Meyer and Palmer isolated the polysaccharide hyaluronic acid (sodium hyaluronate, hyaluronan) in 1934 from the vitreous of bovine eyes. They found a substance, which contained two sugar moieties, one of which was uronic acid.
Therefore, to cite the authors, “we propose, for convenience, the name „hyaluronic acid‟, from hyaloid (vitreous) + uronic acid”. Under physiological conditions the polysaccharide is not present in the acid form but exists as a salt: hyaluronate. The most abundant cation in tissues is sodium, and hyaluronic acid is generally present as sodium hyaluronate both in tissues and in products.
Chemical structure
Hyaluronic acid has a simple chemical structure: a disaccharide unit containing glucuronic acid and N-acetylglucosamine. These are joined together forming a uniform, linear polysaccharide molecule as shown in the following figure:
Figure 17. Hyaluronic acid chemical structure.
The number of repeating disaccharide units is denoted by “n”. These sugar units are hydrophilic. Water is attracted to hyaluronic acid, which is therefore highly soluble in water. Hyaluronic acid contains these, and only these, two sugar units in all tissues and in all species. The identical hyaluronic acid molecule can also be manufactured from a non-animal source by modern biotechnological methods. Hyaluronic acid regardless of method of synthesis only contains the simple disaccharide units without amino acids, proteins or other sugar moieties.
Molecular weight
Hyaluronic acid is a uniform, linear and unbranched molecule consisting of multiple identical disaccharide units so that the only variation between various hyaluronic acid preparations is the length and size of the polymer. For example, the molecular size of hyaluronic acid is often lower in synovial fluid from patients with joint disorders. In healthy tissues the molecular weight of hyaluronic acid is typically in the order of 5 to10 million. In some tissues or species, especially in diseased tissues, the molecular weight may be lower: ~1 million. The molecular weight of synthetic hyaluronic acid products varies from 0.5 to 5 million. For comparison, the molecular weight of typical proteins is <100 000. Most polysaccharides in vertebrates have a molecular weight in the order of 10 000 and are linked to various types of proteins
Concentration
Hyaluronic acid is an essential component of the extra cellular matrix of all tissues. Especially high concentrations are found in tissues such as the umbilical cord (4 mg/g), synovial fluid (3-4 mg/ml) and vitreous (0.1-0.4 mg/g). The average concentration of hyaluronic acid in the human body is 200 mg/kg (0.02%). Thus, a human body weighing 60 kg contains about 12 g of hyaluronic acid. Although the highest concentrations of hyaluronic acid are found in connective tissues, most
hyaluronic acid, 56% (7 g), is found in the skin. The normal state of hyaluronic acid in tissues is as a free polymer. However, in some tissues such as the cartilage and tendons hyaluronic acid is bound to large glycoprotein structures (proteoglycans) or in other tissues to specific cell receptors (e.g. CD 44).
Tissue Hyaluronic acid mg/l
Synovial fluid 3500
Vitreous 200
Oocyte cumulus 500
Extracellular space mg/kg mg/kg
Cartilage 1200
Table 6. Hyaluronic acid concentration in different tissues.
Metabolism
The metabolism – the biosynthesis and the catabolism – of hyaluronic acid is in many ways unique. The biosynthesis occurs via an enzyme complex within the cellular membrane, and the removal and degradation of hyaluronic acid is mediated by receptor binding followed by intracellular degradation. This process is very fast and efficient.
The enzyme complex producing hyaluronic acid is not situated within the cell but is maintained within the cell membrane. The two basic sugar units are added onto the growing hyaluronic acid chain from the cell interior, and the hyaluronic acid product is released directly into the surrounding extra cellular medium. Many different cells have the capacity to produce hyaluronic acid, e.g. fibroblasts, synovial cells, endothelial cells, smooth muscle cells, adventitial cells, and oocytes.
The overall turnover rate of hyaluronic acid is fast compared to other extra cellular components such as collagen. The half-life of hyaluronic acid in most tissues ranges from 0.5 to a few days. In skin the half-life is <24 hours. The daily turnover of
hyaluronan is in the order of one-third of the total body content, a rate similar to that of albumin. In a normal human body, about 3 grams of hyaluronic acid is catabolized each day.
The very fast turnover rate of hyaluronic acid takes place in a series of steps as outlined as follows. First, the large hyaluronic acid molecules move at a remarkable speed by means of a reptation (reptile movement) mechanism. The flexible
molecules disentangle and move out of the molecular network with a snake-like motion. Cell receptors bind the free hyaluronic acid molecules, which are engulfed by the cells. Intracellular enzymes in lysosomes subsequently degrade the hyaluronic acid to its basic constituents.
Physiological function
Hyaluronic acid is an important component of the extra cellular space, helping to maintain proper structure and function of tissues by:
• Creating volume
• Lubricating tissues
• Affecting cell integrity, mobility and proliferation
The physiological function of hyaluronic acid is based on the large volume and viscosity of is hydrophilic molecular network. In the extracellular space, the hyaluronic acid network holds large amounts of water. Elevated levels of extra cellular
hyaluronic acid accompany processes that require cell movement and tissue
reorganization; when cells need space for motility and separation these functions are performed in a hyaluronic acid medium. The hyaluronic acid network assists in cell differentiation, cell migration, tissue morphogenesis, embryogenesis, and wound repair. Moving tissues are lubricated by hyaluronic acid. Such effects are dependent on the rheological status of the fluid which is largely a function of the hyaluronic acid molecular weight. The high viscosity and elasticity of hyaluronic acid solutions creates thick layers of unstirred fluid that protect the tissues under movement.
Figure 18. Disappearance of hyaluronic acid from skin.
Biocompatibility
In general, biomolecules synthesized by different species differ in chemical composition. The difference in amino acid composition of proteins and sugar
components of glycoproteins often makes these molecules antigenic to other species or even other individuals of the same species. In contrast to other biomolecules, hyaluronic acid is independent of source as the chemical structure is invariant. This also applies to the hyaluronic acid produced by bacteria. The bacteria with a
protective coat of hyaluronic acid are not as easily recognized as foreign by the immune system and the inflammatory reaction will be greatly reduced.