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Zhu et al. HA in tissue engineering

HA in cartilage tissue engineering through ultraviolet irradiation after injected into the
In the application of HA-based materials, cartilage ideal site and fill the defect space with various shapes.
tissue engineering is the most extensive due to Chung and Burdick [52] used methacrylated HA with
the fact that HA is quite a suitable scaffold for the human multipotent stromal cells (MSCs) to regenerate
growth of chondrocyte. The extracellular matrix of cartilage, and they demonstrated that both in vitro
chondrocytes is rich in glucosamine and HA while and in vivo cultures of MSC-laden HA hydrogels
the latter one plays an important role in regulating the permitted chondrogenesis, measured by the early
function of chondrocyte [39] . Moreover, since HA can gene expression and production of cartilage specific
also be used as a scaffold in bone regeneration [40] , matrix proteins. This kind of in situ cross-linking ways
it is a suitable material for osteochondral tissue including photo-crosslinking and thermosensitive
engineering [41,42] . HA, as a scaffold, has several crosslinking will be a possible future trend.
possible mechanisms to promote cartilage formation.
First, HA can induce stem cells, cartilage progenitor Besides served as a scaffold, HA can also be used a
cells to differentiate into chondrocytes. Some papers biologically active molecule to modify bio-inert artificial
indicate that HA involves in the maintenance of materials such as polyethylene glycol (PEG), small
chondrocyte phenotype, which is utmost important for intestinal submucosa, etc. [54] . The HA-based cell-
the reason that chondrocyte can lose its phenotype scaffold composite can provide a framework for the
during in vitro culture [43] . Furthermore, HA is favorable regenerated matrix. Skaalure et al. [51] demonstrated
to the deposition of extracellular matrix which is that biodegradable PEG hydrogel modified by high
essential in cartilage tissue engineering [44-48] . Besides, concentration of HA can evidently improve the
HA-containing hydrogel material has a lower oxygen deposition of extracellular matrix and proliferation of
concentration, while the hypoxic environment chondrocytes.
is conducive to the growth of chondrocytes [48] .
Another possible mechanism is that HA interacts HA is most generally used in the cross-linked,
with cells through the cell surface of the CD44 modifiedform or as composite with other materials
receptor, regulating cell migration, proliferation, such as platelet-rich plasma [55] , fibrin [46] , chitosan [45] ,
differentiation, and other close contact with the tricalcium phosphate, collagen [48] , alginate, etc. This is
cytoskeleton to CD44-activated cells within the signal because the cross-linked HA has better mechanical
transduction [49] . HA binds to proteoglycans by the properties than the linear one, while the composite
aid of core proteins. These proteoglycan monomers material can combine the advantages of different
can connect with CD44 receptors on chondrocytes, materials, corresponding with the requirements
while the released ones in the extracellular matrix can of tissue engineering scaf fold materials [22] .
enhance matrix permeability, therefore improve the Chen et al. [55] demonstrated that HA and platelet-rich
stress resistances [39] . Lammi et al. [50] reported that plasma can restore the down-regulation of cartilage
HA deposition would occur in the areas of cartilage gene expression induced by interleukin-1β and tumor
injury and it would attract exogenous mesenchymal necrosis factor-α, including SOX-9, collagen type II
stem cells to the injured area. HA can also act as a and aggrecan.
cell carrier, wrapping stem cells and chondrocytes
in the injected area so that the cells can proliferate In addition, there have been reports of using HA as
and differentiate in situ [45,51] . Chung and Burdick [52] scaffold in the engineering of intervertebral disk [56] ,
demonstrated in both in vivo and in vitro experiments vocal cords [57] , nucleus pulposus [58] , etc.
that methacrylated HA is capable of providing a
microenvironment that facilitates differentiation of HA in bone tissue engineering
mesenchymal stem cells into cartilage, and the effect HA also has a wide range of research and application
can be enhanced in the presence of certain cytokines in bone tissue engineering, it can be used as a
such as transforming growth factor-β3. scaffold or molecular carrier to promote bone
tissue regeneration [40,59] . The existing papers show
Methacrylated HA is gaining increasingly attention that its application has been explored in the field
because it can gelatinize through an easy photo- of skull [60] , alveolar [61] and so on. As in cartilage
crosslinking, moreover, seed cells can be tissue engineering, HA is also usually required for
encapsulated into HA in this way which enables the modification in bone tissue engineering. Since the
cell to live in a 3D environment [52,53] . Conventional mechanical properties of HA are weaker than that
cartilage tissue engineering materials requirea of human natural bones, the use of HA alone as a
much larger incision than injectable ones, andphoto- scaffold material is not sufficient to support the cell-
crosslinkingHA can transform from liquid to hydrogel scaffold composite and requires other materials to

Plastic and Aesthetic Research ¦ Volume 4 ¦ December 29, 2017 223