Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers (such as proteins). When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of cross-links to promote a difference in the polymers' physical properties. When "crosslinking" is used in the biological milieu, it can be in reference to its use as a probe to link proteins together to check protein-protein interactions, as well as other creative cross-linking methodologies.
Cross-linking is used in both synthetic polymer chemistry and in the biological sciences. While 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. Of course, with all science, there are overlaps, and the following delineations are stated as a starting point to understanding the subtleties.
When polymer chains are linked together by crosslinks, they lose some of their ability to move as individual polymer chains. For example, a liquid polymer (where the chains are freely flowing) can be turned into a "solid" or "gel" by crosslinking the chains together.
In polymer chemistry, when a synthetic polymer is said to be "crosslinked", it usually means that the entire bulk of the polymer has been exposed to the crosslinking method, resulting in fairly extensive crosslinking treatment. Crosslinking inhibits close packing of the polymer chains, preventing the formation of crystalline regions. The restricted molecular mobility of a crosslinked structure limits the extension of the polymer material under loading.
Cross-links can be formed by chemical reactions that are initiated by heat, pressure, or radiation. For example, mixing of an unpolymerized or partially polymerized resin with specific chemicals called crosslinking reagents results in a chemical reaction that forms crosslinks. Cross-linking can also be induced in materials that are normally thermoplastic through exposure to a radiation source, such as electron beam exposure, gamma-radiation, or UV light. For example, electron beams are used to cross-link the C type of cross-linked polyethylene. Other types of cross-linked polyethylene are made by addition of peroxide during extruding (type A) or by addition of a cross-linking agent (eg. vinylsilane) and a catalyst during extruding and then performing a post-extrusion curing.
The chemical process of vulcanization is a type of cross-linking and it changes the property of rubber to the hard, durable material we associate with car and bike tires. This process is often called sulphur curing, and the term vulcanization comes from Vulcan, the Roman god of fire. However, this is a slow process, taking around 8 hours. A typical car tire is cured for 15 minutes at 150°C. However, the time can be reduced by the addition of accelerators such as 2-benzothiazolethiol or tetramethylthiuram disulphide. Both of these contain a sulphur atom in the molecule that initiates the reaction of the sulphur chains with the rubber. Accelerators increase the rate of cure by catalysing the addition of sulphur chains to the rubber molecules.
Crosslinks are the characteristic property of Thermosetting plastic materials. In most cases, cross-linking is irreversible, and the resulting thermosetting material will degrade or burn if heated, without melting. Especially in the case of commercially used plastics, once a substance is cross-linked, the product is very hard or impossible to recycle. In some cases, though, if the cross-link bonds are sufficiently different, chemically, from the bonds forming the polymers, the process can be reversed. Permanent wave solutions, for example, break and re-form naturally occurring cross-links (disulfide bonds) between protein chains in hair.
In the biological sciences, crosslinking typically refers to a more specific reaction used to probe molecular interactions. For example, proteins (a type of natural polymer) can be cross-linked together to probe molecular interactions using small-molecule crosslinkers.
The interactions or mere proximity of proteins can be studied by the clever use of crosslinking agents. For example, protein A and protein B may be very close to each other in a cell, and a chemical crosslinker could be used to probe the protein-protein interaction between these two proteins by linking them together, disrupting the cell, and looking for the crosslinked proteins.
A variety of crosslinkers are used to analyze subunit structure of proteins, protein interactions and various parameters of protein function. Subunit structure is deduced since crosslinkers only bind surface amino residues in relatively close proximity in the native state. Protein interactions are often too weak or transient to be easily detected, but by crosslinking, the interactions can be captured and analyzed.
Examples of some common crosslinkers are the imidoester crosslinker dimethyl suberimidate, the NHS-ester crosslinker 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 EDC functions by converting caboxyls into amine-reactive isourea intermediates that bind to lysine residues or other available primary amines.
In-vivo crosslinking of protein complexes using photo-reactive amino acid analogs was introduced in 2005 by researchers from the Max Planck Institute  In this method, 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 angstroms of the photo-reactive amino acid analog.
Cross linking by means of photosensitizers (Riboflavin) and UV light has entered clinical application for the treatment of keratoconus . Keratoconus is a disease of the cornea that makes the cornea become weak and may gradually bulge outward. Approximately half of the keratoconus patients have significant visual problems beyond corrective lenses. The only resolution to keratoconus has been corneal transplantation, with a long healing period and unpredictable refractive error. Today, Corneal Cross Linking is used to increase the biomechanical stability of cornea to avoid corneal transplantation.
Synthetically crosslinked polymers have many uses, including those in the biological sciences, such as applications in forming polyacrylamide gels for gel electrophoresis. Synthetic rubber used for tires is made by crosslinking rubber through the process of vulcanization.
- Cross-linked polyethylene
- Phenol formaldehyde resin and Phenolic resin
- Application in enzyme catalysis: Cross-linked enzyme aggregate
- Crosslinking of DNA
- Crosslinking for Keratoconus
- Fixation (histology)
- Photo-reactive amino acid analog
- ↑ Suchanek, M., Radzikowska, A., and Thiele, C. (2005) Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells. Nature Methods. 2, 261 – 268.
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