Hyaluronic acid

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Hyaluronan
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Hyaluronic acid

Haworth projection
Names
IUPAC name
(1→4)-(2-Acetamido-2-deoxy-D-gluco)-(1→3)-D-glucuronoglycan
Systematic IUPAC name
Poly{[(2S,3R,4R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxane-2,4-diyl]oxy[(2R,3R,4R,5S,6S)-6-carboxy-3,4-dihydroxyoxane-2,5-diyl]oxy}
Identifiers
ChEBI
ChemSpider
  • None
ECHA InfoCard
 100.029.695 Edit this at Wikidata
EC Number
  • 232-678-0
UNII
Properties
(C14H21NO11)n
Pharmacology
D03AX05 (WHO) M09AX01 (WHO), R01AX09 (WHO), S01KA01 (WHO)
Related compounds
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Hyaluronic acid (

Da per molecule, or about 20,000 disaccharide monomers,[3] while other sources mention 3–4 million Da.[4]

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.[5]

As one of the chief components of the

tumors.[6][7] Hyaluronic acid is also a component of the group A streptococcal extracellular capsule,[8] and is believed to play a role in virulence.[9][10][11]

Physiological function

Until the late 1970s, hyaluronic acid was described as a "

lubricin
, it is one of the fluid's main lubricating components.

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.[13]

A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested. A particular type of fibroblasts, 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.[14]

Hyaluronic acid is also a major component of skin, where it is involved in repairing tissue. When skin is exposed to excessive

UVB rays, 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.[15]

While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in a number of

Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. 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

innate immunity
.

There are limitations including the in vivo loss of this compound limiting the duration of effect.[16]

A joint hydration supplement that uses hyaluronic acid

Wound repair

As a major component of the

dermal filler for facial wrinkles; its effect lasts for about 6 to 12 months, and treatment has regulatory approval from the US Food and Drug Administration.[19]

Granulation

Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from the base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation, and organization of the granulation tissue matrix. Initiation of inflammation is crucial for the formation of granulation tissue; therefore, the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing.

Cell migration

Cell migration is essential for the formation of granulation tissue.

neural crest cells migrate is rich in HA. HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy.[20]

By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration.

plasma membrane and released directly into the extracellular environment.[20] This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.[20]

Skin healing

HA plays an important role in the normal

free-radical scavenging
function, and its role in keratinocyte proliferation and migration.

In normal skin, HA is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found.[21] 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.[22] 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).[21] 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.

Medical uses

Hyaluronic acid has been FDA-approved to treat osteoarthritis of the knee via intra-articular injection.[23] A 2012 review showed that the quality of studies supporting this use was mostly poor, with a general absence of significant benefits, and that intra-articular injection of HA could possibly cause adverse effects.[24] A 2020 meta-analysis found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis.[25]

Hyaluronic acid has been used to treat

granulomatous foreign body reaction.[35]

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.[36]

Sources

Hyaluronic acid is produced on a large scale by extraction from animal tissues, such as chicken comb, and from Streptococci.[37]

Structure

Hyaluronic acid is a

Da in vivo. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronic acid purified from human umbilical cord is 3,140,000 Da;[4] other sources mention average molecular weight of 7 million Da for synovial fluid.[3] Hyaluronic acid also contains silicon, ranging 350–1,900 μg/g depending on location in the organism.[38]

Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides.[citation needed] Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.[citation needed]

Hyaluronic acid in aqueous solutions self-associates to form transient clusters in solution.[39] 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.[39]

Biological synthesis

Hyaluronic acid is synthesized by a class of

ABC-transporter through the cell membrane into the extracellular space.[40] The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA.[41][42]

Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (hymecromone), a 7-hydroxy-4-methylcoumarin derivative.[43] This selective inhibition (without inhibiting other

glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells.[44] There is feedback inhibition of hyaluronan synthesis by low-molecular-weight hyaluronan (<500 kDa) at high concentrations, but stimulation by high-molecular-weight hyaluronan (>500 kDa), when tested in cultured human synovial fibroblasts.[45]

Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans,[46] in a patented process producing human-grade product.

Fasciacyte

A fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae.[41]

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.[41]

Biosynthetic mechanism

Hyaluronic acid (HA) is a linear glycosaminoglycan (GAG), an anionic, gel-like, polymer, found in the extracellular matrix of epithelial and connective tissues of vertebrates. It is part of a family of structurally complex, linear, anionic polysaccharides.[7] The carboxylate groups present in the molecule make it negatively charged, therefore allowing for successful binding to water, and making it valuable to cosmetic and pharmaceutical products.[47]

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.[47] There are three existing types of HASs in vertebrates: HAS1, HAS2, HAS3; each of these contribute to elongation of the HA polymer.[7] 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.[48] 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.[48]

UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase).[47]

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.[47]

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.[48]

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.[48]

Degradation

Hyaluronic acid can be degraded by a family of enzymes called

angiogenic properties.[49] 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.[50][51]

Hyaluronan can also be degraded via non-enzymatic reactions. These include acidic and alkaline hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidants.[52]

Etymology

Hyaluronic acid is derived from hyalos (Greek for vitreous, meaning ‘glass-like’) and

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.[54] The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia,[55] 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.[56]

Native hyaluronic acid has a relatively short half-life (shown in rabbits)[57] 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,[58] the introduction of free-radical scavenging molecules such as sorbitol,[59] and minimal stabilisation of the HA chains through chemical agents such as NASHA (non-animal stabilised hyaluronic acid)[60] are all techniques that have been used to preserve its shelf life.[61]

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.[62][63]

The name "hyaluronan" is also used for a salt.[64]

Other animals

Hyaluronan is used in

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.[65]

According to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat.[66] In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.[67]

Research

Due to its high

scaffold in tissue engineering research.[68] 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.[69] Hyaluronan can be crosslinked by attaching thiols (see thiomers) (trade names: Extracel, HyStem),[70] hexadecylamides (trade name: Hymovis),[71] and tyramines (trade name: Corgel).[72] Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).[73]

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.[74]

See also

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External links
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