Hyaluronic Acid Incorporation into Scaffolds for Bone and Cartilage Regeneration - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 26

2.4.2 Amidation
HA amidation modifies the -COOH group by coupling with an amine
[45], and this approach is being increasingly used to make scaffolds
for bone and cartilage repair. For example, tyramines can be reacted
with the -COOH groups on the HA backbone, forming HA-tyramide
( Figure 2.1b ), and then the modified HA can be enzymatically
crosslinked using hydrogen peroxide and horseradish peroxidase [45].
Thiol-modified HA is created by coupling of disulfide-containing
dihydrazide reagents to the -COOH groups via carbodiimide
chemistry, followed by reduction to expose the thiol groups [46, 47].
The thiol-modified HA ( Figure 2.1c ) will spontaneously crosslink to
form hydrogels [46, 47].
A recently developed reaction scheme for forming HA hydrogels
from injectable precursors involves hydrazone crosslinks that form
at physiological pH between HA-hydrazide ( Figure 2.1d ) and HA-
aldehyde ( Figure 2.1e ) [48]. The HA-hydrazide can be formed by
modifying HA with a symmetrical difunctional reagent that reacts
with the -COOH groups in an amide-type reaction. This difunctional
reagent contains a central protecting group that can be removed
under mild conditions to reveal the desired functional group, such
as hydrazide [49]. HA-aldehyde can be formed via synthesis of a
2,3-dihydroxypropyl amide derivative of HA and further reaction
with sodium periodate [48], for example.
2.4.3 Combination with Synthetic Polymers
Two of the most commonly used synthetic polymers in combination
with HA are polyethylene glycol (PEG) and poly(lactic- co -
glycolic acid) (PLGA). Hybrid hydrogels of PEG and HA can be
formed by combining methacrylated HA with acrylated PEG via
photopolymerisation [44]. HA has also been combined with an amine-
terminated PLGA-PEG diblock copolymer. The -COOH groups
of HA can be activated with 1-ethyl-3-(3-dimethylaminopropyl)