Hyaluronic Acid Incorporation into Scaffolds for Bone and Cartilage Regeneration - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 34

2.7.1 Pure Hyaluronic Acid Scaffolds
Hydrogels made of crosslinked HA have been extensively used
as delivery vehicles for osteogenic growth factors, such as bone
morphogenetic protein-2 (BMP-2), and have been shown to lead
to bone regeneration in preclinical animal models. For example,
hydrogels formed from methacrylated HA with different hydrolytic
degradation rates and loaded with BMP-2 led to significant
mineralised tissue formation in a rat calvarial critical size defect model
after 6 weeks of healing ( Figure 2.5 ) [77]. HA as a carrier for BMP-
2 has also led to better bone formation in an ectopic intramuscular
site when compared to chitosan [78]. Interestingly, the pH of the
formulation also played a role with a lower pH leading to better bone
formation [78]. A thiol-modified HA hydrogel, crosslinked via PEG
diacrylate, was developed that exhibited a low burst followed by
sustained release of BMP-2. For a dose of 1 µg BMP-2, this hydrogel
led to a four-fold increase in ectopic bone formation in vivo when
compared with a dose-matched collagen sponge, which had a high
burst [79]. In another formulation, an acrylated HA was crosslinked
via a thiol-modified PEG in a Michael-type addition reaction with
MSC and/or BMP-2 added during gelation. BMP-2 loading increased
cell viability in the hydrogels in vitro , and the hydrogels with MSC
and BMP-2 led to the most mature bone formation as well as the
highest expression of osteocalcin in a rat calvarial defect model in vivo
[80]. A similar Michael-type addition reaction was used to crosslink
acrylated HA with an additional MMP sensitive peptide [81]. The
MMP sensitive hydrogels loaded with MSC and BMP-2 led to the
greatest bone regeneration in a rat calvarial defect model [81].
Additionally, injectable HA formulations, based on the reaction of
hydrazide and aldehyde-modified HA, have been used as carriers
for recombinant human BMP-2. Comparing different commercial
sources, the more stable BMP-2 variant in vitro also led to more bone
formation in an ectopic model in vivo [82]. BMP-2 loaded in the same
HA hydrogel formulation also led to the most bone formation in a
minimally invasive subperiosteal rat model [83]. A similar hydrogel,
using instead a hydrazide-thiol modified HA to allow additional