Chemical Modifications of Hyaluronan for Therapeutic Applications - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 157

currently on the market. The reaction consists of the epoxide ring
opening to form ether bonds with the HA hydroxyl groups.
8.3.4.2 Ether Formation using Divinyl Sulfone
Divinyl sulfone (DVS) is another common crosslinker of HA hydrogel
[39, 40]. This reaction is performed at high pH values (0.2 M
NaOH, pH > 13) and creates sulfonyl bis-ethyl linkages between the
hydroxyl groups of HA. This crosslinking method has the advantage
of occurring at room temperature, which reduces the degradation of
HA at alkaline pH that generally occurs at higher temperatures. Even
though the starting material, DVS, is highly reactive and toxic, the
HA-DVS hydrogels are biocompatible as confirmed by histological
analysis of the regenerated tissue.
8.3.4.3 Hemiacetal Formation using Glutaraldehyde
Several authors have used glutaraldehyde (GTA) for HA crosslinking.
GTA crosslinking needs to be performed under acidic conditions to
obtain the acetal crosslinked product. Since this reaction is reversible
under acidic pH, the acetal crosslinked hydrogel is obtained by
neutralising the gel [41]. Another disadvantage of this strategy is
the toxicity associated with GTA that limits its application in the
biomedical field.
8.3.4.4 Ester Formation with Methacrylic Anhydride
Methacrylated HA was synthesised by esterification with methacrylic
anhydride in water at basic pH. The HA-methacrylate derivative
was photopolymerised into networks with a wide range of physical
properties [42].