Hyaluronan

Hyaluronan (also called hyaluronic acid or hyaluronate) is an anionic, nonsulfated, glycosaminoglycan distributed widely throughout connective, epithelial and neural tissues. It is unique among glycosaminoglycans in that it is nonsulfated, forms in the plasma membrane instead of the Golgi, and can be very large, with its molecular weight often reaching the millions. One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.

The average 70 kg (154 lbs) person has roughly 15 grams of hyaluronan in the body, one-third of which is turned over (degraded and synthesized) every day. Until the late 1970s, hyaluronan was described as a sticky ubiquitous carbohydrate polymer that is part of the extracellular matrix. For example, hyaluronan is a major component of the synovial fluid, and was found to increase the viscosity of this fluid. Along with lubricin, it is one of the fluid’s main lubricating components.
Hyaluronan is an important component of articular cartilage, where it is found in abundance in rooster comb. When aggrecan monomers bind to hyaluronan in the presence of link protein, large highly negatively charged aggregates form. These aggregates pick up water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight of hyaluronan in cartilage decreases with age, but the amount increases.

Hyaluronan is also a major component of skin, where it is involved in tissue repair. High concentrations of hyaluronan in the brains of young rats, and reduced concentrations in the brains of adult rats suggest hyaluronan plays an important role in brain development.

Figure 1. Structure of Hyaluronan

Hyaluronan is a polymer of disaccharides, themselves composed of D-gluconic acid and D-N-acetylglucosamine, linked via alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronan can be 25,000 disaccharide repeats in length. Polymers of hyaluronan can range in size from 5,000 to 20,000,000 daltons in vivo.
Hyaluronan is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.

Figure 2. The Healon GV® OVD is indicated for use in anterior segment ophthalmic surgical procedures. The Healon GV® OVD creates and maintains a deep anterior chamber, to facilitate manipulation inside the eye with reduced trauma to the corneal endothelium and other ocular tissues. (Abbott Medical Optics)

Medical Applications
Hyaluronan is found in many tissues of the body, such as skin, cartilage, and the vitreous humor. Therefore, it is well suited to biomedical applications targeting these tissues. The first hyaluronan 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).

Wound Repair
Skin provides a mechanical barrier to the external environment and acts to prevent the ingress of infectious agents. Once injured, the tissues beneath are exposed to infection; therefore, rapid and effective healing is of crucial significance to reconstruct a barrier function. Skin wound healing is a complex process, and includes many interacting processes initiated by hemostasis and the release of platelet-derived factors. The following stages are inflammation, granulation tissue formation, re-epithelization and remodeling. HA is likely to play a multifaceted role in mediation of these cellular and matrix events.

Skin Care Products
In 2003, the FDA approved hyaluronan injections for filling soft tissue defects such as facial wrinkles. Restylane is a common trade name for the product. Hyaluronan injections temporarily smooth wrinkles by adding volume under the skin, with effects typically lasting for six months. Juvederm is a bacterial hyaluronic acid injectable filler, similar to Restylane, but differing slightly in terms of effect and longevity. It is used for lip augmentation, reduction of folds and wrinkles, and removal of scars.

Figure 3. Target of viscosupplementation for arthritic knee.

Viscosupplementation
The first line of treatment for osteoarthritis of the knee aims to relieve pain. Normally, pain relievers such as ibuprofen or nonsteroidal anti-inflammatory drugs (NSAIDs) are used, along with physical therapy, applications of a topical analgesic and injections of a corticosteroid. However, some people have a reaction to NSAIDs and these agents usually bring only temporary relief.
A relatively new procedure, called viscosupplementation, injects a preparation of hyaluronic acid into the knee joint. Hyaluronic acid is a naturally occurring substance found in the synovial (joint) fluid. It acts as a lubricant to enable bones to move smoothly over each other and as a shock absorber for joint loads. People with osteoarthritis (“wear-and-tear” arthritis) have a lower-than-normal concentration of hyaluronic acid in their joints.
Viscosupplementation has been shown to relieve pain in many patients who cannot get relief from physical therapy or analgesic drugs. The technique has been used in Europe and Asia for several years, but the U.S. Food and Drug Administration did not approve it until 1997, and then only for treating osteoarthritis of the knee. Several preparations of hyaluronic acid are now commercially available.

Viscosupplementation can be helpful for people whose arthritis has not responded to basic treatments. It is most effective if the arthritis is in its early stages (mild to moderate). The long-term efficacy of viscosupplementation is not yet known and research continues in this area.


Select United States Biological Hyaluonan Products

Catalogue No.	Product Name	Type	Host	Source
H7980-11K	Hyaluronic Acid	Pab	Sh x	Hu
H7980-30A	Hyaluronic Acid Binding Protein (Hyaluronan Binding Protein, HABP)	Pab	Rb x	Bo
H7981-02	Hyaluronidase 3 (Hyaluronoglucosaminidase 3, Hyal 3)	Pab	Rb x	Mo
H7981-02A	HYAL3 (Hyaluronidase 3, Hyaluronidase-3, Hyal-3, Hyaluronoglucosaminidase-3, Lung Carcinoma Protein 3, LuCa-3, LUCA3)	Pab	Rb x	Hu
H7981-03	Hyaluronidase 1 (hyaluronoglucosaminidase 1, HYAL-1, LUCA1)	Pab	Gt x	Hu
H7981-03A	Hyaluronidase 1 (hyaluronoglucosaminidase 1, HYAL-1, LUCA1)	Pab	Gt x	Mo
H7981-03B	Hyaluronidase-1 (Hyal-1, Hyal1, Hyaluronoglucosaminidase-1)	Pab	Gt x	Mo
H7981-05B	Hyaluronidase (HYAL)	Pab	Rb x	Sh
H7981-05C	Hyaluronidase (HYAL)	Pabs	Rb x	Sh
H7981-05D	Hyaluronidase (HYAL) (Biotin)	Pab	Rb x	Sh
H7980-11	Hyaluronic Acid, Bovine
H7980-11B	Hyaluronidase, Bovine
H7980-30	Hyaluronic Acid Binding Protein, Bovine (Hyaluronan Binding Protein, HABP)
H7980-35	Hyaluronic Acid Binding Protein (Hyaluronan Binding Protein, HABP) (Biotin)
H7980-36	Hyaluronic Acid Binding Protein 1, Recombinant, Mouse (Hyaluronan Binding Protein 1, HABP1, C1qBP, C1q-R, Human complement component 1, q subcomponent binding protein)
H7980-36A	Hyaluronic Acid Binding Protein 1, Recombinant, Human (Hyaluronan Binding Protein 1, HABP1, C1qBP, C1q-R, Human Complement Component 1, q Subcomponent Binding Protein)
H7981	Hyaluronidase, Bovine, Highly Purified
H7981-01	Hyaluronidase, Bovine
H7981-05	Hyaluronidase, Ovine

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