Chemical Modifications of Hyaluronan for Therapeutic Applications - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 165

Hydrazone crosslinked HA or HA/PVA hydrogel has been exploited
as an efficient scaffold for bone tissue regeneration. HA hybrid gels
containing, collagen and gelatin display good mechanical properties,
degradation resistance and good angiogenesis, which promote
their application in cartilage regeneration [82] and cornea tissue
engineering [83]. HA/chitosan hydrogels have been used for cartilage
tissue engineering because they are biocompatible, biodegradable
and their structure is similar to that of natural cartilage tissue [84].
The mechanical properties, in vivo stability and controlled in vivo
degradation can be tuned by manipulating the crosslinking density or
by increasing the solid content in the hydrogel formulation. However,
the biochemical properties and receptor recognition are compromised
by excessive chemical modification of these polymers. Therefore,
robust conjugation strategies, without increasing the chemical
modification, are required for designing stable hydrogels. Recently,
Oommen and co-workers reported hydrazone crosslinking chemistry
that gives significantly higher stability than conventional hydrazone
linkages [25]. This was achieved by fine-tuning of electronic
distribution across the hydrazone linkage so that it stabilises the
positive charges on the α-amino residue on the hydrazone. This
was achieved by using CDH modified HA which forms intrinsically
stabilised hydrazone linkages that are nearly 15 times more stable
at pH 5 than conventional ADH derived hydrazone. The CDH (C 1 =
N 1 -N 2 H-(C = O)N 3 H) type linker allows delocalisation of N 2 positive
charge due to its urea-type structure, which could prevent protonation
of N 1 and N 2 and hydrolysis of the hydrazone bond ( Figure 8.3 ).