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Wednesday, November 27, 2019

Ehlers–Danlos syndromes

From Wikipedia, the free encyclopedia
 
Ehlers–Danlos syndromes
PMC3504533 1471-2415-12-47-2 (cropped).png
Individual with EDS displaying skin hyperelasticity
Pronunciation
  • ey-lerz dan-los
SpecialtyMedical genetics, rheumatology
SymptomsOverly flexible joints, stretchy skin, abnormal scar formation
ComplicationsAortic dissection, joint dislocations, osteoarthritis
Usual onsetBirth or early childhood
DurationLifelong
TypesHypermobile, classic, vascular, kyphoscoliosis, arthrochalasia, dermatosparaxis, brittle cornea syndrome, others
CausesGenetic
Risk factorsFamily history
Diagnostic methodGenetic testing, skin biopsy
Differential diagnosisMarfan syndrome, cutis laxa syndrome, familial joint hypermobility syndrome
TreatmentSupportive
PrognosisDepends on specific disorder
Frequency1 in 5,000

Ehlers–Danlos syndromes (EDS) are a group of genetic connective tissue disorders. Symptoms may include loose joints, joint pain, stretchy skin, and abnormal scar formation. These can be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.

EDS occurs due to variations of more than 19 different genes. The specific gene affected determines the type of EDS. Some cases result from a new variation occurring during early development, while others are inherited in an autosomal dominant or recessive manner. Typically, these variations result in defects in the structure or processing of the protein collagen. Diagnosis is often based on symptoms and confirmed with genetic testing or skin biopsy. However, people may initially be misdiagnosed with hypochondriasis, depression, or chronic fatigue syndrome.

There is no known cure. Treatment is supportive in nature. Physical therapy and bracing may help strengthen muscles and support joints. While some forms of EDS result in a normal life expectancy, those that affect blood vessels generally decrease life expectancy.

EDS affects at least one in 5,000 people globally. The prognosis depends on the specific disorder. Excess mobility was first described by Hippocrates in 400 BC. The syndromes are named after two physicians, Edvard Ehlers from Denmark and Henri-Alexandre Danlos from France, who described them at the turn of the 20th century.

Signs and symptoms

This group of disorders affects connective tissues across the body, with symptoms most typically present in the joints, skin, and blood vessels. Effects may range from mildly loose joints to life-threatening cardiovascular complications. Due to the diversity of subtypes within the EDS family, symptoms may vary widely between individuals diagnosed with EDS.

Musculoskeletal

Musculoskeletal symptoms include hyperflexible joints that are unstable and prone to sprain, dislocation, subluxation, and hyperextension. There can be an early onset of advanced osteoarthritis, chronic degenerative joint disease, swan-neck deformity of the fingers, and Boutonniere deformity of the fingers. Tearing of tendons or muscles may occur. Deformities of the spine, such as scoliosis (curvature of the spine), kyphosis (a thoracic hump), tethered spinal cord syndrome, and occipitoatlantoaxial hypermobility may also be present. There can also be myalgia (muscle pain) and arthralgia (joint pain), which may be severe and disabling. Trendelenburg's sign is often seen, which means that when standing on one leg, the pelvis drops on the other side. Osgood–Schlatter disease, a painful lump on the knee, is common as well. In infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs.
  • Individual with EDS showing hypermobile fingers, including the "swan-neck" malformation on the 2nd-5th digits, and a hypermobile thumb
     
  • Individual with EDS displaying hypermobile thumb 

  • Individual with EDS displaying hypermobile metacarpophalangeal joints
     
  • Kyphoscoliosis of the back of someone with kyphoscoliosis EDS.

Skin

The weak connective tissue causes fragile skin that tears and bruises easily and atrophic scars that look like cigarette paper. Redundant skin folds occur, especially on the eyelids. Redundant skin folds are areas of excess skin lying in folds. Other skin symptoms include molluscoid pseudotumors, especially on pressure points, petechiae, subcutaneous spheroids, livedo reticularis, and piezogenic papules are less common. In vascular EDS, skin can also be thin and translucent. In dermatosparaxis EDS, the skin is extremely fragile and saggy.
  • Atrophic scar in a case of EDS 

  • Translucent skin in vascular EDS 

  • Individual with EDS displaying skin hyperelasticity 

  • Piezogenic papules on the heel of an individual with hypermobile EDS

Cardiovascular

Other manifestations

  • Gorlin's sign in a case of EDS.
  • An acute case of keratoconus in a case of Brittle cornea syndrome
Because it is often undiagnosed or misdiagnosed in childhood, some instances of EDS have been mischaracterized as child abuse.

The pain associated with the disorders may be severe.

Genetics

The collagen fibril and EDS: (a) Normal collagen fibrils are of uniform size and spacing. Fibrils from a person with dermatosparaxis (b) show dramatic alterations in fibril morphology with severe effects on tensile strength of connective tissues. Person with classical EDS (c) show composite fibrils. Fibrils from a TNX-deficient person (d) are uniform in size and no composite fibrils are seen. TNX-null (e) fibrils are less densely packed and not as well aligned to neighboring fibrils.
 
Every type of EDS, except the hypermobile type, can be positively tied to specific genetic variation.
Variations in these genes can cause EDS:
Variations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. Inheritance patterns depend on the specific syndrome. Most forms of EDS are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. A few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected by a disorder. It can also be an individual (de novo or "sporadic") variation. Sporadic variations occur without any inheritance.

Diagnosis

A diagnosis can be made by an evaluation of medical history and clinical observation. The Beighton criteria are widely used to assess the degree of joint hypermobility. DNA and biochemical studies can help identify affected individuals. Diagnostic tests include collagen gene-variant testing, collagen typing via skin biopsy, echocardiogram, and lysyl hydroxylase or oxidase activity. However, these tests are not able to confirm all cases, especially in instances of an unmapped variation, so clinical evaluation remains important. If multiple individuals in a family are affected, performing prenatal diagnosis may be possible using a DNA information technique known as a linkage study. Knowledge about EDS among all kinds of practitioners is poor. Research is ongoing to identify genetic markers for all types.

Classification

In 2017, 13 subtypes of EDS were classified using specific diagnostic criteria. According to the Ehlers-Danlos society, the syndromes can also be grouped by the symptoms determined by specific gene mutations. Group A disorders are those which affect primary collagen structure and processing. Group B disorders affect collagen folding and crosslinking. Group C are disorders of structure and function of myomatrix. Group D disorders are those that affect glycosaminoglycan biosynthesis. Group E disorders are characterized by defects in the complement pathway. Group F are disorders of intracellular processes, and Group G is considered to be unresolved forms of EDS.

Hypermobile EDS

Hypermobile EDS (formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint subluxations (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, velvety, that bruises easily, and chronic muscle and/or bone pain. It affects the skin less than other forms. It has no available genetic test. Hypermobility EDS (hEDS) is the most common of the 13 types of the connective tissue disorder. Since there is no known genetic test, providers have to diagnose hEDS based on what they already know about the condition and the physical attributes that the patient shows. Other than the general signs, attributes can include; faulty connective tissues throughout the body, musculoskeletal issues and family history. Along with these general signs and side effects, patients can have trouble healing and problems with pregnancy. Women that are pregnant should be warned about things like prelabor rupture of membranes, drop in blood pressure with anesthesia, precipitate birth (very fast active labor), malposition of bleeding, and more. New mothers with hEDS should pay extra attention in taking care of her new baby. Mothers may have trouble taking care of the baby because of the risk of dropping the baby due to weak connective tissue in arms and legs, falling, postpartum depression (more than the general population), and healing from the birthing process.

Classical EDS

Classical EDS (formerly categorized as type 1) is characterized by extremely elastic skin that is fragile and bruises easily; and hypermobility of the joints. Molluscoid pseudotumors (calcified hematomas that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) also are seen often. A side complication of the hyperelasticity presented in many cases of EDS makes it more difficult for wounds to close on their own. Sometimes, motor development is delayed and hypotonia occurs. The variation causing this type of EDS is in the genes COL5A2, COL5A1, and less frequently COL1A1. It involves the skin more than hypermobile EDS. In classical EDS there is often large variation in symptom presentation from patient to patient. Because of this variance EDS has often been an under diagnosed disorder. Without genetic testing healthcare professionals may be able to provide a provisional diagnosis based on careful examination of the mouth, skin, and bones. As well as through neurological assessments. The hyperelasticity of skin in EDS patients can be difficult to use in diagnosis because there is no good standardized way to measure and assess the elasticity of the skin. However, hyperelasticity is still a good indicator as something that may point towards EDS along with other symptoms. A good way to begin the diagnosis process is looking at family history, EDS is an autosomal dominant condition and so is often inherited from family members. Genetic testing remains the most reliable way for an EDS diagnosis to be made. While there is no cure for type 1 EDS, a course of non weight bearing exercising can help with muscular tension which can help correct some of the symptoms of EDS. Anti inflammatory drugs as well as lifestyle changes can help with joint pain. Lifestyle choices should also be made with children that have EDS to try and prevent wounds to the skin. Wearing protective garments can help with this. In the event of a wound often deep stitches are used and left in place for a longer period of time than normal.

Vascular variant of Ehlers–Danlos syndrome

Vascular EDS (formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. It is also characterized by fragile blood vessels and organs that can easily rupture. Affected people are frequently short, and have thin scalp hair. It also has characteristic facial features including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes. Joint hypermobility is present, but generally confined to the small joints (fingers, toes). Other common features include club foot, tendon and/or muscle rupture, acrogeria (premature aging of the skin of the hands and feet), early onset varicose veins, pneumothorax (collapse of a lung), recession of the gums, and a decreased amount of fat under the skin. It can be caused by the variations in the COL3A1 gene. Rarely, COL1A1 variations can also cause it.

Kyphoscoliosis EDS

Kyphoscoliosis EDS (formerly categorized as type 6) is associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility. People may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and osteopenia (low bone density). Other common features include a "marfanoid habitus" which is characterized by long, slender fingers (arachnodactyly), unusually long limbs, and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum). It can be caused by variations in the gene PLOD1, or rarely, in the FKBP14 gene.

Arthrochalasia EDS

Arthrochalasia EDS (formerly categorized as types 7A & B) is characterized by severe joint hypermobility and congenital hip dislocation. Other common features include fragile, elastic skin with easy bruising, hypotonia, kyphoscoliosis (kyphosis and scoliosis), and mild osteopenia. Type-I collagen is usually affected. It is very rare, with about 30 cases reported. It is more severe than the hypermobility type. Variations in the genes COL1A1 and COL1A2 cause it.

Dermatosparaxis EDS

Dermatosparaxis EDS (formerly categorized as type 7C) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. Variations in the ADAMTS2 gene cause it. It is extremely rare, with around 11 cases reported.

Brittle cornea syndrome

Brittle cornea syndrome is characterized by the progressive thinning of the cornea, early-onset progressive keratoglobus or keratoconus, nearsightedness, hearing loss, and blue sclerae. Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often. It has two types. Type 1 occurs due to variations in the ZNF469 gene. Type 2 is due to variations in the PRDM5 gene.

Classical-like EDS

Classical-like EDS is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath). It can be caused by variations in the TNXB gene.

Spondylodysplastic EDS

Spondylodysplastic EDS is characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital, to mild later-onset), and bowing of limbs. It can be caused by variations in both copies of the B4GALT7 gene. Other cases can be caused by variations in the B3GALT6 gene. People with variations in this gene can have kyphoscoliosis, tapered fingers, osteoporosis, aortic aneurysma, and problems with the lungs. Other cases can be caused by the SLC39A13 gene. Those with variations in this gene have protuberant eyes, wrinkled palms of the hands, tapering fingers, and distal joint hypermobility.

Musculocontractural EDS

Musculocontractural EDS is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling. It can be caused by variations in the CHST14 gene. Some other cases can be caused by variations in the DSE gene.

Myopathic EDS

Myopathic EDS (mEDS) is characterized by three major criteria: congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures of the knee, hip, and elbow, and hypermobility of distal joints (ankles, wrists, feet, and hands). There are also four minor criteria that may contribute to a diagnosis of mEDS. This disorder can be inherited through either an autosomal dominant or an autosomal recessive pattern. Molecular testing must be completed to verify that mutations in the COL12A1 gene are present; if not, other collagen-type myopathies should be considered.

Periodontal EDS

Periodontal EDS (pEDS) is an inherited autosomal dominant disorder characterized by four major criteria of severe and intractable periodontitis of early onset (childhood or adolescence), lack of attached gingiva, pretibial plaques, and family history of a first-degree relative who meets clinical criteria. Eight minor criteria may also contribute to the diagnosis of pEDS. Molecular testing may reveal mutations in C1R or C1S genes affecting the C1r protein.

Cardiac-valvular EDS

Cardiac-valvular EDS (cvEDS) is characterized by three major criteria: severe progressive cardiac-valvular problems (affecting aortic and mitral valves), skin problems such as hyperextensibility, atrophic scarring, thin skin, and easy bruising, and joint hypermobility (generalized or restricted to small joints). There are also four minor criteria which may aid in diagnosis of cvEDS. Cardiac-valvular EDS is an autosomal recessive disorder, inherited through variation in both alleles of the gene COL1A2.

History

Until 1997, the classification system for EDS included 10 specific types, and also acknowledged that other extremely rare types existed. At this time, the classification system underwent an overhaul and was reduced to six major types using descriptive titles. Genetic specialists recognize that other types of this condition exist, but have only been documented in single families. Except for hypermobility (type 3), the most common type of all ten types, some of the specific variations involved have been identified and they can be precisely identified by genetic testing; this is valuable due to a great deal of variation in individual cases. However, negative genetic test results do not rule out the diagnosis, since not all of the variations have been discovered; therefore, the clinical presentation is very important.

Forms of EDS in this category may present with soft, mildly stretchable skin, shortened bones, chronic diarrhea, joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns in this group include X-linked recessive, autosomal dominant, and autosomal recessive. Examples of types of related syndromes other than those above reported in the medical literature include:
  • 305200 – type 5
  • 130080 – type 8 – unspecified gene, locus 12p13
  • 225310 – type 10 – unspecified gene, locus 2q34
  • 608763 – Beasley–Cohen type
  • 130070 – progeroid form – B4GALT7
  • 130090 – type unspecified
  • 601776 – D4ST1-deficient Ehlers–Danlos syndrome (adducted thumb-clubfoot syndrome) CHST14

Differential diagnosis

Several disorders share some characteristics with EDS. For example, in cutis laxa, the skin is loose, hanging, and wrinkled. In EDS, the skin can be pulled away from the body, but is elastic and returns to normal when let go. In Marfan syndrome, the joints are very mobile and similar cardiovascular complications occur. People with EDS tend to have a "marfanoid" appearance (e.g., tall, skinny, long arms and legs, "spidery" fingers). However, physical appearance and features in several types of EDS also have characteristics including short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. The palate can have a high arch, causing dental crowding. Blood vessels can sometimes be easily seen through translucent skin, especially on the chest. The genetic connective tissue disorder, Loeys-Dietz syndrome, also has symptoms that overlap with EDS.

In the past, Menkes disease, a copper metabolism disorder, was thought to be a form of EDS. People are not uncommonly misdiagnosed with fibromyalgia, bleeding disorders, or other disorders that can mimic EDS symptoms. Because of these similar disorders and complications that can arise from an unmonitored case of EDS, a correct diagnosis is important. Pseudoxanthoma elasticum (PXE) is worth consideration in diagnosis.

Management

There is no known cure for Ehlers–Danlos syndromes and treatment is supportive. Close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing, casting) may be helpful. This can help stabilize the joints and prevent injury. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances, although individuals are advised not to become dependent on them until other mobility options have been exhausted. People should avoid activities that cause the joint to lock or overextend.

A physician may prescribe casting to stabilize joints. Physicians may refer a person to an orthotist for orthotic treatment (bracing). Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints.

Aquatic therapy promotes muscular development and coordination. With manual therapy, the joint is gently mobilized within the range of motion and/or manipulations. If conservative therapy is not helpful, surgical joint repair may be necessary. Medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. To decrease bruising and improve wound healing, some people have responded to vitamin C. Special precautions are often taken by medical care workers because of the sheer number of complications that tend to arise in people with EDS. In vascular EDS, signs of chest or abdominal pain are considered trauma situations.

Cannabinoids and medical marijuana have shown some efficacy in reducing pain levels.

In general, medical intervention is limited to symptomatic therapy. Before pregnancy, people with EDS should have genetic counseling and familiarize themselves with the risks to their own bodies that pregnancy poses. Children with EDS should be provided with information about their disorder so they can understand why they should avoid contact sports and other physically stressful activities. Children should be taught that demonstrating the unusual positions that they can maintain due to loose joints should not be done, as this may cause early degeneration of the joints. Emotional support along with behavioral and psychological therapy can be useful. Support groups can be immensely helpful for people dealing with major lifestyle changes and poor health. Family members, teachers, and friends should be informed about EDS so they can accept and assist the child.

Surgery

The instability of joints, leading to subluxations and joint pain, often requires surgical intervention in people with EDS. Instability of almost all joints can happen, but appears most often in the lower and upper extremities, with the wrist, fingers, shoulder, knee, hip, and ankle being most common.

Common surgical procedures are joint debridement, tendon replacements, capsulorrhaphy, and arthroplasty. After surgery, the degree of stabilization, pain reduction, and people's satisfaction can improve, but surgery does not guarantee an optimal result: affected peoples and surgeons report being dissatisfied with the results. Consensus is that conservative treatment is more effective than surgery, particularly since people have extra risks of surgical complications due to the disease. Three basic surgical problems arise due to EDS: the strength of the tissues is decreased, which makes the tissue less suitable for surgery; the fragility of the blood vessels can cause problems during surgery; and wound healing is often delayed or incomplete. If considering surgical intervention, seeking care from a surgeon with extensive knowledge and experience in treating people with EDS and joint hypermobility issues would be prudent.

Local anesthetics, arterial catheters, and central venous catheters cause a higher risk of bruise formation in people with EDS. Some people with EDS also show a resistance to local anaesthetics. Resistance to lidocaine and bupivacaine is not uncommon, and mepivacaine tends to work better in people with EDS. There are special recommendations for anesthesia in people with EDS. Detailed recommendations for anesthesia and perioperative care of people with EDS should be used to improve safety.

Surgery in people with EDS requires careful tissue handling and a longer immobilization afterward.

Prognosis

The outcome for individuals with EDS depends on the specific type of EDS they have. Symptoms vary in severity, even in the same disorder, and the frequency of complications varies. Some people have negligible symptoms, while others are severely restricted in daily life. Extreme joint instability, chronic musculoskeletal pain, degenerative joint disease, frequent injuries, and spinal deformities may limit mobility. Severe spinal deformities may affect breathing. In the case of extreme joint instability, dislocations may result from simple tasks such as rolling over in bed or turning a doorknob. Secondary conditions such as autonomic dysfunction or cardiovascular problems, occurring in any type, can affect prognosis and quality of life. Severe mobility-related disability is seen more often in hypermobile EDS than in classical EDS or vascular EDS.

Although all types of EDS are potentially life-threatening, most people have a normal lifespan. However, those with blood-vessel fragility have a high risk of fatal complications, including spontaneous arterial rupture, which is the most common cause of sudden death. The median life expectancy in the population with vascular EDS is 48 years.

Epidemiology

Ehlers–Danlos syndromes are inherited disorders estimated to occur in about one in 5,000 births worldwide. Initially, prevalence estimates ranged from one in 250,000 to 500,000 people, but these estimates were soon found to be too low, as more was studied about the disorders, and medical professionals became more adept at diagnosis. EDS may be far more common than the currently accepted estimate due to the wide range of severities with which the disorder presents.

The prevalence of the disorders differs dramatically. The most commonly occurring is hypermobile EDS, followed by classical EDS. The others are very rare. For example, fewer than 10 infants and children with dermatosparaxis EDS have been described worldwide.

Some types of EDS are more common in Ashkenazi Jews. For example, the chance of being a carrier for dermatosparaxis EDS is one in 248 in Ashkenazi Jews, whereas the prevalence of this variation in the general population is one in 2,000.

Society and culture

Gary "Stretch" Turner showing his extreme Ehlers–Danlos syndrome
 
EDS may have contributed to the virtuoso violinist Niccolò Paganini's skill, as he was able to play wider fingerings than a typical violinist.

Many sideshow performers have EDS. Several of them were billed as the Elastic Skin Man, the India Rubber Man, and Frog Boy. They included such well-known individuals (in their time) as Felix Wehrle, James Morris, and Avery Childs. Two performers with EDS currently hold world records. Contortionist Daniel Browning Smith has hypermobile EDS and holds the current Guinness World Record for the most flexible man as of 2018, while Gary "Stretch" Turner (shown right), sideshow performer in the Circus Of Horrors, has held the current Guinness World Record for the most elastic skin since 1999, for his ability to stretch the skin on his stomach 6.25 inches.

Notable cases

Pageant contestant Victoria Graham has EDS
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Collagen

From Wikipedia, the free encyclopedia
 
Tropocollagen molecule: three left-handed procollagens (red, green, blue) join to form a right-handed triple helical tropocollagen.
 
Collagen /ˈkɒlədʒɪn/ is the main structural protein in the extracellular matrix in the various connective tissues in the body. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen consists of amino acids bound together to form a triple helix of elongated fibril known as a collagen helix. It is mostly found in fibrous tissues such as tendons, ligaments, and skin. 

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 κόλλα (kólla), meaning "glue", and suffix -γέν, -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.

Types

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.
  • Fibrillar (Type I, II, III, V, XI)
  • Non-fibrillar
    • FACIT (Fibril Associated Collagens with Interrupted Triple Helices) (Type IX, XII, XIV, XIX, XXI)
    • Short chain (Type VIII, X)
    • Basement membrane (Type IV)
    • Multiplexin (Multiple Triple Helix domains with Interruptions) (Type XV, XVIII)
    • MACIT (Membrane Associated Collagens with Interrupted Triple Helices) (Type XIII, XVII)
    • Other (Type VI, VII)
The five most common types are:

Medical uses

Cardiac applications

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.

Cosmetic surgery

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.[11] Some points of interest are:
  1. 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.
  2. 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.

Bone grafts

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.

Tissue regeneration

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.

Reconstructive surgical uses

Collagens are widely employed in the construction of the artificial skin substitutes used in the management of severe burns and wounds. These collagens may be derived from bovine, equine, porcine, or even human sources; and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.

Wound healing

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.

Basic research

Collagen is used in laboratory studies for cell culture, studying cell behavior and cellular interactions with the extracellular environment.

Veterinary use

Some studies have shown efficacy of collagen supplementation for dogs with osteoarthritis pain, alone or in combination with other nutraceuticals like glucosamine and chondroitin.

Chemistry

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). 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.

Amino acid Abundance in mammal skin
(residues/1000)		 Abundance in fish skin
(residues/1000)
Glycine 329 339
Proline 126 108
Alanine 109 114
Hydroxyproline 95 67
Glutamic acid 74 76
Arginine 49 52
Aspartic acid 47 47
Serine 36 46
Lysine 29 26
Leucine 24 23
Valine 22 21
Threonine 19 26
Phenylalanine 13 14
Isoleucine 11 11
Hydroxylysine 6 8
Methionine 6 13
Histidine 5 7
Tyrosine 3 3
Cysteine 1 1
Tryptophan 0 0

Synthesis

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.
  1. 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).
  2. 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.
  3. Pre-pro-peptide to pro-collagen: Three modifications of the pre-pro-peptide occur leading to the formation of the alpha peptide:
    1. The signal peptide on the N-terminal is dissolved, and the molecule is now known as propeptide (not procollagen).
    2. 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).
    3. Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.
    4. 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.
  4. 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.
  5. 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.
  6. 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.
Action of lysyl oxidase

Amino acids

Collagen has an unusual amino acid composition and sequence:
  • Glycine is found at almost every third residue.
  • Proline makes up about 17% of collagen.
  • 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.
Cortisol stimulates degradation of (skin) collagen into amino acids.

Collagen I formation

Most collagen forms in a similar manner, but the following process is typical for type I:
  1. Inside the cell
    1. Two types of alpha chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide.
    2. Polypeptide chains are released into the lumen of the RER.
    3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.
    4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (vitamin C) as a cofactor.
    5. Glycosylation of specific hydroxylysine residues occurs.
    6. Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.
    7. Procollagen is shipped to the Golgi apparatus, where it is packaged and secreted by exocytosis.
  2. Outside the cell
    1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
    2. 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.
    3. Collagen may be attached to cell membranes via several types of protein, including fibronectin, laminin, fibulin and integrin.

Synthetic pathogenesis

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. 

An autoimmune disease such as lupus erythematosus or rheumatoid arthritis may attack healthy collagen fibers.

Many bacteria and viruses secrete virulence factors, such as the enzyme collagenase, which destroys collagen or interferes with its production.

Molecular structure

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 silk fibroin.

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.

Associated disorders

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.

Genetic defects of collagen genes
Type Notes Gene(s) Disorders
I 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. COL1A1, COL1A2 Osteogenesis imperfecta, Ehlers–Danlos syndrome, infantile cortical hyperostosis a.k.a. Caffey's disease
II Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye. COL2A1 Collagenopathy, types II and XI
III 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 COL3A1 Ehlers–Danlos syndrome, Dupuytren's contracture
IV Basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney. COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6 Alport syndrome, Goodpasture's syndrome
V Most interstitial tissue, assoc. with type I, associated with placenta COL5A1, COL5A2, COL5A3 Ehlers–Danlos syndrome (classical)
VI Most interstitial tissue, assoc. with type I COL6A1, COL6A2, COL6A3, COL6A5 Ulrich myopathy, Bethlem myopathy, atopic dermatitis
VII Forms anchoring fibrils in dermoepidermal junctions COL7A1 Epidermolysis bullosa dystrophica
VIII Some endothelial cells COL8A1, COL8A2 Posterior polymorphous corneal dystrophy 2
IX FACIT collagen, cartilage, assoc. with type II and XI fibrils COL9A1, COL9A2, COL9A3 EDM2 and EDM3
X Hypertrophic and mineralizing cartilage COL10A1 Schmid metaphyseal dysplasia
XI Cartilage COL11A1, COL11A2 Collagenopathy, types II and XI
XII FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycans COL12A1 –
XIII Transmembrane collagen, interacts with integrin a1b1, fibronectin and components of basement membranes like nidogen and perlecan. COL13A1 –
XIV FACIT collagen, also known as undulin COL14A1 –
XV – COL15A1 –
XVI – COL16A1 –
XVII Transmembrane collagen, also known as BP180, a 180 kDa protein COL17A1 Bullous pemphigoid and certain forms of junctional epidermolysis bullosa
XVIII Source of endostatin COL18A1 –
XIX FACIT collagen COL19A1 –
XX – COL20A1 –
XXI FACIT collagen COL21A1 –
XXII – COL22A1 –
XXIII MACIT collagen COL23A1 –
XXIV – COL24A1 –
XXV – COL25A1 –
XXVI – EMID2 –
XXVII – COL27A1 –
XXVIII – COL28A1 –
XXIX Epidermal collagen COL29A1 Atopic dermatitis

In addition to the above-mentioned disorders, excessive deposition of collagen occurs in scleroderma.

Diseases

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.

Characteristics

Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins, such as enzymes. Tough bundles of collagen called collagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and skin. Along with elastin and soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline 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 the Mesozoic and Paleozoic.

Uses

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 embroidered fabrics, 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, 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 and ethanedial) has been used to repair experimental incisions in rabbit lungs.

History

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. 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.

D-banding

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.
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