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| '''[[Adsorption]]''' (not to be mistaken for [[Absorption (chemistry)|''absorption'']]) is the accumulation and adhesion of molecules, atoms, ions, or larger particles to a surface, but without actually penetrating the surface. The adsorption of larger biomolecules such as proteins is of high physiological relevance, and adsorb with different mechanisms than their molecular or atomic analogs. Some of the major driving forces behind '''protein adsorption''' include: surface energy, intermolecular forces, hydrophobicity, and ionic or electrostatic interaction. By knowing how these factors affect protein adsorption, they can then be manipulated by machining, alloying, and other engineering techniques to select for the most optimal performance in biomedical or physiological applications. | | I'm Chauncey and I live in Shripney. <br>I'm interested in Latin American Studies, Computer programming and Danish art. I like travelling and reading fantasy.<br><br>my site: [http://www.articlesbase.com/metaphysics-articles/why-do-we-have-totally-free-online-psychic-reading-7084134.html Email Psychic] |
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| ==Relevance==
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| Many medical devices and products come into contact with the internal surfaces of the body, such as surgical tools and implants. When a non-native material enters the body, the first step of the [[immune response]] takes place and host extracellular matrix and plasma proteins aggregate to the material in attempts to contain, neutralize, or wall-off the injurious agent.<ref>{{cite web|last=Rechendorff|first=Kristian|title=The influence of surface roughness on protein adsorption|url=http://phys.au.dk/fileadmin/site_files/publikationer/phd/Kristian_Rechen dorff.pdf|work=Thesis|publisher=Interdisciplinary Nanoscience Center University of Aarhus, Denmark|accessdate=23 May 2011}}</ref> These proteins can facilitate the attachment of various cell types such as [[osteoblasts]] and [[fibroblasts]] that can encourage tissue repair.<ref>{{cite journal|last=Maddikeri|first=RR|coauthors=S. Tosatti, M. Schuler, S. Chessari, M. Textor, R.G. Richards, L.G. Harris|title=Reduced medical infection related bacterial strains adhesion on bioactive RGD modified titanium surfaces: A first step toward cell selective surfaces|journal=Journal of Biomedical Materials Research Part A|year=2008|month=Feb|volume=84A|issue=2|pages=425–435|url=http://onlinelibrary.wiley.com.ezproxy.lib.calpoly.edu/doi/10.1002/jbm.a.31323/full|accessdate=25 May 2011|doi=10.1002/jbm.a.31323}}</ref> Taking this a step further, implantable devices can be coated with a [[bioactive]] material to encourage adsorption of specific proteins, fibrous capsule formation, and wound healing. This would reduce the risk of implant rejection and accelerate recovery by selecting for the necessary proteins and cells necessary for endothelialization. After the formation of the [[endothelium]], the body will no longer be exposed to the foreign material, and will stop the immune response.
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| Proteins such as [[collagen]] or [[fibrin]] often serve as scaffolds for cell adhesion and cell growth. This is an integral part to the structural integrity of cell sheets and their differentiation into more complex tissue and organ structures. The adhesion properties of proteins to non-biological surfaces greatly influences whether or not cells can indirectly attach to them via scaffolds. An implant like a hip-stem replacement necessitates integration with the host tissues, and protein adsorption facilitates this integration.
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| Surgical tools can be designed to be sterilized more easily so that proteins do not remain adsorbed to a surface, risking cross-contamination. Some diseases such as [[Creutzfeldt–Jakob disease]] and [[kuru (disease)|kuru]] (both related to [[mad cow disease]]) are caused by the transmission of [[prion]]s, which are errant or improperly folded forms of a normally native protein. Surgical tools contaminated with prions require a [[prion#Sterilization|special method of sterilization]] to completely eradicate all trace elements of the misfolded protein, as they are resistant to many of the normally used cleansing methods.
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| However, in some cases, protein adsorption to biomaterials can be an extremely unfavorable event. The adhesion of [[clotting factors]] may induce [[thrombosis]], which may lead to [[stroke]] or other blockages.<ref>{{cite journal|last=Gorbet|first=MB|coauthors=MV Sefton|title=Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets, and leukocytes|journal=Biomaterials|year=2004|month=Nov|volume=25|issue=26|pages=5681–5703|accessdate=25 May 2011}}</ref> Some devices are intended to interact with the internal body environment such as sensors or drug-delivery vehicles, and protein adsorption would hinder their effectiveness.
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| ==Fundamentals of Protein Adsorption==
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| [[Proteins]] are small biomolecules that can be composed of [[amino acid]] subunits. Each amino acid has a side chain that gains or loses charge depending on the pH of the surrounding environment, as well as its own individual polar/nonpolar qualities.<ref>{{cite web|last=Purdue|title=Amino Acids|url=http://chemed.chem.purdue.edu/genchem/topicreview/bp/1biochem/amino2.html|work=The Amino Acids|accessdate=17 May 2011}}</ref>[[File:Amino acid titration.png|thumb|Amino acid titration]] Charged regions can greatly contribute to how that protein interacts with other molecules and surfaces, as well as its own tertiary structure (protein folding). As a result of their hydrophilicity, charged amino acids tend to be located on the outside of proteins, where they are able to interact with surfaces.<ref name=Dee>{{cite book|last=Dee|first=Kay C|title=An Introduction to Tissue-Biomaterial Interactions|year=2002|publisher=John Wiley & Sons|location=Cal Poly Kennedy Library|isbn=0-471-25394-4|pages=1–50}}</ref> It is the unique combination of amino acids that gives a protein its properties. In terms of [[surface science|surface chemistry]], protein [[adsorption]] is a critical phenomenon that describes the aggregation of these molecules on the exterior of a material. The tendency for proteins to remain attached to a surface depends largely on the material properties such as surface energy, texture, and relative charge distribution. Larger proteins are more likely to adsorb and remain attached to a surface due to the higher number of contact sites between amino acids and the surface (Figure 1).[[File:Effect of protein size on interaction with a surface.jpg|thumb|Figure 1. The effect of protein size on interaction with a surface. Notice that the larger protein composed of more amino acids is capable of making more interactions]]
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| ===Energy of Protein Adsorption===
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| The fundamental idea behind spontaneous protein adsorption is that adsorption occurs when more energy is released than gained according to Gibbs law of free energy.
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| This is seen in the equation:
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| ::<big><math>\Delta_{ads} G = \Delta_{ads} H - {T} \Delta_{ads} S < 0 </math></big>
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| where:
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| * ''∆<sub>ads</sub>'' is net change of the parameters
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| * ''G'' is [[Gibbs free energy]]
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| * ''T'' is the [[temperature]] (SI unit: [[kelvin]])
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| * ''S'' is the [[entropy]] (SI unit: joule per kelvin)
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| * ''H'' is the [[enthalpy]] (SI unit: joule)
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| In order for the protein adsorption to occur spontaneously, ''∆<sub>ads</sub>G'' must be a negative number.
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| ===Vroman Effect===
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| Proteins and other molecules are constantly in competition with one another over binding sites on a surface. The Vroman Effect, developed by Leo Vroman, postulates that small and abundant molecules will be the first to coat a surface. However, over time, molecules with higher affinity for that particular surface will replace them. This is often seen in materials that contact the blood where fibrin, which is usually abundant, will bind to the surface first and over time will be replaced by larger proteins.<ref>{{cite journal|last=Rosengren|first=Asa|title=Cell-protein-material Interactions on Bioceramics and Model Surfaces|journal=Comprehensive Summaries of Uppsala Dissertations of the Faculty of Science and Technology|year=2004}}</ref>
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| ==Forces and Interactions==
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| The four fundamental classes of forces and interaction in protein adsorption are: 1) ionic or electrostatic interaction, 2) [[hydrogen bonding]], 3) [[hydrophobic]] interaction (largely entropically driven), and 4) interactions of charge-transfer or particle electron donor/acceptor type.<ref>{{cite journal|last=Ghosh|first=S|coauthors=H.B. Bull|title=Adsorbed films of bovine serum albumin|journal=Biochim. Biophys.|year=1966|issue=66|pages=150–157}}</ref>
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| ===Ionic or Electrostatic Interactions===
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| The charge of proteins is determined by the [[pKa]] of its [[amino acid]] side chains, and the terminal amino acid and carboxylic acid. Groups with pHs above physiologic conditions have a positive charge and groups with pH below have a negative charge. The net charge of the protein, determined by the sum charge of its constituents, results in [[electrophoretic]] migration in a physiologic electric field. These effects are short-range because of the high di-electric constant of water, however, once the protein is close to a charged surface, electrostatic coupling becomes the dominant force.<ref>{{cite book|last=Andrade|first=Joseph D.|title=Surface and interfacial Aspects of Biomedical Polymers|year=1985|publisher=Plenum|location=New York and London|isbn=0-306-41742-1|pages=10–21}}</ref>
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| ===Hydrogen Bonding===
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| Water has as much propensity to form hydrogen bonds as any group in a [[polypeptide]]. During a folding and association process, peptide and amino acid groups exchange hydrogen bonds with water. Thus, hydrogen bonding does not have a strong stabilizing effect on protein adsorption in an aqueous medium.<ref>{{cite journal|last=Cooper|first=A.|title=Conformational Fluctuations and Change in Biological Macromolecules|journal=Scientific Progress|year=1980|volume=66|pages=473–497}}</ref>
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| <gallery>
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| File:Hydrogen-bonding-in-water-2D.png|Illustration of two water molecules interacting to form a hydrogen bond</gallery>
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| ===Hydrophobic Interactions===
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| [[Hydrophobic]] interactions are essentially [[entropic]] interactions basically due to order/disorder phenomena in an aqueous medium. The free energy associated with minimizing interfacial areas is responsible for minimizing the surface area of water droplets and air bubbles in water. This same principle is the reason that hydrophobic amino acid side chains are oriented away from water, minimizing their interaction with water. The [[hydrophilic]] groups on the outside of the molecule result in protein water solubility. Characterizing this phenomenon can be done by treating these hydrophobic relationships with interfacial free energy concepts. Accordingly, one can think of the driving force of these interactions as the minimization of total interfacial free energy, i.e. minimization of surface area.<ref>{{cite book|last=Tanford|first=C.|title=The Hydrophobic Effect|year=1981|publisher=Wiley|location=New York}}</ref>
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| [[File:Cartoon of protein hydrophobic interaction.jpg|thumb|Illustration of how protein changes shape to allow polar regions (blue) to interact with water while non-polar hydrophobic regions (red) do not interact with the water.]]
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| ===Charge-Transfer Interactions===
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| Charge-transfer interactions are also important in protein stabilization and surface interaction. In general donor-acceptor processes, one can think of excess electron density being present which can be donated to an electrophilic species. In aqueous media, these solute interactions are primarily due to pi orbital electron effects.<ref>{{cite journal|last=Porath|first=J.|title=Charge-transfer Adsorption in Aqueous Media|journal=Pure Applied Chemistry|year=1979|volume=51|pages=1549–1559}}</ref>
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| ==Rate of Adsorption==
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| In order for proteins to adsorb, they must first come into contact with the surface through one or more of these major transport mechanisms: [[diffusion]], [[thermal convection]], [[bulk flow]], or a combination thereof. When considering the transport of proteins, it is clear how concentration gradients, temperature, protein size and flow velocity will influence the arrival of proteins to a solid surface. Under conditions of low flow and minimal temperature gradients, the adsorption rate can be modeled after the diffusion rate equation.<ref name=Dee />
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| === Diffusion Rate equation ===
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| ::<big><math> {dn \over dt} = C_o({D \over \pi t})^{1/2} </math></big>
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| where:
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| * ''D'' is the diffusion coefficient
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| * ''n'' is the surface concentration of protein
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| * ''Co'' is the bulk concentration of proteins
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| * ''t'' is time
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| A higher bulk concentration and/or higher diffusion coefficient (inversely proportional to molecular size) results in a larger number of molecules arriving at the surface. The consequential protein surface interactions result in high local concentrations of adsorbed protein, reaching concentrations of up to 1000 times higher than in the bulk solution.<ref name=Dee /> However, the body is much more complex, containing flow and convective diffusion, and these must be considered in the rate of protein adsorption.
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| === Flow in a thin channel ===
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| ::<big><math> {\partial C \over \partial t} + V(y){\partial C \over \partial x} = D{\partial^2 C \over \partial y^2} </math></big>
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| and
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| ::<big><math> {V(y) = \gamma y(1- {y \over b})} </math></big>
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| where:
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| * ''C'' is concentration
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| * ''D'' is the diffusion coefficient
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| * ''V'' is the velocity of flow
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| * ''x'' is the distance down the channel
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| * ''γ'' is the wall shear rate
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| * ''b'' is the height of the channel
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| This equation<ref name=Dee /> is especially applicable to analyzing protein adsorption to biomedical devices in arteries, e.g. [[stents]].
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| ==Protein Adsorption to Metals==
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| ===Chemical composition===
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| [[Metallic bond]]ing refers to the specific bonding between positive metal ions and surrounding valence electron clouds.<ref>{{cite web|last=Kopeliovich|first=Dimitri|title=Metals Crystal Structure|url=http://www.substech.com/dokuwiki/doku.php?id=metals_crystal_structure|work=SubsTech|accessdate=17 May 2011}}</ref> This intermolecular force is relatively strong, and gives rise to the repeated [[crystal]]line orientation of atoms, also referred to as its [[lattice system]]. There are several types of common lattice formations, and each has its own unique packing density and atomic closeness. The negatively charged electron clouds of the metal ions will sterically hinder the adhesion of negatively charged protein regions due to [[electric charge|charge repulsion]], thus limiting the available binding sites of a protein to a metal surface.
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| The lattice formation can lead to connection with exposed potential metal-ion-dependent adhesion sites (MIDAS) which are binding sites for collagen and other proteins.<ref>[http://www.fasebj.org/content/23/8/2490.full The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding]</ref> The surface of the metal has different properties than the bulk since the normal crystalline repeating subunits is terminated at the surface. This leaves the surface atoms without a neighboring atom on one side, which inherently alters the electron distribution. This phenomenon also explains why the surface atoms have a higher energy than the bulk, often simply referred to as ''[[surface energy]]''. This state of higher energy is unfavorable, and the surface atoms will try to reduce it by binding to available reactive molecules.<ref>{{cite journal|last=Takeda|first=Satoshi|coauthors=Makoto Fukawa, Yasuo Hayashi and Kiyoshi Matsumoto|title=Surface OH group governing adsorption properties of metal oxide films|journal=Thin Solid Films|date=8|year=1999|month=Feb|volume=339|issue=1-2|pages=220–224|url=http://www.sciencedirect.com/science/article/pii/S0040609098011523|accessdate=27 May 2011 | doi=10.1016/S0040-6090(98)01152-3 }}</ref> [[File:Fe4C.png|thumb|Notice in the diagram of Fe4C that the surface atoms are missing neighboring atoms.]] This is often accomplished by protein adsorption, where the surface atoms are reduced to a more advantageous energy state.
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| The internal environment of the body is often modeled to be an aqueous environment at 37°C at pH 7.3 with plenty of dissolved oxygen, electrolytes, proteins, and cells.<ref name=Dee /> When exposed to oxygen for an extended period of time, many metals may become [[redox|oxidized]] and increase their surface [[oxidation state]] by losing electrons.<ref>{{cite journal|last=Over|first=H.|coauthors=Seitsonen|title=A.P.|journal=Science|date=20|year=2002|month=September|volume=297|series=5589|pages=2003–2005|url=http://www.sciencemag.org/content/297/5589/2003.full|accessdate=24 May 2011|doi=10.1126/science.1077063|issue=5589}}</ref> This new [[cation]]ic state leaves the surface with a net positive charge, and a higher affinity for negatively charged protein side groups. Within the vast diversity of metals and metal alloys, many are susceptible to corrosion when implanted in the body. Elements that are more electronegative are corroded faster when exposed to an electrolyte-rich aqueous environment such as the human body.<ref>{{cite journal|last=Xu|first=Liping|coauthors=Guoning Yu, Erlin Zhang, Feng Pan, Ke Yang|title=In vivo corrosion behavior of Mg-Mn-Zn alloy for bone implant application|journal=Journal of Biomedical Materials Research Part A|date=4|year=2007|month=June|volume=83A|issue=3|pages=703–711|url=http://onlinelibrary.wiley.com.ezproxy.lib.calpoly.edu/doi/10.1002/jbm.a.31273/full|accessdate=25 May 2011|doi=10.1002/jbm.a.31273}}</ref> Both oxidation and corrosion will lower the free energy, thus affecting protein adsorption as seen in Eq. 1.<ref>{{cite book|last=Park|first=Joon Bu|title=Biomaterials Science and Engineering|year=1984|publisher=A Division of Plenum Publishing Corporation|location=Cal Poly Library|isbn=0-306-41689-1|pages=171–181}}</ref>
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| ===Effects of Machining===
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| Surface roughness and texture has an undeniable influence on protein adsorption on all materials, but with the ubiquity of metal machining processes, it is useful to address how these impact protein behavior. The initial adsorption is important, as well as maintained adhesion and integrity. Research has shown that surface roughness can encourage the adhesion of scaffold proteins and osteoblasts, and results in an increase in surface mineralization.<ref>{{cite journal|last=Deligianni|first=DD|coauthors=Katsala N, Ladas S, Sotiropoulou D, Amedee J, Missirlis YF|title=Effect of surface roughness of the titanium alloy Ti-6Al-4V on human bone marrow cell response and on protein adsorption.|journal=Biomaterials|year=2001|issue=22|pages=1241–1251|accessdate=25 May 2011}}</ref> Surfaces with more topographical features and roughness will have more exposed surface area for proteins to interact with.<ref name=Dee /> In terms of biomedical engineering applications, [[surface micromachining|micromachining]] techniques are often used to increase protein adhesion to implants in the hopes of shortening recovery time. The technique of laserpatterning introduces grooves and surface roughness that will influence adhesion, migration and alignment. Grit-blasting, a method analogous to sand blasting, and chemical etching have proven to be successful surface roughening techniques that promote the long-term stability of titanium implants.<ref>{{cite journal|last=Hacking|first=SA|coauthors=Harvey EJ, Tanzer M, Krygier JJ, Bobyn JD|title=Acid-etched microtexture for enhancement f bone growth into porous-coated implants|journal=J Bone Joint Surg|year=2003|issue=85B|pages=1182–1189}}</ref> The increase in stability is a direct result of the observed increase in extracellular matrix and collagen attachment, which results in increased osteoblast attachment and mineralization when compared to non-roughened surfaces.<ref>{{cite journal|last=Yang|first=SX|coauthors=L Salvati, P Suh|title=How does silica grit-blasting affect Ti6Al4V alloy mineralization in a rat bone marrow cell culture system|journal=Medical Device Materials|date=23-25|year=2007|month=September|volume=IV|pages=182–187|accessdate=25 May 2011}}</ref> Adsorption is not always desirable, however. Machinery can be negatively affected by adsorption, particularly with [[Protein adsorption in the food industry]].
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| ==Protein adsorption to polymers==
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| [[Polymer]]s are of great importance when considering protein adsorption in the biomedical arena. Polymers are composed of one or more types of "mers" bound together repeatedly, typically by directional covalent bonds. As the chain grows by the addition of mers, the chemical and physical properties of the material are dictated by the molecular structure of the monomer. By carefully selecting the type or types of mers in a polymer and its manufacturing process, the chemical and physical properties of a polymer can be highly tailored to adsorb specific proteins and cells for a particular application.
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| ===Conformation effects===
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| Protein adsorption often results in significant conformational changes, which refers to changes in the [[Secondary protein|secondary]], [[Tertiary protein|tertiary]], and quartary structures of proteins. In addition to adsorption rates and amounts, orientation and conformation are of critical importance. These conformational changes can affect protein interaction with [[ligand]]s, [[Substrate (biochemistry)|substrates]], and [[antigen]]s which are dependent on the orientation of the binding site of interest. These conformational changes, as a result of protein adsorption, can also [[Denaturation (biochemistry)|denature]] the protein and change its native properties.[[File:Proteinadsorption.jpg|thumb|Illustration of protein (green) ligand (red star) binding site alteration by the conformational change of the protein as a result of surface (blue) adsorption. Note how the ligand no longer fits into the binding site.]]
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| ===Adsorption to polymer scaffolds===
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| [[Tissue engineering]] is a relatively new field that utilizes a [[scaffolding]] as a platform upon which the desired cells proliferate. It is not clear what defines an ideal scaffold for a specific tissue type. The considerations are complex and protein adsorption only adds to the complexity. Although architecture, structural mechanics, and surface properties play a key role, understanding degradation and rate of protein adsorption are also key. In addition to the essentials of mechanics and geometry, a suitable scaffold construct will possess surface properties that are optimized for the attachment and migration of the cell types of particular interest.
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| Generally, it has been found that scaffolds that closely resemble the natural environments of the tissue being engineered are the most successful. As a result, much research has gone into investigating natural polymers that can be tailored, through processing methodology, toward specific design criteria. [[Chitosan]] is currently one of the most widely used polymers as it is very similar to naturally occurring [[glycosaminoglycan]] (GAGs) and it is degradable by human [[enzymes]].<ref>{{cite journal|last=Drury|first=J.L.|coauthors=Mooney, D.J.|title=Hydrogels for tissue engineering: scaffold design variable and application.|journal=Biomaterials|year=2003|volume=24|issue=24|pages=4337}}</ref>
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| ====Chitosan====
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| Chitosan is a linear polysaccharide containing linked chitin-derived residues and is widely studied as a biomaterial due to its high compatibility with numerous proteins in the body. Chitosan is cationic and thus electrostatically reacts with numerous [[proteoglycans]], anionic GAGs, and other molecules possessing a negative charge. Since many [[cytokines]] and growth factors are linked to GAG, scaffolds with the chitosan-GAG complexes are able to retain these proteins secreted by the adhered cells. Another quality of chitosan that gives it good biomaterial potential is its high charge density in solutions. This allows chitosan to form ionic complexes with many water-soluble anionic polymers, expanding the range of proteins that are able to bind to it and thus expanding its possible uses.<ref>{{cite book|last=Van Blitterswijk|first=Clemens|title=Tissue Engineering|year=2008|publisher=Elsevier}}</ref>
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| <Center>
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| {| class="wikitable"
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| ! '''Polymer''' !! '''Scaffold structure''' !! '''Target tissue''' !! '''Application cell type''' !! Ref
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| | Chitosan|| 3D porous blocks || Bone || Osteoblast-like ROS ||<ref>{{cite journal|last=Ho|first=Kuo|coauthors=et al|title=Preparation of porous scaffolds by using freeze-extraction and freeze-gelatin methods|journal=Biomaterials|year=2004|volume=25|issue=1|pages=1291}}</ref>
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| | Chitosan-polyester || 3D fiber meshes || Bone || Human MSC ||<ref>{{cite journal|last=Correlo|first=Vitor|coauthors=Luciano F. Boesel, Mrinal Bhattacharya, Joao F. Mano, Nuno M. Neves, Ruis L. Reis|title=Hydroxyapatite Reinforced Chitosan and Polyester Blends for Biomedical Applications|journal=Issue Macromolecular Materials and Engineering Macromolecular Materials and Engineering|year=2005|volume=290|issue=12|pages=1157–1165}}</ref>
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| | Chitosan-alginate || Injectable gel || Bone || Osteoblast-like MG63 ||<ref>{{cite journal|last=Li|first=Z|coauthors=H. Ramay, K. Hauch, D. Xiao, and M. Zhang|title=Chitosan-alginate hybrid scaffolds for bone tissue engineering|journal=Biomaterials|year=2005|volume=26|issue=18|pages=3919–3928}}</ref>
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| | Chitosan-gelatin || 3D porous cylinders || Cartilage || [[Chondrocytes]] ||<ref>{{cite journal|last=Xia|first=W|coauthors=Liu, W|title=Tissue engineering of cartilage with the use of chitosan-gelatin complex scaffolds|journal=Journal of Biomedical Materials Research Part B: Applied Biomaterials|year=2004|volume=71B|issue=2|pages=373–380}}</ref>
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| | Chitosan-GP|| Injectable gel|| Cartilage || Chondrocytes ||<ref>{{cite journal|last=Chenite|first=A|coauthors=C. Chaput, D. Wang, C. Combes, M.D. Buschmann and C.D. Hoemann et al|title=Novel injectable neutral solutions of chitosan form biodegradable gels in situ|journal=Biomaterials|year=2000|volume=21|issue=21|pages=2155–2161}}</ref>
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| | Chitosan-collagen || Porous membranes || Skin || Fibroblast and keratinocyte co-culture ||<ref>{{cite journal|last=Black|first=B|coauthors=Bouez, C., et al|title=Optimization and characterization of an engineered human skin equivalent|journal=Tissue Engineering|year=2005|volume=11|issue=5-6|pages=723–733}}</ref>
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| |} '''Table 1''': Structures, target tissues, and application cell types of chitosan-based scaffolds
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| </Center>
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| ==References==
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| {{reflist}}
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| [[Category:Biochemistry]]
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