Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 272

6.3.2.1 Schiff Base Formation
It is well known that bifunctional aldehydes, such as glutaraldehyde and phthalaldehyde,
can be used to cross-link chitosan. The mechanism of this cross-linking method involves
the formation of Schiff base. A Schiff base bridge is formed via reaction of the aldehyde
groups with the -NH 2 groups of chitosan. Chitosan molecules are then bonded together in
this way and engender gelation. This reaction is very fast and can improve the mechanical
properties and stabilize the hydrogel. However, glutaraldehyde is cytotoxic, and even trace
amounts of unreacted cross-linkers harm the body and impair the global biocompatibility
of a chitosan delivery system [62]. Moreover, glutaraldehyde may react with the drug
loaded and limit its therapeutic efficacy (i.e., denaturing protein drugs bioactivity).
Researchers have developed some new cross-linkers that are relatively safer to make up
for the drawbacks of these hydrogels.
Genipin, as a natural cross-linker, was investigated in order to cross-link chitosan due to
its lower toxicity and slower degradation rate compared to the glutaraldehyde-cross-linked
chitosan gels [62]. Interactions between genipin and chitosan have nothing to do with
Schiff base formation but are just a nucleophilic substitution. Amide linkage was formed
to cross-link the whole network. However, the exact mechanism of reaction depends on
pH, which plays a role in the degree of cross-linking and in the degree of condensation of
genipin in the connection. Yao and coworkers [28] synthesized a noncytotoxic cross-linker
by oxidizing glucose and prepared alkylated chitosan gels cross-linked by oxidized glu-
cose via Schiff base formation. The resultant chitosan-based hydrogel was used as a pH-
sensitive carrier in delivering vitamins.
Cross-linkers for Schiff base formation used above are almost small molecules. More
recently, macromolecules were modified to produce cross-linkers that are more biocom-
patible and less cytotoxic [63-65]. Rinaudo developed a new way to cross-link chitosan in
aqueous solution in order to develop a controlled drug release system [63]. Nonionic poly-
saccharides were oxidized to obtain polyaldehydic derivatives capable of reacting with the
free -NH 2 of chitosan. The Schiff base formed was reduced in the presence of a reducing
agent (NaBH 3 CN). The advantage of this reaction is that the covalent bond between chito-
san and the aldehydic substrate is stable irrespective of the pH. Moreover, considering that
the formation of Schiff base cross-linkage is extremely fast, usually within seconds, it does
not seem an ideal mechanism to form injectable DDSs. However, since the movement flex-
ibility of macromolecules is lower than that of the smaller molecules, the cross-linking
reaction speed may decrease slightly. Weng's report showed that using oxidized dextran
as the macromolecular cross-linker of chitosan, the gelation triggered by Schiff base for-
mation happened within 1-5 min [64]. The higher the oxidation degree of dextran, the
faster the gelation. This made Schiff base formation a possible mechanism for preparing
injectable chitosan hydrogel for drug delivery.
6.3.2.2 Michael Addition
Chitosan hydrogels have also used Michael addition reactions [33,34,66,67] to form cross-
linkages. Michael addition is a kind of reaction between thiols and either acrylates or vinyl
sulfones, forming sulfide linkages. This approach is popular today for in situ hydrogel
preparation because the reaction is highly selective versus biological amines and can be
carried out under physiological conditions [66]. Moreover, its rapid reaction speed, the
relative biological inertness of polymeric precursors, and relatively benign reactivity with
biomolecules have sparked investigators' interest in them [4,10].