hyaluronic acid hyaluronic acid hyaluronic acid (/ˌhaɪ.əljʊəˈrɒnɪk/; abbreviated ha; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. 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 ha averages about 7 million da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million da. hyaluronic acid haworth projection names iupac name (1→4)-(2-acetamido-2-deoxy-d-gluco)-(1→3)-d-glucuronoglycan systematic iupac name poly identifiers cas number 9004-61-9 y31799-91-4 (potassium salt) n9067-32-7 (sodium salt) y chebi chebi:16336 chemspider none echa infocard 100.029.695 ec number 232-678-0 unii s270n0trqy y comptox dashboard (epa) dtxsid90925319 dtxsid7046750, dtxsid90925319 properties chemical formula (c14h21no11)n solubility in water soluble (sodium salt) pharmacology atc code d03ax05 (who) m09ax01 (who), r01ax09 (who), s01ka01 (who) hazards lethal dose or concentration (ld, lc): ld50 (median dose) > 2400 mg/kg (mouse, oral, sodium salt) 4000 mg/kg (mouse, subcutaneous, sodium salt) 1500 mg/kg (mouse, intraperitoneal, sodium salt) related compounds related compounds d-glucuronic acid and n-acetyl-d-glucosamine (monomers) except where otherwise noted, data are given for materials in their standard state (at 25 °c , 100 kpa). n verify (what is yn ?) infobox references 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 migration, and is involved in the progression of many malignant tumors. hyaluronic acid is also a component of the group a streptococcal extracellular capsule, and is believed to play a role in virulence. physiological function until the late 1970s, hyaluronic acid was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix. for example, hyaluronic acid is a major component of the synovial fluid and was found to increase the viscosity of the fluid. along with 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. 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. 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. 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 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 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. a joint hydration supplement that uses hyaluronic acid wound repair as a major component of the extracellular matrix, hyaluronic acid has a key role in tissue regeneration, inflammation response, and angiogenesis, which are phases of wound repair. as of 2016, however, reviews of its effect on wound healing in burns, diabetic foot ulcers or surgical skin repairs show only limited positive clinical research evidence. hyaluronic acid combines with water and swells to form a gel, making it useful in skin treatments as a 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. 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. the early stage of granulation tissue is dominated by a ha-rich extracellular matrix, which is regarded as a conducive environment for the migration of cells into this temporary wound matrix. ha provides an open hydrated matrix that facilitates cell migration, whereas, in the latter scenario, directed migration and control of related cell mechanisms are mediated via the specific cell interaction between ha and cell surface ha receptors. it forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated kinase, focal adhesion kinase, and other non-receptor tyrosine kinases. during fetal development, the migration path through which 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. 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. skin healing ha plays an important role in the normal epidermis. ha also has crucial functions in the reepithelization process due to several of its properties. these include being an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its 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. 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. medical uses hyaluronic acid has been fda-approved to treat osteoarthritis of the knee via intra-articular injection. 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. a 2020 meta-analysis found that intra-articular injection of high molecular weight ha improved both pain and function in people with knee osteoarthritis. hyaluronic acid has been used in various formulations to create artificial tears 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 micro-cannula. some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections. currently, hyaluronic acid is used frequently as a soft tissue filler due to its bio-compatibility and possible reversibility using hyaluronidase complications include the severing of nerves and microvessels, 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. in some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction. sources hyaluronic acid is produced on a large scale by extraction from animal tissues, such as chicken comb, and from streptococci. structure hyaluronic acid is a polymer of disaccharides, which are composed of d-glucuronic acid and n-acetyl-d-glucosamine, linked via alternating β-(1→4) and β-(1→3) glycosidic bonds. hyaluronic acid can be 25,000 disaccharide repeats in length. polymers of hyaluronic acid can range in size from 5,000 to 20,000,000 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; other sources mention average molecular weight of 7 million da for synovial fluid. hyaluronic acid also contains silicon, ranging 350–1,900 μg/g depending on location in the organism. 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. biological synthesis hyaluronic acid is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: has1, has2, and has3. these enzymes lengthen hyaluronan by repeatedly adding d-glucuronic acid and n-acetyl-d-glucosamine to the nascent polysaccharide as it is extruded via abc-transporter through the cell membrane into the extracellular space. the term fasciacyte was coined to describe fibroblast-like cells that synthesize ha. 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 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. fasciacyte a fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae. 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. 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. the carboxylate groups present in the molecule make it negatively charged,