Hyaluronic acid

Hyaluronic acid (HA) is a high molecular weight biopolysaccharide. The naturally occurring biopolymer was discovered in 1934 by Karl Meyer and his assistant John Palmer in the vitreous of bovine eyes. Biological functions for HA are found in organisms from bacteria to animals, including humans. HA is found in most connective tissues and is more concentrated in synovial fluid, the vitreous fluid of the eye, umbilical cords and chicken combs. Integral membrane proteins called hyaluronan synthases synthesize HA and HA is degraded by a family of enzymes called hyaluronidases.

In 1934, Meyer and Palmer isolated the previously unknown substance for the vitreous body of cow eyes. The name was derived from “hyalos”, the Greek word for glass plus uronic acid since one of the two sugar molecules it contained is uronic acid. The term “hyaluronan” was introduced in 1986 which conforms to the international nomenclature of polysaccharides and is attributed to Endre Balazs. The term encompasses the different forms the molecule can take. Hyaluraonic acid is the acid form and the salts, such as sodium hyaluronate form at physiological pH.

HA was used commercially in 1942 as a substitute for egg white in bakery products. In the 1950s hyaluronan was used in humans for eye surgery as a vitreous substitution or replacement.

HA is a type of carbohydrate called a mucopolysaccharide and it can be several thousand of sugars (carbohydrates) long. HA can bind to different molecules. When bound to water HA gives it a stiff viscous quality similar to “Jello”. HA is one of the most hydrophilic molecules in nature.

Chemical structure of hyaluronic acid from Necas et al. Veterinarni Medicina (2008)

In biological organisms, HA is found mainly in the extracellular matrix and pericellular matrix. HA can also occur intracellularly. Biological functions include maintenance of elastoviscosity of liquid connective tissues such as synovial and eye vitreous fluid, control of tissue hydration and water transport, supramolecular assembly of proteoglycans in the extracellular matrix and various receptor-mediated roles in cell detachment, mitosis, migration, tumor development and metastasis and inflammation. By binding water in the body, HA lubricates movable parts like joints and muscles.

HA is a signaling molecule involved in mammalian biological processes and plays roles in disease causing events such as inflammation, tumorigenesis and abnormal immune function. Bacteria such as Streptococcus zooepidemicus synthesise HA and use it to encapsulate their cells and escape detection from the host’s immune system.

Due to tissue-friendliness and consistency HA is used in skin-care products as a moisturizer.

HA has good biocompatibility, is non-immunogenic and has unique viscoelastic properties. HA has been used in supplementation of joint fluid in arthritis, as a surgical aid in eye surgery and to facilitate the healing and regeneration of surgical wounds. In drug delivery, HA has been studied as a delivery agent for ophthalmic, nasal, pulmonary, parenteral and topical administration of drugs. Commercially available preparations of HA derivatives and cross-linked HA materials have been developed for drug delivery in the form of films, microspheres, liposomes, fibers and hydrogels.

HA is used in tissue scaffolding materials used for tissue engineering. In stem cell biology and regenerative medicine, HA hydrogel scaffolds can be used as 3D cell culture systems that mimic the natural stem cell niche. HA hydrogels can be degraded by cell-released enzymes. Functional groups such as thiols, acrylates and amines can be conjugated to the HA backbone.

Large scale production of HA involves extraction from animal tissues, typically rooster combs and bacterial expression systems in Streptococcus. Both methods have safety concerns for use in biomedical products. Alternative sources of HA which have been pursued include engineered microorganisms that are endotoxin-free microorganisms such as Bacilli and Escherichia coli. Biosynthetic enzymes have been used commercially to produce HA in a cell-free system.