The triple helix: three left-handed polyproline type II helices (red, green, blue) assemble by an axial hydrogen bond to form a right-handed triple helix, the tertiary structure of collagen.
Depending on the degree ofmineralization, collagen tissues may be rigid (bone) or compliant (tendon) or have a gradient from rigid to compliant (cartilage). Collagen is also abundant incorneas,blood vessels, thegut,intervertebral discs, anddentin.[3] Inmuscle tissue, it serves as a major component of theendomysium. Collagen constitutes 1% to 2% of muscle tissue and 6% by weight ofskeletal muscle.[4] Thefibroblast is the most common cell creating collagen in animals.Gelatin, which is used in food and industry, is collagen that was irreversiblyhydrolyzed using heat, basic solutions, or weak acids.[5]
As of 2011, 28 types of human collagen have been identified, described, and classified according to their structure.[8] This diversity shows collagen's diverse functionality.[9] All of the types contain at least onetriple helix.[8] Over 90% of the collagen inhumans isType I and Type III collagen.[10]
The collagenouscardiac skeleton, which includes the fourheart valve rings, is histologically, elastically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separatingsepta of the heart chambers – theinterventricular septum and theatrioventricular septum. Collagen contribution to the measure ofcardiac performance summarily represents a continuous torsional force opposed to thefluid mechanics of blood pressure emitted from the heart. The collagenous structure that divides the upper chambers of the heart from the lower chambers is an impermeable membrane that excludes both blood and electrical impulses through typical physiological means. With support from collagen,atrial fibrillation never deteriorates toventricular fibrillation. Collagen is layered in variable densities with smooth muscle mass. The mass, distribution, age, and density of collagen all contribute to thecompliance required to move blood back and forth. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variablepressure. Gradualcalcium deposition within collagen occurs as a natural function of aging. Calcified points within collagen matrices show contrast in a moving display of blood and muscle, enabling methods ofcardiac imaging technology to arrive at ratios essentially stating blood in (cardiac input) and blood out (cardiac output). Pathology of the collagen underpinning of the heart is understood within the category ofconnective tissue disease.[citation needed]
As the skeleton forms the structure of the body, it is vital that it maintains its strength and its structure, even after breaks and injuries. Collagen is used in bone grafting because its triple-helix structure makes it a very strong molecule. It is ideal for use in bones, as it does not compromise the structural integrity of the skeleton. The triple helical structure prevents collagen from being broken down by enzymes, it enables adhesiveness of cells, and it is important for the proper assembly of the extracellular matrix.[12]
Collagen scaffolds are used in tissue regeneration, whether in sponges,[13] thin sheets,[14] gels,[15] or fibers.[16] Collagen has favorable properties for tissue regeneration, such as pore structure, permeability,hydrophilicity, and stability in vivo. Collagen scaffolds also support deposition of cells, such asosteoblasts andfibroblasts, and once inserted, facilitate growth to proceed normally.[17]
Collagens are widely used in the construction ofartificial skin substitutes used for managing severeburns and wounds.[18][19] These collagens may be derived from cow, horse, pig, or even human sources; and are sometimes used in combination withsilicones,glycosaminoglycans, fibroblasts,growth factors, and other substances.[20]
Collagen is one of the body's key natural resources and a component of skin tissue that can benefit all stages ofwound healing.[21] When collagen is made available to the wound bed, closure can occur. This avoids wound deterioration and procedures such as amputation.
Collagen is used as a natural wound dressing because it has properties that artificial wound dressings do not have. It resists bacteria, which is vitally important in wound dressing. As a burn dressing, collagen helps it heal fast by helpinggranulation tissue to grow over the burn.[18]
Throughout the four phases of wound healing, collagen performs the following functions:
Guiding:collagen fibers guide fibroblasts because they migrate along a connective tissue matrix.
Chemotaxis: collagen fibers have a large surface area which attracts fibrogenic cells which help healing.
Nucleation: in the presence of certain neutral salt molecules, collagen can act as a nucleating agent causing formation of fibrillar structures.
Hemostasis: Bloodplatelets interact with the collagen to make a hemostatic plug.
The collagen protein is composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2).[23] The amino acid composition of collagen is atypical for proteins, particularly with respect to its highhydroxyproline content. The most common motifs in collagen's amino acid sequence areglycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline.
The table below lists average amino acid composition for fish and mammal skin.[24]
First, a three-dimensional stranded structure is assembled, mostly composed of the amino acids glycine and proline. This is the collagen precursor procollagen. Then, procollagen is modified by the addition ofhydroxyl groups to the amino acids proline andlysine. This step is important for laterglycosylation and the formation of collagen's triple helix structure. Because thehydroxylase enzymes performing these reactions requirevitamin C as acofactor, a long-term deficiency in this vitamin results in impaired collagen synthesis andscurvy.[25] These hydroxylation reactions are catalyzed by the enzymesprolyl 4-hydroxylase[26] andlysyl hydroxylase. The reaction consumes one ascorbate molecule per hydroxylation.[27] Collagen synthesis occurs inside and outside cells.
The most common form of collagen is fibrillary collagen. Another common form is meshwork collagen, which is often involved in the formation of filtration systems. All types of collagen are triple helices, but differ in the make-up of their alpha peptides created in step 2. Below we discuss the formation of fibrillary collagen.
Transcription of mRNA: Synthesis begins with turning on genes associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3). About 44 genes are associated with collagen formation, each coding for a specific mRNA sequence, and are typically named with the "COL" prefix.
Pre-pro-peptide formation: The created mRNA exits the cell nucleus into the cytoplasm. There, it links with the ribosomal subunits and is translated into a peptide. The peptide goes into the endoplasmic reticulum for post-translational processing. It is directed there by asignal recognition particle on theendoplasmic reticulum, which recognizes the peptide'sN-terminal signal sequence (the early part of the sequence). The processed product is apre-pro-peptide called preprocollagen.
Pro-collagenformation: Three modifications of the pre-pro-peptide form the alpha peptide:
The signal peptide on the N-terminal is removed. This molecule is called 'propeptide.'
Lysines and prolines are hydroxylated by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase', producing hydroxyproline and hydroxylysine. This helps in cross-linking the alpha peptides. This enzymatic step requires vitamin C as a cofactor. In scurvy, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by three alpha peptides).
Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.
Three of the hydroxylated and glycosylated propeptides twist into a triple helix (except for its ends), forming procollagen. It is packaged into a transfer vesicle destined for the Golgi apparatus.
Modificationand secretion: In theGolgi apparatus, the procollagen goes through one last post-translational modification, adding oligosaccharides (not monosaccharides as in step 3). Then it is packaged into a secretory vesicle to be secreted from the cell.
Tropocollagenformation: Outside the cell, membrane-bound enzymes called collagen peptidases remove the unwound ends of the molecule, producing tropocollagen. Defects in this step produce various collagenopathies calledEhlers–Danlos syndrome. This step is absent when synthesizing type III, a type of fibrillar collagen.
Collagen fibril formation:Lysyl oxidase, acopper-dependent enzyme, acts on lysines and hydroxylysines, producing aldehyde groups, which eventually form covalent bonds between tropocollagen molecules. This polymer of tropocollagen is called a collagen fibril.
Collagen contains two unusual derivative amino acids not directly inserted duringtranslation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
Hydroxylysine derived from lysine – depending on the type of collagen, varying numbers of hydroxylysines areglycosylated (mostly havingdisaccharides attached).
Most collagen forms in a similar manner, but the following process is typical for type I:
Inside the cell
Two types of alpha chains – alpha-1 and alpha 2, are formed duringtranslation on ribosomes along therough endoplasmic reticulum (RER). These peptide chains, known as preprocollagen, have registration peptides on each end and asignal peptide.[29]
Polypeptide chains are released into the lumen of the RER.
Signal peptides are cleaved inside the RER; these are known as pro-alpha chains.
Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on and consumesascorbic acid (vitamin C) as acofactor.
Glycosylation of specific hydroxylysine residues occurs.
Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.
Registration peptides are cleaved, and tropocollagen is formed byprocollagen peptidase.
Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction) bylysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
A single collagen molecule, tropocollagen, is used to make up larger collagen aggregates, such as fibrils. It is approximately 300 nm long and 1.5 nm in diameter, and it is made up of threepolypeptide strands (called alpha peptides, see step 2), each of which has the conformation of a left-handedhelix – this should not be confused with the right-handedalpha helix. These three left-handed helices are twisted together into a right-handed triple helix or "super helix", a cooperativequaternary structure stabilized by manyhydrogen bonds. With type I collagen and possibly all fibrillar collagens, if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril isinterdigitated with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.
Threepolypeptides coil to form tropocollagen. Many tropocollagens then bind together to form a fibril, and many of these then form a fiber.
A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the patternGly-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues.[24] Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2 character of collagen alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix, as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links.[24] This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silkfibroin.
Collagen is not only a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation, and infrastructure, many sections of its non-proline-rich regions have cell or matrix association/regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrainedcarboxyl and (secondary)amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.
Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine's singlehydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix – Hyp even more so than Pro because of a stereoelectronic effect;[30] a lower concentration of them is required in animals such as fish, whosebody temperatures are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals.[24] The lower proline and hydroxyproline contents of cold-water fish and otherpoikilotherm animals lead to their collagen having a lower thermal stability than mammalian collagen.[24] This lower thermal stability means thatgelatin derived from fish collagen is not suitable for many food and industrial applications.
The tropocollagensubunits spontaneouslyself-assemble, with regularly staggered ends, into even larger arrays in theextracellular spaces of tissues.[31][32] Additional assembly of fibrils is guided by fibroblasts, which deposit fully formed fibrils from fibripositors. In the fibrillar collagens, molecules are staggered to adjacent molecules by about 67 nm (a unit that is referred to as 'D' and changes depending upon the hydration state of the aggregate). In each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the "overlap", and a part containing only four molecules, called the "gap".[33] These overlap and gap regions are retained as microfibrils assemble into fibrils, and are thus viewable using electron microscopy. The triple helical tropocollagens in the microfibrils are arranged in a quasihexagonal packing pattern.[33][34]
The D-period of collagen fibrils results in visible 67nm bands when observed by electron microscopy.
There is somecovalent crosslinking within the triple helices and a variable amount of covalent crosslinking between tropocollagen helices forming well-organized aggregates (such as fibrils).[35] Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins, and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players.[32] Collagen'sinsolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fullycrosslinked. However, advances in microscopy techniques (i.e. electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structurein situ.[36] These later advances are particularly important to better understanding the way in which collagen structure affects cell–cell and cell–matrix communication and how tissues are constructed in growth and repair and changed in development and disease.[37][38] For example, using AFM–based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.[39]
Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is hydroxylapatite (approximately) Ca10(OH)2(PO4)6.[40] Type I collagen gives bone itstensile strength.
Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, posttranslational modification, secretion, or other processes involved in normal collagen production.
This is the most abundant collagen of the human body. It is present inscar tissue, the end product when tissueheals by repair. It is found intendons, skin, artery walls, cornea, theendomysium surrounding muscle fibers, fibrocartilage, and the organic part of bones and teeth.
This is the collagen ofgranulation tissue and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized.Reticular fiber. Also found in artery walls, skin, intestines and the uterus
One thousand mutations have been identified in 12 out of more than 20 types of collagen. These mutations can lead to various diseases at the tissue level.[42]
Osteogenesis imperfecta – Caused by a mutation intype 1 collagen, a dominant autosomal disorder, results in weak bones and irregular connective tissue; some cases can be mild while others can be lethal. Mild cases have lowered levels of collagen type 1, while severe cases have structural defects in collagen.[43]
Chondrodysplasias – Skeletal disorder believed to be caused by a mutation intype 2 collagen, further research is being conducted to confirm this.[44]
Ehlers–Danlos syndrome – Thirteen different types of this disorder, which lead to deformities in connective tissue, are known.[45] Some of the rarer types can be lethal, leading to the rupture of arteries. Each syndrome is caused by a different mutation. For example, the vascular type (vEDS) of this disorder is caused by a mutation incollagen type 3.[46]
Alport syndrome – Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder. Those with the condition have problems with their kidneys and eyes, and loss of hearing can also develop during childhood or adolescence.[47]
Knobloch syndrome – Caused by a mutation in theCOL18A1 gene that codes for the production of collagen XVIII. Patients present with protrusion of the brain tissue and degeneration of the retina; an individual who has family members with the disorder is at an increased risk of developing it themselves since there is a hereditary link.[42]
When not synthesized, collagen can be harvested from animal skin. This has led to deforestation, as has occurred in Paraguay, where large collagen producers buy large amounts of cattle hides from regions that have beenclear-cut for cattle grazing.[48]
Collagen is one of the long,fibrous structural proteins whose functions are quite different from those ofglobular proteins, such asenzymes. Tough bundles of collagen called "collagen fibers" are a major component of theextracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has greattensile strength and is the main component offascia,cartilage,ligaments,tendons,bone, and skin.[49][50] Along withelastin and softkeratin, it is responsible for skin strength and elasticity, and its degradation leads towrinkles that accompanyaging.[51] It strengthensblood vessels and plays a role intissue development. It is present in thecornea and lens of the eye incrystalline form. It may be one of the most abundant proteins in the fossil record, given that it appears to fossilize frequently, even in bones from theMesozoic andPaleozoic.[52]
Collagen is a complex hierarchical material withmechanical properties that vary significantly across different scales.
On the molecular scale,atomistic andcoarse-grained modeling simulations, as well as numerous experimental methods, have led to several estimates of theYoung's modulus of collagen at the molecular level. Only above a certain strain rate is there a strong relationship between elastic modulus and strain rate, possibly due to the large number of atoms in a collagen molecule.[53] The length of the molecule is also important, where longer molecules have lower tensile strengths than shorter ones due to short molecules having a large proportion of hydrogen bonds being broken and reformed.[54]
On thefibrillar scale, collagen has a lower modulus compared to the molecular scale, and varies depending on geometry, scale of observation, deformation state, and hydration level.[53] By increasing thecrosslink density from zero to 3 per molecule, the maximum stress the fibril can support increases from 0.5 GPa to 6 GPa.[55]
Limited tests have been done on the tensile strength of the collagen fiber, but generally it has been shown to have a lower Young's modulus compared to fibrils.[56]
When studying the mechanical properties of collagen,tendon is often chosen as the ideal material because it is close to a pure and aligned collagen structure. However, at the macro, tissue scale, the vast number of structures that collagen fibers and fibrils can be arranged into results in highly variable properties. For example, tendon has primarily parallel fibers, whereas skin consists of a net of wavy fibers, resulting in a much higher strength and lower ductility in tendon compared to skin. The mechanical properties of collagen at multiple hierarchical levels are given.
Young's modulus of collagen at multiple hierarchical levels
Collagen is known to be a viscoelastic solid. When the collagen fiber is modeled as two Kelvin-Voigt models in series, each consisting of a spring and a dashpot in parallel, the strain in the fiber can be modeled according to the following equation:
where α, β, and γ are defined materials properties, εD is fibrillar strain, and εT is total strain.[61]
A salami and the collagen casing (below) it came in
Collagen has a wide variety of applications. In the medical industry, it is used incosmetic surgery andburn surgery. An example of collagen use for food manufacturing is incasings for sausages.
If collagen is subject to sufficientdenaturation, such as by heating, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII) ofrandom coils. This process describes the formation ofgelatin, which is used in many foods, including flavoredgelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries. It is also used as adietary supplement, and has been advertised as a potential remedy against the ageing process.[62][63][64]
From the Greek for glue,kolla, the word collagen means "glue producer" and refers to the early process of boiling the skin andsinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it inbows about 1,500 years ago. The oldest glue in the world,carbon-dated as more than 8,000 years old, was found to be collagen – used as a protective lining on rope baskets andembroideredfabrics, to holdutensils together, and in crisscross decorations onhuman skulls.[65] Collagen normally converts to gelatin, but survived due to dry conditions. Animal glues arethermoplastic, softening again upon reheating, so they are still used in makingmusical instruments such as fine violins and guitars, which may have to be reopened for repairs – an application incompatible with tough,synthetic plastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial andethanedial) has been used to repair experimental incisions in rabbitlungs.[66]
Bovine collagen is widely used indermal fillers foraesthetic correction of wrinkles and skin aging.[67] Collagen cremes are also widely sold even though collagen cannot penetrate the skin because its fibers are too large.[68] Collagen is a vital protein inskin,hair,nails, and other tissues. Its production decreases with age and factors like sun damage andsmoking. Collagen supplements, derived from sources likefish andcattle, are marketed to improve skin, hair, and nails. Studies show some skin benefits, but these supplements often contain other beneficial ingredients, making it unclear if collagen alone is effective. There's minimal evidence supporting collagen's benefits for hair and nails. Overall, the effectiveness of oral collagen supplements is not well-proven, and focusing on ahealthy lifestyle and proven skincare methods likesun protection is recommended.[69]
The molecular and packing structures of collagen eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s.[70][71] Research then concentrated on the conformation of the collagenmonomer, producing several competing models, although correctly dealing with the conformation of each individual peptide chain. The triple-helical "Madras" model, proposed byG. N. Ramachandran in 1955, provided an accurate model ofquaternary structure in collagen.[72][73][74][75][76] This model was supported by further studies of higher resolution in the late 20th century.[77][78][79][80]
The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal.[34][81][82] As with its monomeric structure, several conflicting models propose either that the packing arrangement of collagen molecules is 'sheet-like', or ismicrofibrillar.[83][84] The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage was imaged directly byelectron microscopy in the late 20th century and early 21st century.[85][86][87] The microfibrillar structure ofrat tail tendon was modeled as being closest to the observed structure, although it oversimplified the topological progression of neighboring collagen molecules, and so did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termedmicrofibril.[33][88][89]
^Sikorski ZE (2001).Chemical and Functional Properties of Food Proteins. Boca Raton, Florida: CRC Press. p. 242.ISBN978-1-56676-960-0.
^Bogue RH (1923). "Conditions Affecting the Hydrolysis of Collagen to Gelatin".Industrial and Engineering Chemistry.15 (11):1154–59.doi:10.1021/ie50167a018.
^Geiger M, Li RH, Friess W (November 2003). "Collagen sponges for bone regeneration with rhBMP-2".Advanced Drug Delivery Reviews.55 (12):1613–1629.doi:10.1016/j.addr.2003.08.010.PMID14623404.
^Houck JC, Sharma VK, Patel YM, Gladner JA (October 1968). "Induction of collagenolytic and proteolytic activities by anti-inflammatory drugs in the skin and fibroblast".Biochemical Pharmacology.17 (10):2081–2090.doi:10.1016/0006-2952(68)90182-2.PMID4301453.
^Hulmes DJ (2002). "Building collagen molecules, fibrils, and suprafibrillar structures".Journal of Structural Biology.137 (1–2):2–10.doi:10.1006/jsbi.2002.4450.PMID12064927.
^abHulmes DJ (1992). "The collagen superfamily--diverse structures and assemblies".Essays in Biochemistry.27:49–67.PMID1425603.
^Twardowski T, Fertala A, Orgel JP, San Antonio JD (2007). "Type I collagen and collagen mimetics as angiogenesis promoting superpolymers".Current Pharmaceutical Design.13 (35):3608–3621.doi:10.2174/138161207782794176.PMID18220798.
^Minary-Jolandan M, Yu MF (September 2009). "Nanomechanical heterogeneity in the gap and overlap regions of type I collagen fibrils with implications for bone heterogeneity".Biomacromolecules.10 (9):2565–2570.doi:10.1021/bm900519v.PMID19694448.
^Ross, M. H. and Pawlina, W. (2011)Histology, 6th ed., Lippincott Williams & Wilkins, p. 218.
^Horton WA, Campbell D, Machado MA, Chou J (December 1989). "Type II collagen screening in the human chondrodysplasias".American Journal of Medical Genetics.34 (4):579–583.doi:10.1002/ajmg.1320340425.PMID2624272.
^Hamel BC, Pals G, Engels CH, van den Akker E, Boers GH, van Dongen PW, et al. (June 1998). "Ehlers-Danlos syndrome and type III collagen abnormalities: a variable clinical spectrum".Clinical Genetics.53 (6):440–446.doi:10.1111/j.1399-0004.1998.tb02592.x.PMID9712532.S2CID39089732.
^Zylberberg L, Laurin M (2011). "Analysis of fossil bone organic matrix by transmission electron microscopy".Comptes Rendus Palevol.11 (5–6):357–66.doi:10.1016/j.crpv.2011.04.004.
^Pradhan SM, Katti DR, Katti KS (2011). "Steered Molecular Dynamics Study of Mechanical Response of Full Length and Short Collagen Molecules".Journal of Nanomechanics and Micromechanics.1 (3):104–110.doi:10.1061/(ASCE)NM.2153-5477.0000035.ISSN2153-5434.
^Buehler MJ (January 2008). "Nanomechanics of collagen fibrils under varying cross-link densities: atomistic and continuum studies".Journal of the Mechanical Behavior of Biomedical Materials.1 (1):59–67.doi:10.1016/j.jmbbm.2007.04.001.PMID19627772.
^Gentleman E, Lay AN, Dickerson DA, Nauman EA, Livesay GA, Dee KC (September 2003). "Mechanical characterization of collagen fibers and scaffolds for tissue engineering".Biomaterials.24 (21):3805–3813.doi:10.1016/s0142-9612(03)00206-0.PMID12818553.
^Vesentini S, Fitié CF, Montevecchi FM, Redaelli A (June 2005). "Molecular assessment of the elastic properties of collagen-like homotrimer sequences".Biomechanics and Modeling in Mechanobiology.3 (4):224–234.doi:10.1007/s10237-004-0064-5.PMID15824897.
^van der Rijt JA, van der Werf KO, Bennink ML, Dijkstra PJ, Feijen J (September 2006). "Micromechanical testing of individual collagen fibrils".Macromolecular Bioscience.6 (9):697–702.doi:10.1002/mabi.200600063.PMID16967482.
^abGentleman E, Lay AN, Dickerson DA, Nauman EA, Livesay GA, Dee KC (September 2003). "Mechanical characterization of collagen fibers and scaffolds for tissue engineering".Biomaterials.24 (21):3805–3813.doi:10.1016/S0142-9612(03)00206-0.PMID12818553.
^Fraser RD, MacRae TP, Suzuki E (April 1979). "Chain conformation in the collagen molecule".Journal of Molecular Biology.129 (3):463–481.doi:10.1016/0022-2836(79)90507-2.PMID458854.
^Okuyama K, Okuyama K, Arnott S, Takayanagi M, Kakudo M (October 1981). "Crystal and molecular structure of a collagen-like polypeptide (Pro-Pro-Gly)10".Journal of Molecular Biology.152 (2):427–443.doi:10.1016/0022-2836(81)90252-7.PMID7328660.
^Fraser RD, MacRae TP, Miller A (January 1987). "Molecular packing in type I collagen fibrils".Journal of Molecular Biology.193 (1):115–125.doi:10.1016/0022-2836(87)90631-0.PMID3586015.
^Wess TJ, Hammersley AP, Wess L, Miller A (January 1998). "Molecular packing of type I collagen in tendon".Journal of Molecular Biology.275 (2):255–267.doi:10.1006/jmbi.1997.1449.PMID9466908.
.jpg)
.svg)
.png)
