Tendon

Extracellular matrix

The dry mass of normal tendons, which is 30–45% of their total mass, is made of:

• 60–85% collagen
  • 60–80% collagen I
  • 0–10% collagen III
  • 2% collagen IV
  • small amounts of collagens V, VI, and others
• 15–40% non-collagenous extracellular matrix components, including:
  • 3% cartilage oligomeric matrix protein,
  • 1–2% elastin,
  • 1–5% proteoglycans,
  • 0.2% inorganic components such as copper, manganese, and calcium.^{[8][9][10][11]}

Although most of a tendon's collagen is type I collagen, many minor collagens are present that play vital roles in tendon development and function. These include type II collagen in the cartilaginous zones, type III collagen in the reticulin fibres of the vascular walls, type IX collagen, type IV collagen in the basement membranes of the capillaries, type V collagen in the vascular walls, and type X collagen in the mineralized fibrocartilage near the interface with the bone.^[8][12]

Tenocytes

The tenocytes produce the collagen molecules, which aggregate end-to-end and side-to-side to produce collagen fibrils. Fibril bundles are organized to form fibres with the elongated tenocytes closely packed between them. There is a three-dimensional network of cell processes associated with collagen in the tendon. The cells communicate with each other through gap junctions, and this signalling gives them the ability to detect and respond to mechanical loading.^[18] These communications happen by two proteins essentially: connexin 43, present where the cells processes meet and in cell bodies connexin 32, present only where the processes meet.^[19]

Blood vessels may be visualized within the endotendon running parallel to collagen fibres, with occasional branching transverse anastomoses.

The internal tendon bulk is thought to contain no nerve fibres, but the epitenon and paratenon contain nerve endings, while Golgi tendon organs are present at the myotendinous junction between tendon and muscle.

Tendon length varies in all major groups and from person to person. Tendon length is, in practice, the deciding factor regarding actual and potential muscle size. For example, all other relevant biological factors being equal, a man with a shorter tendons and a longer biceps muscle will have greater potential for muscle mass than a man with a longer tendon and a shorter muscle. Successful bodybuilders will generally have shorter tendons. Conversely, in sports requiring athletes to excel in actions such as running or jumping, it is beneficial to have longer than average Achilles tendon and a shorter calf muscle.^[20]

Tendon length is determined by genetic predisposition, and has not been shown to either increase or decrease in response to environment, unlike muscles, which can be shortened by trauma, use imbalances and a lack of recovery and stretching.^[21] In addition tendons allow muscles to be at an optimal distance from the site where they actively engage in movement, passing through regions where space is premium, like the carpal tunnel.^[19]

Mechanics

Tendons are viscoelastic structures, which means they exhibit both elastic and viscous behaviour. When stretched, tendons exhibit typical "soft tissue" behavior. The force-extension, or stress-strain curve starts with a very low stiffness region, as the crimp structure straightens and the collagen fibres align suggesting negative Poisson's ratio in the fibres of the tendon. More recently, tests carried out in vivo (through MRI) and ex vivo (through mechanical testing of various cadaveric tendon tissue) have shown that healthy tendons are highly anisotropic and exhibit a negative Poisson's ratio (auxetic) in some planes when stretched up to 2% along their length, i.e. within their normal range of motion.^[32] After this 'toe' region, the structure becomes significantly stiffer, and has a linear stress-strain curve until it begins to fail. The mechanical properties of tendons vary widely, as they are matched to the functional requirements of the tendon. The energy storing tendons tend to be more elastic, or less stiff, so they can more easily store energy, whilst the stiffer positional tendons tend to be a little more viscoelastic, and less elastic, so they can provide finer control of movement. A typical energy storing tendon will fail at around 12–15% strain, and a stress in the region of 100–150 MPa, although some tendons are notably more extensible than this, for example the superficial digital flexor in the horse, which stretches in excess of 20% when galloping.^[33] Positional tendons can fail at strains as low as 6–8%, but can have moduli in the region of 700–1000 MPa.^[34]

Several studies have demonstrated that tendons respond to changes in mechanical loading with growth and remodeling processes, much like bones. In particular, a study showed that disuse of the Achilles tendon in rats resulted in a decrease in the average thickness of the collagen fiber bundles comprising the tendon.^[35] In humans, an experiment in which people were subjected to a simulated micro-gravity environment found that tendon stiffness decreased significantly, even when subjects were required to perform restiveness exercises.^[36] These effects have implications in areas ranging from treatment of bedridden patients to the design of more effective exercises for astronauts.

Injury

Tendons are subject to many types of injuries. There are various forms of tendinopathies or tendon injuries due to overuse. These types of injuries generally result in inflammation and degeneration or weakening of the tendons, which may eventually lead to tendon rupture.^[37] Tendinopathies can be caused by a number of factors relating to the tendon extracellular matrix (ECM), and their classification has been difficult because their symptoms and histopathology often are similar.

Types of tendinopathy include:^[38]

• Tendinosis: non-inflammatory injury to the tendon at the cellular level. The degradation is caused by damage to collagen, cells, and the vascular components of the tendon, and is known to lead to rupture.^[39] Observations of tendons that have undergone spontaneous rupture have shown the presence of collagen fibrils that are not in the correct parallel orientation or are not uniform in length or diameter, along with rounded tenocytes, other cell abnormalities, and the ingrowth of blood vessels.^[37] Other forms of tendinosis that have not led to rupture have also shown the degeneration, disorientation, and thinning of the collagen fibrils, along with an increase in the amount of glycosaminoglycans between the fibrils.^[40]
• Tendinitis: degeneration with inflammation of the tendon as well as vascular disruption.^[8]
• Paratenonitis: inflammation of the paratenon, or paratendinous sheet located between the tendon and its sheath.^[38]

Tendinopathies may be caused by several intrinsic factors including age, body weight, and nutrition. The extrinsic factors are often related to sports and include excessive forces or loading, poor training techniques, and environmental conditions.^[41]

Healing

It was believed that tendons could not undergo matrix turnover and that tenocytes were not capable of repair. However, it has since been shown that, throughout the lifetime of a person, tenocytes in the tendon actively synthesize matrix components as well as enzymes such as matrix metalloproteinases (MMPs) can degrade the matrix.^[41] Tendons are capable of healing and recovering from injuries in a process that is controlled by the tenocytes and their surrounding extracellular matrix.

The three main stages of tendon healing are inflammation, repair or proliferation, and remodeling, which can be further divided into consolidation and maturation. These stages can overlap with each other. In the first stage, inflammatory cells such as neutrophils are recruited to the injury site, along with erythrocytes. Monocytes and macrophages are recruited within the first 24 hours, and phagocytosis of necrotic materials at the injury site occurs. After the release of vasoactive and chemotactic factors, angiogenesis and the proliferation of tenocytes are initiated. Tenocytes then move into the site and start to synthesize collagen III.^[37][40] After a few days, the repair or proliferation stage begins. In this stage, the tenocytes are involved in the synthesis of large amounts of collagen and proteoglycans at the site of injury, and the levels of GAG and water are high.^[42] After about six weeks, the remodeling stage begins. The first part of this stage is consolidation, which lasts from about six to ten weeks after the injury. During this time, the synthesis of collagen and GAGs is decreased, and the cellularity is also decreased as the tissue becomes more fibrous as a result of increased production of collagen I and the fibrils become aligned in the direction of mechanical stress.^[40] The final maturation stage occurs after ten weeks, and during this time there is an increase in crosslinking of the collagen fibrils, which causes the tissue to become stiffer. Gradually, over about one year, the tissue will turn from fibrous to scar-like.^[42]

Matrix metalloproteinases (MMPs) have a very important role in the degradation and remodeling of the ECM during the healing process after a tendon injury. Certain MMPs including MMP-1, MMP-2, MMP-8, MMP-13, and MMP-14 have collagenase activity, meaning that, unlike many other enzymes, they are capable of degrading collagen I fibrils. The degradation of the collagen fibrils by MMP-1 along with the presence of denatured collagen are factors that are believed to cause weakening of the tendon ECM and an increase in the potential for another rupture to occur.^[43] In response to repeated mechanical loading or injury, cytokines may be released by tenocytes and can induce the release of MMPs, causing degradation of the ECM and leading to recurring injury and chronic tendinopathies.^[40]

A variety of other molecules are involved in tendon repair and regeneration. There are five growth factors that have been shown to be significantly upregulated and active during tendon healing: insulin-like growth factor 1 (IGF-I), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor beta (TGF-β).^[42] These growth factors all have different roles during the healing process. IGF-1 increases collagen and proteoglycan production during the first stage of inflammation, and PDGF is also present during the early stages after injury and promotes the synthesis of other growth factors along with the synthesis of DNA and the proliferation of tendon cells.^[42] The three isoforms of TGF-β (TGF-β1, TGF-β2, TGF-β3) are known to play a role in wound healing and scar formation.^[44] VEGF is well known to promote angiogenesis and to induce endothelial cell proliferation and migration, and VEGF mRNA has been shown to be expressed at the site of tendon injuries along with collagen I mRNA.^[45] Bone morphogenetic proteins (BMPs) are a subgroup of TGF-β superfamily that can induce bone and cartilage formation as well as tissue differentiation, and BMP-12 specifically has been shown to influence formation and differentiation of tendon tissue and to promote fibrogenesis.

Culinary uses

Tendon (in particular, beef tendon) is used as a food in some Asian cuisines (often served at yum cha or dim sum restaurants). One popular dish is suan bao niu jin, in which the tendon is marinated in garlic. It is also sometimes found in the Vietnamese noodle dish phở.