:Hyaluronic acid

Until the late 1970s, hyaluronic acid was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.{{cite journal | vauthors = Toole BP | title = Hyaluronan is not just a goo! | journal = J. Clin. Invest. | volume = 106 | issue = 3 | pages = 335–336 | year = 2000 | pmid = 10930435 | pmc = 314333 | doi = 10.1172/JCI10706 }} 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.{{citation needed|date=December 2024}}

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.{{cite journal | vauthors = Holmes MW, Bayliss MT, Muir H | title = Hyaluronic acid in human articular cartilage. Age-related changes in content and size | journal = Biochem. J. | volume = 250 | issue = 2 | pages = 435–441 | year = 1988 | pmid = 3355532 | pmc = 1148875 | doi = 10.1042/bj2500435 }}

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.{{cite journal |vauthors=Stecco C, Stern R, Porzionato A, Macchi V, Masiero S, Stecco A, De Caro R | year = 2011 | title = Hyaluronan within fascia in the etiology of myofascial pain | journal = Surg Radiol Anat | volume = 33 | issue = 10| pages = 891–6 | doi = 10.1007/s00276-011-0876-9 | pmid = 21964857 | s2cid = 19645759 }}

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.{{cite journal | vauthors = Averbeck M, Gebhardt CA, Voigt S, Beilharz S, Anderegg U, Termeer CC, Sleeman JP, Simon JC | title = Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation | journal = J. Invest. Dermatol. | volume = 127 | issue = 3 | pages = 687–97 | year = 2007 | pmid = 17082783 | doi = 10.1038/sj.jid.5700614 | doi-access = free }}

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.{{Cite journal |last=Iaconisi |first=Giorgia Natalia |last2=Ahmed |first2=Amer |last3=Lauria |first3=Graziantonio |last4=Gallo |first4=Nunzia |last5=Fiermonte |first5=Giuseppe |last6=Cowman |first6=Mary K. |last7=Capobianco |first7=Loredana |last8=Dolce |first8=Vincenza |date=December 2024 |title=Targeting mitochondria in Cancer therapy: Machine learning analysis of hyaluronic acid-based drug delivery systems |url=https://linkinghub.elsevier.com/retrieve/pii/S0141813024086501 |journal=International Journal of Biological Macromolecules |language=en |volume=283 |pages=137840 |doi=10.1016/j.ijbiomac.2024.137840|url-access=subscription }}

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.{{cite web |url=https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm133863.htm |title=Synvisc-One (hylan GF-20) – P940015/S012 |website=Food and Drug Administration |access-date=2014-11-23 |archive-url=https://web.archive.org/web/20141129085414/https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm133863.htm |archive-date=2014-11-29 |url-status=dead }}

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.{{cite journal | last1=Shaharudin | first1=A. | last2=Aziz | first2=Z. | title=Effectiveness of hyaluronic acid and its derivatives on chronic wounds: a systematic review | journal=Journal of Wound Care | volume=25 | issue=10 | date=2 October 2016 | issn=0969-0700 | pmid=27681589 | doi=10.12968/jowc.2016.25.10.585 | pages=585–592}} As of 2023, however, reviews of its effect on healing for chronic wounds including burns, diabetic foot ulcers or surgical skin repairs show either insufficient evidence or only limited positive clinical research evidence.{{Cite journal |last1=Roehrs |first1=Hellen |last2=Stocco |first2=Janislei GD |last3=Pott |first3=Franciele |last4=Blanc |first4=Gisely |last5=Meier |first5=Marineli J |last6=Dias |first6=Fernando AL |date=2023-07-27 |editor-last=Cochrane Wounds Group |title=Dressings and topical agents containing hyaluronic acid for chronic wound healing |journal=Cochrane Database of Systematic Reviews |language=en |volume=2023 |issue=7 |pages=CD012215 |doi=10.1002/14651858.CD012215.pub2 |pmc=10373121 |pmid=37497805 }} There is also some limited evidence to suggest that hyaluronic acid may be beneficial for ulcer healing and may help to a small degree with pain control. 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.{{cite web | title=Dermal Fillers Approved by the Center for Devices and Radiological Health | publisher=U S Food and Drug Administration | date=26 November 2018 | url=https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/CosmeticDevices/ucm619846.htm#approved | archive-url=https://web.archive.org/web/20190208082953/https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/CosmeticDevices/ucm619846.htm#approved | url-status=dead | archive-date=February 8, 2019 | access-date=11 March 2019}}

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.{{citation needed|date=December 2024}}

Cell migration is essential for the formation of granulation tissue.{{cite journal | last1=Litwiniuk | first1=M | last2=Krejner | first2=A | last3=Speyrer | first3=MS | last4=Gauto | first4=AR | last5=Grzela | first5=T | title=Hyaluronic acid in inflammation and tissue regeneration. | journal=Wounds | volume=28 | issue=3 | year=2016 | issn=1044-7946 | pmid=26978861 | pages=78–88|url=https://www.woundsresearch.com/article/hyaluronic-acid-inflammation-and-tissue-regeneration}} 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.

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.{{cite journal | vauthors = Tammi R, Ripellino JA, Margolis RU, Maibach HI, Tammi M | title = Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture | journal = J. Invest. Dermatol. | volume = 92 | issue = 3 | pages = 326–32 | year = 1989 | pmid = 2465358 | doi = 10.1111/1523-1747.ep12277125| doi-access = free }} 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.{{cite journal | vauthors = Tuhkanen AL, Tammi M, Pelttari A, Agren UM, Tammi R | title = Ultrastructural analysis of human epidermal CD44 reveals preferential distribution on plasma membrane domains facing the hyaluronan-rich matrix pouches | journal = J. Histochem. Cytochem. | volume = 46 | issue = 2 | pages = 241–8 | year = 1998 | pmid = 9446831 | doi = 10.1177/002215549804600213| s2cid = 42549927 | doi-access = }} 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 FDA-approved to treat osteoarthritis of the knee via intra-articular injection.{{cite web|url=https://www.arthritis.org/living-with-arthritis/treatments/medication/drug-types/other/hyaluronic-acid-injections.php|title=Hyaluronic acid injections for osteoarthritis|publisher=US Arthritis Foundation|author=Gower, Timothy|access-date=16 March 2019|archive-date=14 May 2015|archive-url=https://web.archive.org/web/20150514045549/https://www.arthritis.org/living-with-arthritis/treatments/medication/drug-types/other/hyaluronic-acid-injections.php|url-status=dead}} 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.{{cite journal | vauthors = Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S | title = Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis | journal = Ann. Intern. Med. | volume = 157 | issue = 3 | pages = 180–91 | year = 2012 | pmid = 22868835 | doi = 10.7326/0003-4819-157-3-201208070-00473 | s2cid = 5660398 |url=https://www.researchgate.net/publication/230623196}} A 2020 meta-analysis found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis.{{cite journal |last1=Phillips|first1=Mark|last2=Vannabouathong|first2=Christopher|last3=Devji|first3=Tahira|last4=Patel|first4=Rahil|last5=Gomes|first5=Zoya|last6=Patel|first6=Ashaka|last7=Dixon|first7=Mykaelah|last8=Bhandari|first8=Mohit| title = Differentiating factors of intra‑articular injectables have a meaningful impact on knee osteoarthritis outcomes: a network meta‑analysis | journal = Knee Surgery, Sports Traumatology, Arthroscopy | year = 2020 | volume = 28 | issue = 9 | pages = 3031–3039 | pmid = 31897550 | doi = 10.1007/s00167-019-05763-1| pmc = 7471203 | doi-access = free }}

Hyaluronic acid has been used to treat dry eye.{{cite journal |vauthors=Pucker AD, Ng SM, Nichols JJ |title= Over the counter (OTC) artificial tear drops for dry eye syndrome |journal=Cochrane Database Syst Rev|volume=2016 |pages= CD009729 |date=2016 |issue= 2 |pmid= 26905373 |doi= 10.1002/14651858.CD009729.pub2 |pmc=5045033}} Hyaluronic acid is a common ingredient in skin care products. Hyaluronic acid is used as a dermal filler in cosmetic surgery.{{Cite web | url=https://www.webmd.com/vitamins/ai/ingredientmono-1062/hyaluronic-acid|publisher=WebMD|title=Hyaluronic Acid – Uses, Side Effects, And More|access-date=1 February 2023}} 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.{{cite journal |last1=Wu |first1=Kelun |last2=Xie |first2=Li |last3=Wang |first3=Muyao |last4=Jiang |first4=Yichen |last5=Tang |first5=Yingfeng |last6=Wang |first6=Hang |title=Comparison of the Microstructures and Properties of Different Microcannulas for Hyaluronic Acid Injection |journal=Plastic and Reconstructive Surgery |date=August 2018 |volume=142 |issue=2 |pages=150e–159e |doi=10.1097/PRS.0000000000004573|pmid=29889738 |s2cid=48361201 }}{{cite journal | last1=Lazzeri | first1=Davide | last2=Agostini | first2=Tommaso | last3=Figus | first3=Michele | last4=Nardi | first4=Marco | last5=Pantaloni | first5=Marcello | last6=Lazzeri | first6=Stefano | title=Blindness following Cosmetic Injections of the Face | journal=Plastic and Reconstructive Surgery | publisher=Ovid Technologies (Wolters Kluwer Health) | volume=129 | issue=4 | year=2012 | issn=0032-1052 | doi=10.1097/prs.0b013e3182442363 | pages=995–1012| pmid=22456369 | s2cid=44566627 }} Currently, hyaluronic acid is used as a soft tissue filler due to its bio-compatibility and possible reversibility using hyaluronidase.{{cite journal |vauthors=Borzabadi-Farahani A, Mosahebi A, Zargaran D |title=A Scoping Review of Hyaluronidase Use in Managing the Complications of Aesthetic Interventions|journal=Aesthetic Plastic Surgery |date= 2022 |volume=48 |issue=6 |pages=1193–1209 | pmid=36536092 | doi = 10.1007/s00266-022-03207-9|s2cid=254913847 |doi-access=free |pmc=10999391 }} 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.{{cite journal | last1=Alam | first1=Murad | last2=Dover | first2=Jeffrey S. | title=Management of Complications and Sequelae with Temporary Injectable Fillers | journal=Plastic and Reconstructive Surgery | publisher=Ovid Technologies (Wolters Kluwer Health) | volume=120 | issue=Supplement | year=2007 | issn=0032-1052 | doi=10.1097/01.prs.0000248859.14788.60 | pages=98S–105S| pmid=18090348 | s2cid=28303093 }}{{cite journal | last=Niamtu | first=Joseph | title=New Lip and Wrinkle Fillers | journal=Oral and Maxillofacial Surgery Clinics of North America | publisher=Elsevier BV | volume=17 | issue=1 | year=2005 | issn=1042-3699 | doi=10.1016/j.coms.2004.10.001 | pages=17–28| pmid=18088761 }}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.{{cite journal | last1=Abduljabbar | first1=Mohammed H. | last2=Basendwh | first2=Mohammad A. | title=Complications of hyaluronic acid fillers and their managements | journal=Journal of Dermatology & Dermatologic Surgery | publisher=Medknow | volume=20 | issue=2 | year=2016 | issn=2352-2410 | doi=10.1016/j.jdds.2016.01.001 | pages=100–106| doi-access=free }} In some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction.{{cite journal|last1=Edwards|first1=PC|last2=Fantasia|first2=JE|title=Review of long-term adverse effects associated with the use of chemically-modified animal and nonanimal source hyaluronic acid dermal fillers.|journal=Clinical Interventions in Aging|date=2007|volume=2|issue=4|pages=509–19|pmid=18225451|pmc=2686337|doi=10.2147/cia.s382 |doi-access=free }}

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.{{Cite journal |publisher=Quant Imaging Med Surg|title=The role of radioprotective spacers in clinical practice: a review|date=2018 |pmc=6037953 |last1=Tang |first1=Q. |last2=Zhao |first2=F. |last3=Yu |first3=X. |last4=Wu |first4=L. |last5=Lu |first5=Z. |last6=Yan |first6=S. |journal=Quantitative Imaging in Medicine and Surgery |volume=8 |issue=5 |pages=514–524 |doi=10.21037/qims.2018.06.06 |doi-access=free |pmid=30050786 }}

Hyaluronic acid is produced on a large scale by extraction from animal tissues, such as chicken comb, and from Streptococci.{{Cite journal |vauthors=Sze J, Brownlie JC, Love CA |date=2016-02-15 |title=Biotechnological production of hyaluronic acid: a mini review |journal=3 Biotech |volume=6 |issue=1 |pages=67 |doi=10.1007/s13205-016-0379-9 |issn=2190-572X |pmc=4754297 |pmid=28330137}}

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;{{cite journal | vauthors = Saari H, Konttinen YT, Friman C, Sorsa T | title = Differential effects of reactive oxygen species on native synovial fluid and purified human umbilical cord hyaluronate | journal = Inflammation | volume = 17 | issue = 4 | pages = 403–15 | year = 1993 | pmid = 8406685 | doi = 10.1007/bf00916581| s2cid = 5181236 }} other sources mention average molecular weight of 7 million Da for synovial fluid. Hyaluronic acid was once thought to contain silicon,{{Cite journal|title = A bound form of silicon in glycosaminoglycans and polyuronides|journal = Proceedings of the National Academy of Sciences of the United States of America|date = 1973-05-01|issn = 0027-8424|pmc = 433552|pmid = 4268099|pages = 1608–1612|volume = 70|issue = 5|first = K.|last = Schwarz|doi=10.1073/pnas.70.5.1608|bibcode = 1973PNAS...70.1608S|doi-access = free}} but this was later found to be from contamination in the processing.{{cite book |last1=Schwarz |first1=Klaus |editor1-last=Bendz |editor1-first=Gerd |editor2-last=Lindquist |editor2-first=Ingvar |title=Biochemistry of silicon and related problems: proceedings of the 40. Nobel Symposium held in Lidingö, Sweden, August 23 - 26, 1977 |date=1978 |publisher=Springer Science+Business Media |location=New York, NY |isbn=9781461340201 |page=219 |edition=Softcover repr |chapter=Physiological Significance of Silicon in Animal and Man}}

Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides.{{citation needed|date=June 2022}} Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.{{citation needed|date=June 2022}}

Hyaluronic acid in aqueous solutions self-associates to form transient clusters in solution.{{Cite journal|title = Disappearance of the polyelectrolyte peak in salt-free solutions|journal = Phys. Rev. E|date = 2020-03-12|pmid = 32794995|pages = 012611|volume = 102|issue = 1|first1 = A.|last1 = Chremos|first2 = F.| last2 = Horkay|doi=10.1103/PhysRevE.102.012611| pmc=8243406 | bibcode=2020PhRvE.102a2611C }} 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 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.{{cite journal | vauthors = Schulz T, Schumacher U, Prehm P | title = Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP | journal = J. Biol. Chem. | volume = 282 | issue = 29 | pages = 20999–21004 | year = 2007 | pmid = 17540771 | doi = 10.1074/jbc.M700915200 | doi-access = free }} The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA.{{Cite journal|last1=Stecco|first1=Carla|last2=Stern|first2=R.|last3=Porzionato|first3=A.|last4=Macchi|first4=V.|last5=Masiero|first5=S.|last6=Stecco|first6=A.|last7=De Caro|first7=R.|date=2011-10-02|title=Hyaluronan within fascia in the etiology of myofascial pain|journal=Surgical and Radiologic Anatomy|language=en|volume=33|issue=10|pages=891–896|doi=10.1007/s00276-011-0876-9|pmid=21964857|s2cid=19645759|issn=0930-1038}}

Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (hymecromone), a 7-hydroxy-4-methylcoumarin derivative.{{cite journal | vauthors = Kakizaki I, Kojima K, Takagaki K, Endo M, Kannagi R, Ito M, Maruo Y, Sato H, Yasuda T, Mita S, Kimata K, Itano N | title = A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone | journal = J. Biol. Chem. | volume = 279 | issue = 32 | pages = 33281–33289 | year = 2004 | pmid = 15190064 | doi = 10.1074/jbc.M405918200 | doi-access = free }}

This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells.{{cite journal | vauthors = Yoshihara S, Kon A, Kudo D, Nakazawa H, Kakizaki I, Sasaki M, Endo M, Takagaki K | title = A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells | journal = FEBS Lett. | volume = 579 | issue = 12 | pages = 2722–2726 | year = 2005 | pmid = 15862315 | doi = 10.1016/j.febslet.2005.03.079 | s2cid = 46035041 | doi-access = free | bibcode = 2005FEBSL.579.2722Y }} 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.{{cite journal|last1=Smith|first1=MM|last2=Ghosh|first2=P|title=The synthesis of hyaluronic acid by human synovial fibroblasts is influenced by the nature of the hyaluronate in the extracellular environment|journal=Rheumatol Int|date=1987|volume=7|issue=3|pages=113–122|pmid=3671989|doi=10.1007/bf00270463|s2cid=19253084}}

Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans,{{Cite web |url=http://www.biopharma.novozymes.com/en/products---technologies/hyaluronic-acid.aspx |title=Novozymes Biopharma {{!}} Produced without the use of animal-derived materials or solvents |access-date=2010-10-19 |archive-url=https://web.archive.org/web/20100915070711/http://www.biopharma.novozymes.com/en/products---technologies/hyaluronic-acid.aspx |archive-date=2010-09-15 |url-status=dead }} in a patented process producing human-grade product.

A fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae.{{Cite journal|last1=Stecco|first1=Carla|last2=Fede|first2=Caterina|last3=Macchi|first3=Veronica|last4=Porzionato|first4=Andrea|last5=Petrelli|first5=Lucia|last6=Biz|first6=Carlo|last7=Stern|first7=Robert|last8=De Caro|first8=Raffaele|date=2018-04-14|title=The fasciacytes: A new cell devoted to fascial gliding regulation|journal=Clinical Anatomy|language=en|volume=31|issue=5|pages=667–676|doi=10.1002/ca.23072|pmid=29575206|s2cid=4852040|issn=0897-3806}}

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.

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, therefore allowing for successful binding to water, and making it valuable to cosmetic and pharmaceutical products.{{Cite journal |last1=Sze |first1=Jun Hui |last2=Brownlie |first2=Jeremy C. |last3=Love |first3=Christopher A. |date=June 2016 |title=Biotechnological production of hyaluronic acid: a mini review |journal=3 Biotech |volume=6 |issue=1 |pages=67 |doi=10.1007/s13205-016-0379-9 |issn=2190-572X |pmc=4754297 |pmid=28330137}}

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.{{Cite journal |last1=Moreno-Camacho |first1=Carlos A. |last2=Montoya-Torres |first2=Jairo R. |last3=Jaegler |first3=Anicia |last4=Gondran |first4=Natacha |date=2019-09-10 |title=Sustainability metrics for real case applications of the supply chain network design problem: A systematic literature review |journal=Journal of Cleaner Production |language=en |volume=231 |pages=600–618 |doi=10.1016/j.jclepro.2019.05.278 |s2cid=191866577 |issn=0959-6526|doi-access=free |bibcode=2019JCPro.231..600M }} 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).

File:Part 1.jpg

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.

File:Part 2 HA.jpg

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.

File:Part 3.jpg

UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase), completing the synthesis.

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.{{cite journal | vauthors = Matou-Nasri S, Gaffney J, Kumar S, Slevin M | title = Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and gamma-adducin | journal = Int. J. Oncol. | volume = 35 | issue = 4 | pages = 761–773 | year = 2009 | pmid = 19724912 | doi = 10.3892/ijo_00000389 | doi-access = free }} 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.{{cite journal | vauthors = Yung S, Chan TM | title = Pathophysiology of the peritoneal membrane during peritoneal dialysis: the role of hyaluronan | journal = J. Biomed. Biotechnol. | volume = 2011 | pages = 1–11 | year = 2011 | pmid = 22203782 | pmc = 3238805 | doi = 10.1155/2011/180594 | doi-access = free }}{{cite journal | vauthors = Tesar BM, Jiang D, Liang J, Palmer SM, Noble PW, Goldstein DR | title = The role of hyaluronan degradation products as innate alloimmune agonists | journal = Am. J. Transplant. | volume = 6 | issue = 11 | pages = 2622–2635 | year = 2006 | pmid = 17049055 | doi = 10.1111/j.1600-6143.2006.01537.x | s2cid = 45674285 | doi-access = }}

Hyaluronan can also be degraded via non-enzymatic reactions. These include acidic and alkaline hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidants.{{cite journal|last1=Stern|first1=Robert|last2=Kogan|first2=Grigorij|last3=Jedrzejas|first3=Mark J.|last4=Šoltés|first4=Ladislav|title=The many ways to cleave hyaluronan|journal=Biotechnology Advances|date=1 November 2007|volume=25|issue=6|pages=537–557|doi=10.1016/j.biotechadv.2007.07.001|pmid=17716848}}

The term hyaluronic acid is derived from hyalos (Greek for vitreous, meaning 'glass-like') and uronic acid{{cite journal |last1=Meyer |first1=Karl |last2=Palmer |first2=John W. |title=The Polysaccharide of the Vitreous Humor |journal=Journal of Biological Chemistry |date=December 1934 |volume=107 |issue=3 |pages=629–634 |doi=10.1016/s0021-9258(18)75338-6|doi-access=free }} 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.{{cite book |title=An Introduction to Biomaterials |edition=2nd |editor=Jeffrey O. Hollinger |year=2011 |author1=John H. Brekke |author2=Gregory E. Rutkowski |author3=Kipling Thacker |chapter=Chapter 19 Hyaluronan}}

Hyaluronic acid was first obtained by Karl Meyer and John Palmer in 1934 from the vitreous body in a cow's eye.{{cite journal |last1=Necas |first1=J. |last2=Bartosikova |first2=L. |last3=Brauner |first3=P. |last4=Kolar |first4=J. |title=Hyaluronic acid (hyaluronan): a review |journal=Veterinární Medicína |date=5 September 2008 |volume=53 |issue=8 |pages=397–411 |doi=10.17221/1930-VETMED |doi-access=free }} The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia,{{cite web |title=Ophthalmic Viscosurgical Devices: History |url=https://www.aao.org/focalpointssnippetdetail.aspx?id=65351c63-9407-4dd0-9d2c-fe578fd59a4a |access-date=2021-12-03 |archive-date=2021-12-03 |archive-url=https://web.archive.org/web/20211203010417/https://www.aao.org/focalpointssnippetdetail.aspx?id=65351c63-9407-4dd0-9d2c-fe578fd59a4a |url-status=dead }} 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.{{Cite web |url=https://cen.acs.org/business/consumer-products/Hyaluronic-acid-biobased-medical-cosmetic/99/i16 |title=Hyaluronic acid is just getting started |last=Bettenhausen |first=Craig |date=2021-05-02 |access-date=2022-05-04 |website=cen.acs.org}}

Native hyaluronic acid has a relatively short half-life (shown in rabbits){{cite journal | vauthors = Brown TJ, Laurent UB, Fraser JR | title = Turnover of hyaluronan in synovial joints: elimination of labelled hyaluronan from the knee joint of the rabbit | journal = Exp. Physiol. | volume = 76 | issue = 1 | pages = 125–134 | year = 1991 | pmid = 2015069 | doi=10.1113/expphysiol.1991.sp003474 |doi-access=free}} 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,{{cite journal | vauthors = Frampton JE | title = Hylan G-F 20 single-injection formulation | journal = Drugs Aging | volume = 27 | issue = 1 | pages = 77–85 | year = 2010 | pmid = 20030435 | doi = 10.2165/11203900-000000000-00000 | s2cid = 6329556 }} the introduction of free-radical scavenging molecules such as sorbitol,{{Cite web|url=https://www.anteis.com/en/|title=Home}} and minimal stabilisation of the HA chains through chemical agents such as NASHA (non-animal stabilised hyaluronic acid){{cite journal|last1=Avantaggiato|first1=A|last2=Girardi|first2=A|last3=Palmieri|first3=A|last4=Pascali|first4=M|last5=Carinci|first5=F|title=Bio-Revitalization: Effects of NASHA on Genes Involving Tissue Remodeling.|journal=Aesthetic Plastic Surgery|date=August 2015|volume=39|issue=4|pages=459–64|pmid=26085225|doi=10.1007/s00266-015-0514-8|s2cid=19066664}} are all techniques that have been used to preserve its shelf life.{{Cite web|url=https://www.oakneepainrelief.com/durolane/|title=DUROLANE|website=Bioventus OA Knee Pain Relief}}

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.{{cite journal |last1=Miller |first1=D. |last2=O'Connor |first2=P. |last3=William |first3=J. |title=Use of Na-Hyaluronate during intraocular lens implantation in rabbits |journal=Ophthal. Surg. |volume=8 |pages=58–61 |year=1977}}{{cite book |last1=Miller |first1=D. |last2=Stegmann |first2=R. |title=Healon: A Comprehensive Guide to its Use in Ophthalmic Surgery |publisher=J Wiley |location=New York |year=1983}}

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.{{Cite web|url=https://www.dechra.co.uk/|title=Dechra Veterinary Products|website=www.dechra.co.uk}}

According to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat.{{Cite web|url=https://www.drugs.com/vet/hy-50-can.html|archive-url=https://web.archive.org/web/20110607112840/http://www.drugs.com/vet/hy-50-can.html|title=Hy-50 (Canada) for Animal Use|archive-date=June 7, 2011|website=Drugs.com}} In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.{{Cite web|url=https://www.dechra.co.uk/|archive-url=https://web.archive.org/web/20080601040624/http://www.genitrix.co.uk/2008ProductsHorses-HY502.php|title=Dechra Veterinary Products|archive-date=June 1, 2008|website=www.dechra.co.uk}}

Due to its accumulation in airway epithelial cells in various respiratory diseases, such as COVID-19, cystic fibrosis, influenza, and sepsis, hyaluronic acid is under study as a possible mediator of lung inflammatory mechanisms, as of 2022.{{cite journal |vauthors=Albtoush N, Petrey AC |title=The role of hyaluronan synthesis and degradation in the critical respiratory illness COVID-19 |journal=American Journal of Physiology. Cell Physiology |volume=322 |issue=6 |pages=C1037–C1046 |date=June 2022 |pmid=35442830 |pmc=9126216 |doi=10.1152/ajpcell.00071.2022}}

The high biocompatibility of hyaluronic acid and its common presence in the extracellular matrix of tissues indicate its possible use as a biomaterial scaffold in tissue engineering.{{cite journal | vauthors = Segura T, Anderson BC, Chung PH, Webber RE, Shull KR, Shea LD | title = Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern | journal = Biomaterials | volume = 26 | issue = 4 | pages = 359–371 | year = 2005 | pmid = 15275810 | doi = 10.1016/j.biomaterials.2004.02.067 }} 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.{{cite journal | vauthors = Zheng Shu X, Liu Y, Palumbo FS, Luo Y, Prestwich GD | title = In situ crosslinkable hyaluronan hydrogels for tissue engineering | journal = Biomaterials | volume = 25 | issue = 7–8 | pages = 1339–1348 | year = 2004 | pmid = 14643608 | doi = 10.1016/j.biomaterials.2003.08.014}} Hyaluronan can be crosslinked by attaching thiols (see thiomers) (trade names: Extracel, HyStem),{{cite journal |last1=Griesser |first1=J |last2=Hetényi |first2=G |last3=Bernkop-Schnürch |first3=A |title=Thiolated Hyaluronic Acid as Versatile Mucoadhesive Polymer: From the Chemistry Behind to Product Developments-What Are the Capabilities? |journal=Polymers |date=2018 |volume=10 |issue=3 |page=243 |doi=10.3390/polym10030243 |pmid=30966278|pmc=6414859 |doi-access=free }} hexadecylamides (trade name: Hymovis),{{cite journal | vauthors = Smith MM, Russell AK, Schiavinato A, Little CB | title = A hexadecylamide derivative of hyaluronan (HYMOVIS®) has superior beneficial effects on human osteoarthritic chondrocytes and synoviocytes than unmodified hyaluronan | journal = J Inflamm (Lond) | volume = 10 | page = 26 | year = 2013 | pmid = 23889808 | pmc = 3727958 | doi = 10.1186/1476-9255-10-26 | doi-access = free }} and tyramines (trade name: Corgel).{{cite journal|last1=Darr|first1=Aniq|last2=Calabro|first2=Anthony|title=Synthesis and characterization of tyramine-based hyaluronan hydrogels|journal=Journal of Materials Science: Materials in Medicine|volume=20|issue=1|year=2008|pages=33–44|pmid=18668211|doi=10.1007/s10856-008-3540-0|s2cid=46349004}} Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).{{cite book |veditors=Wnek GE, Bowlin GL |title=Encyclopedia of Biomaterials and Biomedical Engineering |url=https://archive.org/details/encyclopediabiom00wnek |url-access=registration |publisher=Informa Healthcare |year=2008}} 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.{{cite web | title=Method for crosslinking hyaluronic acid using resonant acoustic mixing | website=Google Patents | date=2023-03-29 | url=https://patents.google.com/patent/WO2023184029A1/en | access-date=2024-11-13}}

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.{{cite journal | vauthors = Genasetti A, Vigetti D, Viola M, Karousou E, Moretto P, Rizzi M, Bartolini B, Clerici M, Pallotti F, De Luca G, Passi A | title = Hyaluronan and human endothelial cell behavior | journal = Connect. Tissue Res. | volume = 49 | issue = 3 | pages = 120–123 | year = 2008 | pmid = 18661325 | doi = 10.1080/03008200802148462 | s2cid = 28661552 }}

Research shows that abnormal hyaluronic acid (HA) metabolism is a major factor in tumor progression.{{cite journal |last1=Tan |first1=Tao |last2=Yang |first2=He |year=2023 |title=Inhibition of hyaluronic acid degradation pathway suppresses glioma progression by inducing apoptosis and cell cycle arrest |journal=Cancer Cell International |volume=23 |article-number=163 |doi=10.1186/s12935-023-02998-4 |doi-access=free|pmc=10422813 }}{{cite web |url=https://www.stanfordchem.com/how-is-hyaluronic-acid-related-to-tumor-development.html |title=How is Hyaluronic Acid Related to Tumor Development? |website=Stanford Chemicals |last=Higgins |first=Maria |date=Nov 26, 2023 |access-date=Sep 15, 2024}} 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.{{cite journal |last1=Wu |first1=Ruo |last2=Huang |first2=Lei |year=2016 |title=Hyaluronic acid in digestive cancers |journal= Journal of Cancer Research and Clinical Oncology |volume=143 |pages=1–16 |doi=10.1007/s00432-016-2213-5}}

• Sodium hyaluronate, the sodium salt of hyaluronic acid, a glycosaminoglycan found in various human connective tissue.
• Microbial hyaluronic acid production, the process by which microorganisms are utilized in fermentation to synthesize hyaluronic acid.
• Alguronic acid, trade name for a mix of polysaccharides produced by microalgae. Inhibits production of hyaluronic-acid-degrading enzymes.
• Bloomage, a biomaterial company based in China, primarily specialized in hyaluronic acid and other bioactive substance products.

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• ATC codes: {{ATC|D03|AX05}}, {{ATC|M09|AX01}}, {{ATC|R01|AX09}}, {{ATC|S01|KA01}}
• {{MeshName|Hyaluronan}}

{{Glycosaminoglycans}}

{{Preparations for treatment of wounds and ulcers}}

{{Other dermatological preparations}}

{{Other drugs for disorders of the musculo-skeletal system}}

{{Nasal preparations}}

Category:Uronic acids

Category:Glycosaminoglycans

Category:Veterinary drugs

Category:Sanofi