Hyaluronic Acid (also called Hyaluronan and Hyaluronate)
is a non-sulfated glycosaminoglycan distributed widely
throughout connective, epithelial, and neural tissues.
It is one of the chief components of the extracellular
matrix. The average 70-kg
man has roughly 15 grams of Hyaluronic Acid in his body,
one-third of which is turned over (degraded and
synthesised) every day.
Until the late 1970s, Hyaluronic Acid was described as a
"goo" molecule, a ubiquitous carbohydrate polymer that
is part of the extracellular matrix. For example,
Hyaluronic Acid is a major component of the synovial
fluid and was found to increase the viscosity of the
fluid. Along with lubricin, it is one of the fluid's
main lubricating components.
Hyaluronic Acid is an important component of articular
cartilage, where it is present as a coat around each
cell (chondrocyte). When aggrecan monomers bind to
Hyaluronic Acid in the presence of link protein, large
highly negatively-charged aggregates form. These
aggregates imbibe water and are responsible for the
resilience of cartilage (its resistance to compression).
The molecular weight (size) of Hyaluronic Acid in
cartilage decreases with age, but the amount increases.
Hyaluronic Acid is also a major component of skin, where
it is involved in tissue repair. When skin is
excessively exposed to UVB rays, it becomes inflamed
(sunburn) and the cells in the dermis stop producing as
much Hyaluronic Acid, and increase the rate of its
degradation. Hyaluronic Acid degradation products also
accumulate in the skin after UV exposure.
While it is abundant in extracellular matrices,
Hyaluronic Acid also contributes to tissue
hydrodynamics, movement and proliferation of cells, and
participates in a number of cell surface receptor
interactions, notably those including its primary
receptor, CD44. Upregulation of CD44 itself is widely
accepted as a marker of cell activation in lymphocytes.
Hyaluronic Acid's contribution to tumour growth may be
due to its interaction with CD44. Receptor CD44
participates in cell adhesion interactions required by
Although Hyaluronic Acid binds to receptor CD44, there
is evidence that Hyaluronic Acid degradation products
transduce their inflammatory signal through Toll-like
receptor 2 (TLR2), TLR4 or both TLR2, and TLR4 in
macrophages and dendritic cells. TLR and Hyaluronic Acid
play a role in innate immunity.
High concentrations of Hyaluronic Acid in the brains of
young rats, and reduced concentrations in the brains of
adult rats suggest that Hyaluronic Acid plays an
important role in brain development.
The chemical structure of Hyaluronic Acid was determined
in the 1950s in the laboratory of Karl Meyer. Hyaluronic
Acid is a polymer of disaccharides, themselves composed
of D-glucuronic acid and D-N-acetyl-glucosamine, linked
together via alternating β-1,4 and β-1,3 glycosidic
bonds. Hyaluronic Acid can be 25,000 disaccharide
repeats in length. Polymers of Hyaluronic Acid can range
in size from 5,000 to 20,000,000 Da in vivo. The average
molecular weight in human synovial fluid is 3−4 million
Da, and Hyaluronic Acid purified from human umbilical
cord is 3,140,000 Da.
Hyaluronic Acid is energetically stable in part because
of the stereochemistry of its component disaccharides.
Bulky groups on each sugar molecule are in sterically
favoured positions, whereas the smaller hydrogens assume
the less-favourable axial positions.
Hyaluronic Acid is synthesized by a class of integral
membrane proteins called Hyaluronic Acid synthases, of
which vertebrates have three types: HAS1, HAS2, and
HAS3. These enzymes lengthen Hyaluronic Acid by
repeatedly adding glucuronic acid and
N-acetyl-glucosamine to the nascent polysaccharide as it
is extruded through the cell membrane into the
Hyaluronic Acid synthesis (HAS) has been shown to be
inhibited by 4-Methylumbelliferone (hymecromone,
heparvit), a 7-Hydroxy-4-methylcoumarin derivative. This
selective inhibition (without inhibiting other
Glycosaminoglycans) may prove useful in preventing
metastasis of malignant tumour cells.
Hyaluronic Acid is degraded by a family of enzymes
called hyaluronidases. In humans, there are at least
seven types of hyaluronidase-like enzymes, several of
which are tumour suppressors. The degradation products
of Hyaluronic Acid, the oligosaccharides and very
low-molecular-weight Hyaluronic Acid, exhibit
pro-angiogenic properties. In addition, recent studies
showed that Hyaluronic Acid fragments, not the native
high-molecular mass of Hyaluronic Acid, can induce
inflammatory responses in macrophages and dendritic
cells in tissue injury and in skin transplant rejection.
Hyaluronic Acid is naturally found in many tissues of
the body, such as skin, cartilage, and the vitreous
humour. It is therefore well suited to biomedical
applications targeting these tissues. The first
Hyaluronic Acid biomedical product, Healon, was
developed in the 1970s and 1980s by Pharmacia, and is
approved for use in eye surgery (i.e., corneal
transplantation, cataract surgery, glaucoma surgery and
surgery to repair retinal detachment). Other biomedical
companies also produce brands of Hyaluronic Acid for
Hyaluronic Acid is also used to treat osteoarthritis of
the knee. Such treatments, called visco-supplementation,
are administered as a course of injections into the knee
joint and are believed to supplement the viscosity of
the joint fluid, thereby lubricating the joint,
cushioning the joint, and producing an analgesic effect.
It has also been suggested that Hyaluronic Acid has
positive biochemical effects on cartilage cells.
However, some placebo controlled studies have cast doubt
on the efficacy of Hyaluronic Acid injections, and
Hyaluronic Acid is recommended primarily as a last
alternative to surgery.
Oral use of Hyaluronic Acid has been lately suggested,
although its effectiveness needs to be demonstrated. At
present, there are some preliminary clinical studies
that suggest that oral administration of Hyaluronic Acid
has a positive effect on osteoarthritis, but it remains
to be seen if there is any real benefit to the
Due to its high biocompatibility and its common presence
in the extracellular matrix of tissues, Hyaluronic Acid
is gaining popularity as a biomaterial scaffold in
tissue engineering research.
In some cancers, Hyaluronic Acid levels correlate well
with malignancy and poor prognosis. Hyaluronic Acid is
thus often used as a tumour marker for prostate and
breast cancer. It may also be used to monitor the
progression of the disease.
Hyaluronic Acid may also be used postoperatively to
induce tissue healing, notably after cataract surgery.
Current models of wound healing propose that larger
polymers of hyaluronic acid appear in the early stages
of healing to physically make room for white blood
cells, which mediate the immune response.
Hyaluronic Acid has also been used in the synthesis of
biological scaffolds for wound healing applications.
These scaffolds typically have proteins such as
fibronectin attached to the Hyaluronic Acid to
facilitate cell migration into the wound. This is
particularly important for individuals with diabetes who
suffer from chronic wounds.
In 2007, the European Medicines Agency extended its
approval of Hylan GF-20 as a treatment for ankle and
shoulder osteoarthritis pain.
Hyaluronic Acid is a common ingredient in skin care
products. In 2003 the Federal Drugs Administration
approved Hyaluronic Acid injections for filling soft
tissue defects such as facial wrinkles. Restylane is a
common trade name for the product. Hyaluronic Acid
injections temporarily smooth wrinkles by adding volume
under the skin, with effects typically lasting for six
months. People who have been on any blood medication
with in the last five years should not inject this drug
until the five year span is over. It is alleged that
this drug is not suitable for use in elderly patients
because it can cause memory loss, although there is no
evidence in the literature of any negative cognitive
effects attributable to hyaluronic acid injections.
Hyaluronic acid is derived from hyalos (Greek for
vitreous) and uronic acid because it was first isolated
from the vitreous humour and possesses a high uronic
The term hyaluronate refers to the conjugate base of
hyaluronic acid. Because the molecule typically exists
in vivo in its polyanionic form, it is most commonly
referred to as Hyaluronic Acid.
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Is there any info on
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