Connective tissue


Connective tissue


Structural composition

Together with muscle, nerve and epithelium, connective tissue is one of the basic components in the human body. It binds structures together, helps in mechanical and chemical protection and also plays a principal role in reparative processes.

Connective tissues are defined as those composed predominantly of the extracellular matrix and connective tissue cells. The matrix is made up of fibrous proteins and a relatively amorphous ground substance. Many of the special properties of connective tissues are determined by the composition of the matrix, and their classification is also largely based on its characteristics.

Connective tissue cells

Cells of general connective tissues can be separated into the resident cell population (mainly fibroblasts) and a population of migrant cells with various defensive functions (macrophages, lymphocytes, mast cells, neutrophils and eosinophils), which may change in number and moderate their activities according to demand.

Fibroblasts, the majority of cells in ordinary connective tissue, arise from the relevant undifferentiated mesenchymal stem cells1 and are involved in the production of fibrous elements and non-fibrous ground substance (Fig. 3.1). During wound repair they are particularly active and migrate along strands of fibrin by amoeboid movements to distribute themselves through the healing area to start repair. Fibroblast activity is influenced by various factors such as the partial pressure of oxygen, levels of steroid hormones, nutrition and the mechanical stress present in the tissue.2

The other cell types are migrant cells and only occasionally present, such as: macrophages, lymphocytes, mast cells, and granulocutes (Table 3.1).3,4

Extracellular matrix (ECM)

The extracellular matrix is composed of insoluble protein fibres, the fibrillar matrix and a mixture of macromolecules, the interfibrillar matrix. The latter consists of adhesive glycoproteins and soluble complexes composed of carbohydrate polymers linked to protein molecules (proteoglycans and glycosaminoglycans), which bind water. The extracellular matrix distributes the mechanical stresses on tissues and also provides the structural environment of the cells embedded in it, forming a framework to which they adhere and on which they can move.5

Non-fibrous ground substance

The interfibrillar ground substance is composed of proteoglycans (a family of macromolecules) which bind a high proportion of water (60–70%) and glycoproteins. The latter have a complex shape and are soluble polysaccharide molecules (glycosaminoglycans) bound to a central protein core. In cartilage, the proteoglycans are in turn bound to hyaluronan (a long chain of non-sulphated disaccharides) to form a proteoglycan aggregate – a bottlebrush three-dimensional structure (Fig. 3.2).6 Glycoprotein secures the link between proteoglycan and hyaluronan and also binds the components of ground substance and cells.

The three-dimensional structure of the proteoglycan aggregates and the amount of water bound gives ground substance its high viscosity. A semi-fluid viscous gel is formed within which fibres and fibroblasts are embedded, so facilitating normal sliding movements between connective tissue fibres. In structures subject to high compression forces (e.g. articular cartilage), there is a large amount of proteoglycans but the content is relatively small in tissues such as tendons and ligaments exposed to tension forces.

Fibrous elements

The fibrous elements are collagen and elastin – both insoluble macromolecular proteins. Collagen is the main structural protein of the body with an organization and type that varies from tissue to tissue. Collagen fibres are commonest in ordinary connective tissue such as fascia, ligament and tendon. The fibrillar forms have great tensile strength but are relatively inelastic and inextensible. By contrast elastin can be extended to 150% of its original length before it ruptures. Elastin fibres return a tissue to its relaxed state after stretch or other considerable deformation. They lose elasticity with age when they tend to calcify. Box 3.1 outlines the components of connective tissue.

The basic molecule of collagen is procollagen, synthesized in the fibroblast, illustrated in Figure 3.3, steps 1–4. It is formed of three polypeptide chains (α-chains). Each chain is characterized by repeating sequences of three amino acids – glycine, proline and lysine joined together in a triple helix. The helical molecules are secreted into the extracellular space where they slowly polymerize and crosslink (Fig. 3.4). They overlap each other by a quarter of their length, lie parallel in rows and are collected into large insoluble fibrils. The fibrils unite to form fibres, finally making up a bundle. An aggregate of bundles makes up a whole structure such as a ligament or a tendon. The individual bundles are in coils, which increases their structural stability and resilience, and permits a small physiological deformation before placing the tissue under stress, and in consequence permits a more supple transfer of tractive power in the structure itself and at points of insertion (Fig. 3.5). The process of collagen synthesis is stimulated by some hormones (thyroxine, growth hormone and testosterone), although corticosteroids reduce activity.

Connective tissue collagen can be classified into different types of which at least 14 are now genetically characterized and the others are being investigated. In the context of this book the most important are:

In relation to the degree of orientation of fibrous tissue elements, ordinary connective tissues can also be classified into regular and irregular types.


Dense connective tissues, for example, ligaments, tendons and fascia, have a rich supply of afferent nerve endings. The various sensory receptors transmit information to the central nervous system about changes in length and tension which allows constant monitoring of the position and movement of a joint as well as of injurious conditions that threaten these structures.

Structural and physiological studies8,9 have shown the presence of at least four types of receptor. Three of these have encapsulated endings but the fourth consists of free unencapsulated endings:

• Type 1 (Ruffini endings) are present in the superficial layers of a fibrous joint capsule. They respond to stretch and pressure within the capsule and are slow adapting with a low threshold. They signal joint position and movement.

• Type 2 are particularly located in the deep layers of the fibrous capsule. They respond to rapid movement, pressure change and vibration but adapt quickly. They have a low threshold and are inactive when the joint is at rest.

• Type 3 are found in ligaments. They transmit information on ligamentous tension so as to prevent excessive stress. Their threshold is relatively high and they adapt slowly. They are not active at rest.

• Type 4 are free unencapsulated nociceptor terminals which ramify within the fibrous capsule, around adjacent fat pads and blood vessels. They are thought to sense excessive joint movements and also to signal pain. They have a high threshold and are slow adapting. Synovial membrane is relatively insensitive to pain because of the absence of these nerve endings.

All these receptors influence muscle tone via spinal reflex arcs which are formed by the same nerves that supply the muscles which act on the joint. Parts of the joint capsule supplied by a given nerve correspond with the antagonist muscles. Tension on this part of the capsule produces reflex contraction of these muscles to prevent further overstretching of the capsule. In consequence all receptors have an important function in stabilization and protection of the joint. After rupture of a capsule, ligament perception is considerably disturbed because of the disruption of the transmission of afferent information. For example in a sprained ankle there is loss of control of locomotion. Even months after repair of ligamentous and capsular tissues has taken place, perception may still be distorted.

Structures containing connective tissue

Synovial joints (Fig. 3.7)

In synovial articulations, the bones involved are linked by a fibrous capsule, usually containing intrinsic ligamentous thickenings, and often also internal or external accessory ligaments. The articulating bony surfaces are generally not in direct continuity but are covered by hyaline articular cartilage of varying thickness and precise topology. Smooth movement of the opposing articular surfaces is aided by a viscous synovial fluid, which acts as a lubricant, and whose production requires the presence of a synovial membrane which is one of the defining characteristics of the joint type.

Fibrous capsule and ligaments

In synovial articulations the bones are linked by a fibrous capsule of parallel and interlacing connective tissue fibres – a cuff that encloses the joint cavity. With some exceptions, each end is attached in a continuous line around the articular ends of the bones concerned. Within this the capsule is lined by synovial membrane. A fibrous capsule usually exhibits local thickenings of parallel bundles of collagen fibres, called capsular (intrinsic) ligaments, that are named by their attachments. Some capsules are reinforced by tendons of nearby muscles or expansions from them. Accessory ligaments are separate from capsules and may be extracapsular or intracapsular in position.

All ligaments are slightly elastic: collagen comprises about 70–80% of the dry weight, elastin 3–5%. They are taut at the normal limit of a particular movement but do not resist normal actions, since they are designed to check excessive or abnormal movements. Further they are also protected from excessive tension by reflex contraction of appropriate muscles.

The mechanical response of a ligament to a load can be represented on a load–deformation curve (Fig. 3.8). In the first part of such a curve (its foot) the ground substance is almost completely responsible for absorbing the stress and displaces the fibres in the direction of the stress. When the load is increased, ligamentous tissue responds slowly and maximum resistance to distraction is only possible if there is enough time for realignment of the collagen bundle. The linear part of the curve shows the slow elastic stretching of the collagen. During this stage, recovery of the original shape of the tissue occurs when the deforming load is removed. This slow rate of deformation is known as ‘creep deformation’. Even in this linear part of the curve, breaking of intermolecular crosslinks begins. For this reason it is assumed that, in physiological circumstances, the load on ligaments is kept within that shown in the foot of the curve, where collagen is not yet under undue strain and the role of ground substance is maximal.10 The composition and the amount of gel ground substance are therefore important in load bearing. On reaching the yield point, a non-elastic or plastic deformation occurs and the ligament progressively ruptures. Some investigators have found that in bone–ligament–bone preparations, separation occurs at the point of insertion.11

In normal circumstances, mechanical stress induces early firing of mechanoreceptors in capsuloligamentous tissues. This causes a well-balanced reflex action of all musculotendinous units acting across the joint to avoid inert tissue becoming overloaded and damaged. If this muscular defence fails, strain falls on the ligament which is unable to stabilize the joint and so ruptures.

Synovial membrane and fluid

The synovial membrane lines the non-articular parts of synovial joints such as the fibrous capsule and the intra-articular ligaments and tendons within the margins of articular cartilage. The internal surface of the membrane has a few small synovial villi which increase in size and number with age. It also has flexible folds, fringes and fat pads. These accommodate to movement so as to occupy potential spaces and may promote the distribution of synovial fluid over the joint surfaces (Fig. 3.9).

Structurally the membrane consists of a cellular intima which is one to four cells deep that rests upon a loose connective tissue subintima and contains the vascular and lymphatic network which has an important function in the supply and removal of fluid. On ultrastructural examination, two cell types (A and B) are apparent. These are closely involved not only with the production of synovial fluid12 but also in the absorption and removal of debris from the joint cavity. The A cells especially have marked phagocytic potential.13 Some synovial cells can also stimulate the immune response by presenting antigens to lymphocytes if foreign material threatens the joint cavity.14

Synovial fluid is a clear, viscid (glairy) substance formed as a dialysate containing some protein. It occurs not only in synovial joints but also in bursae and tendon sheaths. Secretion and absorption are functions of the cells of the intima and of the vascular and lymphatic plexus in the subintima. The synovial initima cells also secrete hyaluronan molecules into the fluid and much evidence has accumulated to show that the viscoelastic and plastic properties of the fluid are largely determined by its hyaluronan content. Chains of hyaluronan bind proteins; these complexes are negatively charged and in turn bind water. The biophysical process is similar to that of the proteoglycans in the matrix of connective tissue and a thick viscous liquid which resembles egg white is formed. Its viscosity varies widely according to circumstances. With a low rate of shear, water is driven out of the hyaluronan–protein complexes and the fluid becomes highly viscous; increase in shear lowers viscosity and the fluid tends to behave more like water. In contrast to viscosity, elasticity increases with higher rates of shear. Both viscosity and elasticity decrease with increasing pH and temperature.15


Articular cartilage is essentially a specialized type of connective tissue.


Although the same three tissue elements – cells, ground substance and fibres – are present, their properties differ from ordinary connective tissue and determine its biochemical and biomechanical behaviour.

Cartilage cells or chondrocytes occupy small spaces in the matrix

They are involved in the production and turnover both of type II collagen and ground substance, processes stimulated by variation in load.

Chondrocytes change with increasing depth from the surface1,16 (Fig. 3.10). In the superficial stratum (zone 1), cells are small, flattened and disposed parallel to the surface. They are surrounded by fine tangentially arranged collagen fibres. A thin superficial layer of this zone has been shown to be cell-free. Cell metabolism in this part is low, which is consistent with the absence of wear and tear in normal healthy tissue. The cells of the intermediate stratum (zone 2) are larger and more rounded and those in the radiate stratum (zone 3) are large, rounded and arranged in columns perpendicular to the surface. In these deeper zones, cells are screened from the coarse fibres by a coat of pericellular matrix bordered by a network of fine collagen fibres. In this way, cells are protected against the stresses generated by load conditions.

The collagen fibres vary in structure and position with increasing depth from the surface (Fig. 3.11a)

In the superficial or tangential stratum, a dense network of fine fibrils is arranged tangential to the articular surface to resist tensile forces that result from compression on certain points of the articulating surface during normal activities. Analysis has also shown the existence of certain ‘tension trajectories’ in accordance with the more or less fixed patterns of tensile forces that take place during movements. These preferential directions have been elaborated during growth as a result of forces acting on the joint. Near the border of the joint, the fibrils blend with the periosteum and joint capsule.

In the intermediate stratum, collagen fibres are coarser and more spread out to pursue an oblique course that forms a three-dimensional network. In non-load conditions the fibres are orientated at random but when load is applied they are immediately stretched in a direction perpendicular to that of the applied force (Fig. 3.11c). When the load is removed the fibres return to their original oblique position. This behaviour partly explains the resilience and elasticity of cartilagenous tissue.

In the radiate stratum, collagen fibres are arranged radially and correspond with the fibrous architecture of the subchondral and osseous lamina. The result is a series of arcades which extend from the deepest zone towards the surface.

Characteristics of cartilage

These include low metabolic and turnover rates, rigidity, high tensile strength, and resistance to compressing and shearing forces while some resilience and elasticity is retained. The proportion of collagen in matrix increases with age.

On the basis of variations in the matrix and the number of fibres present, cartilage in the locomotor system is divided into two types: hyaline and fibroelastic.

Most cartilage is hyaline: exceptions are the surfaces of the sternoclavicular and acromioclavicular joints and of the temporomandibular joints, all of which are of dense fibrous tissue. Although the light microscope appearance of hyaline cartilage is translucent, electron microscopy shows a system of fine fibrils and fibres. The water content is up to 80%. Strength, resistance and elasticity are the results of the proteoglycans in the ground substance together with the specific properties of the collagen fibres. Negatively charged proteoglycans bind a large number of water molecules and causes the cartilage to swell. Swelling is limited, however, by the increasing tension of the collagen fibre networks in the superficial and deep layers which are closely interconnected. The result is an elastic buffer that, together with the elasticity of the periarticular structures, dissipates the effect of acute compressive forces. It also provides the articular mechanism with some degree of flexibility, particularly at the extremes of range. If the load is applied over a very short time, cartilage deforms in an ‘elastic’ way almost without disturbance of its water content. However, if compression is maintained for hours, water is displaced to surrounding regions that are under less or no compression and the compressed cartilage undergoes ‘plastic’ deformation. In engineering terms, this slow predictable rate of deformation is known as ‘creep’ and is greatest within the first hour of compression. When the deforming load is removed, recovery of the original shape of the tissue occurs at a rate that is specific for each form of cartilage.

Water transport during dynamic load conditions probably also has significance in the transport of nutrients and metabolites to and from the chondrocytes.

Articular cartilage lacks a nerve supply and is also completely avascular. Nutrition is derived from three sources: synovial fluid, vessels of the synovial membrane and vessels in the underlying marrow cavity which penetrate the deepest part of the cartilage over a short distance. This last source is available only during growth because, after growth is completed, the matrix at the deepest part of the cartilage becomes impregnated with hydroxyapatite crystals which form a zone of calcified cartilage impenetrable by blood or lymph vessels (Fig. 3.10, zone 4).

Articular discs and menisci consist of fibroelastic cartilage and are predominantly fibrous. They separate certain articular surfaces that have a low degree of congruity (e.g. the knee and the radiocarpal joint). Their functional roles are to improve the fit between joint surfaces, distribute weight over a larger surface, absorb impacts and spread lubricant.

With age, articular cartilage becomes firmer but also thinner and more brittle. The number of cells decreases. In normal healthy joints these changes are extremely slow. Erosion particularly occurs when joints become dehydrated or when synovial fluid viscosity permanently alters. Replacement of an eroded surface by proliferation of deeper layers has not been demonstrated. Deposits of calcification and surface ruptures are signs of degeneration. Except in young children, regeneration cannot be expected. However, there is evidence that a defect can be filled with newly synthesized collagen.


Peripheral nerves also possess supporting connective tissue. Within the nerve trunk the efferent and afferent axons are grouped together in a number of fasciculi (Fig. 3.12). The bundled axons in the fasciculi lie roughly parallel, surrounded by loose delicate collagen fibres running longitudinally along them. Both structures show a wavy appearance which disappears when gentle traction is applied.

Each fasciculus is surrounded by a fibrous perineurium, a regular structure of flattened laminae of fibroblasts alternating with fine collagen, running in various directions. These fibroblasts are connected together and form a diffusion barrier against noxious chemical products, bacteria and viruses. In this way, the enclosed axons are to some extent isolated from the external environment. Inside this perineural tube a protein-poor liquid flows centrifugally. This axoplasma is cerebrospinal fluid, which is re-assimilated into the blood circulation at the end of the peripheral nerve. In this respect, the spinal canal and the endoneural spaces are continuous (Fig. 3.13).

The epineurium encases the nerve trunk as a collagen coat with little regular organization. Connective tissue surrounding nerves serves as an important mechanical protection to maintain the conductile properties of the nerve.17 During movement, nerves are potentially exposed to tensile forces that can be avoided by mobility in relation to surrounding structures. Here, the wavy form of both axons and surrounding collagen fibres is an important consideration: this ‘waviness’ of the axons is paramount, allowing them to remain relaxed even when the collagen fibres are stretched. Thus, within the normal range of movement, the axons will be protected by the tensile force of the collagen component. When there is a severe sprain or fracture perhaps with dislocation, the range of plastic deformation of collagen can be exceeded and ultimately rupture of collagen fibres and neurotmesis results.

The tolerance of nerves to tension is much greater than it is to compression. However, the mobility of nerves allows them to move laterally, so avoiding a compressive force. When space is inadequate for such movement or the nerve is firmly anchored – which is the case in cervical nerve roots – the epineurium may absorb a certain amount of pressure but sooner or later the blood supply within the nerve is affected by increasing compression. Further compression may result in interference with the conductile properties of the nerve. In such circumstances, the Schwann cells and subsequently the myelinated sheath are damaged. Although the axons remain intact, action potentials become blocked, leading to loss of sensory and motor function (see Ch. 2).


Muscular tissue consists of specialized cells or myofibrils embedded in a network of fine connective tissue that transmits the pull of the muscle cells during contraction to the adjacent parts of the skeleton. For this purpose, connections exist between the muscle cells and the finest collagen fibres of the connective tissue network.

The muscle cell or myofibril consists of sarcomeres or myofilaments – the basic contractile units of a muscle – arranged in parallel (Fig. 3.14). In each sarcomere two types of filament are distinguishable, chemically characterized as actin and myosin. The actin filaments are each attached at one end to the inner side of the cell membrane forming the so-called Z-line. At the other end they are free and interdigitate with the central myosin filaments. During muscle contraction, the actin filaments slide in relation to the myosin towards the centre of the sarcomere which brings the attachments at the Z-lines closer together with shortening of the whole contractile unit (Fig. 3.15).

Exercises increase the number of myofibrils (hypertrophy). During periods of immobilization cell volume decreases (atrophy).

Groups of sarcomeres are arranged in parallel to form muscle fibres. These in turn are arranged in bundles or fasciculi of various sizes within the muscle.

The network of the fine collagen fibrils within a fasciculus is known as the endomysium and fills the spaces between muscle fibres. In this way, each muscle fibre is surrounded by a thin sheet of connective tissue that provides the pathway for the capillaries, which lie mainly parallel with the muscle fibres and facilitate the exchange of metabolites between muscle fibres and the capillary bed.

The perimysium is the stronger connective tissue that surrounds each fasciculus. It consists of parallel bundles of collagen that are partly arranged in a circular manner around the muscle fibres as well. These bundles are in close connection with the collagen of the endomysium.

Finally, the whole muscle is surrounded by the stout epimysium, which is continuous with the septa of the outer perimysium and blends with the connective tissue that forms the tendon, fascia or aponeurosis (Fig. 3.16).

At the myotendinal junctions the connective tissue of the endo-, peri- and epimysium becomes very fibrous and thickens, whereas the muscle fibres taper or flatten and show terminal expansions. The connection is so strong that rupture seldom occurs at the myotendinal junction.


These structures are largely composed of collagen fibres with a low amount of proteoglycans. On a dry weight basis, collagen represents 60–80% of the total weight of tendon.18

Tendons, which consist of fascicles of collagen fibres running parallel and partly interweaving, are highly resistant to extension. Although elastin is absent and their collagen is difficult to stretch, tendons are nevertheless slightly stretchable. The wavy form of the fibres, together with the interweaving pattern of the fascicles, results in a slight elongation at the moment of muscle contraction which damps any abrupt pull on the insertion.

At the surface, the epitendineum or tendon sheath consists of irregularly arranged condensed collagen as well as elastin fibres. It is continuous with the loosely arranged connective tissue that permeates the tendon between its fascicles and provides a route of ingress and egress for vessels and nerves. At the insertion, the collagen bundles of the tendon permeate into bone. It has been shown19,20,21 that the insertion of the connective tissue of ligaments into bone involves a transition from non-mineralized through mineralized fibrocartilage to bone.

In young growing tendons, fibril diameter and tensile strength can be increased by exercise. In adults, however, the effect is minimal although regularly applied tension is necessary to maintain structural integrity. Immobilization has demonstrated loss of tensile strength (see p. 46).

The nerve supply to tendons appears to be entirely afferent. Vascularization of tendons is low – the reason they appear white. Small arterioles ramify in the interfascicular intervals and are accompanied by veins and lymphatic vessels. Passage of vessels through the teno-osseous junction seems not to occur.

Where tendons pass under ligaments or through osteofibrous tunnels, synovial sheaths are formed which separate the tendon completely from its surroundings. These synovial sheaths have two concentric layers, separated by a thin film of synovial fluid and form a closed double-walled cylinder (Fig. 3.17). The fluid acts as a lubricant and ensures easy mobility of the tendon. The internal (visceral) layer is attached to the tendon and the external (parietal) layer to neighbouring structures such as periosteum and retinaculum.

Trauma to soft connective tissue


Soft tissue injury involves damage to the structural elements of connective tissue with rupture of arterioles and venules. A general inflammatory reaction follows (Table 3.2), one role of which is defensive in that it prompts the subject to restrict activities while recovery takes place.

Regardless of the site of injury and the degree of damage, healing comprises three main phases: inflammation, proliferation (granulation) and remodelling. These events do not occur separately but form a continuum of cell, matrix and vascular changes that begin with the release of inflammatory mediators and end with the remodelling of the repaired tissue. Connective tissue regenerates largely as a consequence of the action of inflammatory cells, vascular and lymphatic endothelial cells and of fibroblasts.22,23

Jun 5, 2016 | Posted by in ORTHOPEDIC | Comments Off on Connective tissue
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