therefore allowing for successful binding to water, and making it valuable to cosmetic and pharmaceutical products. ha consists of repeating β4-glucuronic acid (glcua)-β3-n-acetylglucosamine (glcnac) disaccharides, and is synthesized by hyaluronan synthases (has), a class of integral membrane proteins that produce the well-defined, uniform chain lengths characteristic to ha. there are three existing types of hass in vertebrates: has1, has2, has3; each of these contribute to elongation of the ha polymer. for an ha capsule to be created, this enzyme must be present because it polymerizes udp-sugar precursors into ha. ha precursors are synthesized by first phosphorylating glucose by hexokinase, yielding glucose-6-phosphate, which is the main ha precursor. then, two routes are taken to synthesize udp-n-acetylglucosamine and udp-glucuronic acid which both react to form ha. glucose-6-phosphate gets converted to either fructose-6-phosphate with hase (phosphoglucoisomerase), or glucose-1-phosphate using pgm (α -phosphoglucomutase), where those both undergo different sets of reactions. udp-glucuronic acid and udp-n-acetylglucosamine get bound together to form ha via hasa (ha synthase). precursor 1: synthesis of udp-glucuronic acid synthesis of udp-glucuronic acid udp-glucuronic acid is formed from hasc (udp-glucose pyrophosphorylase) converting glucose-1-p into udp-glucose, which then reacts with hasb (udp-glucose dehydrogenase) to form udp-glucuronic acid. precursor 2: synthesis of udp-n-acetylglucosamine synthesis of n-acetyl glucosamine the path forward from fructose-6-p utilizes glms (amidotransferase) to form glucosamine-6-p. then, glmm (mutase) reacts with this product to form glucosamine-1-p. hasd (acetyltransferase) converts this into n-acetylglucosamine-1-p, and finally, hasd (pyrophosphorylase) converts this product into udp-n-acetylglucosamine. final step of ha synthesis final step: two disaccharides form hyaluronic acid udp-glucuronic acid and udp-n-acetylglucosamine get bound together to form ha via hasa (ha synthase), completing the synthesis. degradation hyaluronic acid can be degraded by a family of 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, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties. in addition, recent studies showed hyaluronan fragments, not the native high-molecular weight molecule, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant. hyaluronan can also be degraded via non-enzymatic reactions. these include acidic and alkaline hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidants. etymology hyaluronic acid is derived from hyalos (greek for vitreous, meaning ‘glass-like’) and uronic acid because it was first isolated from the vitreous humour and possesses a high uronic acid content. the term hyaluronate refers to the conjugate base of hyaluronic acid. since the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan. history hyaluronic acid was first obtained by karl meyer and john palmer in 1934 from the vitreous body in a cow's eye. the first hyaluronan biomedical product, healon, was developed in the 1970s and 1980s by pharmacia, and approved for use in eye surgery (i.e., corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment). other biomedical companies also produce brands of hyaluronan for ophthalmic surgery. native hyaluronic acid has a relatively short half-life (shown in rabbits) so various manufacturing techniques have been deployed to extend the length of the chain and stabilise the molecule for its use in medical applications. the introduction of protein-based cross-links, the introduction of free-radical scavenging molecules such as sorbitol, and minimal stabilisation of the ha chains through chemical agents such as nasha (non-animal stabilised hyaluronic acid) are all techniques that have been used to preserve its shelf life. in the late 1970s, intraocular lens implantation was often followed by severe corneal edema, due to endothelial cell damage during the surgery. it was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed. the name "hyaluronan" is also used for a salt. other animals hyaluronan is used in treatment of articular disorders in horses, in particular those in competition or heavy work. it is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected. it is especially used for synovitis associated with equine osteoarthritis. it can be injected directly into an affected joint, or intravenously for less localized disorders. it may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome. intra-articularly administered medicine is fully metabolized in less than a week. note that, according to canadian regulation, hyaluronan in hy-50 preparation should not be administered to animals to be slaughtered for horse meat. in europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected. naked mole rats have very high molecular weight hyaluronan (6–12 mda) that has been shown to give them resistance to cancer. this large ha is due to both differently sequenced has2 and lower ha degradation mechanisms. research due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research. in particular, research groups have found hyaluronan's properties for tissue engineering and regenerative medicine are significantly improved with cross-linking, producing a hydrogel. crosslinking may allow a desired shape, as well as to deliver therapeutic molecules into a host. hyaluronan can be crosslinked by attaching thiols (see thiomers)(trade names: extracel, hystem), methacrylates, hexadecylamides (trade name: hymovis), and tyramines (trade name: corgel). hyaluronan can also be crosslinked directly with formaldehyde (trade name: hylan-a) or with divinylsulfone (trade name: hylan-b). due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate, hyaluronan can be used to create hydrogels to study vascular morphogenesis. these hydrogels have properties similar to human soft tissue, but are also easily controlled and modified, making ha very suitable for tissue-engineering studies. for example, ha hydrogels are appealing for engineering vasculature from endothelial progenitor cells by using appropriate growth factors such as vegf and ang-1 to promote proliferation and vascular network formation. vacuole and lumen formation have been observed in these gels, followed by branching and sprouting through degradation of the hydrogel and finally complex network formation. the ability to generate vascular networks using ha hydrogels leads to opportunities for in vivo and clinical applications. one in vivo study, where ha hydrogels with endothelial colony forming cells were implanted into mice three days after hydrogel formation, saw evidence that the host and engineered vessels joined within 2 weeks of implantation, indicating viability and functionality of the engineered vasculature.