Biomedical Engineering Reference
In-Depth Information
gel through the pores on the gel. When placed in vivo , the drug will then diffuse back out
of the hydrogel into the environment. This approach is very simple and will not influence
the bioactivity or therapeutic efficiency of the drugs. Small molecular drugs can diffuse
readily into the hydrogel. However, for some molecules with large sizes, it is not so easy for
them to migrate through the small pores of the hydrogel. In the latter case, drugs are
mixed into the polymer solution before gelation begins. After cross-linking of the polymer
solution, drugs are entrapped into the hydrogel as a result. This method may suffer from
possible deactivation of the drugs during gelation.
Although the above methods are very easy to carry out, they have to face the same prob-
lems. The drug entrapment efficiency of these systems is not very high due to little interac-
tion between the matrix and the drug itself. The release of loaded molecules is not well
regulated. A rapid burst release is always observed during the initial hydrogel swelling in
the release medium. These burst releases can lead to losses of an extremely large part of
the loaded molecules, influencing the therapeutic effect of the drugs. To increase drug
loading efficiency, electrostatic interactions between molecules with opposite charges are
utilized to enhance the binding between drugs and hydrogels. Chitosan hydrogels are
usually performed as attractive carriers for protein or gene delivery because positively
charged amines (under slightly acidic conditions) allow electrostatic interaction with car-
boxyl acid groups on protein or with phosphate-bearing nucleic acids to form PECs [103].
Alonso and coworkers [104] prepared insulin-loaded chitosan nanoparticles based on ionic
interaction between both molecules. The loading capacity was up to 55%. Similar high
entrapment efficiency was also reported by others [105]. Despite this improvement, charge
interactions were found to be too weak to prolong the release time [105,106]. A strong burst
effect within a short time was still observed (Figure 6.14). Therefore, binding between a
loaded drug and the hydrogel matrix should be enhanced further to extend the duration
of drug release.
6.5.2 Covalent incorporation
Another strategy to incorporate drugs into a hydrogel matrix is chemical covalent incorpo-
ration. Since a chemical bond is always stronger than a physical one, drugs can be incorpo-
rated more tightly and a high burst release can be avoided to some extent [107-109]. Most
importantly, the release is regulated by chemical/enzymatic cleavage of the polymer-drug
bond or hydrolysis of the polymer backbone [4,110]. Wu et al. [107] developed chitosan-
methotrexate covalently conjugated nanoparticles as a potential delivery system for meth-
otrexate. Methotrexate was chemically conjugated to chitosan by using glutaraldehyde as
a cross-linking agent. An in vitro release test showed that the stable covalent bonding of
chitosan and methotrexate was beneficial for providing slow release for the drug.
Doxorubicin was also reported to be chemically conjugated to acrylated chitosan via an
amide linkage in order to obtain sustained-release profiles [109]. Doxorubicin-chitosan
conjugates significantly reduced the burst release of free doxorubicin from 90% to 10% and
prolonged the release profile from 5 days to 3 weeks, compared with hydrogels without the
conjugates ( cf . Figure 6.15) .
6.5.3 Composite Systems
If the retardation of drug release using cross-linked hydrogels is not sufficient to slow
the release rate for long-term applications, another system may be incorporated into the
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