Depending upon the degree of mineralization, collagen tissues may be rigid (bone), compliant (tendon), or have a gradient from rigid to compliant (cartilage). It is also abundant in corneas, blood vessels, the gut, intervertebral discs, and the dentin in teeth. In muscle tissue, it serves as a major component of the endomysium. Collagen constitutes one to two percent of muscle tissue and accounts for 6% of the weight of strong, tendinous, muscles. The fibroblast is the most common cell that creates collagen. Gelatin, which is used in food and industry, is collagen that has been irreversibly hydrolyzed. Collagen has many medical uses in treating complications of the bones and skin.
The name collagen comes from the Greek (kólla), meaning "glue", and suffix -, -gen, denoting "producing". This refers to the compound's early use in the process of boiling the skin and tendons of horses and other animals to obtain glue.
Over 90% of the collagen in the human body is type I collagen. However, as of 2011, 28 types of collagen have been identified, described, and divided into several groups according to the structure they form: All of the types contain at least one triple helix. The number of types shows collagen's diverse functionality.
The collagenous cardiac skeleton which includes the four heart valve rings, is histologically, elastically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separating septa of the heart chambers - the interventricular septum and the atrioventricular septum. Collagen contribution to the measure of cardiac performance summarily represents a continuous torsional force opposed to the fluid 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 to ventricular fibrillation. Collagen is layered in variable densities with cardiac muscle mass. The mass, distribution, age and density of collagen all contribute to the compliance required to move blood back and forth. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable pressure. Gradual calcium 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 of cardiac 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 of connective tissue disease.
Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic, and surgical purposes. Both human and bovine collagen is widely used as dermal fillers for treatment of wrinkles and skin aging. Some points of interest are:
When used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use.
Most medical collagen is derived from young beef cattle (bovine) from certified BSE-free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia, Brazil, and New Zealand.
As the skeleton forms the structure of the body, it is vital that it maintains its strength, even after breaks and injuries. Collagen is used in bone grafting as it has a triple helical structure, making 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 of collagen prevents it from being broken down by enzymes, it enables adhesiveness of cells and it is important for the proper assembly of the extracellular matrix.
Collagen scaffolds are used in tissue regeneration, whether in sponges, thin sheets, or gels. Collagen has the correct properties for tissue regeneration such as pore structure, permeability, hydrophilicity, and being stable in vivo. Collagen scaffolds are also ideal for the deposition of cells such as osteoblasts and fibroblasts, and once inserted, growth is able to continue as normal in the tissue.
Collagen is one of the body's key natural resources and a component of skin tissue that can benefit all stages of wound healing. When collagen is made available to the wound bed, closure can occur. Wound deterioration, followed sometimes by procedures such as amputation, can thus be avoided.
Collagen is a natural product and is thus used as a natural wound dressing and has properties that artificial wound dressings do not have. It is resistant against bacteria, which is of vital importance in a wound dressing. It helps to keep the wound sterile, because of its natural ability to fight infection. When collagen is used as a burn dressing, healthy granulation tissue is able to form very quickly over the burn, helping it to heal rapidly.
Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing:
Guiding function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix.
Chemotactic properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in healing.
Nucleation: Collagen, in the presence of certain neutral salt molecules can act as a nucleating agent causing formation of fibrillar structures. A collagen wound dressing might serve as a guide for orienting new collagen deposition and capillary growth.
Hemostatic properties: Blood platelets interact with the collagen to make a hemostatic plug.
As a supplement
When hydrolyzed, collagen is reduced to small peptides, which can be ingested in the form of a dietary supplement or functional foods and beverages with the intent to aid joint and bone health and enhance skin health.Hydrolyzed collagen has a much smaller molecular weight in comparison to native collagen or gelatin. Studies suggest that more than 90% of hydrolyzed collagen is digested and available as small peptides in the blood stream within one hour. From the blood, the peptides (containing hydroxyproline) are transported into the target tissues (e.g., skin, bones, and cartilage), where the peptides act as building blocks for local cells and help boost the production of new collagen fibers.
Some studies have shown efficacy of collagen supplementation for dogs with osteoarthritis pain, alone or in combination with other nutraceuticals like glucosamine and chondroitin.
The collagen protein is composed of a triple helix, which generally consists of two identical chains (?1) and an additional chain that differs slightly in its chemical composition (?2). The amino acid composition of collagen is atypical for proteins, particularly with respect to its high hydroxyproline content. The most common motifs in the amino acid sequence of collagen are glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline. The average amino acid composition for fish and mammal skin is given.
First, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen is then modified by the addition of hydroxyl groups to the amino acids proline and lysine. This step is important for later glycosylation and the formation of the triple helix structure of collagen. Because the hydroxylase enzymes that perform these reactions require vitamin C as a cofactor, a long-term deficiency in this vitamin results in impaired collagen synthesis and scurvy. These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-hydroxylase. Vitamin C also serves with them in inducing these reactions. In this service, one molecule of vitamin C is destroyed for each H replaced by OH.
The synthesis of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems, is the other form of collagen. All types of collagens are triple helices, and the differences lie in the make-up of the alpha peptides created in step 2.
Transcription of mRNA: About 34 genes are associated with collagen formation, each coding for a specific mRNA sequence, and typically have the "COL" prefix. The beginning of collagen synthesis begins with turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).
Pre-pro-peptide formation: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm, it links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is known as the signal sequence. The signal sequence on the N-terminal of the peptide is recognized by a signal recognition particle on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the endoplasmic reticulum for post-translational processing. It is now known as pre-pro-collagen.
Pre-pro-peptide to pro-collagen: Three modifications of the pre-pro-peptide occur leading to the formation of the alpha peptide:
The signal peptide on the N-terminal is dissolved, and the molecule is now known as propeptide (not procollagen).
Hydroxylation of lysines and prolines on propeptide by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase' (to produce hydroxyproline and hydroxylysine) occurs to aid cross-linking of 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.
Once these modifications have taken place, three of the hydroxylated and glycosylated propeptides twist into a triple helix forming procollagen. Procollagen still has unwound ends, which will be later trimmed. At this point, the procollagen is packaged into a transfer vesicle destined for the Golgi apparatus.
Golgi apparatus modification: In the Golgi apparatus, the procollagen goes through one last post-translational modification before being secreted out of the cell. In this step, oligosaccharides (not monosaccharides as in step 3) are added, and then the procollagen is packaged into a secretory vesicle destined for the extracellular space.
Formation of tropocollagen: Once outside the cell, membrane bound enzymes known as collagen peptidases, remove the "loose ends" of the procollagen molecule. What is left is known as tropocollagen. Defects in this step produce one of the many collagenopathies known as Ehlers-Danlos syndrome. This step is absent when synthesizing type III, a type of fibrilar collagen.
Formation of the collagen fibril: lysyl oxidase, an extracellular copper-dependent enzyme, produces the final step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.
Collagen contains two uncommon derivative amino acids not directly inserted during translation. 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.
Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction) by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the 18th century, this condition was notorious among long-duration military, particularly naval, expeditions during which participants were deprived of foods containing vitamin C.
Many bacteria and viruses secrete virulence factors, such as the enzyme collagenase, which destroys collagen or interferes with its production.
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 three polypeptide strands (called alpha peptides, see step 2), each of which has the conformation of a left-handed helix - this should not be confused with the right-handed alpha helix. These three left-handed helices are twisted together into a right-handed triple helix or "super helix", a cooperative quaternary structure stabilized by many hydrogen 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 is interdigitated 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.
Three polypeptides coil to form tropocollagen. Many tropocollagens then bind together to form a fibril, and many of these then form a fibre.
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 pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues. 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. 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 constrained carboxyl 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 single hydrogen 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; a lower concentration of them is required in animals such as fish, whose body 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. The lower proline and hydroxproline contents of cold-water fish and other poikilotherm animals leads to their collagen having a lower thermal stability than mammalian collagen. This lower thermal stability means that gelatin derived from fish collagen is not suitable for many food and industrial applications.
The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues. 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". 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.
The D-period of collagen fibrils results in visible 67nm bands when observed by electron microscopy.
There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils). 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. Collagen's insolubility 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 fully crosslinked. 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 structure in situ. 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. 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.
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. Type I collagen gives bone its tensile strength.
Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.
This is the most abundant collagen of the human body. It is present in scar tissue, the end product when tissue heals by repair. It is found in tendons, skin, artery walls, cornea, the endomysium surrounding muscle fibers, fibrocartilage, and the organic part of bones and teeth.
This is the collagen of granulation 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
In addition to the above-mentioned disorders, excessive deposition of collagen occurs in scleroderma.
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.
Osteogenesis imperfecta - Caused by a mutation in type 1 collagen, 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.
Chondrodysplasias - Skeletal disorder believed to be caused by a mutation in type 2 collagen, further research is being conducted to confirm this.
Ehlers-Danlos syndrome - Thirteen different types of this disorder, which lead to deformities in connective tissue, are known. 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 in collagen type 3.
Alport syndrome - Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder, sufferers have problems with their kidneys and eyes, loss of hearing can also develop during the childhood or adolescent years.
Knobloch syndrome - Caused by a mutation in the COL18A1 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 suffering from the disorder is at an increased risk of developing it themselves since there is a hereditary link.
Collagen has a wide variety of applications, from food to medical. For instance, it is used in cosmetic surgery and burn surgery. It is widely used in the form of collagen casings for sausages, which are also used in the manufacture of musical strings.
If collagen is subject to sufficient denaturation, e.g. 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), e.g. random coils. This process describes the formation of gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.
From the Greek for glue, kolla, the word collagen means "glue producer" and refers to the early process of boiling the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about 4,000 years ago, and Native Americans used it in bows 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 and embroideredfabrics, and to hold utensils together; also in crisscross decorations on human skulls. Collagen normally converts to gelatin, but survived due to dry conditions. Animal glues are thermoplastic, softening again upon reheating, so they are still used in making musical instruments such as fine violins and guitars, which may have to be reopened for repairs--an application incompatible with tough, syntheticplastic adhesives, which are permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.
The molecular and packing structures of collagen have 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. Since that time, many prominent scholars, including Nobel laureates Crick, Pauling, Rich and Yonath, and others, including Brodsky, Berman, and Ramachandran, concentrated on the conformation of the collagen monomer. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical "Madras" model of Ramachandran, which provided an essentially correct model of the molecule's quaternary structure although this model still required some refinement.[clarification needed] 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 or quasi-hexagonal. As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibrillar. The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy. The microfibrillar structure of tail tendon, as described by Fraser, Miller, and Wess (amongst others), was modeled as being closest to the observed structure, although it oversimplified the topological progression of neighboring collagen molecules, and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril. Various cross linking agents like L-Dopaquinone, embeline, potassium embelate and 5-O-methyl embelin could be developed as potential
cross-linking/stabilization agents of collagen preparation and its application as wound dressing sheet in clinical applications is enhanced.
The evolution of collagens was a fundamental step in the early evolution of life, supporting the coalescence of multicellular life forms.
Collagen D-banding is viable as periodic formation of ridging on all fibrils forming collagen. D-bands are created due to the semi-crystalline formation of the collagen within the fibrils. The pattern exhibited by D-banding is consistently independent of fibril diameter. When undergoing deformation, collagen fibrils may lose their D-banding, making the disappearance of the d-bands an indicator of the type of damage undergone by then tendon fibrils.
^Di Lullo, Gloria A.; Sweeney, Shawn M.; Körkkö, Jarmo; Ala-Kokko, Leena & San Antonio, James D. (2002). "Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human, Type I Collagen". J. Biol. Chem.277 (6): 4223-4231. doi:10.1074/jbc.M110709200. PMID11704682.
^Franzke, CW; Bruckner, P; Bruckner-Tuderman, L (11 February 2005). "Collagenous transmembrane proteins: recent insights into biology and pathology". The Journal of Biological Chemistry. 280 (6): 4005-8. doi:10.1074/jbc.R400034200. PMID15561712.
^Guillerminet, Fanny; Beaupied, Hélène; Fabien-Soulé, Véronique; Tomé, Daniel; Benhamou, Claude-Laurent; Roux, Christian; Blais, Anne (2010-03-01). "Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study". Bone. 46 (3): 827-834. doi:10.1016/j.bone.2009.10.035. ISSN8756-3282. PMID19895915.
^Guillerminet, F.; Fabien-Soulé, V.; Even, P. C.; Tomé, D.; Benhamou, C.-L.; Roux, C.; Blais, A. (2012-07-01). "Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice". Osteoporosis International. 23 (7): 1909-1919. doi:10.1007/s00198-011-1788-6. ISSN0937-941X. PMID21927918.
^Asserin, Jérome; Lati, Elian; Shioya, Toshiaki; Prawitt, Janne (2015-12-01). "The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo-controlled clinical trials". Journal of Cosmetic Dermatology. 14 (4): 291-301. doi:10.1111/jocd.12174. ISSN1473-2165. PMID26362110.
^Ichikawa, Satomi; Morifuji, Masashi; Ohara, Hiroki; Matsumoto, Hitoshi; Takeuchi, Yasuo; Sato, Kenji (2010-02-01). "Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate". International Journal of Food Sciences and Nutrition. 61 (1): 52-60. doi:10.3109/09637480903257711. ISSN0963-7486. PMID19961355.
^Shigemura, Yasutaka; Kubomura, Daiki; Sato, Yoshio; Sato, Kenji (2014-09-15). "Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion". Food Chemistry. 159: 328-332. doi:10.1016/j.foodchem.2014.02.091. PMID24767063.
^Watanabe-Kamiyama, Mari; Shimizu, Muneshige; Kamiyama, Shin; Taguchi, Yasuki; Sone, Hideyuki; Morimatsu, Fumiki; Shirakawa, Hitoshi; Furukawa, Yuji; Komai, Michio (2010-01-27). "Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats". Journal of Agricultural and Food Chemistry. 58 (2): 835-841. doi:10.1021/jf9031487. ISSN0021-8561. PMID19957932.
^Gupta, R. C.; Canerdy, T. D.; Lindley, J; Konemann, M; Minniear, J; Carroll, B. A.; Hendrick, C; Goad, J. T.; Rohde, K; Doss, R; Bagchi, M; Bagchi, D (2012). "Comparative therapeutic efficacy and safety of type-II collagen (UC-II), glucosamine and chondroitin in arthritic dogs: Pain evaluation by ground force plate". Journal of Animal Physiology and Animal Nutrition. 96 (5): 770-7. doi:10.1111/j.1439-0396.2011.01166.x. PMID21623931.
^d'Altilio, M; Peal, A; Alvey, M; Simms, C; Curtsinger, A; Gupta, R. C.; Canerdy, T. D.; Goad, J. T.; Bagchi, M; Bagchi, D (2007). "Therapeutic Efficacy and Safety of Undenatured Type II Collagen Singly or in Combination with Glucosamine and Chondroitin in Arthritic Dogs". Toxicology Mechanisms and Methods. 17 (4): 189-96. doi:10.1080/15376510600910469. PMID20020968.
^Peterkofsky, B (1991). "Ascorbate requirement for hydroxylation and secretion of procollagen: Relationship to inhibition of collagen synthesis in scurvy". American Journal of Clinical Nutrition. 54 (6 Suppl): 1135S-1140S. doi:10.1093/ajcn/54.6.1135s. PMID1720597.
^Myllylä, R.; Majamaa, K.; Günzler, V.; Hanauske-Abel, H. M.; Kivirikko, K. I. (1984). "Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by propyl 4-hydroxylase and lysyl hydroxylase". J. Biol. Chem. 259 (9): 5403-5. PMID6325436.
^Minary-Jolandan, M; Yu, MF (2009). "Nanomechanical heterogeneity in the gap and overlap regions of type I collagen fibrils with implications for bone heterogeneity". Biomacromolecules. 10 (9): 2565-70. doi:10.1021/bm900519v. PMID19694448.
^Ross, M. H. and Pawlina, W. (2011) Histology, 6th ed., Lippincott Williams & Wilkins, p. 218.
^Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. 2017. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet 175C:8-26.
^Hamel BC, Pals G, Engels CH, van den Akker E, Boers GH, van Dongen PW, Steijlen PM (1998). "Ehlers-Danlos syndrome and type III collagen abnormalities: a variable clinical spectrum". Clin. Genet. 53 (6): 440-6. doi:10.1111/j.1399-0004.1998.tb02592.x. PMID9712532.
^Clark, G.; Parker, E.; Schaad, J. & Warren, W. J. (1935). "New measurements of previously unknown large interplanar spacings in natural materials". J. Am. Chem. Soc.57 (8): 1509. doi:10.1021/ja01311a504.
^Jesior, J. C.; Miller, A. & Berthet-Colominas, C. (1980). "Crystalline three-dimensional packing is general characteristic of type I collagen fibrils". FEBS Lett. 113 (2): 238-240. doi:10.1016/0014-5793(80)80600-4. PMID7389896.
^Okuyama, K; Bächinger, HP; Mizuno, K; Boudko, SP; Engel, J; Berisio, R; Vitagliano, L (2009). "Comment on Microfibrillar structure of type I collagen in situ by Orgel et al. (2006), Proc. Natl Acad. Sci. USA, 103, 9001-9005". Acta Crystallogr D. 65 (Pt9): 1009-10. doi:10.1107/S0907444909023051. PMID19690380.
^Orgel, Joseph (2009). "On the packing structure of collagen: response to Okuyama et al.'s comment on Microfibrillar structure of type I collagen in situ". Journal Logo Acta Crystallographica Section D. D65 (9): 1009. doi:10.1107/S0907444909028741.