View source for Hyaluronate

{{Chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 443055112
| ImageFile1 = Hyaluronan.png
| ImageSize1 = 300px
|Section1={{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = S270N0TRQY

| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 9004-61-9
| CASNo1_Ref = {{cascite|changed|??}}
| CASNo1 = 31799-91-4
| CASNo1_Comment = (potassium salt)
| CASNo2_Ref = {{cascite|changed|??}}
| CASNo2 = 9067-32-7
| CASNo2_Comment = (sodium salt)
| ATCCode_prefix = D03
| ATCCode_suffix = AX05
| ATC_Supplemental = {{ATC|M09|AX01}}, {{ATC|R01|AX09}}, {{ATC|S01|KA01}}
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|Section2={{Chembox Properties
| Formula = (C<sub>14</sub>H<sub>21</sub>NO<sub>11</sub>)<sub>n</sub>
| Solubility = soluble (sodium salt)
 }}
|Section7={{Chembox Hazards
| SPhrases = {{S22}}, {{S24/25}} (sodium salt)
| LD50 = > 2400 mg/kg (mouse, oral, sodium salt) <br /> >4000 mg/kg (mouse, subcutaneous, sodium salt) <br />1500 mg/kg (mouse, intraperitoneal, sodium salt)<ref name="ChemIDplus">{{ChemID|9067-32-7|Hyaluronate Sodium}}, consulté le 12 février 2009</ref>
 }}
|Section8={{Chembox Related
| OtherCpds = [[D-glucuronic acid]] and [[D-N-acetylglucosamine]] (monomers)
 }}
}}
__NOTOC__
{{SI}}
{{CMG}}

==Overview==
'''Hyaluronan''' {{IPAc-en|h|aɪ|ˈ|æ|l|j|ʊ|r|ə|n|ə|n}} (also called '''hyaluronic acid''' {{IPA|/ˌhaɪəl.jʊˈrɒnɨk/}}, '''hyaluronate''' {{IPA|/ˌhaɪəlˈjʊərəneɪt/}} or {{IPA|/ˌhaɪəˈlʊərəneɪt/}}, or HA) is an [[anionic]], [[Sulfation|nonsulfated]] [[glycosaminoglycan]] distributed widely throughout [[connective tissue|connective]], [[epithelial tissue|epithelial]], and [[neural tissue]]s. It is unique among glycosaminoglycans in that it is nonsulfated, forms in the [[plasma membrane]] instead of the [[Golgi apparatus|Golgi]], and can be very large, with its [[molecular weight]] often reaching the millions.<ref>{{vcite2 journal | vauthors = Fraser JR, Laurent TC, Laurent UB | title = Hyaluronan: its nature, distribution, functions and turnover | journal = J. Intern. Med. | volume = 242 | issue = 1 | pages = 27–33 | year = 1997 | pmid = 9260563 | doi = 10.1046/j.1365-2796.1997.00170.x | url = http://www3.interscience.wiley.com.iiiprxy.library.miami.edu/cgi-bin/fulltext/119157843/PDFSTART | format = PDF }}</ref>
One of the chief components of the [[extracellular matrix]], hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant [[tumor]]s.<ref>{{cite book|last=Stern|first=edited by Robert|title=Hyaluronan in cancer biology|year=2009|publisher=Academic Press/Elsevier|location=San Diego, CA|isbn=978-0-12-374178-3|url=http://www.sciencedirect.com/science/book/9780123741783|edition=1st}}</ref>

The average 70&nbsp;kg (154&nbsp;lb) person has roughly 15&nbsp;grams of hyaluronan in the body, one-third of which is turned over (degraded and synthesized) every day.<ref>{{vcite2 journal | vauthors = Stern R | title = Hyaluronan catabolism: a new metabolic pathway | journal = Eur. J. Cell Biol. | volume = 83 | issue = 7 | pages = 317–25 | year = 2004 | pmid = 15503855 | doi = 10.1078/0171-9335-00392 }}</ref>  Hyaluronic acid is also a component of the [[Streptococcus#Group A|group A streptococcal]] extracellular [[capsule (microbiology)|capsule]],<ref>{{vcite2 journal | vauthors = Sugahara K, Schwartz NB, Dorfman A | title = Biosynthesis of hyaluronic acid by Streptococcus | journal = J. Biol. Chem. | volume = 254 | issue = 14 | pages = 6252–6261 | year = 1979 | pmid = 376529 | url = http://www.jbc.org/content/254/14/6252.full.pdf }}
</ref> and is believed to play a role in [[virulence]].<ref>{{vcite2 journal | vauthors = Wessels MR, Moses AE, Goldberg JB, DiCesare TJ | title = Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 19 | pages = 8317–8321 | year = 1991 | pmid = 1656437 | pmc = 52499 | doi = 10.1073/pnas.88.19.8317 | url = http://www.pnas.org/content/88/19/8317.full.pdf }}</ref><ref>{{vcite2 journal | vauthors = Schrager HM, Rheinwald JG, Wessels MR | title = Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes in invasive skin infection | journal = J. Clin. Invest. | volume = 98 | issue = 9 | pages = 1954–1958 | year = 1996 | pmid = 8903312 | pmc = 507637 | doi = 10.1172/JCI118998 | url = http://www.jci.org/articles/view/118998/pdf }}
</ref>

== Medical uses ==
Hyaluronan has been used in attempts to treat [[osteoarthritis]] of the knee via injecting it into the joint. It has not been proven, however, to generate significant benefit and has potentially severe adverse effects.<ref>{{vcite2 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 }}</ref>

Dry, scaly skin ([[xerosis]]) such as that caused by [[atopic dermatitis]] ([[eczema]]) may be treated with a prescription skin lotion containing sodium hyaluronate as its active ingredient.<ref name="hylira">{{cite web | url = http://www.drugs.com/cdi/hylira-gel.html | title = Hylira gel: Indications, Side Effects, Warnings | format = | work =  Drugs.com }}</ref>

In some cancers, hyaluronan levels correlate well with malignancy and poor prognosis. Hyaluronan is, thus, often used as a [[tumor marker]] for [[prostate cancer|prostate]] and [[breast cancer]]. It may also be used to monitor the progression of the disease.<ref>{{vcite2 journal | vauthors = Josefsson A, Adamo H, Hammarsten P, Granfors T, Stattin P, Egevad L, Laurent AE, Wikström P, Bergh A | title = Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome | journal = Am. J. Pathol. | volume = 179 | issue = 4 | pages = 1961–1968 | year = 2011 | pmid = 21854754 | pmc = 3181394 | doi = 10.1016/j.ajpath.2011.06.005 }}</ref><ref>{{vcite2 journal | vauthors = Gritsenko PG, Ilina O, Friedl P | title = Interstitial guidance of cancer invasion | journal = J. Pathol. | volume = 226 | issue = 2 | pages = 185–199 | year = 2012 | pmid = 22006671 | pmc =  | doi = 10.1002/path.3031 }}</ref>

Hyaluronan may also be used postoperatively to induce tissue healing, notably after [[cataract]] surgery.<ref>{{vcite2 journal | vauthors=De Andrés Santos MI, Velasco-Martín A, Hernández-Velasco E, Martín-Gil J, Martín-Gil FJ| title=Thermal behaviour of aqueous solutions of sodium hyaluronate from different commercial sources | journal=Thermochim Acta | year=1994 | pages=153–160| volume=242|doi=10.1016/0040-6031(94)85017-8 }}</ref> Current models of wound healing propose the larger polymers of hyaluronic acid appear in the early stages of healing to physically make room for [[leukocyte|white blood cells]], which mediate the [[immune response]].

Hyaluronan has also been used in the synthesis of biological scaffolds for wound-healing applications. These scaffolds typically have proteins such as [[fibronectin]] attached to the hyaluronan to facilitate cell migration into the [[Wound healing|wound]]. This is particularly important for individuals with [[diabetes]] suffering from [[chronic wound]]s.<ref name="pmid14704979">{{vcite2 journal | vauthors = Shu XZ, Ghosh K, Liu Y, Palumbo FS, Luo Y, Clark RA, Prestwich GD | title = Attachment and spreading of fibroblasts on an RGD peptide-modified injectable hyaluronan hydrogel | journal = J Biomed Mater Res A | volume = 68 | issue = 2 | pages = 365–75 | year = 2004 | pmid = 14704979 | doi = 10.1002/jbm.a.20002 }}</ref>

== Functions ==
Until the late 1970s, hyaluronan was described as a "[[wikt:goo|goo]]" molecule, a ubiquitous [[carbohydrate]] [[polymer]] that is part of the extracellular matrix.<ref>{{vcite2 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 | url = http://www.jci.org/articles/view/10706/pdf }}</ref>  For example, hyaluronan 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.

Hyaluronan 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 [[link protein]], large, highly negatively charged aggregates form.  These aggregates imbibe water and are responsible for the [[Resilience (materials science)|resilience]] of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.<ref>{{vcite2 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 | displayauthors = 1 }}</ref>

Hyaluronan is also a major component of [[skin]], where it is involved in tissue repair. When skin is exposed to excessive [[UVB radiation|UVB rays]], it becomes inflamed ([[sunburn]]) and the [[Cell (biology)|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.<ref name="pmid17082783">{{vcite2 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 }}</ref>

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.<ref>{{cite book|last1=Abate|first1=Michele|last2=Salini|first2=Vincenzo|title=Hyaluronic Acid in the Treatment of Osteoarthritis: What is New, Osteoarthritis - Diagnosis, Treatment and Surgery, Prof. Qian Chen (Ed.),|date=2012|publisher=InTech|location=Italy|isbn=978-953-51-0168-0|pages=102-114|url=http://cdn.intechopen.com/pdfs-wm/30684.pdf}}</ref><ref name="Synvisc-One (hylan GF-20) - P940015/S012"/>

== Structure ==
Properties of hyaluronan were first determined in the 1930s in the laboratory of [[Karl Meyer (biochemist)|Karl Meyer]].<ref>{{vcite2 journal | vauthors = Meyer K, Hobby GL, Chaffee E, Dawson MH | title = THE HYDROLYSIS OF HYALURONIC ACID BY BACTERIAL ENZYMES | journal = J. Exp. Med. | volume = 71 | issue = 2 | pages = 137–46 | year = 1940 | pmid = 19870951 | pmc = 2135078 | doi = 10.1084/jem.71.2.137 }}</ref>

Hyaluronan is a [[polymer]] of [[disaccharide]]s, themselves composed of [[D-glucuronic acid]] and [[D-N-acetylglucosamine]], linked via alternating β-1,4 and β-1,3 [[glycosidic bond]]s. Hyaluronan can be 25,000 disaccharide repeats in length.  Polymers of hyaluronan can range in size from 5,000 to 20,000,000 [[Atomic mass unit|Da]] ''in vivo''. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronan purified from human [[umbilical cord]] is 3,140,000 Da.<ref name="pmid8406685">{{vcite2 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}}</ref>

Hyaluronan 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.

== Biological synthesis ==

Hyaluronan is synthesized by a class of [[integral membrane protein]]s called [[hyaluronan synthase]]s, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding [[glucuronic acid]] and [[N-acetylglucosamine]] to the nascent polysaccharide as it is extruded via [[ABC-transporter]] through the [[cell membrane]] into the extracellular space.<ref name="pmid17540771">{{vcite2 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 = 20999–1004 | year = 2007 | pmid = 17540771 | doi = 10.1074/jbc.M700915200 }}</ref>

Hyaluronan synthesis (HAS) has been shown to be inhibited by 4-methylumbelliferone ([[hymecromone]], heparvit), a 7-hydroxy-4-methylcoumarin derivative.<ref>{{vcite2 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 | displayauthors = 9 }}</ref>
This selective inhibition (without inhibiting other [[glycosaminoglycans]]) may prove useful in preventing [[metastasis]] of malignant tumor cells.<ref>{{vcite2 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 = 2722–6 | year = 2005 | pmid = 15862315 | doi = 10.1016/j.febslet.2005.03.079 }}</ref>

''[[Bacillus subtilis]]'' recently has been genetically modified (GMO) to culture a proprietary formula to yield hyaluronans,<ref>[http://www.biopharma.novozymes.com/en/products---technologies/hyaluronic-acid.aspx Novozymes Biopharma | Produced without the use of animal-derived materials or solvents<!-- Bot generated title -->]</ref> in a patented process producing human-grade product.

== Cell receptors for hyaluronan ==

So far, cell receptors that have been identified for HA fall into three main groups: CD44, Receptor for HA-mediated motility (RHAMM) and intercellular adhesion molecule-1 (ICAM-1). CD44 and ICAM-1 were already known as cell adhesion molecules with other recognized ligands before their HA binding was discovered.<ref name="Wayne D. Comper 1996">Wayne D. Comper, Extracellular Matrix Volume 2 Molecular Components and Interactions, 1996, Harwood Academic Publishers</ref>

CD44 is widely distributed throughout the body, and the formal demonstration of HA-CD44 binding was proposed by Aruffo et al.<ref name="pmid1694723">{{vcite2 journal | vauthors = Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B | title = CD44 is the principal cell surface receptor for hyaluronate | journal = Cell | volume = 61 | issue = 7 | pages = 1303–13 | year = 1990 | pmid = 1694723 | doi = 10.1016/0092-8674(90)90694-a}}</ref> in 1990. To date, it is recognized as the main cell surface receptor for HA. CD44 mediates cell interaction with HA and the binding of the two functions as an important part in various physiologic events,<ref name="Wayne D. Comper 1996"/><ref name="Giovanni Abatangelo 1999">{{vcite2 journal | vauthors = Chen WY, Abatangelo G | title = Functions of hyaluronan in wound repair | journal = Wound Repair Regen | volume = 7 | issue = 2 | pages = 79–89 | year = 1999 | pmid = 10231509 | doi = 10.1046/j.1524-475x.1999.00079.x}}</ref> such as cell aggregation, migration, proliferation and activation; cell–cell and cell–substrate adhesion; endocytosis of HA, which leads to HA [[catabolism]] in macrophages; and assembly of [[pericellular matrix|pericellular matrices]] from HA and [[proteoglycan]]. Two significant roles of CD44 in skin were proposed by Kaya et al.<ref>Kaya G. et al" ''Genes & Development'' 1997, 15: 996–1007</ref> The first is regulation of [[keratinocyte]] proliferation in response to extracellular stimuli, and the second is the maintenance of local HA homeostasis.<ref name="Giovanni Abatangelo 1999"/>

ICAM-1 is known mainly as a metabolic cell surface receptor for HA, and this protein may be responsible mainly for the clearance of HA from lymph and blood plasma, which accounts for perhaps most of its whole-body turnover.<ref name="Wayne D. Comper 1996"/><ref>{{vcite2 journal | vauthors = Laurent UB, Reed RK | title = Turnover of hyaluronan in the tissues | journal = Advanced Drug Delivery Reviews | year = 1991 | volume = 7 | pages = 237–256 | doi=10.1016/0169-409x(91)90004-v}}</ref>  [[Ligand binding]] of this receptor, thus, triggers a highly coordinated cascade of events that includes the formation of an endocytotic [[Vesicle (biology and chemistry)|vesicle]], its fusion with primary [[lysosomes]], enzymatic digestion to [[monosaccharides]], active transmembrane transport of these sugars to cell sap, [[phosphorylation]] of GlcNAc and enzymatic deacetylation.<ref name="Wayne D. Comper 1996"/><ref name="pmid3223897">{{vcite2 journal | vauthors = Fraser JR, Kimpton WG, Laurent TC, Cahill RN, Vakakis N | title = Uptake and degradation of hyaluronan in lymphatic tissue | journal = Biochem. J. | volume = 256 | issue = 1 | pages = 153–8 | year = 1988 | pmid = 3223897 | pmc = 1135381 | doi = }}</ref><ref name="pmid2307398">{{vcite2 journal | vauthors = Campbell P, Thompson JN, Fraser JR, Laurent TC, Pertoft H, Rodén L | title = N-acetylglucosamine-6-phosphate deacetylase in hepatocytes, Kupffer cells and sinusoidal endothelial cells from rat liver | journal = Hepatology | volume = 11 | issue = 2 | pages = 199–204 | year = 1990 | pmid = 2307398 | doi = 10.1002/hep.1840110207}}</ref> Like its name, ICAM-1 may also serve as a cell adhesion molecule, and the binding of HA to ICAM-1 may contribute to the control of ICAM-1-mediated inflammatory activation.<ref name="Giovanni Abatangelo 1999"/>

== Degradation ==

Hyaluronan is degraded by a family of enzymes called [[hyaluronidase]]s. 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.<ref>{{vcite2 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 }}</ref> In addition, recent studies showed hyaluronan fragments, not the native high-molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant<ref>{{vcite2 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 | year = 2011 | pmid = 22203782 | pmc = 3238805 | doi = 10.1155/2011/180594 }}</ref><ref>{{vcite2 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 | pmc =  | doi = 10.1111/j.1600-6143.2006.01537.x }}</ref>

== Wound repair ==

Skin provides a mechanical barrier to the external environment and acts to prevent the ingress of infectious agents.<ref name="Kennedy J. F. 2002">Kennedy J. F., et al., HA, Volume 2 Biomedical, Medical and Clinical Aspects, 2002, Woodhead Publishing Limited.</ref> Once injured, the tissues beneath are exposed to infection; therefore, rapid and effective healing is of crucial significance to reconstruct a barrier function. Skin wound healing is a complex process, and includes many interacting processes initiated by haemostasis and the release of platelet-derived factors.<ref name="Kennndy J. F. 2002">Kennndy J. F., et al., HA, Volume 2 Biomedical, Medical and Clinical Aspects, 2002, Woodhead Publishing Limited.</ref> The following stages are inflammation, granulation tissue formation, reepithelization and remodeling. HA is likely to play a multifaceted role in mediation of these cellular and matrix events. The proposed roles of HA in this sequence of skin wound healing events are elucidated in details below.

===Inflammation===

Many biological factors, such as growth factors, [[cytokines]], [[eicosanoids]] etc., are generated in the inflammation process. These factors are necessary for the subsequent steps of wound healing due to their roles in promoting migration of inflammatory cells, fibroblasts, and endothelial cells into the wound site.<ref name="Giovanni Abatangelo 1999"/>

The wound tissue in the early inflammatory phase of wound repair is abundant in HA, probably a reflection of increased synthesis.<ref name="Giovanni Abatangelo 1999"/> HA acts as a promoter of early inflammation, which is crucial in the whole skin wound-healing process. In a [[murine]] air pouch model of carrageenan/IL-1-induced inflammation, HA was observed to enhance cellular infiltration.<ref name="Giovanni Abatangelo 1999"/><ref name="pmid8568267">{{vcite2 journal | vauthors = Wisniewski HG, Hua JC, Poppers DM, Naime D, Vilcek J, Cronstein BN | title = TNF/IL-1-inducible protein TSG-6 potentiates plasmin inhibition by inter-alpha-inhibitor and exerts a strong anti-inflammatory effect in vivo | journal = J. Immunol. | volume = 156 | issue = 4 | pages = 1609–15 | year = 1996 | pmid = 8568267 | doi = }}</ref> showed a dose-dependent increase of the proinflammatory cytokines TNF-α and IL-8 production by human [[uterine]] [[fibroblasts]] at HA concentrations of 10 μg/mL to 1&nbsp;mg/mL via a CD44-mediated mechanism. [[Endothelial cells]], in response to inflammatory cytokines such as TNF-α, and bacterial [[lipopolysaccharide]], also synthesize HA, which has been shown to facilitate primary adhesion of cytokine-activated lymphocytes expressing the HA-binding variants of CD44 under laminar and static flow conditions.<ref name="Giovanni Abatangelo 1999"/><ref name="pmid9421471">{{vcite2 journal | vauthors = Mohamadzadeh M, DeGrendele H, Arizpe H, Estess P, Siegelman M | title = Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion | journal = J. Clin. Invest. | volume = 101 | issue = 1 | pages = 97–108 | year = 1998 | pmid = 9421471 | pmc = 508545 | doi = 10.1172/JCI1604 }}</ref> It is interesting to note that HA has contradictory dual functions in the inflammatory process. It not only can promote the inflammation, as stated above, but also can moderate the inflammatory response, which may contribute to the stabilization of granulation tissue matrix, as described in the following part.

===Granulation and organization of the granulation tissue matrix===

[[Granulation tissue]] is the [[Perfusion|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.<ref name="Giovanni Abatangelo 1999"/> 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.<ref name="Giovanni Abatangelo 1999"/>

===HA and cell migration===

Cell migration is essential for the formation of granulation tissue.<ref name="Giovanni Abatangelo 1999"/> The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for migration of cells into this temporary wound matrix. Contributions of HA to cell migration may attribute to its physicochemical properties as stated above, as well as its direct interactions with cells. For the former scenario, HA provides an open hydrated matrix that facilitates cell migration,<ref name="Giovanni Abatangelo 1999"/> whereas, in the latter scenario, directed migration and control of the cell locomotory mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. As discussed before, the three principal cell surface receptors for HA are CD44, RHAMM, and ICAM-1. RHAMM is more related to cell migration. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated protein kinase (ERK), p125fak, and pp60c-src.<ref name="pmid1376732">{{vcite2 journal | vauthors = Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D, Cripps V, Austen L, Nance DM, Turley EA | title = Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility | journal = J. Cell Biol. | volume = 117 | issue = 6 | pages = 1343–50 | year = 1992 | pmid = 1376732 | pmc = 2289508 | doi = 10.1083/jcb.117.6.1343}}</ref><ref name="pmid9533523">{{vcite2 journal | vauthors = Wang C, Thor AD, Moore DH, Zhao Y, Kerschmann R, Stern R, Watson PH, Turley EA | title = The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression | journal = Clin. Cancer Res. | volume = 4 | issue = 3 | pages = 567–76 | year = 1998 | pmid = 9533523 | doi = }}</ref><ref name="pmid8950989">{{vcite2 journal | vauthors = Hall CL, Lange LA, Prober DA, Zhang S, Turley EA | title = pp60(c-src) is required for cell locomotion regulated by the hyaluronanreceptor RHAMM | journal = Oncogene | volume = 13 | issue = 10 | pages = 2213–24 | year = 1996 | pmid = 8950989 | doi = }}</ref> During fetal development, the migration path through which neural crest cells migrate is rich in HA.<ref name="Giovanni Abatangelo 1999"/> 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.<ref name="pmid3655652">{{vcite2 journal | vauthors = Morriss-Kay GM, Tuckett F, Solursh M | title = The effects of Streptomyces hyaluronidase on tissue organization and cell cycle time in rat embryos | journal = J Embryol Exp Morphol | volume = 98 | issue = | pages = 59–70 | year = 1986 | pmid = 3655652 | doi = }}</ref>

By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration.<ref name="pmid8912726">{{vcite2 journal | vauthors = Ellis IR, Schor SL | title = Differential effects of TGF-beta1 on hyaluronan synthesis by fetal and adult skin fibroblasts: implications for cell migration and wound healing | journal = Exp. Cell Res. | volume = 228 | issue = 2 | pages = 326–33 | year = 1996 | pmid = 8912726 | doi = 10.1006/excr.1996.0332 }}</ref> Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment.<ref name="Giovanni Abatangelo 1999"/> This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.

===Role of HA in moderation of the inflammatory response===

Although inflammation is an integral part of granulation tissue formation, for normal tissue repair to proceed, inflammation needs to be moderated. The initial granulation tissue formed is highly inflammatory with a high rate of tissue turnover mediated by matrix degrading enzymes and reactive oxygen metabolites that are products of inflammatory cells.<ref name="Giovanni Abatangelo 1999"/> Stabilization of granulation tissue matrix can be achieved by moderating inflammation. HA functions as an important moderator in this moderation process, which contradicts its role in inflammatory stimulation, as described above. HA can protect against free-radical damage to cells.<ref name="pmid2450149">{{vcite2 journal | vauthors = Tammi R, Ripellino JA, Margolis RU, Tammi M | title = Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe | journal = J. Invest. Dermatol. | volume = 90 | issue = 3 | pages = 412–4 | year = 1988 | pmid = 2450149 | doi = 10.1111/1523-1747.ep12456530}}</ref> This may attribute to its free-radical scavenging property, a physicochemical characteristic shared by large polyionic polymers. In a rat model of free-radical scavenging property investigated by Foschi D. and colleagues, HA has been shown to reduce damage to the granulation tissue.<ref name="pmid1966392">{{vcite2 journal | vauthors = Foschi D, Castoldi L, Radaelli E, Abelli P, Calderini G, Rastrelli A, Mariscotti C, Marazzi M, Trabucchi E | title = Hyaluronic acid prevents oxygen free-radical damage to granulation tissue: a study in rats | journal = Int J Tissue React | volume = 12 | issue = 6 | pages = 333–9 | year = 1990 | pmid = 1966392 | doi = }}</ref>

In addition to the free-radical scavenging role, HA may also function in the negative [[feedback loop]] of inflammatory activation through its specific biological interactions with the biological constituents of inflammation.<ref name="Giovanni Abatangelo 1999"/> TNF-α, an important cytokine generated in inflammation, stimulates the expression of TSG-6 (TNF-stimulated gene 6) in fibroblasts and inflammatory cells. TSG-6, a HA-binding protein, also forms a stable complex with the serum proteinase inhibitor IαI (Inter-α-inhibitor) with a synergistic effect on the latter’s plasmin-inhibitory activity. [[Plasmin]] is involved in activation of the [[Proteolysis|proteolytic]] cascade of matrix [[metalloproteinases]] and other [[proteinase]]s leading to inflammatory tissue damage. Therefore, the action of TSG-6/ IαI complex, which may be additionally organized by binding to HA in the extracellular matrix, may serve as a potent negative feedback loop to moderate inflammation and stabilize the granulation tissue as healing progresses.<ref name="Giovanni Abatangelo 1999"/><ref name="pmid9244409">{{vcite2 journal | vauthors = Wisniewski HG, Vilcek J | title = TSG-6: an IL-1/TNF-inducible protein with anti-inflammatory activity | journal = Cytokine Growth Factor Rev. | volume = 8 | issue = 2 | pages = 143–56 | year = 1997 | pmid = 9244409 | doi = 10.1016/s1359-6101(97)00008-7}}</ref> In the murine air pouch model of carragenan/IL-1 (Interleukin-1β)-induced inflammation, where HA has been shown to have a proinflammatory property, reduction of inflammation can be achieved by administrating TSG-6, and the result is comparable with systemic dexamethasone treatment.

===Re-epithelization===

HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties. It serves as an integral part of the extracellular matrix of [[basal keratinocyte]]s, which are major constituents of the epidermis; its free-radical scavenging function and its role in keratinocyte proliferation and migration.<ref name="Giovanni Abatangelo 1999"/>

In normal skin, HA is found in relative high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found.<ref name="Tammi R 1989">{{vcite2 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}}</ref> 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.<ref name="Giovanni Abatangelo 1999"/><ref name="pmid9446831">{{vcite2 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}}</ref> 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. Tammi R. and other colleagues found HA content increases at the presence of [[retinoic acid]] (vitamin A).<ref name="Tammi R 1989"/> The proposed effects of retinoic acid against skin photo-damage and aging may be correlated, at least in part, with an increase of skin HA content, giving rise to increase of tissue hydration. It has been suggested 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.<ref name="Giovanni Abatangelo 1999"/>

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.<ref name="Giovanni Abatangelo 1999"/>{{vcite2 journal | vauthors = Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I | title = Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation | journal = Genes Dev. | volume = 11 | issue = 8 | pages = 996–1007 | year = 1997 | pmid = 9136928 | doi = 10.1101/gad.11.8.996}} Kaya et al. found suppression of CD44 expression by an epidermis-specific [[antisense]] [[transgene]] resulted in animals with defective HA accumulation in the superficial dermis, accompanied by distinct morphologic alterations of basal keratinocytes and defective keratinocyte proliferation in response to [[mitogen]] and growth factors. Decrease in skin elasticity, impaired local inflammatory response, and impaired tissue repair were also observed.<ref name="Giovanni Abatangelo 1999"/> Their observations are strongly supportive of the important roles HA and CD44 have in skin physiology and tissue repair.<ref name="Giovanni Abatangelo 1999"/>

===Fetal wound healing and scarring===

Lack of fibrous scarring is the primary feature of fetal wound healing. Even for longer periods, HA content in fetal wounds is still higher than that in adult wounds, which suggests that HA may, at least in part, reduce collagen deposition and therefore lead to reduced scarring.<ref>{{vcite2 journal | vauthors = Longaker MT, Chiu ES, Adzick NS, Stern M, Harrison MR, Stern R | title = Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid | journal = Ann. Surg. | volume = 213 | issue = 4 | pages = 292–6 | year = 1991 | pmid = 2009010 | pmc = 1358347 | doi = 10.1097/00000658-199104000-00003}}</ref> This suggestion is in agreement with the research of West et al., who showed in adult and late gestation fetal wound healing, removal of HA results in fibrotic scarring.<ref name="Giovanni Abatangelo 1999"/>

== Role in cancer metastasis ==
[[File:metastasis.jpeg|thumb|350px|Figure 1. The process of cancer metastasis in which HA-associated molecules play a role in the steps. Abbreviations: hyaluronic acid (HA), hyaluronic acid synthase (HAS), hyaluronic acid receptor (HAR), hyaluronidase (HAase/HYAL){{citation needed|date=March 2014}}]]
As shown in Figure 1, the various types of molecules that interact with hyaluronan can contribute to many of the stages of [[cancer metastasis]], i.e. further the spread of cancer.{{citation needed|date=March 2014}}

Hyaluronan [[synthase]]s (HAS) play roles in all of the stages of cancer metastasis.  By producing anti-adhesive HA, HAS can allow tumor cells to release from the primary tumor mass, and if HA associates with receptors such as CD44, the activation of Rho GTPases can promote epithelial-mesenchymal transition (EMT) of the cancer cells. During the processes of intravasation or [[extravasation]], the interaction of HAS produced HA with receptors such as CD44 or RHAMM promote the cell changes that allow for the cancer cells to infiltrate the [[vascular]] or [[lymphatic]] systems. While traveling in these systems, HA produced by HAS protects the cancer cell from physical damage. Finally, in the formation of a metastatic lesion, HAS produces HA to allow the cancer cell to interact with native cells at the secondary site and to produce a tumor for itself.<ref name="pmid19218337">{{vcite2 journal | vauthors = Bharadwaj AG, Kovar JL, Loughman E, Elowsky C, Oakley GG, Simpson MA | title = Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing | journal = Am. J. Pathol. | volume = 174 | issue = 3 | pages = 1027–36 | year = 2009 | pmid = 19218337 | pmc = 2665762 | doi = 10.2353/ajpath.2009.080501 }}</ref>

[[HYAL1|Hyaluronidases]] (HAase or HYAL) also play many roles in [[cancer]] metastasis.  By helping to degrade the extracellular matrix surrounding the tumor, hyaluronidases help the cancer cell escape from the primary tumor mass and play a major role in [[intravasation]] by allowing degradation of the basement membrane of the lymph or blood vessel. Hyaluronidases again play these roles in establishment of a metastatic [[lesion]] by helping with extravasation and clearing the extracellular matrix (ECM) of the secondary site.<ref>{{vcite2 journal | vauthors = Bharadwaj AG, Rector K, Simpson MA | title = Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis | journal = J. Biol. Chem. | volume = 282 | issue = 28 | pages = 20561–20572 | year = 2007 | pmid = 17502371 | doi = 10.1074/jbc.m702964200 }}</ref> Finally, hyaluronidases play a key role in the process of [[angiogenesis]]. HA fragments promote angiogenesis and hyaluronidases produce these fragments.<ref name="pmid18544273">{{vcite2 journal | vauthors = Gao F, Yang CX, Mo W, Liu YW, He YQ | title = Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing | journal = Clin Invest Med | volume = 31 | issue = 3 | pages = E106–16 | year = 2008 | pmid = 18544273 | doi = }}</ref> Interestingly, [[Hypoxia (medical)|hypoxia]] also increases production of HA and activity of hyaluronidases.<ref name="pmid16594159">{{vcite2 journal | vauthors = Gao F, Okunieff P, Han Z, Ding I, Wang L, Liu W, Zhang J, Yang S, Chen J, Underhill CB, Kim S, Zhang L | title = Hypoxia-induced alterations in hyaluronan and hyaluronidase | journal = Adv. Exp. Med. Biol. | volume = 566 | issue = | pages = 249–56 | year = 2005 | pmid = 16594159 | doi = 10.1007/0-387-26206-7_33 }}</ref>

The hyaluronan receptors, CD44 and RHAMM, are most thoroughly studied in terms of their roles in cancer metastasis. Increased clinical CD44 expression has been positively correlated to metastasis in a number of tumor types.<ref name="pmid17991717">{{vcite2 journal | vauthors = Ouhtit A, Abd Elmageed ZY, Abdraboh ME, Lioe TF, Raj MH | title = In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver | journal = Am. J. Pathol. | volume = 171 | issue = 6 | pages = 2033–9 | year = 2007 | pmid = 17991717 | pmc = 2111125 | doi = 10.2353/ajpath.2007.070535 }}</ref>  In terms of mechanics, CD44 affects adhesion of cancer cells to each other and to endothelial cells, rearranges the [[cytoskeleton]] through the Rho GTPases, and increases the activity of ECM degrading enzymes.<ref name="pmid18467123">{{vcite2 journal | vauthors = Naor D, Wallach-Dayan SB, Zahalka MA, Sionov RV | title = Involvement of CD44, a molecule with a thousand faces, in cancer dissemination | journal = Semin. Cancer Biol. | volume = 18 | issue = 4 | pages = 260–7 | year = 2008 | pmid = 18467123 | doi = 10.1016/j.semcancer.2008.03.015 }}</ref> Increased RHAMM expression has also been clinically correlated with cancer metastasis. In terms of mechanics, RHAMM promotes cancer cell motility through a number of pathways including [[focal adhesion kinase]] (FAK), [[Map kinase]] (MAPK), [[pp60(c-src)]], and the downstream targets of [[Rho kinase]] (ROK).<ref name="pmid8750188">{{vcite2 journal | vauthors = Hall CL, Turley EA | title = Hyaluronan: RHAMM mediated cell locomotion and signaling in tumorigenesis | journal = J. Neurooncol. | volume = 26 | issue = 3 | pages = 221–9 | year = 1995 | pmid = 8750188 | doi = 10.1007/bf01052625}}</ref> RHAMM can also cooperate with CD44 to promote angiogenesis toward the metastatic lesion.<ref>{{vcite2 journal | vauthors = Savani RC, Cao G, Pooler PM, Zaman A, Zhou Z, DeLisser HM | title = Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis | journal = J. Biol. Chem. | volume = 276 | issue = 39 | pages = 36770–36778 | year = 2001 | pmid = 11448954 | doi = 10.1074/jbc.M102273200 | displayauthors = 1 }}</ref>

== Cosmetic uses ==

Hyaluronan is a common ingredient in skin-care products.

Until recently, hyaluronic acid fillers were injected using a classic sharp [[hypodermic needle]], cutting through nerves and vessels, causing pain and [[bruising]].

In certain cases, the hyaluronic acid fillers results in a granulomatous foreign body reaction.<ref>{{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}}</ref>

== Equine applications ==

Hyaluronan is used in treatment of articular disorders in [[horse]]s, 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.<ref>[http://www.genitrix.co.uk/2008datasheets/DS011_00HY-50.pdf Genitrix HY-50 Vet datasheet]</ref>

Note that, according to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for [[horse meat]].<ref>[http://www.drugs.com/vet/hy-50-can.html HY-50 for veterinary use]</ref> In Europe, however, the same preparation is not considered to have any such effect, and edibility of the [[horse meat]] is not affected.<ref>[http://www.genitrix.co.uk/2008ProductsHorses-HY502.php Genitrix HY-50 Vet brochure]</ref>

== Etymology ==

Hyaluronic acid is derived from ''hyalos'' (Greek for vitreous) 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 acid|conjugate base]] of hyaluronic acid. Because the molecule typically exists ''in vivo'' in its [[polyanionic]] form, it is most commonly referred to as ''hyaluronan''.

==History==

Hyaluronan is found in many tissues of the body, such as skin, cartilage, and the vitreous humour. Therefore, it is well suited to biomedical applications targeting these tissues. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by [[Pharmacia]], and is 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 [[Ophthalmology|ophthalmic]] surgery.<ref>[http://www.alconlabs.com/us/aj/products/Surgical_Cataract/A251_Viscoelastics.jhtml Error 404: Page Not Found | Alcon<!-- Bot generated title -->]</ref><ref>[http://web.archive.org/web/20071221232506/http://www.bausch.com.br/br/resource/surgical/cataract/amviscstatement.jsp Bausch & Lomb: Amvisc and Amvisc Plus – Brief Statement<!-- Bot generated title -->]</ref><ref>[http://www.lifecore.com/ Medical Grade Hyaluronan | Lifecore Biomedical<!-- Bot generated title -->]</ref>

Native hyaluronan has a relatively short half-life (shown in rabbits)<ref>{{vcite2 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}}</ref> 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,<ref>{{vcite2 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 }}</</ref> the introduction of free-radical scavenging molecules such as [[sorbitol]],<ref>[http://www.anteis.com Anteis | Change starts here<!-- Bot generated title -->]</ref> and minimal stabilisation of the HA chains through chemical agents e.g. [[NASHA]] stabilisation are all techniques that have been used.<ref>[http://www.durolane.com Medicijnvrije behandeling van artrose en artritis<!-- Bot generated title -->]</ref>

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.<ref>1. Miller D, O'Connor P,William J: Use of Na-Hyaluronate during intraocular lens implantation in rabbits. Ophthal Surg. 8:58–61, 1977</ref><ref>7. Miller D, Stegmann R: Healon: A Comprehensive Guide to its Use in Ophthalmic Surgery. J Wiley, NY, 1983</ref>

==Approval==
FDA approved formulations are available.<ref name="Synvisc-One (hylan GF-20) - P940015/S012">http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm133863.htm.</ref> In 2007, the [[European Medicines Agency|EMA]] extended its approval of Hylan GF-20 as a treatment for [[ankle]] and [[shoulder]] osteoarthritis pain.<ref>{{cite web|url=http://www.library.nhs.uk/musculoskeletal/ViewResource.aspx?resID=182567 |title=Hylan G-F 20 (Synvisc) approved by EMEA for pain due to ankle and shoulder OA |accessdate=2007-07-09|publisher=[[National Health Service]]}}</ref>

==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.<ref name="pmid15275810">{{vcite2 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 = 359–71 | year = 2005 | pmid = 15275810 | doi = 10.1016/j.biomaterials.2004.02.067 }}</ref><ref>{{vcite2 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 | year = 2005 | pmid = 15275810 | doi = 10.1016/j.biomaterials.2004.02.067 | url = http://hyaluronicacidpowder.net/Segura_et_al_Biomat_2004.pdf }}</ref><ref>[http://web.archive.org/web/20080528102159/http://www.biomateria.com/bio_skin_3.htm Bio-skin FAQ<!-- Bot generated title -->]</ref> In particular, a number of research groups have found hyaluronan's properties for tissue engineering and [[regenerative medicine]] are significantly improved with crosslinking, producing a hydrogel. This added feature allows a researcher to form a desired shape, as well as to deliver therapeutic molecules, into a host.<ref name="Shu XZ 1348">{{vcite2 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 = 1339–48 | year = 2004 | pmid = 14643608 | doi = 10.1016/j.biomaterials.2003.08.014}}</ref> Hyaluronan can be crosslinked by attaching [[thiol]]s (trade names: Extracel, HyStem),<ref name="Shu XZ 1348"/>[[methacrylate]]s,<ref name="pmid17581871">{{vcite2 journal | vauthors = Gerecht S, Burdick JA, Ferreira LS, Townsend SA, Langer R, Vunjak-Novakovic G | title = Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 27 | pages = 11298–303 | year = 2007 | pmid = 17581871 | pmc = 2040893 | doi = 10.1073/pnas.0703723104 }}</ref> hexadecylamides (trade name: Hymovis), <ref>{{vcite2 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 | pages = 26 | year = 2013 | pmid = 23889808 | pmc = 3727958 | doi = 10.1186/1476-9255-10-26 }}</ref> and [[tyramine]]s (trade name: Corgel).<ref>Dar A, Calabro A: Synthesis and characterization of tyramine-based hyaluronan hydrogels. J Mater Sci: Mater Med, 20:33–44, 2009.</ref> Hyaluronan can also be crosslinked directly with [[formaldehyde]] (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).<ref>Wnek GE, Bowlin GL (editors): Encyclopedia of Biomaterials and Biomedical Engineering. Informa Healthcare, 2008.</ref>

Due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate, hyaluronic acid can be used to create hydrogels to study vascular morphogenesis.<ref name="pmid18661325">{{vcite2 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 = 120–3 | year = 2008 | pmid = 18661325 | doi = 10.1080/03008200802148462 }}</ref>   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 cell]]s 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.<ref name="pmid21527523">{{vcite2 journal | vauthors = Hanjaya-Putra D, Bose V, Shen YI, Yee J, Khetan S, Fox-Talbot K, Steenbergen C, Burdick JA, Gerecht S | title = Controlled activation of morphogenesis to generate a functional human microvasculature in a synthetic matrix | journal = Blood | volume = 118 | issue = 3 | pages = 804–15 | year = 2011 | pmid = 21527523 | pmc = 3142913 | doi = 10.1182/blood-2010-12-327338 }}</ref>

== See also ==
* [[Alguronic acid]]
* [[Sodium hyaluronate]]

==References==
{{reflist|2}}

== External links ==
* [[ATC code]]s: {{ATC|D03|AX05}}, {{ATC|M09|AX01}}, {{ATC|R01|AX09}}, {{ATC|S01|KA01}}
* {{MeshName|Hyaluronan}}
{{Glycosaminoglycans}}
{{Preparations for treatment of wounds and ulcers}}
{{Nasal preparations}}

[[Category:Glycosaminoglycans]]