Granulation Tissue

Granulation tissue, granulations (from Latin granum-grain), young connective tissue that forms during the healing of defects in various tissues and organs, during the organization of diverse dead materials (thrombi, infarcts, inflammatory exudates), and during the encapsulation of foreign bodies. From this it follows that the development of granulation tissue pertains to regenerative processes and that it can occur only where derivatives of connective tissue are present. The term granulation tissue ('granular tissue') was originally introduced in connection with the fact that for wound granulations developing in areas of defects in the skin and mucous membranes and possessing a free surface, the granular appearance of this surface is extremely characteristic (see below); however, in later times this term came to be applied to any young connective tissue formed under the above-mentioned conditions, regardless of whether it forms on the surface or in depth, and consequently whether it possesses a free granular surface or not. Depending on the location and duration of existence, granulation tissue has a different appearance and structure. On the skin and mucous membranes, normal granulation tissue has the appearance of meat-red, juicy, fine-granular tissue, often covered with a cloudy, gray-greenish coating or exudate. Touching granulation tissue is painless due to the absence of nerves in it, but it easily causes bleeding due to its delicacy and richness in blood vessels. Within the thickness of tissues and organs, granulation tissue is recognized by its plethora and juiciness. In later periods, granulation tissue becomes paler, denser, the granulation disappears, the volume of granulation tissue decreases, and finally only a whitish dense scar is visible in its place. All granulation tissue ends by transforming into a scar. The very fact of granulation in an area with loss of substance or in an area of tissue separation (e.g., an incision) is designated as healing by secondary intention (secunda intentio), in contrast to primary intention (prima intentio) of a wound, when the period of granulation, if it can be noticed at all, is only microscopic (see Wounds, injuries). Upon histological examination, granulation tissue reveals hyperplastic processes in the connective tissue elements and blood vessels. In the early period of development, the basis of granulation tissue consists of newly formed vessels of capillary type, characterized by the juiciness of the endothelial and adventitial elements; in them, division figures are visible in places with a disorderly accumulation of cells; one can also observe pictures of ongoing formation of blood vessels. In wound granulation tissue, the vessels predominantly run in one direction, from depth to surface; reaching the granulating surface, the vessel gives several branches, then a common collector is formed, sharply turning back into the depth; the very place of turning exactly coincides with the grains visible on the surface of granulation tissue. Between these young blood vessels there is a protein fluid in which young connective tissue cells of various sizes and shapes are located, which are descendants of local connective tissue cells; they are mainly located around the vessels. Among these cells, one can distinguish: 1) small round cells, morphologically similar to blood lymphocytes; 2) large lymphoid cells with a light nucleus and a clearly noticeable protoplasmic layer in which grains, vacuoles, and cellular detritus are found, indicating their phagocytic activity ('phagocytes - macrophages' of Metchnikoff, 'large leukocytoid wandering cells' of Marchand, 'polyblasts' of Maximow); 3) plasma cells; 4) fibroblasts; 5) multinucleated giant cells. [On the origin (histogenesis) of these cellular forms and on their various designations - see Wandering cells.] Among the above-mentioned cells in these early periods of development of granulation tissue, there are many polymorphonuclear leukocytes, as well as some amount of erythrocytes. Later in granulation tissue, the protein fluid is displaced by multiplying cells, while the number of leukocytes decreases; small lymphoid cells also disappear, and in granulation tissue, larger plate-like elements with protoplasmic processes begin to predominate, called 'epigelioid' cells. Subsequently, these cells acquire an elongated shape and are arranged side by side, forming bundles and exhibiting all the properties of fibroblasts. In later periods, the number of cells and vessels in granulation tissue decreases, permanent elements of connective tissue appear in the form of collagen fibers and normally developed vessels; however, along the course of the latter, after a considerable time, one can still see sheaths of lymphocytes and plasma cells. With the increase in the amount of collagen fibers and the decrease in cells, granulation tissue gradually transforms into mature fibrous connective tissue. In the development of permanent elements of connective tissue, all cells of granulation tissue participate, with the possible exception of leukocytes; along with fibroblasts, in this regard, lymphoid forms designated by Maximow as polyblasts have particularly important significance. Granulation tissue does not contain elastic fibers; only in some cases during the period of fibrous transformation of granulation tissue, elastic fibers can also be formed. In wound granulation tissue possessing a free surface, there is an exudate consisting of serous exudate with an admixture of leukocytes, bacteria; sometimes granulations are covered with a fibrinous coating, as if drying up, which is often a poor prognostic sign in terms of, for example, the development of general complications (sepsis), a new exacerbation of the local inflammatory process, etc. With favorable course, the exudate gradually thickens and becomes more scanty. The formation of granulation tissue is closely connected with inflammation. This is clear not only from the fact that in the development of granulation tissue, manifestations of the inflammatory process always participate significantly (exudation of protein fluid from vessels, emigration of leukocytes), but mainly because the very formation of granulation tissue can essentially be considered as an inflammatory reaction (to tissue damage, to the presence of dead substrate or foreign body in the tissue). In general, drawing a precise line between inflammation and granulation is not always possible, and the very question of granulation tissue is sometimes even considered in parallel with inflammation, designating the latter in appropriate cases as granulation, or reparative inflammation. The basis for this is that inflammation from the very beginning (and necessarily in its height) proceeds with more or less expressed proliferative phenomena on the part of connective tissue elements. Despite this, one must fundamentally distinguish the concept of inflammatory tissue neoplasm and so-called granuloma from the concept of granulation tissue, remembering that every inflammation is accompanied to one degree or another by inflammatory tissue neoplasm, but it does not necessarily lead to the development of granulation tissue; furthermore, granulation tissue is essentially a restorative tissue, which cannot be said about inflammatory neoplasms and granulomas, for example the tuberculous tubercle. Finally, in inflammatory tissue neoplasms, there is often not neoplasm of vessels, but rather destruction of former ones; in granulation tissue, on the contrary, there is an abundance of new vessels (see below). The rate of development and volume of granulation tissue vary depending on the nature and conditions of inflammation, the properties of the organ, and the peculiarities of the carrier of the process. In the presence of constant irritations, granulation tissue can develop excessively, acquiring the appearance of fungoid papillary proliferations (e.g., 'flesh' on the gums in caries of teeth and paradentoses). Under the same conditions, but in the depth of tissues, granulation tissue can, by its size, and later by its density, simulate a tumor (see Granulomas, granulomatosis). With prolonged circulatory disorders (e.g., in the area of leg ulcers with varicose veins), granulations proceed extremely sluggishly; they do not have a lively red color, are dry, bleed; their edges are often whitish, sclerosed; upon microscopic examination, they sometimes reveal atypical epithelial proliferations that can transform into cancer. A similar outcome is possible in old ulcers of the stomach, larynx, etc. In rare cases, granulation tissue serves as the starting material for the development of sarcomas; sometimes on the site of granulation tissue, as a permanent formation, an angioma develops. Under normal conditions, 7-8 days are sufficient for the development of granulation tissue; in young animals and children, the rate of development is significantly accelerated, reaching 4-5 days; therefore, in children, relatively fresh processes (for example in the lungs) sometimes appear far advanced. Recognition of granulation tissue is usually not difficult, but errors are still not uncommon; the latter most often concern tumors mistaken for granulation tissue, and vice versa. In doubtful cases, it is necessary to resort to biopsy. Normal granulations require rather observation than treatment. In pathological (sluggish, excessive, etc.) granulation, it is necessary to treat the underlying disease, locally apply cauterizing agents, freshen the granulating surface with blood, etc. (Pakhionov's granulations have nothing in common with granulation tissue).