Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 269

molecular entanglements and secondary forces such as H-bonding, ionic force and
hydrophobic association while covalently cross-linked hydrogels are called chemical gels
[6]. The biggest advantage of physical hydrogels as drug vehicles is that no toxic cross-
linking entities are involved during gel formation. Yet they have their limitations. These
vehicles always suffer from weak mechanical strength, uncontrolled dissolution of the
hydrogel, and fast release of drugs. It is also difficult to precisely control physical gel pore
size, chemical functionalization, and degradation or dissolution, leading to inconsistent
performance in vivo . Compared with physical gels, chemical hydrogels provide good
mechanical strength and controllable drug release profiles but suffer from side effects [48].
A wide range of cross-linking strategies can be used, including using some cross-linking
agents, polymerization, and various other chemical cross-linking techniques. The main
disadvantage of this approach is that toxic reagents need to be completely removed prior to
hydrogel implantation, which may be difficult to achieve without also leaching loaded
drugs out of the hydrogel [10]. Another issue is that chemical hydrogels have a defined
dimensionality and high elasticity, which hinder their extrusion through a needle when
implanted in vivo . Converting the preformed gel into micro- or nanoparticles, or an in situ
gelation system can sometimes solve the latter problem; however, potential risks of expo-
sure to irradiation and the use of toxic cross-linkers should be deliberatively considered.
Today, both physical and chemical cross-linking strategies are being pursued to achieve in
situ gelation [10].
6.3.1 Physical Cross-linked Hydrogels
There are three major physical interactions (i.e., charge interactions, hydrophobic associa-
tions, and H-bonding) that lead to the gelation of a chitosan solution in response to the
environmental stimuli of pH, temperature, or ionic strength.
6.3.1.1 Charge Interactions
Charge interactions may occur between a polymer and a small molecule or between two
polymers of opposite charge to form a hydrogel.
As for small-molecule cross-linking, chitosan, as a polycation owing to the protonation
of amino groups, interacts with negatively charged molecules through an electrostatic
force. Small negatively charged molecules, that is, sulfate, citrate, and tripolyphosphate
(TPP), were reported to be capable of forming ionic complexes with chitosan [49,50]. The
properties of their hydrogels were influenced by the degree of deacetylation and concen-
tration of chitosan and particularly by the charge density and size of the anionic agents. In
this kind of system, attention should be paid to the fact that chitosan has a p K a of ca. 6.5
and may possess little or no charge above pH 6, limiting its ability to form ionic complexes.
Therefore, anionic molecules that retain a high charge density must be chosen to ensure
strong ionic interactions and to have a small enough molecular weight to freely diffuse
throughout the polymer matrix and quickly form electrostatic bonds [4].
As for polymer-polymer cross-linking, chitosan, a cationic polysaccharide, has been
complexed with anionic polymers, such as proteins (i.e., collagen, gelatin, and fibroin),
anionic polysaccharides (i.e., pectin, carboxymethyl cellulose, and alginate), and anionic
synthetic polymers (i.e., polyalkyleneoxide-maleic acid (PAOMA) copolymer), to form
polyelectrolyte complexes (PECs) [51]. The properties of PECs are mainly determined by
the degree of interaction between individual polymers. The latter condition depends
essentially on their global charge densities and determines their relative composition in