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Chemical Structure It would take an additional 20 years before Meyer's laboratory finally completed the work that determined the precise chemical structure of the basic disaccharide motif that forms Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) . During these years they showed that the uronic acid and aminosugar in the disaccharide are D-glucuronic acid and D-N-acetylglucosamine, and that they are linked together through alternating beta-1,4 and beta-1,3 glycosidic bonds, Figure 1. Both sugars are spatially related to glucose which in the beta configuration allows all of its bulky groups ( the hydroxyls, the carboxylate moiety and the anomeric carbon on the adjacent sugar ) to be in sterically favorable equatorial positions while all of the small hydrogen atoms occupy the less sterically favorable axial positions. Thus, the structure of the disaccharide shown in the Figure 1 is energetically very stable.

Polymer Structure Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) synthase enzymes synthesize large, linear polymers of the repeating disaccharide structure of hyaluro-nan by alternate addition of glucuronic acid and N-acetylglucosamine to the growing chain using their activated nucleotide sugars ( UDP - glucuronic acid and UDP-N-acetlyglucosamine ) as substrates.1 The number of repeat disaccharides, n, in a completed Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate)molecule can reach 10,000 or more, a molecular mass of ~4 million daltons (each disaccharide is ~400 daltons). The average length of a disaccharide is ~1 nm. Thus, a Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate) molecule of 10,000 repeats could extend 10 µm if stretched from end to end, a length approximately equal to the diameter of a human erythrocyte. Figure 2 shows an electron micrograph of a few intertwined Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate) molecules that have been deposited on a flat surface and rotary shadowed with heavy metal for contrast.

Solution Structure In a physiological solution, the backbone of a Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate) molecule is stiffened by a combination of the chemical structure of the disaccharide, internal hydrogen bonds, and interactions with solvent. The axial hydrogen atoms (indicated in Figure 1B) form a non-polar, relatively hydrophobic face while the equatorial side chains form a more polar, hydrophilic face, thereby creating a twisting ribbon structure.2 Consequently, a Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate) molecule assumes an expanded random coil structure in physiological solutions which occupies a very large domain, Figure 3. The actual mass of Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate) within this domain is very low, ~0.1% (wt/vol) or less when the macromolecule is present at a very dilute concentration in saline. This means that the domains of individual molecules would overlap each other at concentrations of 1 mg hyaluro-nan per ml or higher.
Hyaluronan in Tissues .Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) is present in all vertebrates, perhaps arising in animals with notochords. It is also present in the capsule of some strains of Streptococci that quite likely pirated the enzymatic machinery for its synthesis from vertebrate hosts. Hyaluro-nan is a major constituent of the extracellular matrices in which most tissues differentiate.3 It is also an essential component of many extracellular matrices in mature tissues. In some cases, Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) is a major constituent; as, for example, in the vitreous of the human eye (0.1-0.4 mg/g wet weight), or in synovial joint fluid (3-4 mg/ml), or in the matrix produced by the cumulus cells around the oocyte prior to ovulation (~0.5 mg/ml),4 or in the pathological matrix that occludes the artery in coronary restenosis.5 In others, while representing less of the mass of the tissue, hyaluro-nan serves as an essential structural element in the matrix. For example, Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) is present at ~1 mg/g wet weight in hyaline cartilages, enough to fill the tissue volume in the absence of other constituents. However, aggrecan, the large chondroitin sulfate proteoglycan, is present at a much higher concentration (25-50 mg/g wet weight), and hyaluro-nan retains aggrecan molecules in the matrix through specific protein-hyaluro-nan interactions which mask the Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) backbone.6 Hyaluro-nan is less concentrated in the matrix of other connective tissues, such as those surrounding smooth muscle cells in the aorta and fibroblasts in the dermis of skin. Like cartilage however, hyaluro-nan forms a scaffold for binding large chondroitin sulfate proteoglycans in the matrices of these tissues.

The largest amount of hyaluro-nan (7-8 g per average adult human, ~50% of the total in the body) resides in skin tissue, where it is present in both the dermis (~0.5 mg/g wet tissue) and the epidermis (~0.1 mg/g wet tissue). Interestingly, while dermis consists primarily of extracellular matrix with a sparse population of cells, the epidermis is the reverse; the keratinocytes fill all but a few percent of the tissue. Thus, the actual concentrations of hyaluro-nan in the matrix around the cells in the epidermis (estimated to be 2-4 mg/ml) is an order of magnitude higher than in the dermis (estimated to be ~0.5 mg/ml).7 The matrix around keratinocytes, then, may have a Hyaluronic Acid (HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) concentration as high as that in umbilical cord (~4 mg/ml) considered to be the mammalian tissue with one of the highest concentrations. Interestingly, rooster comb, a specialized piece of skin, has even higher amounts of hyaluro-nan (up to 7.5 mg/ml).
Metabolism of Hyaluronan. The metabolism of Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) is very dynamic. Some cells, such as chondrocytes in cartilages, actively synthesize and catabolize hyaluro-nan throughout the lifetime of the tissue. Synthesis is usually balanced by catabolism, thereby maintaining a constant concentration in the tissue. Metabolic studies have shown that the half life of a hyaluro-nan molecule in cartilage is normally 2-3 weeks. Keratinocytes in epidermis are another example of cells that actively synthesize and catabolize Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum). In this case, the half life of a hyaluro-nan molecule is surprisingly short, less than a day.

Sometimes cells either predominantly synthesize or they catabolize hyaluro-nan. For example the cells in the dermis actively synthesize more hyaluro-nan than they catabolize. A large proportion of the Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) molecules escape from this tissue only to be rapidly captured by receptors on reticulo-endothelial cells in lymph nodes and in the liver which internalize them for subsequent catabolism in lysosomes. The half life of a hyaluro-nan molecule in the blood is very short, only a few minutes. Tissues in joints, such as the lining cells of the joint capsule of the knee, synthesize Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) and release it into the synovial fluid, where it becomes a major component that contributes to the viscoelastic properties of the fluid. Also, the synovial fluid drains through the lymphatics before entry into the bloodstream. Reticulo-endothelial cells lining the lymphatics actively remove almost 90 percent of the hyaluro-nan before the remainder reaches the vascular system. It has been estimated that almost one-third of the total Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) in the human body is metabolically removed and replaced during an average day.

Medical Application. Appropriately, the first medical application of Hyaluronic Acid ((HA,Hyaluronan,sodium hyaluronate):supplements,beauty,power,cosmetics,fillers,gel,serum) for humans was as a vitreous supplement/replacement during eye surgery in the late 1950s. The hyaluro-nan used was isolated initially from human umbilical cord, and shortly thereafter from rooster combs in a highly purified and high molecular weight form. This latter preparation, now sold under the trade name of Healon (Pharmacia), is currently widely used for ophthalmic viscosurgery and in other forms of surgery, as is Opegan (Seikagaku), a hyaluro-nan product also prepared from rooster comb. Another hyaluronan product, Artz (Seikagaku), was developed for use as a supplement in the synovium of osteoarthritic joints, and a covalently cross-linked form of hyaluro-nan, Synvisc (Biomatrix), with more pronounced viscoelastic properties, is also being used for the same purpose.

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