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Zhu et al. HA in tissue engineering

be compounded. For example, Subramaniam et al. [61] skin tissue.
demonstrated that HA can be compounded with
hydroxyapatite (one of the components of the bone In addition to tissue engineering of skin substitute, HA
matrix) and modified with calcium sulfate, which has also been used to increase the retention rate of
encapsulates collagenase. The composite above can fat grafts. Alghoul et al. [70] used HA as a cell carrier,
serve as a substitute for alveolar bone to produce mixing with autologous fat of the same volume and
satisfactory outcomes. transplanted into the back of a nude mouse. They
found that HA can improve the survival rate of early fat
HA can regulate cell differentiation and bone formation transplantation and prolong the fat maintenance time.
by binding to CD44, CD168 on seed cells, such as
mesenchymal cells [62] . Zhu et al. [63] demonstrated DISCUSSION
that N-cadherin modified HA can promote the
differentiation of human mesenchymal cells into bone,
leading to more bone matrix deposition. N-cadherin is Tissue engineering is one of the most promising
an important factor in mediating cell-cell interactions methods in wound healing, while HA is one of the
during the cluster of mesenchymal cells in bone most suitable natural materials in hydrogel scaffolds.
formation [64] . In the experiment, they also modified HA HA has similar water content as human tissue, has
with RGD peptide because only the calcium cadherin good tissue compatibility, and it plays an important
was sufficient to provide sufficient cell adhesion. role in promoting the proliferation and differentiation
of seed cells. In addition, high molecular weight
As a molecular carrier, HA has a wide range of HA has a certain anti-inflammatory effect, and low
applications on the in vivo experiments. Of all the molecular weight HA oligomers have been shown to
researches, carrying bone morphogenetic protein 2 promote angiogenesis. At present, HA as a scaffold
(BMP-2) to promote bone formation, fracture healing is material, connecting molecules, carrier of drugs
the most commonly used method. BMP-2 is a potent and other small molecules has been widely used
bone-forming molecule that has been approved by the in tissue engineering. Since the microenvironment
Food and Drug Administration for intervertebral fusion, formed by HA is particularly suitable for the growth
open tibial fractures, and alveolar bone expansion [65] . of chondrocytes, the application of HA in cartilage
Bhakta et al. [66] confirmed that the thiolated-HA tissue engineering is the most popular. Researchers
exhibited a low burst followed by a sustained release have also devoted themselves to the regeneration of
of BMP-2 while collagen sponge rapidly released bone tissues, myocardial tissues, skin and soft tissues
BMP-2 with a high burst phase that was followed by with the utilization of HA. Natural HA has a short
a low sustained phase. Analysis of bone formation by reservation time in vivo due to the rapid degradation
micro-computed tomography revealed that low burst by hyaluronidase, therefore appropriate cross-linking
followed by sustained release of BMP-2 from a HA and modification of the active group is essential. HA
hydrogel induced up to 456% more bone compared to after cross-linking and modification has been widely
a BMP-2 dose-matched collagen sponge that has a used alone or compounded with other materials in
high burst and sustained release. Bhakta et al. [67] also the tissue engineering. Since HA itself doesn’t have
reported that heparin-modified HA also had a similar a satisfying cell adhesion, modification with RGD
controlled release effect. sequence or heparincan be considered as anecessary
improvement.
HA in skin and soft tissue engineering
Tissue engineering skin equivalents (substitutes) is The current problem is that there are a variety of
one of the most successful and most widely used cross-linking and modification methods of HA.
products in tissue engineering so far. It is usually Moreover, the raw materials from different origins
manufactured by seeding keratinocytes and fibroblasts owning divergent molecular weight (ranging from
into non-human (e.g. type I bovine collagen) matrix [68] . hundreds to millions), thus exhibiting different
However, this tissue engineering skin can only last for biological properties, which brings about quite a lot
approximate 8 weeks due to its high shrinkage of the of difficulties to the research and application of HA.
extracellular matrix, which is not sufficient to form a Since the high cross-linking (high molecular weight)
normal human extracellular matrix consisting of fat, and low cross-linking (low molecular weight) HA make
fibrin, glycosaminoglycans and polysaccharides [68] . such a great difference in the biological properties
Stark et al. [69] seeded keratinocytes on esterified HA that how to combine the anti-enzymatic ability of high
fibers, producing the dermal equivalents that could molecular weight HA with the high biological activity of
last for a longer period and was more similar to normal low molecular weight HA remains to be explored.

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