Introduction
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.

Description
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 tumour cells.

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.

Structure
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.


Synthesis
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 extracellular space.

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.

Degradation
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.

Medical Applications
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 ophthalmic surgery.

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 treatment.

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.

Cosmetic Applications
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.

Etymology
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 acid content.

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.