Blood vessels (blood vessel), both large and small, course through connective tissue, which is therefore closely associated with the nourishment of tissues and organs throughout the body. All nutrient materials and waste products exchanged between the organs and the blood must traverse perivascular spaces occupied by connective tissue. One of the important functions of the connective-tissue cells is to maintain conditions in the extracellular spaces that favour this exchange.

All forms of connective tissue are composed of (1) extracellular fibres, (2) an amorphous matrix called ground substance, and (3) stationary and migrating cells. The proportions of these components vary from one part of the body to another depending on the local structural requirements. In some areas, the connective tissue is loosely organized and highly cellular; in others, its fibrous components predominate; and in still others, the ground substance may be its most conspicuous feature. The anatomical classification of the various types of connective tissue is based largely upon the relative abundance and arrangement of these components.

Collagen is of commercial as well as medical interest, because leather is the dense collagen of the dermis of animal skins preserved and toughened by the process called tanning. Fresh collagen dissolves in hot water, and the product is gelatin. Under appropriate conditions, collagen can be brought into solution without chemical change. The fundamental units in such solutions are slender tropocollagen molecules about 14 Å wide and 2800 Å long. Collagen appears to be secreted in this form by the connective-tissue cells called fibrocytes, and the tropocollagen molecules assemble extracellularly to form striated collagen fibrils. By an alteration of the physicochemical conditions, tropocollagen in solution can be induced to polymerize with the formation of cross-striated fibrils identical to native collagen, thus simulating in the test tube the process of assembly that is believed to take place during fibrogenesis in the living organism. Analysis of the structure of collagen by X-ray diffraction has shown that the tropocollagen molecule consists of three side-by-side polypeptide chains—linear combinations of a number of amino acids (amino acid), which are subunits of proteins—each in the form of a left-handed helix. These three left-handed helices are further twisted around one another to form a major right-handed helix. Upon chemical analysis, the amino acid composition of collagen is found to be unique in its extremely high proline content (22 percent) and in the fact that one-third of the amino acid residues are glycine. It is the only naturally occurring protein known to contain hydroxyproline and hydroxylysine. Two of the three polypeptide chains comprising the tropocollagen molecule are similar in amino acid composition, while the third is distinctly different. In the tissues, the collagen fibrils are believed to be held together by a polysaccharide component that has not been fully characterized.

Reticular fibres (reticular fibre) are distinguished by their tendency to form fine-meshed networks around cells and cell groups and by virtue of their property of staining black, because of adsorption of metallic silver, when they are treated with alkaline solutions of reducible silver salts. They were formerly believed to be composed of a distinct protein, reticulin, but electron microscopy has revealed that reticular fibres are small fascicles of typical collagen fibrils interwoven to form a network. It is now apparent that reticular fibres are simply a form of collagen, and their distinctive staining depends upon the mode of association of the fibrils and possibly upon subtle differences in their relation to the polysaccharide material that binds them together.

The amorphous ground substance of connective tissue is a transparent material with the properties of a viscous solution or a highly hydrated thin gel. Its principal constituents are large carbohydrate molecules or complexes of protein and carbohydrate, called glycosaminoglycans (formerly known as mucopolysaccharides). One of these carbohydrates is hyaluronic acid, composed of glucuronic acid and an amino sugar, N-acetyl glucosamine. Other carbohydrates of the connective tissue are chondroitin-4-sulfate (chondroitin sulfate A) and chondroitin-6-sulfate (chondroitin sulfate C). The sugars of the sulfates are galactosamine and glucuronate. Multiple chains of chondroitin sulfate seem to be bound to protein. These substances in solution are viscous. All substances passing to and from cells must pass through the ground substance. Variations in its composition and viscosity may therefore have an important influence on the exchange of materials between tissue cells and the blood. Its physical consistency also constitutes a barrier to the spread of particulates introduced into the tissues. It is interesting, in this relation, that some bacteria produce an enzyme, hyaluronidase, which breaks up hyaluronic acid into subunits and alters the viscosity of ground substance. The ability of these bacteria to produce this enzyme is probably responsible for their invasiveness in the tissues.

The cells of connective tissue include two types that are relatively stationary—fibrocytes and adipose cells—and several types of motile migrating cells—mast cells, macrophages, monocytes, lymphocytes, plasma cells, and eosinophils.

All the cells of connective tissue develop during embryonic life from the mesenchyme, a network of primitive stellate cells that have the potential for differentiating along several different lines depending upon local conditions. In addition to the specialized cell types of adult connective tissue described below, it is believed that small numbers of mesenchymal cells (stem cells (stem cell)) persist into postnatal life in the walls of small blood vessels (blood vessel) and elsewhere and that these retain the capacity to differentiate into fibrocytes, adipose cells, macrophages, or a multitude of other cell types as the need arises.

The ubiquitous fibrocytes are the principal cells of connective tissue, occurring as long spindle-shaped cells stretched along bundles of collagen fibrils. Their function is to secrete tropocollagen and constituents of the ground substance and to maintain these extracellular tissue components. When organs are injured, the fibrocytes of the stroma are stimulated to proliferate and become fibroblasts (fibroblast); fibroblasts migrate into the defect and deposit an abundance of new collagen, which forms a fibrous scar.

Adipose (adipose cell), or fat, cells are connective-tissue cells that are specialized for the synthesis and storage of reserve nutrients. They receive glucose and fatty acids from the blood and convert them to lipid, which accumulates in the body of the cell as a large oil droplet. This distends the cell and imposes upon it a spherical form. The nucleus is displaced to the periphery, and other metabolically active constituents of the cell are confined to a thin rim of cytoplasm around the large central droplet of lipid. Adipose cells may occur in small numbers anywhere in connective tissue, but they tend to develop preferentially along the course of small blood vessels. Where they accumulate in such large numbers that they become the predominant cellular element, they constitute the fat or adipose tissue of the body.

Eosinophils are a type of white blood cell, or leukocyte. Some of these migrate through the walls of capillaries and take up residence in the connective tissues. They have polymorphous nuclei and, in the cell substance outside the nuclei, coarse granules that stain with eosin and other acid dyes. In electron micrographs, the granules contain conspicuous crystals. The granules have been isolated and shown to contain a variety of hydrolytic enzymes. Eosinophils are normally widespread in connective tissues of the body, but they are especially abundant in persons suffering from allergic diseases. The cells are believed to phagocytose and break down antigen-antibody complexes.

Another of the leukocytes that enter the connective tissues from the blood is the monocyte, a mononuclear cell larger than the lymphocyte and with different potentialities. These migratory cells can divide and, when appropriately stimulated, can transform into highly phagocytic macrophages. The reaction of the blood and connective-tissue cells to injury is called inflammation and is usually accompanied by local heat, swelling, redness, and pain. Under these conditions, the neutrophilic leukocytes (white blood cells called neutrophilic because of their neutral staining characteristics with certain dyes), which are not normally present in connective tissue in significant numbers, may migrate through the capillary walls in astronomical numbers and join the macrophages in the work of ingesting and destroying bacteria. Voraciously phagocytic, the neutrophils have a short life span; having accomplished their mission, they die in great numbers. pus, which may accumulate at sites of acute inflammation, is composed largely of dead and dying neutrophilic leukocytes.

The description presented thus far applies to the widely distributed loose areolar connective tissue, which is relatively unspecialized and can therefore be considered prototypic. In the more specialized forms of connective tissues, one component or another may predominate over all the others, depending upon the local structural or metabolic requirements.

Adipose tissue, for example, is a variant of loose areolar tissue in which large numbers of adipose cells make up the bulk of the tissue.

The synovial (synovial tissue) membrane, which lines joint capsules, is composed of loose vascular connective tissue but has cells specialized for secretion of the viscous synovial fluid, which is rich in hyaluronic acid, and for phagocytic functions. This fluid serves as a lubricant and nutrient for the avascular joint surfaces. Similar tissue forms sheaths around tendons where they pass over bony prominences.

Hyaline cartilage, the most widely distributed form, has a pearl-gray semitranslucent matrix containing randomly oriented collagen fibrils but relatively little elastin. It is normally found on surfaces of joints and in the cartilage making up the fetal skeleton. In elastic cartilage, on the other hand, the matrix has a pale yellow appearance owing to the abundance of elastic fibres embedded in its substance. This variant of cartilage is more flexible than hyaline cartilage and is found principally in the external ear and in the larynx and epiglottis. The third type, called fibrocartilage, has a large proportion of dense collagen bundles oriented parallel. Its cells occupy lacunae that are often arranged in rows between the coarse bundles of collagen. It is found in intervertebral disks, at sites of attachment of tendons to bone, and in the articular disks of certain joints. Any cartilage type may have foci of calcification.