Hyaluronan (also called hyaluronic acid or hyaluronate or HA) is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. Hyaluronan is a polymer of disaccharides which is composed of D-glucuronic acid and D-N-acetylglucosamine. In the dermal connective tissue, Hyaluronan is the most abundant glycosaminoglycan (GAG) and the main GAG components of the extracellular matrix ground substance – an amorphous viscoelastic gel to hold cells and fibers in place. It is unique among glycosaminoglycan in that it is nonsulfated, and can be very large. Hyaluronan is synthesized by a class of integral membrane proteins called hyaluronan synthases on fibroblast cell surface. There are at least three types of hyaluronic acid synthases: HAS1, HAS2, and HAS3. HAS1 and HAS2 synthases produce high molecular weight HA whereas HAS3 produces low molecular weight HA. Hyaluronic acid is degraded by the enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan (hyaluronan fragments) may have some biological function that is distinct and different from the nonhydrolyzed hyaluronan.
The biological functions of hyaluronan in skin include hydration due to its strong water-binding and retention capacity, cell proliferation and migration, tissue repair, and is also involved in inflammatory or immune response where it can interact and bind to a number of cell surface receptors including its primary receptors CD44 and RHAMM. Hyaluronan also contributes to hydrodynamics and biomechanical properties of the skin. Epidermal hyaluronan also have proinflammatory role and free-radical scavenging function in the inflammatory or immune response which contradicts its role in inflammatory stimulation initially. The amount and synthesis of hyaluronan is significantly increased at the site of tissue injury. Hyaluronan is also abundant in granulation tissue matrix, the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. HA plays an important role in the normal epidermis and has crucial functions in the reepithelization processes. Epidermal cells are also able to synthesize HA. It is an integral part of the extracellular matrix of basal keratinocytes, the major constituents of the epidermis that is able to activate keratinocyte proliferation and migration.
The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties. In addition, recent studies showed hyaluronan fragments (degraded or hydrolyzed form of hyaluronic acid), not the native high-molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury. Recent studies have shown that degraded or hydrolyzed form of hyaluronic acid has a strong inhibition of lipid peroxidation and scavenging activities of hydroxyl radical, 1,1-diphenyl-2-picryldydrazyl radical and superoxide anion, suggesting that the reduced size of Hyaluronan has antioxidant property.
The skin content of unfragmented hyaluronic acid decreases with age. The most dramatic histochemical change observed in senescent skin is the evident decrease in epidermal HA. In contract to previous in vitro and in vivo observation, recent studies document that the total HA level remain constant in skin with aging. It is rather the avidity of HA with dermal structure and the HA extractability that changes with aging, suggesting dysfunctional change of HA 3D-molecular structure. The major changes include the increasing avidity and the concomitant loss of extractability. Such intercalated HA may have diminished ability to bind water for hydration. Progressive loss in the size of the HA polymer in skin as a function of age has also been reported. The increased bonding of HA with dermal structure with aging correlates with the progressive crosslinking of collagen and the steady loss of collagen extractability. These changes in structure, size and avidity of hyaluronan result in the clinical signs of aging skin.
When skin is exposed to excessive UVB rays, the cells in the dermis stop producing as much hyaluronan, and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure. There is also an abnormal pattern of distribution where HA appears to be deposited on the elastotic material that comprise elastosis and diffusely associated with the actinic damaged collagen.
Topical hyaluronic acid in the form of gels, serums and so forth is widely available and is a very common anti-aging ingredient used in the topical skin care products. Hyaluronic acid-based anti-aging dermal filler are one of the earliest FDA approved wrinkle fillers on the market. Two well known commercially available HA dermal filler is Restylane® (see Restylane Review) and Juvederm® (see Juvederm Review). In addition, hyaluronic acid level may be stimulated by using ingredients that can activate hyaluronic acid synthases or ingredients that can inhibit hyaluronidases (the enzyme degrades HA). However, there is little data and research to prove the availability and effectiveness of such ingredients. One additional approach would be to provide the body with more building blocks for hyaluronic acid, such as glucosamine and N-acetyl-glucosamine. Research is needed, however, to determine whether oral or topical administration of the HA building blocks increases its synthesis in the skin.