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			{{Short description|Anionic, nonsulfated glycosaminoglycan}}
			{{cs1 config|name-list-style=vanc|display-authors=6}}
	{{Chembox		{{Chembox
			| Verifiedfields = changed
	| verifiedrevid = 396493356
			| Watchedfields = changed
	| ImageFile1 = Hyaluronan.png
			| verifiedrevid = 443055112
	| ImageSize1 = 300px
			| Name =
	| Section1 = {{Chembox Identifiers
			| ImageFile =
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| ImageFile1 = Hyaluronan.svg
	| ChemSpiderID = 2341172
			| ImageSize1 = 250px
	| SMILES = .O=C(N4(O)O(CO)(O)4O3O(C(=O)O)(O2O((O)(O1O(C(=O)O)(O)(O)1O)2NC(=O)C)CO)(O)3O)C
			| ImageFile2 = Haworth projection of hyaluronan.svg
	| UNII_Ref = {{fdacite|correct|FDA}}
			| ImageSize2 = 330px
	| UNII = S270N0TRQY
			| ImageCaption2 = Haworth projection
	| InChIKey = YWIVKILSMZOHHF-QJZPQSOGBN
			| OtherNames =
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
			| IUPACName = (1→4)-(2-Acetamido-2-deoxy-<small>D</small>-gluco)-(1→3)-<small>D</small>-glucuronoglycan
	| StdInChI = 1S/C28H44N2O23.Na/c1-5(33)29-9-18(11(35)7(3-31)47-25(9)46)49-28-17(41)15(39)20(22(53-28)24(44)45)51-26-10(30-6(2)34)19(12(36)8(4-32)48-26)50-27-16(40)13(37)14(38)21(52-27)23(42)43;/h7-22,25-28,31-32,35-41,46H,3-4H2,1-2H3,(H,29,33)(H,30,34)(H,42,43)(H,44,45);/q;+1/t7-,8-,9-,10-,11-,12-,13+,14+,15-,16-,17-,18-,19-,20+,21+,22+,25-,26+,27-,28-;/m1./s1
			| SystematicName = Poly{oxyoxy}
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			| Section1 = {{Chembox Identifiers
	| StdInChIKey = YWIVKILSMZOHHF-QJZPQSOGSA-N
			| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
			| ChemSpiderID = None
			| PubChem = 3084050
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = S270N0TRQY
			| EINECS = 232-678-0
			<!-- | pronounce = Hyaluronic acid, {{IPAc-en|ˌ|h|aɪ|ə|l|.|j|ʊ|ˈ|r|ɒ|n|ɨ|k}} or {{IPAc-en|ˌ|h|aɪ|ə|l|uː|ˈ|r|ɒ|n|ɨ|k}}); hyaluronate, {{IPAc-en|ˌ|h|aɪ|ə|l|ˈ|j|ʊər|ə|n|eɪ|t}} or {{IPAc-en|ˌ|h|aɪ|ə|ˈ|l|ʊər|ə|n|eɪ|t}}; hyaluronan, {{IPAc-en|ˌ|h|aɪ|ə|l|uː|ˈ|r|ɒ|n|ə|n}} -->
	| CASNo_Ref = {{cascite|correct|CAS}}		| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo = 9004-61-9		| CASNo = 9004-61-9
			| ChEBI = 16336
	| CASOther = <br />31799-91-4 (potassium salt) <br /> 9067-32-7 (sodium salt)
			}}
	| InChI = 1/C28H44N2O23.Na/c1-5(33)29-9-18(11(35)7(3-31)47-25(9)46)49-28-17(41)15(39)20(22(53-28)24(44)45)51-26-10(30-6(2)34)19(12(36)8(4-32)48-26)50-27-16(40)13(37)14(38)21(52-27)23(42)43;/h7-22,25-28,31-32,35-41,46H,3-4H2,1-2H3,(H,29,33)(H,30,34)(H,42,43)(H,44,45);/q;+1/t7-,8-,9-,10-,11-,12-,13+,14+,15-,16-,17-,18-,19-,20+,21+,22+,25-,26+,27-,28-;/m1./s1
			| Section2 = {{Chembox Properties
	}}
			| Formula = (C<sub>14</sub>H<sub>21</sub>NO<sub>11</sub>)<sub>''n''</sub>
	| Section2 = {{Chembox Properties
			| Solubility =
	| Formula = (C<sub>14</sub>H<sub>21</sub>NO<sub>11</sub>)<sub>n</sub>
			}}
	| Solubility = soluble (sodium salt)
			| Section3 =
	}}
			| Section4 =
	| Section7 = {{Chembox Hazards
			| Section5 =
	| SPhrases = {{S22}}, {{S24/25}} (sodium salt)
			| Section6 = {{Chembox Pharmacology
	| 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>
			| ATCCode_prefix = D03
	}}
			| ATCCode_suffix = AX05
	| Section8 = {{Chembox Related
			| ATC_Supplemental = {{ATC|M09|AX01}}, {{ATC|R01|AX09}}, {{ATC|S01|KA01}}
	| OtherCpds = ] and ] (monomers)
	}}		}}
			| Section7 = {{Chembox Hazards
			}}
			| Section8 = {{Chembox Related
			| OtherCompounds = {{ubl|] and ] (monomers)|]}}
			}}
	}}		}}
	'''Hyaluronan''' (also called '''hyaluronic acid''' or '''hyaluronate''') is an ], ] ] distributed widely throughout ], ], and ]s. It is unique among glycosaminoglycans in that it is nonsulfated, forms in the ] instead of the ], and can be very large, with its ] often reaching the millions.<ref>{{cite journal		'''Hyaluronic acid''' ({{IPAc-en|ˌ|h|aɪ|.|ə|l|j|ʊəˈr|ɒ|n|ɪ|k}};<ref name="Lexico Dictionaries">{{Cite web|url=https://www.lexico.com/en/definition/hyaluronic_acid|archive-url=https://web.archive.org/web/20191006195737/https://www.lexico.com/en/definition/hyaluronic_acid|url-status=dead|archive-date=October 6, 2019|title=Hyaluronic Acid &#124; Definition of Hyaluronic Acid by Oxford Dictionary |website=Lexico Dictionaries &#124; English}}</ref><ref>{{Cite web|url=https://www.wordreference.com/definition/Hyaluronic+acid|title=Hyaluronic acid |website=wordreference.com}}</ref> abbreviated '''HA'''; ] '''hyaluronate'''), also called '''hyaluronan''', is an ], ] ] distributed widely throughout ], ], and ]s. It is unique among glycosaminoglycans as it is non-sulfated, forms in the ] instead of the ], and can be very large: human ] HA averages about {{val|7|ul=MDa}} per molecule, or about 20,000 ] monomers,<ref name="Fraser-1997">{{cite 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|s2cid=37551992 |doi-access=free }}</ref> while other sources mention {{val|3|–|4|u=MDa}}.<ref name="Saari-1993" />
	| last=Frasher| first=J.R.E ''et al'
	| title=Hyaluronan: its nature, distribution, functions and turnover
	| journal=Journal of Internal Medicine
	| year=1997 | volume=242
	| pages=27&ndash;33
	| format=PDF | accessdate=2009-06-05
	| doi=10.1046/j.1365-2796.1997.00170.x
	| url=http://www3.interscience.wiley.com.iiiprxy.library.miami.edu/cgi-bin/fulltext/119157843/PDFSTART
	| last2=Laurent
	| first2=T. C.
	| last3=Laurent
	| first3=U. B. G. | pmid=9260563}}</ref>
	One of the chief components of the ], hyaluronan contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant ]s.
			Medically, hyaluronic acid is used to treat osteoarthritis of the knee, dry eye, for wound repair, and as a cosmetic filler.<ref>, Stanford Chemicals Company</ref>
	The average 70&nbsp;kg (154&nbsp;lbs) person has roughly 15&nbsp;grams of hyaluronan in the body, one-third of which is turned over (degraded and synthesized) every day.<ref>{{cite journal|author=Stern R | title=Hyaluronan catabolism: a new metabolic pathway | journal=Eur J Cell Biol|volume=83 | issue=7 | pages=317–25 | month=August | year=2004 | pmid = 15503855 | accessdate= | doi=10.1078/0171-9335-00392}}</ref> Hyaluronic acid is also a component of the ] extracellular ],<ref>{{Cite journal
	| last =Sugahara
	| first =K.
	| coauthors =N.B. Schwartz and A. Dorfman
	| year =1979
	| title =Biosynthesis of hyaluronic acid by ''Streptococcus''
	| journal =Journal of Biological Chemistry
	| volume =254
	| issue =14
	| pages =6252–6261
	| url =http://www.jbc.org/content/254/14/6252.full.pdf
	| pmid =376529
	}}
	</ref> and is believed to play a role in ].<ref>{{Cite journal
	| last =Wessels
	| first =M.R.
	| coauthors =A.E. Moses, J.B. Goldberg and T.J. DiCesare
	| year =1991
	| title =Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci
	| journal =PNAS
	| publisher =
	| volume =88
	| issue =19
	| pages =8317–8321
	| url =http://www.pnas.org/content/88/19/8317.full.pdf
	| pmid =1656437
	| doi =10.1073/pnas.88.19.8317
	| pmc =52499
	}}
	</ref><ref>{{Cite journal
	| last =Schrager
	| first =H.M.
	| coauthors =J.G. Rheinwald and M.R. Wessels
	| year =1996
	| title =Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes in invasive skin infection
	| journal =Journal of Clinical Investigation
	| volume =98
	| issue =9
	| pages =1954–1958
	| url =http://www.jci.org/articles/view/118998/pdf
	| pmid =8903312
	| doi =10.1172/JCI118998
	| pmc =507637
	}}
	</ref>
			The average 70&nbsp;kg (150&nbsp;lb) person has roughly 15&nbsp;grams of hyaluronan in the body, one third of which is turned over (i.e., degraded and synthesized) per day.<ref>{{cite 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>
	== Functions ==
			As one of the chief components of the ], it contributes significantly to ] and ], and is involved in the progression of many malignant ]s.<ref>{{cite book|editor=Stern, Robert|title=Hyaluronan in cancer biology|url=https://archive.org/details/hyaluronancancer00ster|url-access=registration|year=2009|publisher=Academic Press/Elsevier|location=San Diego, CA|isbn=978-0-12-374178-3|edition=1st}}</ref><ref name="Itano-2002">{{cite journal|author=Itano, Naoki|title=Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration|journal=Proceedings of the National Academy of Sciences|doi-access=free|year=2002|volume=99|issue=6|pages=3609–3614|publisher=Proc Natl Acad Sci USA|doi=10.1073/pnas.052026799|pmid=11891291|pmc=122571|bibcode=2002PNAS...99.3609I }}</ref> Hyaluronic acid is also a component of the ] extracellular ],<ref>{{cite 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 | doi = 10.1016/S0021-9258(18)50356-2 | pmid = 376529 | url = http://www.jbc.org/content/254/14/6252.full.pdf | doi-access = free }}</ref> and is believed to play a role in ].<ref>{{cite journal | last1=Rao | first1=Shreesha | last2=Pham | first2=Trung Hieu | last3=Poudyal | first3=Sayuj | last4=Cheng | first4=Li-Wu | last5=Nazareth | first5=Sandra Celenia | last6=Wang | first6=Pei-Chi | last7=Chen | first7=Shih-Chu | title=First report on genetic characterization, cell-surface properties and pathogenicity of '''Lactococcus garvieae''', emerging pathogen isolated from cage-cultured cobia ('''Rachycentron canadum''') | journal=Transboundary and Emerging Diseases | publisher=Hindawi Limited | volume=69 | issue=3 | date=2021-04-27 | issn=1865-1674 | doi=10.1111/tbed.14083 | pages=1197–1211| pmid=33759359 | s2cid=232338928 | doi-access=free }}</ref><ref>{{cite 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 | bibcode = 1991PNAS...88.8317W | doi-access = free }}</ref><ref>{{cite 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 }}</ref>
	Until the late 1970s, hyaluronan was described as a "]" molecule, a ubiquitous ] ] that is part of the extracellular matrix.<ref>{{cite journal |last=Toole |first=B.P. |year=2000 |month=August |title=Hyaluronan is not just a goo! (.pdf) |journal=Journal of Clinical Investigation |volume=106 |issue=3 |pages=335–336 |id= |url=http://www.jci.org/articles/view/10706/pdf |accessdate= |quote= |doi=10.1172/JCI10706 |pmid=10930435 |pmc=314333 }}</ref> For example, hyaluronan is a major component of the ], and was found to increase the viscosity of the fluid. Along with ], it is one of the fluid's main lubricating components.
			== Physiological function ==
	Hyaluronan is an important component of articular ], where it is present as a coat around each cell (]). When ] ] bind to hyaluronan in the presence of ], large highly negatively-charged aggregates form. These aggregates imbibe water and are responsible for the ] of ] (its resistance to compression). The ] (size) of hyaluronan in ] decreases with age, but the amount increases.<ref>Holmes et al. (1988) Hyaluronic acid in human articular cartilage. Age-related changes in content and size. Biochem J 250:435-441.</ref>
			Until the late 1970s, hyaluronic acid was described as a "]" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.<ref>{{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 }}</ref> For example, hyaluronic acid is a major component of the ] and was found to increase the ] of the fluid. Along with ], it is one of the fluid's main lubricating components.{{cn|date=December 2024}}
			Hyaluronic acid is an important component of articular ], where it is present as a coat around each cell (]). When ] monomers bind to hyaluronan in the presence of ] (hyaluronic acid and proteoglycan link protein 1), large, highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the ] of ] (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.<ref>{{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 }}</ref>
	Hyaluronan is also a major component of ], where it is involved in tissue repair. When ] is exposed to excessive ], it becomes inflamed (]) and the ] in the dermis stop producing as much hyaluronan, and increase the rate of its degradation. Hyaluronan degradation products also accumulate in the skin after UV exposure.<ref>Averbeck M et al. (2007) Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation. J Invest Dermatol 127:687-697.</ref>
			A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested. A particular type of ]s, 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.<ref>{{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 }}</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, ] and ]. 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.
			Hyaluronic acid is also a major component of skin, where it is involved in repairing tissue. When skin is exposed to excessive ], it becomes inflamed (]), and the cells in the ] stop producing as much hyaluronan and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after ].<ref name="Averbeck-2007">{{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 }}</ref>
	Although hyaluronan binds to receptor ], there is evidence hyaluronan degradation products transduce their inflammatory signal through ] (]), ] or both ], and ] in ] and ]. TLR and hyaluronan play a role in ].
			While it is abundant in ], hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in a number of ] interactions, notably those including its primary receptors, ] and ]. ] of CD44 itself is widely accepted as a marker of cell activation in ]s. Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in ] interactions required by tumor cells.
	High concentrations of hyaluronan in the brains of young rats, and reduced concentrations in the brains of adult rats suggest hyaluronan plays an important role in brain development.<ref>Glycosaminoglycans of Brain during Development. R. U. Margolis, R. K. Margolis, L. B. Chang, and C. Preti. BIOCHEMISTRY VOL. 14, NO. I , 1975. Pg. 85. Retrieved 1/17/08.</ref>
			Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through ] (]), ], or both TLR2 and TLR4 in ] and ]. TLR and hyaluronan play a role in ].
	== Structure ==
	Properties of hyaluronan were first determined in the 1930s in the laboratory of ].<ref>{{cite journal |doi=10.1084/jem.71.2.137 |author=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 |month= January |pmid=19870951 |pmc=2135078}}</ref>
			There are limitations including the ''in vivo'' loss of this compound limiting the duration of effect.<ref>{{cite web |url=https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm133863.htm |title=Synvisc-One (hylan GF-20) – P940015/S012 |website=] |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 }}</ref>
	Hyaluronan is a ] of ]s, themselves composed of ] and ], linked via alternating β-1,4 and β-1,3 ]s. Hyaluronan can be 25,000 disaccharide repeats in length. Polymers of hyaluronan can range in size from 5,000 to 20,000,000 ] ''in vivo''. The average molecular weight in human ] is 3−4 million Da, and hyaluronan purified from human ] is 3,140,000 Da.<ref>Saari H et al. (1993) Differential effects of reactive oxygen species on native synovial fluid and purified human umbilical cord hyaluronate. Inflammation 17:403-415.</ref>
			=== Wound repair ===
	Hyaluronan is energetically stable, in part because of the ] 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.
			As a major component of the ], hyaluronic acid has a key role in ], ] response, and ], which are phases of ].<ref name="Shaharudin-2016">{{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}}</ref> As of 2023, however, reviews of its effect on healing for chronic wounds including ]s, ]s or surgical skin repairs show either insufficient evidence or only limited positive ] evidence.<ref name="Shaharudin-2016" /><ref name="Roehrs-2023">{{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 }}</ref> 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.<ref name="Roehrs-2023" /> Hyaluronic acid combines with water and swells to form a ], making it useful in skin treatments as a ] for facial ]s; its effect lasts for about 6 to 12 months, and treatment has regulatory approval from the US ].<ref name="USDA-2018">{{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 | access-date=11 March 2019}}</ref>
	== Biological synthesis ==		=== Granulation ===
			] is the ], fibrous connective tissue that replaces a ] 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.{{cn|date=December 2024}}
			=== Cell migration ===
	Hyaluronan is synthesized by a class of ]s called ]s, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding ] and ] to the nascent polysaccharide as it is extruded via ] through the ] into the extracellular space.<ref>Schulz,T.; Schumacher,U.; Prehm,P. Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP. J.Biol.Chem.282,20999-21004</ref>
			Cell migration is essential for the formation of granulation tissue.<ref name="Litwiniuk-2016">{{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}}</ref> 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.<ref name="Litwiniuk-2016" /> 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.<ref name="Litwiniuk-2016" /> It forms links with several ]s associated with cell locomotion, for example, ], ], and other ]s.<ref name="Litwiniuk-2016" /> During fetal development, the migration path through which ] 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.<ref name="Litwiniuk-2016" />
			By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration.<ref name="Litwiniuk-2016" /> Basically, HA is synthesized at the ] and released directly into the extracellular environment.<ref name="Litwiniuk-2016" /> This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.<ref name="Litwiniuk-2016" />
	Hyaluronan synthesis (HAS) has been shown to be inhibited by 4-methylumbelliferone (], heparvit), a 7-hydroxy-4-methylcoumarin derivative.<ref>{{cite journal | doi = 10.1074/jbc.M405918200 | last1 = Kakizaki | first1 = I. | last2 = Kojima | first2 = K. | last3 = Takagaki | first3 = K. | last4 = Endo | first4 = M. | last5 = Kannagi | first5 = R. | last6 = Ito | first6 = M. | last7 = Maruo | first7 = Y. | last8 = Sato | first8 = H. | last9 = Yasuda | first9 = T. ''et al.'' | year = 2004 | title = A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone | url = | journal = J. Biol. Chem. | volume = 279 | issue = 32| pages = 33281–33289 | pmid = 15190064 }}</ref>
	This selective inhibition (without inhibiting other ]) may prove useful in preventing ] of malignant tumor cells.<ref>{{cite journal | last1 = Yoshihara | first1 = S | last2 = Kon | first2 = A | last3 = Kudo | first3 = D | last4 = Nakazawa | first4 = H | last5 = Kakizaki | first5 = I | last6 = Sasaki | first6 = M | last7 = Endo | first7 = M | last8 = Takagaki | first8 = K | title = A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells. | journal = FEBS letters | volume = 579 | issue = 12 | pages = 2722–6 | year = 2005 | pmid = 15862315 | doi = 10.1016/j.febslet.2005.03.079 }}</ref>
			=== Skin healing ===
	] recently has been genetically modified (GMO) to culture a proprietary formula to yield hyaluronans,<ref></ref> in a patented process producing human-grade product.
			HA plays an important role in the normal ]. 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 ]s, which are major constituents of the epidermis; its ] 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.<ref name="Tammi-1989">{{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 }}</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="Tuhkanen-1998">{{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 = }}</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. A report found HA content increases in the presence of ] (vitamin A).<ref name="Tammi-1989" /> The proposed effects of retinoic acid against skin photo-damage and ] 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.
	== Cell receptors for hyaluronan ==
			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.
	So far, cell receptors that have been identified for HA fall into three main groups: CD44, Receptor for HA-mediated motility (RHAMM) and intracellular 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>
			== Medical uses ==
	CD44 is widely distributed throughout the body, and the formal demonstration of HA-CD44 binding was proposed by Aruffo et al.<ref>Aruffo A., et al. Cell, 1990, 61: 1303-1313</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">W. Y. John Chen and Giovanni Abatangelo, Wound Repair and Regeneration, 1999, 7: 79-89</ref> such as cell aggregation, migration, proliferation and activation; cell-cell and cell-substrate adhesion; endocytosis of HA, which leads to HA ] in ]; and assembly of ] from HA and ]. 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 ] proliferation in response to extracellular stimuli, and the second is the maintenance of local HA homeostasis.<ref name="Giovanni Abatangelo 1999"/>
			Hyaluronic acid has been FDA-approved to treat ] of the knee via ].<ref name="Gower-2015">{{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}}</ref> 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 ]s.<ref>{{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}}</ref> A 2020 ] found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis.<ref>{{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 }}</ref>
	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>Laurent U. B. G. and Reed R. K. Advanced Drug Delivery Reviews, 1991, 7: 237-256</ref> ] of this receptor, thus, triggers a highly coordinated cascade of events that includes the formation of an endocytotic ], its fusion with primary ], enzymatic digestion to ], active transmembrane transport of these sugars to cell sap, ] of GlcNAc and enzymatic de].<ref name="Wayne D. Comper 1996"/><ref>Fraser J. R. E. et al. Biochemical Journal, 1988, 356: 153-158</ref><ref>Campbell P. et al. Hepatology, 1990, 11: 199-204</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"/>
			Hyaluronic acid has been used to treat ].<ref name="Pucker-2016">{{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}}</ref> Hyaluronic acid is a common ingredient in ] products. Hyaluronic acid is used as a ] in cosmetic surgery.<ref>{{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}}</ref> It is typically injected using either a classic sharp ] or a ]. Some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections.<ref name="Wu-2018">{{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 }}</ref><ref>{{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 }}</ref> Currently, hyaluronic acid is used as a soft tissue filler due to its bio-compatibility and possible reversibility using ].<ref>{{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 }}</ref><ref name="Wu-2018" /> Complications include the severing of nerves and ]s, pain, and ]. 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.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>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.</ref><ref>{{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 }}</ref><ref name="Wu-2018" /> In some cases, hyaluronic acid fillers can result in a ] ].<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|pmc=2686337|doi=10.2147/cia.s382 |doi-access=free }}</ref>
	== Degradation ==
			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.<ref>{{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 }}</ref>
	Hyaluronan is degraded by a family of enzymes called ]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 ] and very low-molecular-weight hyaluronan, exhibit pro-] properties {{Citation needed|date=January 2011}}. 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 rejection {{Citation needed|date=January 2011}}.
			== Sources ==
	== Role of hyaluronan on wound repair process ==
			Hyaluronic acid is produced on a large scale by extraction from animal tissues, such as chicken ], and from ].<ref>{{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}}</ref>
	Skin provides a mechanical barrier to the external environment and acts to prevent the ingress of infectious agents.<ref name="Kennndy J. F. 2002">Kennndy 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"/> 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.
			== Structure ==
	;Inflammation
			Hyaluronic acid is a ] of ]s, which are composed of ] and ], linked via alternating β-(1→4) and β-(1→3) ]s. 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 ] ''in vivo''. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronic acid purified from human ] is 3,140,000 Da;<ref name="Saari-1993">{{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 }}</ref> other sources mention average molecular weight of 7 million Da for synovial fluid.<ref name="Fraser-1997" /> Hyaluronic acid also contains ], ranging 350–1,900{{nbsp}}μg/g depending on location in the organism.<ref>{{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}}</ref>
			Hyaluronic acid is energetically stable, in part because of the ] of its component disaccharides.{{fact|date=June 2022}} Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.{{fact|date=June 2022}}
	Many biological factors, such as growth factors, ], ] 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"/>
			Hyaluronic acid in aqueous solutions self-associates to form transient clusters in solution.<ref name="Chremos-2020">{{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 }}</ref> 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.<ref name="Chremos-2020" />
	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 ] air pouch model of carrageenan/IL-1-induced inflammation, HA was observed to enhance cellular infiltration.<ref name="Giovanni Abatangelo 1999"/><ref>Wisniewski H. G., et al., The Journal of Immunology, 1996, 156: 1609-1615</ref> Kobayashi and colleagues <ref name="Giovanni Abatangelo 1999"/><ref>Kobayashi H. and Terao T. American Journal of Physiology, 1997, 276: C1151-1159</ref> showed a dose-dependent increase of the proinflammatory cytokines TNF-α and IL-8 production by human ] ] at HA concentrations of 10μg/ml to 1&nbsp;mg/ml via a CD44-mediated mechanism. ], in response to inflammatory cytokines such as TNF-α, and bacterial ], 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>Mohamadzadeh M., et al., The Journal of Clinical Investigation, 1998, 101: 97-108</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.
			== Biological synthesis ==
	;Granulation and organization of the granulation tissue matrix
			Hyaluronic acid is synthesized by a class of ]s called ]s, of which vertebrates have three types: ], ], and ]. These enzymes lengthen hyaluronan by repeatedly adding <small>D</small>-glucuronic acid and ''N''-acetyl-<small>D</small>-glucosamine to the nascent polysaccharide as it is extruded via ] through the cell membrane into the extracellular space.<ref name="Schulz-2007">{{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 }}</ref> The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA.<ref name="Stecco-2018" /><ref>{{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}}</ref>
			Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (]), a 7-hydroxy-4-methylcoumarin derivative.<ref>{{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 }}</ref>
	] is the ], fibrous connective tissue that replaces a ] 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"/> Absolutely, initiation of inflammation is extremely crucial for the formation of granulation tissue, therefore the pro-inflammatory role of HA as discussed above also contribute to this stage of wound healing.<ref name="Giovanni Abatangelo 1999"/>
			This selective inhibition (without inhibiting other ]) may prove useful in preventing ] of malignant tumor cells.<ref>{{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 }}</ref> 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.<ref>{{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}}</ref>
			'']'' recently has been genetically modified to culture a proprietary formula to yield hyaluronans,<ref>{{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<!-- Bot generated title --> |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 }}</ref> in a patented process producing human-grade product.
	;HA and cell migration
			=== Fasciacyte ===
	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>Hall C. L., et al., The Journal of cell biology, 1992, 117: 1343-1350</ref><ref>Wang C. et al., Clinical Cancer Research, 1998, 4: 567-576</ref><ref>Hall C. L., et al., Oncogene, 1996. 13: 2213-2214</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>Morriss-Kay G. M., et al., Journal of Embryology and Experimental Morphology, 1986, 98: 59-70</ref>
			A fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle ].<ref name="Stecco-2018">{{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}}</ref>
			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.
	By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration.<ref>Ellis I. R., et al., Experimental Cell Research, 1996, 228: 326-342</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.
			Fasciacytes produce hyaluronan, which regulates fascial gliding.<ref name="Stecco-2018" />
	;Role of HA in moderation of the inflammatory response
			== Biosynthetic mechanism ==
	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>Tammi R., et al., Journal of Investigative Dermatology, 1988, 90: 412-414</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>Foschi D., et al., International Journal on Tissue Reaction, 1990, 12: 333-339</ref>
			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.<ref name="Itano-2002" /> 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.<ref name="Sze-2016">{{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}}</ref>
			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.<ref name="Sze-2016" /> There are three existing types of HASs in vertebrates: HAS1, HAS2, HAS3; each of these contribute to elongation of the HA polymer.<ref name="Itano-2002" /> 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.<ref name="Moreno-Camacho-2019">{{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 }}</ref> 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.<ref name="Moreno-Camacho-2019" />
	In addition to the free-radical scavenging role, HA may also function in the negative ] 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. ] is involved in activation of the ] cascade of matrix ] and other ]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>Wisniewski H. G. and Vilcek J. Cytokine & Growth Factor Reviews, 1997, 8: 143-156</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.
			UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via ''hasA'' (HA synthase).<ref name="Sze-2016" />
	;Reepithelization
			]
	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 ]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"/>
			=== Synthesis of UDP-glucuronic acid ===
	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">Tammi R, et al., Journal of Investigative Dermatology, 1989, 92: 326-332</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>Tuhkanen A-L, et al., Journal of Histochemistry and Cytochemistry, 1998, 46: 241-248</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 <ref name="Tammi R 1989"/> found HA content increases at the presence of ] (vitamin A). 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"/>
			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.<ref name="Sze-2016" />
			]
	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"/><ref>Kaya G. et al., Genes & Development, 1997, 15: 996-1007</ref> Kaya et al. found suppression of CD44 expression by an epidermis-specific ] ] 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 ] 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"/>
			=== Synthesis of N-acetyl glucosamine ===
	;Fetal wound healing and scarring
			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.<ref name="Moreno-Camacho-2019" />
			]
	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>Longaker M. T., et al., Annals of Surgery, 1991, 213: 292-296</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"/> Though the exact role of HA in skin scarring is still under investigation, based on all the facts that have been observed, it must be a great contributor to the less fibrous scarring.
			=== Final step: Two disaccharides form hyaluronic acid ===
	== Role of hyaluronan in cancer metastasis ==
			UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via ''hasA'' (HA synthase), completing the synthesis.<ref name="Moreno-Camacho-2019" />
	]
	As shown in Figure 1, the various types of molecules that interact with hyaluronan can contribute to many of the stages of ].
			== Degradation ==
	Hyaluronan ]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 ], 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 ] or ] 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>Baradwaj AG, et al. Spontaneous metastasis of prostate cancer is promoted by excess hyaluornan synthesis and processing. Am J Path. 2009;174:1027-1036</ref>
			Hyaluronic acid can be degraded by a family of enzymes called ]s. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are ]s. The degradation products of hyaluronan, the ] and very low-molecular-weight hyaluronan, exhibit pro-] properties.<ref name="Matou-Nasri-2009">{{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 }}</ref> 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.<ref name="Yung-2011">{{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 }}</ref><ref name="Tesar-2006">{{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 = }}</ref>
			Hyaluronan can also be degraded via non-enzymatic reactions. These include ]ic and ]ne ], ], ], and degradation by ].<ref name="Stern-2007">{{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}}</ref>
	] (HAase or HYAL) also play many roles in ] ]. By helping to degrade the ] surrounding the tumor, hyaluronidases help the cancer cell escape from the primary tumor mass and play a major role in ] by allowing degradation of the basement membrane of the lymph or blood vessel. Hyaluronidases again play these roles in establishment of a metastatic ] by helping with extravasation and clearing the ECM of the secondary site.<ref>Bharadwaj AG, et al. Inducible hyaluornan production reveals differential effects of prostate tumor cell growth and tumor angiogenesis. J Cell Biol. 2007;282:20561-20572</ref> Finally, hyaluronidases play a key role in the process of ]. HA fragments promote angiogenesis and hyaluronidases produce these fragments.<ref>Gao F, et al. Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Clinical and Investigative Medicine. 2008;31:E106-116</ref> Interestingly, ] also increases production of HA and activity of hyaluronidases.<ref>Gao, et al. Hypoxia-induced alterations in hyaluronan and hyaluronidase. Adv Exp Med Biol. 2005;566:249-256</ref>
			== Etymology ==
	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>Ouhtit A, et al. ''In vivo'' evidence for the role of CD44s in promoting breast cancer metastasis to the liver. Am J Path. 2007;171:2033-2039</ref> In terms of mechanics, CD44 affects adhesion of cancer cells to each other and to endothelial cells, rearranges the ] through the Rho GTPases, and increases the activity of ECM degrading enzymes.<ref>Naor, et al. Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Sem Cancer Biol. 2008;18:260-267</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 ] (FAK), ] (MAPK), ], and the downstream targets of ] (ROK).<ref>Hall CL, et al. Hyaluronan: RHAMM mediated cell locomotion and signaling in tumorigenesis. J Neuro-oncology. 1995;103:203-207</ref> RHAMM can also cooperate with CD44 to promote angiogenesis toward the metastatic lesion.<ref>Savani, et al. Differential involvement of the hyaluornan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. J Biol Chem. 2001;276:36770-36778</ref>
			Hyaluronic acid is derived from ''hyalos'' (Greek for vitreous, meaning 'glass-like') and ]<ref>{{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 }}</ref> because it was first isolated from the ] and possesses a high uronic acid content. The term ''hyaluronate'' refers to the ] of hyaluronic acid. Since the molecule typically exists ''in vivo'' in its ] form, it is most commonly referred to as ''hyaluronan''.
	== Medical applications ==		== History ==
			Hyaluronic acid was first obtained by ] and John Palmer in 1934 from the vitreous body in a cow's eye.<ref>{{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 }}</ref> The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by ],<ref name="Ophthalmic Viscosurgical Devices">{{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 }}</ref> and approved for use in ] (i.e., ], cataract surgery, ] surgery, and surgery to repair ]). Other biomedical companies also produce brands of hyaluronan for ] surgery.<ref>{{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}}</ref>
			Native hyaluronic acid has a relatively short half-life (shown in rabbits)<ref>{{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}}</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>{{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 }}</ref> the introduction of free-radical scavenging molecules such as ],<ref>{{Cite web|url=https://www.anteis.com/en/|title=Home}}</ref> and minimal stabilisation of the HA chains through chemical agents such as NASHA (non-animal stabilised hyaluronic acid)<ref>{{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}}</ref> are all techniques that have been used to preserve its shelf life.<ref>{{Cite web|url=https://www.oakneepainrelief.com/durolane/|title=DUROLANE|website=Bioventus OA Knee Pain Relief}}</ref>
	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 ], and is approved for use in ] (i.e., ], ] surgery, ] surgery, and surgery to repair ]). Other biomedical companies also produce brands of hyaluronan for ] surgery.<ref></ref><ref></ref><ref></ref>
			In the late 1970s, ] implantation was often followed by severe ] ], due to ] damage during the surgery. It was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed.<ref>{{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}}</ref><ref>{{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}}</ref>
	Native hyaluronan has a relatively short half-life (shown in rabbits)<ref>>{{cite journal | author=Brown TJ | coauthors=Laurent UBJ Fraser JRE | title=Turnover of hyaluronan in synovial joints: elimination of labelled hyaluronan from the knee joint of the rabbit| journal=Experimental Physiology | volume=76 | issue=1 | pages=125–134 | year=1991 | pmid = 2015069 }}</</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>{{cite journal | doi=10.2165/11203900-000000000-00000 | author=Frampton JE | coauthors=| title=Hylan GF-20 Single injection formulation| journal=Drugs Aging| volume=27 | issue=1 | pages=77–85| year=2010 | pmid=20030435 }}</</ref> the introduction of free-radical scavenging molecules such as ]<ref></ref> and minimal stabilisation of the HA chains through chemical agents e.g. NASHA stabilisation are all techniques that have been used.<ref></ref>
			The name "hyaluronan" is also used for a salt.<ref>{{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}}</ref>
	In the late 1970s, intraocular lens implantation was often followed by severe ] ], 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 it’s Use in Ophthalmic Surgery. J Wiley, NY, 1983</ref> ] patented a process for purifying hyaluronic acid, a physiologic lubricant (which he called Healon) from rooster combs in the early 1970s. At first, Balazs saw Healon as a noninflammatory vitreous substitute. ] had used Balazs’ Healon in one case in which the anterior chamber flattened after a complicated corneal transplant. Although one might imagine the viscous hyaluronic acid would have caused a rise in ], Dohlman reported no such rise in his case{{Citation needed|date=April 2011}}. Since that time, Balazs had licensed the synthesis process to Pharmacia, a Swedish drug company. Although Pharmacia saw no market for a vitreous substitute, when their scientists figured out a way to increase the viscosity of hyaluronic acid, they felt it might work as an injectable agent in the treatment of both human and ] ]. The equine arthritis market proved to be small and the treatment of human ] produced only marginal improvement{{Citation needed|date=April 2011}}, so Pharmacia decided to abandon Healon. At this time, David Miller realized that Healon was the lubricant needed by the eye surgeon{{Citation needed|date=April 2011}}.
			== Other animals ==
	Balazs arranged to have Pharmacia send 20 sterile vials to ] for rabbit experiments. By 1976, Miller and colleagues published a study showing Healon worked well in protecting the rabbit corneal endothelium during IOL implantation{{Citation needed|date=April 2011}}. With a new possible use for Healon, Miller met with Pharmacia and performed a lens extraction and IOL implantation using Healon in a rabbit eye. The demonstration ignited a new enthusiasm for eye surgery with Healon. A small human pilot study at Boston’s Beth Israel Hospital by Miller confirmed Healon’s beneficial effects{{Citation needed|date=April 2011}}.
			Hyaluronan is used in ], in particular those in competition or heavy work.<ref>, Stanford Chemical Company (SCC), 2024.5.27</ref> It is indicated for ] and ] joint dysfunctions, but not when joint ] or fracture are suspected. It is especially used for ] 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>{{Cite web|url=https://www.dechra.co.uk/|title=Dechra Veterinary Products|website=www.dechra.co.uk}}</ref>
			According to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for ].<ref>{{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}}</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>{{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}}</ref>
	In a large, well-controlled clinical trial, ], of ], South Africa was able to quantify the advantages of Healon in IOL implantation by showing significantly higher postoperative corneal endothelial counts in the Healon eyes as opposed to the controls{{Citation needed|date=April 2011}}.
			== Research ==
	The U.S. ] quickly approved Healon as a surgical device in 1980, and Healon was successfully launched. By the year 2009, an estimated quarter of a billion patients had benefited from the useful properties of Healon in eye surgery{{Citation needed|date=April 2011}}.
			Due to its accumulation in airway ]s in various ]s, such as ], ], ], and ], hyaluronic acid is under study as a possible mediator of lung ] mechanisms, as of 2022.<ref name="Albtoush-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}}</ref>
			The high ] of hyaluronic acid and its common presence in the ] of tissues indicate its possible use as a ] ] in ].<ref name="Segura-2005">{{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 }}</ref> In particular, research groups have found hyaluronan's properties for tissue engineering and ] 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.<ref name="Zheng Shu-2004">{{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}}</ref> Hyaluronan can be crosslinked by attaching ]s (see ]s) (trade names: Extracel, HyStem),<ref>{{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 }}</ref> hexadecylamides (trade name: Hymovis),<ref>{{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 }}</ref> and ]s (trade name: Corgel).<ref>{{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}}</ref> Hyaluronan can also be crosslinked directly with ] (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B).<ref>{{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}}</ref> Hyaluronic acid can also be crosslinked with a bifunctional crosslinking agent ] (BDDE) using a ResonantAcoustic mixer over a period of time ranging from about 1 minute to about 10 minutes.<ref name="Google Patents-2023">{{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}}</ref>
	In 1992, Miller and Stegmann received the Innovators Award by the ] for developing the use of Healon in repairing injured eyes{{Citation needed|date=April 2011}}.
			Due to its ability to regulate ] by stimulating endothelial cells to proliferate in vitro, hyaluronan can be used to create hydrogels to study vascular morphogenesis.<ref name="Genasetti-2008">{{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 }}</ref>
	Hyaluronan is also used to treat ] of the knee.<ref>{{cite journal | author=Puhl W | coauthors=Scharf P | title=Intra-articular hyaluronan treatment for osteoarthritis | journal=Ann Rheum Dis | volume=56 | issue=7 | pages=637–40 | year=1997 | month=July | pmid = 9486013 | accessdate= | doi=10.1136/ard.56.7.441 | pmc=1752402}}</ref> Such treatments, called ''viscosupplementation'', are administered as a course of injections into the knee joint, and are believed to supplement the viscosity of the joint fluid, thereby lubricating the joint, cushioning the joint, and producing an analgesic effect. It has also been suggested that hyaluronan has positive biochemical effects on ]. However, some placebo-controlled studies have cast doubt on the efficacy of hyaluronan injections, and hyaluronan is recommended primarily as a last alternative before surgery<ref></ref> Oral use of hyaluronan has been lately suggested, although its effectiveness needs to be demonstrated. At present, there are some preliminary clinical studies that suggest oral administration of hyaluronan has a positive effect on osteoarthritis, but it remains to be seen if there is any real benefit from the treatment.
			Research shows that abnormal hyaluronic acid (HA) metabolism is a major factor in tumor progression.<ref>{{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 }}</ref><ref>{{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}}</ref> HA and HA fragment-tumor cell interaction could activate the downstream signaling pathways, promoting ], ], migration and invasion, and inducing ], ], epithelial-mesenchymal transition, stem cell-like property, and chemoradioresistance in digestive cancers.<ref>{{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}}</ref>
	Dry, scaly skin (]) such as that caused by ] (]) may be treated with a prescription skin lotion containing sodium hyaluronate as its active ingredient.<ref name="hylira">http://www.drugs.com/cdi/hylira-gel.html.</ref>
			== See also ==
	Due to its high ] and its common presence in the ] of tissues, hyaluronan is gaining popularity as a ] ] in ] research.<!--ref></ref--><ref></ref> In particular, a number of research groups have found hyaluronan's properties for ] and ] 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">Shu XZ, Liu Y, Palumbo FS, Luo Y, Prestwich GD: In situ crosslinkable hyaluronan hydrogels for tissue engineering. Biomaterials, 25:1339-1348, 2004.</ref> Hyaluronan can be crosslinked by attaching ]s (trade names: Extracel, HyStem),<ref name="Shu XZ 1348"/> ]s,<ref>Gerecht S, Burdick JA, Ferreira LS, Townsend SA, Langer R, and Vunjak-Novakovic G: Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc Natl Acad Sci USA, 104:11298-11303, 2007.</ref> and ]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 ] (trade name: Hylan-A) or with ]] (trade name: Hylan-B).<ref>Wnek GE, Bowlin GL (editors): Encyclopedia of Biomaterials and Biomedical Engineering. Informa Healthcare, 2008.</ref>
			* ], the sodium salt of hyaluronic acid, a glycosaminoglycan found in various human connective tissue.
			* ], the process by which microorganisms are utilized in fermentation to synthesize hyaluronic acid.
	In some cancers, hyaluronan levels correlate well with malignancy and poor prognosis. Hyaluronan is, thus, often used as a ] for ] and ]. It may also be used to monitor the progression of the disease{{Citation needed|date=April 2011}}.
			* ], trade name for a mix of polysaccharides produced by microalgae. Inhibits production of hyaluronic-acid-degrading enzymes.
			* ], a biomaterial company based in China, primarily specialized in hyaluronic acid and other bioactive substance products.
	Hyaluronan may also be used postoperatively to induce tissue healing, notably after ] surgery.<ref>{{cite journal | author=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 ], which mediate the ].
	Hyaluronan has also been used in the synthesis of biological scaffolds for wound-healing applications. These scaffolds typically have proteins such as ] attached to the hyaluronan to facilitate cell migration into the ]. This is particularly important for individuals with ] suffering from ]s.<ref>Shu XZ, Ghosh K, Liu Y, Palumbo FS, Luo Y, Clark RAF, Prestwich GD: Attachment and spreading of fibroblast on an RGD peptide-modified injectable hyaluronan hydrogel. J Biomed Materials Res, 68:365-75, 2004.</ref>
	In 2007, the ] 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=]}}</ref>
	Hyaluronan is also used in anti-adhesive products such as ], widely used in pelvic and abdominal surgery to prevent postoperative ].
	In May, 2011, Dr Endre Balazs was awarded the ] Award for Vision Research for his work in championing the development of hyaluronan and Healon. The award was presented by the Helen Keller Foundation for Research and education.{{Citation needed|date=June 2011}}
	== Cosmetic applications ==
	Hyaluronan is a common ingredient in skin-care products.
	In 2003, the FDA approved hyaluronan injections for filling soft tissue defects such as facial wrinkles. ] is a common trade name for the product. Hyaluronan injections temporarily smooth wrinkles by adding volume under the skin, with effects typically lasting for six months.
	] is a bacterial hyaluronic acid injectable filler, similar to Restylane, but differing slightly in terms of effect and longevity. It is used for lip augmentation, reduction of folds and wrinkles, and removal of scars. The effects of Juvéderm treatments are also temporary, and costs are similar to those of Restylane.<ref></ref>
	The presence of hyaluronic acid in epithelial tissue has been shown to promote keratinocyte proliferation and increase the presence of retinoic acid, effecting skin hydration. Hyaluronic acid's interaction with ] drives collagen synthesis and normal skin function. Present in the extracellular matrix of basal keratinocytes, hyaluronic acid is critical to the structural integrity of the dermal collagen matrix. These benefits make hyaluronic acid a very effective topical ]; however, results may only be sustained as part of an ongoing treatment program.<ref> ''Essential Actives'', KAVI.</ref>
	== Equine applications ==
	Hyaluronan is used in treatment of articular disorders in ], in particular those in competition or heavy work. It is indicated for ] and ] joint dysfunctions, but not when joint ] or fracture are suspected. It is especially used for ] associated with equine ]. 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></ref>
	Note that, according to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for ].<ref></ref> In Europe, however, the same preparation is not considered to have any such effect, and edibility of the ] is not affected.<ref></ref>
	== Etymology ==
	Hyaluronic acid is derived from ''hyalos'' (Greek for vitreous) and ] because it was first isolated from the ] and possesses a high uronic acid content.
	The term ''hyaluronate'' refers to the ] of hyaluronic acid. Because the molecule typically exists ''in vivo'' in its ] form, it is most commonly referred to as ''hyaluronan''.
	==See also==
	* ].
	== References ==		== References ==
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	== External links ==		== External links ==
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	{{Nasal preparations}}		{{Nasal preparations}}
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