Product Code Database
Hyaluronic acid (; abbreviated HA; conjugate acid hyaluronate), also called hyaluronan, is an anionic, Sulfation glycosaminoglycan distributed widely throughout connective, epithelial, and . It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human Synovial fluid HA averages about per molecule, or about 20,000 disaccharide monomers, while other sources mention .
Medically, hyaluronic acid is used to treat osteoarthritis of the knee and dry eye, for wound repair, and as a cosmetic filler.
The average 70 kg (150 lb) person has roughly 15 grams of hyaluronan in the body, one third of which is turned over (i.e., degraded and synthesized) per day.
As one of the chief components of the extracellular matrix, it contributes significantly to cell proliferation and Cell migration, and is involved in the progression of many malignant . Hyaluronic acid is also a component of the group A streptococcal extracellular capsule, and is believed to play a role in virulence.
Hyaluronic acid is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of HAPLN1 (hyaluronic acid and proteoglycan link protein 1), large, highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.
A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested. A particular type of , embedded in dense fascial tissues, has been proposed as being cells specialized for the biosynthesis of the hyaluronan-rich matrix. Their related activity could be involved in regulating the sliding ability between adjacent muscular connective tissues.
Hyaluronic acid is also a major component of skin, where it is involved in repairing tissue. When skin is exposed to excessive UVB radiation, it becomes inflamed (sunburn), and 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.
While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in a number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM. Upregulation of CD44 itself is widely accepted as a marker of cell activation in . Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells.
Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4, or both TLR2 and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity.
There are limitations including the in vivo loss of this compound limiting the duration of effect.
By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration. Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment. This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.
In normal skin, HA is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found. CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the HA-rich matrix pouches. Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. A report found HA content increases in the presence of retinoic acid (vitamin A). The proposed effects of retinoic acid against skin photo-damage and photoaging may be correlated, at least in part, with an increase of skin HA content, giving rise to increased tissue hydration. It has been suggested that the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis.
Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes.
Hyaluronic acid has been used to treat dry eye. Hyaluronic acid is a common ingredient in skin care products. Hyaluronic acid is used as a dermal filler in cosmetic surgery. It is typically injected using either a classic sharp hypodermic needle or a cannula. Some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections. Currently, hyaluronic acid is used as a soft tissue filler due to its bio-compatibility and possible reversibility using hyaluronidase. Complications include the severing of nerves and , pain, and bruising. Some side effects can also appear by way of erythema, itching, and vascular occlusion; vascular occlusion is the most worrisome side effect due to the possibility of skin necrosis, or even blindness in a patient.Niamtu J. Rejuvenation of the lip and perioral areas. In: Bell WH, Guerroro CA, eds. Distraction Osteogenesis of the Facial Skeleton. Hamilton, Ontario, Canada: Decker; 2007:38–48. In some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction.
Hyaluronic acid is used to displace tissues away from tissues which are going to be subjected to radiation, for instance in one treatment option for some prostate cancers.
Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.
Hyaluronic acid in aqueous solutions self-associates to form transient clusters in solution. While it is considered a polyelectrolyte polymer chain, hyaluronic acid does not exhibit the polyelectrolyte peak, suggesting the absence of a characteristic length scale between the hyaluronic acid molecules and the emergence of a fractal clustering, which is due to the strong solvation of these molecules.
Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (hymecromone), a 7-hydroxy-4-methylcoumarin derivative. This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells. There is feedback inhibition of hyaluronan synthesis by low-molecular-weight hyaluronan (<500 kDa) at high concentrations, but there is stimulation by high-molecular-weight hyaluronan (>500 kDa) when tested in cultured human synovial fibroblasts.
Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans, in a patented process producing human-grade product.
Fasciacytes are fibroblast-like cells found in fasciae. They are round-shaped with rounder nuclei and have less elongated cellular processes when compared with fibroblasts. Fasciacytes are clustered along the upper and lower surfaces of a fascial layer.
Fasciacytes produce hyaluronan, which regulates fascial gliding.
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).
Hyaluronan can also be degraded via non-enzymatic reactions. These include and hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidizing agent.
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.
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.
The high biocompatibility of hyaluronic acid and its common presence in the extracellular matrix of tissues indicate its possible use as a biomaterial Tissue scaffold in tissue engineering. In particular, research groups have found hyaluronan's properties for tissue engineering and regenerative medicine may be 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 (see ) (trade names: Extracel, HyStem), hexadecylamides (trade name: Hymovis), and (trade name: Corgel). Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B). Hyaluronic acid can also be crosslinked with a bifunctional crosslinking agent 1,4-Butanediol diglycidyl ether (BDDE) using a ResonantAcoustic mixer over a period of time ranging from about 1 minute to about 10 minutes.
Due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate in vitro, hyaluronan can be used to create hydrogels to study vascular morphogenesis.
Research shows that abnormal hyaluronic acid (HA) metabolism is a major factor in tumor progression. HA and HA fragment-tumor cell interaction could activate the downstream signaling pathways, promoting cell proliferation, adhesion, migration and invasion, and inducing angiogenesis, lymphangiogenesis, epithelial-mesenchymal transition, stem cell-like property, and chemoradioresistance in digestive cancers.
|
|
