal–ligand
coordination, and peptide interactions as crosslinking methods for the preparation
of hydrogels.
Stereocomplexed hydrogel is a stereoselective interaction between two com-
plementary stereoregular polymer chains, which interlock and form a new com-
posite demonstrating altered physical property in comparison with the constituting
polymers (Slager and Domb 2003). In 1953, Pauling and Corey reported the first
example of stereocomplexation between polypeptide chains (Pauling and Corey
1953). In 1987, Ikada et al. studied stereocomplexation between enantiomeric
polylactide chains (Ikada et al. 1987). Since 2000, stereocomplexation between
enantiomeric PLLA and PDLA blocks in amphiphilic copolymers has been applied
4 Updates on Stimuli-Responsive Polymers: Synthesis Approaches … 133
for injectable hydrogels (De Jong et al. 1998; Fukushima and Kimura 2006; Tsuji
2005). Several examples of stereocomplexed hydrogels were prepared from
pluronics (Chung et al. 2008), oligolactide-functionalized pHEMA (Lim et al.
2000), and 2-methacryloyloxyethyl phosphorylcholine (Takami et al. 2011) poly-
mers. On 2012, Bertin summarized recent publications that focused on stereo-
complex polymers in biomedical applications (Bertin 2012).
Cyclodextrins (CDs), cyclic oligosaccharides containing a hydrophobic cavity
that can host a variety of molecules, are good examples for physically crosslinked
hydrogels. In 1994, Li et al. reported the first hierarchical self-assembly process to
create a physically crosslinked CDs hydrogel (Li et al. 1994). The low stability and
long gelation times were the main disadvantages of these formed systems, where
PEG was used as the guest (loaded) molecule. An improved version of physically
crosslinked CDs hydrogels was obtained when their aqueous solutions were mixed
with amphiphilic block copolymers like pluronics (Li et al. 2003), reverse pluronics
(PPO–PEO–PPO) (Kuo and Lai 2011), and polycaprolactone (PCL)-based block
copolymer, PCL–PEG–PCL (Zhao et al. 2006). Also, CDs hydrogels were prepared
with PEG-dextran (Huh et al. 2001), PEG-chitosan (Huh et al. 2004), and
PEG-heparin (Ma et al. 2010).
In the last decade, various chemically crosslinked hydrogels have been synthesized
through different organic synthesis techniques. The fourth-generation hydrogels
were also called smart hydrogels due to their capability to enhance loaded drugs
bioactivity through tailoring hydrogels properties like mechanical stability or
control the release of the loaded drugs. These customized characteristics were
accomplished via covalent or ionic crosslinking between polymer chains possessing
complementary functional groups in order to form double-network hydrogels.
Fig. 4 Schematic illustration of the interpenetrating polymeric network (IPN) and semi-IPN
formation; a IPN preparation pathway from monomers; b IPN preparation pathway from polymers
(Matricardi et al. 2013)
136 I. M. El-Sherbiny et al.
Synthetic polymers are combined with natural polymers to obtain hydrogels with
enhanced mechanical properties (Langer and Tirrell 2004; Sionkowska 2011).
Many natural polymers are used in the synthesis of hydrogels such as agarose,
alginate, cellulose, gelatin, chitosan, collagen, fibrin, hyaluronic acid, lignin, soya
bean, and matrigel (Fig. 5) (Hoffman 2012; Lee and Mooney 2001). The
non-chemically crosslinked hydrogels of these polymers showed enhanced cell
adhesion and improved mechanical properties (Cascone et al. 1995; Coombes et al.
2002; Santin et al. 1996). Recently, hybrid hydrogels formed of natural and syn-
thetic polymers have been designed through covalent crosslinking of the functional
groups abundant in both polymers (Censi et al. 2010). In situ crosslinked hydrogels
were synthesized using PNIPAAm-based polymers and natural carbohydrate
polymers such as methylcellulose, carboxymethyl cellulose (CMC), hyaluronic
acid, and dextran (Patenaude and Hoare 2012). Furthermore, many examples of
hybrid hydrogels were successfully prepared through a combination of
gelatin-methacrylamide, gelatin-PEG (Daniele et al. 2014), fibrin-polyurethane
(Huang et al. 2013), and chitosan-PEG (Tan et al. 2013).
other side has been explored and used for bioseparation and tissue regeneration (de
las Heras Alarcón et al. 2005; Ionov et al. 2009; Lutolf et al. 2003). Second, the
possibility of controlling functional moieties at the film surfaces has been explored
for regulating signals and associated biomolecule activity modulation in bioengi-
neering (Ebara et al. 2004; Hayashi et al. 2007). Third, surface-grafted
stimuli-responsive polymers provide an opportunity for controlling molecules
permeation through cellular membranes (Lue et al. 2008), interaction of biomole-
cules with film responsive surfaces (Motornov et al. 2009) in bioseparation (Wong
et al. 2009), or controlling drug permeation by nano/microporous membranes (Lue
et al. 2008).
pH-responsive
Physiological Redox
Enzyme
SƟmuli-
responsive Thermal
polymers
Light
External Electrical
MagneƟc
Mechnaical
the protonation of polymer ionizable groups (Gu et al. 2013; Lee et al. 2005), while
the second strategy is to integrate acid-cleavable bonds in polymer chains (Bae and
Kataoka 2009; Bae et al. 2003).
One of the important targets for certain applications such as drug delivery is the
abundance of certain enzymes with certain concretions as they play a vital role in
biochemical processes within the human body cells (la Rica et al. 2012). Polymers
can be designed in such a way to release certain cargoes in response to specific
enzymatic levels in target tissue. Enzyme-based carriers are able to program
delivery of sensitive bioactive materials such as proteins with both high sensitivity
and selectivity to target sites (Guo et al. 2012). In the past few years, significant
numbers of articles have been published in the field of enzyme-responsive protein
delivery systems (Guo et al. 2012).
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Chapter 5
Polysaccharide-Based Polymer Gels
Abstract Hydrogels are special polymer systems with unique properties due to
their high water content. They hold a relative large importance in several appli-
cation fields, especially in the medicine and sanitary products. Moreover, their
potential utility is intensively studied in several other fields. While most com-
mercially available hydrogels are synthetic polymer-based, there is an increasing
interest in the use of various renewable resources. Such materials have several
advantageous properties, like biodegradability and good biocompatibility.
Polysaccharides are the most important group of the renewable materials due to
their abundance and low cost. In the present chapter, we give an account of the
potential use of polysaccharide systems for the formation of hydrogels. After a short
introduction to the chemical structure of polysaccharides, their dissolution, possible
crosslinking methods, and the studies related to the most important representatives
are discussed. The modification of gel properties by grafting, copolymerization, and
blending is also a very common route. The non-polysaccharide component can
range from other renewable resources like polypeptides to synthetic polymers to
inorganic additives. Finally, we give a summary of the potential applications of the
polysaccharide-based hydrogels.
T. Fekete
Centre for Energy Research, Hungarian Academy of Sciences,
Institute for Energy Security and Environmental Safety, Budapest
114, P.O. Box 49, 1525, Hungary
e-mail: [email protected]
J. Borsa (&)
Faculty of Light Industry and Environmental Engineering, Óbuda-University,
Doberdó str. 6, Budapest 1034, Hungary
e-mail: [email protected]
1 Introduction
Gels are special three-dimensional polymer networks where the polymer matrix is
filled with liquid or gas. The polymer network can be physically or chemically
crosslinked. In case of physical gels, the network formation occurs due to various
weak interactions, like the entanglement of the polymer chains, hydrogen bonds, or
van der Waals interactions. Such structures are usually not permanent and they
dissolve over the time when immersed in their solvents. However, the polymer
chains can also be crosslinked through chemical reactions, leading to strong
covalent bonds. The chemically crosslinked network is much more stable and
cannot be dissolved without the degradation of the polymer. Therefore, chemical
gels are usually preferable in the majority of the application fields.
Hydrogels are special gels filled with water or are capable of absorbing large
amounts of it. The swelling behavior heavily depends on the chemical structure of
the polymer: for high water uptake, the presence of hydrophilic groups in the
polymer backbone is favored. Moreover, other effects like the electrostatic repul-
sion between charged groups also contribute to the network expansion, leading to
improved swelling. Hydrogels with an exceedingly high water absorbing capacity
(usually hundreds or even thousands times of their own weight) are called super-
absorbents. The high water content has a major impact on the gel behavior: such
gels are very soft and special properties like biocompatibility are also easier to
develop. Moreover, depending on the chemical structure, hydrogels can also exhibit
responsive behavior to the environmental conditions, such as the pH or the tem-
perature. This sensitivity can be very advantageous and allows new possible
applications.
Nowadays hydrogels already have a wide array of commercial applications due
to the intensive research thanks to their unique properties. They are especially
widespread in the medicine and pharmacy, where they are used mainly in drug
delivery, tissue engineering, and wound dressing. Their use is widespread in
hygienic products like diapers, as well. Moreover, there are a large number of
studies focusing on the application in new fields such as the agriculture and
wastewater treatment. Most commercially available hydrogels are synthetic
polymer-based. The use of acrylates (various salts and esters of acrylic acid) holds
an especially important place in the hydrogel production and application. Such gels
exhibit excellent swelling properties, non-toxicity, and responsive behavior.
However, in certain fields their potential use is limited. For example, their agri-
cultural application is hindered by their poor biodegradability.
There is also a growing interest in the replacement of synthetic polymers with
different renewable resources. Such materials are not only cheap and available in
abundance but also more environmentally friendly. A very important aspect is the
lack of toxicity: unlike their polymers, the acrylate monomers are toxic; thus, their
residues need to be carefully removed after the synthesis. Hydrogels based on
natural polymers show excellent biodegradability, which is a possible requirement
depending on the application. The most important renewable materials are the
5 Polysaccharide-Based Polymer Gels 149
Cellulose is the most abundant material in the world. It is present mostly in plant
cells, but it is synthesized by some bacteria, as well. It consists of b-D-glucose units
which form a linear chain with b(1 ! 4) linkages. The presence of hydroxyl
groups leads to the formation of intermolecular and intramolecular hydrogen bonds,
while apolar parts of the macromolecules are linked with van der Waals interactions
(Gross and Chu 2010). The cellulose chains form a semicrystalline structure con-
sisting of crystalline and amorphous regions. Moreover, in the latter region,
semi-ordered structures are also present to a certain degree. The polysaccharide has
multiple crystalline polymorphs: Cellulose I, II, III, and IV. In the nature,
Cellulose I is the dominant structure, which consists of parallel polymer chains and
is formed by two different phases: the monoclinic Ia and the triclinic Ib. While both
phases are present simultaneously, in higher plants the Ib, in bacteria and algae the
Ia phase are the dominant (Sugiyama et al. 1991). The other cellulose polymorphs
are usually synthesized by the conversion of Cellulose I, but the natural formation
of the thermodynamically more stable Cellulose II was also observed (Hirai et al.
2002).
Due to the strong intermolecular interactions, the cellulose is insoluble in water.
However, the partial substitution of hydroxyl groups results in the weakening of
these bonds, leading to improved solubility. The water solubility increases with the
degree of substitution which leads to weaker polymer–polymer interactions. For the
hydrogel synthesis, mostly the cellulose ethers are utilized; the importance of its
esters is minimal in this field. Cellulose ethers are important industrial materials
with a wide array of applications such as surfactants, coatings, and thickeners.
During the derivatization, the cellulose is disintegrated first in concentrated alkali
followed by the substitution reaction (the alkaline environment also functions as a
catalyst) (Woodings 2001). Carboxymethylcellulose is prepared with the addition
of chloroacetic acid, leading to the formation of the sodium salt of the derivative.
For the synthesis of alkylcelluloses alkyl chloride, in case of hydroxyalkylcelluloses
alkene oxide is used as a reagent. Alkylhydroxyalkylcelluloses are also common
derivatives, where both types of pendant groups are present in the structure.
2.2 Starch
helices which form the crystalline structure. Starch has two allomorphs: type A and
type B starch (Buléon et al. 1998). Both structures consist of ordered double
helices, but their position differs significantly. In A-type starch, the helices are
closely packed, and the water molecules are positioned between the helices. For
B-type starch, the helices form a hexagonal lattice, where the water is inside the
hexagonal structure. C-type starch consisting of the mixture of the A and B-type
structures also exists, though related studies are limited (Bogracheva et al. 1998).
The oriented helices form the crystal lamellae, while the branch points are part of
the amorphous phase, leading to a semicrystalline structure. Starch is present in the
plant cells in granule form, which consists of alternating amorphous and crystalline
regions; lipids and proteins are also present on its surface. Moreover, other com-
ponents like phosphates and phospholipids are also found in the granule depending
on the source. As the granular structure is not destroyed before the starch is used for
the hydrogel synthesis, it has a major effect on the mechanism of the gelation.
While there is a large interest in the derivatization of the starch (Gotlieb and
Capelle 2005), currently only the carboxymethylation (prepared with chloroacetic
acid in sodium hydroxide solution similarly to the other polysaccharides) is relevant
for the gel synthesis.
Chitin is the most abundant material after the cellulose. It is a very important
structural unit in the nature, especially for the fungi in the cell walls and as the
exoskeleton for a wide array of animals. The chemical structure of chitin is similar
to the structure of cellulose. It consists of b-D-glucose groups linked by b(1 ! 4)
linkages, but the hydroxyl groups in the C(2) position are substituted by an acet-
amido group; thus, N-acetyl-b-D-glucosamine is the structural unit. There are strong
intermolecular interactions between the chitin chains due to the hydrogen bonds
between the NH and CO groups, leading to a strong crystalline structure and
insolubility in water. Chitin forms three different crystalline polymorphs: a-chitin
consists of antiparallel chains, and b-chitin is formed by parallel macromolecules,
while the c polymorph has a more unique structure as two parallel chains are
followed by an antiparallel one (Hudson and Smith 1998). Unlike the cellulose, all
three polymorphs are present in the nature.
Chitin derivatization is usually achieved through modification of the acetamido
groups. The most important derivative is the chitosan which is prepared by the
deacetylation of chitin, leading to amino groups in the C(2) position. While full
deacetylation is possible (Domard and Rinaudo 1983), the process is usually
incomplete; thus, N-acetyl-b-D-glucosamine units are still present in the polymer
structure. Unlike the chitin, chitosan is soluble in aqueous solutions at acidic pH
due to the protonation of the amine groups (Rinaudo et al. 1999).
The hydroxyl groups in the polymer chain can also be utilized for the func-
tionalization. For example, by introducing carboxymethyl groups, a fully
152 T. Fekete and J. Borsa
2.4 Alginate
Alginates are the salts of the alginic acid, from which the sodium salt is present in
abundance in the nature. Alginate is synthesized by various algae and bacteria; for
the industrial use, usually brown algae is used as alginate source. Unlike alginic
acid, the alginate is water soluble. It is a linear copolymer of two monomers: b-D-
mannuronic acid (M) and a-L-guluronic acid (G), with (1 ! 4) linkages between
the units. These bonds can also form between the same units, leading to the for-
mation of homopolymer (GG and MM) and copolymer blocks (MG) with different
properties in an alternating structure (Donati and Paoletti 2009). The properties of
the alginate heavily depend on the ratio of the two monomers and the distribution of
the blocks (Johnson et al. 1997).
3 Dissolution of Polysaccharides
While gels can be synthesized from both solution and in dry state, the latter method
is very rarely used for polysaccharide-based systems; thus, the dissolution of the
polysaccharide is a key factor in the gel preparation. Unlike low molecular weight
molecules, the dissolution of macromolecules is much more difficult. The solubility
depends on the polymer–solvent and polymer–polymer interaction: if the latter one
is dominant, the solvent cannot disrupt the intermolecular bonds between the
macromolecules. Thus, the solvent properties are decisive. The most important
solvent is the water due to its advantages. A wide array of polysaccharides like
alginate and hyaluronic acid are water soluble. Therefore, water is the standard
solvent for these polymers unless other water-insoluble components are also added.
However, the most abundant polysaccharides (cellulose, starch, and chitin) are not
5 Polysaccharide-Based Polymer Gels 153
soluble in water; thus, special solvents are required. While a wide array of solvents
are available for the dissolution of these polymers, in the following section, only
solvents utilized for the hydrogel synthesis are reviewed.
The dissolution of cellulose was extensively studied in the past decades. There were
major efforts to find cost-effective, environmentally friendly solvents. For the
hydrogel synthesis, usually its industrial solvents are used, but there is strong
interest toward novel systems like ionic liquids, as well. However, not all common
solvents were investigated for this application so far. For example, dimethyl sul-
foxide (DMSO)-based solvent systems are mostly used only for the synthesis of
aerogels (Innerlohinger et al. 2006). Similarly, N-methylmorpholine-N-oxide, the
solvent used for manufacturing regenerated cellulose fibers (e.g., Lyocel, Tencel),
currently holds little importance in the gel preparation, but it might gain more
attention in the future. Several solvents, such as cupriethylenediamine (CUEN)
hydroxide, depend on the formation of metal–ion complexes with cellulose. CUEN
and its relatives with different metals and ammonium hydroxide find substantial
industrial use (Johnson 1985). Cuprammonium hydroxide (a mixture of copper
hydroxide and ammonium hydroxide) and phosphorous acid had been used for
regenerated cellulose fiber production for a long time (Kotek 2007); they might
attract the interest of the cellulosic gel producers in the future.
For the hydrogel synthesis, multiple solvents of cellulose are widely used. The
dimethylacetamide/lithium chloride (DMAc/LiCl) system is one of the most com-
mon such solvents. The mechanism of the process was in-depth investigated: the
hydrogen bonds between the cellulose chains break up due to the chloride ions
forming hydrogen bonds with the hydroxyl groups (Striegel 1997). Solvent
exchange further improves the dissolution: the cellulose is immersed in water,
which is gradually exchanged to methanol, and finally to DMAc/LiCl (McCormick
et al. 1985). Such systems are not only stable, but the dissolution occurs without
degradation even for high molecular weight cellulose at low temperatures (Dupont
2003). However, Potthast et al. (2002b) observed that elevated temperatures (over
85 °C) lead to the rapid degradation of the polymer.
Another method to dissolve cellulose is the addition of urea or thiourea to alkali
hydroxide aqueous solutions. Sodium hydroxide is a cheap solvent of cellulose, but
it is suitable only for the dissolution of low molecular weight polymer (Isogai and
Atalla 1998). However, the introduction of urea or thiourea leads to the significantly
improved solubility of the polysaccharide. The process is explained by the stabi-
lizing effect of the components: Na+ cations interact with the hydrophilic groups of
the cellulose (Cai and Zhang 2005), while the urea stabilizes the hydrophobic parts,
preventing the intermolecular interactions between the polymer chains (Xiong et al.
2014). Due to this dual effect, the ratio of the two components is important: both too
high hydroxide and too high urea content lead to decline in the solubility (Zhang
et al. 2010).
154 T. Fekete and J. Borsa
Recently, the use of ionic liquids as novel solvents is also showing a growing
tendency. Ionic liquids are organic salts with melting point below 100 °C, com-
monly even below the room temperature. Unlike the aforementioned solvents, they
offer a more environmentally friendly option due to the low toxicity and
biodegradability. However, this is not universally true for all salts: depending on the
chemical structure, some ionic liquids not only show poor biodegradability but also
are more hazardous than conventional solvents (Gatherhood et al. 2004; Romero
et al. 2008). The chemical structure of the salt also plays a major role in the process:
it not only affects the dissolution but some salts can also react with the cellulose
(Clough et al. 2015). The latter process may lead to undesirable changes in the
polymer properties; thus, it should be avoided. Swatlowski et al. (2002) investi-
gated the dissolution of cellulose in different alkyl-methylimidazolium systems and
noted that the alkyl chain and the anion have a major effect on the solubility. While
a wide array of methylimidazolium-based ionic liquids proved to be an efficient
solvent (Feng and Chen 2008), most commonly 1-allyl-3-methylimidazolium
chloride (AMIMCI) is used for the hydrogel synthesis (Zhang et al. 2005b). These
salts are not only capable of dissolving large amounts of cellulose, but the polymer
degradation is observed only at high temperatures. While they also have some
disadvantages like the high viscosity or the slow dissolution, its widespread use is
mainly hindered by the high production costs compared to the classic solvents.
Another method to achieve water solubility is the partial substitution of the
hydroxyl groups, which weakens the strong intermolecular interactions, thus
improving water–polymer interactions. Water solubility heavily depends on the
molecular mass, degree of substitution (DS), and substituent, as well. For example, a
minimum DS of 0.4 is required for carboxymethylcellulose to be fully water soluble
(Wertz et al. 2010). In case of nonpolar substituents like methyl groups, an even
higher degree of substitution is needed for optimal solubility. Moreover, hetero-
geneous distribution also leads to a decrease in the solubility, as the intermolecular
bonds are not disrupted in certain segments of the chains. The derivatization is
especially important for the cellulose, for which a wide array of substituents groups
are used. The most common derivatives are the carboxyalkyl, alkyl, hydroxyalkyl,
and alkylhydroxyalkylcelluloses.
Similarly to the cellulose, native starch does not dissolve in water due to the strong
polymer–polymer interactions. Amylose and amylopectin, the two components of
starch form a semicrystalline granule structure. These granules are resistant to
external effects and while they show some swelling in water, they are insoluble.
However, increasing the temperature of the aqueous dispersion leads to gela-
tinization: the interactions between the polymer chains are weakened, the ordered
structure is disrupted, and the swelling of the granules increases significantly (Miles
et al. 1985; Hoover 2001). The high viscosity of the gelatinized starch allows the
5 Polysaccharide-Based Polymer Gels 155
Chitin is highly crystalline as the acetamide groups also participate in the formation
of the intermolecular bonds. Solvents similar to the ones utilized for the cellulose
dissolution are used to disrupt the intermolecular interactions. For example, sodium
hydroxide/urea system proved to be excellent solvents for the chitin (Hu et al.
2007). Low temperature promotes the destruction of the intermolecular bonds as the
polymer–solvent interactions become more stable (Chang et al. 2011a). Another
popular solvent is the so-called Ca solvent, which is CaCl2 dihydrate dissolved in
methanol. The water present in the CaCl2 also plays a major role in the mechanism
as Ca solvent prepared from anhydrous chloride salt does not dissolve the chitin
(Tamura et al. 2006). Tetrabutylammonium fluoride/dimethyl sulfoxide and lithium
chloride systems were also applied successfully; for the latter system, N-
methyl-2-pyrrolidone was used for the dissolution of the salt (Yoshimura et al.
2005). Recently, the application of ionic liquids was also studied and the imida-
zolium salts proved to be very efficient.
Chitosan, the deacetylated derivative of chitin is an even more popular choice for
the hydrogel preparation. While pure water is an inadequate solvent, aqueous
solution of chitosan can be prepared in presence of acidic medium like acetic acid;
thus, the gel synthesis is easier compared to chitin. However, chitosan is also often
derivatized further to modify the gel properties: the swelling properties of the
hydrogels significantly improve at nonacidic pH if carboxymethyl groups are
introduced to the polymer (Vaghani et al. 2012). Thus, the carboxymethylchitosan
is also a major subject of such experiments. Moreover, carboxymethylation is also a
viable route to increase the water solubility of the chitin polymer; thus, deacety-
lation is not required to allow the use of aqueous solutions for the gelation (Zhao
et al. 2001).
4 Crosslinking Methods
employed for the synthesis of hydrogels. The properties of the polysaccharide are
the determining factor which crosslinking steps are applicable; thus, the preferred
method is polymer-dependent. For the physical crosslinking, three major strategies
are available: gelation induced by high temperature, solvent exchange, or com-
plexation through ionic interactions. On the other hand, chemical crosslinks are
reached by adding crosslinking agents or initiating the formation of reactive free
radicals. The latter method can be initiated either by chemical initiators or by
high-energy irradiation. In the following, a short general summary is given for these
methods.
An interesting method to prepare physical gels is the solvent exchange. After the
dissolution a non-solvent is added to the solution—as the ratio of the good solvent
decreases, the interaction between the macromolecules increases, ultimately leading
5 Polysaccharide-Based Polymer Gels 157
to aggregation and formation of the physical gel. To utilize this method for the
hydrogel formation, the polymer must be insoluble in water so they do not dissolve
in the aqueous environment. This strategy is mostly used for the cellulose-based
gels, where the cellulose is dissolved in various solvents and then water is added to
promote the gel formation (Potthast et al. 2002a; Kadokawa et al. 2008; Östlund
et al. 2009). However, gelation of the whole system occurs only over a critical
polymer concentration: in very dilute solutions only the aggregation and precipi-
tation of the polymer was observed (Ishii et al. 2006). In LiCl/DMAc solutions the
ionic strength is also a determining factor in the dissolution of cellulose. Therefore,
the deionization of the system also leads to reduced solubility and gelation. The
precipitation method is also used in the manufacturing of some regenerated cellu-
lose fibers: after dissolution of cellulose in NMMO/water system, the precipitation
is carried out by stepwise addition of water (Loubinox and Chaunis 1987). As this
technology shows, the change of the solvent system properties to promote the
aggregation does not necessarily need the introduction of another solvent.
The ionic interactions can also be exploited for the formation of physical crosslinks.
Several polysaccharides have charged pendant groups on the polymer chains, most
commonly carboxylic groups. These groups can interact with their counterions and
weak ionic bonds are formed between them. However, if multivalent counterions or
polymers with oppositely charged groups are present, they can interact with mul-
tiple charged pendant groups and form intramolecular and intermolecular bonds
(George and Abraham 2006). This method allows a relatively easy gel formation,
though the physical network is relatively weak. The ion complexation is the most
important gelation method for the alginates, including the industrial production.
Alginate gels are formed with the addition of calcium ions through the interaction
with the carboxyl groups, leading to a special egg-box structure (Grant et al. 1973).
However, not only other divalent cations proved to be efficient crosslinkers (Yang
et al. 2013) but also the ion complexes formed with trivalent cations like Al3+ led to
an even stronger network structure (Rochefort et al. 1986). Moreover, valence is not
the singular determining factor as ions with the same valence show different effi-
ciency in the gel formation (Menakbi et al. 2016).
The most common method for chemical crosslinking is the use of crosslinking
agents. These reagents contain groups which can easily react with the pendant
functional groups on the polymer backbone. To form crosslinks, the crosslinking
158 T. Fekete and J. Borsa
agents need to be at least bifunctional so they can react with at least two pendant
groups on different chains. For polysaccharides, usually a large number of reactive
hydroxyl groups are present on the polymer backbone; therefore, crosslinkers which
easily react with these groups have the largest importance. Reactions involving
other common pendants groups like carboxyl groups are also common, but their
utility is more limited.
One of the major crosslinking agents is the divinyl sulfone (DVS). The crosslink
formation occurs through the reaction of the vinyl and hydroxyl groups (Fig. 2a).
However, this requires alkaline pH because the hydroxyl groups are needed to be
deprotonated. Therefore, dilute aqueous solutions of potassium hydroxide are used
as solvents instead of water to promote the crosslinking (Esposito et al. 1996). The
major drawback of the DVS is the high toxicity: while it does not have a harmful
effect on the environment after the reaction, the unreacted molecule itself is haz-
ardous. As it has a negative impact on the biocompatibility (Yeom et al. 2010), the
unreacted DVS needs to be removed by washing from the gel structure. Recently,
new methods for the treatment of the DVS-polluted water were established. UV
irradiation in presence of TiO2 photocatalyst is capable of fully degrading the
remains of the crosslinker (Marci et al. 2006). This method allows a more envi-
ronmentally friendly application of the divinyl sulfone as the wastewater is
reusable.
Epichlorohydrin (ECH) is another very significant crosslinking molecule.
The reaction is similar to the divinyl sulfone as it needs alkaline environment to
catalyze the reaction with the hydroxyl groups (McKelvey et al. 1963) (Fig. 2b).
This makes it an excellent reagent for a wide array of polysaccharides. However,
similarly to the DVS, its toxicity is a major disadvantage.
Crosslinking with glutaraldehyde and other dialdehydes is also a relatively
common method due to their low toxicity. As the aldehyde groups can easily react
with amine groups, it is usually used for the crosslinking of various proteins
(Hopwood et al. 1970); thus, for the polysaccharides it is relatively rarely used with
the exception of the chitosan, as the presence of amine groups makes it a perfect
candidate for the reaction. However, the aldehyde groups can also react with the
hydroxyl groups, leading to the formation of hemiacetal or even acetal if there is
another nearby hydroxyl group (Tomihata and Ikada 1997b) (Fig. 2c). This requires
acid component to catalyze the reaction, which is generally achieved with the
addition of hydrochloric acid.
Carbodiimides are also primarily used to crosslink various polypeptides. The
monomer, depending on the conditions, can easily react with a carboxyl groups and
form an unstable intermediate which can then react with an amine (Nakajima and
Ikada 1995). Unlike most crosslinking agents, the carbodiimide is a zero-length
crosslinker: it only helps the crosslink formation between the two pendant groups,
the crosslinking molecule itself is not part of the formed crosslink (Fig. 2d). As
various carbodiimides are somewhat toxic, this is a big advantage as the removal of
all crosslinkers after the gelation is possible. This makes it more favorable com-
pared to other toxic molecules. They are usually used to crosslink carboxyl and
amine groups, which is rarely exploitable for polysaccharides. However, the
5 Polysaccharide-Based Polymer Gels 159
Fig. 2 Crosslinking
mechanism of divinyl sulfone
(a), epichlorohydrin (b),
glutaraldehyde (c), and
carbodiimide (d)
carbodiimide can also be utilized to crosslink the chains with carboxyl and hydroxyl
groups. After the reaction with a carboxyl group, the anhydride formation with
another nearby carboxyl substituent is promoted, which is followed by a reaction
with a hydroxyl group. This method was successfully applied for multiple
polysaccharides, like hyaluronic acid (Tomihata and Ikada 1997a) and car-
boxymethylcellulose (Sannino et al. 2010).
The largest problem of the major crosslinking agents is their toxicity. Therefore,
there is a considerable interest in the use of more environmentally friendly
crosslinking agents like various polycarboxylic acids. Under normal conditions, the
ester bond formation does not occur between the carboxyl and hydroxyl groups.
However, if the polycarboxylic acid is dehydrated, the anhydride formed from two
carboxyl groups can easily react with a hydroxyl pendant group (Fig. 3). The
formation of anhydride is easily reached by heat treatment as even moderate
temperatures (70–80 °C) promote the water loss. After esterification, one carboxyl
group is freed up and it can participate in the anhydride formation with another
nearby carboxyl group. Therefore, at least three carboxyl groups are required for the
crosslinking effect. Due to the relatively low cost, the most important polycar-
boxylic acid is the citric acid which contains three carboxyl groups (Demitri et al.
160 T. Fekete and J. Borsa
2008; Shi et al. 2008). However, the application of various tetracarboxylic acids
was also investigated (Nazari et al. 2009). Usually, low temperatures and long
treatment times are used. The latter is due to the water content of the solutions: the
presence of the water molecules hinders the anhydride formation. The application
of these green crosslinking agents was mostly investigated for the preparation of
cellulose derivative gels, and in other areas like for fixation of cellulosic fiber
structure in order to get crease resistant textiles.
The number of less common crosslinking agents is large. The crosslinking of N,
N′-methylene-bis-acrylamide occurs through free-radical crosslinking; thus, it will
be discussed in the next section. Other crosslinkers are rather specific and are used
only for the crosslinking of certain polysaccharides; thus, they are reviewed in
Sect. 5 under the subsection of the corresponding polymer.
The crosslinking reactions can also occur through the highly reactive free radicals.
The process requires initiation, which leads to the formation of the radicals. The
radicals initiating the process are usually formed either during the degradation of the
initiators or directly on the polymer chain by high energy irradiation. The radicals
easily react with another macromolecule and the resulting product can also participate
in further reactions. The reaction is terminated by the disproportionation or the
combination of radicals. However, it is important to note that the radicals can not only
initiate the crosslinking, but their reactions may also lead to chain scission, hindering
the network formation. The relationship of the two processes heavily depends on
various environmental parameters such as the presence of the solvent and the
atmosphere, thus conditions favoring the crosslinking should be used. Crosslinking
agents are also often introduced even for high energy irradiation to improve the
crosslink formation, most common being the N, N′-methylene-bis-acrylamide.
Fig. 3 Crosslinking
mechanism of citric acid
5 Polysaccharide-Based Polymer Gels 161
If two or more polymers are present in the solution, different polymer networks can
be formed depending on their chemical structure and the crosslinking method.
Usually, the two components contain same reactive groups; thus, one crosslinking
agent can react with both polymers. This method is the most common as it makes
the crosslinking process much simpler. The polymers can also contain different
groups which can react with each other, thus making the formation of the
copolymer possible.
The two polymers do not need to be necessarily connected with covalent bonds,
they can also form an interpenetrating network (IPN) structure (Dragan 2014).
In this case, the polymer networks are not chemically crosslinked but their entan-
glement sterically prevents their separation. Such gels are usually synthesized in
two steps where only one polymer is crosslinked in each step. This is most com-
monly achieved by the addition of two different crosslinking agents. However, as
multiple polymers are present, gel can form even if a single component is cross-
linked: the three-dimensional network forms the gel matrix, while the intermolec-
ular interactions prevent the not crosslinked polymer component from leaving the
gel structure during the swelling. Such structures are called semi-interpenetrating
networks (semi-IPN). Similarly to the synthesis of IPN gels, crosslinking agents
which react with a single component are needed for their preparation.
5 Polysaccharide-Based Hydrogels
While the aforementioned crosslinking strategies are widely used for polysaccha-
ride systems, the importance of the individual methods shows a large difference
depending on the type of the carbohydrate. Moreover, there is a wide array of other
crosslinking routes which were only utilized for specific polymers so far, thus were
not discussed previously. Therefore, in the following section, studies related to the
gelation of different polysaccharide-based systems are reviewed separately, high-
lighting the specific considerations and unique methods for the various systems.
5 Polysaccharide-Based Polymer Gels 163
Unmodified cellulose as a hydrogel material is widely studied due to its very low
cost, but insolubility in water renders it less important than its derivatives. While
chemically crosslinked gels were also prepared, the physical gelation has a much
bigger role. The physical network is usually achieved by solvent exchange or
temperature change. In the former method, water is used to disrupt the solvent–
polymer interactions. Potthast et al. (2002a) investigated the behavior of cellulose
dissolved in LiCl/DMAc and observed the slow aggregation of cellulose chains due
to the hydrogen bonds. However, the presence of water even in very low con-
centrations led to the formation of larger aggregates. Ishii et al. (2006) prepared
physical gels by two methods: coagulation with water and deionization with ion
exchange resins. The addition of water led to instantaneous gel formation, while the
slower deionization resulted in a more homogenous structure. Similar behavior was
observed for tetrabutylammonium fluoride (TBAF)/DMSO solutions: the water
disrupted the interaction between the hydroxyl groups of the cellulose and the
fluoride; thus, intermolecular hydrogen bonds between the cellulose chains became
dominant (Östlund et al. 2009). As very low water concentrations are required for
the process, even the storage in humid environment is enough for the gelation of the
solution (Patchan et al. 2013). The method is applicable for cellulose dissolved in
ionic liquids, as well (Kadokawa et al. 2008).
The gelation can be induced by the change in the temperature, as well. Frey et al.
(1996) studied the gelation of cellulose/ammonia/ammonium thiocyanate systems
and observed that lower temperatures led to shorter gelling time. There is a much
richer literature available about NaOH systems. Opposed to the ammonia/
ammonium thiocyanate system, increasing the temperature was beneficial for the
self-association of the cellulose in this solvent (Roy et al. 2003). Interestingly,
lowering the temperature has a similar effect: Cai and Zhang (2006) studied the
behavior of cellulose/NaOH/urea systems at different temperatures and noted that
hydrophobic interactions between the cellulose chain become stronger at low
temperatures (under 0 °C). LiOH-based systems were also used for the gelation of
cellulose with higher molecular weight (Wang et al. 2013d). It is also important to
note that unlike the physical gels of methylcellulose, the thermal gelation of the
cellulose is an irreversible process under such conditions.
Epichlorohydrin (ECH) is the most common monomer for the chemical
crosslinking of cellulose hydrogels. Westman and Lindström (1981) used cellulose
xanthan as a precursor: the solution of the derivative was crosslinked with ECH,
followed by regeneration with acid hydrolysis. However, recent studies focus on the
direct crosslinking of cellulose. The method is similar to the physical gelation:
cellulose is dissolved in NaOH/urea, stored in frozen state and after thawing the
crosslinking agent is added. The chemical reaction occurs at room or slightly ele-
vated temperature (Zhou et al. 2007). Chang et al. (2010b) also investigated the
164 T. Fekete and J. Borsa
effect of the post-treatment of the hydrogels: the samples were frozen or heated for
20 h. The former method resulted in better mechanical properties, while gels treated
with the latter one had higher water uptake and better optical properties. There were
also considerable efforts toward the copolymerization of cellulose with synthetic
polymers. Chang et al. (2008) compared cellulose/PVA hydrogels both chemical
gels with epichlorohydrin and physically crosslinked samples: the properties of the
latter were inferior compared to the chemical gels. Wu et al. (2012a) used
free-radical crosslinking to synthesize cellulose/acrylic acid/acrylamide hydrogels
in the presence of MBA crosslinker. In a later work, Chang et al. (2011b) combined
the two methods: after the gelation of cellulose with ECH, they prepared poly(N-
isopropylacrylamide) (PNIPAAm)/cellulose gels by free-radical crosslinking the
cellulose gel and the NIPAAm monomers.
formation. Shifting the pH toward acidic character led to the protonation of the
carboxyl groups and the lack of interaction between them promoted the gelation.
Several other factors such as the storage time before the irradiation (Wach et al.
2000) also affected the gel fraction. Liu et al. (2002) observed that not only the lack
of oxygen leads to better gelation, but the type of the inert atmosphere also has an
impact on the process. The radiation-initiated crosslinking can be further improved
by adding crosslinking agents in low concentrations. While they are used mostly for
the synthesis of copolymer gels, they can also improve the gelation of pure cel-
lulose derivative solutions (Fekete et al. 2016a). In their presence, the crosslinking
requires significantly milder conditions and better gel properties can be achieved
than for the crosslinker-free hydrogels.
Methylcellulose hydrogels
The most important representative of the alkylcelluloses is the methylcellulose. It is
a major additive in the food industry, where its thermogelling behavior is also
utilized to affect the baking of pastes (Sanz et al. 2004). The gelation mechanism of
the methylcellulose is explained with the interaction of the hydrophobic methyl
substituents (Sarkar 1979). At low temperatures, the hydrophobic interactions are
hindered by the hydration of the polymer chains; however, increasing the tem-
perature leads to lower hydration, thus the interactions between the methyl groups
are less obstructed. Haque and Morris (1993) attributed the gelation also to the
changes in the solution structure. During the derivatization of the cellulose, the
crystalline structure is not completely destroyed; thus, small aggregates are present
in the methylcellulose solution. However, at high temperatures, the aggregates are
partly broken up and the free ends of the polymer chains forming the aggregates
also become more mobile. The degree of substitution and the distribution of the
substituents also affect the gelling behavior. Higher degree of substitution leads to
lower gel temperature due to the higher number of hydrophobic groups. This also
explains the importance of the distribution of the substituents: the regions with
higher degree of substitution play a larger role in the gelation than other regions
(Desbrières et al. 1998). High molecular weight is also beneficial for the process,
leading to a shift toward lower gelation temperatures (Takahashi et al. 2001). The
required temperature can also be altered by chemical modification: Liu et al. (2004)
prepared N-isopropylacrylamide/methylcellulose copolymers, where the ratio of the
two components determined the gelation temperature.
The chemical gelation of methylcellulose holds a relatively small significance due
to the importance of the thermal gelation. Chemically crosslinked hydrogels of
methylcellulose were prepared through free-radical crosslinking: Wach et al. (2003a)
crosslinked concentrated methylcellulose solutions by high-energy irradiation. They
found electron beam significantly more efficient than gamma irradiation, leading to
higher gelation. Methylcellulose gels showed good swelling properties but were
inferior to hydroxyethylcellulose-based hydrogels due to the hydrophobic pendant
groups. Photoinitiated crosslinking also proved to be a viable route, but in this case,
acrylate was also present in the system besides the photoinitiator. Aouada et al.
(2009) synthesized methylcellulose/polyacrylamide copolymer gels in presence of
5 Polysaccharide-Based Polymer Gels 167
redox initiator with Fe2+). This allowed the substitution of the (4-benzoylbenzyl)
trimethylammonium chloride photoinitiator with a more environmentally friendly
additive.
High-energy irradiation was used for initiation to a lesser extent. Both
hydroxyalkylcelluloses formed gels when their concentrated solutions were irra-
diated (Wach et al. a, b). The dependence of the properties on the synthesis
parameters was similar to the carboxymethylcellulose systems. Moreover, the
introduction of low concentrations of MBA crosslinker had a positive impact on the
gel formation (Fekete et al. 2016a).
Alkylhydroxyalkylcellulose-based hydrogels
The gelation of alkylhydroxyalkylcelluloses was investigated only for two repre-
sentatives: the hydroxypropylmethylcellulose and the ethylhydroxyethylcellulose.
Similarly to the methylcellulose, the physical crosslinking by heat treatment shows
a large importance due to the industrial applications. However, the hydrogel syn-
thesis of the two derivatives was investigated at somewhat different conditions. For
the hydroxypropylmethylcellulose, the thermal gelation is very similar to the
behavior of the methylcellulose due to the methyl substituents in both derivatives
(Sarkar 1979). On the other hand, the presence of the hydroxypropyl groups hinders
the gelation process, leading to higher gelation temperature. This is attributed to
two effects: the hydroxypropyl groups are less hydrophobic than the methyl groups
and the larger substituents also sterically interfere with the formation of the
hydrophobic ordered structures (Haque et al. 1993).
The thermal behavior of the ethylhydroxyethylcellulose is quite different. Its
aqueous solution shows a decrease in the viscosity with the temperature. Above the
cloud point phase, separation occurs, leading to even lower viscosity. However, the
presence of ionic surfactants significantly alters this process: the hydrophobic
polymer–surfactant interactions promote the formation of the polymer–polymer
interactions, leading to the formation of physical gels (Carlsson et al. 1990). The
effect also heavily depends on the type of the surfactant as depending on the
chemical structure it interacts differently with the polymer chains (Nyström and
Lindman 1995; Wang and Olofsson 1995).
Pure cellulose derivative chemical gels were only prepared from hydrox-
ypropylmethylcellulose. Pekel et al. (2004) used gamma irradiation to crosslink
HPMC solution. The swelling of the gels was sensitive to the pH and the tem-
perature. The sensitivity was further improved by introducing phthalate groups into
the polymer structure (Xu et al. 2002b). However, the phthalate derivative has low
solubility in water; thus, it requires the addition of Na2CO3 for full dissolution.
The application of starch as a hydrogel material is less widely studied than the other
major polysaccharides. Moreover, studies focus on the use of starch as a copolymer
5 Polysaccharide-Based Polymer Gels 169
5.3.1 Chitin
Precipitation is a common method for the preparation of chitin hydrogels due to the
water insolubility of the polymer: chitin is dissolved by one of its solvents and the
solution is slowly added to a water bath. The dissolution is usually achieved by
CaCl2/methanol solvent system (Tamura et al. 2006; Nagahama et al. 2008), but in
some experiments hydrogels were prepared from chitin dissolved in NaOH/urea by
freeze-drying (Chang et al. 2011a) and in DMA/LiCl systems (Tsioptsias and
170 T. Fekete and J. Borsa
Panayiotou 2008), as well. There is also a large interest regarding the composites
from physically crosslinked chitin gels, where the nanoparticles are incorporated
into the gel structure after the precipitation. As the application of chitin-based
physical gels is centered on the medical field, achieving antibacterial activity by
silver (Madhumathi et al. 2010) or metal oxide (Kumar et al. 2013) particles is
widely studied.
Multiple crosslinking strategies were examined for the preparation of chemically
crosslinked networks. Tang et al. (2012) crosslinked dissolved chitosan with
epichlorohydrin through the hydroxyl groups. NaOH/urea was used as solvent
which also provided the alkaline environment required for the reaction.
Epichlorohydrin was also utilized for the preparation of chitin-based copolymer gel
with carboxymethylcellulose (Tang et al. 2014) and composite with hydroxyapatite
(Chang et al. 2013).
Crosslinking with the more environmentally friendly polycarboxylic acids was
also studied. Yoshimura et al. (2005) used succinic anhydride to crosslink chitosan
solution: the acid anhydride reacted with the hydroxyl groups of the chitin.
Moreover, the free carboxyl group formed after the reaction could also react with
another hydroxyl group. The solvent present during the crosslinking had a major
effect on the gelation: in DMSO/TBAF solutions, the chemical crosslinks easily
formed, while in LiCl/N-methyl-2-pyrrolidone (NMP) solutions, the second reac-
tion was inhibited; thus, minimal gelation was observed. Opposed to the polycar-
boxylic acids, the use of anhydride and the lack of water allowed bypassing the heat
treatment. Kono and Zakimi (2013) synthesized gels with the dianhydride of
butanetetracarboxylic acid from blends of chitin and cellulose in LiCl/NMP. The
two anhydride groups allowed the formation of crosslinks despite the free carboxyl
groups not participating in the crosslinking. However, the presence of non-reacted
carboxyl groups led to responsive behavior: unlike the native polymers, the
copolymer exhibited sensitivity to the pH of the environment.
5.3.2 Chitosan
Chitosan-based physical gels are prepared either by various additives which interact
with the chitosan chains or by chemical modification. In the latter case, new
functional groups are introduced into the polymer structure by grafting; thus, the gel
formation can occur through new mechanisms. Qu et al. (1999) prepared lactic acid
modified chitosan through heat treatment. The lactic acid reacted with the amine
group, which was followed by polyesterification. The formation of the physical gel
was attributed to the hydrophobic interactions between the substituents and the
hydrogen bonds. By introducing hydrophobic groups thermoreversible gelling can
be also achieved: grafting chitosan with poly(ethylene glycol) led to a water-soluble
chitosan derivative, but at higher temperature, the stronger hydrophobic interactions
resulted in physical gelation (Bhattarai et al. 2005). Freeze-thawing is also a pos-
sible method for gelation: Yang et al. (2008) prepared PVA/chitosan solution by
multiple freeze-thaw cycles at −20 °C.
5 Polysaccharide-Based Polymer Gels 171
The second strategy for the physical gelation is the introduction of various
additives to the chitosan solution. These can also induce the thermal gelation of the
solution through hydrophobic interactions. Such behavior was observed in the
presence of polyols. Chenite et al. (2001) used b-glycerophosphate disodium salt to
neutralize the chitosan solution, leading to thermogelating systems at body tem-
perature. Other polyols exhibited similar effect on the chitosan systems (Schuetz
et al. 2008). Chitosan gels grafted with monomers of thermosensitive polymers like
N-isopropylacrylamide exhibited similar behavior (Chen and Cheng 2006). The
gelation is often achieved through ionic interactions, as well. This requires the
presence of polymers with negative charges which can interact with amine groups
in the chitosan backbone. As anionic polymers are relatively common in the nature,
most studies focus on the application of various natural polymers for the synthesis
as a cheap, green alternative to synthetic polymers (Berger et al. 2004). While
polymers with carboxyl groups are the most common choice, the addition of
polysaccharides containing sulfate or phosphate groups is also a viable route.
Glutaraldehyde is a common chemical crosslinker for chitosan as the aldehyde
groups easily react with the amines (Mirzaei et al. 2013). However, the crosslink
formation can be initiated by a single aldehyde group, as well. Singh et al. (2006a)
utilized formaldehyde to gelate chitosan solution at acidic pH. The reaction of the
formaldehyde and the amine pedant group resulted in the formation of imine which
in acidic environment can react with a second amine, thus forming a crosslink.
A more environmental friendly alternative is the genipin due to its low toxicity,
which is isolated from gardenia fruits. The molecule with a carboxyl and two
hydroxyl groups does not only react with the amine groups to form crosslinks, but
its homopolymerization is also observed (Mi et al. 2000). The pH has a major effect
on the reaction. Alkaline environment promotes the formation of homopolymer
chains; thus, long crosslinks are formed between the chitosan macromolecules. On
the other hand, in acidic environment, the crosslinks are short (dimers, trimers, and
tetramers of genipin), and the more compact gel structure leads to worse swelling
properties (Mi et al. 2005).
Free-radical crosslinking is usually initiated by UV irradiation. Ono et al. (1999)
prepared water-soluble photocrosslinkable chitosan by reacting chitosan with azide
(p-azidobenzoic acid) and lactose (lactobionic acid). The introduction of lactose
groups improved the solubility in water; thus, aqueous solutions formed even at
neutral pH. On the other hand, the azide group is sensitive to the UV irradiation,
leading to the formation of reactive nitrene group which reacts with another nitrene
or a free amine group to form azo crosslinks.
Vinyl groups are also commonly introduced for easier crosslink formation. Hong
et al. (2006) achieved this by grafting methacrylic acid on chitosan, while grafted
lactic acid provided the water solubility. The crosslinking reaction was initiated via
ammonium persulfate and N,N,N′,N″-tetramethylethylenediamine redox system.
Due to the fast gelation at body temperature, these gels show large potential as
injectable hydrogels.
High-energy irradiation also proved to be suitable for the gelation of chitosan.
Yang et al. (2008) synthesized chitosan/poly(vinyl alcohol) gels by gamma
172 T. Fekete and J. Borsa
irradiation. While the gels showed high water uptake, the mechanical properties
were poor. However, irradiated samples treated with freeze-thawing had higher
mechanical strength.
The crosslinking of alginate systems has a wide literature, the most important
gelation method being the complex formation with multivalent ions. The applica-
tion of divalent cations was extensively studied, from which the calcium cation has
the largest significance. The interaction between the Ca2+ and the alginate chains
leads to the formation of an egg-box structure, where the cations are surrounded by
the polymer layers (Grant et al. 1973). The calcium complexes are still held a large
importance due to the easily achieved gelation and are widely used especially in
medical fields. The calcium source has a major effect on the gelation. Usually,
CaCl2 is used due to its good water solubility and fast crosslink formation. While
5 Polysaccharide-Based Polymer Gels 173
short gelation times are preferred in the practice, too fast gelation can lead to an
inhomogeneous structure. Calcium salts with low solubility like CaCO3 allow an
even distribution of the cations at the expense of slower gelation, leading to
homogeneous gel (Kuo and Ma 2001). A major disadvantage of the Ca-alginate
gels is the low stability which leads to cation release during application (Ng and
Cheng 2007); thus, the applicability of other divalent ions like Fe2+ (Kroll et al.
1996), Sr2+, Ba2+, and Zn2+ (Yang et al. 2013; Harper et al. 2014) was also
investigated: the cation type had a significant effect on the gel properties.
Interestingly, while Mg2+ is often considered as a non-gelling cation, in very high
ion concentrations (5–10 times higher than for Ca2+) in fact it is capable of
crosslinking the alginate; however, the gelation is very slow compared to other
multivalent cations (Topuz et al. 2012). Trivalent ions also show a large potential as
they can interact stronger with the alginate, leading to faster gelation and a more
stable structure. Rochefort et al. (1986) investigated the effect of the treatment of
weakly crosslinked Ca-alginate with Al(NO3)3 solution. The presence of the Al3+
ions led to a significant improvement in the gelation. Al-alginate complexes can
also form without a pre-crosslinking step with calcium ions. Banerjee et al. (2013)
prepared alginate/methylcellulose hydrogels where the Al-complex provided the gel
structure. Depending on the other components in copolymer systems, the cations
can also interact with the other polymer: in alginate/carboxymethylxanthan sys-
tems, the cations interacted with both polymers due to the carboxyl groups (Ray
et al. 2011). Menakbi et al. (2016) also investigated the complexation of several
trivalent cations like Sc3+, Cr3+, and La3+. The binding strength depended on the
cation, but in all cases, it was stronger than for the divalent cations.
While the ionic crosslinking with multivalent cations is a simple method, it also
has disadvantages like the sensitivity to the presence of non-crosslinking ions.
Therefore, other possible crosslinking paths were also investigated. Physical
crosslinking can be achieved alternatively by modifying the chemical structure of
the alginate so new interactions appear between the chains. Boisseson et al. (2004)
introduced long alkyl chains through substitution: the hydrophobic interaction
between the alkyl chains resulted in a gel stable in the presence of ions, although
complexing multivalent cations further improved the stability of the network
structure.
Alginate gels crosslinked with covalent bonds were also prepared both by
chemical crosslinking agents and free-radical crosslinking. In the former case, both
the hydroxyl and carboxyl groups can participate in the crosslink formation
depending on the crosslinking agent. Crosslinkers containing amine groups can
easily react with the carboxyl groups. Moreover, derivatives of hydrophilic poly-
mers like poly(ethylene glycol) used as crosslinking agents also improve the
swelling of the gels (Lee et al. 2000a). On the other hand, glutaraldehyde crosslinks
alginate by reacting with the hydroxyl groups in acidic environment (Kulkarni et al.
2000). Kim et al. (2000b) also used this agent to synthesize alginate-based gel
fibers. Water-soluble carbodiimides as zero-length crosslinking agents were used to
form crosslinks between the hydroxyl and carboxyl groups of the alginate (Xu et al.
2002a).
174 T. Fekete and J. Borsa
Studies focus solely on the chemical gelation of the hyaluronic acid. The
crosslinking routes are somewhat different than for the other polysaccharides:
hyaluronic acid is usually chemically modified by the introduction of new pendant
groups before the gelation. However, the gelation of unmodified hyaluronic acid
was also studied to a smaller extent. First experiments involved crosslinking with
glutaraldehyde (Tomihata and Ikada 1997b); the removal of solvent by
freeze-drying led to a porous chemical gel structure (Collins and Birkinshaw 2011).
Divinyl sulfone is another classic crosslinker which was first utilized for the
preparation of cellulose derivative/hyaluronic acid hydrogels (Sannino et al. 2004).
However, later the focus is shifted to the crosslinking of pure hyaluronic acid
systems. Collins and Birkinshaw (2008) compared the gelation by DVS, glu-
taraldehyde, and freeze-thawing. Covalently crosslinked systems showed better
mechanical properties than the physical gels; moreover, the crosslinking efficiency
of the two molecules also differed as the addition of glutaraldehyde led to higher
crosslink density. It is also important to note that high DVS concentration has a
negative impact on the cytocompatibility, which is a crucial factor for medical
applications (Lai 2014). Ibrahim et al. (2010) also observed that the modification of
gel properties is possible through addition of hyaluronic acid oligomers.
Carbodiimides also play an important role in the synthesis of hyaluronic acid gels:
during the chemical modification of the carboxyl groups, the introduction of the
new functional groups is often carried out with its utilization due to the zero-length
crosslinking. However, the direct crosslinking of the polysaccharide is also feasible
with crosslinking agents containing multiple amine groups: Jeon et al. (2007) used
this method to prepare hyaluronic acid/polyethylene-glycol copolymer gels by
crosslinking hyaluronan with the diamine derivative of PEG. Carbodiimide cross-
linker was also utilized for the crosslinking of pure hyaluronan through esterifi-
cation (Tomihata and Ikada 1997a).
As discussed above, there is an even larger interest toward the use of chemically
modified hyaluronic acids. These newly introduced functional groups are not only
5 Polysaccharide-Based Polymer Gels 175
the participants of the crosslinking process but also affect the gel properties. Even
the formation of autocrosslinkable hyaluronic acid gels is possible, where the
presence of air is adequate to initiate the gelation: through the oxidation of thiol
groups by the oxygen disulfide crosslinks form between the macromolecules (Shu
et al. 2002). The rate of the crosslink formation can be increased by the addition of
crosslinkers which easily react with thiols such as the a,b-unsaturated esters and
amides of poly(ethylene glycol) (Shu et al. 2004). A large variety of substituents
were investigated, typically molecules containing hydrazide, thiol, or aldehyde
groups (Burdick and Prestwich 2011). Acryloyl groups are especially popular as
they are not only capable to react with certain groups like thiols (Hahn et al. 2006)
but also allow the free-radical crosslinking of the polymer. Most commonly
methacrylate groups are introduced through the functionalization with glycidyl
methacrylate (Leach et al. 2003) or methacrylic anhydride (Burdick et al. 2005), but
other acrylates are also often utilized (Sahoo et al. 2008). The formation of free
radicals is usually initiated by UV irradiation in the presence of photoinitiators; the
application of redox initiators is rarely used. The degree of substitution has a major
impact on the gel properties: Bencherif et al. (2008) noted that the crosslink density
increased with the degree of methacrylation, leading to better mechanical properties
at the expense of lower water uptake. To promote the crosslink formation,
co-monomers such as N-vinyl-2-pyrrolidone (NVP) are also sometimes added to
the functionalized hyaluronic acid (Patterson et al. 2010).
5.6.1 Dextran
copolymerization with polymers containing amine groups like gelatin (Draye et al.
1998) or chitosan (Gómez-Mascaraque et al. 2014); the synthesis of pure dextran
hydrogels is also possible with adipic acid dihydrazide modification (Maia et al.
2005). Methacrylated dextran is easily crosslinked in presence of chemical initiator
through free-radical crosslinking (van Dijk-Wolthuis et al. 1997). Moreover, the
acrylated (Kim et al. 1999) and methacrylated (Kim and Chu 2000) derivatives are
used for the formation of photocrosslinkable hydrogels.
5.6.2 Agarose
5.6.3 Xanthan
of various animals. Due to its water solubility, mainly the chemical gelation was
investigated. While pure chondroitin sulfate gels can be prepared with crosslinkers
like ethylene glycol diglycidyl ether (Jensen et al. 2002), most studies focus on the
synthesis of copolymer hydrogels with various natural and synthetic polymers.
The chondroitin sulfate functionalization with N-hydroxysuccinimide (Strehin et al.
2010), adipic acid dihydrazide (Gilbert et al. 2004; Zhang et al. 2011b),
methacrylates (Bryant et al. 2004; Li et al. 2004), or through oxidation (Dawlee
et al. 2005) is carried out for the covalent crosslinking with the other polymer
component even for systems capable of forming ionic complexes like chondroitin
sulfate/gelatin solutions (Kuijpers et al. 2000). The copolymerization can also occur
without functionalization with appropriate crosslinkers like epichlorohydrin (Oprea
et al. (2012).
A wide array of other polysaccharides like the guar gum (Das et al. 2006), tara gum
(Huang et al. 2007, Abd Alla et al. 2012), tragacanth gum (Singh and Sharma
2014), carrageenan (Xu et al. 2003), lignin (Thakur and Thakur 2015), pectin (Sutar
et al. 2008), hemicellulose (Gabrieli and Gatenholm 1998), and psyllium
polysaccharide (Thakur and Thakur 2014) were also investigated to a lesser extent
for the hydrogel formation. Sometimes their pure solution is also used for gel
formation (especially for thermogelling polymers), but usually, they are added as a
natural component for the copolymerization with synthetic polymers, although
rarely they are also mixed with natural polymers to modify their properties.
A large part of such studies focuses on the blends and copolymers of different
polysaccharides due to the similarities in the chemical structure. However, the
modification with other major natural polymers used for hydrogel synthesis such as
collagen also plays an important role.
oxidation; thus, they fulfill the function of the crosslinker (Li et al. 2012b).
Nonionic polymers are often used to improve the gelation: while the electrostatic
repulsion between polymer chains containing charged groups hinders the
crosslinking process, the nonionic component is not affected by it; thus, the
crosslinks form more easily between the macromolecules. Hydroxyethylcellulose is
a good example as it is often utilized to help the crosslink formation of car-
boxymethylcellulose systems (Demitri et al. 2008).
both polymers are generally used. While mostly glutaraldehyde is utilized (Wu
et al. 2007), other less common crosslinkers containing aldehyde groups such as
glyoxal (Wang and Stegemann 2011) or formaldehyde (Zhang et al. 1997) are also
used to a lesser extent. Other agents like genipin (Yan et al. 2010) and carbodi-
imide/N-hydroxysuccinimide system (Rafat et al. 2008; Deng et al. 2010) were
likewise utilized in some studies; the latter one was also used to crosslink hydrogels
based on collagen and the carboxymethyl derivative of chitosan (Chen et al. 2006).
The physical gelation is usually achieved by incubation at 37 °C to promote the
formation of the fibrous structure of collagen, while the chitosan is aggregated with
the increase of the pH (Tan et al. 2001; Chiu and Radisic 2011; Reis et al. 2012).
There is a major interest in the preparation of systems capable of thermal gelation,
as well. Most studies investigated chitosan/b-glycerophosphate systems where the
addition of collagen has a beneficial effect on several properties: such systems not
only gel faster, but they show lower cytotoxicity and slower degradation (Song
et al. 2010; Wang and Stegemann 2010; Li et al. 2012a). As even body temperature
is sufficient for the thermal gelation, these properties make such systems an
excellent material for injectable hydrogels in the medical field.
In case of cellulose-based copolymers, most commonly the native (especially
bacterial) cellulose is used as a second polymer with collagen. Due to the poor
water solubility of the components, the preparation of physical gels is very com-
mon. Two different strategies were utilized: either the two polymers were dissolved
simultaneously and then precipitated (Wang et al. 2013b), or the prepared cellulose
gel is immersed in the collagen solution to allow its absorption and interaction with
the cellulose chains (Zhijiang and Guang 2011). Chemical crosslinking of the two
components is also possible through chemical modification: Saska et al. (2012)
used amino acid or its derivative to modify the polysaccharide, which then cova-
lently reacted with the collagen in presence of carbodiimide crosslinker. This
zero-length crosslinker was also utilized for the solution of carboxymethyl
derivative of cellulose and collagen in presence of adipic acid dihydrazide (Liu
et al. 2013). On the other hand, Cheng et al. (2014) directly introduced aldehyde
groups into the cellulose structure through oxidation, which then reacted with the
amine groups of the collagen.
The literature regarding alginate/collagen hydrogels is even more limited,
despite the complexation of alginate with multivalent cations allowing easy for-
mation of physical composite gels (de Cunha et al. 2014). Moreover, similarly to
the carboxymethylcellulose, the chemical crosslinking of the two polymers with
carbodiimide is also possible due to the presence of carboxyl pendant groups on the
alginate chain (Liu et al. 2008b).
Gelatin-based blend and copolymer hydrogels
While non-modified collagen is widely used, there is an even larger interest in the
utilization of gelatin, the product of the degradation or denaturation of collagen.
Unlike the original polymer, gelatin is soluble in water over 30 °C and cooling its
solution leads to the formation of physical gels (Eldridge and Ferry 1954; Hayashi
and Oh 1983). While chemical crosslinking strategies used for the collagen gelation
5 Polysaccharide-Based Polymer Gels 181
are also applicable for the gelation, due to its larger importance the utilized methods
are much more diverse. Similarly to the collagen, the most commonly used
copolymer polysaccharides are the hyaluronic acid and the chitosan, but there is a
major interest in alginate/gelatin systems and mixing with starch, cellulose, and its
derivatives, as well.
For the synthesis of hyaluronic acid/gelatin hydrogels, the chemical gelation is
utilized in most studies. Similarly to hyaluronic acid/collagen copolymers, car-
bodiimides are the usual chemical crosslinking agents (Zhang et al. 2011a; Zhou
et al. 2013a, b). Derivatization is another common approach for the chemical
gelation. Unlike the collagen-based gels, gelatin is also modified along with the
hyaluronic acid component; thus, both polymers participate in the chemical gela-
tion. Methacrylation is very common to prepare autocrosslinkable hydrogels
(Skardal et al. 2010; Camci-Unal et al. 2013), but reagents containing thiol groups
are also often used to modify both polymers, which then react with each other to
form disulfide crosslinks when exposed to air (Shu et al. 2003). Moreover, the
introduction of crosslinkers like derivatives of poly(ethylene glycol) does not only
increase the gelation rate of the thiolated derivatives, but it also offers a convenient
way to modify the gel properties (Mironov et al. 2005; Vanderhoogz et al. 2009).
Enzymatic crosslinking was also used to a lesser extent: Crescenzi et al. (2002)
utilized transglutaminase-catalyzed copolymerization after the modification of
hyaluronan with dipeptide.
Physical gels of chitosan and gelatin are prepared in multiple steps: the two
components are dissolved separately by adding acid or heating, the two solutions
are mixed, followed by cooling and neutralization (Chang et al. 2002; Nagahama
et al. 2009). For crosslinking through the amine groups, several crosslinking agents
were utilized, such as glutaraldehyde (Yao et al. 1995; Zhao et al. 2002; Franco
et al. 2011), genipin (Cui et al. 2014), and proanthocyanidins (Kim et al. 2005).
They are usually added to the polymer solution, but the immersion of physical gels
in the crosslinker solution is also possible (Shen et al. 2000). Carbodiimides are also
applicable, although in this case only gelatin has the carboxyl groups required for
the crosslink formation; thus, the chitosan chains are not directly crosslinked
(Gorgieva and Kokol 2012). The molecule was utilized for the synthesis of hya-
luronic acid/chitosan/gelatin hydrogels, as well (Tan et al. 2009). Enzymatic
crosslinking catalyzed by transglutaminase is also more advantageous for copoly-
merization with chitosan than for hyaluronic acid/gelatin systems, as the former
polysaccharide does not require functionalization due to the amine groups (Chen
et al. 2003). Besides the chitosan its carboxymethyl derivative was also used for the
copolymerization: Yang et al. (2010) utilized gamma irradiation to initiate the
free-radical crosslinking. Moreover, gelatin-based composite hydrogels containing
chitin nanofibers showed excellent mechanical properties (Hassanzadeh et al.
2016).
While combining alginate with collagen was barely studied, the use of its
denatured form was in-depth investigated. Like for other polysaccharide/gelatin
systems, glutaraldehyde is commonly utilized as a chemical crosslinker for
semi-IPN hydrogels (Dong et al. 2006; Liu and Zhao 2006). The addition of Ca2+
182 T. Fekete and J. Borsa
cations is also often used to achieve IPN structures from semi-IPN through the ionic
crosslinking of alginate (Fadnavis et al. 2003). Another interesting approach is the
enzymatic crosslinking of gelatin instead of the addition of classic crosslinker
molecules (Wen et al. 2014). Moreover, IPN structure was also observed under the
sol-gel temperature of gelatin: in this case, both polymers form physical networks
(Awad et al. 2004; Duan et al. 2013). The major strategy for the covalent
crosslinking of the polymers is the derivatization of alginate through oxidation,
which then reacts with the amine groups in presence of catalyst (usually borax)
(Balakrishnan et al. 2005); the application of such hydrogels is widely investigated
as scaffolds in tissue engineering. Another possible route is the addition of car-
bodiimide for the formation of amide groups (Yang et al. 2009). Aroguz et al.
(2014) used a two-step crosslinking process: first crosslinked oxidized alginate with
adipic dihydrazide and in the following step, the gelatin was added with the car-
bodiimide. The modified alginate can also function as a crosslinker: Sakai et al.
(2008) prepared Ca-alginate/gelatin hydrogel fibers, which were then immersed into
a solution containing oxidized alginate to crosslink the gelatin component, as well.
The application of native cellulose with gelatin is more limited compared to the
collagen. Nakayama et al. (2004) prepared IPN structures by chemically
crosslinking gelatin with carbodiimide, while the cellulose formed a separate
physical network. On the other hand, Dash et al. (2013) used oxidized cellulose
nanowhiskers to covalently crosslink the gelatin solution. However, there is also an
interest toward the use of cellulose derivatives; in these experiments, the formation
of IPN hydrogels was carried out by the addition of glutaraldehyde crosslinker. This
method was used for the gelation of solutions formed with the carboxymethyl
(Rathna et al. 1996; Rokhade et al. 2006) and hydroxyethyl (Kajjari et al. 2011)
derivatives of cellulose, as well.
For starch-based systems, physical gelation is the standard route for the gel
formation. Elevated temperatures, sufficient not only for the gelatin dissolution but
also for the gelatinization of the starch, are used in this process (Abdulmola et al.
1996). Besides the ratio of two polymers, the starch type also has a major impact
on the gel properties (Mallick et al. 2014). Porous gels were also prepared from
such systems: Jaya et al. (2009) used microwave vacuum drying as a more
efficient method compared to freeze-drying for starch/gelatin/hydroxyapatite
composites.
Copolymers based on other amino acid-based polymers
Other polypeptides like albumin were also utilized to a very small extent. Tada et al.
(2007) chemically crosslinked alginate with albumin in presence of carbodiimide
crosslinker; thus, the polypeptide formed the crosslinks between the polysaccharide
chains. On the other hand, Boppana et al. (2010) prepared IPN hydrogel from
carboxymethylcellulose and albumin: multivalent cations were used for the physical
crosslinking of the cellulose derivative, while albumin was crosslinked with glu-
taraldehyde. Interestingly, oligopeptides were also capable to crosslink function-
alized dextran to form hydrogels (Lévesque and Shoichet 2007).
5 Polysaccharide-Based Polymer Gels 183
Most commercial products are based on acrylates due to their low cost and
advantageous properties like responsivity to various environmental conditions.
Therefore, it is not surprising that the copolymers formed with acrylates are the
most widely studied. The first studies involved the application of acrylic acid for the
copolymer gel formation with chitosan: a large advantage over the other polysac-
charides is the presence of amine groups, as in charged form they can interact with
the carboxyl groups of the acrylic acid depending on the pH. Such copolymers were
prepared by Wang et al. (1997) first: the chitosan was chemically crosslinked with
glutaraldehyde, while the poly(acrylic acid) was bound by the electrostatic inter-
action. Moreover, the chemical crosslinking of chitosan is not required for the
formation of such physical gels (de la Torre et al. 2003). While in this case the
acrylic acid was added as a polymer, in most studies its monomer is used instead.
Chemical initiators (Yazdani-Pedram et al. 2000), UV (Lee et al. 1999) and
high-energy irradiation (Shim and Nho 2003) are all common methods to initiate
the reactions of the acrylic acid. Hydrogels by grafting acrylic acid on chitin
(Tanodekaew et al. 2004) and alginate (Yin et al. 2008) were also prepared, but
currently their importance is very small. As for the cellulose, only its car-
boxymethyl derivative was gelated in presence of the acrylic acid (Bajpai and
Mishra 2004; Zhang et al. 2014a). In most studies very high acrylic acid content is
used compared to the polysaccharide; however, very low amount of acrylic acid can
be also utilized to improve the gelation of the polysaccharide solution. This leads to
not only better gel properties but also milder synthesis conditions are required
(Fekete et al. 2016b).
Acrylamide is another common acrylic monomer; its polymerization is likewise
achieved through free radicals. Similarly to the acrylic acid, copolymerization with
chitosan was in-depth studied (Risbud and Bhonde 2000; Kumbar et al. 2003; Xia
et al. 2005). While usually chemical initiator/MBA crosslinker systems are used,
Sokker et al. (2011) also achieved gel formation by high-energy irradiation in the
absence of the crosslinking agent. The irradiation method is also common for the
carboxymethylcellulose/acrylamide systems; while MBA monomer is often used to
improve the gelation (El-Din et al. 2010; Hemvichian et al. 2014), crosslinker-free
184 T. Fekete and J. Borsa
gels were also synthesized (Abd El-Mohdy 2007). Alternatively, the carboxyl
groups of the cellulose derivative allow the preparation of semi-IPN gels by mul-
tivalent cations with polyacrylamide (Aalaie et al. 2013). Alginate/acrylamide gels
also have considerable literature; such gels are synthesized in two-step crosslinking:
acrylamide is crosslinked by free-radical crosslinking, while multivalent cations are
added for the complexation of the alginate (Omidian et al. 2006). Ca2+ cations are
usually used as a crosslinker, but better mechanical properties can be reached
through their replacement with trivalent ions (Yang et al. 2013). Moreover,
free-radical crosslinking alone is also capable of crosslinking alginate/acrylamide
solutions (Kulkarni and Sa 2009b). An interesting method to accelerate the process
is microwave irradiation: Singh et al. (2006b) observed that the gelation was sig-
nificantly faster and low initiator content and air atmosphere proved to be adequate.
While both acrylic acid and acrylamide are widely used separately for copoly-
merization as discussed above, the copolymer of the two is also common due to the
excellent swelling properties related to the presence of both amine and carboxyl
groups. Their first polysaccharide-based copolymers were prepared with starch via
free-radical grafting (Athawale and Lele 2000; Kiatkamjornwong et al. 2000). The
ratio of the two monomers had a major impact on the water uptake: the use of their
mixtures led to better swelling properties than when only one of them was added.
Acrylic acid-co-acrylamide gels were prepared with several polysaccharides such as
cellulose (Wu et al. 2012a), chitosan (Mahdavinia et al. 2004), and their derivatives
(Suo et al. 2007; Yin et al. 2007). Alginate-based copolymers were also synthe-
sized: in this case, crosslinking with multivalent cations was also utilized next to the
chemical crosslinking (Yahși et al. 2005). Other components like methacrylates (Li
2010) or clay minerals (Rashidzadeh et al. 2014) are also commonly introduced to
improve the properties. While the acrylamide and acrylic acid is mostly added in
monomer form, other synthesis routes are also available: Sadeghi and Hosseinzadeh
(2007) copolymerized CMC and polyacrylonitrile (PAN); the amino and carboxyl
groups were formed by the alkaline hydrolysis of PAN in presence of ammonia.
An even more intensively studied monomer is the N-isopropylacrylamide
(NIPAAm) as its thermosensitivity even at low temperatures makes it an excellent
candidate for medical hydrogels. Copolymer and IPN hydrogels formed with
alginate and chitosan have the largest literature. The former polysaccharide is used
mostly for the preparation of IPN structures achieved by free-radical crosslinking of
the alginate/NIPAAm solution, followed by complexation of the alginate with Ca2+
cations (Guilherme et al. 2005; Petrusic et al. 2012). Semi-IPN structures are also
attainable: Ju et al. (2002) and Shi et al. (2006) used the polymer of the acrylamide
derivative to prepare ionically crosslinked alginate/PNIPAAm solution: the physi-
cally crosslinked alginate matrix bound the acrylate chains through weak interac-
tions. However, the alginate does not necessarily form the crosslinked network: if
only the free-radical crosslinking of the mixture solution is carried out, then the
covalently crosslinked network is formed by the PNIPAAM (Zhang et al. 2005a;
Dumitriu et al. 2010). Semi-IPN gels show better swelling properties than their
full-IPN counterparts, but the deswelling is slower (Lee et al. 2006).
Functionalization also offers another route to chemically crosslink the two
5 Polysaccharide-Based Polymer Gels 185
6.2.2 Polyvinylpyrrolidone
Synthetic polymers other than acrylates are also widely used for the copolymer-
ization with polysaccharides. Other common synthetic polymers, especially ones
widely applied in the medical field, are also investigated to achieve better properties
than the homopolymer gels. Polyvinylpyrrolidone is a popular material for hydrogel
synthesis as its thermosensitivity is very advantageous in the medicine similarly to
the PNIPAAm. However, the relatively low swelling and poor mechanical prop-
erties (especially fragility) led to the investigation of its copolymers to counter these
disadvantages, for which polysaccharides also proved to be effective besides the
usual acrylate copolymers (Wang et al. 2007). While in some studies the monomer
of the PVP was added to the solution (Ișıklan et al. 2008), usually its polymer with
varying molecular weight is utilized. There is an especially large focus on chitosan/
PVP hydrogels; in earlier studies, semi-IPN gels were synthesized by chemically
crosslinking the chitosan with glutaraldehyde (Risbud et al. 2001; Risbud and Bhat
2001) or genipin (Khurma et al. 2005). However, recently the interest shifted
toward the radiation-induced crosslinking (Nho and Park 2002; Dergunov et al.
2005; Archana et al. 2013). The latter method was also used for the copolymers
formed with carboxymethylchitosan (Zhao et al. 2006), starch (Zhai et al. 2002),
and alginate (Singh and Singh 2012), as well. For the latter polysaccharide, com-
plexation was also utilized for the preparation of physical gels (Doria-Serrano et al.
2002). Out of the cellulose-based copolymer gels, the major focus is on the car-
boxymethylcellulose (Wang et al. 2007; Lü et al. 2010); besides the chemical
crosslinking, heat treatment under pressure similarly proved to be a viable method
for physical gel formation (Roy et al. 2010). The addition of hydroxypropyl
(Marsano and Bianchi 2002) and methylhydroxyethyl (Plungpongpan et al. 2013)
derivatives of cellulose also had a positive impact on the properties of PVP gels.
PVP is also a frequent copolymer for less studied polysaccharides like pectin
(Mishra et al. 2008) and j-carrageenan (Relleve et al. 1999; Abad et al. 2003) in the
hydrogel formation.
lead to the gel formation (Minoura et al. 1998). Moreover, while heat treatment at
higher temperatures is common (Koyano et al. 1998; Jin and Bai 2002; Zhu et al.
2012), the gelation may occur under body temperature or even room temperature
depending on the ratio of the components, making it ideal for medical applications
(Tang et al. 2007). Chemical gels were also prepared by various methods, such as
the addition of glutaraldehyde (Wang et al. 2004b; Costa-Júnior et al. 2009; Kumar
et al. 2009), ethylene glycol diglycidyl ether (Liu et al. 2010), UV (Kim et al.
2003), or gamma irradiation (Nho and Park 2002). Yang et al. (2008) combined
freeze-thawing and irradiation: they observed that even the order of the two
crosslinking steps affected significantly the gel properties. Besides chitosan, its
carboxymethylated derivative was also used for the formation of physical (Lee et al.
2009) and chemical (Zhao et al. 2003b) gels with PVA. For starch/PVA systems,
the pregelatinization of the starch is generally utilized. While films were also
prepared through pure physical crosslinking by heat treatment (Spiridon et al. 2008;
Tang et al. 2008), for the hydrogel synthesis, the pregelatinized systems are also
chemically crosslinked in the following step. This is achieved with crosslinkers
capable of reacting with hydroxyl groups like citric acid (Shi et al. 2008) or
formaldehyde (Han et al. 2009); free-radical crosslinking initiated with gamma
irradiation is another possible way to avoid the use of such additives (Zhai et al.
2002). Interestingly, physical gels were also prepared by freeze-thawing after
grafting PVA onto the starch backbone (Xiao and Yang 2006). Studies involving
unmodified cellulose hydrogels focused on its physical gelation by the freezing
method (Millon and Wan 2006; Chang et al. 2008). On the other hand, for the
carboxymethyl derivative physical (Barkhordari et al. 2014), chemical crosslinking
(Taleb et al. 2009; Rao et al. 2012) and a mixture of the two steps (El-Salmawi
2007) were also examined. So far there was only minor interest in other cellulose
derivatives, although Park et al. (2001) studied the gelation of methylcellulose/PVA
solutions in presence of glutaraldehyde. For hyaluronic acid-based copolymers,
both physical crosslinking with freeze-thawing (Guerra et al. 1994) and chemical
gelation with glutaraldehyde (Kim et al. 2004) were investigated.
previously functionalized through reaction with DVS, as well (Jin et al. 2010).
Likewise, PEG is also often chemically modified with various reagents to make the
direct reaction with the polysaccharide possible. The diglycidyl ether of PEG is an
excellent crosslinker due to the reactive epoxy groups (Kono 2014). Another good
example is the introduction of amine groups which in the presence of carbodiimide
crosslinker easily react with polymer containing carboxyl groups, such as the
alginate (Eiselt et al. 1999) or hyaluronic acid (Jeon et al. 2007). UV-initiated
crosslinking is a viable strategy if vinyl groups are present in the polymer—this is
usually achieved by various acrylates (Leach and Schmidt 2005; Zhong et al. 2010).
In such systems, both PEG and the polysaccharide are modified to contain double
bonds. The two components can also be functionalized using different groups which
easily react with each other: Shu et al. (2004) used thiolated hyaluronic acid and
PEG modified with various acrylates for chemical crosslinking. If only PEG is
functionalized, hydrogels with interpenetrating network can be prepared; this is
especially characteristic for chitosan/PEG systems, where the chitosan is cross-
linked with glutaraldehyde, while the reaction of the acrylated PEG is initiated by
UV irradiation (Lee et al. 2000b; Kaewpirom and Boonsang 2006). The gelation is
often carried out by high-energy irradiation, as well; this allows the crosslinking
without the functionalization of the polymers due to the free radical formation. This
strategy was utilized for carboxymethylcellulose/PEG copolymer hydrogels (Lee
et al. 2005; El-Din et al. 2013).
Recently, there are major efforts for the use of various inorganic materials for the
preparation of composite gels. Studies focus on two major groups of inorganic
components: clays and metal nanoparticles. The application of the two groups is
fueled by very different goals. Clays are very cheap resources available in abun-
dance. While their presence also modifies the gel properties, the main reason for
their use is to reduce the costs of the gel preparation. On the other hand, the aim of
the metal nanoparticle incorporation is the introduction of novel properties, such as
the antibacterial behavior. The mineral content of the composites shows a large
variety: in some experiments, only very low amounts of it are added, while in others
the inorganic content is over 50%.
6.3.1 Minerals
While minerals are usually added in their natural form to lower the production
costs, the chemical modification of clays is also an interesting approach to adjust
their properties depending on the application field. So far, only the organic modi-
fication (achieved through the replacement of cations with molecules containing
hydrophobic groups like cationic surfactants) is relevant for the hydrogels, espe-
cially in case of montmorillonite. The change in the structure leads to a more
hydrophobic character which hinders the gelation process (Xu et al. 2006).
However, this property can be utilized in the water treatment: the hydrophobic
interactions participate in the adsorption of certain pollutants, leading to higher
adsorption capacity (Wang and Wang 2013). Recently, organically modified illite
was also employed for the preparation of composite gels with alginate for dye
adsorption (Wang et al. 2013g).
Double layered hydroxides (DLH) have a very different structure compared to
the silicates. The cations form a layer structure which is surrounded by the anions
and other molecules like water. Hydrotalcite is the most often used native mineral,
but synthetic double layered hydroxides are also significant. The multivalent ions
present in their structure interact with negatively charged groups on the polymers,
thus leading to complex formation. Barkhordari et al. (2014) prepared
carboxymethylcellulose/DLH composite hydrogels by heating the alkaline solution
of the two components; the high pH promoted the deprotonation of the carboxyl
groups so it was possible for the multivalent metal ions to interact with them. The
cationic layer can also bind other anions; thus, they also show potential as adsor-
bents (see Sect. 7.2). The cations present in the structure also affect the gel prop-
erties: Yadollahi et al. (2015c) compared different carboxymethylcellulose/DLH
composites, and they found that DLH containing zinc or copper cations also pro-
vided antibacterial activity to the gels.
The preparation of gels containing metal particles has two major requirements: the
nanoparticles need to be homogeneously dispersed in the gel structure and inter-
actions with the polymer should prevent their diffusion into the environment. They
are usually added in salt form to the polymer gel: as they are present as ions due to
the dissociation, charged groups on the polymer chain can bind them to the gel
network. In earlier studies, copolymers with synthetic polymers were used, but
recently the nanoparticles were also incorporated in a wide array of pure
polysaccharide hydrogels: systems based on cellulose derivatives (Hebeish et al.
2013), starch (Villanueva et al. 2016), chitin and chitosan (Kumar et al. 2012,
2013), alginate (Obradovic et al. 2012), and even dextran (Ma et al. 2009). The
synthesis heavily depends on the metal type. Silver is a very popular choice for
antibacterial nanoparticles; it is added to the gel as aqueous solution of AgNO3.
There are two available methods: either the crosslinked gel is immersed in the silver
nitrate solution (Ma et al. 2009), or the salt is added to the dissolved polymer before
the crosslinking (Yadollahi et al. 2015a); this ensures the homogeneous dispersion
5 Polysaccharide-Based Polymer Gels 191
of the nanoparticle. The next step is the reduction of the silver cations, leading to
the formation of silver particles. Antibacterial hydrogels containing gold
nanoparticles were also synthesized. Marsich et al. (2011) used HAuCl4 precursor
to prepare modified chitosan/alginate/gold hydrogels.
While the effect of the silver and gold nanoparticles is widely studied, their high
cost is a relatively big disadvantage, leading to the investigation of the applicability
of cheaper alternatives. Various metal oxides with antibacterial properties like the
copper (Yadollahi et al. 2015b) and zinc (Kumar et al. 2012) oxides proved to be
perfect candidates. Similarly to the silver, they are added in salt precursor form
(CuCl2, Zn(NO3)2, or zinc acetate); the synthesis is analogous to the silver
nanocomposite gels: the hydrogels are immersed in their solution and oxides are
formed during an oxidation step. Metal oxide nanoparticles exhibit very good
antibacterial properties despite their significantly lower cost; thus, their importance
shows a constant growth. Titan dioxide is another interesting nanoparticle as it not
only exhibits antibacterial activity but also improves the mechanical strength of the
hydrogel (Archana et al. 2013). Unlike other oxides, it is mixed with the
polysaccharide solution in its oxide form instead of using precursors.
Another interesting application is the preparation of hydrogels with magnetic
properties. This is especially advantageous in the utilization as adsorbents, where
the hydrogel is used in form of small beads or particles. Incorporating the magnetic
particles allows the removal of these beads from the water by a magnetic field,
making their recovery a lot easier. The polysaccharide also plays a major role in the
synthesis: the polymer forms a coating around the nanoparticles, preventing their
aggregation. Magnetic properties were first achieved by Fe2O3 (Kroll et al. 1996);
however, in more recent experiments Fe3O4 nanoparticles are used as magnetic
nanoparticles (Shen et al. 2011).
While there is a vast literature available about the potential application of hydro-
gels, studies related to polysaccharide-based gels are much more limited and
focused on certain fields. The largest interest toward their use is in the medical field
due to the biocompatibility and the common responsive behavior. The absorption
and desorption of various chemicals are also utilized in the water treatment and
agricultural applications—the good biodegradability is another important advantage
in the latter field. Studies related to applications in other fields are so far pretty
limited; thus, only a short summary is given for them.
Studies focus mainly on three major applications: controlled drug delivery systems,
wound dressings, and scaffolds for tissue engineering. However, to a lesser extent,
192 T. Fekete and J. Borsa
the utility of carbohydrate-based systems was investigated for the use as bulking
agents and components for contact lenses, as well. Moreover, it is important to note
that these applications are not strictly separate: for example, wound dressings and
scaffolds often contain bioactive agents; thus, such systems function as drug
delivery systems, as well.
Another major application of the hydrogels is the wound dressing. The function of
the dressings is not only to prevent the infection but also promote the healing
process. Moreover, several factors can hinder the healing—for such
healing-impaired wounds, further considerations are required in the dressing
preparation. Hydrogels are only one of the numerous types of dressings, but their
properties such as the high water content or the ability to absorb wound fluids make
them preferable compared to other products (Stashak et al. 2004). This not only
provides a cooling effect for the damaged skin, but the moist environment is also
beneficial during the healing process. Physically crosslinked alginate dressings are
especially important polysaccharide-based systems; such products are widely
available even in commercial use (Boateng et al. 2008). However, they are mostly
used in non-gel form like fibers. Moreover, recently adverse effects were also
reported during their application due to the high Ca2+ concentration in the product
(Ng and Cheng 2007).
Chitosan and other chitin derivatives are subjects of intense research as materials
for hydrogel dressings. The degradation during their use leads to the release of
various glucosamine monomer and oligomer molecules which accelerate the
healing processes (Muzzarelli 1993). The healing is even faster if tissue culture
medium is incorporated in the hydrogel (Kiyozumi et al. 2006). Due to these
degradation products, they are also often added to other dressing systems such as
alginate fibers (Knill et al. 2004) or grafted polypropylene fabrics (Yang and Lin
2004) to enhance their beneficial effect. Pure chitosan systems are mostly utilized
for the preparation of photocrosslinkable hydrogels; this method offers a nonin-
vasive way to protect the wound: the chitosan is chemically modified and after the
injection onto the surface it is gelled by UV irradiation (Ishihara et al. 2001; Lu
et al. 2010).
194 T. Fekete and J. Borsa
While the utilization of hyaluronic acid was in-depth investigated (Price et al.
2005), it is rarely used in hydrogel form. Cellulose-based gels also hold little
importance in this application, although there are recent investigations concerning
the use of hydrogels of poly(vinyl alcohol) combined with cellulose (Gonzalez et al.
2014) or its acetate derivative (Abd El-Mohdy 2013).
Hydrogels in this field often contain other components which further enhance their
positive effects. Additives exhibiting antibacterial activity are especially common as
the disinfection of the wound also accelerates the healing. Such effect is easily
achieved by the incorporation of various antibiotics, where controlled release ensures
its long-term effect. Usually, chitosan-based hydrogels are used for such systems
(partly due to the antibacterial activity of native chitosan), although hydrogels based
on other carbohydrates like alginate were also investigated to a lesser extent. A wide
array of drugs like ciprofloxacin lactate (Yu et al. 2006) sulfadiazine (Mi et al. 2002),
nitrofurazone (Kim et al. 2008b), and minocycline (Sung et al. 2010) were used as
model molecules. However, there are major efforts to avoid the use of such drugs.
Honey is a natural material very effective to help the healing process; it was used as a
bioactive component in chitosan/gelatin hydrogels (Wang et al. 2012). Chitosan/
fucoidan (sulfated polysaccharide extracted from algae) hydrogels similarly showed
superior properties compared to pure chitosan (Sezer et al. 2008).
Various metal nanoparticles also exhibit antimicrobial behavior; thus, such
dressings are capable to disinfect the wound. In hydrogels, the nanoparticles are
dispersed in the polymer matrix (see 5.6.3.2). Silver nanoparticles are widely
known for their antibacterial activity. While there is a large interest in
chitosan-based composites (Lu et al. 2008), this property is also useful for
polysaccharides which do not exhibit antibacterial activity like cellulose
(Maneerung et al. 2008). Madhumathi et al. (2010) also observed faster blood
clotting when chitin/silver nanoparticle hydrogel was applied to the wound.
However, due to the relatively high cost, cheaper alternatives like metal oxides were
also investigated. Archana et al. (2013) utilized TiO2 nanoparticles to enhance the
properties of chitosan–PVP gels as they show minimal cytotoxicity compared to
other nanoparticles. Similar results were observed when ZnO was dispersed in
chitosan hydrogel (Kumar et al. 2012).
however, their medical utility is not solely limited to this field as they show a large
potential in the urology, as well. Urinary incontinence is a common disorder for
women and injectable hydrogels allow a minimally invasive way for its treatment.
Currently, only hyaluronic acid-based bulking agents are available in the com-
mercial use as polysaccharide-based products (Vaizey and Kamm 2005; Mohr et al.
2013). However, Thornton et al. (2004) also investigated the application of various
alginate hydrogels. They noted that covalently crosslinked alginate shows good
potential for such use, although very high crosslink density increases the inflam-
matory response.
There are some advances toward their use in the dietary applications, as well.
Such products are utilized to promote the weight loss as an alternative for more
drastic strategies like surgery. Hydrogels offer a novel way to achieve such effect
compared to the currently available products due to their very high water absorbing
capacity. Sannino et al. (2006, 2010) investigated the use of carboxymethylcellulose/
hydroxyethylcellulose hydrogels as stomach bulking agents: the copolymer not only
showed high water uptake at acidic pH, but the results of tests regarding biocom-
patibility were also favorable. Another interesting approach for the hydrogel uti-
lization is the preparation of oil bulking agents: by incorporating oil droplets in the
gel structure, such systems can serve as replacement for animal fat (Ruiz-Capillas
et al. 2013; Herrero et al. 2014).
The preparation of contact lenses is another field where the properties of the
hydrogels excel. However, studies related to the preparation of polysaccharide-based
contact lenses are much more limited. While contact lenses based on chitosan/gelatin
composites were successfully synthesized and the products showed good properties
(Shi and Tan 2004), no further advancement toward their commercial use was made.
On the other hand, the incorporation of non-crosslinked hydrophilic polysaccharides
such as hyaluronic acid (Ali and Byrne 2009) and hydroxypropylmethylcellulose
(White et al. 2011) in contact lens offers a way to reduce ocular dryness caused by
the lenses and reduced protein sorption through their slow release, effectively
functioning as a wetting agent on the lens surface. A more long-term effect can be
achieved by photocrosslinked hyaluronic acid, where the properties are also affected
by the crosslink density (Weeks et al. 2012). Moreover, polysaccharide coatings
even allow the incorporation of bioactive molecules to prepare lenses capable of
controlled drug delivery (Hu et al. 2014).
to the adsorption of the pollutant, excellent adsorption can be only achieved when
charged groups capable of ionic interactions are present.
For pure polysaccharide hydrogels, the adsorption of anionic dyes was mainly
investigated. For this application, chitosan-based hydrogels show a large potential.
The amine groups at low pH become protonated; thus, they form ionic bonds with
the anionic dye. Opposed to the adsorbents used for cationic dyes, chitosan-based
gels show the highest adsorption at acidic pH. Increasing pH leads to the depro-
tonation of amine groups and the dye is bound only with weak interactions,
resulting in a significantly lower adsorption capacity. The adsorption capacity can
be further enhanced by additives like surfactants (Chatterjee et al. 2009). Shen et al.
(2000) also compared chitosan with chitosan-Fe(III) hydrogels prepared from FeCl3
solution. The Fe(III) groups can also interact with the dye molecules, improving
their sorption. By introducing Fe3O4 nanoparticles, the chitosan-Fe(III) complex
also exhibited magnetic properties. Cationic hydrogels can be prepared from other
polysaccharides, as well. Yan et al. (2009) synthesized hydroxypropylcellulose gels
by crosslinking the polymer with epichlorohydrin and ammonia at alkaline pH. The
amino groups in the crosslinks led to a high adsorption capacity toward anionic
dyes.
Studies related to the removal of cationic dyes are more limited. While alginate
hydrogels showed good potential in this field (Aravindhan et al. 2007), most studies
investigated the use copolymer systems formed with acrylates (Cai et al. 2013;
Zhang et al. 2014a). Composite gels with a mineral component are also commonly
used for this application. The cationic dyes interact with the anionic clay through
the exchange of cations surrounding the surface (Wang et al. 2004a).
Polymers with charged groups were also utilized for other pollutants.
Methylcellulose/acrylamide hydrogels proved to be successful in adsorbing para-
quat pesticide from water (Aouada et al. 2009). Chatterjee and Woo (2009) used
chitosan hydrogels for the removal of nitrate as an alternative method for denitri-
fication. However, the efficiency of the adsorption heavily depends on the pollutant,
as well. Sowyma and Meenakshi (2013) investigated the effect of various ionic
molecules on the adsorption: different ions showed different affinity toward the
hydrogels; thus, the hydrogels show a degree of selectivity toward certain pollu-
tants. This is advantageous as lower adsorption capacity is required for the removal
of target pollutants during water treatment.
separated into two categories: delivery of chemicals and soil conditioning. As the
cost efficiency is a major factor due to the volume of the hydrogels required for the
modification of the soil, only the most abundant polysaccharides are of large
interest.
(Zhong et al. 2013). Recently, pure polysaccharide-based gels were also investi-
gated for slow fertilizer delivery. Both ionically (Davidson et al. 2013) and
chemically (Ni et al. 2011) crosslinked cellulose derivative superabsorbents proved
to be a viable alternative for the copolymer-based fertilizers. Interestingly, chemical
cellulose acetate hydrogels crosslinked with polycarboxylic acid were also studied
besides the usual cellulose ethers (Senna et al. 2015).
While the focus of the studies is on the application as fertilizers, hydrogels also
allow the controlled release of other chemicals, which offer protection against pests
(pesticide), weeds (herbicide), and fungi (fungicide). The largest interest is shown
toward the controlled release of pesticides. The incorporation of the molecules is
similar to the method detailed for fertilizers. A wide array of pesticides were
examined in such experiments, and the release kinetics was also determined. This is
important because the chemical structure of the bioactive agents also affects the
release kinetics (Abd El-Mohdy et al. 2011). First, such experiments were carried
out with starch matrices crosslinked with formaldehyde (Kulkarni et al. 1999;
Kumbar et al. 2001), but later the interest shifted toward alginate-based systems.
Both ionically and chemically crosslinked alginate system showed good potential
for the incorporation. While Ca2+ cations are the standard crosslinkers of the
physical gels (Roy et al. 2009). Ișıklan (2007) observed that by using different
multivalent cations, the release kinetics is controllable. Chemical crosslinking with
glutaraldehyde was utilized for blends with other polysaccharides and polypeptides
(Kulkarni et al. 2001; Ișiklan 2006). Chitosan-based controlled release systems
were also prepared: while Rao et al. (2006) used AAm-g-PVA IPN structured gels,
Yi et al. (2011) avoided the use of crosslinkers and copolymers by using azide
functionalized photocrosslinkable chitosan.
Herbicides were investigated to a smaller extent, despite their encapsulation in
starch already being studied decades ago (Trimnell et al. 1985). Cellulose
derivative-based gels show a large potential in this field. In earlier experiments, the
copolymers of hydroxyethylcellulose were used (Rehab et al. 1991), but recently
the carboxymethylcellulose/clay gels became more important: the easy ionic
crosslinking through the carboxyl groups renders the copolymers redundant (Li
et al. 2008, 2009). The presence of clay not only slows the release of the agent, but
its rate can be adjusted by the clay type and ratio. The encapsulation also leads to
lower environmental impact: Grillo et al. (2014) observed that herbicide in chitosan
gels showed lower toxicity despite its activity being not affected.
Studies related to the controlled release of fungicides are few. Singh et al. (2007,
2009a, b) investigated the application of various starch gels in this field. While
copolymers with acrylates were also prepared, the addition of ionically crosslinked
alginate proved to be a good alternative for the synthetic polymer component.
Experiments were carried out with thiram as a model fungicide; the release rate was
controlled by the crosslink density.
5 Polysaccharide-Based Polymer Gels 201
Another application field with a growing significance is the soil conditioning: the
goal is to improve the water retention of the soil, thus increasing the yield of the
agricultural plants and lowering the need of the irrigation. Moreover, such modi-
fication may allow cultivation even in lands with very poor retention such as sandy
soil. Superabsorbents are capable of trapping large amounts of water, thus
decreasing the gravitational drain of free water after the irrigation. However, the
water is not strongly bound in the gel structure; thus, it is available for the plants.
As gels with superabsorbent properties are used usually for the controlled release of
bioactive agents, a large part of the related studies also investigated the effect of the
gels on the water retention and plant growth. Similarly, the majority of such
experiments used polysaccharide/acrylate systems as model superabsorbents.
Acrylamide is an especially popular co-monomer which was used for copolymer-
ization with carboxymethylcellulose (Ibrahim et al. 2007), starch (Qiao et al. 2016)
and alginate (Abd El-Rehim 2006). The application of pure polysaccharide
superabsorbents was also studied. Nnadi and Brave (2011) prepared
carboxymethylcellulose/starch gels by pregelatinization and ionic crosslinking. The
superabsorbent mixed into the soil in 0.3–0.6% concentration significantly pro-
moted the plant growth. Biodegradability is also a crucial factor in this field.
Superabsorbent gels from succinic acid-crosslinked starch (Yoshimura et al. 2006)
showed similar or only slightly slower biodegradability than pure starch depending
on the synthesis conditions. Alginate and chitosan hydrogels are also very good
candidates for this application: as mentioned previously, the products of the
hydrogel degradation promote the plant growth, leading to more desirable prop-
erties (Abd El-Rehim 2006). In the future, chitosan-based gels might also have a
larger role, as they show fungicidal activity (Badawy et al. 2004).
The potential application of hydrogels is much wider than the fields covered so far
in this section. However, there are only a few studies related to these uses con-
cerning polysaccharide-based hydrogels. For example, while the application of
polysaccharides in catalysis was investigated, especially in case of chitosan (Guibal
2005), they are not utilized in hydrogel form. In the few available studies, the
polysaccharide hydrogels are used as a matrix for the immobilization of the
nanoparticle catalyst (Saha et al. 2010; Wu et al. 2012b). In some cases, the
hydrogel itself catalyzes the reaction: Reddy et al. (2006) used chitosan gel as a
catalyst for aldol and Knoevenagel reactions. In sensors, the hydrogel functions as
the structural component; glucose (Brown et al. 2005), phenol (Zhang and Ji 2010),
and enzyme-sensing (Ebrahimi and Schonherr 2014) systems were prepared from
chitosan-based hydrogels. Another interesting utility is the synthesis of self-healing
gels. In such systems, defects and cracks can heal over time; thus, the structural
202 T. Fekete and J. Borsa
8 Conclusions
The application of polysaccharides for hydrogel formation has a bright future. They
are not only cheap and abundant materials, but a wide array of methods are
available for the gel formation. The large variety in the functional groups results in
properties advantageous in several applications, such as the responsive behavior.
Moreover, the easy chemical modification and mixing with other natural polymers
allow a convenient way to achieve the desired properties. Such systems offer a more
environmentally friendly and sustainable alternative for the acrylate-based products.
Currently, the main interest lies in copolymers and blends with synthetic polymers;
thus, the advantages of both components can be utilized simultaneously. However,
the trend is shifting toward pure polysaccharide and other natural polymer-based
systems as they proved to be a good substitute for acrylates in an increasing number
of fields.
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5 Polysaccharide-Based Polymer Gels 227
Keywords Polymeric gels Hydrogels Biopolymers Polysaccharides
Pharmaceutical formulations Topical delivery Gel systems
1 Introduction
The topical delivery treatment is a preferred route for various skin diseases. Most of
the medicated products are applied directly on the skin or at the level of the mucous
membrane which either enhances or restores a fundamental functions of the skin.
Such products are referred as dermal or transdermal products. Within Fig. 1 is
shown a representative image of the skin describing its physiology and functions
described by Venus et al. (2011).
The dermal preparations are applied to local act. The drug remains on the skin
surface or in some cases, it penetrates through the epidermal layers and may reach
the dermis. For local applications, the drugs are not absorbed into the blood
Fig. 1 Structure of the skin. With permission from Elsevier from (Venus et al. 2011)
Many of biodegradable polymers are coming form natural sources (Trache et al.
2017; Corobea et al. 2016; Voicu et al. 2016; Miculescu et al. 2016). They become
even more attractive by the time passing as combination of their properties e.g.
biocompatibility, lack of toxicity, biodegradability some of them exhibiting specific
characteristics like responsivity to external stimuli, gelling abilities, susceptibility to
be chemically modified to obtain new materials; moreover, the natural polymers
have more than one functional group on the structural unit as compared with
synthetic polymers, therefore an increased reactivity and possibility to form inter-
polymeric associations (Kontogiorgos et al. 2015; Cheaburu and Bumbu 2009;
Pappu et al. 2015, 2016).
In the last decades a huge number of scientific reports were dedicated to gels/
hydrogels and many having as common subject of biopolymers within pharma-
ceutical, food and medical applications, fields which all require non-toxicity for
human health (Sagiri et al. 2014; Pamfil and Vasile 2017). The class of bio-derived
polymers which are found naturally, includes proteins (peptides, proteins, collagen,
silk, keratin, elastin, etc.), nucleic acids (e.g., self-assembling DNA hydrogel
(Nishida et al. 2016); Y-shaped DNA units functionalized with Ag-nanoclusters as
fluorescent hydrogels (Guo et al. 2013), lignin (Thakur and Thakur 2015) and
polysaccharides (chitosan, alginate, carragenan, hyaluronic acid, psyllium, etc.)
(Babu et al. 2013; Thakur and Thakur 2014). These bio-based polymers have
shown enormous interest in recent years as regarding the developments in their
structure modification and their applications.
The present chapter deals with the reviewing of state-of-art of gel/hydrogels used
for pharmaceutical applications, enphasizing on the role of polysaccharides-based
systems within the prepared formulations for different topical applications.
Conventionally, polymers were used just as tablet binders; in modern and
advanced dosage forms, the role of polymers became more important as they need
to protect the loaded drug for a determined time period, mask the taste, to release
drugs in a controlled manner and to target them to a specific site, therefore the drug
bioavailability will increase as well. The rheology modification represents another
property that is considered important in liquid dosage forms (Sagiri et al. 2014).
2 General Aspects
The concept of gel was mentioned for the first time by (Papkov 1974) and later by
(Tanaka 1985).
The terms, gels and hydrogels are interchangeably used by scientists to describe
polymeric crosslinked network structures able to absorb a high amount of liquids,
respectively water (Gulrez et al. 2011). Rogovina et al. (2008) described a gel as
being a solid which comprises at least two constituents, the polymeric one, which
may form the three-dimensional network via covalent or noncovalent bonding
234 C. N. Cheaburu-Yilmaz et al.
(giving chemical and physical gels, respectively) in the medium of the second
constituent (a liquid one). The minimum amount of the liquid is theoretically
enough to ensure elastic properties to the gel. The network structure is formed as
result of physical bonding (namely, physical gels) or chemical bonding (i.e.,
chemical gels), crystallites or other junctions persisting in the same state within the
extending fluid (Huang et al. 2002). Peppas and Buri (1985) reported a theory for
polymer gels based on so-called Single-Chain Mean-Field (SCMF) theory. This
theory uses the mesh chain or the star polymer as the characteristic units for the
polymer gels, and it grants the study of chain conformation in its different gel
stages.
A general accepted classification of the gels/hydrogels was done by various
researchers and two main categories were evidenced: permanent or chemical gel;
the terms “permanent” or “chemical” gels reflect the covalently crosslinked net-
works and reversible or physical gels (Hennink and Nostrum 2002). The permanent
type of gel reaches a steadiness of swelling state (equilibrium) which depends on
the polymer–water interaction parameter and the crosslink density (Rosiak and
Yoshii 1999).
In the second one the crosslinks are clamped together by molecular entangle-
ments, and/or secondary forces including ionic, hydrogen bonding, or hydrophobic
interactions. In the case of these gels, dissolution is limited by physical interactions,
which exist between the different polymer chains (Hennink and Nostrum 2002). All
of these interactions are reversible, and can be destroyed by the changes which
occur in physical conditions or in the case of a stress or shear load application
(Rosiak and Yoshii 1999).
Gels are also categorized as weak or strong depending on their flow behavior in
steadystate (Russo 1987; Ferry 1961) Singhal and Gupta in their comprehensive
review (Singhal and Gupta 2016) took into account the presence or absence of
electrical charge located in the crosslinked chains and classified the gels
accordingly.
In past decades an increased interest on the gel preparation was observed as the
applicative aspect started to become more important. Correlations between the
characteristics of the polymeric material and the practical needs in various fields
became a “must.” Various reports and reviews were published emphasizing the
importance of the preparation method of the gel/hydrogels to obtain the desired
properties for specific applications (Singhal and Gupta 2016; Ahmad and
Asifmahmood 2016; Secchi et al. 2013).
As a general accepted concept, gelation process is assigned to the phenomena of
linking the macromolecular chains together, up to the structure of polymers and
their conformation producing a highly branched polydisperse, yet soluble polymers
defined as “sol.”
6 Polysaccharide Containing Gels … 235
Propagation of the linking process leads to the increasing the extent of the
crosslinked polymer with decreasing solubility. This “limitless polymer” is named
as “gel” or “network” (Gulrez et al. 2011).
This evolution from a system with soluble finite branched polymer to infinite
molecules is claimed as being a “sol-gel transition” (or “gelation”) and the crucial point
at what gel is firstly formed is so-called the “gel point” (Rubinstein and Colby 2003).
Most of the biopolymers form gels more readily in water than in organic sol-
vents, e.g., renaturation to the triple helical conformation in gelatin and double
helical conformation in polysaccharides controls the nucleation and growth of
crystallites during gel formation. At high temperatures, they have a random coiled
conformation (Jeong et al. 2012). As temperature decreased, they form double
helices and aggregates and further behave like crosslinking joints. One example on
how a polysaccharide-based matrix is forming the gel in water is shown in Fig. 2.
The random coils are changing the conformations into helices-like, which further
aggregate and form the gel with its junction’s sites.
An example was reported by Jeong et al. (2012). They attached hydrophilic
segments on the water insoluble cellulose and obtained water-soluble cellulose
derivatives. At a specific hydrophilic and hydrophobic balance, macromolecular
chains suffer a sol-to-gel transition in water, depending on the type and degree of
substitution of cellulose at the hydroxyl group (Jeong et al. 2012). As water evolves
Fig. 2 Gelation of polysaccharides in water. With permission from Elsevier from (Jeong et al. 2012)
236 C. N. Cheaburu-Yilmaz et al.
3 Preparation Methods
Various gel/hydrogel preparation procedures were reported in the past years (Ullah
et al. 2015; Ahmed 2015; Gulrez et al. 2011; Aroguz et al. 2010; Hoare and Kohane
2008; Buwalda et al. 2014). Natural biopolymers, e.g., alginate, chitosan, car-
rageenan, hyaluronan, carboxymethyl cellulose (CMC), pectin, etc., were preferred
within the pharmaceutical formulations and various preparation techniques were
adopted up to the aimed properties of the final gel/hydrogel.
6 Polysaccharide Containing Gels … 237
Alginate gels are consistently developed via physical based crosslinking procedures
(ionic bonds with divalent cations such as Ca2+ and Mg2+). Ionic gelation with Ca2+
represents the most applied method to obtain hydrogels and its mechanism was
explained based on the distinct and effective interactions between calcium ions and
blocks of galacturonic and guluronic acid residues (Braccini and Perez 2001).
Calcium ions induce chain–chain associations and form joint regions which are
responsible for the gel formation. Grant and Morris developed before a model for
the joint zone, well-known as the “egg box” (Grant et al. 1973; Morris et al. 1978).
According to the model proposed, couples of helical chains are packed by the
calcium ions placed between the helices forming the “boxes.” A representative
illustration is presented within the Fig. 3.
It was assumed that polyguluronates segments are responsible for the egg boxes
formation. Plazinski (2011) improved the theory of (Braccini and Perez 2001) and
(Morris et al. 1978) proving by using a theoretical approach that Guluronic acid
residues (G blocks) onward the alginate chains took a helical conformation; two of
such chains are packed together with the calcium ions located between them.
Another crosslinking method has been proposed as physical gelation can lead to
structural inhomogeneity and by chemical crosslinking, structural biocompatibility
can be reduced due to the presence of the crosslinking agents. Radiation-induced
crosslinking is considered more efficient and milder than the other two methods
(Fan et al. 2016). In the gelation induced by irradiation, there is no need of adding
additional crosslinking agents. Fan et al. used c-irradiation to prepare a hydrogel
composed of chitosan/gelatin/PVA. They found as an optimal parameter for the
Table 1 Summary of the preparation methods for gels/hydrogel preparation with selected examples for each type
238
(continued)
C. N. Cheaburu-Yilmaz et al.
Table 1 (continued)
Preparation method Structural characteristics Selected examples Composition Application References
Chitosan (CS)-based CS solutions 1, 1.25, 1.75 Ocular delivery of Fathalla et al.
nanoparticles and 2 mg/mL in acetic KT (2016)
(NPs) loaded with acid 1%
ketorolac tromethamine 2.5:1 v/v of CS:TPP
(KT)
Chitosan nanoparticles CTS:TPP 2:1 until 6:1a Pharmaceutical De Pinho Neves
applications et al. (2014)
Dermatan sulfate/ 1:1, 2:1, 3:1 and 9:1 v/vb Endothelial uptake Rasente et al.
chitosan (CS/DS) and vascular (2016)
disease, drug
6 Polysaccharide Containing Gels …
delivery
Double physically crosslinked Sodium alginate and 1:1 w/w% Magnetic response Mahdavinia et al.
magnetic hydrogel beadsc poly(vinyl alcohol) of hydrogels for (2016)
(PVA) containing adsorption of
magnetic laponite RD bovine serum
albumin (BSA) on
the hydrogels
Polymer-polymer Complex structure directly Chitosan (CH) and CH/CMC 1:3d Colon delivery of Cerchiara et al.
complexes depends on the degree of carboxymethylcellulose vancomycin (2016)
ionization of cationic and (CMC) (VM)c
anionic polymers that, in turn, is Chitosan/hyaluronic SCS/HA and CS/HA Sulfadiazine Dumitriu et al.
determined by the pH and ionic acid (CS/HA) PECs 1:1 mass ratio release (2015)
strength of the reaction
environment
Spray drying Solid and liquid active Cross-linked alginate Emulsion: alginate Drug delivery Strobel et al.
constituents are encapsulated by microcapsules suspension 1:1 (w/w)e (2016)
a polymer solution through the (CLAMs)
(continued)
239
Table 1 (continued)
240
hydrogel preparation, the gamma radiation dose as being of 40 kGy. For this value,
properties of the gels were very good and it was noticed that with the addition of
chitosan the crosslinking density of the polymer molecules was increased leading to
enhanced mechanical properties of the hydrogel.
Javvaji et al. (2011) studied photogelation of alginate or any other biopolymer
by using a simple method of physically (noncovalently) crosslinking, namely the
UV irradiation. They combined a non-soluble salt of a cation (e.g., calcium car-
bonate, CaCO3) with an aqueous solution of the biopolymer (e.g., alginate) and a
third constituent, a photoacid generator (PAG). During the UV irradiation, the PAG
dissociated and released H+ ions, which further reacted with the CaCO3 generating
free Ca2+ which bind the alginate chains creating the crosslinked network
(“egg-box” junctions) (Dumitriu 2004). Javvaji et al. (2011) claimed that the same
method can be applied for other biopolymers and the formed gels seem to be
reversible as calcium chelators were added, e.g., sodium citrate.
Similar results were obtained also by Higham et al. (2014). They detailed the
gelation of alginate by ionic crosslinking under the ultraviolet (UV) irradiation
treatment and characterized the gels by in situ dynamic rheology. They found out
that the gel point is inversely proportional to UV intensity (I), gelling point being
expressed as GP * I−0.65. Lowering the UV intensity, the emitted energy is less
causing a delay of the release of the acidic species from the PAG and thus, the
crosslinking in the presence of Ca2+. As result they observed also that the network
structure developed slower and forming a compact structure.
Recently, ionic gelation of alginate in the presence of Ca2+ was induced by
X-ray scattering and reported by Yoshiaki et al. (2016). They found out that the
short oligoguluronates, oligoG’s affected the gelation mechanism.
An interesting study was reported by Molina et al. (2014). They analyzed the
effect of atmospheric dielectric barrier discharge (DBD) plasma on the gelation/
crosslinking process of chitosan. The DBD plasma chitosan gelation process did not
damage the chemical structure of the biopolymer. During the plasma treatment,
solvent evaporation and local heating of the chitosan solutions were observed after
15 min of treatment. It is assumed that partial de-protonation of amide group
244 C. N. Cheaburu-Yilmaz et al.
occurred (Fig. 4) and additional hydrogen bonding with hydroxyl groups of other
chitosan molecules were formed.
The bombardment of charged ions on the surface of the chitosan aqueous
solution advanced to the formation of reactive radicals of H, OH and the solvated
electrons. After the reaction with new molecules of chitosan, carbonyl (i.e., alde-
hyde) groups were mostly formed (Prasertsung et al. 2012). The higher plasma
treatment duration is the stronger gel is formed due to formation of covalent bonds
by Shift-base reactions between chitosan polymeric chains (Fig. 4) A higher con-
centration of chitosan (up to 2%) seemed to be optimal as Molina et al.
(2014) observed from rheological results.
Fig. 4 Scheme of chitosan gelation under plasma treatment. With permission from Elsevier from
(Molina et al. 2014)
6 Polysaccharide Containing Gels … 245
Fig. 5 Schematic diagram for the preparation of pLysAAm/HA hydrogels with dually crosslinked
networks. With permission from Elsevier from (Xu et al. 2016)
248 C. N. Cheaburu-Yilmaz et al.
Fig. 6 Crosslinked networks formed by different gelation techniques. With permission from
Springer modified from (Peak et al. 2013)
4.1 Thermosensitivity
Temperature is one of the most common stimuli to control the responsive hydro-
gels. At higher (i.e., LCST) or lower (i.e., UCST) temperatures, the aqueous
solutions of temperature responsive polymers show a sol-gel transition together
with a self-assembly process taking place due to hydrophobic interactions (Singh
and Lee 2014) The thermosensitive hydrogels, as a type of smart hydrogels, have
attracted considerable attention, because their aqueous polymeric solution have low
viscosity at ambient temperature, which favors the drug encapsulation and further
the drug delivery. Thermogels exhibit a reversible sol-gel transition as temperature
changes. This phase change behavior at the temperature variation is reversible as
the gel is formed by physical crosslinks between the polymer chains. These
thermo-responsive polymers or copolymers consist of hydrophilic and hydrophobic
segments, which can self-assemble into polymeric micelles in water. The
hydrophobic segments form the core of the micelles while the hydrophilic chains
interact with water molecules at the corona (Liow et al. 2016; Klouda 2015).
The most common thermosensitive polymers, especially among the polysac-
charide are: methylcellulose (LCST 60–80 °C), xyloglucan, carrageenan, agars,
gelan, guar gum, etc. Also, they can be obtained by chemical derivatization,
grafting/blending of polysaccharides such as chitosan, alginate, cellulose, dextran
and their derivatives with thermosensitive polymers (Klouda and Mikos 2008;
Prabaharan and Mano 2006).
Wang et al. (2013) reported a chitosan derivative, N-[(2-hydroxy-3-
trimethylammonium) propyl] chitosan chloride, which interacted with glyc-
erophosphate to produce a thermosensitive hydrogel. Gels with high mechanical
strength are obtained by crosslinking in the presence of glutaraldehyde (GA) and
polyvinyl alcohol (PVA), aiming intratumoral delivery of paclitaxel (PTX).
250 C. N. Cheaburu-Yilmaz et al.
4.2 pH Sensitivity
pH variations occur at several body sites, e.g., the gastrointestinal tract, vagina, and
blood vessels and there can provide an adequate medium for pH-responsive
hydrogels aimed as drug carriers. Additionally the pH changes in response to
specific substrates can be used for controlling the drug release. Generally, the
pH-responsive drug delivery systems are aimed to be used for per oral controlled
drug delivery, taste-masking of bitter drugs or intravascular drug release (Gupta
et al. 2002).
Many polysaccharide components such as chitosan, alginate, hyaluronic acid,
heparin, carboxy methyl celulose, cyclodextrin, confer to hydrogels
pH-responsiveness. Among the various hydrogels, the pH-sensitive type, which are
based on biocompatible polymers or copolymers have been used extensively in
drug delivery systems (Shi et al. 2004; Jabeen et al. 2016; Guo and Kaletunc 2016;
Mercado and Slater 2016; Cheaburu-Yilmaz et al. 2017).
Their special particular pH sensitivity combined with the fact that pH varies
throughout the digestive system make them suitable for oral administration when
targeting the intestinal tract, especially the colon. More specific, most of the in vitro
and in vivo experiments supported that when drugs are to be delivered to the
gastrointestinal tract, they are usually sustained and protected within the hydrogel in
the acidic gastric environment (pH 1.2), while in the less acidic intestinal regions
(pH 6.8–7.4), swelling of the hydrogel basically releases the drugs.
A pH-sensitive system was reported by Eldin et al. (2015) from grafted alginate
hydrogel-based matrix for protein controlled release applications. L-arginine was
grafted onto the alginate backbone via amine groups and the system was designed
to enhance the sustained protein release especially in acidic medium, by comparison
with neat alginate hydrogels. They found out that the increase of L-arginine con-
centration, pH, time, and temperature of grafting reaction increased the grafting
efficiency and swelling ability of the crosslinked Arg-g-Alg hydrogels.
6 Polysaccharide Containing Gels … 251
Guo and Kaletunc (2016) designed a system based on alginate and pectin. The
mixture of the two polymers resulted in a hydrogel when the pH was below 3.0,
showing pH responsivity. This pH responsivity was due to the presence of a high
amount of carboxylate groups on the polymer chains and inducing a strong
hydrophilic character. Guo et al. claimed that they can control the particles size and
it can be formed disc-shaped particles which can potentially enhance the particle
adhesion in intestines. Their study reported a model to predict the dissolution of
alginate-pectin hydrogels under various pH and temperature conditions in order to
release the biologically active compounds.
A self-healing pH-responsive polysaccharide-based hydrogel was prepared by
Liu et al. (2016). They mixed cellulose acetoacetate (CAA) aqueous solution with
chitosan aqueous solution at room temperature. Prior to this, they synthesized CAA
by means of reaction of cellulose with tert-butyl acetoacetate (t-BAA) in ionic
liquid 1-allyl-3-methylimidazo-lium chloride (AMIMCl). The pH response of the
polysaccharide hydrogel was assessed and described as shown within Fig. 8.
252 C. N. Cheaburu-Yilmaz et al.
Fig. 8 pH responsiveness of the hydrogel. a neat hydrogel, b sol phase after addition of aqueous
HCl, c regeneration of the hydrogel after addition of aqueous solution of NaOH, d regenerated
hydrogel converted into hydrosol after addition of aqueous solution of HCl, e regenerated hydrogel
after five cycles. With permission from John Wiley and Sons, from (Liu et al. 2016)
4.3 Swelling
Fig. 9 Viscoelastic
properties as function of pH
of the preparation medium.
With permission from
Science direct from (Jabeen
et al. 2016)
are also capable of interacting with water molecules. In this case it is named as
“secondary bound water” or hydrophobically bound water. Primary and secondary
bound water form “total bound water.”
Thanks to the osmotic driving force of the network chains, hydrogel’s network
continues to absorb additional water up to infinite dilution. The supplementary
swelling is prevented by the covalent or physical crosslinks, leading to an elastic
network retraction force. Thus, the hydrogel will reach an equilibrium swelling level.
The additional absorbed water, called as “free water” or “bulk water,” is
expected to fill the space between the network chains, and/or the center of larger
pores, macropores, or voids. Further swelling, depends on the nature and compo-
sition of the hydrogel and, may lead to the disintegration and/or dissolution of the
matrix if the network chain or crosslinks are degradable.
Generally the swelling ability is determined by swelling degree defined by
applying the kinetic model and the mechanism of swelling/drug release can be
established (Korsmeyer et al. 1968)
Wt
¼ ksw tnsw ; ð1Þ
Weq
where: Wt and Weq represent the amount of solution absorbed by the matrices at
time t and at equilibrium, respectively; ksw is the swelling rate constant or specific
254 C. N. Cheaburu-Yilmaz et al.
rate characteristic of the system and nsw is the power diffusion law exponent which
takes into account the type of solvent transport. Equation (1) applies to initial stages
of swelling (swelling degree less than 60%).
Recently, Tulain et al. (2016) explained that pH and ionic concentration are the
principal parameters which influence the swelling ability of pH-sensitive hydrogels
as result of electrostatic repulsion between the ionic charges. At high pH, an ionic
polymeric network (due to acidic or basic functionalities) exhibited higher swelling.
They developed a pH-responsive hydrogel prepared via free radical polymerization
in aqueous media aimed to protect the rabeprazole sodium from acidic environment
from stomach. They reported that the swelling behavior of prepared hydrogels in
buffer solutions of various pH indicated highly pH-dependent swelling of hydro-
gels. The swelling ratio of the hydrogel was low in acidic medium and high with the
increasing pH. This was due to the presence of ionized COOH groups of acrylic
acid groups at pH 7.4. At low pH values, the anionic group is protonated, swelling
rate and ratio being low.
Fig. 10 Hysteresis loop of chitosan nanoparticles when subjected to a shear load. With permis-
sion from Elsevier from (Al-Kassas et al. 2016)
4.6 Erosion/Degradability
4.7 Morphology
The concentration of the polymer within the gel played an important role as for
different concentrations, different morphologies could be observed. Particularly, in
the case of a chitosan-based hydrogel or a concentration lower than 0.5 wt%, an
ordinary random 3D network could be considered as isotropic (Nie et al. 2015).
With the increasing concentration, higher than 1.0 wt%, a different type, a more
complex one, in three dimensions, may be attributed. This complex 3D mrphology
can be as: multilayered structure, an oriented structure which had been observed in
the hydrogel of Nie et al. (2015) they found out that the arrangement appeared to be
onward the direction of OH− diffusion and joined every layer at about 90°. It is
seems that between that spatial arrangement and direction of diffusion process is an
interrelationship. The last 3D orientation of the complex hydrogel structure is based
on a structural conversion with the increasing distance between the primary and the
afterward hydrogel layer. The region located right close to the initial hydrogel layer
has a smooth and compact structure. At higher distance, oriented region appeared
and transformed into porous structure. Analyzing the characteristics of the obtained
gel, Nie et al. (2015) referred to a typical structure as a layered-wise-oriented
structure, described within Fig. 11.
In last decade, controlled drug delivery systems and the polymers used in these
systems have become much more complex, with more broaden functions. Diffusion is
the main mechanism for the drug delivery and its rate depends on the physical
structure of the polymer network and its chemical nature. If the gel is highly hydrated
the drug could diffuse through the pores. In gels with lower hydration the release of the
drug could be completed either by dissolution in the polymer or could be transported
through the network. The crosslinking degree also modifies diffusion rate.
Recent studies aimed developing of these types of biopolymeric-based systems
meant to improve the drug release efficiency. Li et al. (2016) prepared thiolated
6 Polysaccharide Containing Gels … 259
Fig. 11 Schematic representation of the layered CS hydrogel and the possible mechanism.
a CLSM images assigned to the compact region, oriented region and porous region b–
d Macromolecular interactions in ‘‘gel-sol consecutive reaction units’’ during the gelation process,
b semi-dilute regime, c concentrated regime, and d formation of oriented structure by stacking of
reaction units. With permission from Nature from (Nie et al. 2015)
method not only as additionally crosslinking path but also to enhance and to control
the cohesive properties of the final formulation based on thiolated chitosan. The
obtained a high cohesiveness of the formulation and dependency on the polymer
concentration. The optimal composition was found to be the one containing 3% CTS
regarding mechanical and viscoelastic properties which are likely to be obtained for
topical applications. Additionally their texture studies confirmed the same outcome.
The same composition was found to release the most efficient and a more
controlled drug release profile was achieved.
Chitosan nanoparticles loaded with dexamethasone sodium phosphate (DEX) for
topical ocular delivery were prepared by (Kalam 2016) aiming to improve the
precorneal retention and corneal permeability. The chitosan nanoparticles based
formulation was optimized in the way of improving the mucoadhesiveness of the
formulation and to delay the release of dexamethasone. For this purpose the chi-
tosan nanoparticles were coated with hyaluronic acid (HA), and the burst release
profile of the drug obtained for the uncoated formulation was overcame and,
additionally, the release of dexamethasone was slowed down.
Similar results regarding the delayed release of dexamethasone was obtained by
Calles et al. (2016a) in their approach to use crosslinked crosslinked hyaluronic acid
and itaconic acid films loaded with dexamethasone sodium phosphate salt
(DEX) for topical treatment of surface inflammatory ocular diseases. The
crosslinking of the mixture was done with polyethylene glycol diglycidyl ether.
Wick’s group (Carmona-Moran et al. 2016) reported a transdermal drug delivery
formulation. They prepared a semisolid gel and a solid hydrogel film formulations
with gellan gum as a rheology modifier agent. The effect of penetration intensifier
(e.g., dimethylsulphoxide, etc.) and gellan gum on the transport of sodium
diclofenac from the semisolid gel and solid hydrogel film formulations were studied
by using a synthetic membrane and a Transwell diffusion system. The main
parameters affecting the transport of sodium diclofenac were the concentration of
gellan within the formulation and the temperature. Low gellan content induced low
permeability and concentration of transported sodium diclofenac in the semisolid
formulation and higher concentration in the solid hydrogel film. This behavior was
assigned to a specific 3D swollen configuration of the polymer in the solid hydrogel
film, in this case the delivery being diffusion controlled. The Transwell diffusion
system provided a way to quantify the drug diffusion for many types of formula-
tions. This system together with the thermo-responsive properties of the nanogels
provided a better control over the drug release mechanism.
Bioadhesion describes the interfacial forces that hold together two bodies that one
or both of them, are of biological nature, for extended periods of time
(Solomonidou et al. 2001).
6 Polysaccharide Containing Gels … 261
The skin irritation studies of gel formulations could be tested by in vivo study. As
a general accepted procedure, the gel formulation is applied directly on human or
animal skin and irritation potential of formulation is measured. The shaved skin
from back area is marked done both the sides. One side serves as control while
the other side is for the test. Gel/hydrogel is applied for certain time and the site
is monitorized for any sensitivity such as erythema and melanin by using a
Mexameter device (Langasco et al. 2016) Gavini’s group (Langasco et al. 2016)
measured the skin parameters, e.g., skin hydration, elasticity, and sebum content
before application and after different application time periods of gel formulations
and obtained favorable results due to their slow and linear drug permeation
profile.
262 C. N. Cheaburu-Yilmaz et al.
5 Applications
Topical delivery is an interesting route for local and systemic application of drug.
Topical application has many advantages by comparison with the conventional
routes. The gastrointestinal (GI)-irritation could be avoided, the drug metabolism in
the liver would be prevented and drug bioavailability increased via this route.
Topical formulations include creams, ointments, pastes, gels, etc. Gel systems have
better application properties and stability than cream and ointment. The gel for-
mulations should be prepared with a gelling agent that is inert, safe and compatible
with other components. The topical gel should not be tacky and it should be sterile
if it is ophthalmic gel. Gel formulations can have prolonged drug contact at the site
of application due to their rheological and mucoadhesive properties.
The smart polymer gels are in focus of pharmaceutical research. Polymers could
change the physicochemical properties in response to an altered environment and
they are easy to administer into desired body cavities. From pharmaceutical point of
view, smart polymeric gels are defined as liquid formulations which are trans-
formed to solid or semisolid after application by external stimuli as temperature, pH
and ionic strength (He et al. 2008; Gupta et al. 2002; Chaterji et al. 2007).
Vagina as a route for drug delivery (Hussain and Ahsan 2005) provides various
advantages such as easy and accessible path, delayed retention of the formulations,
high surface and permeation area, high vascularization, relative low enzymatic
activity and it is avoids first-pass metabolism (Das Neves and Bahia 2006;
Bernkop-Schnurch and Hornof 2003). Vaginal formulations could be prepared
under various pharmaceutical forms, e.g., semisolids, tablets, capsules, liquid
preparations, vaginal films, vaginal rings, foams, and tampons. Among all these, the
most used are semisolid preparations, i.e., cream, ointments, and gels (Das Neves
and Bahia 2006) due to their patient acceptability, easy preparation methods, and
feasibility. The only limitations reported for these types of formulations were
leakage and rapid removal from the teated site.
Vaginal administration was used to treat various diseases like osteoporosis,
hormone replacement therapy, contraception, infections, infertility, and other
female-related conditions as is a feasible alternative way compared to oral or par-
enteral administration. By comparison, conventional gel formulations have diffi-
culties to be applied onto the infected site of the vagina. The use of mucoadhesive
polymers such as thiomers could offer not only an easy application but also
enhancement of the intravaginal retention time of the drug delivery systems.
Furthermore, the therapeutic efficiency of locally acting drugs could be improved
by their prolonged availability at the target membrane (Bernkop-Schnurch and
Hornof 2003).
6 Polysaccharide Containing Gels … 263
Smart polymer gels and in situ gelling systems, offer multiple advantages as they
are combining the advantages of both gels and solutions (Patel and Patel 2015)
These formulations are liquid formulations before the administration but turn into
gel after administration into the vaginal cavity due to the action of the environ-
mental stimuli like temperature and pH. Mucoadhesive, thermosensitive vaginal
gels with prolonged release were formulated for a better therapeutic efficacy and
improved patient compliance. The formulation should stay long enough inside the
vagina for the best therapeutic effect. The conventional formulations are removed
faster from vagina and therefore a constant cure could not obtain, varying the
efficiency of the cure and decreasing the bioavailability of the drug. Patel et al.
(2015) reported in situ gel formulations of clindamycin HCl comprising
hydroxyl-propyl-methyl cellulose (HPMC) as bioadhesive polymer (0.1%) and
gellan gum (as gelling agent) in order to modulate the sol-gel transition temperature
so that to obtain gelation at physiological conditions. Addition of mucoadhesive
polymer decreased the gelation temperature but it is still close body temperature.
Gel of hydroxyethylcellulose (HEC) alone or mixed with chitosan (CS) or its
derivative 5-methylpyrrolidinone-chitosan (MPCS) and loaded with the antibacte-
rial metronidazole (MET) (0.75%) were prepared by Perioli et al. (2008) They tried
to optimize the local vaginal therapy by increasing the formulation retention and
increasing drug–mucosa contact time. They found out that CS amount plays an
important role on drug release. A higher concentration of CS would decrease the
drug diffusion through the gel network. A correlation between gel consistency (i.e.,
viscosity) and drug release was observed; higher content of CS higher the gel
consistency is; polymeric network would be very dense and responsible for tortuous
channel formation would decrease the MET diffusion.
Another reports state that the liquid applied on the topical areas is transformed
into gel by varying several parameters, e.g., pH of cellulose acetate phthalate, the
concentration of calcium ions for gellan gum, temperature for poloxamers, etc.
(Gupta and Sharma 2009; Patel and Koyani 2014). Bioadhesion and retention at the
site of application could be obtained by incorporating bioadhesive polymers like
hydroxypropyl methycellulose (HPMC) within the formulations.
A study on mucoadhesive chitosan was done by Ay Senyigit et al. (2014) on
chitosan with different molecular masses and viscosity properties. They claimed
that chitosan was very successful as a vaginal mucoadhesive gel base for econazole
nitrate and miconazole nitrate, drugs used to topical fungal and yeast infections.
Drug release was directed by the gel viscosity; increased gel viscosity of the gel led
to slower release of the drug. Choosing the adequate gel consistency which is done
based on the rheological characteristics of the prepared gels, makes the gel for-
mulation to remain over 24 h over the vaginal mucosa ensuring a complete treat-
ment. This was observed by infrared imaging techniques (Ay Senyigit et al. 2014).
The combination of a natural polymer of marine origin, e.g., like chitosan or
kappa-carrageenan, with a semisynthetic polymer such as hydroxyl-propyl-
methylcellulose (HPMC) in solid compacted formulations for sustained release of
acyclovir (ACV) was studied by Veiga’s group (Sanchez et al. 2015).
264 C. N. Cheaburu-Yilmaz et al.
Mucosa of the buccal cavity is considered a very convenient and easily accessible
site for the drugs administration aimed for both local and systemic delivery (Russo
et al. 2016).
Recently Russo et al. reviewed the polymers used for preparation of buccal
dosage forms and the general requirements of a polymeric system to fall into
relevant field. They listed general requirements for an ideal muco-buccal delivery
system to be considered when this type of system is planned to be designed
• Particle size up to 1–3 cm2 and a daily dose of 25 mg or less (Alur et al. 2001)
• Duration of the buccal delivery up to 4–6 h
• To mask the taste-masking strategies, on the basis of target population;
• To reduce the possible mucosal irritation at the site of application;
• To have adequate mechanical and rheological properties, e.g., thixotropic,
pseudoplastic, or plastic flow so that the buccal formulations to be easy to apply;
• To possess hardness and resistance to handling.
The conventional dosage forms have difficulties to maintain their effects in
buccal cavity. They are easily eliminated by salivation, temperature controlled,
tongue movement, and swallowing. The mucoadhesive polymers are suitable to
improve duration of formulation in cavity (Gandhi and Robinson 1994; Fini et al.
2011). The most proper dosage forms are the semisolid one like gels because of
their large and soft surface area by comparison with the solid and liquid forms.
Moreover, the delivery in the buccal area can take place for an extended period of
time, due to their viscosity (Ishida et al. 1983; Khairnar and Sayyad 2010).
A characteristic “must have” of polymeric-based gel formulation is mucoadhe-
sivity. Mucoadhesion is similarly defined as the bioadhesion having one of the
substrate a mucosal surface (Shaikh et al. 2011).
Adhesive gels used in local delivery of drugs for buccal application were
reported. Among them chlorhexidine was used for the treatment of periodontitis, for
infectious diseases fluconazole, for inflammatory benzydamine hydrochloride, with
high efficacy and patient acceptability (Senel et al. 2000; Vinholis et al. 2001).
6 Polysaccharide Containing Gels … 265
Transdermal systems are desirable for drug delivery due to their advantages by
comparison with other routes of delivery (Paudel et al. 2010; Vintiloiu and Leroux
2008). Transdermal delivery was described as a beneficial and pain-free
self-administration route for patients. By this method, frequent and overdoses are
avoided and plasma level peaks of the drug showed a constant concentration, the
main motivation of these being the compliance of the patient, especially when a
long period cure is needed, e.g., chronic pain treatment or smoking cessation
therapy. Another advantage of the transdermal route reported is that the hepatic
first-pass metabolism is prevented (Paudel et al. 2010; Vintiloiu and Leroux 2008).
Thus the amount of delivered drug is lower and safer in the case of
hepato-compromised patients and avoiding the side effects. Transdermal systems
are generally cheap when compared with other therapies and, as patches, are
designed to deliver drugs for a period from 1 to 7 days. Another advantage of
transdermal delivery is the possibility to use successive doses, on-demand or var-
ious delivery rates of drugs by using the latest technology regarding programmable
266 C. N. Cheaburu-Yilmaz et al.
Hyaluronic acid based hydrogels are used for ophthalmic preparations and wound
healing due to non-irritating properties of polymer. Sodium hyaluronate gels are
used to separate tissues during ophthalmic surgery and prevent postoperative
adhesion formation. Hyaluronic based gels also improve duration of drug on site of
application due to mucoadhesive properties (Saettone et al. 1989). Recently, Calles
et al. (2016b) proposed a system based on hyaluronic acid itaconic acid to be used
within ocular delivery. They studied the effect of the homogeneous crosslinking of
hyaluronic acid and itaconic acid in the presence of glutaraldehyde and triacetin as
plasticizers on the properties of the materials. They found out that crosslinking with
glutaraldehyde showed favorable results regarding the bioadhesive properties of the
hyaluronan based hydrogels. Addition of itaconic acid increased even more the
adhesiveness and lowered the wettability and swelling capacities. Thus the mate-
rials become more fragile and less elastic. To overcome exceeded stiffness required
used plasticizers (Calles et al. 2016b).
Collagen is connective fundamental combinatorial tissue protein in animals.
Collagen gels with a transparent appearance have been considered adequate
forophthalmic drug delivery applications. The patented ocular inserts of collagen
are soluble devices for drug delivery (Miyata et al. 1979).
Pilocarpine hydrochloride loaded crosslinked collagen inserts are maintaining
constant and controlled release of drug for 5–15 days (Vasanthra et al. 1988; Agban
et al. 2016) Agban et al. (2016) found out that crosslinked collagen shields which
they developed are suitable for topical ocular drug delivery devices. They observed
that the nanoparticles (NPs) based on ZnO/polyvinyl pirolidone (PVP) seemed to be
the best as crosslinker as concerning the cytotoxicity, shield transparency, and
tensile strength. The optimum ratio was found as 1:1 collagen to ZnO/PVP NPs.
268 C. N. Cheaburu-Yilmaz et al.
Rose et al. (2014) reviewed the possibility of using gelatin within the pharma-
ceutical formulations due to its good biocompatibility, it is inexpensive, ease of
processing and availability. Gelatin and its derivatives were mostly handled as
potential scaffolds for corneal epithelium (De la Mata et al. 2013), corneal
endothelium (Lai et al. 2013a) and retinal pigment epithelium (Lai 2013b) and as a
potential bioadhesive in treatment of retinal detachment (Yamamoto et al. 2013).
They also highlighted methods of crosslinking which are exhibiting a low risk of
toxicity.
Acknowledgements This work was partially supported by “The Scientific and Technological
Research Council of Turkey (TUBITAK), cofunded by Marie Curie Actions under FP7,” project
number 115C078; Romanian National Authority for Scientific Research, ANCS-UEFISCDI,
project number PN-II-ID-PCE-2011-3-0906/274/2011 and grant BIONANOMED no 164/2012.
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Chapter 7
Design of Multifunctional Nanogels
with Intelligent Behavior
1 Introduction
Intelligent materials are those that can respond predictably to certain external
stimuli by modifying some of their properties. These materials differ from intelli-
gent “devices” in that they do not require complex sensor systems, sampling and
calculations to provide feedback and respond to the stimulus (Hu et al. 2012): the
response of smart materials is inherent to their nature.
The preparation of synthetic intelligent materials able to respond to stimuli in a
controllable and predictable manner is an important objective at both the scientific
and technological levels. Nature provides several examples of biological systems
that can assist researchers in designing new materials, among which are: the rota-
tion of sunflowers towards the sun for a phototropic effect; the change in skin color
of chameleons by rearrangement of the crystals within the specialized skin cells;
and the case of the Mimosa pudica plant collapsing rapidly when touched or the
Dionaea muscipula, which traps insects upon closing (Teyssier et al. 2015). There
are a variety of polymers comparable to the materials involved in these systems
which respond to stimuli such as temperature, pH, ionic strength, light, electric
field, magnetic field, among others by undergoing physical or chemical change. The
materials can also be designed to respond to more than one stimulus at a time,
making multiple responses possible (Ayano et al. 2012; Thomas et al. 2012; Nash
et al. 2012; Li et al. 2014). These stimuli can cause changes in dimension and/or in
form, as well as in some mechanical properties such as stiffness, flexibility, opacity,
porosity, among others. Depending on the final form in which these materials are
obtained—as gels, nanoparticles, films, etc.—intelligent materials have potential
applications in modern technologies for controlled drug delivery, tissue engineer-
ing, cell immobilization, separation of biomolecules, theranostics, diagnostic
agents, packaging, biosensors, optoelectronics, and others.
To yield an intelligent polymeric material, it is very important to achieve high
efficiency in the reversible response of the used polymers and thus be able to
transfer the material to a particular application. The criteria for choosing the
monomers in terms of the degree of crosslinking, the functional groups present in
the structure and the final physical shape required of the polymeric material, are
crucial. The desired properties can also be achieved through a combination of more
than one polymer or other material, inorganic or organic, conforming hybrid
282 G. Rimondino et al.
As NGs are reticular crosslinked particles, their links drastically reduce the
mobility of the chains and their conformational entropy. However, crosslinking
allows the preparation of NGs with a more complex architecture, leading to the
introduction of functional groups at different positions within, which may affect the
overall degree of swelling. It is known that a balance between the osmotic pressure
and elasticity of the polymer determines the physical dimensions of an NG particle.
Osmotic pressure results from the net difference between the concentration of
mobile ions inside the nanogel particle and the solution outside. In the case of ionic
NGs, the charged groups attract hydrated counterions that tend to expand the
nanogel, while conformational entropy elasticity of the crosslinked polymer chains
counteracts this expansion. The neutralization of the nanogel reduces the difference
in the net concentration of the ions, resulting in the dehydration of the nanogel and
a diminution of its volume (Rayo and Guerrero 2014).
As stimuli-responsive nanostructures based on polymeric compositions, smart
NGs are one of the most interesting nanomaterials. Thermo-sensitive NGs, in
particular, have shown great potential in biomedical areas. Two types of swelling
transitions are observed; the transition from upper solution critical temperature
(UCST) (generally for acrylic acid derivatives) and lower critical solution tem-
perature (LCST) (for N-acrylamide derivatives). LCST-type nanogels swell
abruptly at temperatures below a critical point whereas UCST-type nanogels swell
sharply at temperatures above a critical point. Since NGs do not dissolve, the
temperature at which the nanogel passes from a swollen to a collapsed state is called
volume phase transition temperature (VPTT) (Rayo and Guerrero 2014; Cuggino
et al. 2011; Witting et al. 2015; Quesada-Perez et al. 2014).
The structure–property relationship of polymeric systems provides the basis for
the development of intelligent stimuli-responsive NGs. Success in obtaining a smart
NG requires synthetic design criteria that combine the right choice of functional
groups present in the nanostructure, flexibility and the final shape of the chains in
the structure to be used.
This Chapter covers various topics: in the first part, the different methodologies
for synthesizing nanogels are detailed. Following this, the second part comments on
prominent work relating to the structure/properties ratio required for intelligent
behavior and novel application properties. In the third part, desirable characteristics
for smart and hybrid NGs are described. Finally, the last part describes the
importance of size for different applications and reports on the most significant
progress achieved in recent years in the field of nanocarriers for biomedical
applications.
2 Synthesis Methodologies
There are two major approaches for creating nanometer-scale particles: the
top-down approach (lithography) and the bottom-up approach, in which the
nanometer scale is controlled by designing molecular structures and assemblies.
284 G. Rimondino et al.
This latter methodology is the most widespread in nanotechnology and the for-
mation of polymeric NGs is an example. The synthesis of NGs, like classical
polymers, can be carried out through polymerization of functionalized monomers or
from preformed polymers. Natural (Wang et al. 2014) or synthetic (Chem et al.
2012) polymers may be employed, depending on the application. Precursor poly-
mers, such as amphiphilic copolymers, can form nanogels by self-assembly in
solution, physical crosslinking or by chemical crosslinking, depending on the
reactive sites. Synthesis via monomer polymerization is more efficient and the
yielded crosslinked NGs show great promise as drug delivery vehicles (Zhang et al.
2015). Generally, NGs in the size range of 20–200 nm are useful for the treatment
of a variety of diseases.
Depending on the structure and functionality of monomers, radical, cationic and
anionic polymerizations are synthetic alternatives. Due to the difficulty in con-
trolling the molecular architecture through these mechanisms, new synthetic routes
were opened up by the use of controlled radical polymerization (CRP). In recent
years, CRP techniques such as radical polymerization atom transfer (ATRP)
(Huang et al. 2007; Zampano et al. 2009; Wang et al. 2011), nitroxide mediated
polymerization (NMP) (Gromadzki et al. 2010) and transfer polymerization
reversible addition-fragmentation chain (RAFT) (Roy et al. 2005) have been used.
Both ATRP and RAFT are based on the dynamic equilibrium between active and
disabled species. CRP techniques are a good way of yielding NGs with controlled
molecular weight and low polydispersity (Jafari and Kaffashi 2016). RAFT in water
has emerged as a simple method of preparing well-defined NGs with core–shell
structures (Liu et al. 2012). Other methodologies including ring opening, coupling
reactions, and click chemistry are also used to synthesize NGs from functional
monomers. A series of pH-responsive disulfide crosslinked NGs based on poly
(L-histidine) has been synthesized by a one-step ring-opening polymerization
process (Bilalis et al. 2016). The progress in copper-free click chemistry such as
that involved in strain-promoted azide-alkyne cycloaddition, radical mediated thi-
olene chemistry, Diels-Alder reaction, tetrazole-alkene photo-click chemistry, and
oxime reaction has enabled the formation of NGs without the use of potentially
toxic catalysts (for example copper catalyst) or immunogenic enzymes that are
commonly used in both chemical and physical crosslinking, as in the crosslinking
of casein with microbial transglutaminase (Jiang et al. 2014). The combination of
controlled polymerization techniques with efficient chemical reactions is funda-
mental in the synthesis of NGs. By combining the ATRP method and click
chemistry it was possible to synthesize well-defined crosslinked poly(styrene)
nanoparticles with diameter in the range of 50–150 nm (Xu et al. 2009).
Crosslinks are essential for the structural stability of the NGs since they prevent
dissolution of the polymer chains in the aqueous environment. The physical
crosslinkings can be promoted by hydrophobic and electrostatic interactions, chain
entanglements, Van der Waals forces or hydrogen bond between the polymer
chains of the nanogel. NGs formed by physical crosslinking in aqueous media and
mild conditions can easily collapse as a result of changes in their environment.
Environmental parameters such as pH value, ionic strength, temperature, and
7 Design of Multifunctional Nanogels with Intelligent Behavior 285
others, that affect particle size, must be controlled. Atiyoshi et al. reported the first
physically crosslinked NGs using self-assembly of polysaccharides. The system
was colloidally stable with monodispersive nanoparticles above the critical con-
centration (Akiyoshi et al. 1993). Chemical crosslinking involves the formation of
covalent bonds rendering stable, rigid structures; the bonds are formed during
polymerization, employing a bifunctional crosslinking agent, or after polymeriza-
tion with reactive groups present in the monomers. The reactions generally require
purification steps to remove residual monomers and/or crosslinking agents. It is
therefore convenient to design efficient reactions between functional groups to
avoid the use of crosslinking agents. Michael additions of amines and thiols or
condensation reactions between acids and amines or alcohols are examples of such
reactions (Rahimian et al. 2015). Many precursors used for addition or coupling
reactions are biologically inert and this is important when NGs are to be used in
biomedicine. In particular, the formation of a disulfide bond between polymer
chains using suitably functionalized monomers avoids the use of additional
crosslinking agents (Gyarmati et al. 2013). Moreover, a disulfide bond is
biodegradable to biochemical reductants and the nanogel is stimuli-responsive to
specific analytes (Heffernan and Murthy 2009). The first chemically crosslinked
NGs were prepared by crosslinking polyethyleneimine with
carbonyldiimidazole-activated poly(ethylene glycol) (PEG) for the delivery of
oligonucleotides. The synthesis was reported by Kabanov and col. (Vinogradov
et al. 1999). The developed NGs showed effective diameters ranging from 20 to
220 nm and were stable in solution, revealing no aggregation. The NGs showed
enhanced drug loading capacity and improved drug release behavior compared to
common nanoparticles.
In order to avoid the use of crosslinkers in chemical crosslinking, an alternative
approach is to use ionizing radiation (gamma rays, X-rays, accelerated electrons,
ion beams, or ultraviolet rays), which is useful for the synthesis of NGs from linear
polymers in aqueous medium. This method avoids the use of monomers,
crosslinking agents, initiators and surfactants. The water molecules absorb most of
the radiation, generating reactive species (hydroxyl protons, solvated electrons,
hydrogen peroxide) which react with the polymer chains, producing radicals. The
effect of irradiation on the polymer depends on its chemical structure, concentra-
tion, molecular weight and the irradiation conditions (Jafari and Kaffashi 2016;
Dailing et al. 2015). The crosslinking may be intra- or intermolecular, depending on
the average number of radicals per chain. By increasing irradiation, the average
number of radicals per chain also increases and the probability of intramolecular
recombination is greater.
The degree of crosslinking determines the swelling degree of NGs, which is one
of their most important properties.
286 G. Rimondino et al.
3 Synthesis Techniques
agent) are dissolved in water, including a surfactant in some cases (Chem et al.
2012).
As the reaction proceeds, a precursor of particles can be added to form a col-
loidally stable system. In addition, when the chains reach a critical size, the charge
incorporated from a radical initiator gives rise to an electrostatic stabilization
mechanism. The temperature is subsequently lowered to below the transition
temperature and the swollen nanogel particles are stabilized by a steric mechanism
as a consequence of the formation of a hydrogen bond between the polymer chains
and water molecules. An ionic surfactant can be added to impart colloidal stability
during the polymerization reaction. The diameter of the particles depends on the
concentration of surfactant, so small particles can be obtained by increasing the
surfactant concentration (McPhee et al. 1993).
Miniemulsion and inverse miniemulsion polymerization require the surfactants
to be oil dispersed in water and water in oil emulsions, respectively. Miniemulsion
polymerization is conducted using surfactants such as sodium dodecyl sulfate
(SDS) or sodium dodecylbenzene sulfonate (SDBS), which is dissolved in water.
The hydrophobic monomers and crosslinkers are added to the aqueous solution and
polymerized in oil dispersed in excess water. After polymerization, the surfactant is
removed by dialysis. Controlled polymerization methods have been used in
miniemulsions to prepare NGs.
The inverse nanoemulsion (water/oil) system has been used to prepare NGs by
direct polymerization of hydrophilic monomers such as electrolyte monomers and
PEG-containing monomers. In this methodology, the hydrophilic monomers and
the crosslinker agent are dissolved in water droplets emulsified into a continuous
hydrophobic phase. The aqueous droplets in the presence of oil-soluble surfactants
[sorbitan monooleate, Span—80 or sodium bis(2-ethylhexyl)sulfosuccinate, AOT]
are generated by sonication in an organic solvent as the continuous phase. The
thermodynamically stable emulsion is reached at a surfactant concentration below
or near its critical micelle concentration. Cationic [(3-acrylamidopropyl) trimethy-
lammonium chloride], (Sahiner et al. 2006) anionic (2-acrylamido-2-methylpropane
sulfonic acid) (Bhardwaj et al. 2009) and neutral monomers (N-vinylformamide)
were polymerized via inverse miniemulsion (Shi et al. 2008).
Hydrophilic drugs including anticancer drugs (e.g., doxorubicin, DOX) and
biomacromolecules (e.g., DNA and proteins) can be incorporated into NGs using
inverse emulsion. Several NGs coated in PEG chains have been synthesized by
emulsion (Iijima and Nagasaki 2006).
An alternative is an oil-in-water emulsion achieved by stirring (suspension
polymerization), useful for hydrophobic monomers which do not require the sur-
factant to be removed after polymerization.
Nanoemulsion synthesis can be applied to different mechanisms of controlled
radical polymerization such as RAFT and atomic transfer radical polymerization
(ATRP) (Raemdonck et al. 2009; Kuo et al. 2015).
Several examples have been reported for the synthesis of NGs from gelatin using
this methodology. Crosslinked NGs from gum arabic aldehyde and gelatin
nanoparticles were prepared by the inverse miniemulsion process. The nanosize and
288 G. Rimondino et al.
spherical particles were nontoxic and showed high potential for application in drug
and gene delivery (Sarika and James 2015).
For biomedical applications, the synthesis and purification of the delivery system
should be easy and scalable. Several polymerization conditions in emulsion require
the use of surfactants, which as mentioned, need to be removed after synthesis
(Chacko et al. 2012). Surfactants always favor the stabilization of nanogel particles
and minimize the aggregation process; they also lower interfacial tension and
reduce the size of nanogels. Park et al. reported an emulsion-free surfactant of
heparin NGs (Bae et al. 2008). This green alternative was used by An et al. in the
synthesis of a dual-responsive NG. Hydroxypropylcellulose (HPC) NGs were
synthesized using HPC as a template in surfactant-free aqueous media. The con-
centration of the crosslinker determined the size of the NGs, which show promise
for use as nano-biomaterials (An et al. 2015).
Others technologies have emerged for the preparation of NGs with well-defined
molecular architectures (Liu and An 2014), for instance lyposomes (Hong et al.
2008) and inorganic nanoparticles (Singh et al. 2007) as nanosized reactors. Also,
hollow NGs can be prepared using nanoparticles as template. For example, gold
and monodisperse silica nanoparticles were used as a nanotemplate to grow a
polymer shell, after which the template was removed to yield a hollow nanogel.
These NGs possess the ability to function as nanocapsules (Liu et al. 2015).
4 Characterization Methods
5 Intelligent Nanogels
As explained in the introductory section of this Chapter, smart NGs can undergo a
reversible phase transition in response to external or internal stimuli. Several
recently published and reviewed papers have reported nanosystems responding to
Of special interest are nanoparticles prepared from polymers having a lower critical
temperature or VPTT in water, giving rise to a reversible collapsing process trig-
gered by a shape-temperature change in the surrounding medium.
For this particular class of polymer networks, the enthalpy term, mostly caused
by the hydrogen-type bonding between polar groups of polymer and solvent, water
in this case, dominates at temperatures below VPTT, leading to the swelling of the
system. Above VPTT, the entropic term arises due to the hydrophobic polymer–
polymer interactions, resulting in a shrinking nanogel, and the consequent solvent
expulsion of the network (Jeong et al. 2002; Schild 1992; Nayak and Andrew Lyon
2005).
N-Substituted acrylamides are very attractive monomers owing to their ability to
generate polymer networks with lower critical temperatures. Table 2 summarizes
some homopolymer structures and experimentally determined VPTT (Müllen and
Ober 2013).
One of the first reports of thermo-responsive NGs was the pioneer work pub-
lished by Pelton and Chibante in 1986, which described the principles of the thermo
precipitation-polymerization technique, using NIPAm and N,N′-methylene
bisacrylamide (BIS) as model monomer and crosslinker, respectively, for the
preparation of aqueous lattices with different VPTT (Pelton and Chibante 1986).
7 Design of Multifunctional Nanogels with Intelligent Behavior 291
Poly(vinylcaprolactam) 32–40
(pVCL)
Poly(N-isopropylmethacrylamide) 38–42
Poly(N-ethyl-N-methylacrylamide) 56
Poly(N,N-diethylacrylamide) 32
Poly(vinylisobutyroamide) 35
Since then, numerous articles have focused on the synthesis and characterization of
smart nanoparticles based on thermo-sensitive polymers.
NiPAm and vinyl caprolactame (VCL) monomers and their base polymers are
probably the most widely used since their VPTT is close to the physiological one.
As seen before, both monomers are excellent candidates for nanogel formation via
the polymerization-precipitation method. Surfactant-free polymerization or the use
of ionic surfactant was previously reported, showing a high degree of ruggedness of
both monomers to form thermo-responsive nanogels under different conditions.
Figure 2 shows a schematic representation of pNiPAm and pVCL nanogels and the
reversible phase transition equilibrium.
As regards synthetic procedures, NiPAm is a very robust monomer, while VCL
can undergo a hydrolysis process as a competitive reaction during polymerization in
acid media. Ramos and coworkers reported the hydrolysis of the polymerizable
vinyl group of VCL, leading to caprolactam and acetaldehyde as products.
292 G. Rimondino et al.
The other important group of smart NGs besides thermo-responsive NGs are
pH-sensitive polymer-based nanomaterials. This class of materials is formed by
synthetic or natural polymer networks containing ionizable pendant groups, capable
of donating or accepting protons from the surrounding medium. The equilibrium
between the protonated and deprotonated state is achieved at pKa value. When the
pH of the environment reaches the pKa value, the degree of ionization of the
polymer backbone changes dramatically, triggering the presence of an absolute
charge at the nanogel structure. A non-charged nanogel shows a collapsed con-
formation owing to the polymer–polymer predominant interactions, whereas when
the polymer is charged, it adopts an expanded or swelling state as a result of
electrostatic repulsion between chains and the consequent entry of solvent.
Two different types of pH-dependent monomers can be used to generate this
kind of smart NGs. Monomers containing acid functionalities, mainly carboxylic
acids or sulfonates, can transfer their acid proton when the pH of the surrounding
medium rises up to pKa, leaving a negative charge value. In this case, AAc and
methacrylic acid (pKa: 4.2 and 4.6, respectively) are the most frequently used
monomers for preparing pH-responsive NGs (Cuggino et al. 2016; Abu Samah and
Heard 2013; Peng et al. 2013; Oh et al. 2009). Alternatively, amine-based mono-
mers or polymers are employed to give polymeric structures that arrest protons from
the medium, giving a net positive charge on the nanogel when the pH is lower than
pKa (Salehi et al. 2015; Fleige et al. 2012).
In this kind of NGs, different physiological pH values can trigger the reversible
phase transition. In the human body, two different behaviors give rise to a similar
result: changes in normal tissues or changes in sick tissues. Inside healthy cells, the
physiological pH gradient ranges from a neutral value close to 7.4 at the cytosol to a
relatively acidic condition inside lysosomal compartments with pH values of 4.5–
5.0, or a basic condition at the mitochondria, in which pH values rises to 8.0
(Asokan and Cho 2002). The pH values presented by pathologic tissues such as in
cases of cancer, infection or inflammation, are significantly different. The cytosolic
pH of a cell undergoing an inflammatory reaction drops to 6.5 compared to the
cytosolic pH of normal tissues. Thus, the high glycolytic activity in tumor cells
produces a slight diminution in the pH of damaged tissue (Gerweck and
Seetharaman 1996; Ganta et al. 2008).
The rational design of smart NGs leads to materials that can undergo a phase
transition during the endocytosis process or a response at a particular intracellular
294 G. Rimondino et al.
6 Hybrid Nanogels
Hybrid NGs are those where inorganic particles are incorporated into the polymer
matrix. Montoro et al. classified hybrid NGs into three categories according to their
morphology: (1) core-shell hydrogels with the inorganic nanoparticles placed in the
core; (2) inorganic nanoparticles distributed in the hydrogel matrix; and (3) hy-
drogels covered with inorganic nanoparticles (Montoro et al. 2014). Different
nanoparticles (NPs) such as magnetic nanoparticles (MNPs), gold nanoparticles
(AuNPs), silicate nanoparticles, quantum dots (QDs), silver nanoparticles (AgNPs),
etc., have been used in hybrid NG synthesis. Depending on the nature of the
inorganic NP, different functionalities can be achieved. Figure 3 shows an example
of a multifunctional hybrid nanogel (Online 2015).
There are two main ways of incorporating inorganic NPs into the polymer
network, one physical the other covalent: they can be introduced physically into the
NG matrix before or after gelation, so that they become trapped in the NG; or they
can be covalently incorporated using NPs as crosslinkers or moieties having a
covalent interaction between the matrix and NPs (Thoniyot et al. 2015).
7 Design of Multifunctional Nanogels with Intelligent Behavior 295
The most common magnetic nanoparticles (MNPs) used are iron oxide NPs
(IONPs), magnetite (Fe3O4) and maghemite (Fe2O3), alone or with another metal
such as manganese or zinc as dopant. Various MNPs have been synthesized using
ZnS or CoPt, among others (Peng et al. 2015; Dürr et al. 2013). MNPs are an
important class of biomaterials used for a variety of purposes such as imaging, cell
labeling, drug delivery, gene delivery and hyperthermia (Choi et al. 2012).
Treatment with MNPs produces intracellular heat stress in the temperature range of
296 G. Rimondino et al.
41–46 °C, which leads to activation and/or initiation of intracellular and extracel-
lular degradation (Verma et al. 2014). The ability of MNPs to generate heat under
the influence of external high-frequency field (Alternating Magnetic Field, AMF)
makes them a promising device for hyperthermia treatment (Karimi et al. 2016).
In addition, imaging is one of the most important tools in cancer diagnostics.
MNPs can be used for Magnetic Resonance Imaging (MRI), the standard clinical
test for determining the presence, location and size of a tumor. MNPs are ideal for
localized therapy, such as chemotherapy, radiation, immunotherapy or hyperther-
mia, or a combination of these (Brazel 2009). For example, the combination of
MNPs and a thermo-responsive network facilitates the optimal release of drugs,
since the heat generated by MNPs under AMF increases the temperature of the
nanogels above their VPTT, enhancing drug diffusion across the nanogel into the
blood (Merino et al. 2015). Some of the polymers used for obtaining MNG are
pNIPAm, thermo-responsive polyglycerol, oligoethylenglycol-based polymers, etc.
(Chen et al. 2011; Asadian-birjand et al. 2016; Boularas et al. 2015).
The potential use of AuNPs as a simultaneous imaging and therapeutic agent has
been demonstrated by many researchers, mainly because they are bio-inert and can
be easily modified with various biomolecules or chemical moieties (Choi et al.
2012). The shape of Au Nanorods generates several interesting characteristics such
as unique optical absorption and photo-thermal properties (Ryu et al. 2012). Gold
nanoparticles are able to absorb from visible to near infrared (NIR) which can be
used to generate local heat for use in photo-thermal therapy (PTT). In the presence
of an incident light at a specific wavelength, free electrons in the gold surface
undergo collective coherent oscillations known as surface plasmon resonance
(SPR) that can decay by heat emission (Online 2015).
The local heating produced by the nanoparticles after light stimulation causes
tissue necrosis, together with controlled delivery of the entangled chemotherapeutic
molecules (Merino et al. 2015). In addition to the direct effect of these particles on
heat delivery to the site when illuminated using an NIR laser, the transduction of
heat to thermo-responsive drug reservoirs, such as nanogels, allows a more efficient
delivery (Yeh 2014). Furthermore, AuNPs can also generate secondary electrons
under X-ray or gamma radiation, becoming ideal radiosensitizers that lead to DNA
and protein breakdown.
Several AuNPs-hybrid NGs have been synthesized using different AuNPs, such
as spherical NPs, nanorods, nanoshells, nanocages, and nanostars. Combining them
with different polymer matrices, a number of smart NGs have been designed with
responsiveness to one or more stimuli such as pH, temperature, and NIR among
others (Vigderman and Zubarev 2013). The most common polymers used in this
kind of NGs are polyacrylamide, poly(oligoethylenglycol), polyglycerol, poly(vinyl
7 Design of Multifunctional Nanogels with Intelligent Behavior 297
alcohol), and pVCL, known for their stimuli-responsive behavior (Lu et al. 2013;
Fuchs et al. 2015; Lutz 2011; Motornov et al. 2010).
Silica NPs are robust, bio-inert and easy to control in terms of size and morphology.
There are two main types of silica NPs—mesoporous silica NPs (MSNPs) and
amorphous NPs. MSNPs have been at the center of attention of researchers for
several reasons: they have finely controllable pores and considerable pore volume;
they can incorporate or bind high concentrations of a wide variety of molecules;
their diverse honeycomb-like architecture provides a large surface area and pore
diameter (Choi et al. 2012); the nanoplatform can be fine-tuned during synthesis;
their inner part can be modified in order to improve the interaction with the cargo
loaded inside and also the surface with a polymer matrix (Baek et al. 2015).
Combining MSNPs with a stimuli-responsive polymer matrix can improve drug
delivery by encapsulation of the active molecule not only in the polymer network
but also in the NPs. Furthermore, delivery can be triggered by an external stimulus
such as temperature or pH. The polymer used for the synthesis of silica NP-hybrid
nanogels are polyglycerol, oligoethylenglycol-based polymers, poly(N-vinylca-
prolactam) and others (Wu et al. 2015).
The impact of polymers on medicine has been widely recognized for more than
40 years, during which time they have received acclaim not only for their use as
biomedical materials but also for their application in pharmaceutical and biotech-
nology products. Their biodegradability, yielding optimal materials for resorbable
sutures, orthopaedic implants and macro or microscale drug delivery systems; their
versatility and adaptability to different forms; and their targeting capacity and tai-
lored mechanical properties all make them valuable materials for applications in
different areas of medicine, particularly in controlled release therapy and as diag-
nostic agents. (Molina et al. 2015; Calderón et al. 2010).
The application of nanotechnology to the development of safer and more
effective medicines, giving rise to nanomedicine, has signified an enormous chal-
lenge for the pharmaceutical and biotechnology industries. NGs play a very
important role in new advances in this field: in addition to their nanometer size
advantage, their chemical composition can be tailor-made to address specific
requirements.
As mentioned, the design of polymeric NGs with new properties represents a
field of constant interest owing to their 3D dimensional structure, good mechanical
properties, high water content and biocompatibility. They are usually the material of
298 G. Rimondino et al.
choice for introducing improvements into existing applications and for the devel-
opment of new applications in tissue engineering, as diagnostic agents and for cell
immobilization drug release and specific therapies (Chacko et al. 2012).
Undoubtedly, the nanometer size of NGs is the most important property in terms
of promising use in delivery systems. The key aspects for the design of
nanovehicle-based delivery systems will now be briefly dealt with.
– Toxicity and biodegradability: monomers or polymers used for synthesising
NGs should ideally be biodegradable and nontoxic and the nontoxicity of their
degradation products should also be assured. Another requirement is the con-
trolled release of the loaded drug at the specific site and in the appropriate
concentration, since its release above the therapeutic window would cause toxic
or other undesirable side effects.
– Stability: the ability to maintain their integrity and size once the NGs are cir-
culating in the bloodstream is key for the effectiveness of nanosystems.
Furthermore, the encapsulation stability of the loaded agent is essential to avoid
premature leakage of the drug during circulation: faced with the turbulent flow
conditions of the vascular system, delivery vehicles encounter blood cells,
serum, lipid membranes, and several potential hydrophobic components which
can trigger undesired drug leakage. Previous works reporting a lack of corre-
lation between in vitro and in vivo studies highlighted the need to measure
stability in more quantifiable and universal terms (McNeil 2005; Jeong et al.
2002; Liggins and Burt 2002). The encapsulation factor, when the NGs are
employed as a delivery system, is reported as the weight percent of the drug
loaded per unit weight of the vehicle, which is the thermodynamic distribution
coefficient of the drug molecule from the interior of the nanocarrier. Values
considered reasonable fall in the range between 5 and 25% (Bickerton et al.
2012).
While the stability of the drug encapsulated in a carrier is desirable during
circulation, the drug will only be effective if released once it reaches its intended
target. As discussed in the previous section, this can be achieved by designing the
chemical composition of the carrier to be effective against a particular stimulus or to
recognize the site of action through target receptors.
– Long circulation time: it is important for NGs to be able to remain in circulation
for sufficiently long to reach the site of the disorder, avoiding natural clearance
routes. Unfortunately, most nanocarriers are eliminated by the reticuloen-
dothelial system within minutes after injection. NGs are taken up by liver and
spleen macrophages via phagocytosis. Opsonins serve as an adjunct immune
system, combining with blood proteins at the surface and accelerating nanogel
elimination. In general, nanoparticles of 30–200 nm in diameter show longer
circulation times, shifting the equilibrium to extravasation and leading to
improved accumulation in the tumor. The slightly negative zeta potential of
nanoparticles also predicts reduced clearance (Khandare et al. 2012). In order to
reduce interactions with serum proteins, achieve prolonged circulation time in
7 Design of Multifunctional Nanogels with Intelligent Behavior 299
therapeutic efficacy. The report published by Hsin-Cheng Chiu et al. (Chiang et al.
2013) provides an interesting example of a well-designed nanosystem with the
mentioned double function (see Fig. 5).
The reported hollow hybrid nanogel system with theranostics properties was
prepared via the covalent stabilization of the co-assembly of magnetic nanoparticles
with poly(AA-co-MEA)-g-mPEG/pNiPAm. As previously commented, the pres-
ence of co-monomers such as AA and NiPAm conferred pH- and
thermo-sensitivity, respectively, on the nanogels. PEG segments were used as
stabilizer to prevent particle aggregation and to enhance biocompatibility and
long-time circulation. The incorporation of MNPs enables magnetic resonance
imaging contrast, magnetic guidance and hyperthermia therapy, which trigger rapid
drug release as a consequence of the thermo-responsiveness of the conjugated
polymer. Doxorubicine (Dox), a well-studied anthracycline used in chemotherapy,
was incorporated into the NGs, and both controlled drug elution and cellular uptake
were observed. The nanocarriers enter into the blood circulation at 37 °C and are
guided by a magnetic field to the targeted site of action. As a consequence of the
hyperthermia produced by magnetic resonance or by changes in pH values, the drug
is released at the tumor site. All these desirable characteristics lead to a prominent
in vitro cytotoxic effect against tumor cells. Although an evaluation of the in vivo
performance of this system is obviously required, this work demonstrates the great
potential of the multimodal theranostics system for cancer treatment.
Another important example, but using gold NPs, is presented in the paper by
Chunying Chen et al. (Zhang et al. 2014).
Figure 6 shows a photo-thermal and thermo-responsive nanocomposite with a
core of Au@SiO2. These NPs were coated with a polymer shell of
thermo-responsive pNiPAm. The activation stimulus in this work was an NIR laser.
NIR radiation range (from 650 to 900 nm) can penetrate deeply into the body and
causes minimal damage. Gold NPs served as transducers for NIR transformation
into confined local heat, which could be used to promote the size control of NGs
and trigger drug release. This system showed low cytotoxicity and high biocom-
patibility in cell experiments. The improved accumulation in tumor with NIR laser
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Chapter 8
Radiation Dosimetry—A Different
Perspective of Polymer Gel
Abstract Medical physics has gained much interest in the past few decades with
the introduction of polymer gels which act both as a phantom and a dosimeter.
These polymer gels act as the substrate for the dose to act upon, after which the
distribution can be read three-dimensionally. Mainly consisting of a gelling agent,
monomer, crosslinker, and an antioxidant, these dosimeters on exposure to ionizing
radiation polymerize as a function of the absorbed dose. This dose can be readout
using modalities like MRI, X-ray CT, optical CT scanner, etc. Various combina-
tions of polymer gels are presented including ones made with modifications to the
present ingredients or addition of nanoparticles. The additions of nanoparticles
enhance the dose for improved therapeutic efficiency. Being tissue equivalent and
having good spatial resolution make it a new class of dosimeter which can replace
the conventional dosimeters. The fundamental science behind the technique, gel
preparation, and areas of future potential developments to improve the validation
for lower dose than current fractional radiotherapy dose is also discussed.
Keywords Polymer gel Dosimeter Dose Three-dimensional
Ionizing radiation Tissue equivalent Radiotherapy
1 Introduction
The wide applications of polymer material are familiar to the modern era.
Increasing usage of these in medicine and drug delivery has benefits due to their
unique properties. Several biorenewable polymers have drawn interest for its
D. Titus E. J. J. Samuel
Medical Gel Dosimetry Lab, Department of Physics, School of Advanced Sciences,
Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
S. M. Roopan (&)
Department of Chemistry, School of Advanced Sciences, Chemistry of Heterocycles &
Natural Product Research Laboratory, Vellore Institute of Technology, Vellore 632014,
Tamil Nadu, India
e-mail: [email protected]; [email protected]
diverse applications which include water purification, biomedical, etc. (Thakur and
Thakur 2014, 2015). Some polymer nanocomposites possess self-healing property
(Thakur and Kessler 2015). Moreover, polymer-loaded nanoparticles which are
capable to target-specific cells are also in demand. Here, we bring to you another
aspect of polymer gels which are of greater importance in the field of radiotherapy.
The current-day practice of sophisticated techniques in the field of cancer
therapy includes Three-Dimensional Conformal Radiotherapy (3D CRT),
Image-Guided Radiotherapy (IGRT), Intensity-Modulated Radiotherapy (IMRT),
Brachytherapy, Stereotactic Radiosurgery/Radiotherapy (SRS/SRT), particle ther-
apy, and so on. All these methods need a qualitative assessment prior to application
on patient. Although the conventional methods like ionization chambers provide
point dose measurement, films, being a two-dimensional dosimeter, provide better
spatial resolution and relative dose measurement and so does the thermolumines-
cent dosimeters (TLDs) and other detectors. There was always a constant need for a
radiation dosimetry technique which allows to capture the dose distribution
three-dimensionally and that led to the development of radiation sensitive gels as
we call it the gel dosimeter.
Gel dosimeter as the name suggests, a type of dosimeter, is tissue equivalent and
enacts the role of both the phantom and a dosimeter. The history with the gels
started off with the development of ferrous sulfate-doped gel (Fricke and Morse
1927). Later on, radiation-induced color change was observed in dyed gels espe-
cially methylene blue which paved way for the proposal of the use of gels for
radiation therapy (Day and Stein 1950). Further investigation was done in-depth
dose measurements using chloral hydrate agar gel with the aid of pH probe and
spectrophotometry (Andrews et al. 1957). Then, the dose distribution via NMR
imaging was introduced (Gore et al. 1984). Easy preparation, tissue equivalent
nature of Fricke, which depended on the conversion of ferrous ions to ferric ions by
radiation, gained much interest but had a limitation of ion diffusion, thereby not
able to retain a spatially stable dose distribution. This put forth a time constraint
between the time of irradiation and the time of scanning which is a maximum of
two hours. So, soon after the irradiation, the dosimeters have to be scanned for
results (Olsson et al. 1992). The problem of diffusion was reduced with the addition
of glyoxal but the gel got partially bleached (Kalin and Mequanint 2013). Fricke
Xylenol Orange is the common recipe studied and reported (Bero et al. 2000) which
contain Xylenol orange which acts as the metal ion indicator and gelatin as the gel
matrix. Fricke gels are composed of ferrous sulfate solution in gelatin matrix. The
metal ion indicator used here is xylenol orange, to identify the conversion of ferrous
ions to ferric ions. The indicator shows light orange color in ferrous environment
and turns to dark brown in ferric. This property (color change) is used for scanning
via optical CT scanner. The irreplaceable role of Fricke in the gel dosimetry field is
evident from the progress of considerably more stable Fricke systems (Schreiner
2004) and improved optical technologies to view the dose pattern.
Through the polymer gel introduction, an alternative aspect based on the
radiation-stimulated polymerization of monomers in solution, the problem of dif-
fusion as in Fricke was solved. Figure 1 shows the basic idea of gel dosimetry.
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 311
Various recipes of polymer gels have been described which increased the stability
and sensitivity of the gel. This chapter gives an outline of the polymer gel
dosimetry, its development, fundamental science sustaining the technique, different
combinations, applications, and future scope.
remove the oxygen in the gel solution. The first normoxic gel developed was named
as MAGIC that stands for methacrylic acid, ascorbic acid, gelatin, and copper.
Ascorbic acid along with copper takes away the oxygen (De Deene et al. 2002).
Later on, the usage of tetrakis (hydroxymethyl) phosphonium chloride (THPC) was
introduced as an oxygen scavenger (Baldock 2006). Some of the advancements in
the field include the introduction of the gels namely MAGAT monomer–
methacrylic acid (De Deene et al. 2002), PAGAT, monomer–acrylamide (Venning
et al. 2005a), BANG (Maryanski et al. 1994a), and MICELLE are radiochromic
gels which used dyes like leuco violet crystal and leucomalachite green (Jordan and
Avvakumov 2009) and PRESAGE (Adamovics and Maryanski 2003). The
potential hazards of the chemicals used in the manufacture are identified and
suggested some less harmful gels like NIPAM, which uses N-isopropylacrylamide
as the monomer (Senden et al. 2006), GENIPIN (Jordan 2009), HEMA,
2-hydroxyethyl methacrylate (Trapp et al. 2005), and other variations in the
abovementioned formulae.
Reviews on polymer gel dosimeters have already been reported (Baldock et al.
2010; McJury et al. 2000) and additional works have been reported in the DOSGEL
conference proceedings (DOSGEL 1999, 2001, 2004, 2006, 2008).
The basic methodology includes the fabrication of the gel dosimeter, irradiation
using Co-60 or linear accelerators, and finally scanning (imaging).
2.1 Preparation
Polymer gels are majorly composed of 80% water, a monomer, crosslinker, gelling
agent, and an oxygen scavenger. Monomer, such as acrylamide, is added, which is
upon irradiation to ionizing radiation polymerizes. It also consists of a gelling
agent, gelatin, which acts as the stabilizing agent as well as the gel matrix where the
polymer is kept intact. Deionized distilled water is used in order to remove any
oxygen present in it. The preparation was formerly done using glove box with
nitrogen environment or in sealed reaction flasks. Oxygen scavengers are used for
this purpose nowadays to get rid of any oxygen present in the mixture while
preparing. On exposure to oxygen, the free radicals created and might interfere the
process of polymerization. A crosslinker is also added to link the monomers. Gels
are prepared and stored in PET containers which are then kept for refrigeration for
further use. The prepared gel samples are irradiated using Co 60 or LINAC which
are then scanned to extract the dose information (Baldock et al. 2010).
Similar preparation methods are reported and mentioned by the authors and
sometimes slight variations in the combinations are adapted, which improve the
stability and sensitivity of the gel.
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 313
The radiation sensitive chemicals when exposed to ionizing radiation will exhibit
changes in the properties of the gel which are further analyzed by various tech-
niques. 80% of the gel is composed of water; basically, polymer gels are hydrogels
containing dissolved vinyl monomers present in it. The radiation induces free
radical production by water radiolysis. These free radicals further lead to poly-
merization of the gel. For Fricke gel dosimeter, the radiation-induced free radicals
help in ferrous to ferric ion conversion and so the color changes, whereas in
polymer gels the monomers get converted into polymer which is instigated by the
free radical produced by water radiolysis and there is significant change in the
density, optical density, and binding of the water molecules. All these properties are
made use of in choosing the appropriate modality for scanning the gel dosimeter for
extracting the dose distribution. The polymers stay intact in place with the help of
gelatin which acts as the stabilizing agent here. The exposed region in gel turns
from colorless (transparent) to milky white (opaque) which can be seen visually.
The amount of polymerization depends on the absorbed dose.
2.3 Irradiation
The water molecules in the gel before and after irradiation play a significant role
here. Polymerization of gel has an influence on the nearby water in the gel, which
changes the binding of water molecules. It is this change which can be assessed by
the two parameters of MRI, namely spin–lattice relaxation rate (R1) and spin–spin
314 D. Titus et al.
relaxation rate (R2). Though R1 has been found to vary only slightly, R2 is the
parameter often used as this varies with regard to the absorbed dose, as the extent of
polymerization increases (Maryanski et al. 1993).
2.4.2 X-Ray CT
There is an increase in the physical density of the gel as the polymer chain is
formed and the resultant variation in attenuation coefficient can be readout using
X-ray CT. The density change which is apparently small is found to be proportional
to the dose absorbed. When examined with CT, this eventually leads to variation in
the CT number (Hilts et al. 2000). Image averaging and filtering techniques should
be done for multiple acquisitions in order to get high signal-to-noise ratio (Hilts and
Duzenli 2004).
2.4.3 Optical CT
understand the fundamental properties and structure of the dosimeter (Baldock et al.
1998b). Ultrasound computed tomography scanner was also developed to evaluate
the dose distribution (Mather et al. 2003) as this makes use of the ultrasonic speed
and attenuation which are dependent on the absorbed dose.
3 Gel Dosimeter—Characteristics
The gel mixture, after adding the monomer and crosslinker, should be kept away
from light and oxygen as it can degrade the sensitivity of the gel made.
Photopolymerization can happen when exposed to light and free radical-induced
polymerization can be stopped as the oxygen can react with the free radicals pro-
duced making it impossible to polymerize (Maryanski et al. 1993, 1994b; Baldock
et al. 1998a).
Nitrogen bubbling into the gel can lead to fogging of the gel dosimeter. Use of
high-grade chemicals is instructed as any free radical impurities present in the gel
(chemical) can be responsible for this. Polymerization prior to irradiation does not
serve the purpose of dosimetry (Maryanski et al. 1993, 1994b).
Temperature is yet another important factor which has to be noted while the
preparation, irradiation, and scanning. The corresponding temperature has to be
maintained during preparation as some overheating can damage the gel. Though
effect of temperature has not much effect on the irradiation part, it plays a major role
in scanning. Decrease in temperature increases the relaxation rate of gelatin. Hence,
the gels are to be maintained at uniform temperature before doing MRI. The
temperature of the calibration gels and the experimental gel has to match
(Maryanski et al. 1994b, 1997; Vachier and Rutledge 1996).
316 D. Titus et al.
It might take hours or even weeks for the complete polymerization of the gel once
irradiated. Imaging the gel few hours of the irradiation can lead to errors. So it has
to be kept overnight for stable complete polymerization for better results (McJury
et al. 1999a).
Various gelling agents are used like agar-agar, agarose, gelatin, Sephadex, and
polyvinyl alcohol (PV-A). Gelatin replaced the formerly used agarose as the gels
made were much clearer than those made of agarose. 300 Bloom Gelatin is usually
used (Vachier and Rutledge 1996), as the gel strength is more and so there is an
increase in the melting point. Usually used in 5% by weight for the preparation,
gelatin plays an important role by keeping the polymer intact in place forming a
matrix. Increasing the concentration affects the sensitivity of the gel (Maryanski
et al. 1994b).
3.6 Toxicity
Maryanski et al. (1994b) noticed edge enhancing effects at relatively high dose
levels in the polymer gels near the regions of high-dose gradient. Outcome of the
high dose in a particular region is the monomer depletion in that region, and thus
the monomers start diffusing from low-dose to high-dose region and react with the
polymer macro-radicals that are generated in the high-dose area. This can be a
reason for the overshoot in the dose near the edge of the region exposed to high
dose. The dependency of post-irradiation time with the overshoot amplitude was
also discussed (De Deene et al. 2002). Based on the hypothesis that the
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 317
macro-radicals are accountable for the temporal and spatial instabilities detected in
gel post-radiation, a mathematical model was proposed (Vergote et al. 2004).
Increasing the gelatin concentration reduces the monomer diffusion constant;
however, a decrease in sensitivity is also observed.
3.8 pH Effect
The dose sensitivity and the R2 max were found to be dependent on the crosslinker
fraction. The dose saturation point is extended which can be due to the monomer
reactivity and the relaxation properties of gel (Baldock et al. 1996; Maryanski et al.
1997; Farajollahi et al. 1997). Kennan et al. (1996) and Maryanski et al. (1997)
found that due to the low reactivity of BIS, crosslinker when compared to acry-
lamide, as the crosslinker fraction increases, the monomer-to-polymer conversion
per unit dose decreases thereby decreasing the sensitivity of the gel.
The tissue equivalent nature of the gel is yet another important aspect which is one
of the major criteria for a gel dosimeter. Before applying, one must always estimate
the water equivalence of the polymer gel. The gel dosimeters should display water
equivalent radiological properties. The water equivalence of a particular gel can be
estimated using effective atomic number (Khan 2003) denoted as Zeff,
318 D. Titus et al.
1=2:94
Zeff ¼ a1 Z2:94
1 þ a2 Z2:94
2 þ a3 Z2:94
3 þ . . . þ ai Z2:94
i
X 1=2:94
¼ ai Z2:94
i where, ai is the fractional weight of the ith element:
5 Calibration
Each gel prepared should be calibrated individually at the time of use for getting the
proper response (Baldock et al. 1998a). The sensitivity and accuracy of the gel
depend on the conditions of preparation and the chemicals used. Any impurity
present or carelessness can lead to damage to the gel and its behavior. Different
methods are adopted by which the gels are shifted to calibration phantoms and are
irradiated with doses known. MRI scanning of the calibrated phantom produces T2
relaxation. A plot of R2 (1/T2) against the doses is made, and this was used as a
standard to calibrate the rest of the data (Maryanski et al. 1994b). Errors in fitting
the data can determine the quality of the method and also on the quality of the gel.
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 319
The three methods used for the calibration are multibeam method, multiflask
method, and depth dose method.
Multibeam method comprises the irradiation of a large volume of gel with
several small beams. Depending on the sensitivity of the gel used, a number of
doses can be given over a range (Oldham et al. 1998). Alternate to this, Maryanski
et al. (1996) did a method where the phantom was irradiated with odd number of
circular beams such that it converges at a central target point for which the dose was
calibrated at Dmax. Major disadvantages include the use of a large amount of gel and
only few numbers of data points could be obtained for the plot.
For mutiflask method, small flasks are taken, packed with the respective gel and
each flask is subjected to radiation to a known dose with parallel-opposed beam
arrangement so as to get a uniform dose throughout the gel sample. Similar errors in
multibeam method can happen here but only less gel is needed for this method. The
flasks should be taken such that they are thin walled and completely filled with gel
with no space for air cavity and should be surrounded by tissue equivalent phantom
which is safe enough to ensure equilibrium. This removes the issue of the inter flask
variation, thus ensuring that the conditions of full backscatter are met. The gels will
therefore get a uniform irradiation which leads to error in calibration fit (Back et al.
1998; Baldock et al. 1998a; Ibbott et al. 1997).
In a water tank, a long test tube containing gel is vertically positioned and from
the closed end it is irradiated with a single beam. This contributes to the charac-
teristic depth dose distribution; the data should be plotted against ion chamber
measurements or known depth dose distribution for the beam energy. To cover the
entire range of 0–10 Gy, using multiple short test tubes may be ideal than using a
single test tube taking into consideration the limitation of RF coil homogeneity. To
increase the signal-to-noise ratio, adjacent points were averaged together at each
depth (Ibbott et al. 1997; Maryanski et al. 1994b).
The first ever made gel for dosimetric purpose was BANANA, a hypoxic polymer
gel which was prepared by agarose infused with the co-monomers N,N-
methylene-bis-acrylamide (BIS) and Acrylamide, nitrous oxide and agarose. Later,
gelatin replaced the agarose in BANANA and the new formulation was referred to
as BANG (Maryanski et al. 1992, 1994a). The two current models of BANG gel
available are BANG-1TM, which uses powdered form of acrylamide and
BANG-2TM, acrylic acid replaces the acrylamide together with NaOH. Improved
gel response was seen in BANG-2TM. BANG-3TM replaced acrylic acid with
methacrylic acid which delivered good MRI and optical response (McJury et al.
2000; Oldham et al. 2001).
Fong et al. (2001) introduced the normoxic polymer gels which can be prepared
in normal atmospheric conditions. Here, the nitrogen environment used for oxygen
320 D. Titus et al.
scavenging was replaced by the use of oxygen scavengers. First such developed gel
is MAGIC which is the acronym for methacrylic acid, gelatin, ascorbic acid, and
copper sulfate. Methacrylic acid here acts both as the monomer and crosslinker. The
function of copper sulfate and ascorbic acid is that of an oxygen scavenger (De
Deene et al. 2002). Later, different compositions and formulations of MAGIC
dosimeter were developed. The use of tetrakis (hydroxymethyl) phosphonium
chloride (THPC) was investigated which brought profound interest to the field
(Baldock 2006). MAGAT was one among the findings which composed of
methacrylic acid, gelatin, and THPC. For making a 500 g of gel sample, 430 g of
distilled water is mixed with 40 g of gelatin under continuous stirring heated to a
temperature of 48 °C for the complete dissolution of gelatin in the solution. The
mixture was then allowed to cool and when it reached 35 °C, 30 g of methacrylic
acid was added and mixed properly. 0.117 g of THPC was added at the end, mixed,
and cooled (Govi et al. 2013).
A vital factor that can restrict the wider use of MAGIC gel is temperature; if the
gel melts, it can take away the three-dimensional information. This was overcome
by the addition of formaldehyde to the gel (Fernandes et al. 2008) during prepa-
ration, thus gaining an increase in the melting point making it viable to use in
warmer conditions. 3% formaldehyde raised the melting point of the gel to 69 from
25 °C and a 12.5% increase in gel sensitivity was accomplished.
Sensitivity of MAGIC gel was studied with the addition of inorganic salts like
LiCl, NaCl, KCl, and MgCl2 which can act as the accelerator for polymerization.
Among the salts examined, MgCl2 acted as the most effective sensitizer (Hayashi
et al. 2012). Urea and glucose added to MAGIC gel resulted in the increase of
sensitivity and tissue equivalence (Zhu et al. 2010). Cho et al. (2014) examined the
dose–response of MAGIC gel with several saccharide types to clarify its role in
polymerization.
PAGAT was yet another invention. The commonly used PAGAT recipe fol-
lowed is 5% gelatin mixed with 89% of double distilled water and the solution is
heated to 40 °C. As the gelatin gets dissolved, it is continuously stirred using a
magnetic stirrer. Once it is dissolved, the crosslinker namely N,N-
methylene-bis-acrylamide is added to the solution and heated till 45 °C. After
dissolving, the solution is allowed to cool and when it reached 40 °C, the monomer
acrylamide is added to it and finally 10 mm THPC added at around room tem-
perature (32 °C). The gel solutions are then poured into PET containers and kept for
refrigeration (4 °C) overnight for complete gelation (Venning et al. 2005a;
Subramanian et al. 2006).
Figure 2 shows the UV–Visible spectrum for PAGAT, and Fig. 3 shows the
irradiated PAGAT gel. This shows the increase in the intensity as the dose pro-
gresses as depicted in the graph and visually. The gels were irradiated with
0–18 Gy (Samuel et al. 2015). PAGAT was also studied with the addition of
formaldehyde (Yun et al. 2010) and succeeded in attaining an increase in the
melting point and good linear response for the doses absorbed. Another modifi-
cation of PAGAT gel by replacing the THPC with green tea due to its antioxidant
nature was reported (Samuel et al. 2015). Green tea extract inhibits the
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 321
polymerization in gel but when used in small quantity with sugar, it allows poly-
merization and increased the sensitivity.
PRESAGE is a new class of polymer gel, first proposed in 2003 (Adamovics and
Maryanski 2003) which was based on leucomalachite green, a leuco dye, combined
with clear polyurethane. The ingredients consist of an alkyl di-isocyanate pre-
polymer and a hydroxyl reactive polyol together with a catalyst. This is
322 D. Titus et al.
THPC is added which acts as the antioxidant. The dose, dose rate, temperature
dependence, and post-irradiation time were observed and were in agreement with
the previously reported PAGAT gel dosimeter. The dose–response was linear for a
greater range than the PAGAT and better sensitivity. A co-solvent isopropanol was
incorporated in NIPAM with the purpose of increasing the concentration of total
monomer/crosslinker. Poor contrast and reduced dose resolution which arise due to
the low-dose sensitivity of the PAGAT were improved with this ingredient. The
gels made were stable and reproducible (Jirasek et al. 2010).
A new combination which makes use of 2-hydroxyethyl methacrylate (HEMA)
as an alternative to the methacrylic acid in MAGIC gel was introduced. 82.48% of
water was mixed with 8% gelatin, 0.5% ascorbic acid, 0.02% copper sulfate, and
9% HEMA, which was used as the formulation of the recipe (Trapp et al. 2005).
Another combination reported with HEMA was with the use of polyethylene glycol
400 dimethacrylate (9G), triethylene glycol monoethyl ether monomethacrylate
(TGMEMA), THPC, and gellan gum (gelling agent) (Hiroki et al. 2001). A linear
dose–response which depended on the concentration of HEMA was seen in the case
of gel with 9G and HEMA, while for the other gel having HEMA, TGMEMA, and
9G, the exposed region exhibited a thermos-responsive behavior and the absor-
bance increased after a certain dose. Yet, another using HEMA along with 9G and
hydroxypropylcellulose (HPC) gel, a gelling agent used in place of gelatin, was
studied for doses from 1 to 10 gray and the response was linear (Hiroki et al. 2013).
An additional class of polymer gel was developed with propylene acid based
named DEMBIG. The preparation is as follows. Deionized water was filled with
argon which was done in a glove box and then mixed with 7% gelatin under
continuous stirring. The solution is heated to 45 °C for the gelatin to dissolve just
like other preparation. Here, 5% DEMA and 4% BIS were added to the mixture and
stirred again for some time. Then, the gel was filled with argon for half an hour,
transferred to tubes and kept for cooling (Hsieh et al. 2011).
Turnbull dye-based dosimeter involves a gel matrix and an acidic medium with
potassium ferricyanide and ferric compound. An insoluble dye K [FeIIFeIII(CN)6] is
formed upon irradiation as the ferric ions get converted to ferrous ions and showed
maximum absorption at 600 nm. When compared with the PAGAT gel, advantages
of TB gel are its inhibited diffusion when compared to Fricke dosimeter and lin-
earity for 0–400 gray (Solc and Spevacek 2009). Disadvantage includes gel aging
due to interaction of ferric ions with other organic compounds. While preparing
larger volumes, solidification can take several days and this was another problem
which was encountered (Pilarova et al. 2014). PAGAT has a linear range up to
9 Gy, higher noise level in the response than TB gels, and also the toxicity issues
due to monomer.
N-(Hydroxymethyl) acrylamide (NHMA)-based polymer gels (Basfar et al.
2015) were fabricated in a nitrogen glove box. 8% NHMA monomer was combined
with 3% BIS, 4% gelatin, and 0.02 mM hydroquinone. For at least 5 hours,
nitrogen was used in the chamber to remove the oxygen which can inhibit the
polymerization of gels. The same procedure methods were used for the manufacture
324 D. Titus et al.
and were characterized using MRI. The rate of polymerization was dose-dependent,
that is irradiated to 20 Gy and studied the effect of dose rate and radiation energy
but found no effect on the same.
Two dyed gelatin gels were formulated. The first gel makes use of Fuchsin acid
cyanide dye (Gafar and El-Ahdal 2015) which diffuses in gelatin, thereby changing
the colorless sample to a pink color after radiation. Using UV–Visible spec-
troscopy, the absorption was found at 550 nm. By varying the concentration of the
dye, the formulations were studied and evaluated the radiation chemical yield, its
stability, and sensitivity. Toluene Blue O (TBO) gelatin gel dosimeter (Gafar et al.
2014) was the second one which was studied with UV–Visible spectrophotometer
having an absorbance at 635 nm. The G value increased with the dye concentration
and the useful range being 1–150 Gy. The parameters like sensitivity, storage, and
dose–response were also investigated.
A reusable radiochromic polymer gel named crystal ball was studied for its
accuracy and for use in patient QA in proton therapy. It is tissue equivalent as well
as commercially available (Avery et al. 2015). Mattea et al. (2015) studied a
polymer gel using itaconic acid and BIS.
Yao et al. (2014) used the monomer tertiary-butyl acrylate, TBA which played
the role of forming a transparent, quasi-rigid and 3D gel matrix and also the role of
going through the process of polymerization with the fluorogenic material. The
various combinations of gel are listed in (Table 1).
To improve the sensitivity and efficiency of the polymer gel, researchers are
spending quality time on as to being used for lower dose range also that is below 1
gray. Aiming at giving minimum dose to the healthy tissues and maximum to the
tumor cells, several approaches are implemented to serve the purpose. One of the
novel methods is the incorporation of nanoparticle into the polymer gel dosimeter.
Nanoparticle which finds its extensive application in almost all fields (Kalaiselvi
et al. 2015; Elango and Roopan 2016; Kumar et al. 2015; Surendra et al. 2016;
Helan et al. 2016) is a boon to the modern medical field. Interaction of the ionizing
radiation with the healthy tissues may damage DNA, and therefore further care has
to be taken to spare the healthy tissues.
Nanoparticles of the order of 1–100 nm have been in use in the past few years. It
has been used for drug delivery, diagnostics, and treatment. The nanoscale particle
has significant properties comparing the bulk material such as magnetic properties,
fluorescence, and others. Prepared via various means, the nanoparticles exhibit
properties which are applicable in medical field. Physical, chemical, and biological
methods of preparation are the main methods of preparation. The physical method
being a top-down approach includes ball milling, laser ablation, bead milling, etc.,
whereas the chemical method involves the use of chemicals as reducing agent to
reduce the metal ions to nanoparticles. Electrochemical method, microwave
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 325
irradiation, sonication, co-reduction method, micelle, and sol–gel are some of the
methods opted for fabrication. An alternative to these methods is the biological
method which is using plant extract and microorganisms which in turn reduces the
metal ions. Plant-mediated synthesis or green synthesis is much more preferred as
the microorganism-based synthesis is difficult to maintain. Prepared nanoparticles
are then characterized using UV–Visible spectrophotometry for initial confirmation
and further on to X-ray Diffraction (XRD) for finding the crystalline nature,
Scanning Electron Microscope (SEM), Atomic Force Microscope (AFM), and
Transmission Electron Microscope (TEM) for studying the morphology, topology,
and size of the particle, Energy-Dispersive X-ray Spectroscopy (EDAX) for ele-
mental composition, vibrating sample magnetometer for studying magnetic
326 D. Titus et al.
properties, and various other methods depending on the need (Cheow et al. 2013;
Roopan et al. 2012, 2014; Kumar et al. 2014; Pal et al. 2011; Elango et al. 2015;
El-Alaily et al. 2015).
High atomic number nanoparticles have the ability to enhance the dose.
Materials like gold, platinum, bismuth, etc. can be used for this purpose. The
principle behind radiosensitization is discussed: When a target or metal is hit by an
X-ray, part of the incident radiation energy will be imparted to eject an electron
from its orbital and part of the energy goes as its kinetic energy. The corresponding
kinetic energy can be calculated as the difference between the binding energy of the
electron and the energy of the wave. The photoelectric effect is dependent on the
atomic number of the material and also on the incident wave energy. Possibility of
auger electron generations is also there if elements, with mid- to high atomic
number, are ionized by X-ray or gamma ray; this can also enhance the dose. Here,
the vacancy of the electron is filled by another electron and the energy is released
(Khan 2003; Kobayashi et al. 2010). Depending on the size of the particle, its
composition, uptake of these particles into the cells, and the energy of the applied
radiation, the nanoparticles can provide radiation dose enhancements. Figure 4
depicts the dose enhancement mechanism.
Gold, having atomic number Z = 79, nanoparticle (Au NP) considered as one of the
less toxics and has been demonstrated to overcome the limitations of renal toxicity,
short imaging timing, and poor contrast by other X-ray contrast agents. When
compared to iodine, gold nanoparticles delivered 2.7% higher contrast (Hainfeld
et al. 2006). No toxicity was observed with reduced bone interference and
improvement in delineation of blood capillaries. The characteristics like being inert
to interactions with the tissues and high atomic number element make it promising
for photosensitization reaction. As radiosensitizer, these can perform well as it
enhances the radiotherapy efficiency. When used combined with the kV X-rays, the
nanoparticles enhance the dose deposited in the tumor and an increase in the
absorption was seen as a result of the element’s photoelectric cross section. The
process which utilizes Au NPs as means for dose amplification is referred to as the
gold nanoparticle-assisted radiation therapy abbreviated as GNRT (McMahon et al.
2008). Radiosensitization effect is governed by factors like the size, concentration
of the particle, and the incident X-ray energy (Brun et al. 2009). The possibility of
using GNRT via brachytherapy was done by Cho et al. (2009). Other GNRT works
are reported by Rahman et al. (2009), Van den Heuvel et al. (2010), Leung et al.
(2011), Zhang et al. (2012), Kakade and Sharma (2015), and review works have
been reported (Jelveh and Chithrani 2011; Butterworth et al. 2012; Jain et al. 2012;
Babaei and Ganjalikhani 2014; Su et al. 2014).
Au NPs of 2–3 cm average diameter were synthesized and mixed with MAGIC
—f (methacrylic acid, ascorbic acid, gelatin, copper sulfate, and formaldehyde) in
three different concentrations and subjected to irradiation using a 250 kV X-ray
beam. Monte Carlo simulations were executed and the dose enhancement due to the
Au NPs matched with the Monte Carlo simulations (Marques et al. 2010). Further,
the dose variation due to Ag NPs was quantified in nPAG dosimeters using syn-
chrotron and conventional beams used for radiotherapy (Rahman et al. 2010).
Kamiar et al. (2013) prepared Au NPs of size 57 nm by reduction of gold precursor
using trisodium citrate. These prepared NPs increased the effectiveness of radiation
dose by about 21% and at 400 ppm; they exhibited major antibacterial property
against Escherichia coli. The performance evaluation and the physicochemical
characterization were thus done.
MAGICA gel was utilized to demonstrate the effect of dose enhancement due to
Au NPs when used with megavoltage therapy. The R2 increased with the addition
of Au NPs and the optimum concentration was found out to be 0.1 mM which
contributed to 10% dose enhancement (Khadem et al. 2013). Comparison studies
with the Monte Carlo simulations were done too. Also, the effect of percentage
depth dose was studied using energy in MV range in MAGICA gel. It was con-
cluded that for concentrations greater than 0.1 mM, shielding effect was created and
the simulation work suggests that the increase in gold concentration decreases the
absorbed dose enhancement factor (Mahdavi et al. 2013).
328 D. Titus et al.
Another promising material (high atomic number) proven for cancer therapy is
platinum (Pt, Z = 78). Based on the addition of platinum nanoparticles with the fast
ion irradiation like in hadron therapy, a new approach was formulated (Porcel et al.
2010). Fatal damage could happen to the DNA due to the presence of nanoparticles.
The efficiency was calculated to be a factor of about 2. The enhancement is due to
the auto-amplified electron cascades which are in the nanoparticles. Consequently,
Pt NPs were combined with X-ray energies of different ranges to study the effect on
DNA. The effect predominant in this study was the photoelectric effect and the
platinum atoms were ionized by the photoelectrons. Any high atomic number
nanoparticle can enhance the radiation dose irrespective of the nature of ionizing
radiation and also is dependent on the source of the energy used for irradiation
(Porcel et al. 2011).
The feasibility of using Pt NPs, produced by the technique of laser ablation
having an average size of 10 nm, with PAGAT gel dosimeter was studied.
Deyhimihaghighi et al. (2014) considered this possibility to investigate the usage of
platinum nanoparticle as a dosimeter and as a tool for dose enhancer. Using Co-60,
the nanoparticle-embedded PAGAT gel has been irradiated for different concen-
trations of NPs. The samples were analyzed with the presence and absence of the
nanoparticle to study the enhancement effect. Here, the predominant effect is
Compton effect since the mean energy of Co-60 is 1.25 meV and Z is 78. The
results showed that 1 10−2 mg/l contributed to an increase of about 27.10% in
dose, which is considered to be as the optimum concentration.
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 329
7.3 Silver
7.4 Bismuth
Bismuth has high electron density, having atomic number 83, and makes it a better
dose enhancer. Properties like less toxicity and less expensive nature of the Bismuth
make it exceptional to use inefficient radiotherapy. All these were taken into con-
sideration and investigation on the use of bismuth sulfide nanoparticles on the
imaging technique namely computed tomography was explored. The
polymer-coated nanoparticle was presented as an injectable CT imaging agent
instead of the conventional iodine as they overcome the limitations (Rabin et al.
2006). Remarkable absorption than iodine, stability at 0.25 M Bi3+, more than 2 h
circulation time of the agent makes it more efficient and safer when compared to the
conventional iodine agent. In vivo imaging can be enhanced utilizing these
nanoparticles as agents.
Gold nanoparticle having high atomic number has already been reported to
absorb the low-energy X-rays and was found to achieve dose enhancement within
330 D. Titus et al.
Commonly used contrast agents for X-ray CT and MRI are iodine having atomic
number 53 and gadolinium having atomic number 64 can be opted as a radioen-
hancer. Contrast agent iodine was incorporated in NIPAM gels and studied that led
to measurable dose enhancement ratio post-irradiation with low energy (Meesat
et al. 2009; Chang et al. 2013).
Gadolinium, in addition to being used as a contrast agent, has a high atomic
number. Ultra-small gadolinium-based nanoparticles exhibit an interesting potential
for image-guided radiotherapy. Equally, a radio-sensitizing effect and a contrast for
MRI are favored by these nanoparticles (Le Duc et al. 2011, 2014). Polysiloxane
shell where the Gd2O3 nanoparticles were encapsulated was delivered to be a
potential IGRT tool in aglio sarcoma rat model. The nanoparticle accumulation was
shown using MRI, and the rats were subjected to microbeam therapy. Miladi et al.
2013 used a brain tumor rat model with Gd nanoparticle. Effect of 0.1 mM of
gadolinium oxide nanoparticles in dose enhancement with MAGIC-f gel was
estimated. The gadolinium nanoparticles are much more effective than the contrast
agents. Taupin et al. 2015 demonstrated the radiosensitization using both materials
and found that enhancement is dependent on energy. The mechanism behind the
increase in dose enhancement in Gd NPs may be due to the alterations in cell cycle,
whereas in contrast agent, secondary electron emission plays the key role.
8 Radiation Dosimetry—A Different Perspective of Polymer Gel 331
7.6 Hafnium
Hafnium oxide has not been introduced to a dose enhancer to the field of gel
dosimetry as it causes stress damage to cell and is believed to be a good agent for
enhancement. Theoretically, using Monte Carlo calculations, the effectiveness of
Hafnium oxide was proved. NBTXR3 nanoparticles, when exposed to the ionizing
radiation, act as a dose enhancer (Maggiorella et al. 2012). Another study revealed
the dependence of dose enhancement on radiosensitivity of cancer cell line and the
delivered dose showed in vitro that the radioenhancement depended on the dose
delivered (Marill et al. 2014). This can further be investigated and used, it means
that can improve the therapy. The different methods of preparation can be adapted
and can be used with some polymer gels to validate the dose enhancing nature of
the material.
8 Extensive Applications
Polymer gel dosimetry has been utilized to confirm and validate several procedures.
Validation of gel response was of focus exploring the three-dimensional imaging.
The validated applications of gel dosimeters till date include depth dose, wedge
profiles and penumbra, basic dosimetry in photon, neutron, electron and proton
beams, conformal therapy SRS, IMRT, low dose rate and high dose rate
brachytherapy, internal dosimetry, and estimation of heterogeneities in tissue. Some
of the developments have been discussed below.
332 D. Titus et al.
8.2 Brachytherapy
Gel dosimeters are good candidate for evaluating IMRT dose distribution. Simple
phantoms are used generally but anthropomorphic phantoms are also used which
can allow direct comparison of measurements done with film or TLD. Several
methods have been adopted (Vergote et al. 2003; Low et al. 1999).
Gambarini et al. (1994) worked with gel dosimeter and BNCT. Using BANG3 gel,
the exactness of ArcCHECK-3DVH system was evaluated. Accurate estimation of
dose distribution was done. But due to MRI noise, slight variations were found
between iPAGAT and 3DVH planning (Ono et al. 2015; Watanabe and Nakaguchi
2013).
Nagahata et al. (2014) proposed a useful method with semi-solid polymer gel
making use of agar to deal with metallic substances. In addition, Hassani et al. 2014
validated the help of polymer gels in getting three-dimensional distributions in
small field sizes as the highly complex treatments like SRS or IMRT use small
fields, thus becoming very useful for the treatment.
Also, polymer gels are being used for HDR and verification with treatment
planning system (TPS) (Senkesen et al. 2014) as well as for validating circular
irradiation fields of 10–30 mm diameter. The results are compared with the planned
data (Kawamura et al. 2013).
Gel dosimetry fits in place for the idea of acquiring three-dimensional distribution
of the absorbed dose when used with complex radiotherapy techniques. The nec-
essary requisites for a typical gel dosimeter are in terms of tissue equivalence,
stability, dose rate, spatial integrity, energy dependence, and temperature insensi-
tivity. Since the ultimate goal is to verify the response three-dimensionally and this
is the only method to do, care has to be taken at the initial level of preparation of
gel, in ensuring the absence of oxygen in the gel that can hinder the polymerization
process. Polymer gels with good reproducibility can be achieved when the same
protocols are followed with much attention to the concentration of each component
in the gel and by maintaining the temperature. Every stage of the process that
includes irradiation, storage of the gel, and imaging needs to be monitored to
prevent any alterations in the dose response. Readymade gels are also available
which can be used as an alternate (MGS, Guildford, New Haven, CT, USA).
Advantages of the polymer gel include to be used in various shapes depending upon
the need. This technique of extracting dose has been used with various radiation
techniques where the conventional dosimeters have failed to do so.
Rapid development is being happened in the area of polymer gel dosimeters.
Several aspects in the field of polymer gel as dosimeter have been covered as
research. Enormous studies on the gel chemistry and various gel combinations have
been carried out. More understanding of the chemical and physical interaction
within the gel is required to attain high sensitivity. Different recipes and alternatives
for monomers, crosslinkers, antioxidant, and gelling agent are being introduced to
fulfill the basic requisite. Furthermore, alternatives can be found which can be less
toxic when compared to the existing chemicals used for the manufacture. The
different scanning techniques and the gel system scanned have to be optimized for
better imaging. Currently, the focus is on less toxic and user-friendly gel dosimeters
334 D. Titus et al.
and making use of X-ray CT and Optical CT as an alternate for the expensive MRI
unit. Optimal gel systems have to be found for different scanning modalities; in
MRI, the relaxation rates show significant change, and in X-ray CT the density
changes. Using dyes in gel which is radiation sensitive can make it apt for imaging
in optical CT.
Focus will also be on investigation on some new ingredients or additives in order
to improve the sensitivity of gel and also stability after irradiation. Usage of
nanoparticles (high atomic number) as an agent for dose enhancement throws
limelight to unexplored paths. So far, only less work has been reported on the
application of nanoparticles in gel dosimetry. The most studied nanoparticle among
them is gold, though it is not used yet clinically. Research on increasing the
efficiency of the treatments based on nanoparticle is underway. Less expensive and
alternatives like silver, bismuth, platinum, and hafnium have been produced but not
taken to a level as that of gold. Metal or metal oxide nanoparticles can be of scope
for dose enhancement which is dependent on the atomic number, electron density,
and the energy or irradiation used. Gadolinium and iron nanoparticles can also be
used as a favorable for dose enhancement as well as for imaging based on mag-
netism as they exhibit magnetic properties. Nanoparticles can be prepared by
physical, chemical, and biological means and can be introduced into the system.
Different sizes, with dopants, can be studied with its effect on sensitivity and factors
related to response. Polymer gels thus create a milestone in radiation therapy as
carriers of dose distribution which can be identified and evaluated using the readout
techniques discussed. New polymer dosimeters that can validate doses below 1 gray
are the need of the hour.
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Chapter 9
Polymeric Gels: Vehicles for Enhanced
Drug Delivery Across Skin
Abstract Polymeric gels have emerged as promising vehicles for drug delivery
across the skin. Stratum corneum, the topmost layer of the skin, does not allow
hydrophilic and high molecular weight drugs to permeate without enhancing
techniques. A number of enhancement techniques are being developed to increase
the transdermal drug permeation. The transdermal route has many advantages and
has therefore evolved as an attractive and convenient alternative to the existing
routes of drug delivery that causes many side effects. In the present chapter, we
shall be focusing on the physical enhancement techniques of iontophoresis, elec-
troporation and sonophoresis for transport of drug molecules across skin using
polymeric gels.
Keywords Polymeric gels Transdermal drug delivery Skin
Iontophoresis Electroporation Sonophoresis
1 Introduction
Polymeric gels have emerged as promising vehicles for drug delivery across the
skin. Skin, a complex and heterogeneous biological barrier is the main hurdle for
transdermal delivery of drugs. Drug delivery through the skin is an attractive and
convenient alternative to the conventional routes. To facilitate drug transport across
the skin, polymeric gels have been employed to encapsulate the drug and allow its
permeation in a controlled manner. The word ‘gel’ was coined by a Scottish
R. Prasad
Centre for Biomedical Engineering, Indian Institute of Technology,
New Delhi, India
V. Koul (&)
Biomedical Engineering Unit, All India Institute of Medical Sciences,
New Delhi, India
e-mail: [email protected]
2 Polymeric Gels
Transdermal drug delivery systems have gained importance over the other modes of
delivery both in research and marketable products. However, designing a suitable
vehicle for drug delivery through the skin is challenging.
Vehicles (polymeric gels, creams, emulsions, lotions, etc.) have a noticeable
effect especially on the skin preparations and play an important role in delivering
the drug molecules to the application site/target organ.
Gels are suitable vehicle for transdermal drug delivery systems especially for
iontophoresis, electroporation, sonophoresis, and other device-based non-invasive
enhancement approaches because they can easily mix with the delivery system and
also match the contours of the skin. Thus, these polymeric gels act as an important
connector/link between the skin, drug and the device. Being soft and wet material,
these gels can withstand huge deformation and form a backbone for the control of
drug release (Osada and Gong 1998). They are either semi-solid or cross-linked,
three-dimensional polymeric network structure. They comprise small amount of
solid particles dispersed in large amount of liquid/water, thus giving them a
semi-solid character that has the ability to swell or shrink (Bhoyar et al. 2012).
Because of their inherent remarkable properties, these gels have wide applications
in medicine, biotechnology, food industry and cosmetics (Rehman and Zulfakar
2014). Many polymeric gels possess charges in their network and are important for
electrically enhanced drug delivery (Oosawa 1957; Gong et al. 1997).
Gel-forming polymers can be classified as natural, semisynthetic and synthetic.
The different polymers that are commonly used for application on skin are
derivatives of polyacrylic acid like carbomers, polyvinylpyrrolidone, polyvinylal-
cohol, carrageenan, chitosan, cellulose derivatives like carboxymethyl cellulose,
hydroxypropyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellu-
lose (Fig. 1). They are safe and non-toxic, and they also do not permeate through
the skin and do not cause skin irritation (Saroha et al. 2013; Uma et al. 2002). The
polymers are used in the concentration range of 1–5% for gel formulations and are
responsible for its consistency and viscoelastic property (Valenta and Auner 2004).
9 Polymeric Gels: Vehicles for Enhanced Drug … 345
Gels
Semi -synthetic
Natural polymers Synthetic polymers polymers (cellulose
derivatives)
Collagen Carbomer
Hydroxypropyl cellulose
Gelatin Poloxamer
Hydroxypropyl methyl cellulose
Carageegan Polyacrylamide
Hydroxyethyl cellulose
Guar gum Polyvinyl alcohol
Carboxymethyl cellulose
Agar Polyethylene
They are classified as physical gels and chemical gels based on their internal
structure. As the name suggests, physical gels are the noncovalent gels and are held
together by physical bonds, i.e. the crosslinking is due to weak physical forces like
hydrogen bonding, ionic interactions, van der Waals, etc., and are thus reversible,
whereas chemical gels are the covalently crosslinked gels that are held by chemical
bonds and are irreversible and are categorized under hydrogels (Jagur-Grodzinski
2010).
Polymeric gels can be deformed by various external stimuli like temperature,
pH, ionic strength, electric field, etc. This ability to withstand swelling and col-
lapsing as a function of their environment is the most significant property of these
materials. The gel volume transitions have motivated/impelled the researchers to
explore these polymeric gels for many different applications like drug delivery,
sensors, actuators, etc. (Osada and Gong 1998).
2.2 Hydrogel
Hydrogels – classification
The advantages of gel formulation for transdermal drug delivery include ease of
application, controlled drug release, greaseless, non-staining, easily removable,
emollient and compatible with many drugs. Moreover, these formulations can
348 R. Prasad and V. Koul
increase the skin compliance as they can absorb the skin secretion, which may
become irritating under long-term occlusion (Banga and Chein 1993).
Different gels have been tried for transdermal delivery of drugs and a successful
product, Testogel for testosterone delivery, is in commercial use. This product is
based on polyacrylate (carbomer) (Valenta and Auner 2004).
Many other drugs are also being tested for transdermal delivery with the help of
gels, e.g. insulin delivery has been tried with poloxamer gel in rats and promising
results were obtained (Pillai and Panchagnula 2003). Transdermal delivery of
Ibuprofen loaded in silicone and cellulose polymer gel has been tested across rat
skin both in vitro and in vivo (Aliyar et al. 2014). poly (N-vinyl caprolactam)
[PNVCL]-based polymeric gel and copolymer of chitosan and poly (N-vinyl
caprolactam) [PNVCL]-based gel were explored for delivery of hydrophilic as well
as hydrophobic drug. They showed the feasibility of being used as transdermal drug
delivery systems for the management of pain (Indulekha et al. 2016). Release of
silver sulfadiazine from hydrogels was examined for antimicrobial topical appli-
cations, and the results suggested that these hydrogels can be used topical drug
delivery (Jodar et al. 2015). Recently, Kong et al. (2016) studied transdermal
delivery of isoliquiritigenin loaded in hyaluronic acid (HA)-hydroxyethyl cellulose
(HEC) hydrogels and reported that the hydrogel significantly improved drug per-
meation (Kong et al. 2016).
The hydrogels which have been studied for the purpose of iontophoresis include
polyacrylamide, poly (2-hydroxyethyl methacrylate), cellulose polymers,
polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP) and hydrogels from natural
source, for example, agar and chitosan. Banga and Chein (1993) investigated the
polyacrylamide and poly (2-hydroxyethyl methacrylamide) hydrogels for the ion-
tophoretic delivery of peptide drugs, viz., vasopressin, calcitonin and insulin. Fang
et al. (1999; 1998a, b, 1996) investigated several hydrogels belonging to cellulose
derivatives like methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC),
hydroxypropyl cellulose (HPC) and carboxymethyl cellulose sodium (SCMC) for
iontophoresis application. Studies of Gupta et al. (1994) demonstrated that
non-ionic hydrogels provide better iontophoretic flux than ionic polymers.
More recently hydrogels are also being used as microneedles to facilitate drug
delivery across the skin (Kearney et al. 2016). It has been reported that when these
hydrogel microneedles are inserted into the skin, they absorb body fluids and swell,
thus creating porous network and channels for the movement of drug from the patch
to the skin dermal circulation. These hydrogel microneedles have unique features
and are thus suitable for a wide variety of drug delivery applications. They also
overcome the shortcomings of the conventional ones. The commercialization of this
technology is in progress (Donnelly et al. 2012, 2013). Kearney et al. (2016) have
successfully demonstrated the transdermal delivery of Donepezil for Alzheimer’s
disease using hydrogel microneedles. Jeong et al. (2008) have reported that this
system possesses the convenience of a transdermal patch along with the effec-
tiveness of a needle.
9 Polymeric Gels: Vehicles for Enhanced Drug … 349
In the broadest sense, transdermal drug delivery includes all topically applied
formulations with the purpose of bringing the therapeutic molecules into the sys-
temic circulation. Transdermal drug delivery systems (TDDS) include a number of
non-invasive to minimally invasive technologies for the delivery of therapeutic
molecules through the skin (Prausnitz and Langer 2008; Schuetz et al. 2005; Barry
2001). The delivery of drugs transdermally has enormous potential as the skin offers
a large surface area for the non-invasive administration of drugs. Transdermal
application permits localized drug delivery to the site of interest, thus enhancing the
therapeutic effect and minimizing the systemic side effects. It totally avoids pain
and presystemic metabolism, and the drug pharmacokinetics is more uniform
(Quinn et al. 2016; Ita 2014; Barry 1983).
The clinical reality of transdermal drug delivery began with the scopolamine
patches that were approved in 1979. However, it was the nicotine patch introduced
for smoking cessation in 1991 that revolutionized the transdermal market. In the last
four decades, TDD has made significant progress and now represents a successful
method of delivering a large number of drugs, namely, scopolamine, nitroglycerine,
nicotine, clonidine, lidocaine, estradiol, fentanyl, testosterone and oxybutynin
(Lane 2013; Prausnitz et al. 2004; Langer 2004; Kalia et al. 1998). Hence, it is
considered to be one of the most successful controlled release technologies in terms
of number of approved products that are in the market (Guy 1996; Nair et al. 1999).
In the USA, 51 out of the 129 drug delivery candidates under clinical evaluation
and 23 out of 77 drug candidates are under preclinical evaluation belong to
transdermal/dermal systems. Thus, transdermal drug delivery is the most successful
research area in drug delivery. The worldwide market for transdermal patches is
approximately $32 billion, which is based on the abovementioned few drugs.
Table 1 lists the drugs which are clinically used as transdermal systems for
patients. These drugs are loaded either in patch, matrix or gel system and do not use
any assistive devices for drug release and permeation (Paudel et al. 2010).
Rotigotine patch introduced in 2007 was recalled in 2008 because of delivery
problems but was reformulated and the reintroduced in 2012.
Some therapeutic agents are used as topical gel and patch mainly for the local
treatment of pain and for local anaesthesia, e.g. Capsaicin patch for pain relief,
diclofenac gel for osteoarthritis, lidocaine cream for local anaesthesia, menthol and
capsaicin for arthritic pain, trolamine salicylate as cream for muscle and joint pain
and salicylic acid patch for acne vulgaris and hyperkeratotic psoriasis (Paudel et al.
2010). Few drug formulations are under different stages of FDA-approved clinical
trials and would soon be available for commercial use.
The main advantages of TDDS over conventional dosage forms are as follows:
1. Easy accessibility of skin.
2. Non-invasive mode of drug delivery, thus no trauma or risk of infection.
350 R. Prasad and V. Koul
4 Skin
Skin is the largest, multifunctional and most complex organ of the body with a
surface area of 2 m2 in human adults. From the very beginning of mankind, skin
has played the role of a unique interface and important barrier between the internal
organs of the body and external environment. It is also the basis for multi-billion
dollar industries of personal care, cosmetics and beauty and fashion business. For
pharmaceutical industry, the skin offers a big opportunity due to the large surface
area for painless and patient-friendly drug delivery/administration but at the same
time also poses a big challenge due of the barrier property of its outermost stratum
corneum layer. This layer of the skin serves as the barrier to both the entry and exit
of molecules.
The stratum corneum is composed of dead cells, corneocytes that are filled with
keratin and are embedded in an extracellular matrix of multilamellar lipid bilayers.
For the effective/proper functioning of the skin, it has to be continuously regen-
erated and hence has a very unique structure to meet this demand. There is a
transition from living cells of stratum basale to the dead corneocytes of stratum
corneum embedded in skin lipids, thus imparting/offering a high degree of barrier
property to it.
The skin has emerged from its classical brick-and-mortar model to a smart,
composite and intelligent biopolymer which responds to every external stimulus.
A lot of literature and knowledge have been generated in the last 3–4 decades,
still the optimal use/usage of skin as delivery route needs to be established.
Skin is a complex, multicomponent, dynamic organ and has many functions beyond
its role as a barrier to the environment (Mitragotri 2004). It receives about a third of
the total blood supply and is a physical and chemical barrier separating the external
environment and the internal organs, is a site of thermoregulation (controls and
regulates body temperature) and acts as a sensory organ. The skin is also part of our
immune system. It is completely renewed every month to maintain its properties
(Christophers et al. 1989).
The skin consists of two layers, epidermis and dermis (Williams 2003).
The epidermis is mainly made of keratinocytes (95%). It is 100–150 µm thick
and divided into four layers: stratum corneum (SC), the topmost layer, stratum
granulosum (SG), stratum spinosum (SS) and stratum basale (SB).
SB is a single layer of oval-shaped cells on the dermal–epidermal junction,
nucleated and has intracellular organelles and is metabolically active. In normal
skin, only basal cells divide. It also contains a variety of other cells, melanocytes
that provide colour (melanin pigment), Langerhans cells that play a critical role in
the immunology of skin and Merkel cells functioning as mechanoreceptors to skin.
352 R. Prasad and V. Koul
Stratum spinosum (SS) and stratum granulosum (SG) cells undergo rapid differ-
entiation. During differentiation from basal cells to stratum corneum, the entire
cellular make-up changes. During the movement of cells towards SC across the SS
and SG, they shrink, flatten and initiate production of keratohyalin granules,
lamellar bodies and filaments. At the interface of SG and SC, differentiation of cells
ceases and apart from granules and filaments, other intracellular constituents are
degraded into protein forming insoluble matrix of keratin. Granules are extruded
from cell by exocytosis and form intercellular lipid domain ‘mortar’, in between
keratin-filled cells (corneocytes). Lipids are covalently bound to corneocyte pockets
and serve as template for orientation of initially extruded granule contents (Chang
et al. 1993; Swartzendruber et al. 1987). This configuration of lipids over cor-
neocytes imparts high degree of barrier property to SC for permeation of drug
molecules. The SC consists of cells (corneocytes, 20–40 µm in diameter) that are
elongated and flattened, hexagonal in shape, completely devoid of intracellular
organelles, organized in columns (Christophers et al. 1974). It is about 15–20 cell
layers thick, filled with keratin and embedded in lamellar body secretions which
gives the classical brick-and-mortar arrangement. This thin (l–10%), outermost
layer of the skin causes around 80% of the resistance in permeation. Lipids between
the corneocytes act as ‘glue’ that helps in sealing the spaces between the cells in the
skin. All this causes the tightness and impermeability of the intact skin, and hence
efficient permeation of molecules greater than 200–350 Da is restricted in the intact
skin. SC and viable epidermis comprise the diffusion resistance in series or two
barriers in series.
Dermis is up to 4 mm in depth. Similar to the epidermis, drug diffusion through
dermis is also restricted due to the aqueous medium. The dermis forming the bulk
of the skin is l0–20 times thicker than the epidermis, made up of connective tissue
elements and stabilized by a network of collagen fibres (Cevc et al. 1996). It is
mainly composed of fibrous proteins, collagen and elastin produced by the
fibroblasts. Collagen protein comprises about three-fourths of the dermal dry weight
and is the principle component imparting tensile strength to the dermis. Dermis is
highly vascular and also contains different glands. It contains the blood and lymph
capillaries and nerve endings. It also contains the hair follicles, sebaceous glands
and sweat glands which open directly into the environment at the skin surface.
These openings can provide points of entry, the shunt pathways for topically
applied materials to enter into the skin. These pathways have varied distribution
over the entire skin, for example, hair follicles in humans cover 0.l–0.5% of the
total skin surface. Appendages extend up to 500 µm (beyond the depth of epi-
dermal–dermis junction). The glands are located in the lower dermis or hypodermis
and are connected to the skin surface by a duct which has a diameter of approx.
100 µm. The skin appendages offer an alternative/attractive pathway for transder-
mal drug delivery and also avoid the challenges of drug delivery through the SC.
Permeation of the drug into the dermis suggests the scope for systemic drug dis-
tribution. The vascularized hair follicles and appendageal glands also offer the
possibility of systemic drug distribution through these routes.
9 Polymeric Gels: Vehicles for Enhanced Drug … 353
Despite the extensive research and wealth of experimental studies, the mecha-
nisms which promote drug transport through the glands and hair follicle need/
remain to be clearly understood and established.
The chemical constituents of SC are 15% water, 70% protein and 15% lipids (Law
et al. 1995) and of the SC lipids, it is the sphingolipids that are important for the
epidermal barrier. In SC, intercellular lipids are arranged as ‘mortar’ (Fig. 3) and
have been the focus of research as it imposes maximum resistance to permeation of
drugs. At the interface of SC/SG, lipids extruded from lamellar bodies undergo
hydrolysis, resulting in the formation of ceramides and free fatty acids (Elias and
Menon 1991). SC lipids are constituted by 50% ceramides, 25% cholesterol and
15% free fatty acids (Law et al. 1995).
The electrical properties of the skin are often characterized by impedance spectra.
Skin tissues offer polarized electrical impedance, because cell membrane behaves as
tiny capacitors, and the intercellular channels as shunt resistance pathways
(Yamamoto and Yamamoto 1976; DeNuzzio and Bemer 1990; Oh et al. 1993).
The skin’s electrical properties can be altered by various conditions, like degree
of hydration, pH and the presence of chemical additives, electrolyte concentration
and valence, thyroid activity, emotional state, temperature, time of year, perspira-
tion and skin disease (Tagami et al. 1980; Allenby et al. 1969; Oh et al. 1993;
Yamamoto and Yamamoto 1976). Electrical properties of the skin can also be
varied by application of external current, where increased current/voltage/power
reduces resistivity (Yamamoto and Yamamoto 1976; Oh et al. 1993; Pikal 1992;
Pikal and Shah 1991; Sims et al. 1991; Scott et al. 1993; Rosendal 1943). The
electrical properties of skin also depend on the duration of applied electrical current,
because the changes occur over time. Moreover, the rate of decrease in resistance
depends on the current and voltage applied but the rate of tissue recovery is
dependent upon the duration and magnitude of the electrical field (Inada et al.
1994).
Reduction in skin resistance results in increased permeability which can persist
even after cessation of electrical exposures (Allenby et al. 1969; Oh et al. 1993;
Burnette and Ongpipattanakul 1988; Dinh et al. 1993). Application of current
causes local heating of the stratum corneum which could also lead to the changes in
skin electrical properties.
Stratum
Corneum
Epidermis
Dermis
Microcirculation
molecules and drugs requiring large dose, methods that physically disrupt the skin
(for example, electroporation, low-frequency ultrasound and microneedles) are
employed (Prausnitz 1997).
The barrier property of the skin renders difficulty in transdermal delivery of drug
molecules, and overcoming the biological barrier in an effective way is a key hurdle
for transdermal drug delivery. Several modes of enhancement have been advocated
to increase the transdermal delivery of drugs for effective delivery through this
route. Technologies used can be divided into chemical or passive and physical or
active methods depending on whether an external source of energy is employed for
increasing the skin permeation (Wong 2014) (Fig. 5):
1. Chemical or passive methods and
2. Physical or active methods.
The chemical methods are the formulation-based approach, whereas physical
methods are device-based approaches. Devices require an external physical unit,
which are driven by a power source to deliver the energy required to overcome the
barrier and enhance drug delivery (Mitragotri 2013).
These permeation enhancing technologies change the skin’s chemical and/or
physical environment, thus increasing stratum corneum permeability and allowing
the drug molecules to penetrate into the stratum corneum. Additionally, in case of
physical methods, an external driving force is applied across the skin, which causes
increase in drug transport across the stratum corneum. All these enhancers have
356 R. Prasad and V. Koul
Electrical Mechanical
Liposomes
Emulsions
Penetration enhancers
Solid lipid nanoparticles
Cell penetrating peptides
Iontophoresis Ultrasound
Electroporation Microneedles
Radiofrequency Jet injectors
shown to increase drug permeation across the skin, and their combinations have been
shown to be more effective as compared to each of them alone (Mitragotri 2000).
Passive methods use chemical enhancers, emulsions, liposomes and biological
methods such as cell penetrating peptides to increase drug permeation across the
skin (Schreier and Bouwstra 1994; Karande et al. 2004; Prausnitz et al. 2004;
Schuetz et al. 2005; El Maghraby et al. 2006; Kim et al. 2012). FDA-approved
GRAS chemicals are employed to enhance the transdermal drug permeation.
However, these methods are generally associated with a lag time and thus are not
well suited for rapid onset or time-dependent delivery which may be needed for
delivery of drugs like insulin.
Active or physical methods of skin permeability enhancement include ion-
tophoresis, electroporation, sonophoresis, microneedles, jet injection, tape strip-
ping, etc. to facilitate the drug permeation across the skin (Prausnitz et al. 1993;
Mitragotri et al. 1996; Guy 1998; Bashir et al. 2001; Prausnitz et al. 2004; Kalia
et al. 2004; Karande et al. 2004; Arora et al. 2007; Lopez et al. 2011; Prasad and
Koul 2012). These methods increase drug transport across the skin with the help of
an external driving force or by physically disrupting the skin barrier. These
enhancement methods have an advantage over chemical/passive methods as they
offer more control over drug delivery and shorter lag time between drug application
and drug reaching the systemic circulation. Moreover, the device parameters can be
altered to suit individual’s skin properties and drug requirement (Tezel et al. 2001;
Davis et al. 2004). These devices are particularly useful in targeting the skin and
mucosal membranes as they can be placed in direct contact with these membranes.
The devices can also be easily designed, modified and tested for skin applications.
However, they have the limitation of requiring a power source and can also be
expensive (Mitragotri 2013).
9 Polymeric Gels: Vehicles for Enhanced Drug … 357
+ -
CURRENT
DRUG
(hydrophilic,
charged) Buffer
D+ A- Na+ Cl-
Epidermis
D+ Na+ Cl-
Blood vessel
Mouse
skin
Franz Diffusion
Cell
Magnetic
Bead
(Kalia et al. 2004). Thus, the iontophoretic enhancement is not only restricted to
charged molecules but neutral molecules have also shown enhancement (Sieg et al.
2004). Electroosmotic effect has also led to an interesting development of reverse
iontophoresis, in which the molecules present in circulation can be extracted at the
surface of the skin and estimated, e.g. glucose and the glucose monitoring system.
GlucoWatch Biographer has been developed which monitors the blood glucose
level using this method (Naik et al. 2000).
Many different types of electrodes are used for iontophoresis like platinum, gold,
silver, carbon, etc. However, Ag/AgCl electrodes are most suited for iontophoresis
as its electrolysis occurs at voltages lower than that required for electrolysis of
water.
The first scientific experiment using the mechanism of iontophoresis was per-
formed by Leduc in 1900, but the idea of applying electric current to enhance
permeation of charged molecules was given by Veratti in 1747 (Leduc 1900).
Iontophoresis increases the hydration of stratum corneum, thus reducing the
skin’s electrical resistance (Kalia et al. 1996). Changes in skin structure are caused
due to the applied electrical field (Prasad et al. 2007). Reorientation of lipid
structure could possibly explain these observations. Changes in skin capacitance
involve lipids, since the skin’s capacitance is generally attributed to the stratum
corneum lipids (DeNuzzio and Bemer 1990; Oh et al. 1993).
It has been reported that iontophoresis increases the pore size of the hair follicles,
thus providing shunt pathways for drug permeation (Cullander 1992; Prasad et al.
2007). This method of enhancement is generally well tolerated, although mild skin
irritation, non-painful sensation and erythema and are sometimes reported.
Iontophoresis (DC) has shown to improve the transdermal delivery of many low
molecular (lidocaine, dexamethasone) as well as high molecular (insulin, luteiniz-
ing hormone-releasing hormone) weight drugs. However, for delivery of proteins,
genes and electrochemotherapy, the scientists are employing the different wave-
forms like exponentially decaying pulses (Prausnitz et al. 1993; Pliquett and
Weaver 1996) and square-wave pulses (Heller et al. 1999; Denet and Preat 2003)
9 Polymeric Gels: Vehicles for Enhanced Drug … 359
Square Exponential
Current
Current
Time
Time
Triangle Sine
Current
Current
Time Time
and have reported that they give more enhancement in drug permeation as com-
pared to constant DC iontophoresis. The effect of the different waveforms like sine,
square, exponential and triangle (Fig. 8) on drug permeation and tissue injury have
been studied by Prasad et al. (2007) and they have reported it to be safe for skin
application.
When direct current electrical field is applied to the skin in a continuous manner,
electrochemical polarization develops in the capacitor, Csc. This operates against
the applied electric field, thus decreasing the magnitude of effective current across
the skin. So, pulsed direct current (pulsed DC) is used to avoid the polarization of
SC, (Bagniefski and Burnette 1990). In the pulsed mode, there is an alternating ‘on’
and ‘off’ period of the applied voltage. During the ‘on’ state, the charged molecules
are pushed into the skin and the stratum corneum becomes polarized, whereas in the
‘off’ state, the stratum corneum becomes depolarized as no external stimulation is
present. This ‘on/off’ ratio controls the polarization and depolarization during each
cycle.
Thus, the pulsed mode DC or modulated DC (mDC) iontophoresis increases
drug permeation by avoiding the polarization of the skin (Odia et al. 1996; Johnson
et al. 1998). Moreover, it has been reported by Prasad et al. (2007) that the tissue
injury caused by mDC iontophoresis is less as compared to DC, but the flux
obtained is higher. They have reasoned that this reverse behaviour is mainly
because in mDC iontophoresis the current is given in pulses, which depolarizes the
skin and thus reduces skin resistance more effectively. Earlier researchers Denet
et al. (2004) and Dujardin et al. (2002) have also reported that square-wave pulses
360 R. Prasad and V. Koul
temporarily impair the barrier function of the skin and the decreased skin resistance
causes increase in skin permeability and therefore increased flux.
Our group at IIT Delhi, India has been working on iontophoresis for the last
10 years, and Prasad and coworkers have shown that modulated DC
(mDC) iontophoresis significantly increased the permeation of methotrexate across
the skin, as compared to DC iontophoresis (Prasad et al. 2007). mDC iontophoresis
avoids the polarization effect of skin, thus supporting higher flux. They have also
reported that mDC iontophoresis with square-wave pulses showed higher
bioavailability, as compared with oral delivery (Prasad et al. 2009). They conducted
histopathological studies on mice and found that mDC iontophoresis is well tol-
erated by the skin tissues and reversal of skin injury takes place within 48 h. They
have also reported that the scanning electron micrographs of DC as well as mDC
iontophoresis clearly showed increase in the pore size of the hair follicles. This
supports the involvement of shunt pathways for drug permeation during ion-
tophoresis (Cullander 1992).
Later, in our lab, Rastogi et al. (2010a, b) have shown the feasibility of using mDC
iontophoresis for insulin delivery. They reported higher flux of 0.096 ± 0.040 IU/
cm2h with mDC iontophoresis as compared to 0.0244 ± 0.009 IU/cm2h with con-
stant DC iontophoresis. These results are comparable to many reports that state the
advantages of pulsed DC iontophoresis over constant DC iontophoresis (Craane-van-
Hinsberg et al. 1994; Raiman et al. 2004; Prasad et al. 2007).
A combination of iontophoresis with other physical enhancers or chemical
enhancers allows greater drug permeation than either technique employed alone.
Mitragotri has also reported that the combinations of enhancers are more efficient
than compared to each of them when used alone (Mitragotri 2000, 2004).
Combinations of iontophoresis with chemical enhancers, sonophoresis and elec-
troporation have been evaluated to increase the transdermal drug permeation and
decrease the possible side effects and tissue injury (Batheja et al. 2006; Choi et al.
1999; Wang et al. 2000).
Prasad et al. (2009) have reported that combination of chemical enhancers (ethyl
acetate, ethanol and menthol) and mDC iontophoresis resulted in 161% enhance-
ment in methotrexate loaded in polyacrylamide hydrogel. They showed that the
combination of enhancers resulted in synergistic increase in drug permeation,
whereas the tissue injury was not the additive of that caused by the individual
enhancers, thus resulting in decreased skin injury (Prasad et al. 2009).
Rastogi et al. (2010a, b) have also reported that a combination of chemical
enhancers (sodium deoxycholate, oleic acid, 1,8 cineole in ethanol: propylene
glycol (3:7) mixture) followed by 1 h mDC iontophoresis significantly increased
the transdermal permeation of insulin loaded in PVA hydrogel. They have also
showed that in vivo studies in diabetic Wistar rats showed lowering of blood
glucose levels by 84%.
Effect of iontophoretic duration on insulin release from polyacrylamide hydro-
gels has been studied by Banga and Chien (1993). They also evaluated poloxamer
P407 gel formulation of insulin for ex vivo and in vivo skin permeation studies in
rats, with chemical enhancer and/or iontophoresis.
9 Polymeric Gels: Vehicles for Enhanced Drug … 361
Application of high-voltage pulses (>100 V) for a very short duration of time from
microsecond to milliseconds is called electroporation (Prausnitz 1999; Weaver and
Chizmadzhev 1996). It is also called electropermeabilization as it causes temporary
structural disturbance in the skin due to application of large voltages, thereby
increasing the permeation many folds. The structural changes lead to the formation
of pores or aqueous pathways, thus increasing drug permeation. While ion-
tophoresis acts on the charged drug molecules, electroporation mainly acts on the
skin to increase its permeation. It exerts some force on the drug during the pulse,
362 R. Prasad and V. Koul
and hence, the contribution of electroosmosis in drug transport is low because of the
very short time of current application in electroporation. Electrophoresis and dif-
fusion are the main modes of drug permeation across the skin (Denet et al. 2004).
Many small as well as large molecules have been delivered successfully under
experimental conditions. Moreover, a large number of drugs and even macro-
molecules, vaccines, etc. can be delivered across the skin with the help of elec-
troporation technique either used alone or in combination with other enhancement
modes.
Electroporation has been used for gene transfer, DNA vaccination, transdermal
delivery of low molecular weight peptide of protein vaccines and transdermal
delivery of other drug molecules like fentanyl, insulin and methotrexate (Sardesia
and Weiner 2011; Wong et al. 2011; Yarmush et al. 2014).
An important application of electroporation is in electrochemotherapy, where
high-voltage pulses are applied to permeabilize the tumour cells to increase the
transport of cytotoxic drugs. High-voltage electroporation (Fig. 9) causes structural
changes in the stratum corneum’s lipid bilayers, thus creating new pathways for
drug transport (Fig. 10) and also provides an electrophoretic driving force on the
drug molecules during the pulse (Prausnitz 1998; Banga et al. 1999).
This technique was first reported by Sale and Hamilton in 1967, wherein
application of electrical pulses for transformation and fusion of cells were shown to
cause the death and lysis of cells (Sale and Hamilton 1967). Further studies revealed
that the membrane permeability barrier might be weakened temporarily and
reversibly, by subjecting cells to well-controlled, high-intensity electric field pulses
(Neumann and Rosenheck 1972). Electroporation was first used medically by
Neumann and coworkers in 1982 for the delivery of DNA into the cells (Neumann
et al. 1982). This technology is now being extensively used for biomedical appli-
cations such as electrochemotherapy, electrogene therapy and transdermal drug
delivery (Hofmann et al. 1995, 1996). Huang et al. (2005) have reported that
iontophoresis and electroporation increased the transdermal delivery of nalbuphine
loaded in hydrogel formulation.
Fig. 9 Schematic
VOLTAGE
representation of the SOURCE
mechanism of electroporation
Pulse duration ( μs-
ms)
Voltage (>30 V)
Electrodes
Drug
Epidermis
9 Polymeric Gels: Vehicles for Enhanced Drug … 363
Blood vessel
The use of ultrasound (US) as an external physical force to increase the permeation
of drug molecules through the skin is called sonophoresis (Fig. 11). The use of
sonophoresis was first reported in the 1950s (Mitragotri and Kost 2004).
Frequencies in the range of 20 kHz–16 MHz are used to increase skin permeability,
and thus sonophoresis has been done using both high-frequency and low-frequency
ultrasound. However, in the last two decades, researchers have shown that
low-frequency ultrasound (20–100 kHz) is more effective for transdermal drug
delivery and has been used to increase transdermal permeation of many drugs like
lidocaine, insulin, etc. and also in extraction of interstitial fluid for glucose moni-
toring (Ogura et al. 2008; Mitragotri and Kost 2004).
For therapy, high-frequency ultrasound (1–3 MHz) is used and the therapeutic
ultrasound can be in continuous mode, which has thermal effect, or in pulsed mode,
which has mechanical effect like cavitation (Shipton 2012; Wong 2014).
High-frequency ultrasound is mainly used for imaging and physiotherapy, and
delivery of a few high molecular weight drugs (more than 1000 Da) has also been
tried with it (Polat et al. 2011; Azagury et al. 2014). Increase in transdermal
permeation of mannitol and physostigmine with ultrasound (1 MHz) across hairless
rat in vivo has been reported by Levy et al. (1989). They also demonstrated that the
lag time present with transdermal delivery was almost eliminated with ultrasound
exposure.
With high-frequency ultrasound, the enhancement is mainly because of a
pressure-driven driving force along with the physical disruption of stratum corneum
lipids, which causes creation of pathways, but at low-frequency, ultrasound-induced
cavitation is the main mechanism that causes physical disruption of stratum cor-
neum and also renders a pressure-driven driving force on the drug (Mitragotri et al.
Cymbal transducers
Drug
Epidermis
9 Polymeric Gels: Vehicles for Enhanced Drug … 365
1996; Mitragotri and Kost 2004; Park et al. 2014). When the ultrasound wave
travels through the body, physical changes like local hyperthermia, cavitation and
pressure variation occur and these help in transdermal drug delivery as well as in
diagnostics (Sirsi and Borden 2014). The skin enhancement induced by ultrasound
depends on different parameters like duty cycle, frequency, intensity and applica-
tion time.
Two different ways of applying low-frequency ultrasound to enhance transder-
mal drug delivery are the simultaneous method, where the drug and ultrasound are
applied simultaneously to the skin, and the pretreatment method, where the skin is
first permeabilised with the application of ultrasound followed by drug delivery.
The main mechanism responsible for enhanced skin permeation with low-frequency
ultrasound is the formation of gaseous cavities and its collapse, acoustic cavitation.
Application of hydrocortisone with ultrasound for the treatment of polyarthritis
of hand joints has been successfully reported by Fellinger and Schmidt in 1954.
Later in 1960, Coodley demonstrated that hydrocortisone injection along with
ultrasound massage gave better results for bursitis treatment as compared to
injection alone. Ultrasound has also shown to improve the permeation of local
anaesthetics (Cameroy 1966).
Low-frequency sonophoresis (48 kHz) increases the transdermal permeation of
lidocaine and insulin as reported by Tachibana and Tachibana (1991, 1993). The
effectiveness of low-frequency ultrasound for delivery of proteins was first reported
by Mitrogotri et al. in 1995 (Mitragotri et al. 1995a, b). They have also reported that
ultrasound application using 20 kHz frequency increases the transdermal perme-
ation of many low as well as high molecular weight drugs. They showed that there
was an increase in skin permeability with decreasing frequency, and also with
increasing the intensity and the time of exposure. They identified collapse cavitation
as the main causative mechanism (Mitragotri et al. 1996). It has also been reported
that these cavitations create reversible channels in the stratum corneum lipid layers,
thus providing pathways of transport for many drug molecules and even macro-
molecules (Tezel et al. 2002).
Kost et al. (2003) have shown clinically that skin pretreatment with 55 kHz
ultrasound gave better level of anaesthesia with EMLA cream as compared to
EMLA alone.
Histological studies with rat and pig skin after low-frequency sonophoresis
showed no structural changes suggesting its safety.
Low-frequency ultrasound has shown to increase the permeation of large
molecular weight molecules across skin and is currently under clinical trials for the
delivery of insulin and pain medication (Langer 2003).
Ogura et al. (2008) have reported that application of 20 kHz ultrasound
increased the permeation of many proteins across human skin in vivo.
Application of ultrasound and iontophoresis has shown synergistic effect on the
permeation of heparin with 56-fold enhancement (Le et al. 2000).
Extensive work has been carried out on transducer design to enhance its
portability without comprising with the efficiency of the technique. A cymbal
transducer design has been used to attain intensities in the range of 12.5–225 mW/
366 R. Prasad and V. Koul
cm2. This transducer has been chosen because of its light and compact structure and
also low resonance frequency in water (Maione et al. 2002; Smith et al. 2003a; Luis
et al. 2007). The efficacy of the technique has been investigated in vivo in various
animal models, Sprague Dawley rats, rabbits and large animals, viz., swine (Lee
et al. 2004a, b; Smith et al. 2003b; Park et al. 2007). A fall in blood glucose levels
was noted for nearly 60 min for all experiments, which continued even after
removal of the transducer. In a recent study, Park et al. (2008) have compared the
effectiveness of ultrasound-mediated delivery using a cymbal transducer array to
that of subcutaneously administered insulin over a 90 min experiment in rat model.
The change in blood glucose level with ultrasound treatment was greater, thus
suggesting that a higher effective dose of insulin was delivered.
Researchers have reported that low-frequency ultrasound was effective in
increasing the delivery of insulin and vasopressin loaded in hydrogel (Zhang et al.
1996; Peppas et al. 1999). This proved that poly (ethylene glycol) containing
hydrogel was useful for protein delivery. Meshali et al. (2011) have demonstrated
the efficiency of gels over emulsion in the transport of ibuprofen using ultrasound
across rabbit skin. Bani et al. (2015) showed that hydrogel formulation of
manganese-containing antioxidant drug showed significant transepidermal perme-
ation with the application of ultrasound. Jiang et al. (2016) have recently reported
the efficiency of ultrasound for delivery of mimosa from cellulose gel.
Ultrasonic-mediated enhanced delivery of hydrocortisone and lidocaine has been
tested clinically. Moreover, ultrasound is also used to extract interstitial fluid for
diagnostics, e.g. in blood glucose monitoring system. Preclinical research with
ultrasound-enhanced transdermal delivery of insulin (Smith et al. 2003a), low
molecular weight heparin, oligonucleotides and vaccines are in progress.
The future of ultrasound-enhanced transdermal drug delivery has a lot of
potentials. Ultrasonic skin permeation system, SonoPrep® developed by Prof.
Robert Langer and Prof. Joseph Kost, Massachusetts Institute of Technology, USA,
is the first FDA-approved system based on this technique. The system has been
tested for transdermal delivery of proteins, viz., insulin and heparin and local
anaesthesia. SonoPrep® is also used to induce local dermal anaesthesia using
lidocaine prior to cutaneous procedures. Moreover, application of SonoPrep with
EMLA cream before any IV cannulation has shown benefits in terms of pain
reduction and patient satisfaction (Kim et al. 2012). Furthermore, Gupta and
Prausnitz (2009) have reported that SonoPrep showed increased skin permeability
for a long time and the skin recovery was also very fast.
The use of low-frequency ultrasound for delivery of local anaestheics has been
approved by FDA (Shipton 2012).
Sonophoresis is expected to be a useful tool for both diagnosis and treatment of
diseases, such as diabetes in the near future.
9 Polymeric Gels: Vehicles for Enhanced Drug … 367
Skin has the natural protective function in the body, and it limits the delivery of
drug molecules into the body. Skin represents an important drug delivery route
especially for molecules destroyed by the liver after oral intake. Drug delivery
through the skin is an attractive and challenging area for research, and optimization
of drug delivery is important in modern therapy.
The drug formulations play an important role in transdermal drug delivery and
are a critical link between the drug, device and skin.
Transdermal delivery is particularly advantageous for localized effect and hence
more appropriate to use for targeting the skin directly.
The acceptance of transdermal products is very high, and this can be clearly seen
from the increasing market for such products. Thus, it has made significant con-
tribution to the medicinal world but has still not achieved its goal as an alternative
to the conventional modes of drug delivery. Research should be aimed at better
designing of the transdermal device, with minimum skin irritation and higher flux
for a large number of molecules.
A lot of researches are being done to explore the feasibility of using ion-
tophoresis to increase transdermal drug delivery and to use it as a treatment
modality for a number of therapeutic molecules. However, till date only two
transdermal iontophoretic patches are available in the market. These assisted
delivery devices will expand the scope of transdermal permeation of many
macromolecules like proteins, vaccines, hormones, enzymes, genes, etc. An
increasing effort and effective collaboration are required between the medical
practitioners, research scientists and device manufacturers to develop the devices
and achieve the desired goals for assisted transdermal drug delivery.
The ongoing clinical trials for a number of drugs represent a great future for
transdermal delivery of drugs. However, the challenge lies in getting useful prod-
ucts out of these discoveries for the benefit of mankind.
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Chapter 10
Graphene Oxide–Polymer Gels
1 Introduction
A gel is described as a soft, solid, or liquid-like unique condensed material that has
a three-dimensional network composed of several components such as long poly-
mers, species of small molecules, and a large amount of solvent. These 3D
network-condensed materials usually form through chemical, physical, or
supramolecular crosslinking. The weight and size of gels are more like a liquid, but
they are treated like a solid. Two important characteristics of gels are phase state
and their rheological properties. In addition to the customary gels, the progress in
technology and fabrication has led to the development of a new generation of gels
known as smart gels, which are sensitive to different kinds of stimuli agents. In the
other words, their network gel structures can alter upon changes in pH, temperature,
ionic strength, solvent type, or electrical potential (Lloyd and Steed 2009; Jung
et al. 2013; Chaterji et al. 2007; Mao et al. 1998; Rogovina and Vasil’ev 2010; Liu
et al. 2016; Jagur‐Grodzinski 2010; Can et al. 2003).
Polymeric gels are known as 3D network polymer solvent systems comprised of
flexible polymer chains, crosslinking agent, and large amount of solvent (Thakur
and Thakur 2014, 2015). An interesting feature of polymeric gels is their ability to
swell in liquids without dissolving in them and their capability to retain a large
quantity of solvent (from tens to thousands of times larger than the amount of the
polymeric matrix weight). The distance between the crosslinking points is an
important parameter in the increment of the equilibrium swelling capacity of
polymeric gels. The phase state, structure, and rheological properties are also
important characteristics of polymer gels. Hydrogels and organogels are two main
types of polymeric gels. Hydrogels containing hydrophilic groups in their struc-
tures, and consequently can absorb water and swell, while organogels can swell in
the liquid organic phases due to their hydrophobic nature. Moreover, polymeric gels
in another classification can be classified as covalently crosslinked gels and non-
covalent crosslinked networks that are also known as supramolecular polymer gels.
Supramolecular polymeric gels usually fabricate through supramolecular interac-
tions such as hydrophobic interactions, electrostatic forces, hydrogen bonds, p–p
interactions, and metal–ligand coordination bonding (Chaterji et al. 2007; Liu et al.
2016; Jagur‐Grodzinski 2010; Can et al. 2003). Polymer gels due to their specific
mechanical characteristics like low elastic moduli and large deformability have
attracted considerable attention. The elasticity of polymer gels is mostly due to a
large amount of solvent and the flexibility of polymer chains. An important
property of polymer gels, versus polymer solutions, is that they maintain their shape
under their own weight.
To further understand the importance and application of polymeric gels and gels,
many studies have been conducted on them. Polymeric hydrogels can swell in
aqueous solutions and also due to their phase state, structure and rheological
properties, have great importance in different industries. Polymer hydrogels espe-
cially those prepared from biopolymers are biocompatible and, therefore, are
appropriate candidates for biomedical applications. In fact, polymer hydrogels have
been widely used as drug delivery systems because of their high solute diffusion
rate. On the other hand, these gels due to their high transparency and their ideal soft
and wet surface are considered as one of the best choices for contact lenses (Lee
et al. 2014; Alam et al. 2016). Polymeric gels usually contain huge number of
functional groups and consequently can adsorb a variety of organic and inorganic
10 Graphene Oxide–Polymer Gels 379
materials (Franklin and Guhanathan 2015; Cha et al. 2014; Tai et al. 2013; Zhang
et al. 2011; Gan et al. 2015). They exhibited many applications in diverse tech-
nologies including templates for biomedical devices, biological scaffolds for tissue
engineering (Yamato et al. 2002; Yeo and Kohane 2008; Cong et al. 2013; Luo and
Shoichet 2004; Nowak et al. 2002), biosensors (Lee et al. 2008), actuators
(Hoffmann et al. 1999; Yu et al. 2015b), catalysis (as supports) (Lloyd and Steed
2009), enzyme immobilization, molecular separation (Shen et al. 2009), energy
storage devices, electric fields, and chronobiology. Biocompatible hydrogels are the
potential candidates for applications such as drug and gene delivery and tissue
engineering (Chaterji et al. 2007; Fan et al. 2013; Ma et al. 2013; Hong et al. 2008).
Moreover, porous GO-biopolymer gels can be applied as an adsorbent for removal
of cationic dyes and heavy metal ions from wastewater (Deng et al. 2013; Wang
et al. 2014a). Polymeric gels have also been used as an electrolyte in rechargeable
batteries (Sun et al. 2016).
However, gels have several limitations in their applications due to their poor
mechanical properties, but via incorporating with nanoparticles especially graphene
and its derivatives, they showed improved new properties, such as large surface
areas, very low density, and enhanced mechanical performance (Zhao et al. 2015;
Shen et al. 2012).
Graphene, a one-atom-thick two-dimensional crystal with high planar surface,
remarkable electronic, mechanical, optical, and thermal properties has attracted
tremendous attention in various fields (Mao et al. 2013; Zhu et al. 2010a; Park and
Ruoff 2009; Eigler and Hirsch 2014; Zheng and Kim 2015; Miculescu et al. 2016).
Large-scale production of graphene and its homogeneous dispersion in the polymer
matrices are the main issues in the preparation of graphene-based nanocomposites
and hydrogels. In fact, graphene oxide (GO) considered as an excellent precursor
for large-scale fabrication of graphene. GO generally provided by oxidation of
graphite powder to produce graphite oxide using suitable oxidizing agents and then
exfoliation of graphite oxide to form GO sheets by sonication. GO is the most
important derivative of graphene because of its two specific characters: (1) due to
the existence of polar functional groups on its surface, GO easily can be dispersed
in aquatic environment; (2) GO can be functionalized with wide spectrum of
compounds through covalent and noncovalent interactions to prepare functionalized
GO derivatives (Li et al. 2014; Chen et al. 2012; Su and Loh 2012; Dreyer et al.
2010, 2014).
Meanwhile, GO has a flexible 2D structure and is containing plenty of car-
boxylic acid groups, which can be the source of repulsive electrostatic forces as
well as hydrogen bonding interaction, and consequently considered as a suitable
candidate for fabricating 3-dimensional (3D) graphene-based materials. The bal-
ance between attractive and repulsive forces due to covalent and noncovalent
interactions, by addition of crosslinkers (organic molecules, polymers, or ions) or
by adjustment of pH of the solution can lead to the adjustment of interlayer distance
and preparation of self-assembled structures and can promote gelation of GO.
Compared with the graphene oxide, graphene-based gels exhibit improved struc-
tural features such as larger specific surface areas, higher interpenetrated porous
380 A. Dadkhah Tehrani et al.
network architecture, and better electronic properties that remark its potential
applications in the fields of electrochemical biosensors, energy storage, superca-
pacitors, biological fuel cells, drug delivery systems, and wastewater treatment (Li
and Shi 2014; Bai et al. 2011a; Yuan et al. 2014). The studies on the
GO-based polymer gels have been grown because these types of gels benefited
from the advantages of both the graphene oxide and the polymer used.
Also, grafting of the polymers to the surface of graphene oxide and its derivatives
during GO-based polymeric hydrogel fabrication can prevent aggregation of its
sheets and could alter the chemical structure of GO (Gan et al. 2015; Zhang et al.
2014).
3.1 Synthesis of GO
The present section deals with the history and the most important preparation
methods of graphene oxide. GO as an amphiphilic macromolecule, is significantly
used in the construction of 3D graphene-based materials. Normally, GO is syn-
thesized by the controlled oxidation of graphite in acidic media. The obtained
graphite oxide at the next step undergoes an exfoliation process. Mechanical
shaking and ultrasonication are most commonly used approaches for exfoliation of
graphite oxide layers. The quality of resulting GO after exfoliation process sig-
nificantly depends on starting materials, oxidation process, and the method used for
exfoliation (Dreyer et al. 2010; Chen et al. 2012; Li et al. 2014). The first study on
the chemistry of graphite has been done by Brodie (1859). He succeeded to prepare
GO with the net molecular formula of C2.19H0.80O1.00 by adding potassium
chlorate (KClO3) and nitric acid (HNO3) to a slurry of graphite, for the first time.
Resulting GO showed better dispersion in basic and neutral media than acidic
media. Nearly 40 years later, Staudenmaier (1899) made a slight change in Brodie’s
procedure for the preparation of GO. He used concentrated H2SO4 and potassium
chlorate solution and successfully synthesized GO nanosheets with higher oxidation
level compared with GO that was provided by Brodie. Nearly 60 years after
Staudenmaier, Hummers and Offeman (1958) oxidized graphite to graphite oxide
using a mixture of oxidizing agents consist of sulfuric acid, sodium nitrate, and
potassium permanganate. In general, the strategies used by Brodie and
Staudenmaier not only required a longer time to react but also these methods were
not safe due to ClO2 gas that was produced during the reaction. However, Hummers
method was usually carried out in a very short time (about 2 h at 45 °C). This
method is also more safe due to the absence of hazardous ClO2 gas. Kovtyukhova
et al. (1999), introduced modified Hummers method and improved the efficiency of
the oxidation by adding H2SO4, K2S2O8, and P2O5 to graphite powder. In 2010,
10 Graphene Oxide–Polymer Gels 381
Marcano used different oxidizing agents such as KMnO4, H2SO4, and H3PO4. This
method is also known as improved Hummers method. Improved Hummers’ method
has some significant advantages over Hummers’ method such as increment in the
number of isolated aromatic rings that are produced in this process in comparison
with other related processes, easy temperature control, and more regular structure.
Moreover, this method avoids the release of NOx (Marcano et al. 2010). In fact,
improved Hummers’ method is a more favorable choice than other methods
because of its convenient operation, safety, and its better reaction efficiency (Chen
et al. 2013a, 2015).
activation energies can promote the chemical reactions compared with traditional
thermal methods (Chen et al. 2010; Zhu et al. 2010b; Wang et al. 2015b).
Photothermal approach also can be used for reduction of the GO sheets via thermal
deoxygenation process (Yeh et al. 2014; Guo et al. 2013; Mukherjee et al. 2012).
As an example, organic photocatalysts have been utilized to produce reduced
graphene with high electrical conductivity (Zhang et al. 2012).
Inorganic nanomaterials are rarely used to reduce graphene oxide because the
remaining metals in the produced rGO dramatically influence the electrical properties
of the produced graphene (Wu et al. 2011; Williams and Kamat 2009).
Electrochemical reduction is another route for the preparation of rGO. The reduction
process is carried out either by exposure of GO films to a negative potential or by
electrophoretic and potentiostatic routes. Reduction process by electrophoretic and
potentiostatic routes leads to simultaneous assembly and reduction. In these methods,
electrons act as reducing agents and effectively eliminate oxygen-containing func-
tional groups of graphene oxide surface and lead to the production of rGO without
heteroatom contaminations (Moraes et al. 2015; Low et al. 2013). The hydrothermal
or solvothermal process also can be used to reduce GO. However, heteroatoms,
various metal oxides, and sulfides can be introduced into graphene under
hydrothermal or solvothermal conditions (Moussa et al. 2016; Liu et al. 2015b).
In the literature, there are two different types of methods for the synthesis of
graphene, top-down and bottom-up approaches that each of these methods include
several different ways (Zheng and Kim 2015; Edwards and Coleman 2013; Avouris
and Dimitrakopoulos 2012). In top-down approach, single graphene sheets can be
achieved from graphite, whereas in bottom-up approaches usually
carbon-containing sources have been used for the synthesis of graphene sheets.
Top-down methods involve micromechanical cleavage, solvent-based and electro-
chemical exfoliation, graphite and graphite oxide intercalation compounds exfoli-
ation, and unzipping of carbon nanotubes. In top-down methods, there are several
challenges including reaction yields, numerous steps, and production of defect-free
graphene sheets (Edwards and Coleman 2013). Bottom-up methods are generally
carried out in a simple manner and produce a large area of graphene sheets but
require higher temperature and lead to fabrication of sheets which are containing
higher levels of defects (Zhu et al. 2010a; Eigler and Hirsch 2014; Edwards and
Coleman 2013; Avouris and Dimitrakopoulos 2012; Choi and Jo-won 2013).
Micromechanical cleavage also known as “scotch tape” or “peel-off” method is
the first method that is used to experimentally isolate graphene. This method is
suitable for the preparation of high-quality graphene. However, high-scale pro-
duction of graphene using this technique is difficult and requires more time
(Edwards and Coleman 2013; Choi and Jo-won 2013). Also, various strategies
reported on the preparation of graphene by using electrochemical approaches
10 Graphene Oxide–Polymer Gels 383
(Aqil et al. 2013; Wei et al. 2012). Solvent assisted and thermal exfoliation are two
main methods for preparation of graphene from graphite intercalation compounds
(GICS). In solvent-assisted strategies, exfoliation is performed by sonicating of
graphite intercalation compounds (GICS) in solution. In thermal exfoliation, GICS
is exfoliated to a nanoscale level along the c-axis of the graphene layer by thermal
decomposition of the intercalated species (Vallés et al. 2008; Li et al. 2008b).
Moreover, sonication of unmodified graphite flakes in aqueous surfactant solutions
and organic solvent like N-methylpyrrolidone (NMP 230 °C) is another method to
produce graphene. However, exfoliation and reduction of graphite oxide is the most
common method to produce graphene. Also, it is worth noting that the reducing of
GO to graphene is not complete even if the reduction process is complete (Gounko
et al. 2008). Therefore, high levels of defects which are created during the oxidation
process will remain in the resulting graphene sheets. As previously mentioned
unzipping single or multiwalled carbon nanotubes by chemical and physical
treating is an effective technique for preparation of graphene “nanoribbons”.
Regular nanoribbons are achieved via unzipping of flattened carbon nanotubes
(Edwards and Coleman 2013; Kosynkin et al. 2009).
Sublimation of silicon from the silicon carbide (SiC) surface and graphitization
of the excess carbon atoms left behind is a bottom-up method for preparation of
graphene (Sutter 2009; Srivastava et al. 2012). Besides, chemical vapor deposition
(CVD), using pyrolysis of carbon-containing compounds in gaseous form, as
another bottom-up method was first reported in 2008 and 2009 and is known as an
effective technique for the synthesis of single- or few-layer graphene (Edwards and
Coleman 2013; Avouris and Dimitrakopoulos 2012; Reina and Kong 2012; Miao
et al. 2011). Depending on the type of metal that is used as substrate, preparation of
graphene through CVD approach can be performed by surface catalyzed or seg-
regation methods. In addition to the methods mentioned above, many other
methods have been reported in the literature for synthesizing few-layer graphene
(Reina and Kong 2012; Miao et al. 2011).
4 GO-Based Hydrogels
graphene oxide gelation by polymers and other approaches which lead to prepa-
ration of GO-based hydrogels is partially discussed.
Fig. 1 The mechanism for Cu2+ induced the rapid formation of PmPD/rGO hydrogel. Reprinted
with permission from Chai et al. (2015), Copyright © 2014 Elsevier Ltd
10 Graphene Oxide–Polymer Gels 385
As a new class of gels, polymer–GO gels due to the combination of both the
characteristics of GO and polymers were highly regarded in recent years. Fan et al.
(2013), prepared a novel ternary nanocomposite composed of sodium alginate (SA),
polyacrylamide (PAM), and GO nanosheets. The composite prepared by
free-radical polymerization of acrylamide in the presence of SA and GO and then
calcium ions were added to the composite for ironically crosslinking of composite
components. In fact, the resulting hydrogel is containing two kinds of crosslinking,
ionic crosslinking that acts between alginate chains and covalent crosslinking which
forms during polymerization of AM. Also, an enhanced mechanical performance
have been reported after the combination of GO into the hydrogels. Ionic
crosslinking along with covalent crosslinking leads to the strong interfacial inter-
actions between GO nanosheets and polymer chains and cause the hydrogels
illustrate good flexibility.
Zhang et al. (2014) similarly synthesized a novel ternary nanocomposite
hydrogel composed of GO, poly acrylamide, and carboxymethylcellulose sodium.
They finally used aluminum ions for ionically crosslinking of carboxymethylcel-
lulose sodium (Fig. 2). Moreover, this nanocomposite showed improved mechan-
ical strength due to the formation of homogeneous and strong interactions between
the composite components. As the authors stated that the strong interaction between
the polymer chains and GO nanosheets plays an important role in improving gel
mechanical properties. This hydrogel due to its high level of swelling index and
swelling rate constant could be applied in bioengineering and drug delivery system.
388 A. Dadkhah Tehrani et al.
Also, the X-ray diffraction studies indicated that GO has been distributed
homogenously in all of the obtained composites.
In addition to polymers, copolymers also have been used as polymer matrices.
For example, Yang et al. (2013), prepared an ion gel based on GO using poly
(vinylidenefluoride-hexafluoro propylene), [P(VDF-HFP)]. This GO-doped ion gel
due to homogenous distribution of GO can act as ion “highway” to simplify the ion
transport. P(VDFHFP)-EMIMBF4-GO gels due to its excellent compatibility and
long-term stability can be applied for the design of energy storage devices in the
future. Using a new technique, through a one-step method, Sun and Wu (2011),
prepared the GO/PNPIPAM interpenetrating polymer network through covalently
bonding of carboxyl groups of GO and PNPIPAM by epichlorohydrin
(ECH) (Fig. 3). They reported that this hydrogel network due to its high elasticity
can quickly recover to its initial order under the cooling mode. Also, this hydrogel
is pH sensitive due to the existence of carboxyl groups and may be able to use for
biological applications as a carrier for controlled drug delivery.
In a new research, using ECH, Guo et al. (2015b), prepared chitin/graphene
oxide hybrid hydrogels. They stated that this hydrogel due to the layered porous
structure has high mechanical properties and can be used to design the criteria for
tissue engineering. The resulted hydrogels showed higher compressive strength
(260 kPa) in the presence of 35% GO, as compared with pure chitin hydrogel
(72.6 kPa).
10 Graphene Oxide–Polymer Gels 389
Fig. 4 Photo images of PAA and PAA hybrid samples, reprinted with permission from Yu et al.
(2015b), Copyright © 2015, Springer Science + Business Media New York
390 A. Dadkhah Tehrani et al.
Fig. 5 Scheme of functionalized GO with HPC and HPC-GO/HPC hydrogels, reprinted with
permission from Liu et al. (2015a), Copyright © 2015, Springer Science + Business Media New
York
10 Graphene Oxide–Polymer Gels 391
Fig. 6 Mechanical behavior of GO/polyacrylamide gel upon bending (a) and compression (b),
reprinted with permission from Shen et al. (2012), Copyright © 2012 Elsevier Ltd
photothermal properties are promising materials for biomedical issues such as drug
delivery, microdevices, etc. Zhang et al. (2013) alternatively used free-radical
polymerization technique for the polymerization of N-isopropyl acrylamide as a
vinyl monomer in the presence of an aqueous dispersion of GO. Unfortunately, the
composite components did not show appropriate compatibility and do not have
strong interaction and therefore they tried to overcome this problem by the addition
of hectorite clay as additional nanoparticles to the hydrogels. As the prepared
hydrogel exhibited high mechanical strength and can be used as a stimuli-response
material. Through the incorporation of graphene oxide (GO) into N,N-dimethyla-
minoethyl methacrylate (DMAEMA), Wang et al. (2014a, b), prepared hybrid
hydrogels with excellent adsorption performance. They also used in situ poly-
merization route and investigated composite sensitivity attribute to alterations in pH
and temperature. This hydrogel due to excellent adsorption performance (the
maximum Cr(VI) adsorption of 180 mg/g) can be a suitable candidate for water
treatment. In another work, via c-ray pre-irradiation technique, Lee et al. (2014)
proposed a controllable route for synthesizing of hydrogels using covalent
crosslinking of GO and poly(acrylic acid). The mechanical properties and thermal
stability investigations demonstrated that the composite hydrogel containing only
0.05 wt% GO showed enhanced modulus and thermal stability properties (Fig. 7).
Fig. 7 a Digital image and b SEM micrograph of hydrogel which stored at pH 12 for 3 days,
reprinted with permission from Lee et al. (2014), Copyright © 2014, The Polymer Society of
Korea and Springer Science + Business Media Dordrecht
Fig. 8 Illustration of the proposed structure of the GHA gels. Reprinted with permission from Cui
et al. (2015), Copyright © 2015, Royal Society of Chemistry
Fig. 9 Schematic of the synthesis of PAM/GO hydrogels. Reprinted with permission from Liu
et al. (2012), Copyright © 2012, Royal Society of Chemistry
394 A. Dadkhah Tehrani et al.
bonding between GO and PVA restricts the segmental motion of the PVA chains
and leads to gradually increase of the glass transition temperature (Tg). The results
also showed that even low concentrations of the graphene sheets can significantly
influence the thermal stability and mechanical properties of the nanocomposites.
The obtained hydrogels systems have the ability to absorb methylene blue (MB).
Besides, desorption studies indicated that electrostatic interaction, hydrogen
bonding, p–p conjugation, and chemisorption interaction between MB and PVA/
GO nanocomposites are driving forces of absorption.
Rui-Hong et al. (2016) used PVA in combination with regenerated cellulose as a
biocompatible polymer in the preparation of PVA/cellulose/GO composites. They
prepared graphene oxide-regenerated cellulose/polyvinyl alcohol ternary hydrogel
with high pH sensitivity and good mechanical properties via the freeze-thaw
method. In fact, the studies revealed that polymers could be intercalated between
GO layers and formed a ternary hybrid material with strong interfacial adhesion
between GO and polymer matrix (Fig. 10). Swelling behaviors of the ternary
hydrogel showed that the GO contents and pH effectively can influence the water
uptake rate and swelling ratio. With 0.8wt% GO loading, ternary hydrogel showed
maximum swelling ratio under the alkaline conditions (150%; pH = 2 and 310%;
pH = 14). It was also found that mechanical properties of GO-RCE/PVA hydrogels
have been significantly improved compared with RCE/PVA. The presence of only
1.0 wt% of GO, improved the tensile strength of composite about 40.4% (from 0.52
to 0.73 MPa). Also, elongation at break was increased from 103 to 238%.
Hydrogels with excellent mechanical property and self-healing characteristic
simultaneously is an interesting topic in hydrogel science and has attracted much
attention in different fields (Liu et al. 2012; Xue et al. 2015). Cong et al. (2013),
reported a novel class of graphene oxide (GO)/poly(acryloyl-6-aminocaproic acid)
(PAACA) composite hydrogel with both enhanced mechanical behavior and
self-healing properties. In the GO/PAACA composite hydrogel, Ca2+ introduced as
the secondary crosslinker to form a robust and flexible polymer network. The 3D
hydrogen bonding network between functional groups of PAACA side chains with
both its own functional groups and GO surface functional groups nanosheets as
well as coordination interactions between Ca2+ and carboxylate groups of GO
nanosheets and polar groups of poly(acryloyl-6-aminocaproic acid) side chains,
endowed GO/PAACA composite hydrogel with the rapid self-healing properties
and higher mechanical strength than that of PAACA hydrogel.
Conducting polymer (CP) hydrogels as another class of hydrogels have been
broadly examined for various potential applications. Application of appropriate
methods in the preparation of the conducting polymer (CP) hydrogels is essential
due to insolubility and low hydrophilicity of CP. This kind of hydrogels generally
shows high conductivities and good electrochemical activity (Guiseppi-Elie 2010;
Dai et al. 2010). In this context, Bai et al. (2011b), synthesized conducting polymer
(CP)/Graphene oxide(GO) composite hydrogels by the growth of pyrrole (Py), 3,
4-ethylenedioxythiphene and aniline on GO sheets in aqueous media through
chemical polymerization. GO/PPy composite hydrogels showed higher storage
moduli (>10 kPa), stronger electrical conductivity and electrochemical activity
396 A. Dadkhah Tehrani et al.
Fig. 10 The schematic illustration of the preparation of the GO-RCE/PVA ternary hydrogels.
Reprinted with permission from Rui-Hong et al. (2016), Copyright © 2015 Elsevier Ltd
ions. These hydrogels were prepared from the crosslinking of GO sheets in the
presence of different biopolymers through the noncovalent interactions (Fig. 11).
Since negatively charged bovine serum albumin (BSA) and DNA contain the
hydroxyl and carboxylic acid groups as well as hydrophobic groups in their
polymer chains then, in gelation process hydrogen bonding and hydrophobic
interactions are the main crosslinking forces. However, chitosan as cationic
polysaccharide can effectively attract the anionic GO sheets through electrostatic
interactions and hydrogen bond because of the presence of –NH2 and –OH groups
in its polymer chains. The studies revealed that biopolymers effectively improved
the blood compatibility of GO gels because the biopolymers can effectively mediate
the surfactant-like property of GO sheet.
Moreover, GO/biopolymer gels could act as appropriate adsorbents for cationic
dyes as well as removal of heavy metal ions such as Pb2+ and Cd2+. In fact, these
synergistic effects take place because of the static electrical attraction and the
complexation ability of the surface functional groups of GO. Furthermore, GO/
biopolymer gels showed the higher releasing speed of DOX as an anticancer drug in
comparison with pristine GO. GO/biopolymer gels demonstrated the superior
releasing speed of DOX in acidic solution due to the increasing hydrophilicity and
solubility of DOX in acidic solutions.
Fig. 11 Schematic illustration of the preparation of 3D GO/biopolymers gels and their application
for removal of toxic molecules. Reprinted with permission from He et al. (2013), Copyright ©
2013, Royal Society of Chemistry
398 A. Dadkhah Tehrani et al.
Yu et al. (2015a) investigated the gelation behavior of welan gum in the pres-
ence of GO. Welan gum as a biocompatible and biodegradable microbial
polysaccharide could effectively reduce the critical gelation concentration through
H-bonding, hydrophobic interaction and electrostatic interaction with graphene
oxide sheets. Furthermore, the resulting hydrogels examined for removal of various
dyes such as methylene blue, methyl violet, amido black 10B, rhodamine 6G, and
chrome Azurol S from wastewater.
GO-based hydrogels with their superior properties have been opened new
opportunities for biomimetic researches. Peng et al. (2016) reported a polyvinyl
alcohol/graphene oxide (PVA/GO) nanocomposite hydrogel with properties very
similar to jellyfish mesogloea collagen. More interestingly, jellyfish-like PVA/GO
nanocomposite hydrogels showed anisotropic porous structures consisting of
microsized fibers and lamellar structure, high tensile and compressive strengths,
pH-responsive properties, appropriate mechanical properties, and high water con-
tents (97–99 wt%), which are suitable for design of soft robots, catalyst, carrier, etc.
These hydrogels could be fabricated through a simple and effective directional
freezing-thawing process as a result of the strong hydrogen bond formation between
PVA and GO.
The application of graphene oxide to purify the water contaminant is restricted
due to problems related to its separation from the water. GO-based hydrogels could
provide a perfect solution to solve these problems. Li et al. have used the polymeric
networks of poly(vinyl alcohol) (PVA) with sulfonated graphene (SG) for selective
removal of cationic dyes from wastewater. SG/PVA (SP) composite hydrogel
formed through physical interactions between the SG and PVA. Investigations
showed that pH and ionic strength have minimum effect on the adsorption of
methylene blue (MB). Moreover, SG/PVA (SP) composite hydrogel exhibited
enhanced mechanical property (maximum tensile strength of 37.34 kPa) than that
of pure PVA hydrogel.
NIR light-responsive hydrogels with high tensibility exhibited better perfor-
mance in many areas such as smart sensors/actuators, controlled release systems,
cell scaffolds compared with other stimuli-responsive hydrogels. Recently, Shi et al.
(2015), reported new nanocomposite hydrogel by a combination of PNIPAM with
GO nanosheets and N,N′-methylenebisacrylamide (BIS) molecules as chemical
crosslinkers. The as-prepared hydrogel exhibited excellent NIR light-responsive
property, ultrahigh tensibility, excellent chemical stability, and extreme stability in
both polar solvent and strong acid condition. GO nanosheets can act as a physical
crosslinking agent. Formation of hydrogen bonds between GO carboxylic acids and
the amide groups of PNIPAM chains can effectively disperse the strain energy in
the deformation process of hydrogels. Also, the use of N, N′-methylenebisacryla-
mide (BIS) molecules as chemical crosslinkers leads to strong chemical stability
and ultrahigh tensibility of the hydrogels.
Zhao et al. (2015) prepared a composite composed of graphene oxide and chi-
tosan composite through the self-assembly of chitosan molecules and GO. They
reduced graphene layers after preparation by an in situ reduction process. Also, they
investigated their adsorption capacity for three different dyes, congo red, methylene
10 Graphene Oxide–Polymer Gels 399
blue, and rhodamine b. The results of their study showed that this hydrogel can be a
good adsorbent for wastewater remedy as well as the elimination of toxic dyes from
wastewater. Polyethylenimine (PEI), just like chitosan is containing many amino
groups and, therefore, can be used for the preparation of GO-based hydrogels. In a
new work, GO/polyethylenimine (PEI) hydrogels were reported by Guo et al.
(2015a). They applied a facile approach to prepare GO/polyethylenimine as the
consequence of H-bonding and attractive forces due to the electrostatic forces
between PEI amino groups and GO sheets (Fig. 12). This hydrogel can be used in
wastewater treatment. They also studied the dye removal ability of the hydrogel by
evaluation of both their rates and adsorption capacity toward methylene blue and
rhodamine B. For the present hydrogel, adsorption of PEI into the surface of GO
significantly altered ordered stacking of GO sheets and leads to better dispersion
and exfoliation of GO layers.
Wang et al. (2014b) used a green method to prepare graphene–agarose
(AG) multifunctional hydrogels. These hydrogels are formed through strong
hydrophobic interactions and hydrogen bonding between surface groups of gra-
pheme oxide and agarose (AG) as physical crosslinking sites. Furthermore, AG acts
Fig. 12 Schematic depiction of the formation of GO/PEI gels a GO and b amine-rich PEI were
combined to give (c) GO/PEI hydrogels gelation pictures (d) and Gelation behavior (e), reprinted
from Guo et al. (2015a), available under a Creative Commons Attribution License CC-BY 4.0.
©2015 Geo et al.
400 A. Dadkhah Tehrani et al.
as stabilizer agent and leads to stability of hydrogels in strong acidic, basic, salty,
phosphate buffer aqueous solution, and organic solvents. The adsorption ability of
this hydrogel for removal of cationic dyes such as malachite green (MG) and its
antibacterial activity against Escherichia coli and Staphylococcus aureus bacteria
make it suitable for miniature-scale water purification.
Graphene- and reduced graphene (rGO)-based polymer gels have better mechani-
cal, electrical, and thermal properties rather than GO-based ones. They also have
more chemical and electrochemical stability compared with GO hydrogels (Li et al.
2014).
Zeng et al. (2013), investigated the effect of various amounts of rGO incorpo-
rated into two different hydrogels: poly(sodium acrylate) (PSA) and poly(sodium
acrylate)-poly(N-isopropylacrylamide) (PSA-NIPAM) and realized that composite
hydrogels which contained small amounts of rGO sheets showed remarkably
enhanced swelling ratios. The resulting composite is a promising material for use as
draw agents in the forward osmosis process and can be used in the confectionery
industry, water treatment, and food processing. It should be pointed out that
polymer hydrogel composites (e.g., 1.2 wt%) exhibited higher flexibility and better
swelling behavior rather than the polymer. Synthesis of a catechol-containing
organogel in the presence of reduced graphene oxide (RGO) through H-bonding
has been reported by Ghavami Nejad et al. (2016). They proposed that N-iso-
propylacrylamide (NIPAM) and dopamine methacrylate (NIDO)/RGO agglomerate
through hydrogen bonding and complexation. This pH-sensitive supramolecular
hydrogel can be useful in the medical fields especially in drug delivery systems and
artificial limbs.
In an interesting work, Yuan et al. (2014), synthesized conducting gel elec-
trolytes from incorporating graphene, graphene oxide, or nanographite dissolved in
a liquid electrolyte using freeze-dried poly(acrylic acid)-cetyltrimethyl ammonium
bromide (PAA-CTAB). Graphene, graphene oxide, and nanographite by
hydrophobic interaction with the 3D framework of PAA-CTAB matrix could create
interconnected channels for charge transfer and consequently enhance the ionic
conductivity of composites in comparison with pure PAA-CTAB gel electrolyte.
Compared with PAA-CTAB gel electrolyte, the nanocomposite gel electrolytes
showed higher ionic conductivity and better electrical, electrochemical, and pho-
tovoltaic performance.
Nowadays, quantum dot-sensitized solar cells (QDSC), considered as useful
compounds, can be used as the third generation of solar cells. Duan et al. (2015)
prepared QDSC using conducting polymer gel electrolytes. This conducting
polymer gel electrolyte is prepared by incorporating graphene nanosheets into
polyacrylamide hydrogel. The gel showed increased photovoltaic performances.
Researchers achieved a power conversion efficiency of 2.34% via optimization of
the amount of graphene in the composite. The conductive polymer nanocomposites
10 Graphene Oxide–Polymer Gels 401
with 3D framework was also reported by Spasevska et al. (2015). They prepared
crosslinked nanocomposites by in situ polymerization of methacrylate monomers in
the presence of rGO platelets and polyurethane prepolymer containing isocyanate
(Spasevska et al. 2015). Meanwhile, nanocomposites showed enhanced stability,
electrical conductivity, and mechanical properties due to a higher degree of
crosslinking between polymer chains and graphene platelets.
Huang et al. (2013) prepared a new double-network hydrogel consisting of
graphene 3D network as the first network and poly(acrylic acid) as the second. They
prepared the double-networks system through adsorption of acrylic acid monomer
into the 3D graphene network and then polymerization of AA. This hydrogel
showed good flexibility, elasticity, and electrical conductivity. Based on the stress–
strain curves, in the first step (below 300% strain) of the deformation process, a
quick increase with stress is shown (Fig. 13). But in the second step (up300%
strain), slower increase for Young modulus and tensile strength is showed pre-
sumably due to the stretch of PAA.
Using a simple approach, Zu and Han (2009) reported the formation of the stable
aqueous copolymer-coated graphene solution via the noncovalent interaction
between the hydrophobic PPO segments of a triblock copolymer, poly(ethylene
oxide)-block-poly(propylene oxide)-block-poly-(ethylene oxide), with the
hydrophobic graphene surface (Fig. 14). They also by using a simple approach,
synthesized the supramolecular hybrid hydrogel by host–guest interaction of
cyclodextrin with polyethylene oxide (PEO) of pluronic copolymer containing
polypropylene oxide, polyethylene oxide, and graphene. They obtained
supramolecular hydrogel which could be useful for drug delivery system. This
hydrogel has the shear-thinning property that is the main feature of supramolecular
hydrogels.
Graphene as a nanosize flexible-layered structure inorganic material has been
used widely to produce organic–inorganic hybrid gel compounds. In an interesting
work, hybrid graphene inclusion complex (HGIC) was synthesized through the
noncovalent grafting of poly-(N,N-dimethylacrylamide)-b-poly(N-iso-
propylacrylamide) which was functionalized at the end of its chains by azobenzene
groups (AZOPDMA-b-PNIPAM). The researchers demonstrated that the
GO-graft-block copolymer is thermo- a sensitive polymeric compound and can
form supramolecular gels with increasing the temperature. Also, investigation of the
thermo-sensitive behavior of the hydrogel composite during gelation revealed that
gelation temperature increases with increasing the length of PDMA block rather
than PNIPAM block. This hydrogel due to its high biocompatibility can have
numerous potential applications in different fields, especially biomedical applica-
tions such as drug carriers and tissue engineering (Liu et al. 2011). Hydrogels with
enhanced mechanical hardness have been also reported (Cha et al. 2014). Cha et al.
in a research study have addressed the successful modification of a GO using
methacrylate groups. They used this modified graphene oxide, as active
crosslinking agent for the covalent crosslinking of GO into a hydrogel system
through radical copolymerization. The results of scanning electron microscopy
402 A. Dadkhah Tehrani et al.
Fig. 13 a Mechanical properties of the reduced GO/PAA double networks. (a–c) Images of the
reduced GO/PAA, under press, and after the press removed; (d and e) Stretch of the reduced GO/
PAA; (f and g) the reduced GO/PAA DN hydrogel with different thickness and their flexibility,
b compressive stress–strain curves of the reduced GO/PAA gel with PAA contents of 20, 30, 40,
and 50%, reprinted with permission from Huang et al. (2013), Copyright © 2013, Royal Society of
Chemistry
Fig. 15 SEM micrographs of the cross sections of (a) graphene oxide-GelMA (3 mg mL−1 GO)
hydrogel and (b) Methacrylate graphene oxide-GelMA (3 mg mL−1 MeGO) hydrogel. (Scale bar:
200 lm), reprinted with permission from Cha et al. (2014), Copyright © 2013 WILEY-VCH
Verlag GmbH & Co. KGaA, Weinheim
404 A. Dadkhah Tehrani et al.
Fig. 16 Digital image of hydrogel (a) X-ray diffraction diagrams (b), FTIR data (c), and Raman
spectra (d), reprinted with permission from Hou et al. (2012), Copyright © 2012 Elsevier Ltd
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Chapter 11
Transport in and Through Gel
Masayuki Tokita
Abstract Gel is a state of matter that classified into the solid because it consists of
the three-dimensional cross-linked polymer network. It, however, shows some
liquid-like properties since it also contains a considerable amount of fluid.
According to such a characteristic structure, many substances can pass the gel. In
many separation technologies, therefore, gel is used as a molecular sieve. Although
the gel plays many important roles in the separation technologies, the detailed roles
played by the gel in the transport phenomena is not well understood yet. The
transport phenomena in the gel are necessary to be clarified. In this chapter, we
discuss tow transport phenomena that is related to the gel. The one is the friction of
the gel against the liquid that flows through the gel, and the other is the resistance of
the gel for the diffusional translation of the substances in the gel.
Keywords Stokes–Einstein law Diffusion coefficient Darcy’s law
Gel-solvent friction Scaling law
1.1 Introduction
Gel is a complex system of the polymer network and a huge amount of fluid. Today,
gel is familiar not only in science but also in our daily life as the food, the medicine,
and many commodities. Gels are known to show many unique behaviors. The
unique properties of gels are deeply related to the characteristic structure of the gel
(Tanaka 1981). In earlier studies of the science of gels, the elastic properties of gel
are studied extensively because the formation of the gel is thought to be similar
phenomenon to the solidification except a lot of solvent. The phenomenon is simply
M. Tokita (&)
Department of Physics, Faculty of Science, Kyushu University, 744 Motooka, Fukuoka,
Fukuoka 819-0395, Japan
e-mail: [email protected]
called as the gelation or the sol-gel transition. The elastic property of the gel is
believed to reflect directly the transition of the state from the solution to the gel.
Therefore, the critical elasticity of the gel is studied extensively (Tokita 1982, 1985,
1987; Tokita et al. 1985). The scientific knowledge on the sol-gel transition is
gained and the phenomenon is believed to belong the class of the percolation
transition (De Gennes 1976, 1979).
A new insight into the viscoelasticity of gel is developed theoretically, later that
is called as THB theory, with the pioneering experimental studies (Tanaka et al.
1973). In THB theory, the viscoelastic property of gel is explained in terms of the
competition between two forces. The one is the entropy elasticity of the polymer
network, and the other is the frictional resistance due to the polymer chain and the
gel fluid (hereafter, it will be called as friction, frictional property, and/or hydro-
dynamic friction for the sake of simplicity). It should be emphasized here that the
friction that will be discussed in this review do not mean the friction between two
surfaces of solids. In the similar ages from 70s to 80s, a new transition phenomenon
is discovered in the gel where the gel changes its volume more than thousand times
against the infinitesimal change of, say, the solvent composition reversibly (Tanaka
1978). Then the kinetic studies are made to solve the transition phenomena, which
also help the use of gels in many applications (Tanaka and Fillmore 1979). In these
kinetic studies of the gel, the important roles played by the friction of the gel are
revealed eventually. Although the importance, detailed study of the frictional
property of gel is postponed because of the reason that the accurate and the reliable
determination of the friction in the gel is considerably difficult. However, the sit-
uation changes drastically in 1991 by the discovery of the critical slowing down of
the friction in a gel (Tokita and Tanaka 1991a, b). The finding opens a new insight
into the transport phenomena of the gel. Then, the frictional property of gel draws
attention eventually as one of important transport properties of the soft matters. It is
well known that the viscoelasticity is a common property of the soft matter from the
dilute solution to the gel including the semi-dilute solution. In contrast, the friction
is, by its definition, only defined for the porous solid. Today, we believe that the
friction between the gel and the gel fluid is most characteristic property that reflects
the state of the gel.
It has been well established by the THB theory that the viscoelasticity of gel is
uniquely determined by the longitudinal elastic modulus, E ¼ K þ 4l=3, and the
friction of the gel, f, as follows.
E K þ 4l=3
Dc ¼ ¼ ð1Þ
f f
Here, Dc is the collective diffusion coefficient of the gel, which can be deter-
mined from the decay rate, sc , of the dynamic light scattering measurement from the
gel as follows.
11 Transport in and Through Gel 415
k2
sc ¼ ð2Þ
4pDc
It is clear from Eqs. (1) and (2) that the viscoelasticity of a gel can be determined
two of three physical quantities, that is, E, f , and Dc , are experimentally deter-
mined. Since the experimental determination of Dc and E are rather easy, the
measurements of these physical quantities are extensively made so far to determine
the viscoelastic properties of gels (Tanaka et al. 1977; Munch et al. 1977a, b;
Takebe et al. 1989). In contrast, systematic studies of the frictional properties of gel
have not been made extensively.
In Fig. 1, we show the principle of the friction experiments schematically. The
measurement is mechanical as shown in this figure. A slab shaped gel with the
thickness, L, is fixed in a space of glass tube with the peripheral portion is attached
to the wall of the tube. As shown in Fig. 1, the pressure, P, is applied to the fluid to
generate the flow of fluid in gel. The velocity of water flowing in gel, vs , is
determined in a stationary state of the flow. The friction coefficient of the gel, f , is
expressed as follows.
P
f ¼ ð3Þ
Lvs
Here, P=L is the pressure gradient applied to gel. Since P and L are given as the
experimental conditions, only vs is necessary to be determined to obtain the friction
coefficient of the gel. The principle of the friction measurement itself is quite
simple. The Eq. (3) is sometime called as “Darcy’s law” that also holds for the fluid
flow in the porous materials. Darcy’s law is firstly applied to study the transport
phenomena in the hard material systems such as the fluid flow through the sintered
glass filter and the flow of groundwater through the bedrock.
Since the principle of friction is simple, as described above, many pioneering
studies have been reported (Tanaka et al. 1973; Weiss et al. 1979; Hecht and
Geissler 1980; Geissler and Hecht 1982). It becomes, however, clear that the
friction measurement is not trivial because of the reason that the gel is soft, elastic,
and fragile. Most experimental studies on the frictional properties of the gel so far
reported have been made not under ideal conditions. Hence, the frictional properties
of the gel thus obtained are less accurate and also less reliable from today’s
knowledge. Such uncertainty of the friction arises from the fact that the frictional
resistance of the polymer network is considerably huge. For instance, the amount of
water that flows out of the gel in a unit time is usually very small indicating that the
larger gel has the advantage to increase the amount of water that flows out of the
gel. If one use a large gel sample, it is required to apply a large pressure to the gel
since the flow rate is determined by the pressure gradient, P=L, rather than the
pressure itself, P as shown in Eq. (3). However, the relaxation time of the
mechanical deformation, which is caused by the applied pressure and the flow of
the gel fluid, becomes longer if the size of the gel becomes larger. The THB theory
indicates that the relaxation time of deformation of a typical gel with a characteristic
size of about 1 cm becomes about 10 days. The THB theory, therefore, indicates
that more than 10 days is required to obtain the stationary flow of the fluid in
sample gel. Of course, such long-time measurement is not realistic and has never
been made so far. In addition to this, the other additional effects become pro-
nounced under the conditions of larger applied pressure. Namely, the structure of
the gel would be damaged by the extensive flow of water. The nonlinear effects of
water flow and the pressure would be also taking into account. Finally, the shrink of
the gel due to the frictional force also occurs at higher applied pressures. All these
additional effects occur because of the reason that the gel is soft, elastic, and fragile,
those are also the unique characters of the gel. Therefore, there are many compli-
cated problems to be solved when the Darcy’s law is applied to study the
gel-solvent friction in gel. It may be of importance to solve the problems raised
above to construct a newly designed apparatus to study the frictional properties of
the gel. This point is described in the following section in detail.
1.2 Experimental
It may be natural to begin with the description about the apparatus of the friction
measurement because the concept of the friction in the gel is not very much familiar
even for the researchers who are working with the gel (Tokita and Tanaka 1991a,
b). Here, we describe the difficult points of the friction measurements in the gel, and
then, how the difficulties are solved. The difficulties we find are ranging from the
11 Transport in and Through Gel 417
simple mechanical problem to the one that is arisen from the characteristic features
of the gel. Therefore, the description of analysis and the classification of the dif-
ficulties we should solve will assure the reliability of the experimental results. We
believe that one can discuss the experimental results on secure ground after these
difficulties are solved properly.
First of all, the pressure that is applied to the gel in the measurement of the
friction is required to be small enough not to alter the network structure of the gel
since the gel is fragile. To avoid the substantial shrink of the gel, the smaller applied
pressure is advantageous. Since the osmotic compressibility of the gel is of the
order of about 103–104 N/m2, the pressure applied to the gel should be comparable
with these values. We designed the apparatus to fix the gel volume by choosing the
condition at which the gel has a positive osmotic pressure. It also prohibits the gel
to swell. A simple calculation using the THB theory yields that the friction coef-
ficient of poly(acrylamide) gel is the order of 1014–1015 Ns/m4 (Tanaka et al. 1977).
According to the Eq. (3), the velocity of the fluid flow in the gel with L = 1 cm
becomes of the order of 10−8–10−9 m/s when the applied pressure is 103 N/m2. In
order to determine such a slow velocity, the velocity of the flow in the gel should be
amplified. The total volume of water, which flows out of the gel in a measurement,
is found to be about 10 ll or less under present conditions. Therefore, it is possible
to determine the velocity of water inside the gel if all the water that flows out of the
gel is lead in a thin micropipette. We, therefore, set a micropipette having a capacity
of 10 ll at the out-flow side of the apparatus. It is also clear from above conditions
that the leakage around the gel sample deteriorates the final accuracy of the friction
measurement of gel because the total amount of water that flows through the gel is
only few micro-little. Generally, this is the crucial point in designing the friction
apparatus. This point is avoided completely by using a plastic film that has the
functional groups, which forms the chemical bond with the sample gel, on the
surface. The plastic film used here is called as “Gel Bond Film” (BioRad) and is
used in the gel electrophoresis to chemically fix the gel on the surface of the film.
By using the gel bonding film, we avoid the leakage of water completely.
Water begins to flow in the gel immediately after pressure is applied to the gel.
The apparent velocity of water flow is fast in the initial state. Then it slows down
with the time, and finally, it reaches to a steady state velocity. Two effects are
responsible for the apparent fast initial velocity of the flow. The first one is the
bending of the gel-gel holder system, and the second one is the collapse of the gel
that is arisen from the friction between the gel and the flowing water. The effects of
the bending of the gel-gel holder system occurs from the structure of the measuring
cell. Even though the gel holder is tightly fixed between the thick plastic plate, it
can deform slightly. The displacement of the gel-gel holder system causes the
volume change of the elution side as a whole. Since the volume change is enhanced
by the micropipette, the change of the volume is enhanced. The relaxation time of
the bending deformation in gel and gel holder system is found to be about 30 min.
The relaxation time for the bending deformation is estimated from the control
experiments where the gel is molded between two bonding films while the gel bond
film has no openings to prevent water flows out of the gel. The movement of water
418 M. Tokita
in the micropipette, which is observed in the initial state of the friction experiment,
is mostly due to the bending of the gel-gel holder system. It is also important to use
a stiff material, such as the stainless steel, as the gel holder to decrease the
amplitude of the bending deformation. We find that the deformation of the stainless
steel gel holder is ten times less deformation than the plastic gel holder. In our
experiments, most measurements are made using the stainless steel gel holder.
Secondary, the retardation effects of the velocity of the flowing water arise from the
relaxation of the deformed polymer network that caused by the flowing water.
Because the gel is elastic, the polymer network of the gel deforms at lower applied
pressure. The velocity of the flow inside the gel, therefore, generally depends on
time. The relaxation time where the flow of the fluid in the gel reaches a stationary
state is estimated by the kinetic theory of the volume change of the gel. It is found
that the relaxation time of the volume change of a gel is proportional to the square
of a typical linear size of the gel (Tanaka and Fillmore 1979). The relaxation time
for the present case of the gel with the thickness of L is written as (relaxation time)
¼ L2 =p2 Dc . The relaxation time with a gel of thickness L = 10−3 m is the order of
104 s 3 h. Here, the typical collective diffusion coefficient of Dc ¼ 1011 m2/s is
employed. It also indicates that the relaxation time becomes shorter as the thickness
of the gel becomes thinner. There is further advantage to use a thinner gel as the
sample. According to Eq. (3), the velocity of fluid becomes larger if the thickness of
gel becomes thinner. Therefore, the accuracy of the resultant friction coefficient
increases in a thinner gel. The steady state flow of water is observed after all these
relaxation phenomena are diminished.
All the aspects described above are taking into account to construct the appa-
ratus. The outline of the apparatus is schematically shown in Fig. 2. The cell is
made of Plexiglass plates. In other part of the apparatus, we employed the stainless
steel pipes and stainless steel valves to prevent the volume change of total system
that is caused by the pressure applied to the sample gel. As a reservoir for water, the
chromatography column of about 50 cm in length is used that also behaves the
pressure generator. By changing the volume of water that is contained in the
chromatography column, the height of water column is changed from about 20 to
60 cm. The pressure is, thus, changed from about 2 103 to 6 103 N/m2. The
temperature of the water bath is controlled by a circulating bath system within an
accuracy better than 0.1°. The apparatus is set on an optical table by which any
external mechanical disturbances are avoided.
The gel holder, that is used in this study is made of stainless steel, is shown in
Fig. 3 schematically. The gel bonding films, to which the sample gel is fixed
chemically, are glued on both sides of the mold. The final thickness of the gel mold
with the gel bond films is found to be from about 1 to 2 mm that is measured after
the gel is cast. Since the gel is chemically attached to the gel bonding film, the
leakage of water from the gel mold is completely prohibited.
After the polymerization of the gel, the glass plates are removed from the gel
mold carefully under water to avoid the destruction at the surface portion. Then, the
gel mold is tightly fixed between two cells made of plexi-plates of about 1 cm in
11 Transport in and Through Gel 419
Fig. 2 The apparatus used to determine the friction coefficients of uniform poly(acrylamide) gel
and the critical behavior of poly(N-isopropylacrylamide) gel is schematically shown in the left
figure. The apparatus is set on a vibration free optical table to avoid the mechanical disturbances.
The cross section of the sample cell is also illustrated in the right figure. Both plexi-plates in this
figure are tightly fixed to avoid the swelling of gel
thickness. We embed the most part of O-rings in the plexi-plates to avoid the
bending of gel mold. At the end of the stainless steel pipe, a calibrated micropipette
of inner diameter ranging from 0.34 to 0.50 mm is attached to measure the flow
rate. Different micropipettes are used depending on the applied pressure and the
friction coefficient of gel. The micropipettes are commercially available and indi-
cated as 5 and 10 ll.
420 M. Tokita
Before the measurement of the friction coefficient, the gel is left in the cell for
overnight to reach equilibrium state under certain temperature. During this time
interval, the valve A in Fig. 2 is closed while the valve B is opened not to exert the
pressure on the gel. When we measure the friction of gel, firstly the valve B is
closed. Then, the valve A is opened immediately to exert the pressure upon the gel.
After the pressure is applied, the position of the meniscus of water in the micro-
pipette is measured with the elapsed time by a microscope. The valve A is closed
and the valve B is opened to release the applied pressure when the measurement of
the friction is done. The gel is left at least overnight to recover the initial equi-
librium state. This apparatus is employed to study the frictional properties of poly
(acrylamide) gel and poly(N-isopropylacrylamide) gel.
h0 hð t Þ
¼ exp ðt=se Þ ð4Þ
h0
Lf
se ¼ ð5Þ
qg
Here, g, q, and L are the acceleration of gravity, the density of fluid, and
thickness of the sample gel, respectively. The friction coefficient of the gel f is
11 Transport in and Through Gel 421
calculated from the characteristic time, se . This apparatus is suitable for the mea-
surement of the friction coefficient less than about 1013 Ns/m4.
1.2.3 Sample
Poly(acrylamide) gel is mainly used as the sample in this study. The gel is prepared
by free radical polymerization method. All reagents used here are the elec-
trophoresis grade (BioRad) and used as obtained. The calculated amount of acry-
lamide (main chain component) and N,N′-methylenebisacrylamide (cross-linker)
are dissolved into distilled and de-ionized water (purified using Milli-Q system).
The pre-gel solution, thus prepared, is de-gassed in a decompression chamber for
30–40 min after adding N,N,N′,N′-tetramethylethylenediamine (accelerator, added
240 ll–100 ml of pre-gel solution). Ammoniumpersulfate solution (initiator solu-
tion, added 1 ml of 4 wt% solution to 100 ml of pre-gel solution) is added to the
pre-gel solution to initiate the polymerization reaction. During the reaction, the
solution is kept at the desired temperature. The solution is also kept undisturbed
until the reaction is completed. In the preparation of the opaque poly(acrylamide)
gel, ammoniumpersulfate is changed to the non-ionic light sensitive initiator,
VA-086 (Wako, Tokyo). The pre-gel solution is introduced into the micropipette of
known inner diameter after the solution is de-gassed, and then polymerization
reaction is initiated by irradiating UV light of about 360 nm for 20 min.
In the case of poly(N-isopropylacrylamide) gel, the monomer is re-crystallized
before polymerization. The polymerization is made mostly in the same manner with
that of poly(acrylamide) gel. The reaction temperature is, however, controlled
422 M. Tokita
carefully since the gel becomes opaque by the reaction heat if the temperature is not
controlled. The polymerization reaction is made at a temperature of 20 °C.
First of all, the accuracy of the apparatus described in the previous section of 1.2.1
is checked. Typical experimental results of the elution time course from the poly
(acrylamide) gels are shown in Fig. 5. The sample gel used here is poly(acrylamide)
gel that is prepared at a total concentration of about 8 g/100 ml with a cross-linking
density of about 1 mol%. The time course of the elution of water from the gel is
determined by measuring the position of the meniscus of water in the micropipette
of 10 ll in capacity. The results are, then, plotted in Fig. 6. The curves given in this
figure represent the results gained at different applied pressures. We find that the
position of the meniscus moves rapidly in the beginning of the measurements.
The velocity of the movement of meniscus in the micropipette changes with
time, then it approaches to the stationary state after about 1 104 s. The velocity of
water in the micropipette at the stationary state, vsc , is calculated from the slope of
the elution time course in Fig. 6. The rapid movement of meniscus in the very
initial stage of the measurement can be considerably decreased in the case of the
improved friction apparatus. The friction measurement using such an improved cell
is reported elsewhere. In such a case, the elution time course from gel can be fitted
to the theoretical one (Suzuki et al. 2009).
The values of vsc thus determined are plotted against the applied pressure in
Fig. 6.
The velocity of water flow, vsc , is proportional to the applied pressure as pre-
dicted from Eq. (3). The friction coefficient, f ¼ 1:0 1015 Ns/m4, is obtained
from the results given in Fig. 6 using the following equation.
1 2
dvsc 1 R
f ¼ ð6Þ
dP L r
Here, ðdvsc =dPÞ ¼ 8:95 1011 m3/Ns represents the slope of the straight line in
Fig. 6. The gel has the thickness of L ¼ 1:9 103 m. The factor ðR=r Þ2 represents
the ratio of the areas of the cross section of the micropipette and the opening on the gel
bonding film. The radii of the micropipette and the hole are measured to be
r ¼ 2:5 104 m and R ¼ 3:3 103 m, respectively. This factor is necessary to
convert vsc to the actual velocity of water flow in the gel vs . The friction coefficient of
gel thus obtained agrees well with the one expected from the THB theory. These
results confirm that the friction coefficient of the gel can be determined accurately by
our apparatus.
easy, and the gel prepared from acrylamide is usually transparent, and so forth. In
this study, therefore, poly(acrylamide) gels are prepared at various conditions, then
the friction of the gel is measured.
First, we study the relationship between the friction and the temperature. In
Fig. 7, we show the results. The concentrations of the two sample gels used in this
measurement are 5 and 8 g/100 ml, respectively. We find that the law value of the
friction coefficient decreases upon increasing temperature (open symbols in Fig. 7).
Then, it increases with decreasing the temperature (closed symbols in Fig. 7). The
friction coefficient of poly(acrylamide) gel changes monotonously with the tem-
perature. Besides, it is also clear that the temperature change is entirely reversible.
Any singular behavior could not be observed in the temperature dependence of the
friction coefficient of poly(acrylamide) gel.
As long as the law value of the friction coefficient is concerned, it decreases with
the temperature monotonously as shown in Fig. 7. It can be expected easily that the
viscosity of the fluid effects the flow rate of fluid, and hence it also effects the
observed values of the friction coefficient of gel. Since the viscosity of the fluid
depends on the temperature, gðT Þ, the temperature variation in the friction observed
here includes the effects of the temperature variation of the viscosity of fluid. On the
other hand, the pore size of polymer network also depend on the temperature since
the gel may swell or shrink in response to the temperature change. The frictional
pore size of the gel, therefore, depends both on the concentration of the gel and the
temperature as nðC; T Þ. Therefore, the friction coefficient of the polymer network of
the gel, f ðC; T Þ, can be expressed as follows in general.
gð T Þ
f ðC; T Þ / ð7Þ
n ðC; T Þ
2
Here, n2 ðC; T Þ represents the cross section of the frictional pore in the polymer
network that expressed by the correlation length of the gel. We, thus, plot the
f / Ctotal
1:5
ð8Þ
The scaling indicates that the relationship between the correlation length and the
concentration in the gel system is expressed by the following equation (De Gennes
1979).
3=4
n / Ctotal ð9Þ
We, therefore, find following relationship by substituting the Eq. (9) into (7).
3=2
f / Ctotal ð10Þ
Hence, the exponent of the power law relationship that is obtained experimen-
tally agrees well with the one expected from the scaling theory (Fig. 9).
The concentration dependence of the friction on the cross-linking density, CCL ,
is also studied. In these measurements, the gels are synthesized at various mole
fractions of the cross-linking agent. The mole fraction is changed from 0.002 to 0.5
at a fixed total concentration of the gel of 700 mM (Tokita and Tanaka 1991a; Doi
and Tokita 2005b). The results are summarized in Fig. 10. The inset figure shows
the expanded view of the lower cross-linking density region, which is obtained in
earlier study. On the other hand, the results in the concentration region above 20%
are obtained in recent studies. The friction of the gel slightly decreases in the
cross-linking density region from 0.003 to 0.1 as seen in the inset figure. The
friction, however, decreases suddenly at the cross-linking density of about 0.2. The
friction becomes smaller more than four orders of magnitude above this
cross-linking density. The friction coefficient in this region is measured by the
simple method that is described in the Experimental section in this concentration
region. It is also found by the naked eye inspection that the gel gets opaque at the
higher regions of the cross-linking density. We also find that the opaque gel lost the
high elasticity and becomes brittle. In contrast, the gel becomes considerably sticky
as the concentration of the cross-linker is decreased to 0.002 at which the friction
decreases suddenly. The results suggest that the solution is close to the sol-gel
transition point. The sudden decrease of the friction coefficient at this concentration
may reflects that the system get closer to the sol-gel transition.
The appearance of the gel varies from transparent, translucent, and then to
opaque when the cross-linking density is increased. It suggests that the structure of
the polymer network becomes heterogeneous with the cross-linking density. The
phenomenon observed here is already reported so far, and the phase diagram and
the structure of the opaque gel have been discussed (Richards and Temple 1971;
Bansil and Gupta 1980). However, it is only recently that we obtain the information
on the real space structure of opaque gel. The recent advancement of the optical
microscope technology enables us to observe the structure of the inside of the
materials invasively by using the confocal laser scanning microscope (CLSM)
(Hirokawa et al. 1999). Therefore, we use the CLSM imaging to reveal the structure
of opaque poly(acrylamide) gel in real space. Such a real space structural analysis
of the gel yields that the opaque poly(acrylamide) gels consist of the aggregate of
spherical particles. The diameter of the particle grows up to about sub-micrometer
in diameter (Doi and Tokita 2005a, b).
The detailed real space structural analysis of the opaque gel suggests that the
spherical particles, which forms the aggregate, has almost the same density with
that of acrylamide and/or N,N′-methylenebisacryamide in the solid state. The results
strongly suggest that all reagents in feed are tightly polymerized into spherical
particles. The particles observed in the CLSM image of opaque gels are, therefore,
reasonably assumed to be a colloid particle of the hard sphere. As a result of this,
the opaque poly(acrylamide) gels do not contain the long chain molecule, which is
deformable under the flow of the gel fluid. The opaque gel is, therefore, simply
regarded as an aggregated colloidal gel rather than a percolated network gel.
It may be easily expected that the friction of a porous material is mainly gov-
erned by the largest pore in the system. The CLSM images of opaque gel indicate
that there are many large pores in the opaque gel that is represented by the darker
regions of the image. Water, therefore, mainly flows choosing the darker region,
which serves as an open space for water flow, avoiding the spherical particles that
behave as an obstacle for the flow. Since the size of darker regions are more than
few micrometers, water can flow in the gel easily. This is reason why the opaque
428 M. Tokita
gels show the smaller friction. Because the colloidal particle is found to be regarded
as a hard sphere, we expect that the friction of opaque gel can be explained in terms
of the hydrodynamic friction of obstacle that made of the spherical particles. It is
well established in the hydrodynamic theory that the resistance of the sphere against
the fluid flow, fobstacle , can be expressed by the Stokes law that is written as
fobstacle ¼ 6pgR where R represents the diameter of the particle. In opaque gel, the
friction of gel is simply regarded as the superposition of the friction of each particle
that consists the aggregate. Therefore, the friction of the gel is reasonably assumed
to be expressed as follows:
Here, N represents the number of the particle in a unit volume of the gel.
Fortunately, we can determine the parameter N by analyzing the CLSM image.
Because the colloidal particles are located in the brighter region in the CLSM
image. Hence, the total area of the brighter region in the CLSM image, r, is
proportional to the number of the particle in the observation volume. The number of
the particle in the observation volume can be calculated form r if the average radius
of the particle, R, is determined. Both the total area of the brighter region and the
average radius of the colloidal particle are easily determined by the image analyses
of the CLSM image. Then, the number of the particle in the observation volume is
calculated as, N ¼ r=pR2 . The result of the calculation of fobstacle is shown in the
Fig. 11 (Doi and Tokita 2005a, b).
Although the experimental values of friction are about twice of the calculated
values, the calculated values well reflect the experimental tendency of the con-
centration dependence. Since the model used here is crude, several reasons can be
considered for the discrepancy. One and the most conceivable reason of the dis-
crepancy may be follows. Generally, the microscope image is the projection of the
three-dimensional into the two-dimensional plane. The thickness of the observation
volume is usually determined by the performance of the microscope. In the case of
the CLSM imaging, the thickness is thinner than the simple optical microscopes,
which is the characteristic feature of the CLSM imaging. Even though the thickness
is thin, the observation volume of the CLSM image also have a definite thickness.
Therefore, this effect should be taking into account when we evaluate the friction of
gel from the analyzed results of the CLSM imaging. In our CLSM apparatus, the
thickness of the focal plane is about 1 m according to the manufacturer. On the
other hand, the radius of the spherical particle obtained by the analysis of the CLSM
images is the order of around 1 m. Taking into account this fact, the overlap of the
particles in two-dimensional image is unavoidable. The calculated value of the
number of the particle is obviously under estimated because of the overlapping. The
maximum number of the particles in the observation volume, however, does not
exceeds twice of the calculated value, which corresponds the case that the same
structure is hidden behind the observed image. We believe that the calculated
values of the friction are, therefore, within the expected maximum error. The results
obtained here indicate that the structural of the polymer network of poly(acry-
lamide) gel changes from the percolated network to the aggregated colloid particle
with the increase of cross-linking density.
When a system is brought near the phase transition point, many physical quantities
show the critical behaviors (Stanley 1971; Papon et al. 2002). It has been shown
that the spatial density fluctuation that emerges in the critical region is time
dependent and reversible against the temperature change. The distance over which
the density fluctuations correlates, n, diverges in the critical region that causes many
singular behaviors to the physical quantities. When the gel is brought near the
transition point, the polymer network is regarded as an assembly of the pores of the
typical size of about n. It is intuitively expected that the friction of the gel
diminishes and eventually disappears as the transition point is approached because
of the divergence of the correlation length. The gel fluid, therefore, can pass
through the gel without experiencing the frictional resistance of the polymer net-
work in the critical region.
The critical behaviors of the gel are studied extensively after the discovery of
thermos-reversible volume phase transition of poly(N-isopropylacrylamide) gel.
The critical behaviors of gel are studied using poly(N-isopropylacrylamide) gel in
detail and the results so far obtained indicate following behaviors in the critical
region of the gel (Hirokawa and Tanaka 1984; Tanaka et al. 1985).
430 M. Tokita
E!0 ð12Þ
Dc ¼ E=f ! 0 ð13Þ
The Eq. (12) indicates that the polymer network becomes infinitely compressible
in the critical region of the gel. Besides, the Eq. (13) indicates that the collective
motion of the polymer network slows down at the critical point. The critical
behaviors of E and Dc are observed and confirmed by experimental studies
extensively. The critical behavior of f is not clarified at these days. Although our
intuition strongly suggest that the friction of gel diminishes near the volume phase
transition point, such a critical behavior is not confirmed by above Eqs. (12) and
(13) because the Eq. (13) is sorely confirmed by the Eq. (12). The critical behavior
of f is indefinite only from these results. Therefore, the critical behavior of the
friction is one of the open question in the physics of the phase transition in gels, and
hence, it should be determined experimentally. This is the reason why we study the
friction of poly(N-isopropylacrylamide) gel.
The sample gel used here is free from the frozen-in density fluctuations and the
gel looks completely transparent at a temperature of 20 °C. As is shown in Fig. 12,
poly(N-isopropylacrylamide) gel shows the discrete volume change at about 33.6 °
C. The volume phase transition of poly(N-isopropylacrylamide) gel is believed to
be caused by the hydrophobic interaction between bulky side chains that promotes a
lower critical solution temperature. The swelling curve shown in Fig. 12 corre-
sponds to the isobaric behavior. In contrast the friction experiment is, in the case of
our apparatus, carried out under the constant volume conditions of V=V0 ¼ 1. Such
an experimental path is called as the isochoric conditions and is also shown in
Fig. 12.
When the gel is changed along the isochoric line, the gel may firstly bring into
the negative osmotic pressure region, and then, it proceeds into the coexistence
regime. Since the volume of the gel changes with the temperature, many effects,
which prevent the accurate determination of the friction, can be occur. Hence, the
swelling behaviors of the gel should be checked before friction experiments. This is
made on a gel that is prepared in the same gel mold for the friction experiments.
The open portion of the gel slightly swells at lower temperatures since the sample
gel is not clumped into the friction cell. It is confirmed that visible shrinkage of the
gel does not occur within the highest temperature of the friction experiment. It is
also find that the attachment between the gel and the gel bonding film remains intact
within the whole temperature range of the friction measurement. The decrease of
the linear size of monitor gel from that of the isochoric gel is found to be less than
10% even at the maximum temperature of our experiment. By these preliminary
experiments, we confirm that the swelling or shrinking of the gel do not affect the
frictional measurement in the present experimental conditions. A gel, which is
freely suspended in water, is soaked in the water bath for the friction measurement
to continuously monitor the swelling behavior of the gel. We find that the gel shows
a slight opacity near the temperature where the friction diminishes. The increase in
11 Transport in and Through Gel 431
the opaqueness may be due to the emergence of the dynamic density fluctuations.
The emergence of the fluctuations seems to be responsible for the decrease of the
gel-solvent friction.
The friction coefficient of poly(N-isopropylacrylamide) gel is measured as a
function of temperature, f ðT Þ. The friction coefficients thus obtained are normalized
by the viscosity of water, gðT Þ, that is taken from a table. The normalized friction
coefficient of poly(N-isopropylacrylamide) gel, f ðT Þ=gðT Þ, is plotted as a function
of the temperature in the lower figure of Fig. 12. It is clear that the friction of poly
(N-isopropylacrylamide) gel is independent of the temperature in the lower tem-
perature regions. The friction, however, abruptly decreases about three orders of
432 M. Tokita
magnitude around 33.6 °C, which is close to the volume phase transition temper-
ature of poly(N-isopropylacrylamide) gel. This drastic change of the friction is
entirely reversible. Since the viscosity of water does not show any singularity in the
temperature region of this friction experiments, the results primarily reflect the
temperature dependence of the frictional pore size in poly(N-isopropylacrylamide)
gel. It is found that the values of normalized friction of poly(N-iso-
propylacrylamide) gel in the lower temperature regions is almost the same with that
of poly(acrylamide) gel that is shown in Fig. 7. The results suggest strongly that the
frictional pore size of poly(N-isopropylacrylamide) gel and that of poly(acrylamide)
gel is almost the same with each other when the temperature is far below the
volume phase transition temperature of poly(N-isopropylacrylamide) gel. Since the
frictional pore size of poly(acrylamide) gel is determined by the distance between
the nearest neighbor contact points of polymers, that is the correlation length of the
polymer network n, in the case of poly(acrylamide) gel, it may be reasonably
concluded that the frictional pore size of poly(N-isopropylacrylamide) gel is also
governed by the correlation length of the polymer network of gel at the lower
temperature regions. When the temperature is raised near the phase transition point,
however, the polymer network undergoes substantial density fluctuations in time
and space. According to the dynamic density fluctuations, some portions of the gel
swell while the other portions shrink to maintain the constant volume of gel. The
effective pore size of such a fluctuated polymer network is determined by the
correlation length of the density fluctuations rather than the distance between the
nearest neighbor contact points of polymers. Water, thus, passes through the
swollen portion of the polymer network of the gel which serve as the open space for
water flow. On the other hand, the densely shrunken regions behave as the obstacles
for water flow. The pore size of the gel diverges when the gel is brought into the
two-phase region. One of the following two reasons are probably possible for the
divergence of the pore size of polymer network.
(1) The gel may remain in the metastable single phase as a superheated gel. The
fluctuations are dynamic and should diverge at the spinodal point in this case.
Such a metastable state of the gel is actually observed in the phase transition
point of many gels as the hysteresis in the swelling curve. Poly(N-iso-
propylacrylamide) gel is also the case. The temperature gap at a hysteresis can
become several degrees.
(2) The gel may undergo phase separation. The domains of swollen and shrunken
phases are created within the polymer network in this case. The density fluc-
tuations are static in this case. It, hence, would diverge near the coexistence
curve.
Unfortunately, it is difficult to decide which process occurs in the present study.
In each case, however, the effective pore size of the gel diverges, and hence, the
friction becomes smaller. Clearly, the pore structure is not fixed because the phase
transition is reversible. It is, thus, reversibly enlarged or reduced against the tem-
perature change near the phase transition point. Therefore, the friction of the gel
11 Transport in and Through Gel 433
changes reversibly against the temperature change. It is find that the friction of
thermos-sensitive gel shows the critical behavior of f ðT Þ ! 0 as the phase tran-
sition temperature is approached. The results obtained here indicate that the critical
behavior of the collective diffusion coefficient becomes indefinite since
Dc ¼ E=f ! 0=0. On the other hand, the behavior Dc ! 0 is actually observed
experimentally. The results obtained here, therefore, further suggest that the lon-
gitudinal elasticity of gel diminishes faster than the friction of gel as the critical
point is attained. As the volume phase transition is a universal behavior of the gel,
the reversible decrease of the gel-solvent friction is also universal phenomenon.
Under an optimal combination of solvent and temperature, the reversible decrease
of the gel-solvent friction should be observed in any gel.
2.1 Introduction
In the previous section, we have discussed about the transport of the gel fluid by the
macroscopic flow, which is caused by the mechanical pressure that is applied to the
gel fluid. In this section, we discuss another transport phenomenon that related with
the gel, namely, the diffusion of substances in the gel. When a substance molecule
is dissolved into the fluid, it moves in the fluid randomly due to the thermal
agitation of the surrounding fluid molecules. Such a random motion of the molecule
is studied in detail in the statistical physics. One of the characteristic parameter that
reflects the random motion of the substance molecule suspended in the fluid is the
diffusion coefficient of a molecule in attention. The diffusion coefficient of a sub-
stance, D0 , in a simple fluid of the viscosity, g, is written as follows (Einstein 1956):
kT
D0 ¼ ð14Þ
6pgR
Here, k, T, and R are the Boltzmann’s constant, the temperature, and the radius
of the substance, respectively. Equation (14) is called as the Stokes-Einstein
equation for the diffusion coefficient. The Stokes–Einstein relation for the diffusion
coefficient indicates that the diffusion of a substance is uniquely determined by the
temperature of the system, the characteristics of the fluid, and the size of the
substance. However, the diffusional motion of the substance is altered when it is
introduced into the gel. Since the polymer network coexists in the system, the
substance experiences the additional resistance from the polymer network of the gel
(Muhr and Blanshard 1982; Park et al. 1990; Gibbs and Johnson 1991). The
resistance of the polymer network is caused by the interactions between the sub-
stance and the polymer network. The interaction that causes the resistance on the
motion of the substance can be classified into four classes in the case of hydrogel
and the substance systems as follows:
434 M. Tokita
2.2 Experimental
simplicity because the circumstances around the substance is searched from the
diffusive motion of the substance molecules.
The spectrum of the probe molecules is required to be observed separately in the
high-resolution spectrum of entire system when the diffusion coefficient is deter-
mined by PFG-NMR method. In the case of high-resolution NMR measurements,
the motional narrowing conditions are required to obtain the spectrum. This con-
dition is generally satisfied in the simple solution of substances. We have made the
preliminary experiments before the measurements of the diffusion coefficient of the
probe molecules. The high-resolution NMR spectra of the gel-probe molecule
systems are gained. It is found the probe molecules are observable in the NMR
spectrum of gel-probe molecule systems. It indicates that the motional narrowing
conditions are also satisfied in our system of poly(acrylamide) gel and the
water-soluble probe molecules. It further suggests strongly that the microscopic
motion of the probe molecule is rather fast even they are introduced into the gel. In
contrast, high-resolution NMR spectrum of acrylamide segment is not observed in
the NMR spectrum at a frequency of 60 MHz in proton resonance. It indicates that
the collective motion of the polymer network is much slower than the motion of the
probe molecules as is expected from the collective diffusion coefficient of gel. The
results coincide with the THB theory. The results also indicate that the interaction
of the gel and the probe molecules is not very strong in the present system. The
polymer network of gel, therefore, can be regarded as a fixed obstacle for the
diffusive motions of the probe molecules under the present experimental conditions.
Finally, the diffusion coefficient of the probe molecules can be determined by
PFG-NMR.
In this study, five substances with different molecular weights are chosen from
highly water-soluble non-ionic molecules as the probe molecules, namely, water
(solvent), ethanol, glycerin, poly(ethylene glycol), and sucrose, and the gel used in
this study is poly(acrylamide) gel. The molecular weights of these probe molecules
are, 18, 46, 92, 200, and 342, respectively. The sample gel of poly(acrylamide) is
polymerized in an NMR tube of 10 mm in diameter. First of all, water and the
heavy water is mixed at a ratio of 9:1. Then, the predetermined amount of the probe
molecule is dissolved in this mixture of water and the heavy water. The concen-
tration of the probe molecule is fixed at 10 wt%. Then, the calculated amount of the
reagents, acrylamide, N,N′-methylenebisacrylamide, and ammonium persulfate
(initiator), are dissolved into water that contains the probe molecule. The pre-gel
solution thus obtained is de-gassed for 20 min, and then, the reaction is initiated by
heating the pre-gel solution at a temperature to 60 °C for 1 h. The total concen-
tration of the gel is charged from 2 to 50 g/100 ml under a constant concentration
of the cross-linker at 2 mol%.
The diffusion coefficients of probe molecules are determined by a JEOL FX-60Q
spectrometer (60 MHz, JEOL, Japan). The field gradient component NMPL-502
(JEOL, Japan) is also equipped to the spectrometer. The temperature is fixed at
30.0 ± 0.5 °C. Details of the experimental procedure have been reported
previously.
436 M. Tokita
The diffusion coefficients of all probe molecules are measured in the gels having
various concentrations, and then plotted in Fig. 13. First of all, it is clearly seen
from this figure that the diffusion coefficients of the probe molecules decrease upon
increasing the concentration of the gel, Ctotal gradually and monotonously. The
diffusion coefficient of water molecule in the gel, for instance, becomes about 40%
of that in the simple solution in the highest concentration of the gel, Ctotal ¼ 50 g/
100 ml. The similar tendency is observed in all probe molecules studied here.
Secondly, the diffusion coefficients of the probe molecules also decrease as the
molecular weight of the probe molecule is increased. These results indicate that the
resistance due to the polymer network of the gel against the diffusional motion of
the probe molecule is not very strong, and is a smooth function of the total con-
centration of the gel. In other words, the interactions that exist between the polymer
network and probe molecules are rather weak. These results are what we expected
when choosing the present system of poly(acrylamide) gel and the water-soluble
non-ionic probe molecules. The diffusion coefficient of the probe molecules does
not show any singular behaviors in poly(acrylamide) gel.
The diffusion coefficient of the probe molecule is essentially determined by the
ratio of the thermal fluctuation and the hydrodynamic friction applied to the probe
molecule, Eq. (14). Since the probe molecules used here are rather compact, it is
natural to assume that the radius of the probe molecule increases with the molecular
weight. Thus, the diffusion coefficient decreases with the molecular weight of the
probe molecule. This is quite simple view of diffusion in the simple fluid. When the
probe molecules are introduced into the gel, however, the probe molecules are
enforced to move through the mesh of the polymer network. The resistance due to
the polymer network increases when the concentration of gel is increased. This is
because the size of the maze created by the polymer network becomes narrower
when the concentration of gel is increased. The diffusion coefficient of the probe
molecule, thus, decreases as the concentration of the gel is increased. It is easily
expected, however, whenever the size of the probe molecule is small it can diffuse
in the gel rather easily. In contrast, the diffusion of larger probe molecule is con-
siderably decreased when the concentration of gel is increased. However, the larger
probe molecule also can diffuse rather easily in the gel when the mesh size of the
polymer network of is large enough than the size of the probe molecule. This is the
idea of the scaling. Namely, it may be of useful to discuss the diffusion result in
terms of the normalized values by the diffusion coefficient of probe molecules in
simple fluid of water, D=D0 , rather than the law values of the diffusion coefficients
in the gel to deduce the physical picture of the diffusion phenomenon in the gel. It is
worth noting here that such a simple scaling idea is only applicable to the system
that the series of the probe molecules studied interact with the polymer network of
gel through the same interaction. We, therefore, assume that the normalized dif-
fusion coefficient of the probe molecules, D=D0 , is the relevant parameter to discuss
the diffusion of probe molecules in the gel.
11 Transport in and Through Gel 437
Fig. 13 The total concentration dependence of the diffusion coefficient of the probe molecules.
The probe molecule is, water, ethanol, glycerin, poly(ethylene glycol), and sucrose, from top to
bottom. The data points shown at the zero concentration of the horizontal axis represent the
diffusion coefficient of probe molecules in the solution that is obtained by the same experimental
setup
It has been clarified eventually that many physical quantities of the polymer
systems follow the scaling law (De Gennes 1979). The gel is also a system where
the idea of the scaling law plays important roles. We, therefore, expect that the
scaling law is capable of describing the probe diffusion in the gel as intuitively
explained in the previous section. The scaling suggests that the normalized diffusion
coefficient of the probe molecule, D=D0 , is expressed by a non-dimensional uni-
versal function, f ð xÞ.
D ð xÞ
¼ f ð xÞ ð15Þ
D0
Here, the scaling variable x is written by the concentration of the gel and the size
of the probe molecule as x ¼ xðCtotal ; RÞ. The scaling variable itself should be a
non-dimensional parameter though it is a function of Ctotal and R. Taking into
account the previous intuitive discussion, an appropriate the scaling variable in this
system is the ratio of two length scales of the problem, x ¼ R=n, where R and n are
the radius of the probe molecule and the correlation length of the polymer network
of the gel, respectively. The probe molecules studied here is compact that is chosen
from the hydrophilic non-ionic substances. We, therefore, expect that the radius of
the probe molecule R is written as follows by using the molecular weight of probe
molecules, M, as follows:
438 M. Tokita
R / M 1=3 ð16Þ
3=4
On the other hand, the correlation length of the gel, n, is written as, n / Ctotal ,
which is already given as Eq. (9). The combination of the Eqs. (9) and (16) yields
that the scaling variable, x ¼ R=n, is expressed as follows:
R 3=4
x¼ / M 1=3 Ctotal ð17Þ
n
The scaling function thus obtained here is similar with the one expected for the
semi-dilute solutions (Langevin and Rondelez 1978; Cukier 1984).
Fig. 14 The diffusion coefficient of the probe molecules in the gel are normalized by its diffusion
coefficient in water, D=D0 , and plotted as a function of the scaling variable, x, in a
semi-logarithmic manner. The straight line is the result of the least-squares analysis
11 Transport in and Through Gel 439
The results obtained here indicates that the diffusion coefficient of a substance in
the gel becomes smaller than that in a simple fluid. The rate of the decrease in the
diffusion coefficient is, however, determined only by a parameter x ¼ R=n, that is,
the ratio of the radius of the probe molecule and the correlation length of the gel.
Although the size of the probe molecule is increased, the relative diffusion coeffi-
cient of the probe molecule, D=D0 , becomes the same if one change the value R=n
becomes the same. These conditions are usually realized by decreasing the con-
centration of the gel. The results of the scaling are schematically illustrated in
Fig. 15.
3 Concluding Remarks
The transport phenomena that is related to the gel are reviewed. The frictional
properties of the gels, poly(acrylamide) gel and poly(N-isoprpylacrylamide) gel, are
described and many features that characterizes the state of the gel are clarified. We
find that why the frictional properties of the gel play important roles in the
dynamics of the swelling and shrinking of the gel. The friction of the gel also plays
the essential roles in the pattern formation of gel and the large deformation pro-
cesses of the (Tanaka et al. 1987; Matsuo and Tanaka 1992; Tokita et al. 1999,
2000; Nakamura et al. 2001). The information on the frictional property of gel is,
therefore, of useful in many applications such as the medicine, food, chemical
engineering, and biotechnology.
The knowledge gained so far is, however, still limited. For instance, we do not
have any information on the numerical constant of Eq. (7). In the case of
well-defined flow of the fluid, the equation can be written definitively including the
numerical constant. The Hagen–Poiseuille law for the capillary flow, which is used
Fig. 15 The schematic illustration of the scaling results. The smaller probe molecule in the dense
gel (left) and the larger probe molecule in the tenuous gel (right). The relative size of the probe
molecule and the mesh size of the gel are similar in both cases. The relative rate of the diffusion is
similar in these two conditions
440 M. Tokita
in determining the viscosity of the fluid, is such a case. In many literatures of the
hydrodynamics, the Hagen-Poiseuille law is expressed as follows:
P 8g
¼ v ¼ fv
L r2
Here, P=L, r, g, and v are the pressure gradient in a capillary of length L, the
radius of the capillary, the viscosity of the fluid, and the velocity of the flowing fluid
in the capillary. The friction of the capillary of the radius r is, therefore, written as
follows.
8g
f ¼
r2
The above equation agrees with the Eq. (7) since the radius is the typical length
scale that describes the cylindrical capillary. Furthermore, the proportional constant
is exactly written in the case of the Hagen–Poiseuille flow, which is a numerical
constant of 8. Therefore, Eq. (7) should generally be written as follows:
g
f ¼ Qshape
n2
The constant, Qshape , is determined by the structure of the pore, and hence it may
be regarded as the structure factor of porous material. Clearly, Qshape ¼ 8 in the case
of Hagen–Poiseuille flow in a capillary of rod shape. If we can determine the
structure factor of the porous material experimentally and/or theoretically, it will be
possible to design a material with the desired frictional properties. Recently, the
frictional property of a well-defined polymer network of the gel is studied in detail
(Fujiki et al. 2016). The continuous accumulation of such information will promote
the better understanding of the frictional properties of the gel.
The experimental results on the friction of the gel and diffusion within the gel are
mostly discussed in terms of the scaling theory in this review. Therefore, it is worth
noting here about another scaling analysis of the total concentration dependence of
the friction coefficient that is given in Eq. (8). It is shown that the Eq. (8) can be
explained by assuming the scaling law for the correlation length, Eq. (9). However,
Eq. (8) is also explainable in terms of the scaling results of the longitudinal
modulus, E, and the collective diffusion coefficient of the gel, Dc . Both the scaling
form of the longitudinal modulus of the gel and the collective diffusion coefficient
of the gel are given as follows.
9=4
E / Ctotal
3=4
Dc / Ctotal
Substitution of these equations into Eq. (1) yields the following result:
11 Transport in and Through Gel 441
E 6=4
f ¼ / Ctotal
Dc
The scaling of the longitudinal modulus and the collective diffusion coefficient
also well describe the experimental results on the friction of the gel. Above result is
the experimental confirmation of the relationship between the collective diffusion
coefficient of the gel, the elastic modulus of the gel, and the friction coefficient of
the gel, that is the Eq. (1). This is a complete confirmation of the THB theory.
The relationship between phase transition and the frictional property is another
topic to be studied in future. The friction coefficient of poly(N-isopropylacrylamide)
gel disappears at the volume phase transition point of the gel due to the critical
slowing down. The critical slowing down is a universal behavior that is observed in
the system near the phase transition point. Since the critical behavior of the friction
is also believed to be a universal phenomenon in the gel, we are interested in the
critical transport in the biopolymer gel systems. Recently, we find similar phe-
nomena in the biopolymer gel systems that the gel becomes opaque by the frozen-in
density fluctuation due to the phase separation of the system. In such systems, the
gelation and the phase separation occur simultaneously (Morita et al. 2013;
Yamashita et al. 2014). The frictional properties of such heterogeneous biopolymer
gels will contribute to the understanding of the biological transport phenomena.
The probe diffusion in the gel also requires the further detailed studies. We only
described on the system of the hydrophilic gel and the hydrophilic probe molecules
here. Since this system is an idealized system, we obtain a quite simple scaling
results for the probe diffusion phenomena. There are, however, many candidates for
the probe molecules that have many chemical structures, and hence, it interacts with
the polymer network of the gel in various way. Various diffusional behaviors of the
probe molecules can be observed by the carefully designed studies of the diffusion
in the gel. The classification of such diffusion results in terms of the four funda-
mental interactions in water will be of importance in designing the separation
systems and the studying the biological transport phenomena. It is reported recently
that the Liesegang pattern is formed in the one-dimensional diffusion-reaction
system. In such a system, the gelation and the phase separation is coupled, and
hence, it suggests strongly that the diffusion of the substances plays the essential
roles in pattern formation in the gel (Narita and Tokita 2006, 2010). Further detailed
study of the transport phenomena in the gel is, therefore, clearly required not only
for the applications but also for the better understanding of the physics of the gel
because the gel is a universal state of matter.
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Chapter 12
Incorporation of Filler/Additives
in Polymer Gel for Advanced
Application
Abstract This chapter is aimed to review the literature concerning the filler and
additive effect on polymer gel for various advanced applications including food,
agriculture, pharmaceutical, and others. To date, polymer gel utilization is impor-
tant due to its superior properties. Moreover, polymer gel is very responsiveness
toward small environmental changes and significantly altered the gel behavior.
Currently, incorporation of filler into polymer gel matrices is beneficial to enhance
the characteristics of the gel such as mechanical, chemical, physical, and biological
properties. Metallic compound, cellulosic material, and crosslinker are the various
categories of filler that broadly used based on application and processing.
Therefore, filler-loaded polymer gel could be a potential tool or vehicle for different
advanced applications.
Keywords Polymer gel Filler Metallic compound Cellulosic material
Crosslinker Advanced application
1 Introduction
Polymer gel, in general term, often designates as soft and wet material (Osada
and Gong 1998). In specific definition, a polymer gel is a solid structure that
composed of at least two components. One component which is polymer forms a
1.2 Filler/Additive
1.3 Composite
When two or more materials are combined and created a new mixed material, it is
described as a composite material (Thakur and Kessler 2014, 2015). This material
could improve the material’s characteristics and properties compared to those of the
individual materials used alone (Affatato et al. 2015; Bernardo et al. 2016; Cevallos
et al. 2016; Guilherme et al. 2015). The general structure of these biomaterial
composites is divided into two main structures:
1. “Matrix” which always in the form of continuous phase.
2. “Reinforcement” which could be in the form of continuous or discontinuous
In polymer composite, various polymer applications have been explored due to
their availability in various forms, properties, and compositions that allow the
fabrication of different shapes and structures (Thakur et al. 2013a, b). Polymer
composite material could provide significant impact on the final element such as
2.1 Carrageenan
The Ɩ- (iota-), қ- (kappa), and k- (lambda) carrageenan are the most fundamental
commercial carrageenan (Steinbuchel and Rhee 2005) which consists of many
naturally occurring arrangements of components that will manipulate gel strength,
texture, solubility, synergisms, and melting temperature of the carrageenan (Imeson
1997). These three types of carrageenan differ essentially in their degree of
sulphation (Necas and Bartosikova 2013; Williams and Philips 2000). Typical
k- carrageenan contains sulfate (22% w/w), i-carrageenan (32% w/w), and
450 I. I. Muhamad et al.
The gelling and thickening behavior of Ɩ-, қ-, and k-carrageenan is different. Table 2
briefly describes the properties of Ɩ-, қ-, and k- carrageenan:
(b)
(c)
12 Incorporation of Filler/Additives in Polymer Gel … 451
Fig. 3 Illustrative image for application of carrageenan in food industries (Prajapati et al. 2014)
2.2 Alginate
Various algae species were used in the alginate production that involves extraction
of polysaccharide. Naturally, it consists of b-D-mannuronic and a-L-guluronic acids
and structure sequential distribution arrangement could be either in blockwise
fashion as homopolymer blocks (MM, GG) or alternating blocks of M and G with
different M/G ratios as illustrated in Fig. 4 (Burgain et al. 2011; Dragan 2014). It is
widely available in the market molecular weights from tens to hundreds of kilo
Daltons (Cook et al. 2012).
The advantages of using alginate for producing hydrogel are because of its
simplicity, GRAS (generally recognized as safe) status, non-toxicity, biocompati-
bility, and low cost (Krasaekoopt et al. 2003; Burgain et al. 2011; Cook et al. 2012).
However, several aspects could be considered such as the process is difficult to
scale-up and the hydrogel is very porous. Different approaches have been per-
formed previously in reducing the porous effect such as mixing or coating the
alginate hydrogel with other polymer compounds or incorporate different additives
to modify the alginate structure (Burgain et al. 2011; Krasaekoopt et al. 2003). This
characteristic allows alginate to be widely applied in agriculture, food, and phar-
maceutical industries (Dragan 2014).
In the alginate transformation, the presence of divalent ions such as Ca2+ is
crucial to bind to guluronic residues and subsequently crosslinking the alginate
structure. This is due to negative charge present in the alginate which attributed to
the structure of carboxylic acid groups (Cook et al. 2012; Dragan 2014). The size of
alginate hydrogel formed depends on the methodology used in producing the
hydrogel. For example, the hydrogel size approximately of ten microns could be
produced using spray technology; however, the extrusion method produces up to
millimeter size of hydrogel (Cook et al. 2012).
Polyvinyl alcohol is a non-ionic synthetic polymer that has the linear formula [–
CH2CHOH–]n (Fig. 5). It is derived from polyvinyl acetate through partial or full
hydroxylation to remove acetate group. PVA is non-toxic, odorless, and
water-soluble that has a melting point of 230 °C (for fully hydrolyzed grade) and
180–190 °C (partially hydrolyzed grade). The degree of hydroxylation can influ-
ence the chemical, physical, and mechanical properties of the PVA (Baker et al.
2012). The higher the degree of hydroxylation and polymerization of the PVA, the
lower the solubility in water and the more difficult it is to crystallize (Jones 1973).
At high temperature above 200 °C, PVA decomposes rapidly as it can undergo
pyrolysis within that temperature range.
PVA has outstanding properties in terms of film-forming, emulsifying, and
adhesiveness. Because of its properties which is highly soluble, some modifications
have been done by addition of filler/additives such as crosslinker for use in several
applications. It provides the structural stability of the hydrogel during swelling in
the presence of water or biological fluids. Over the years, there are various appli-
cations of PVA-based polymer gel that has been developed.
For instance, phosphorylated PVA can be used for the immobilization of bac-
terial and yeast cells or activated for bioremediation and water filtration systems
(Myoga et al. 1991; Wise 2000). In his finding, a PVA that in is spherical-bead
form was produced by crosslinked with saturated boric acid solution. The reaction
time was minimized to reduce the damage to the immobilized microorganisms. It
was then followed by esterification of the PVA with phosphate to harden it. Other
researcher also reported the development of PVA-based gel polymer composite by
mixing it with other polymer such as alginate (Dave and Madamwar 2006;
Vogelsang et al. 1997). The addition of alginate in PVA was expected to give
functional stability of temperature-compensated polymer and also change the poor
gas permeability of PVA gels (Jegal and Lee 1996). Different concentrations of
dimethyl sulfoxide (DMSO) aqueous solutions are dissolved in PVA to obtain 16.7
2.4 Chitosan
The pKa value of the equation is approximately 6.3. Chitosan solubilizes when
more than 50% of the amino groups are protonated (Rinaudo 1999), so the solu-
bility of most chitosan preparations decreases sharply at the solution pH rises above
456 I. I. Muhamad et al.
6.0–6.5. Many uses of chitosan are based on its positive charge, which is attracted
to negatively charged materials. Chitosan is inexpensive, biodegradable, biocom-
patible (Koide 1998; Shahidi et al. 1999), as a hydrating agent in cosmetics, and
more recently as a pharmaceutical agent in biomedicine (Dodane and Vilivalam
1998; Illum 2003; Khor and Lim 2003). Furthermore, it provides films with good
mechanical and oxygen barrier properties (Chen et al. 1996; Caner et al. 1998;
Sangsuwan et al. 2008). The functional properties of chitosan films are improved
when chitosan is combined with other film-forming materials (Xu et al. 2005).
Chitosan is a polycationic polymer with a specific structure and properties. It
contains more than 5000 glucosamine units and is obtained commercially from
shrimp and crab shell chitin (a N-acetylglucosamine polymer) by alkaline deacety-
lation 2–4 (NaOH, 40–50%) (Fig. 7). Recent advances in fermentation technology
Fig. 7 Preparation of
chitosan from chitin (Rabea
et al. 2003)
12 Incorporation of Filler/Additives in Polymer Gel … 457
suggest that the cultivation of fungi (Aspergillus niger) can provide an alternative
source of chitosan (Rabea et al. 2003).
2.5 Starch
Starch is originated from variety of crops such as potato, wheat, rice, and corn. The
source is abundant and readily available at low cost (Chang et al. 2010). Starches in
chemical term are known as polysaccharides. It consists of a number of
monosaccharides or glucose molecules joined together with a -D-(1–4) and/or a -D-
(1–6) linkages. Main structural components of the starch include amylose and
amylopectin (Tester et al. 2004).
Figure 8 shows the structure of starch. However, the relative amount of these
components is varied as a function of the starch source (e.g., corn, potato, tapioca,
and wheat) and affects the molecular order and crystallinity of the polysaccharide
(Ellis et al. 1998). Amylose is linear or slightly branched, while amylopectin is
highly branched. About 70% of the mass of starch granule is considered as
amorphous and about 30% as crystalline and less than 1% lipids and protein from
Fig. 8 Structure of amylopectin and amylose in starch. Adapted from Lu et al. (2009)
458 I. I. Muhamad et al.
plant (Zhai et al. 2003). Starch can be converted into gel in a thermally three-step
assisted, hydration–plasticization of the polymeric network (Ismail et al. 2013).
Initially, adsorption of water in hydrophilic starch granules makes it swell.
Next, gelatinization process will occur after starch is dissolved by heating,
resulting in leaching of the amylose component, irreversible physical changes, and
the destruction of the granule structure. Finally, retrogradation step will continue
where the starch hydrogel network is created upon cooling and aging, resulting in
partial recrystallization and reorganization of the polysaccharide structure. Here, the
amount of amylase and gelatinization temperature are the two main process
parameters affecting the gel formation (White et al. 2008; García-González et al.
2011).
Synthesis of hydrogel is achievable via various pathways. There are also studies
that have been conducted on hydrogel synthesis. Preparation of the
polysaccharide-based hydrogels via reaction can be classified into two main groups:
(1) graft copolymerization of vinyl monomers on polysaccharide in the presence of
a crosslinker and (2) direct crosslinking of polysaccharide. For example, previous
study reported the preparation of starch-based hydrogel through graft copolymer-
ization of acrylic acid onto maize starch (Athawale and Lele 1998).
As different from graft copolymerization, direct crosslinking of polysaccharides
uses polyfunctional compounds (e.g., glycerol, glyoxal, and epichlorohydrin) or
polyvinyl compounds (e.g., divinyl sulphone, DVS) (Zohuriaan-Mehr and Kabiri
2008). An example for direct crosslinking was reported by Demitri et al. (2008)
where the preparation of superabsorbent hydrogels is derived from cellulose and
crosslinked with citric acid (CA). (Demitri et al. 2008)
a limited condition such as when not enough carbon sources, change of pH (Zahan
et al. 2014), or when the bacterial cellulose fills the disks in fermentation using
rotary disk reactor (Pa’e et al. 2011).
Bacterial cellulose pellicle is extremely hydrophilic, absorbing 60–700 times its
weight in water. The nanofibers present in a structure of multiple cellulose layers in
bacterial cellulose which is capable to hold an extensive amount of liquid between the
fibrous layers to form a hydrogel (Gao et al. 2016). Wood or cotton must be physi-
cally disintegrated to make them hydrophilic (Brown 1991), compromising strength in
the process. Since bacterial cellulose is formed in a hydrophilic matrix and needs no
treatment, it will retain its long fibrils and exceptional strength. These properties open
the doors to new applications in aqueous systems, such as exchanging chemicals and
dyes with the water while retaining the native form and properties of the pellicle.
Modification of bacterial cellulose had been done to enhance properties of native
BC and impart some additional properties for certain specific application.
Microfibrils of BC become denser with time and produce a web-shaped structure
(Horii et al. 1997; Tang et al. 2010) that can trap various materials added to the
medium (Ul-Islam et al. 2012). The encaged materials become part of the bacterial
cellulose fibril network, resulting in bacterial cellulose composites (Buyanov et al.
2010; Wang et al. 2010; Shi et al. 2014). A variety of additives materials had been
used as a filler resulted in the development of many new composites materials
design for application in different fields. By adding certain substrates as filler, it is
possible to change the properties of the cellulose.
In polymer technology, there are fundamentally two main filler classes, either
extracted or fabricated. Minerals such as clays and talc (Al2O3, 2SiO2, and 2H2O)
are grinded, extracted, and probably treated and thus categorized in the first class.
Calcite (CaCO3) on the other hand fits both classes, as it can be either extracted and
12 Incorporation of Filler/Additives in Polymer Gel … 461
plant pathogens (Cioffi et al. 2004; Park et al. 2006). For advance biomedical
application, Ag-NPs are incorporated into pH-responsive hydrogels with the
enzyme glucose oxidase function as glucose concentration sensors (Endo et al.
2008). In other findings, electrical-conducting hydrogel was also been developed by
incorporating metal into hydrogel. It highlights the important relation between
initial precursor Ag+ ions concentration and swelling ratio of the hydrogel that has a
direct impact toward conductivity of the hydrogel. Better conductivity reached
when a higher concentration of Ag+ ions added with reduced swelling ratios, and
vice versa (Saravanan et al. 2007). In muscle-like application, a soft magnetic
field-driven actuators for muscle-like was prepared by incorporation of magnetic
NPs of cobalt (Co) or nickel (Ni) (Fuhrer et al. 2009). Magnesium oxide has been
incorporated into carrageenan-based hydrogel to control the delivery of drug
(Hezaveh and Muhamad 2012a, b).
Secondary Wall S1
Amorphous region
mainly consisting of Primary Wall
lignin and
hemicellulose
Disorderly arranged
crystalline cellulose
microfiber networks
Fig. 12 Structure and contents of biofiber (John and Thomas 2008)
low-cost preparation and high cellulose production (Xie et al. 2013). It also pro-
duces high purity of cellulose content that can be used as biomaterial filler for
medical field, electrical instrument, and food ingredient (Backdahl et al. 2008; Chin
et al. 2014). Basically, cellulose from plant derivation except cellulose bacteria can
exist as macro- or nanoscale form. Both can be used as reinforcement in composite
materials because of enhanced mechanical, thermal, and biodegradation properties
of composites that will be explained in next subchapters.
Various definitions of these nanofibers are often referred in previous and current
works which include “nanowhiskers” (or just simply “whiskers”), “nanocrystals”,
or even “monocrystals”. Regardless of their nanoscale dimensions, these crystallites
have also often been referred to in literature as “microfibrils”, “microcrystals”, or
“microcrystallites”. “Whiskers” is a term that is used to designate elongated crys-
talline rod-like nanoparticles (Abdul Khalil et al. 2012). The diameters of whisker
range from 2 to 20 nm and their lengths can reach several tens of microns
depending on its sources.
Understanding the structural hierarchy of cellulose is crucial. It enables the
production of finer individualized cellulose in finer form (nanoscale) with high
crystallinity (Siqueira et al. 2010). Previous study shows that the crystalline parts
such as in whiskers, also known as nanocrystal, nanorods, or rod-like cellulose
microcrystal or cellulose crystal can be isolated by several treatments. Cellulose
nanofiber in the form of nanofibrils or whiskers is produced by hydrolyzing
plant-based fiber with sulfuric acid and through other chemical and physical pro-
cess. Cellulose whiskers have become an utmost interest as a source of nanometer
size filler because of its great mechanical properties.
It started two decades ago when cellulosic nanofibers were studied as a rein-
forcing phase in nanocomposites (Dufresne 2012; Eichhorn et al. 2010).
High-crystalline cellulose nanofibers, which abundantly present in natural plant
bodies, naturally have unique properties and sizes. These scientists believe that
cellulose nanofibers can potentially be used as transparent and very strong
composite/nanocomposite in many different areas. This could lead to environ-
mentally compatible and high-performance polymer gel components
12 Incorporation of Filler/Additives in Polymer Gel … 465
3.2.4 Lignocellulose
Within the agricultural and forestry sectors, large amount of lignocellulosics were
produced as it became most abundant and inexhaustible or renewable natural
resource. Furthermore, Kuhad et al. (2007) also stated that this potential “waste” is
burnt, instead of producing beneficial products, which can cause the pollution of the
environment. They elaborated that, however, many processes involving lignocel-
luloses biotechnology have received numerous attentions from researchers and have
encouraged its improvement over the past few years.
Many advantages could be obtained by using natural fibers as they are
eco-friendly, grown abundantly, and have a high stiffness level and great thermal
stability (Laksono et al. 2014). Some of the characteristics of lignocellulosic fibers
include high length–thickness relation and low density which makes them easily
biodegradable and as a cheap resource, respectively (Mulinari et al. 2010; Silva
et al. 2012). These fibers generally have a high hygroscopicity and moisture
adsorption properties (Mulinari et al. 2010). Consequently, high interest in reuti-
lizing these by-products in various applications was shown. Proven studies of its
various applications have been previously conducted such as in animal feed, bio-
transformation, bioremediation, production of chemical, stabilization of food and
beverages, fillers, paper manufacture, furniture, architectural materials, and auto-
motive sector (Kuhad et al. 2007; Mulinari et al. 2010; Shaharuddin et al. 2014a).
In general, cellulose is the main structure of a lignocellulosic by-product fol-
lowed by hemicelluloses, cellulose, and lignin (Fig. 14) (Musatto and Teixeira
2010). According to Sun and Cheng (2002), the fraction of these three major
components varies depending on the type of lignocellulosic in which cellulose,
hemicelluloses, and lignin were ranged from 35–50%, 20–35%, and 10–25%,
466 I. I. Muhamad et al.
Lignin
Hemicellulose
Cellulose
Fig. 14 The general structure of lignocellulosic residues comprises cellulose, hemicellulose, and
lignin (adapted from Musatto and Teixeira 2010)
respectively. The remaining factions were completed by proteins, essential oils, and
ash. Non-covalent crosslinkages are their binders as they were strongly bonded
(Kuhad et al. 2007). The macromolecules of hemicelluloses and cellulose were
fabricated from different sugars. In addition, lignin is known as an aromatic
polymer and formed from phenylpropanoid precursors.
3.3 Crosslinker
Fig. 15 Schematic diagram of polymeric chain before and after crosslinks (Mendes et al. 2012)
12 Incorporation of Filler/Additives in Polymer Gel … 467
3.3.1 Genipin
Genipin (Fig. 18) is a non-toxic and natural crosslinker. It is obtained from its
parent compound, geniposide, via enzymatic hydrolysis with b-glucosidase.
Geniposide is isolated from the fruits of Gardenia jasmindides Ellis and Genipa
Americana and it composes about 4–6% of dried fruits (Cui et al. 2014; Butler et al.
2003). Gardenia is an evergreen shrub native to southeastern China. Although it has
been adapted to gardens around the world, it prefers warm, humid weather.
Gardenia grows up to ten feet tall and produces white flowers in the spring. Genipin
has been broadly used in herbal medicine including for diuretic, laxative, choleretic,
and hemostatic in the treatment of traumatosis by external application. Genipin
itself is colorless. It will form blue pigment when it reacts with amino acid (Butler
et al. 2003; Mi et al. 2001). The edible blue pigments are currently being used as a
blue food colorant in East Asia. Genipin’s naturally occurring properties and
biodegradable material with low cytotoxicity have recently been investigated as a
crosslinking material in many applications especially in pharmaceutical industry
such as bioadhesive, wound dressing, bone substitutes, and drug delivery system.
The characteristics of genipin are shown in Table 3, and Fig. 19 shows the
mechanisms of genipin crosslinking.
3.3.2 Glutaraldehyde
4.1 Agriculture
There have been rising concerns on the usage of antibiotic residues as they may
affect the meat products to the point of being harmful for human consumption
(Nousiainen et al. 2004; Riddell et al. 2010). Therefore, alternative applications
have been considered to decrease the use of antibiotic, and consequently, the
introduction of probiotic is one of them. Beneficial additive of these probiotics into
the animal feed could provide improvement in health and growth of animal (Fuller
1989; Shaharuddin et al. 2014b).
Seo et al. (2010) stated that many researchers were previously interested in
direct-fed microbial (DFM) using probiotic as one of the methodologies in animal
feeding. The base of DFM is the presence of probiotic and has been defined as
“microbial-based feed additive”. It was explained by Seo et al. (2010) that the
maintenance of probiotics viability is an important aspect of DFM in order to ensure
the maximum delivery of its benefits to host health or growth. They also elaborated
on the fact that the dosages of probiotics, timing, strains of DFM, and animal
condition are some of the other factors which contribute to the efficiency of DFM.
Many studies on direct-fed microbial in animal feeding have been performed over
the years (Wallace and Newbold 1993; Keady and Steen 1996; Malik and Sharma
1998; Khuntia and Chaudhary 2002). However, the efficiency of DFM was low due
to adverse environments during processing, storage, and in a gastrointestinal
system.
One alternative approach in addressing this issue is the introduction of immo-
bilization and microencapsulation technology using hydrogel in animal feed. In
animal feed industry, immobilization technique has been used extensively which
offers better protection for the probiotic in their survival and could be delivered at
the desirable target (Nimrat et al. 2011; Rosas-Ledesma et al. 2012; Ross et al.
2008; Soto et al. 2011; Voo et al. 2011; Woraharn et al. 2010).
In practice, the probiotic hydrogel would be incorporated into pelleted animal
feeds as the pellet was used in most animal feeding for easier and better feeding and
distribution (Chitprasert et al. 2012; Shaharuddin and Muhamad 2015). However,
major stress may be suffered by probiotic from the heat exposure during pelleting
and storage that could decrease its viability (De Angelis et al. 2006). The
heat-sensitive probiotic could not withstand the high stress from high temperature
and caused low viability after the pelleting process (Kosin and Rakshit 2010; Seo
et al. 2010). The incorporation of reinforcement (filler) in a matrix would enhance
the thermotolerance of probiotic due to improved thermal protection wall. For
example, this could be achieved using lignocellulosic materials such as rice bran
(Chitprasert et al. 2012) and sugarcane bagasse (Shaharuddin and Muhamad 2015).
Chitprasert et al. (2012) studied the effects of aluminum carboxymethyl cellu-
lose–rice bran (AlCMC–RB) composites at weight ratios of 1:0, 1:1, and 1:1.5.
They found that both free cells and microencapsulated cells were almost fully
destroyed after heat treatment. However, a significant effect could be seen as the
higher amount of microencapsulated cells survived compared to the free cells.
Thus, composite of AlCMC–RB showed high potentials as wall materials in pro-
tection against heat (Chitprasert et al. 2012).
472 I. I. Muhamad et al.
4.2 Pharmaceutical
Fig. 22 Accumulate release profile of b-carotene under in vitro release condition (pH 1.2,
followed by pH 6.6 and pH 7.4 medium) (Muhamad et al. 2012)
changed by the addition of genipin. The results indicated that suitable amount of
genipin causes a decrease in the release rate in acidic, neutral, and alkaline medium.
In neutral medium, the genipin has been proven to be useful for a controlled release
of b-carotene delivery.
Yuan et al. (2007) showed the effect of genipin crosslinked chitosan micro-
spheres on protein (albumin) release. Ninhydrin assay was carried out to determine
the degree of crosslinking. Based on their study, the degree of chitosan crosslinking
microsphere was increased with increasing amount of genipin and crosslinking
time. The swelling ratio was decreased as genipin concentration and crosslinking
time increased. The albumin released from crosslinked chitosan microspheres was
slower than non-crosslinked microspheres.
Distantina et al. (2013) prepared crosslinked kappa carrageenan hydrogels using
glutaraldehyde as crosslinking agent. They found that the crosslinking treatment
enhances the thermal stability of carrageenan film, and this might be due to acetal
bridges formed during crosslinking mechanisms in crosslinked kappa carrageenan
film.
In another study, glutaraldehyde and potassium sulfate were used as crosslinkers
to stabilize kappa carrageenan film to be used as a controlled drug delivery system
(Distantina et al. 2014). Crosslinked kappa carrageenan showed swelling ability of
pH sensitive, wherein distilled water (pH * 7) and phosphate buffer (pH * 7.4)
potassium sulfate crosslinked films exhibited a higher swelling degree compared to
glutaraldehyde. While in NaOH solution (pH * 13), the films that were cross-
linked with glutaraldehyde exhibited a higher swelling degree than potassium
sulfate. This study suggested that both glutaraldehyde and potassium sulfate
crosslinking agents can be used for controlled drug delivery system.
12 Incorporation of Filler/Additives in Polymer Gel … 475
The genipin crosslinked silk sericin/poly(vinyl alcohol) (PVA) films were devel-
oped as two-dimensional wound dressings for the treatment of superficial wounds
(Siritientong et al. 2013). The effects of genipin crosslinking concentration on the
physical and biological properties of the films were investigated. It was found that
genipin crosslinked silk sericin/PVA films showed the increased surface density,
tensile strength, and percentage of elongation. Meanwhile, the percentage of light
transmission, water vapor transmission rate, and water swelling decreased due to
the mobility of molecular chains reduce within the films and become more rigid
molecular structure because of crosslinked process. It was found that silk sericin
was released in a sustained manner from the genipin crosslinked films. The in vivo
test (ISO 10993-6) confirmed that the genipin crosslinked silk sericin/PVA films
were safe for the medical usages. The results show that genipin crosslinked silk
sericin/PVA films would be promising wound dressings for superficial wounds.
476 I. I. Muhamad et al.
This study was conducted to investigate the in vitro characteristics of the genipin
crosslinked gelatin membrane for wound dressing purpose and was compared with
glutaraldehyde crosslinked gelatin membrane (Chang et al. 2003). A rat model was
used to study an in vivo experiment and it was found that the degree of inflam-
matory reaction for the wound treated with the genipin crosslinked dressing was
significantly less severe than that covered with the glutaraldehyde crosslinked
dressing throughout the entire course of the study. Additionally, the healing rate for
the wound treated with the genipin crosslinked dressing was notably faster than its
glutaraldehyde crosslinked counterpart.
In another study, bio-polymeric films were prepared for wound healing appli-
cation by varying the proportion of chitosan and PVA and it was crosslinked with
glutaraldehyde to improve the stability using solvent casting method (Panchal et al.
2014). Results suggest that the crosslinked films being compact influence swelling
than the uncrosslinked film and water uptake properties of the composites indicate
that the films could be tuned for wound healing management.
A previous study has proved that hydrogel with filler can be used as a promising
material in many applications. In wastewater treatment, hydrogel such as bacterial
cellulose provides properties that make it suitable to be used in wastewater treat-
ment to remove heavy metal (Wang et al. 2015; Lu et al. 2010). Those properties
include great mechanical strength, porous structure, and high water-holding
capacity. Besides that, bacterial cellulose has large surface area with many hydroxyl
groups in the chain that makes it effective for separation of heavy metals ions (Lu
et al. 2013). Most importantly, bacterial cellulose is simple to produce and the
modification can be done using various materials and methods. Furthermore, the
physiochemical properties of this bacterial cellulose can be controlled by modifying
the fermentation condition or by physical or chemical treatment in order to attain
preferred functionality (Pa’e et al. 2011; Sokolnicki et al. 2006; Serafica et al.
2002). These features along with its biocompatibility and low production render
this type of hydrogel ideal for use as eco-friendly biosorbent for heavy metal
removal.
However, bacterial cellulose itself as biosorbent had several disadvantages such
as low adsorption capacity, high hydrophilicity which leads it to swell easily in
water and poor selectivity. Therefore, new functional group is added to bacterial
cellulose to modified its properties and improve activity of bacterial cellulose on
adsorption of heavy metal ions. Table 5 listed previous works on the use of bac-
terial cellulose for heavy metal removal.
12 Incorporation of Filler/Additives in Polymer Gel … 477
Table 5 Bacterial cellulose as biosorbent for heavy metal removal in wastewater treatment
Adsorbent Adsorbate Reference
Bacterial cellulose coated with polyethylenimine Copper Wang et al. (2015)
Lead
Amino—bacterial cellulose Lead Lu et al. (2014)
Cadmium
Copper
Ammonium sulfamate—bacterial cellulose Chromium Lu et al. (2013)
Spherical iron oxide—bacterial cellulose composite Lead Zhu et al. (2011)
Manganese
Chromium
Carboxymethylated—bacterial cellulose Copper Chen et al. (2009)
Lead
Alginate
Sugarcane
bagasse (grey)
L.rhamnosus
(yellow)
Table 6 Cell survival of free and microencapsulated L.rhamnosus NRRL 442 under different
conditions of synthesis after heat exposure at 90° for 30 s
NaA NaA: Initial cells Final cells Cell
concentration SC concentration (log concentration (log survivability
(%) ratio CFU/g microcapsule) CFU/g microcapsule) (%)
Free cells – 8.62 ± 0.30 3.00 ± 0.19 34.51 ± 2.15*
Microencapsulated cells
1 1:0 7.90 ± 0.16 3.34 ± 0.12 42.39 ± 1.54*
1:1.1 7.93 ± 0.07 5.68 ± 0.11 71.67 ± 1.44*
1:1.5 8.13 ± 0.09 6.50 ± 0.17 80.02 ± 2.13*
2 1:0 7.93 ± 0.07 4.88 ± 0.32 61.57 ± 4.01*
1:1.1 8.13 ± 0.04 6.21 ± 0.14 76.33 ± 1.73*
1:1.5 8.13 ± 0.03 6.25 ± 0.06 76.87 ± 0.75*
3 1:0 7.75 ± 0.08 5.94 ± 0.04 77.67 ± 0.54*
1:1.1 7.98 ± 0.10 5.96 ± 0.11 74.78 ± 1.40*
1:1.5 8.04 ± 0.08 6.53 ± 0.06 81.30 ± 0.30*
*
Means with different superscripts within a column were significantly different [P < 0.05, n = 3]
(a) (b)
(c) (d)
Fig. 24 SEM of NaA and NaA–SB microcapsule areas. Outer surface of heated NaA–SB (1:0)
and NaA:SB (1:1.5) microcapsules loaded with L. rhamnosus NRRL 442 (a and b, respectively).
Inner surface of heated NaA–SB (1:0) and NaA:SB (1:1.5) microcapsules loaded with L.
rhamnosus NRRL 442 (c and d, respectively)
(Fig. 25). Therefore, the probiotic survivability after heat exposure was improved
with the incorporation of SB in alginate hydrogel via double heat protection. As a
conclusion, this study demonstrated the advantage of filler incorporation in polymer
gel with higher thermotolerance for probiotic and a great potential for inclusion in
the pelleted feed as probiotic additive.
The recommended parameters for immobilization and microencapsulation pro-
cess were 1:8 of the SB:L.rhamnosus ratio and 3% of NaA concentration with NaA:
SB ratio of 1:1.5, respectively. As a conclusion, the incorporation of filler could
significantly improve the probiotic survival up to approximately 47% after the
immobilization process and simulated heat treatment.
480
CaA
1431.25
1081.41
ME CaA+Lr
1634.52
2853.22
1431.25
2923.67
%T
1061.87
1634.52
1124.41
3432.48 2919.76 1431.25
1057.96
3432.48
1640.38
3432.48
4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 370.0
cm-1
Fig. 25 FTIR spectra of calcium alginate (CaA), microencapsulated microcapsule without Lr (ME CaA + Lr), and microencapsulated microcapsule loaded
with L.rhamnosus (ME CaA Immo SB + Lr)
I. I. Muhamad et al.
12 Incorporation of Filler/Additives in Polymer Gel … 481
In this study genipin, a natural and non-toxic crosslinker was used to prepare
crosslinked floating kappa carrageenan/sodium carboxymethyl cellulose hydrogels
and the effect of genipin on hydrogels characterization was investigated. Figure 26
shows the mechanisms of genipin in kappa carrageenan hydrogel networks. Fourier
transform infrared spectroscopy (FTIR), X-ray diffraction, and thermogravimetric
analysis (TGA) were carried out to study the changes in the characteristics of
hydrogels. FTIR analysis confirmed the mechanisms of genipin crosslinking in
kappa carrageenan hydrogel network. Figure displayed the mechanisms of genipin.
On the other hand, incorporation of genipin enhances the crystallinity properties
of kappa carrageenan hydrogels. It is believed that the mechanical properties of
hydrogels will be improved with high crystallinity properties. A clear variation has
been observed in TGA experiments that crosslinked kC/NaCMC floating hydrogels
exhibit excellent thermal stability than kC/NaCMC floating hydrogels. The
crosslinking mechanisms between kappa carrageenan and genipin confine the
polymeric network which will slow down the degradation. In vitro floating prop-
erties showed that all formulated hydrogels had excellent floating behavior. Genipin
as crosslinker affected the overall structure of hydrogels where gel strength was
improved as genipin amount increased. It was discovered that the crosslinking
reaction showed significant effect on swelling ratio compared to non-crosslinked
hydrogels where the swelling ratio decreased as crosslinked with genipin. This may
be due to the presence of a high amount of genipin that could result to a great extent
of chemical crosslinking of the kC/NaCMC/CaCO3 chains. This confines the
movement and hydration of the macromolecular chain in the beads and leads to less
Fig. 26 Mechanisms of
genipin in kappa carrageenan
hydrogel networks
482 I. I. Muhamad et al.
(a)
(b)
Fig. 27 Swelling ratio of non-crosslinked and genipin crosslinked floating kappa carrageenan
hydrogels in acidic (pH 1.2) and alkaline (pH 7.4) medium
12 Incorporation of Filler/Additives in Polymer Gel … 483
6 Conclusion
According to the text reported above, it showed the importance of filler incorpo-
ration in polymer gels in various applications and this enforcement step has caught
much attention from researchers. As mentioned earlier, the filler could bring ben-
eficial and positive impacts on the polymeric gel characteristics and properties.
Therefore, this step is crucial and should be highly considered in the development
of advanced polymer gel functionality. The development of such should be
emphasized and further improved for more global applications.
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