Chemical Modifications of Hyaluronan for Therapeutic Applications - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 164

reaction, this purification is inefficient. Therefore, dialysis should
be performed under acidic conditions (if acid-sensitive functional
groups are absent) in the presence of 100 mM sodium chloride. The
high saline condition breaks the electrostatic association between the
carboxylate residues of HA and the impurities possessing cationic
charges. Several published articles show high coupling yields when
using EDC to conjugate amines with HA, which is in fact due to
inefficient purification [71]. This results in burst release of drugs such
as Dox when encapsulated in a HA micelle [72]. If purification is done
properly under saline conditions, these complications can be avoided.
8.6 Designing Hyaluronic Acid Hydrogels
HA hydrogels are suitable for application in the pharmaceutical
and medical fields due to their large water retaining capacity,
biocompatibility and tunable viscoelastic properties which are similar
to those of natural tissues [47]. The simple strategy to tailor HA
hydrogels is by physical association via hydrophobic interactions,
without using any toxic crosslinking reagent [73]. However, these
types of hydrogel display low stability and are not suitable for long-
term drug release. The other strategy involves chemically crosslinking
the two HA polymers using bifunctional crosslinking reagents such
as polyfuctional epoxides [74], glutaraldehyde [75], DVS [76], or by
enzymatic crosslinking [77]. These hydrogels are successfully utilised
in drug delivery and tissue engineering applications. The mechanical
properties and stability of these hydrogels can be tuned by varying
the crosslink density by optimising the ratio of HA to crosslinker.
The disadvantage of this however, is the toxicity associated with
the excess of crosslinking reagents used to develop this hydrogel.
Another elegant and biocompatible route to tailor hydrogels is by in
situ crosslinking of appropriately modified hydrogels. This method
facilitates the complete removal of any crosslinker or toxic reagents
used, as individual HA components could be suitably dialysed
and purified. These in situ HA hydrogels are prepared by various
methods such as hydrazone chemistry [25, 29], Michael addition [78],
disulfide linkage [79], photocrosslinking [80] or click chemistry [81].