Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 273

Chitosan-based hydrogel has been prepared by using acrylated chitosan with thiolated
PEO. Unsaturated C=C of acrylated chitosan reacted via Michael addition with the -SH
group of thiolated PEO [34]. Chitosan hydrogel can also be prepared by Michael addition of
thiolated chitosan and the arylated group bearing polymer, such as PEG diacrylate, as
described recently in the literature [33]. The gelation time varies from 30 min to ca. 2 h,
depending on the content of free thiols in thiolated chitosan, the ratio of thiol groups to
arylate groups, and temperature [33]. In addition, as mentioned in Section 1.1.2, this chito-
san-based hydrogel also benefits from enhanced mucoadhesive properties, which can assist
in the oral delivery of therapeutics.
Efficient design of Michael addition cross-linked hydrogels is further facilitated by the
development of kinetic modeling approaches for predicting the rates of hydrogel forma-
tion and degradation and/or the release kinetics of model proteins entrapped or covalently
bonded to the hydrogel network [10]. Such model approaches have considerable potential
for the bottom-up design of future drug delivery vehicles.
6.3.2.3 Enzyme-Catalyzed Reaction
The enzyme-catalyzed cross-linking reaction using, for example, peroxidase is an emerg-
ing approach for the formation of in situ hydrogels, and many recent research works have
focused on it [68-72]. The cross-linkages were formed as follows: First, a phenolic hydroxyl
(Ph) group is incorporated into a polymer. Then HRP, an enzyme, was used to catalyze the
oxidation of electron donors using H 2 O 2 , resulting in polyphenols linked at the aromatic
ring by C-C and C-O coupling between Ph groups. This reaction can be carried out under
mild conditions, such as under physiological environments.
Chitosan-based in situ hydrogels can be formed by following this mechanism. In a typical
reaction, Ph groups were introduced into the chitosan through the conjugation of chitosan
and 3-( p -hydroxyphenyl)propionic acid using EDC/NHS [68]. The resultant chitosan deriv-
atives became soluble at neutral pH. Hydrogels were obtained through the HRP-catalyzed
cross-linking reaction by consuming H 2 O 2 in neutral aqueous solution. The gelation time of
the solution was within seconds and was dependent on the extent of introduced Ph groups,
temperature, and concentrations of HRP and H 2 O 2 . Similar routes were used by Jin et al.
[69] to prepare chitosan-based in situ hydrogel. The gelation times reported by them varied
from 10 s to 4 min with a decrease of the polymer concentration from 3 to 1 wt%. Although
the enzyme-catalyzed reaction was considered as a safe principle for in situ hydrogel forma-
tion, the concentration of toxic H 2 O 2 required to speed up gelation should be controlled
below a certain value. Hence, there may be a balance between gelation time and bioactivity
of the system.
6.3.2.4 Polymerization
Apart from the reaction of functional groups on the polymer, another useful principle to
form hydrogel is through polymerization.
Photopolymerization to form hydrogels has attracted considerable interest in the field of
tissue engineering and drug delivery. Photosensitive functional groups are incorporated
into polymers, and then by adding photoinitiator, polymerization can occur on irradiation
with ultraviolet (UV) light. The latter step helps to cross-link the original polymer, build-
ing up the whole hydrogel network.
A water-soluble photopolymerizable chitosan has been prepared by grafting 4-azido-
benzoic acid to free amine groups of lactose-modified chitosan [73,74]. Thus, azide groups