Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 270

the PECs. The lower the charge density of the polymer, the higher the polymer proportion
in the PECs, since more polymeric chains are required to react with the other polymers. In
addition, as PECs are reported to be formed between two oppositely charged polymers, a
PEC-forming reaction can only occur at pH values in the vicinity of the p K a interval of the
two polyelectrolytes. For instance, Yao and coworkers found that interaction between gela-
tin (pH iso 4.7) and chitosan (p K a 6.5) in the aqueous medium was enough to form PECs at a
pH range from 4.7 to 6.2 [52]. Research also showed that the stability of PEC hydrogel
depends on charge density, solvent, ionic strength, pH, and temperature [4].

6.3.1.2 Hydrophobic Interactions

Polymers with hydrophobic domains can cross-link in aqueous environments via reverse
thermal gelation, known as “sol-gel” chemistry. That is, they are liquid at room tempera-
ture or below and form a solid-like hydrogel when the temperature increases. This special
type of physical hydrogel has been studied. They are called injectable thermosensitive
hydrogels and have been adapted for in vivo use, where they solidify in situ upon injection,
and are attractive in DDSs due to less invasive delivery. Polymers with such gelation prop-
erties are typically moderately hydrophobic, and hydrophobic interactions between chains
are proposed as the main driving force of gelation. As shown in Figure 6.10 [10], with an
increase of temperature, hydrophobic domains aggregate to minimize the hydrophobic
surface area contacting bulk water, reducing the amount of structured water surrounding
the hydrophobic domains and maximizing solvent entropy. The temperature at which
gelation occurs depends on the concentration of the polymer, the length of the hydropho-
bic block, and the chemical structure of the polymer: the more hydrophobic the segment,
the larger the entropic cost of water structuring, the larger the driving force for hydropho-
bic aggregation, and the lower the gelation temperature [10].
One successful chitosan-based injectable thermosensitive system was developed by
Chenite et al. [53,54] utilizing chitosan and polyol salts. In their study, glycerophosphate
(GP), a polyol-phosphate salt, was added to an aqueous chitosan solution where it neutral-
ized the ammonium groups of chitosan and permitted chitosan solutions with pH values
of 7 without precipitation. Gelation by increasing temperature was believed to be mainly
caused by the increased hydrophobic association between the chitosan chains at elevated
temperatures [53,54]. The temperature of gelation in this chitosan-GP system can be con-
trolled primarily through the regulation of solution pH [55]. If desired, gelation at human
body temperature can be achieved, such as a solution with a 2% chitosan concentration

Hydrophilic block
Hydrophobic block

Te mperature

Hydrophobic
domains

Figure 6.10
Mechanism of in situ physical gelatin driven by hydrophobic interactions. (From Hoare, T. R. and Kohane, D. S.
2008. Polymer 49: 1993-2007. With permission.)