Editing Cross-link

{{Short description|Bonds linking one polymer chain to another}}
{{Hatnote|Several terms redirect here. You may be looking for [[Crosslinking of DNA]], [[London Crosslink]], or [[Infrastructure#Water management infrastructure|Water management infrastructure]]; see also [[Reticular (disambiguation)]].}}
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[[File:Vulcanization of POLYIsoprene V.2.png|thumb|[[Vulcanization]] is an example of cross-linking. Schematic presentation of two "polymer chains" (<span style="color: blue;">'''blue'''</span> and <span style="color: green;">'''green'''</span>) cross-linked after the vulcanization of natural rubber with [[sulfur]] (n = 0, 1, 2, 3, ...).]]

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{{Quote box
|title= [[International Union of Pure and Applied Chemistry|IUPAC]] definition
|quote= A small region in a [[macromolecule]] from which at least four chains<br />emanate, and formed by reactions involving sites or groups on existing<br />macromolecules or by interactions between existing macromolecules.

''Notes''

1. The small region may be an atom, a group of atoms, or a number of<br />branch points connected by bonds, groups of atoms, or oligomeric chains.

2. In the majority of cases, a crosslink is a covalent structure but the term<br />is also used to describe sites of weaker chemical interactions, portions of<br />crystallites, and even physical interactions and entanglements.<ref>{{cite journal|title=Glossary of basic terms in polymer science (IUPAC Recommendations 1996)|journal=[[Pure and Applied Chemistry]]|year=1996|volume=68|issue=12|pages=2287–2311|quote= 1.59 Crosslink (p.2298)|doi=10.1351/pac199668122287|url=http://www.iupac.org/publications/pac/1996/pdf/6812x2287.pdf |last1= Jenkins |first1= A. D.|s2cid=98774337}}</ref>
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[[File:IUPAC definition for a crosslink in polymer chemistry.png|thumb|right|493x493px|link=https://goldbook.iupac.org/terms/view/C01409|IUPAC definition for a crosslink in polymer chemistry]]
In [[chemistry]] and [[biology]], a '''cross-link''' is a bond or a short sequence of bonds that links one [[polymer]] chain to another. These links may take the form of [[covalent bond]]s or [[ionic bond]]s and the polymers can be either synthetic polymers or natural polymers (such as [[protein]]s).

In [[polymer chemistry]] "cross-linking" usually refers to the use of cross-links to promote a change in the polymers' physical properties.

When "crosslinking" is used in the biological field, it refers to the use of a probe to link proteins together to check for [[protein–protein interaction]]s, as well as other creative cross-linking methodologies.{{Not verified in body|date=September 2018}}<!-- probe is used as a verb elsewhere in the article; but not as a noun. Could not find a source to support this statement that the term always refers to use a a probe. -->

Although the term is used to refer to the "linking of polymer chains" for both sciences, the extent of crosslinking and specificities of the crosslinking agents vary greatly.

==Synthetic polymers==
:[[image:DryOilSteps.svg|thumb|260px|left|Chemical reactions associated with crosslinking of [[drying oil]]s, the process that produces [[linoleum]].]]
Crosslinking generally involves covalent bonds that join two polymer chains. The term ''[[curing (chemistry)|curing]]'' refers to the crosslinking of [[thermosetting]] resins, such as unsaturated [[polyester]] and [[epoxy]] resin, and the term ''[[vulcanization]]'' is characteristically used for [[rubber]]s.<ref>{{cite book|author1=Hans Zweifel|author2=Ralph D. Maier|author3=Michael Schiller|title=Plastics additives handbook |date=2009 |publisher=Hanser |location=Munich |isbn=978-3-446-40801-2 |page=746 |edition= 6th}}</ref> When polymer chains are crosslinked, the material becomes more rigid. The mechanical properties of a polymer depend strongly on the cross-link density. Low cross-link densities increase the viscosities of [[Crystallization of polymers|polymer melt]]s. Intermediate cross-link densities transform gummy polymers into materials that have [[elastomer]]ic properties and potentially high strengths. Very high cross-link densities can cause materials to become very rigid or glassy, such as [[phenol formaldehyde resin|phenol-formaldehyde]] materials.<ref>{{cite book|url=https://books.google.com/books?id=q034u2kLAagC&pg=PA22|title=Engineering with Rubber: How to Design Rubber Components|first=Alan N.|last=Gent|date=1 April 2018|publisher=Hanser|access-date=1 April 2018|via=Google Books|isbn=9781569902998}}</ref>

[[File:MethmethacrylateBPA-glyc.png|thumb|left|352px|Typical [[vinyl ester resin]] derived from [[bisphenol A diglycidyl ether]]. Free-radical polymerization gives a highly crosslinked polymer.<ref name="Ullmann">{{cite encyclopedia|last1=Pham|first1=Ha Q.|last2=Marks|first2=Maurice J.|title=Epoxy Resins|encyclopedia=Ullmann's Encyclopedia of Industrial Chemistry|year=2012|doi=10.1002/14356007.a09_547.pub2|isbn=978-3527306732}}</ref>]]

In one implementation, unpolymerized or partially polymerized [[resin]] is treated with a '''crosslinking reagent'''. In [[vulcanization]], sulfur is the cross-linking agent. Its introduction changes [[rubber]] to a more rigid, durable material associated with car and bike [[tire]]s. This process is often called sulfur curing. In most cases, cross-linking is irreversible, and the resulting thermosetting material will degrade or burn if heated, without melting. Chemical covalent cross-links are stable mechanically and thermally. Therefore, cross-linked products like car [[tire]]s cannot be recycled easily.

A class of polymers known as [[thermoplastic elastomer]]s rely on physical cross-links in their microstructure to achieve stability, and are widely used in non-tire applications, such as [[snowmobile]] tracks, and [[catheter]]s for medical use. They offer a much wider range of properties than conventional cross-linked elastomers because the domains that act as cross-links are reversible, so can be reformed by heat. The stabilizing domains may be non-crystalline (as in styrene-butadiene block copolymers) or crystalline as in thermoplastic copolyesters.

[[File:Si69.svg|thumb|The compound [[bis(triethoxysilylpropyl)tetrasulfide]] is a cross-linking agent: the [[siloxy]] groups link to silica and the [[polysulfide]] groups vulcanize with [[polyolefin]]s.]]

[[Enamel paint|Alkyd enamels]], the dominant type of commercial oil-based paint, cure by oxidative crosslinking after exposure to air.<ref>{{Citation |last1=Abraham |first1=T.W. |title=Lipid-Based Polymer Building Blocks and Polymers |date=2012 |url=https://linkinghub.elsevier.com/retrieve/pii/B9780444533494002533 |work=Polymer Science: A Comprehensive Reference |pages=15–58 |publisher=Elsevier |language=en |doi=10.1016/b978-0-444-53349-4.00253-3 |isbn=978-0-08-087862-1 |access-date=2022-06-27 |last2=Höfer |first2=R.|url-access=subscription }}</ref>

===Physical cross-links===
In contrast to chemical cross-links, physical cross-links are formed by weaker interactions. For example, sodium [[alginate]] gels upon exposure to calcium ions, which form ionic bonds that bridge between alginate chains.<ref>{{cite journal |doi= 10.1021/acs.biomac.6b00378|pmid= 27177209|title= Structural Characterization of Sodium Alginate and Calcium Alginate|journal= Biomacromolecules|volume= 17|issue= 6|pages= 2160–2167|year= 2016|last1= Hecht|first1= Hadas|last2= Srebnik|first2= Simcha}}</ref> [[Polyvinyl alcohol]] gels upon the addition of [[borax]] through hydrogen bonding between [[boric acid]] and the polymer's alcohol groups.<ref>{{cite web |title=Experiments: PVA polymer slime |url=https://edu.rsc.org/experiments/pva-polymer-slime/756.article |website=Education: Inspiring your teaching and learning |publisher=Royal Society of Chemistry |access-date=2 April 2022 |date=2016 |quote=A solution of polyvinyl alcohol (PVA) can be made into a slime by adding borax solution, which creates cross-links between polymer chains.}}</ref><ref>{{cite journal |doi= 10.1021/ed063p57|title= The gelation of polyvinyl alcohol with borax: A novel class participation experiment involving the preparation and properties of a "slime"|journal= Journal of Chemical Education|volume= 63|issue= 1|pages= 57|year= 1986|last1= Casassa|first1= E.Z|last2= Sarquis|first2= A.M|last3= Van Dyke|first3= C.H|bibcode= 1986JChEd..63...57C}}</ref> Other examples of materials which form physically cross-linked gels include [[gelatin]], [[collagen]], [[agarose]], and [[agar agar]].

==Measuring degree of crosslinking==
Crosslinking is often measured by [[swelling capacity|swelling]] tests. The crosslinked sample is placed into a good solvent at a specific temperature, and either the change in mass or the change in volume is measured. The more crosslinking, the less swelling is attainable. Based on the degree of swelling, the Flory Interaction Parameter (which relates the solvent interaction with the sample), and the density of the solvent, the theoretical degree of crosslinking can be calculated according to Flory's Network Theory.<ref>Flory, P.J., "Principles of Polymer Chemistry" (1953)</ref>

Two ASTM standards are commonly used to describe the degree of crosslinking in thermoplastics. In ASTM D2765, the sample is weighed, then placed in a solvent for 24 hours, weighed again while swollen, then dried and weighed a final time.<ref>{{cite web|url=http://www.astm.org/Standards/D2765.htm|title=ASTM D2765 - 16 Standard Test Methods for Determination of Gel Content and Swell Ratio of Crosslinked Ethylene Plastics|website=www.astm.org|access-date=1 April 2018}}</ref> The degree of swelling and the soluble portion can be calculated. In another ASTM standard, F2214, the sample is placed in an instrument that measures the height change in the sample, allowing the user to measure the volume change.<ref>{{cite web|url=http://www.astm.org/Standards/F2214.htm|title=ASTM F2214 - 16 Standard Test Method for In Situ Determination of Network Parameters of Crosslinked Ultra High Molecular Weight Polyethylene (UHMWPE)|website=www.astm.org|access-date=1 April 2018}}</ref> The crosslink density can then be calculated.

==In biology==
[[Image:Lignin structure.svg|thumb|500px|Idealized structure of lignin, a highly crosslinked polymer that is the main structural material in many plants.|left]]

===Lignin===
[[Lignin]] is a highly crosslinked polymer that comprises the main structural material of higher plants.  A hydrophobic material, it is derived from precursor [[monolignol]]s.  Heterogeneity arises from the diversity and degree of crosslinking between these lignols.

===In DNA===
[[Image:Ethyl-S.svg|thumb|200px|HN1 ([[bis(2-chloroethyl)ethylamine]]), a DNA crosslinker. Like most crosslinkers, this molecule has two reactive groups.]]
Intrastrand [[DNA crosslink]]s have strong effects on organisms because these lesions interfere with [[Transcription (biology)|transcription]] and [[DNA replication|replication]]. These effects can be put to good use (addressing cancer) or they can be lethal to the host organism. The drug [[cisplatin]] functions by formation of intrastrand crosslinks in DNA.<ref>{{cite journal |doi=10.1038/sj.onc.1206933 |title=Cisplatin: Mode of cytotoxic action and molecular basis of resistance |date=2003 |last1=Siddik |first1=Zahid H. |journal=Oncogene |volume=22 |issue=47 |pages=7265–7279 |pmid=14576837 |s2cid=4350565 |doi-access=free }}</ref>  Other crosslinking agents include [[mustard gas]], [[mitomycin]], and [[psoralen]].<ref>{{cite journal |doi=10.1021/cr040478b |title=Formation and Repair of Interstrand Cross-Links in DNA |date=2006 |last1=Noll |first1=David M. |last2=Mason |first2=Tracey Mcgregor |last3=Miller |first3=Paul S. |journal=Chemical Reviews |volume=106 |issue=2 |pages=277–301 |pmid=16464006 |pmc=2505341 }}</ref>

===Proteins===
In [[proteins]], crosslinks are important in generating mechanically stable structures such as [[hair]] and [[wool]], [[skin]], and [[cartilage]]. [[Disulfide bond]]s are common crosslinks.<ref>{{cite book |doi=10.1002/0471238961.2315151214012107.a01.pub2 |chapter=Wool |title=Kirk-Othmer Encyclopedia of Chemical Technology |date=2005 |last1=Christoe |first1=John R. |last2=Denning |first2=Ron J. |last3=Evans |first3=David J. |last4=Huson |first4=Mickey G. |last5=Jones |first5=Leslie N. |last6=Lamb |first6=Peter R. |last7=Millington |first7=Keith R. |last8=Phillips |first8=David G. |last9=Pierlot |first9=Anthony P. |last10=Rippon |first10=John A. |last11=Russell |first11=Ian M. |isbn=9780471484943 }}</ref>  [[Isopeptide bond]] formation is another type of protein crosslink.

The process of applying a [[permanent wave]] to hair involves the breaking and reformation of disulfide bonds. Typically a mercaptan such as ammonium thioglycolate is used for the breaking. Following this, the hair is curled and then "neutralized". The neutralizer is typically an acidic solution of hydrogen peroxide, which causes new disulfide bonds to form, thus permanently fixing the hair into its new configuration.

Compromised [[collagen]] in the cornea, a condition known as [[keratoconus]], can be treated with clinical crosslinking.<ref>Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003 May;135(5):620-7.</ref>
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It also happens for [[gluten]] which change structure of foods.
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In biological context crosslinking could play a role in [[atherosclerosis]] through [[advanced glycation end-product]]s (AGEs), which have been implicated to induce crosslinking of collagen, which may lead to vascular stiffening.<ref>{{cite journal|last1=Prasad|first1=Anand|last2=Bekker|first2=Peter|last3=Tsimikas|first3=Sotirios|date=2012-08-01|title=Advanced glycation end products and diabetic cardiovascular disease|journal=Cardiology in Review|volume=20|issue=4|pages=177–183|doi=10.1097/CRD.0b013e318244e57c|issn=1538-4683|pmid=22314141|s2cid=8471652}}</ref>

====Research====
Proteins can also be cross-linked artificially using small-molecule crosslinkers.  This approach has been used to elucidate [[protein–protein interaction]]s.<ref>{{cite web|url=http://www.piercenet.com/Objects/View.cfm?type=Page&ID=FE7F690D-58AE-4342-AE85-BA94DCA642F8|title=Pierce Protein Biology - Thermo Fisher Scientific|website=www.piercenet.com|access-date=1 April 2018}}</ref><ref name="Kou Qin">{{cite journal |author1=Kou Qin |author2=Chunmin Dong |author3=Guangyu Wu |author4=Nevin A Lambert |date=August 2011 |title= Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers |journal= Nature Chemical Biology |volume= 7 |issue= 11 |pages= 740–747 |doi=10.1038/nchembio.642 |pmid=21873996 |pmc=3177959}}</ref><ref>{{Cite journal|last1=Mizsei|first1=Réka|last2=Li|first2=Xiaolong|last3=Chen|first3=Wan-Na|last4=Szabo|first4=Monika|last5=Wang|first5=Jia-huai|last6=Wagner|first6=Gerhard|last7=Reinherz|first7=Ellis L.|last8=Mallis|first8=Robert J.|date=January 2021|title=A general chemical crosslinking strategy for structural analyses of weakly interacting proteins applied to preTCR-pMHC complexes|journal=Journal of Biological Chemistry|volume=296|pages=100255|doi=10.1016/j.jbc.2021.100255|pmid=33837736|pmc=7948749|issn=0021-9258|doi-access=free}}</ref> Crosslinkers bind only surface residues in relatively close proximity in the [[native state]]. Common crosslinkers include the [[imidoester]] crosslinker dimethyl suberimidate, the [[N-Hydroxysuccinimide]]-ester crosslinker [[bisSulfosuccinimidyl suberate|BS3]] and [[formaldehyde]]. Each of these crosslinkers induces nucleophilic attack of the amino group of [[lysine]] and subsequent covalent bonding via the crosslinker. The zero-length [[carbodiimide]] crosslinker [[Carbodiimide#EDC|EDC]] functions by converting carboxyls into amine-reactive isourea intermediates that bind to lysine residues or other available primary amines. SMCC or its water-soluble analog, Sulfo-SMCC, is commonly used to prepare antibody-hapten conjugates for antibody development.

An ''in-vitro'' cross-linking method is PICUP ([[photo-induced cross-linking of unmodified proteins]]).<ref name=":0">{{cite journal|last1=Fancy|first1=David A.|last2=Kodadek|first2=Thomas|date=1999-05-25|title=Chemistry for the analysis of protein–protein interactions: Rapid and efficient cross-linking triggered by long wavelength light|journal=Proceedings of the National Academy of Sciences|language =en|volume=96|issue=11|pages=6020–6024|doi=10.1073/pnas.96.11.6020|issn=0027-8424|pmid=10339534|pmc=26828|bibcode=1999PNAS...96.6020F|doi-access=free}}</ref> Typical reagents are [[ammonium persulfate]] (APS), an electron acceptor, the photosensitizer [[tris(bipyridine)ruthenium(II) chloride|tris-bipyridylruthenium (II) cation]] ({{chem2|[Ru(bpy)3](2+)}}).<ref name=":0"/> In ''in-vivo'' crosslinking of protein complexes, cells are grown with [[photoreactive]] [[diazirine]] analogs to [[leucine]] and [[methionine]], which are incorporated into proteins. Upon exposure to ultraviolet light, the diazirines are activated and bind to interacting proteins that are within a few [[ångström]]s of the photo-reactive amino acid analog (UV cross-linking).<ref>{{cite journal |last=Suchanek |first=Monika |author2=Anna Radzikowska |author3=Christoph Thiele |title=Photo-leucine and photo-methionine allow identification of protein–protein interactions in living cells |journal=Nature Methods |volume=2 |issue=4 |pages=261–268 |date=April 2005 |pmid=15782218 |doi= 10.1038/nmeth752|doi-access=free }}</ref>

==See also==
*[[Branching (polymer chemistry)]]
*[[Cross-linked enzyme aggregate]]
*[[Cross-linked polyethylene]] (PEX)
*[[Crosslinking of DNA]]
*[[Fixation (histology)]]
*[[Phenol formaldehyde resin]] (phenolic resin)

==References==
{{Reflist|30em}}

==External links==
*[http://www.campoly.com/index.php/download_file/view/380/108/ Application note on how to measure degree of crosslinking in plastics] {{Webarchive|url=https://web.archive.org/web/20131102060502/http://www.campoly.com/index.php/download_file/view/380/108/ |date=2013-11-02 }}

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[[Category:Ageing processes]]
[[Category:Polymer chemistry]]
[[Category:Protein–protein interaction assays]]
[[Category:Rubber properties]]