Polymer Gels: Synthesis and Characterization

Full text

Chapter 4
Polysaccharide-Based Polymer Gels
and Their Potential Applications
Nabil A. Ibrahim, Ahmed A. Nada and Basma M. Eid
1 Introduction
1.1 Polymer Gel Definition
Although gel is very popular and can be found everywhere, it is difficult to define
polymer gels as a type of materials. Gel can be described as a state of matter
intermediate between solid and liquid. It is a diluted matrix of cross-linked system
which contains fluids and shows no flow at its steady-state condition (Jen et al.
1996). Such systems can be cross-linked through physical or chemical bonds in the
presence of an extender (medium) which fills the pores of this network such as
water (hydrogel) (Kabiri et al. 2011; Wakhet et al. 2015), oil (oil–gel) (Lee et al.
2008b), or air (aerogel) (Soleimani Dorcheh and Abbasi 2008). Technically, gel
network swells to the equilibrium state (Fig. 1) that is established between osmotic
forces and the capability of polymer chains to extend (Hong et al. 2009).
Such polymer extension leads to a large swelling ability and medium absorption
to reach as much as 10–20 times its molecular weight (Singh et al. 2010). It is worth
to mention that gel swells but does not dissolve and this ability of swelling arises
from hydrophilic functional groups attached to the polymeric chains, while the
resistance of dissolution arises from the cross-links between polymer chains. This
promotes gel to be considered as an ideal substance for absorbing materials
employed in numerous applications such as baby diaper and plant soil (Singh et al.
2010; Ahmed 2015).
N. A. Ibrahim (&)A. A. Nada B. M. Eid
Textile Research Division, National Research Center, Giza, Egypt
e-mail: nabibrahim@hotmail.com; nabibrahim49@yahoo.co.uk
©Springer Nature Singapore Pte Ltd. 2018
V. K. Thakur and M. K. Thakur (eds.), Polymer Gels, Gels Horizons: From Science
to Smart Materials, https://doi.org/10.1007/978-981-10-6083-0_4
97

1.2 General Features
Generally speaking, gels possess characteristics of both liquid and solid; high
diffusion coefficients for small molecules; and mechanical properties of soft solids
(Singh et al. 2010). Gel properties depend on polymer constituents; cross-links in
terms of cross-linking mechanisms and density; and interactions between the
polymer and solvent (Pal et al. 2013).
1.3 Mechanism of Gel Formation
The mechanism of gel formation is divided into two types: chemical cross-linking
and physical cross-linking (Park et al. 2010).
The chemical cross-linking mechanism provides permanent bonding between
chains due to the formation of covalent bonds. Such cross-linked gels are not
processed after formation so that is called irreversible gels.
Irreversible gels can technically be fabricated by two different methods, namely
cross-linking during polymerization and cross-linking polymer chains.
Cross-linking during polymerization can be formed via different routes of poly-
merizations such as condensation polymerization; free radical polymerization
(Thakur et al. 2014; Thakur and Thakur 2014a); photo-polymerization; and plasma
polymerization. However, in the cross-linking polymer chain method, gel network
cross-links by reaction of substituents, attached to polymer chains, also via either
radiation cross-linking, photo-cross-linking, or plasma cross-linking (Ito 2007).
The physical cross-linking mechanism provides reversible gel with temporary
bonding between chains, and it occurs as a result of changes in temperature, pH,
Fig. 1 Gel equilibrium
98 N. A. Ibrahim et al.

and solvent composition. Reversible gels typically formed as mentioned before via
temporary bonds through different mechanisms such as hydrogen bonding, ionic
bond, coordination bonding, helix formation, and hydrophobic association (Fig. 2)
(Hurtado et al. 2007).
Fig. 2 Forces controlling gel behavior; ahydrogen bonding; bcoordination bonding; cionic
interactions; dhydrophobic interactions
4 Polysaccharide-Based Polymer Gels and Their Potential …99

2 Hydrogels
Hydrogels are polymeric network with chains containing hydrophilic functional
groups which absorb large amount of water. Hydrogel can be created either from
natural polymers (Thakur and Thakur 2015) or from synthetic polymers. In this
review, there is no intention to provide further details of the synthetic polymers.
Natural polymers include collagen, hyaluronate, fibrin, alginate, agarose, chi-
tosan, and cellulose have a number of advantages over synthetic polymers (Thakur
and Thakur 2014b). Basically, natural polymers are not toxic, biologically com-
patible, biodegradable, and abundant.
The second part of this review will provide more details about polysaccharides,
their chemical structures, physical properties, chemical modifications, polysaccha-
ride derivatives, their reactions to fabricate hydrogels, their characterization, and
potential utilizations.
2.1 Alginate
2.1.1 General Features
Alginate, water-soluble sodium salt of alginic acid, is an anionic natural polymer
that can be extracted from affordable resources such as brown seaweed. Alginate
has been used in medical applications due to its biocompatibility, low toxicity, and
rapid gelation in the presence of divalent cations commonly such as calcium cation
(Ca
2+
). Chemical structure of alginate is composed of blocks of mannuronic acid
units (M) and guluronic acid units (G) to form linear copolymer of different and
long sequences of Ms and/or Gs (Fig. 3) (Augst et al. 2006). It has been reported
that differences in M and G contents and alternation depend on the extracted
sources (Pawar and Edgar 2012). Also, it is believed that G sequences in alginate
copolymer are responsible for gel formation of alginate in the presence of calcium
cations (Lee and Mooney 2012).
Fig. 3 Chemical structures of mannuronic acid units (M) and guluronic acid units (G) of alginate
100 N. A. Ibrahim et al.

The commercial alginate has an average molecular weight between 32,000 and
400,000 g/mol. to provide wide broad viscosity value applicable to varied appli-
cations. Alginate viscosity depends mainly on pH to reach maximum at pH 3 at
which carboxylic groups are converted to acid form and form hydrogen bonds.
Regarding alginate biocompatibility, highly pure alginate that is heavy metal-free
did not show any reaction or significant inflammation when tested in vivo models
(Augst et al. 2006).
Chemical structure of alginate containing hydroxyl groups and carboxylic
groups can share in multiple chemical reactions to modify the final characteristics of
the modified derivatives. Alginate can be modified through the hydroxyl groups by
oxidation, reductive amination, sulfation, copolymerization reactions and coupling
of cyclodextrin units. However, it can be modified through the carboxylic groups by
esterification and amidation reactions (Yang et al. 2011).
In the following section, related alginate derivatives contributed to gel formation
will be summarized.
2.1.2 Alginate Hydrogel Formation
Reversible Hydrogel of Alginate
Generally speaking, alginate readily can form reversible hydrogel when sodium
alginate solution combines with calcium chloride solution to form physical
hydrogel through ionic cross-linking (Fig. 2c). It is worth to mention that such ionic
bonds take place mainly with guluronic acid units (G) where the coordination
between the divalent ions and carboxylic groups reaches the highest degree (Fig. 4).
Different ionic cross-linkers have been reported (Lee and Mooney 2012) for the
alginate gelation such as calcium chloride, sodium hexametaphosphate, calcium
sulfate, and calcium carbonate. Preferred agent is the one that allows slower
gelation process to facilitate the way to control the hydrogel properties. For
instance, alginate has been mixed with calcium carbonate which is very poor sol-
uble in water at pH7 and by lowering the pH value using Glucono-alpha-lactone,
Ca
2+
starts to be released and performs alginate hydrogel in a controlled manner
(Lee and Mooney 2012). Also, polyols have been reported to slow down the
gelation process which hinders the immediate complexation of the divalent ions and
alginate (Van Vlierberghe et al. 2011).
One of the most important drawbacks of the ionic cross-linking of alginate is the
short-term stability due to loss of divalent ions in the surrounding medium.
Irreversible Hydrogel of Alginate
Alginate can form irreversible hydrogel via creating permanent bonds between
alginate chains either by chemical cross-linking agents or by photo-cross-linking
4 Polysaccharide-Based Polymer Gels and Their Potential …101

using photo-initiators. In chemical cross-linking hydrogel, network can be per-
formed in the presence of either bifunctional or multifunctional cross-linkers.
In case of bifunctional cross-linker, adipic dihydrazide was used to cross-link the
oxidized alginate which possesses dialdehyde groups along with their chains.
Oxidation has been carried out via sodium periodate in mild and controlled con-
dition to monitor the oxidation process (Augst et al. 2006). Figure 5shows
hydrogel formation of alginate in the presence of poly(ethylene glycol) diamine by
which reductive amination reaction takes place by reacting with the amino groups
of the cross-linker and aldehyde groups groups of oxidized alginate (Yang et al.
2011). In Fig. 6, glutaraldehyde was used as bifunctional chemical cross-linker for
alginate performing an acetal link with alginate hydroxyl groups (Chan et al. 2009).
Such bifunctional cross-linkers have shown higher capacity in absorbing water
than other networks performed in the presence of multifunctional cross-linkers
(West et al. 2007). Poly(acrylamide-co-hydrazide) has been reported for alginate
irreversible hydrogel which showed higher mechanical properties and longer
degradation than those treated with bifunctional cross-linkers (Lee et al. 2004).
Photo-cross-linked alginate hydrogel has been studied to perform irreversible
hydrogel applicable for medical purposes (Jeon et al. 2009). It requires modifying
alginate with photo-active groups such as methyl acrylate, in the first place, and then
initiates via energy source for few seconds. The advantage of such route is to produce
hydrogel in mild conditions even with direct contact with bioactive materials.
Fig. 4 Physical cross-linking of guluronic acid units (G) with calcium cations
102 N. A. Ibrahim et al.

2.2 Chitosan
2.2.1 General Features
Chitosan is regarded as the most valuable biopolymer in polysaccharides in terms of
the tremendous involved medical applications: high biocompatibility; non-toxicity;
biodegradability; etc. It has been reported (Nada et al. 2014) that chitosan showed
multiple bioactive potentials such as hemostatic, bacteriostatic, fungistatic, and
even anticancer agent. Chitosan applications are not limited to medical purposes but
also include textile treatments (Ibrahim et al. 2013a,b,c,e,2017), food industry,
and cosmetics (Thakur and Thakur 2014a).
In general, chitosan is produced from chemical treatments of chitin that is
extracted and purified from shrimp shells, oysters, and squid pens. Chitosan
Fig. 5 Reductive amination of dialdehyde alginate
Fig. 6 Glutaraldehyde chemical cross-linking of alginate
4 Polysaccharide-Based Polymer Gels and Their Potential …103

polymeric structure is composed of liner sequence of D-glucosamine and N-acetyl-
D-glucosamine (Fig. 7). Therefore, chitosan family consists of different series that
differ in percentage of those units in liner chains and the term of degree of
deacetylation (DD) which is defined as the percentage of the amino groups com-
pared to the molecular weight of the polymer. The average molecular weight of
chitosan spans from 50,000 to 300,000 g/mol. depending upon the source of
extraction.
Chitosan is water-insoluble and dissolved in acidic medium to provide very
viscous solution (depending upon the molecular weight) in low concentrations
(2–3% wt/v) due to the rigidity of its crystalline structure. Therefore, much has been
done to modify chitosan chemical structure by blocking the amino groups in order
to reduce such rigidity and obtain moderate viscosity for higher concentrations
(12–15% wt/v) (Nada et al. 2014). Chitosan possesses two reactive types of
functional groups: first, the free amino groups existing in the D-glucosamine units
and second, the free hydroxyl groups attached to both the N-acetyl-D-glucosamine
units and D-glucosamine units. Many studies have been conducted to impart
superior functionalities to chitosan backbone via chemical modifications or grafting
through such active functional groups. For example, chitosan has been covalently
bonded with tertiary amine in order to impart and broaden its antimicrobial activ-
ities (Lim and Hudson 2004).
In the following section, related chitosan derivatives contributed to gel forma-
tion will be summarized.
2.2.2 Chitosan-Based Hydrogel Formation
Chitosan has served for hydrogels in different forms such as liquid gel, micro-
spheres, nanospheres, impregnated films, capsules, and beads. In each type of
chitosan hydrogels, networks can be achieved either by physical or by chemical
cross-linking process.
Fig. 7 Chitosan chemical structure
104 N. A. Ibrahim et al.

Reversible Hydrogel of Chitosan
As mentioned above, the physical cross-linking hydrogel can be created under
different types of forces controlling the gel behavior. Our discussion will focus on
each approach in preparation for chitosan reversible hydrogel and its characteristics
(George and Abraham 2006; Ishihara et al. 2006; Chang et al. 2007; Hong et al.
2007; Lawrie et al. 2007; Alves and Mano 2008; Prabaharan 2008; Chatterjee et al.
2009a,b,2010a,b; Ribeiro et al. 2009; Bhattarai et al. 2010; Rickett et al. 2011;
Van Vlierberghe et al. 2011; Sudheesh Kumar et al. 2012).
Non-covalent cross-linked chitosan networks can occur by the ionic complex
between the cationic amino groups of chitosan and negatively charged molecules or
anions such as sodium sulfate ions (Fig. 8) (Bacaita et al. 2014), metal ions like
platinum (Bhattarai et al. 2010), pentasodium tripolyphosphate (Csaba et al. 2009),
and many other anions. The preformed hydrogel from those ionic interactions
provides reversible, unstable, hydrogel toward processing conditions such as tem-
perature and pH with short lifetime.
However, such ionic interactions can be enhanced by using polyelectrolyte
complexes instead such as alginate (George and Abraham 2006). The advantage of
this approach is that hydrogel networks cross-linked without organic precursors,
catalyst, or reactive agents. Plus, because in such system there are only chitosan and
the other polyelectrolyte polymer, their complexions are straightforward and
reversible.
Hydrogen bonding is considered as an important approach of the physical
cross-linking chitosan hydrogel when chitosan chains are mixed with polyvinyl
alcohol (PVA) solution in which polymer chains form junction points that act like
cross-linking sites. In this case, hydrogel network is taking place after a series of
freeze–thaw cycles in order to affect the formation of the PVA crystallites resulting
Fig. 8 Ionic complex
between chitosan amino
groups and sodium sulfate
4 Polysaccharide-Based Polymer Gels and Their Potential …105

in hydrogel with less ordered structure (Bhattarai et al. 2010). Interestingly,
hydrogen bonding forces can be employed in very amazing manner to provide
hydrogel status at a certain temperature degree. The latter phenomenon is called
thermoreversible hydrogel that occurs when chitosan solution mixed with glycerol
phosphate disodium salt at 37 °C hydrogen bonding increases to create the physical
cross-linking networks. It is believed that glycerol phosphate disodium salt neu-
tralizes the amino groups of chitosan and increases the hydrogen bonding between
chitosan chains. Such special characteristic can be employed in performing
injectable hydrogel that is in liquid state at room temperature and turns into gel at
body temperature (Cheng et al. 2010).
Irreversible Hydrogel of Chitosan
Irreversible chitosan hydrogel has been investigated in order to overcome the
physical cross-linking limitations such as instability for temperature and pH.
Chemical cross-linking can provide precise pore size of hydrogel, controllable
functionalities, governed degradation rate, and dissolution (Hong et al. 2007; Alves
and Mano 2008; Muzzarelli 2009; Azlan et al. 2009; Cheng et al. 2010; Rickett
et al. 2011; Mirzaei et al. 2013). On the other hand, this type of cross-linking
requires multiple steps of preparations and purifications with serious concerns about
the cross-linker cytotoxicity.
Chemical cross-linking can be achieved via different routes such as using small
bifunctional cross-linkers and photo-reactive and enzymatic molecules. Much has
been reported for chitosan chemical cross-linking via small molecules such as
glutaraldehyde (Mirzaei et al. 2013). The latter molecule is very reactive
cross-linker toward polymeric materials with amino groups. It reacts with chitosan
through the primary amino groups resulting imine bond (Schiff’s base reaction) that
requires a reduction step to convert it to stable bond (Fig. 9). The mechanical
properties of the prepared network depend on the glutaraldehyde amount and
chitosan concentration.
Similar to glutaraldehyde, different bifunctional molecules such as diglycidyl
ether (Azlan et al. 2009), diisocyanate, epichlorohydrin (Xu et al. 2015) (Fig. 10),
and diacrylate (Bhattarai et al. 2010) react with chitosan mainly through the amino
groups and provide chitosan hydrogel with different spacers that possesses different
pore size and mechanical properties.
Unlike the previous small cross-linkers, genipin has been used as chemical
cross-linker with higher biocompatibility and unremarkable cytotoxicity than others
(Fig. 11) (Xu et al. 2015). Genipin showed slower degradation than glutaraldehyde
which results in longer duration to release the encapsulated drugs (Muzzarelli 2009).
Instead of using small molecules for chemical cross-linking, some studies have
been concerned to use polymeric materials possessing multiple functional groups
that are capable of reacting with chitosan amino and/or hydroxyl functional groups.
Oxidized dextran has been employed as chemical cross-linker to chitosan in which
carbon–carbon sigma bond between carbon 2 and carbon 3 cleaved into dialdehyde
106 N. A. Ibrahim et al.

groups along the polymeric chains providing hydrogel with good mechanical
properties with limited biological toxicity (Cheng et al. 2014).
Other studies have been conducted to investigate the reaction of acrylated chi-
tosan derivatives with thiolated polyethylene glycol (Kim et al. 2007) to achieve the
hydrogel networks and avoid the small cross-linking molecule cytotoxicity. In vice
versa, thiolated chitosan was reacted with acrylated chitosan to achieve the same
results (Teng et al. 2010).
Fig. 9 Glutaraldehyde cross-links with chitosan (Schiff’s base reaction), R = glutaraldehyde
Fig. 10 Proposed reaction mechanism of chitosan and epichlorohydrin (Xu et al. 2015)
4 Polysaccharide-Based Polymer Gels and Their Potential …107

In general, thiol-ene reaction (Fig. 12) is considered as a promising method to
achieve cross-linked chitosan in mild conditions with less purification steps and
high yield in which thiol groups react with alkene groups to form alkyl sulfide.
Photo-cross-linkable chitosan derivatives have widely employed to produce
in situ hydrogel network that is suitable for tissue engineering, wound dressing, and
drug delivery applications (Jameela et al. 2002). The typical approach of the
photo-cross-linkable chitosan derivatives relies on grafting acrylate monomers onto
chitosan backbone and in the presence of photo-initiator associated with UV light
radiation, the cross-linking process starts up. However, new approach has been
Fig. 11 Proposed mechanism of chitosan cross-linked by genipin (Xu et al. 2015)
108 N. A. Ibrahim et al.

discovered in which chitosan backbone grafted with 4-azidobenzamide results in a
water-soluble chitosan derivative with viscous solution that turns into hydrogel
instantaneously upon UV curing (Rickett et al. 2011).
Although photo-crosslinking procedures for producing irreversible chitosan
hydrogel have many advantages over conventional methods, photo-processing
requires photo-initiators and prolonged radiation that result in an increase in local
temperature and ruin the encapsulated bioactive materials.
Enzymatic cross-linking approach has been recently reported as a mild process
for in situ hydrogel formation. The main representative for this category is horse-
radish peroxidase, metalloenzyme, which catalyzes the phenolic or aniline hydroxyl
groups, introduced to chitosan backbone and amino groups of chitosan to create
hydrogel network. The main idea of such enzyme applies on the decomposition of
hydrogen peroxide resulting in active species capable of initiating the cross-linking
process in the presence of either phenolic or aniline groups on chitosan backbone
(Jin et al. 2009).
2.3 Cellulose
2.3.1 General Features
Cellulose is the most abundant natural polymer that is found as the main component
of cotton linen and other plants. The chemical structure of cellulose depends on
glucose units that are connected to each other through 1, 4–beta-glucosidic linkages
(Fig. 13). Cellulose can be also biosynthesized via certain types of bacteria (for
instance, Acetobacter xylinum) with slightly different physical and macromolecular
properties. Cellulose is obtained either from plant or from bacterial source that
shows high degree of crystallinity usually 40–60% in plant cellulose and 61–72%
for bacterial cellulose. Such high crystallinity is due to the extended hydrogen
bonding along the cellulose chains resulting in very tight and well-packed chains
hindering cellulose dissolution in common solvents (Sannino et al. 2006,2009).
Glucose unit, repeating unit of cellulose, has three hydroxyl functional groups in
carbon atoms 6 (primary) and 2 and 3 (secondary) that open wide possibilities of
chemical modifications in order to produce cellulose derivatives with distinguished
characteristics. Nowadays, a great attention has been focused on environmental,
Fig. 12 Thiol-ene prototype reaction
4 Polysaccharide-Based Polymer Gels and Their Potential …109

ecofriendly, and biocompatible products, thus, cellulose-based substrates have been
used in numerous new applications in diverse fields. In the following sections,
cellulose-based hydrogel formation and applications will be covered in more
details.
2.3.2 Cellulose-Based Hydrogel Formation
In this subsection, recent literature was cited to summarize the hydrogel formation
of cellulose-based substrates including pure cellulose, modified cellulose, and
cellulose composites (Sannino et al. 2006,2009; El-Hag Ali et al. 2008; Chang and
Zhang 2011; Koschella et al. 2011).
As mentioned above, hydrogel forms when hydrophilic polymer chains
cross-link by either physical or chemical bonds to create a three-dimensional net-
work. Such mechanism requires water- or solvent-soluble polymers in order to
facilitate the physical or chemical interactions with cross-linkers. Due to the diffi-
culties to dissolve cellulose, some studies have been done on native cellulose
through chemical or even physical cross-linking (Farag and Al-Afaleq 2002; Zhou
et al. 2002,2005,2007; Song et al. 2008a,b; Qi et al. 2009; Dahou et al. 2010).
Studies concerned mainly about developing the dissolution methods of native
cellulose and then using cross-linkers matching the solvent system condition.
Special solvent systems have been used for such task such as N-methylmorpholine-
N-oxide (NMMO), ionic liquids (ILs), and alkali/urea (Zhou et al. 2004; Qin et al.
2013). Those new solvent systems have opened new horizon of native cellulose for
chemical modifications such as reversible and irreversible cellulose-based hydro-
gels (Chang and Zhang 2011).
On the other side, cellulose derivatives such as carboxymethylcellulose and
hydroxyethyl cellulose (Marcìet al. 2006; Sannino et al. 2006,2009; El-Hag Ali
et al. 2008; Kulkarni and Sa 2008; Vinatier et al. 2009; Chang et al. 2010,2011)
have been widely utilized in hydrogel preparation.
2.3.3 Reversible Hydrogel Based on Cellulose
Reversible cellulose-based hydrogel can be obtained using either native cellulose or
cellulose derivatives.
Fig. 13 Repeating unit of
cellulose and cellulose
derivatives
110 N. A. Ibrahim et al.

Native cellulose solution which is dissolved in lithium chloride/dimethyl acet-
amide (LiCl/DMAc) system leads to 3D network hydrogel upon dropping into
non-solvent systems such as azeotropic methanol and isopropanol (Müller et al.
2006). Same technique of hydrogel formation has been reported by using different
dissolution systems such as paraformaldehyde/dimethylsulfoxide (DMSO), tri-
ethylammonium chloride/DMSO, and tetrabutylammonium chloride/DMSO
(Müller et al. 2006).
However, NMMO solvent system for cellulose dissolution can form physical
cross-linking hydrogel when cellulose/NMMO solution is heated up to 150 °C at
which water molecules replace NMMO solvent between chains to create regener-
ated cellulose in the form of hydrogel (Müller et al. 2006).
The replacement of the dissolving system by water molecules has been reported
(Ruel-Gariépy and Leroux 2004), once again, when cellulose solution, dissolved in
1-butyl-3-methylimidazolium chloride and 1-allyl-3-methylimidazolium chloride,
was mixed with water, ethanol, or acetone to end up with regenerated cellulose
hydrogel.
Other regenerated cellulose hydrogel has been prepared by dissolving cellulose
in sodium hydroxide/urea system (Zhou et al. 2002,2004; Song et al. 2008a,b;Qi
et al. 2009; Qin et al. 2013).
Reversible cellulose-based hydrogels have been made by using water-soluble
cellulose derivatives. Partially substitution of the hydroxyl groups of the glucose
units by methyl, hydroxyethyl, hydroxypropyl, and many other functional groups,
resulting in decreases the hydrogen bonding between cellulose chains and provides
water-soluble cellulose derivatives.
Interestingly, methylcellulose (MC) has thermoreversible characteristic. MC
solution turns into hydrogel as a result of hydrophobic interactions at particular
temperature. Such unusual characteristic promotes MC for special use in
medical-related applications (Ruel-Gariépy and Leroux 2004). Similar to MC,
hydroxypropyl methylcellulose shows thermoreversible hydrogel with higher
gelation temperature than that of MC (Müller et al. 2006).
Irreversible Cellulose-Based Hydrogel
Chemical cross-linking of cellulose and mainly cellulose derivatives depends on
few small molecules that react with the free hydroxyl functional groups of the
glucose units such as citric acid, divinyl sulfone (Marcìet al. 2006; Chang et al.
2010; Guo et al. 2013), diglycidyl ether (Mathur et al. 1996), epichlorohydrin
(Zhou et al. 2007; Chang et al. 2010,2011), and water-soluble carbodiimide
(Sannino et al. 2006,2009; Guo et al. 2013). For example, divinyl sulfone (Kriegel
2004) was reported for cross-linking carboxymethylcellulose (CMC) and hydrox-
yethyl cellulose to create superabsorbent hydrogel (Fig. 14).
Another chemical cross-linking hydrogel of cellulose was investigated by using
diglycidyl ether with hydroxypropylcellulose (Marsano et al. 2003) to end up with
thermosensitive hydrogel (Fig. 15).
4 Polysaccharide-Based Polymer Gels and Their Potential …111

In general, the swelling and mechanical properties are manipulated by changing
the cross-linker concentrations where stiffer hydrogel comes from intense
cross-linking between cellulose derivatives chains (Sannino et al. 2009; Chang et al.
2010,2011; Chang and Zhang 2011).
Radical cross-linking is another type of the chemical cross-linking to cellulose
derivatives. CMC was cross-linked via gamma ray treatment to perform stable and
non-toxic hydrogel (El-Hag Ali et al. 2008).
Accordingly, cellulose and cellulose derivative-based hydrogel showed a low
toxic final product that is biodegradable, biocompatible, and stable. Therefore,
cellulose-based hydrogels are used in numerous applications in diverse fields as
well as those produced from alginate or chitosan.
2.4 Hyaluronic Acid
2.4.1 General Features
Hyaluronic acid (HA) is a liner copolymer of an alternative repeating disaccharide
units, namely beta-1′,4′-D-glucuronic acid and beta-1,3-N-acetyl-D-glucosamine
(Fig. 16).
Hyaluronic acid is naturally found in the extracellular tissue in many parts of the
human body. HA is playing an important role in many biological processes due to
its excellent water-holding capacity that retains moisture in joints, eyes, and skin
tissue. Plus, HA degrades readily by body enzymes resulting in non-toxic
by-products. Therefore, HA shows better biocompatibility to tissue-related appli-
cations and is considered as a promising biopolymer among many other polysac-
charides (Bhattacharyya et al. 2008; Tan et al. 2009; Burdick and Prestwich 2011;
Collins and Birkinshaw 2013). It is notable that according to the poor mechanical
Fig. 14 Prototype reaction between water-soluble cellulose derivatives and divinyl sulfone
Fig. 15 Prototype reaction between diglycidyl ether and water-soluble cellulose derivatives
112 N. A. Ibrahim et al.

properties and rapid degradation of HA hydrogel, some studies are done to improve
its performance.
2.4.2 Hyaluronic Acid Hydrogel Formation
Chemical structure of native HA possesses different accessible functional groups,
namely hydroxyl and carboxyl groups which are responsible for its solubility in
water and fast degradation. These functional groups have contributed to either
physical or chemical cross-linking of HA to create 3D network hydrogel.
2.4.3 Reversible Hydrogel of Hyaluronic Acid
Few studies have been published on the physical cross-linking of HA, and only
phosphatidylethanolamine was reported to form reversible HA hydrogel by making
hydrogen bonding or hydrophobic interactions between HA chains (Kitazono and
Kaneko 2012).
Irreversible Hydrogel of Hyaluronic Acid
On the other hand, few studies have been focused on the chemical crosslinking of
HA in which cross-linking molecules react with the accessible functional groups in
HA. It is believed that HA reacts with divinyl sulfone via the hydroxyl groups
creating ether bonds. Also, glutaraldehyde cross-links with HA chains through
reaction with the hydroxyl groups creating hemiacetal or ether bonds in acidic
medium.
Fig. 16 Chemical structure of hyaluronic acid
4 Polysaccharide-Based Polymer Gels and Their Potential …113

On the other side, new techniques have been emerged by starting with modified
HA and then crosslinking with the suitable cross-linkers. Furan-modified HA
(Fig. 17) was synthesized and reacted with dimaleimide poly(ethylene glycol)
(Fig. 18) (Nimmo et al. 2011). Also, HA hydrogel was done by using
photo-polymerization of methacrylated-HA and N-vinylpyrrolidone. Such HA
hydrogel is potentially applicable in injectable cell delivery for tissue engineering
(Ki et al. 2006).
Like chitosan enzymatic crosslinking, horseradish peroxidase (HRP) was used
with modified HA (HA–tyramine conjugate) to perform controllable mechanical
strength and gelation rate as injectable hydrogel (Lee et al. 2008a).
Fig. 17 Synthesis of furan-HA in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-
4-methylmorpholinium chloride (DMTMM) and 2-(N-Morpholino)-ethanesulfonic acid
(MES) (Nimmo et al. 2011)
114 N. A. Ibrahim et al.

Fig. 18 Chemical crosslinking of furan-HA with dimaleimide poly(ethylene glycol) (Nimmo
et al. 2011)
4 Polysaccharide-Based Polymer Gels and Their Potential …115

2.5 Starch
2.5.1 General Features
Starch is a renewable polysaccharide produced from potatoes, rice, and other locally
available resources. Starch is consisting of glucose repeating units in two different
types, namely linear and helical amylose and branched amylopectin. Starch is
insoluble in cold water and has been described by some limitations such as poor
processability (Reis et al. 2008).
2.5.2 Starch-Based Hydrogel
Reversible Hydrogel of Starch
Several studies have been done on starch grafting with acrylic acid and glycidyl
methacrylate (Fig. 19) (Reis et al. 2008) in order to obtain higher capability of
water absorbance and retention. Also, acrylonitrile has been grafted on starch by
free radical polymerization using ceric ions. The resultant starch derivatives were
used to prepare superabsorbance hydrogels.
Chemical cross-linking of native starch to form hydrogel shows exceptional
properties. Thus, these produced starch-based hydrogels can be used for drug
delivery, agriculture, and filtrations (Reis et al. 2008; Li et al. 2009; Laftah et al.
2011; Ahmed 2015).
3 Hydrogel Characterization
3.1 Spectral Analysis
The chemical structure of produced hydrogel, in most cases, has been character-
ized via infrared (IR) by which new covalent bonds can be detected. Also, C
13
and
H
1
nuclear magnetic resonance (NMR) spectroscopes for sold materials have been
used to detect the physical and the chemical properties of atoms in hydrogel matrices.
3.2 Gelation Time
Gelation time of the polysaccharide-based hydrogel represents the time at which
the polymer status changes from fluid-like to soild-like matrix. Typically,
polymer-producing hydrogel is incubated into the conditions of crosslinking, and
time for complete gelation will be reported.
116 N. A. Ibrahim et al.

3.3 Mechanical Properties
Mechanical properties and hydrogel stiffness can be demonstrated by using oscil-
latory shear measurements of elastic (G′) and viscous modulus (G″) of hydrogel
matrices that have been measured at varied temperatures using constant stress
rheometer.
Fig. 19 Reaction mechanism of starch with glycidyl methacrylate, A: via trans-esterification, B:
via opening the epoxy ring (Reis et al. 2008)
4 Polysaccharide-Based Polymer Gels and Their Potential …117

3.4 Swelling Test
Swelling characteristic of prepared hydrogels is one of the most important prop-
erties that give hydrogel-wide applications. Basically, swelling behavior depends
mainly on the presence of the hydrophilic functional groups in the matrices. The
extent of water absorption by the freeze-dried composite hydrogels is evaluated by
incubating the hydrogels in phosphate buffered saline (PBS) solution at 37 °C.
Typically, the initial weights (Wa) of the freeze-dried samples of hydrogel were
determined before incubation while the weights of the wet hydrogel (Wb) are
reported after 7 days of incubation (Laftah et al. 2011). The swelling percentage
was calculated by:
%Swelling percentage ¼Wb WaðÞ=Wa 100
3.5 Scan Electron Microscope for Morphology
The surface and cross-sectional morphology are very crucial parameter that will
provide the porous structure of the produced hydrogel to confirm their applications
accordingly. Typically, hydrogel morphology has been examined by scan electron
microscopy (SEM).
3.6 Encapsulation Efficiency
The encapsulation efficiency is defined as the measurement of the remaining con-
tent of the core material which is encapsulated in the wall material compared to the
starting core material content:
EE%¼Practical loading drug½=Theoretical loading drug½100
The practical loading bioactive materials were measured as mentioned.
The release rate of encapsulated substance is usually determined by incubating
few mg of the freeze-dried hydrogel samples in 10 mL PBS at specificpHat37°C
in shaking water bath. At time intervals, 1 mL of the released medium was taken
and 1 mL of the fresh medium is replaced. The absorbance readings of the filtered
supernatant are recorded at specific nm using UV-Vis spectrophotometer, and
finally, the released amount was calculated from standard calibration curve.
118 N. A. Ibrahim et al.

3.7 Biological Impact
In general, any substance or formula that comes into contact with human body
should be clean and liberate no chemical agent that may be toxic or have adverse
effects. In vitro cytotoxicity test is a useful technique for detecting such agents by
using the yellow tetrazolium dye (MTT) assay to measure the cell viability (Nada
et al. 2011).
The reduction of tetrazolium salts is now recognized as a safe and accurate
method. The yellow tetrazolium salt is reduced in metabolically active cells to form
insoluble purple formazan crystals, which are solubilized by the addition of a
detergent. The color can then be quantified by spectrophotometric means. For each
cell type, a linear relationship between cell number and absorbance is established to
enable an accurate and straightforward quantification of changes in cell prolifera-
tion. Among the applications for MTT method are drug sensitivity, cytotoxicity,
response to growth factors, and cell activation.
4 Hydrogel Applications
Alginate has been known for many applications such as food applications and
textile printing (Ibrahim et al. 2006,2011,2013d) and recently used in the phar-
maceutical applications. However, in the last few decades, alginate hydrogels have
been explored in tissue engineering (Rowley et al. 1999) applications. Alginate
hydrogel has been reported as stem cell (Zhao et al. 2010) scaffolds to guarantee
cell proliferation (Ashton et al. 2007). Also, alginate cross-linked networks have
gained great attention such as drug delivery matrices in which bioactive materials,
protein (George and Abraham 2007), cells (Novikova et al. 2006; Tan and Takeuchi
2007), and drugs can be encapsulated and their release profiles are controlled
(George and Abraham 2006).
Chitosan hydrogel has numerous applications in varied fields starting from
textile industries, cosmetics, and medical purposes. Utilization of chitosan in tissue
engineering, drug delivery, and medicine-related application makes chitosan as an
important, exciting, and promising polysaccharide nowadays. Several studies have
been done in using chitosan hydrogels in encapsulating bioactive molecules such as
cells (includes stem cells), proteins, enzymes, and sensitive drugs. Chitosan and
chitosan derivatives have covered a broad spectrum of pharmaceutical applications,
providing wide degree of flexibility for reshaping and fitting the targeting sides.
Also, chitosan-based hydrogel has been used as color and heavy metal removal
substrate from water wastes (Ishihara et al. 2006; Hong et al. 2007; Chatterjee et al.
2009a; Ribeiro et al. 2009; Bhattarai et al. 2010).
Cellulose hydrogel is superior candidate over other polymers when biocom-
patibility and biodegradability are required for the final applications. Due to cel-
lulose low cost and large availability, cellulose is regarded as appealing precursor
4 Polysaccharide-Based Polymer Gels and Their Potential …119

for hydrogel (Sannino et al. 2009). Final application of the produced cellulose-
based hydrogel depends on the mechanical properties. Azide–alkyne functional
cellulose hydrogel showed inert response to the active biomaterials. However, low
mechanical properties of such cellulose-based hydrogel showed limited factor of
wide applications (Koschella et al. 2011). Hydroxypropyl methylcellulose has
been developed as suitable matrix for injectable hydrogel in the in vitro
three-dimensional culture for rabbit articular chondrocytes (Vinatier et al. 2009).
Also, cellulose-based graft by acylated monomers is provided in the market as
superabsorbent hydrogels for personal care products (Sannino et al. 2009).
Cellulose-based superabsorbent hydrogel can absorb up to 1000 mL of water per
one gram of dry material. Such characteristic is main reason behind using
cellulose-based hydrogel as water reservoirs in agriculture by which water con-
sumption will be controlled and water resources will be optimized. Moreover,
nutrients and/or plant pharmaceuticals have been encapsulated into such
cellulose-based hydrogel to support plant by water and such loaded materials as
needed (Sannino et al. 2009).
Cellulose-based hydrogel is also used to absorb the excess water from human
body that is known in the market as body’s water retainer. It requires pH-sensitive
hydrogel that goes through the acid medium without swelling and it swells at
pH 6–7 existed in the intestine region.
On contrary, hydrogel that swells in acidic medium has been employed as meal
replacement to absorb liquids and swell inside the stomach resulting as sense of
fullness. The latter characteristic of cellulose-based hydrogel is known in the market
as stomach bulking agents.
Carboxymethylcellulose hydrogel and anionic hydrogel have been used exten-
sively in oral drug delivery that relays mainly on polyelectrolyte hydrogels.
Cellulose-based hydrogels have been reported as biodegradable and biocompatible
matrices for scaffolds, regenerative medicine and for wound dressing.
Hyaluronic acid-based hydrogels, chemically crosslinked with divinyl sulfone,
have been employed in preparing biocompatible hydrogels as scaffolds in order to
deliver therapeutic molecules (Bhattacharyya et al. 2008). However, thermosensi-
tive, hyaluronic acid-based hydrogels, crosslinked by using poly(N-iso-
propylacrylamide), have been used as an injectable matrices for adipose tissue
engineering (Tan et al. 2009). In different manner, hyaluronic acid has been attached
to contact lens, made of poly(2-hydroxyethyl methacrylate), as wetting agent in order
to reduce the deposition of protein and lipid from tear fluids (Van Beek et al. 2008).
Hydrogel prepared by the reaction between hyaluronic acid and phosphatidyl etha-
nolamine has been suggested to treat knee joint (Kitazono and Kaneko 2012). Due to
the distinguished biological potentials of hyaluronic acid, many applications of the
hyaluronic hydrogels have been reported especially in cell encapsulation (Ki et al.
2006) and scaffolds for bone regeneration (Patterson et al. 2010).
Starch is regarded as renewable, biocompatible, and abundant polysaccharide
that has shown wide attraction for medical applications. For instance, starch-based
hydrogel, crosslinked by glycidyl methacrylate, has been reported as potential
carrier for drug delivery matrices (Reis et al. 2008).
120 N. A. Ibrahim et al.

5 Conclusion and Future Prospective
An overview of the polymer gel principles, definition, and types was covered in the
first section of this review. Hydrogel formation based on hydrophilic polymers was
covered in order to represent the difference between the physical and chemical
crosslinking. Forces controlling each type of the crosslinking were described as
well. Famous candidates of polysaccharides, namely alginate, chitosan, cellulose,
hyaluronic acid, and starch, were highlighted with several examples on their
physical and chemical crosslinking. Applications for each hydrogel have been
represented with their potentials and limitations.
In conclusion, new trends have been emerged to design new shapes of hydrogel
by using the bio-3D-printer in order to form suitable scaffolds for tissue engi-
neering. Introducing amino acids to the carbohydrate polymers will enhance the
biocompatibility of the final products in terms of cell attachments, cell proliferation,
and cell migration. Different chemical cross-linkers with different spacing link will
control the pore size of the hydrogel to cope with the encapsulation efficiency
targeting specific applications. New series of interactive hydrogel can be generated
to be sensitive to the surrounding environment such as pH, temperature, light/
darkness, heavy metals, and bacterial infection. In polymeric carbohydrates whose
chemical structures possess mainly hydroxyl functional groups, chemical modifi-
cations require high temperatures, agitation, and long reaction times to carry out
any chemical reactions. However, such requirements are not favorable for phar-
maceutical carriers designed for hosting and delivery bioactive materials such as
drugs, cells, proteins, and enzymes. Click chemistry is a new expression for
chemical reactions taking place in mild conditions with high-efficient and simple
purification methods. Click chemistry that lies mainly in azide and alkyne pre-
cursors shows potentials to serve as a promising route in performing pharmaceutical
materials taking in consideration ecoconcerns related to their synthesis and uti-
lization in addition to economic issues.
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