Chemical Modifications of Hyaluronan for Therapeutic Applications - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 154

hydrogels by performing a thiol-ene or Michael addition reaction
with crosslinkers such as PEG diacrylates [26]. Hydrogels containing
different ECM components such as heparin and chondroitin sulfate
have also been obtained by simple air oxidation of the thiols or via
thiol-disulfide exchange reaction with a disulfide crosslinker [27, 28].
Thiol modified HA has also been used for conjugating biomolecules
or for NP preparation. Though thiol chemistry is easy to perform,
the major drawback is its slow crosslinking kinetics. Though this
chemistry is used for hydrogel preparation to deliver growth factors
and other sensitive proteins, this strategy however has a potential
risk of reacting with disulphide-linked multimeric proteins, thereby,
interfering with the tertiary structure of proteins which might reduce
their bioactivity.
8.3.2 Aldehyde Modified Hyaluronic Acid
Aldehyde modified HA has wide applications in the selective
conjugation of N -terminal peptides and other nucleophiles using
Schiff base chemistry. The most common method employed to prepare
such modification is partial oxidation of the HA sugar backbone using
sodium periodate. Such backbone oxidation is easy to perform as it
could be achieved under aqueous and neutral conditions. However,
such oxidation results in reduction of molecular weight and opening
of the sugar ring, which is detrimental for its cellular recognition
properties and impairs biological function [29]. Recently Wang
and co-workers developed an alternative method by grafting amino
glycerol units on to HA employing EDC chemistry. The flexible
vicinal diols of glycerol were selectively oxidised to yield aldehyde
modification using a short (5 min) oxidation step with periodate.
Under these conditions, HA sugar backbone integrity was preserved
and only the glycerol unit was oxidised [30]. Other methods to
graft an aldehyde residue involve generation of double bonds in
the glucuronic acid by the biodegradation of HA with hyaluronate
lyase followed by ozonolysis and reduction, acidic deprotection of
acetal protected aldehydes, as well as the use of other radical-based
oxidants such as the 2,2,6,6-tetramethyl-1-piperidinyloxy radical