Regeneration

REGENERATION, the process of forming a new organ or tissue at the site of a part of the organism removed in one way or another. Very often, regeneration is defined as the process of restoring what has been lost, i.e., the formation of an organ similar to the one removed. Such a definition, however, proceeds from a false teleological point of view. First of all, the part of the organism arising during regeneration is never completely identical to the one that previously existed; it always differs from it in one respect or another (Schaxel). Furthermore, the fact that a completely different, dissimilar part is formed instead of the removed section is well known. The corresponding phenomenon is also attributed to regeneration, although it is called atypical regeneration. However, there is no data suggesting that the processes occurring here differ in essence from other types of regeneration. Thus, it would be more correct to define regeneration in the manner indicated above. Classification of regeneration phenomena. Two main types of regenerative processes are distinguished: physiological and reparative regeneration. Physiological regeneration takes place in cases where the process occurs without the presence of any special external influence. This type of regeneration is represented by the phenomena of periodic molting in birds, mammals, and other animals, the replacement of sloughing skin epithelium in humans, and the replacement of dying cells in glands and other structures with new cells. Reparative regeneration includes cases of new formation resulting from the organism receiving some kind of injury, whether due to artificial intervention or independently of it. Below, the phenomena of reparative regeneration will be primarily discussed, as it is the most studied.

Depending on the final result of the process, reparative regeneration is divided into typical, when the formed organ is more or less similar to the one that previously existed, and atypical, when no such similarity exists. Deviations from the typical course of regeneration may consist either in the formation of a completely different organ instead of the previously existing one or in its modification. In the case where the appearance of a different organ is connected with a reversal of polarity, e.g., when a head regenerates instead of the cut-off tail end of a worm, the phenomenon is called heteromorphosis. Modification of an organ can be expressed in the presence of any additional parts, up to the doubling or tripling of the organ, or in the absence of usually characteristic structures. It should be remembered that the subdivision of regeneration into typical and atypical, based on a teleological view and oriented toward the previously existing organ, does not reflect the essence of the phenomena and is entirely conventional.

The capacity for regeneration is an extremely widespread phenomenon among both animals and plants, although individual species differ from one another both in the degree of regenerative capacity and in the course of the process itself. In general, it can be considered that the higher the organization of the organism, the lower its regenerative capacity; however, there are a number of exceptions to this rule. Thus, many related species differ very strongly from one another in their regenerative manifestations. On the other hand, a number of higher-ranking species are more capable of regeneration than lower-ranking ones. In amphibians, for example, even individual organs such as the tail and limbs can regenerate, while some worms (Nematoda) are distinguished by an almost complete absence of regeneration. As a rule, however, the greatest capacity for regeneration is found among lower animals. Single-celled organisms are characterized by a strongly expressed regenerative capacity (Fig. 1). In some species, pieces equal to one-hundredth of the animal are capable of restoring it entirely. Among multicellular organisms, coelenterates and worms are distinguished by the greatest regenerative capacity. Some hydroids restore the animal from one two-hundredth of its part. Worms (especially Annelida and Turbellaria) can form all missing parts from a few segments. A group as highly placed as tunicates does not lag far behind these species, where

regeneration of the entire animal can take place from a single section of it (e.g., the branchial basket in Clavellina). Regenerative capacity is also well expressed in some echinoderms; thus, starfish form an entire animal from a single ray (Fig. 2). Regenerative capacity is significantly narrowed in mollusks and arthropods. Here, only individual body appendages can regenerate: limbs, tentacles, etc. Among vertebrates, regenerative phenomena are best expressed in fish and amphibians. In reptiles, regeneration of the tail and tail-like appendages at the site of limbs is possible; in birds, only the beak and skin coverings regenerate from external parts. Finally, mammals, including humans, are capable of replacing only small sections of organs and skin injuries.

Regenerative capacity does not remain equally expressed throughout the life of an individual: different stages of development are each distinguished in this respect by their own characteristic features. As a rule, it can be said that the younger the animal, the higher its regenerative capacity. A tadpole, for example, can regenerate limbs at early stages of development, while it loses this ability upon entering the period of metamorphosis. The indicated general rule, however, has a number of exceptions. Cases are known where an earlier stage of development possesses a lesser regenerative capacity. Planarian larvae are distinguished by less development

of regenerative phenomena compared to adult animals (Steinmann); the same holds true for the larvae of some other animals. It could already be seen from the above that different regions of the organism differ from one another in their regenerative capacity. Weismann assumed that the capacity for regeneration depends on how much a given part is exposed to the danger of injury, with the greater the latter, the greater the regenerative capacity—a property developed as a result of natural selection. However, recent studies have shown that such a regularity cannot be established.

organs that are not usually subject to injury during the free life of an individual and are well protected nevertheless possess a high regenerative capacity (Morgan, Przibram). Ubisch connects regenerative phenomena with the differentiation of the organism; in his opinion, earlier-developing parts cease to regenerate sooner with age, or their regeneration is distinguished by less intensity. Thus, in amphibians, where organs lying more anteriorly differentiate earlier, a corresponding gradient of regeneration can be established—from front to back. Ubisch's assertions, in favor of which a number of data speak, nevertheless require further confirmation on a larger amount of material. In some species (predominantly in worms), Child and his collaborators established a similarly defined gradient of regeneration in relation to the longitudinal axis of the body, but its direction does not always go from front to back, but is connected with more complex regularities. Child believes that this gradient depends on the degree of physiological activity of different sections of the organism. Lower-organized animals possess the ability to regenerate both parts located proximally from the site of amputation and

those located distally. In higher animals, only the latter regenerate. In amphibians, for example, an organ, even when transplanted in an inverted position, regenerates the same structure as in its normal position.

Figure 1. Regeneration of the ciliate Stentor, cut into three parts. (According to Korschelt.)

Figure 2. Regeneration of the starfish Linckia multifora from a single ray. Successive stages of regeneration. (According to Korschelt.)

Figure 3. Solid line—change in the intensity of mitogenetic radiation of the regenerating tail of an axolotl. On the ordinate—arbitrary units of radiation intensity. Dashed line—changes in the active reaction of the tissues of the regenerating limb of an axolotl. On the ordinate—pH values (data of Okunev). On the abscissa—days of regeneration. (From Blacher and Bromley.) Figure 4. Regeneration of an amputated forelimb in a salamander after 1/4 (a) and 12 (b) days. a: 1—blastema cells; 2—stump of the humerus; 3—nerve; 4—epidermis; b: 1—blastema cells; 2—cartilage; 3—epidermis; 4—stump of the humerus. Figure 5. Regeneration of...

Course of the regeneration process. The regeneration process proceeds differently depending on which organism we are dealing with and which part of it is subjected to removal. As an example, we can consider the most studied object—the regeneration of an amphibian limb. In this case, the following phenomena occur. After amputation of the organ, the edges of the wound draw together due to the contraction of the severed musculature. The blood on the surface of the wound coagulates, releasing fibrin threads. The clotted blood, with the participation of damaged tissues, forms a scab on the wound surface. As a result of tissue damage and the impact of the external environment on the surface unprotected by skin, decay processes arise in the organ. The latter are revealed in a change in the acidity of the regenerate (a decrease in pH from 7.2 to 6.8, Okunev) and the appearance of mitogenetic radiation (Blyakher and Bromley). The wound surface, however, does not remain unprotected for long: already within the next few hours, a process of epithelial creeping from the edges of the wound is observed, as a result of which an epithelial film forms on the wound surface. Under this epithelial cover, further processes occur, which reduce to the destruction and restructuring of the old organ and the formation of a new one. These processes are expressed, on the one hand, in continued decay. The latter is revealed morphologically as a result of histolysis, showing a picture of tissue destruction and the arrival of numerous blood cells into the regenerate.

Decay is especially strong in the period from 5 to 10 days, starting from the moment of amputation, when it apparently reaches its greatest intensity. Physiological indicators also testify to this. Okunev found the greatest acidity on the 5th day, when pH=6.6. Simultaneously, the intensity of mitogenetic radiation increases compared to previous days (Bromley). The curves of increasing acidity and intensity of mitogenetic radiation turn out to be parallel to each other throughout the entire regeneration process. Both have two maximum peaks—on the 1st and 5th day of regeneration (Fig. 3). Along with this, already in the first week of regeneration, neoformative processes are clearly designated. They manifest themselves predominantly in the formation under the epithelial film of an outgrowth of homogeneous cells, which bears the name blastema. The development of the new organ proceeds predominantly

Figure 7. Regeneration of the am-

at the expense of blastema cells (Figs. 4-7). After a certain period of growth, differentiation of individual parts occurs in the regenerate. In this case, the more proximal parts differentiate first, and then the distal ones. In this regard, the process does not proceed the same way in all organisms. In some, it can even be reversed. The physiological features of the regenerate are certainly not the same as those of the formed organ. This is manifested, in particular, in the fact that the regenerate possesses histolytic properties. In the case where its surface comes into contact with other tissues, for example, when covering the regenerate with a skin flap, histolysis of the latter occurs (Bromley and Orekhovich). One should not think that the process of regeneration manifests itself only in the amputated, regenerating organ. It exerts its influence on the rest of the organism as well, which can manifest itself in various respects. Thus, a change can be detected in the animal's blood, the mitogenetic radiation of which deviates from normal intensity, and these fluctuations have a characteristic curve. During regeneration in hydras, the decay of organs not in immediate proximity to the regenerate has been noted, namely of germ cells, and predominantly male ones (Goetsch). The influence of regeneration also affects the growth and other properties of the organism—a phenomenon mostly described under the name of regulation.

Regenerate material. The question of the material at the expense of which the formation of the regenerate occurs must be resolved differently depending on the species of the animal and the nature of the inflicted damage. If it is a matter of damage to any one tissue, then usually the process proceeds at the expense of the proliferation of the remainder of the corresponding tissue. The matter is more complex in the case of the regeneration of an organ or the restoration of an organism from a separate section of it. In this case, however, it can be established that, in the main, at least in amphibians, regeneration proceeds at the expense of material directly adjacent to the wound surface, and not at the expense of cells arriving from other areas of the organism. This is shown by experiments on the regeneration of a haploid-nucleated limb of a newt transplanted onto a diploid-nucleated animal. The regenerate arising in this case consists of haploid-nucleated cells (Hertwig). The same follows from transplants of limbs from a black race of axolotls to a white one, when the regenerating limb turns out to be black. These facts exclude the idea of regeneration at the expense of various cellular elements arriving with the bloodstream. When considering the material used for regeneration, one has to reckon with a twofold possibility. Regeneration can occur either at the expense of so-called reserve, indifferent cells that remain undifferentiated during embryonic development, or the use of already specialized cellular elements takes place.

The important significance of reserve cells has been shown for a number of animals. Thus, regeneration in hydras occurs mainly at the expense of so-called interstitial cells. The same takes place in turbellarians. In annelids, this role belongs to neoblasts, which relate to elements of a similar kind. In ascidians, indifferent cells also play an important role in regeneration. The matter is more complex in vertebrates, where various authors attribute the main role in regeneration to different tissues. Although there are indications here too of the origin of blastema cells from unspecialized elements, this fact cannot be considered firmly established. Nevertheless, the tenets of the previously dominant theory of Gewebesprossung, which recognized the possibility of the development of cells of any tissue only from cells of the same tissue, were thoroughly shaken. But if one can accept the formation of a significant mass of the regenerate at the expense of unspecialized cells, this does not exclude the possibility of the development of part of the regenerate from differentiated elements. In this case, one can speak both about the development of tissues at the expense of the multiplication of identical elements and about the transition of cells of one type into another (metaplasia). In fact, in many cases, it can be shown that both of these processes take place. Thus, musculature usually in a significant part originates from remaining undestroyed muscle cells. In annelids, one can establish the formation of muscles from epithelial elements. The same takes place in some crustaceans (Przibram). The formation of the nervous system from ectodermal cells has been established in ascidians (Schultze). In amphibians, it is known that the regeneration of the lens can occur from the edge of the iris (Wolff, Colucci). It is also possible to accept the formation of cartilaginous and bony skeletons without the participation of cartilaginous and bony elements of the previously existing organ.

Since the regeneration process includes both development from indifferent elements and the participation of specialized elements, in each individual case, a special study is necessary to clarify the role of each of these processes in regeneration. If we consider as an example regeneration in amphibians, again by virtue of its being the most studied, then the matter here appears in the following form. Nerves are always formed at the expense of the growth of the endings of old nerve trunks. The situation is different with bone tissue in the case of limb regeneration. It has been shown that even when removing the entire bony skeleton of a limb, including the shoulder girdle, upon amputation of such a boneless limb, regeneration of an organ possessing a skeleton occurs (Fritsch, 1911; Weiss, Bischler) (Fig. 8). The situation is different during tail regeneration. In this case, bony parts are formed only when there is damage to old skeletal parts in the area of the regenerate.

Figure 8. X-ray of the regeneration of a boneless limb of a salamander. The shoulder girdle and humerus are removed; amputation is above the elbow. The forearm with the bones of the forearm and the hand with phalanges have regenerated. The carpus is still cartilaginous, the radius and ulna are shifted into the boneless humerus. (According to Korschelt.)

and the bone elements of the latter can take part in regeneration (Fig. 9). Regarding the connective tissue part of the skin, corium, we also have proof of the possibility of its formation without the participation of the old corium (Weiss). As for the musculature, the removal of the greater part of the limb musculature did not lead to any anomalies in the development of the regenerate. Furthermore, in the case of transplanting a piece of the notochord in an Anura larva into the tail region, which was devoid of musculature, it was possible to induce the formation of a tail in this place with the corresponding direction of the tail incision. The organ formed in this process possessed musculature (Marcucci). However, histological studies show that during normal regeneration of the tail, its muscles are formed from the corresponding elements of the old organ (Naville). Thus, a significant part of the regenerate in amphibians can be formed not as a result of the multiplication of old tissues, but from the mass of the blastema, the origin of the elements of which, as already indicated, has not yet been established to a sufficient degree. At the same time, other relationships may take place, which we have in the regeneration of the tail, the axial organs of which regenerate only in the presence of old ones. It should be noted that even the regeneration of one and the same organ can proceed at the expense of different material depending on the conditions, as could be verified by the example of the formation of the muscle elements of the tail. The cited experiments, although they indicate the possibility of the development of certain tissues (e.g., bone) not from cells of the same tissue, do not, however, resolve the question of how things stand under normal conditions of regeneration. Further research is necessary in this direction.

Conditions of regeneration. A. Regenerating region. The course of regeneration is, of course, in close dependence on which part of the organism is subjected to amputation and, consequently, in which region the regenerative phenomena take place. First of all, we may encounter an absence of regeneration in certain parts of the organism, or rather, a weak expression of the corresponding phenomena. Philippeau discovered the absence of regeneration in a salamander in the case of extirpation of the limb with the entire shoulder girdle. Schotte showed that amputation of the tail is accompanied by regeneration only in that Figure 9. X-ray of a regenerated tail of the lizard Lacerta muralis. Rupture in the region of the IV caudal vertebra. (According to Korschelt.)

Figure 10. Triton cristatus after complete removal of the tail territory; no traces of regeneration within 8 months.

case if the incision passes sufficiently distally (Fig. 10). Vallette and Guyenot note the absence of regeneration of the nasal parts of the head upon amputation of too large a section. Likewise, regeneration of the eye does not occur upon complete enucleation (Schaxel). Gills do not regenerate upon complete removal. Guyenot interprets these phenomena in such a way that regeneration can occur only

Figure 12. Regeneration of the anterior section in an earthworm. The position of the regenerate is determined by the nerve trunk: 1—plane of regeneration; 2—end of the severed nerve trunk.

Figure 11. Replacement of the left eye, removed together with the optic ganglion, by an antenna-like appendage (1): 2—supraesophageal ganglion; 3—eye; 4—optic ganglion. (According to Korschelt.) in the presence of certain cellular complexes, which can be completely removed with a sufficient degree of damage. Reliable proof of this position, however, has not yet been given, and it is not excluded that in some cases the absence of regeneration discovered by the indicated authors is also connected with other conditions. The character of the formation that arises during regeneration also depends on the regenerating region. It is well known that upon the removal of various parts of the organism, various formations arise. One should not, however, explain this phenomenon by the fact that the newly forming organ must be similar to the removed one. Thus, the experiment of Herbst is known, confirmed also by other authors, when upon the removal of an eye in a crayfish, while leaving the optic ganglion, an eye regenerates, and upon the simultaneous removal of the ganglion, regeneration of an antenna is observed (Fig. 11). Upon extirpation of an antenna in one species of insect (Dixippus morosus) in the distal part, the formation of an antenna is observed, while upon amputation at the base, a limb regenerates. The corresponding phenomena bear the name of homeosis. It is understandable that the speed of regeneration also depends on the regenerating region, as has already been mentioned. B. Parts of the amputated organ. As could be seen from the experiments of removing the limb skeleton, regeneration can take place even in its absence. However, as Bichler showed, during the regeneration of a boneless organ, it is not the segment that is subjected to amputation that regenerates, but only a more distal one, so that during the regeneration of, for example, a limb, an organ arises that is shortened by one segment. Since development is observed even in the absence of bone tissue, the connection of the specificity of regeneration with the skeleton is denied. Furthermore, transplantations of some bones into the place of others, e.g., the femur into the place of the humerus, do not change the morphology of the regenerate. An important role in regenerative phenomena belongs to the nervous system. The necessity of the presence of nerve connections for the formation of a regenerate has been proven, however, not for all species. For a number of animals, such a regularity apparently does not exist.

The clearest data are available for worms, echinoderms, and especially amphibians. In worms, Morgan showed the necessity of the presence of nerve endings in the region undergoing regeneration in order for the regenerative process to be able to take place (Fig. 12). The same has been shown for starfish (Morgulis). However, there are data contradicting those just mentioned, so that further research is necessary in this direction. For amphibians, it has been shown that the presence of the central nervous system is not a necessary condition for regeneration (Barfurth, Rubin, Godlewski). However, in the case of a disturbance of peripheral innervation Figure 13. Heterotopic regeneration of an organ obtained by diverting the brachial plexus. (According to Guyenot.) the process of restoration does not exist. The relationships taking place here were

(Guyenot)

clarified as a result of detailed experiments by Schotte and Weiss. Both of them showed that in the case of complete denervation, regeneration does not take place. Schotte showed that only the sympathetic nervous system is of importance here, because upon cutting the sympathetic nerves and leaving the sensory and motor innervation, the formation of the organ does not occur. Conversely, regeneration is present when only the sympathetic innervation is preserved. The significance of the nervous system has been proven by Schotte not only for adult animals but also for larvae. Schotte's data regarding sympathetic innervation, however, evoke objection from some authors who believe that the main role in the regenerative process belongs to the spinal ganglia (Locatelli). The obtained data also indicate that the role of the nervous system is not limited only to the initial stages of the process; for the continuation of regeneration, the presence of the nervous system is also necessary. A number of authors link the specificity of the regenerate with the nervous system. In their opinion, there is a specific influence of the latter. Interesting data in favor of this assumption were presented by Locatelli, who obtained the formation of additional limbs in newts by bringing the central end of the severed n. ischiadici to the surface of the body in the region of the flank and hind limb (Figure 13). However, Guyenot and Schotte showed by their research that the specificity of the nerves does not play a role in this phenomenon. True, bringing the severed end of a nerve into one or another region of the organism induces the formation of an organ here, but the character of the organ is connected with the specificity of the region, and not the nerve. One and the same nerve, being brought into a region surrounding a hind limb, induces the development of a hind leg here, and upon entering a region located closer to the tail, it induces the formation of the latter organ. Upon bringing the nerve into intermediate regions, it is possible to

Figure 14. Inhibited regeneration of the right hind limb of an axolotl due to the formation of a skin scar. (According to Korschelt.)

obtain chimeric formations between the tail and the limb. A number of other data in favor of the specificity of the nervous system (Wolff, Walter) have also received a different explanation. In connection with this, the assumption about the specificity of nervous influence on regeneration must be rejected. Removal of the skin at the site of amputation for a certain distance leads to the fact that the regeneration of the organ is delayed until the epithelium, creeping from the edge of the skin onto the open surface, covers it and reaches the site of amputation. Degeneration of the open area may also occur, and then regeneration begins from the moment when the degeneration of the area reaches the edge of the skin and the corresponding parts fall off. Thus, the presence of skin, or rather the epithelial cover, is a necessary condition for the regeneration of an organ. This position explains the absence of regeneration when the wound surface is closed with a skin flap (Fig. 14), shown by a number of authors both in amphibians (Tornier, Schaxel, Godlewski, Efimov) and in insects (Schaxel and Adensamer). This phenomenon is caused by the fact that the skin epithelium does not have access to the wound surface, being separated from it by the connective tissue part of the skin; for regeneration to occur, it is necessary to cover the wound with young epithelium. If a piece of skin is transplanted under the skin flap covering the wound surface, then regeneration occurs in these cases (Efimov). This fact suggests that a mechanical obstacle to the growth of the regenerate does not play a role in this phenomenon. The specificity of the skin does not affect the character of the regenerate. This is supported by the experiment of Taube, who transplanted a cuff of red abdominal skin onto the limb of newts and, after regeneration from the area covered with red skin, obtained a normal black limb. The same is confirmed by the transplantation of internal parts of the tail into a skin sleeve of the limb, when regeneration of the tail is observed (Bischler). Removal of most of the musculature has an effect only on the speed of the process. It is also necessary to deny the specific influence of the musculature, since replacement by transplanting musculature from one region to another does not change the character of the regenerate (Bischler). Thus, one has to admit that each of the mentioned parts of the organ (nerves, skeleton, musculature, skin), taken separately, is not a specific condition for regeneration. B. Parts of the regenerate. The regenerating organ is heterogeneous not only in the sense that it consists of different tissues; it contains areas that differ extremely strongly from each other in their properties. If one divides the regenerating organ into two different parts, as is usually done, the blastema and the rest of the regenerate, then their behavior turns out to be sharply different. When the blastema is removed, it is re-formed by the remaining parts; the same happens when a part of the organ that does not contain the blastema is transplanted into some other region of the organism. In this case, even very small pieces of the transplanted area can develop the corresponding organ (Fig. 15). The situation is different when transplanting the other part of the regenerate—the blastema. It was discovered that up to a certain age, approximately two weeks, blastemas, when transplanted, do not develop further and are resorbed (Schaxel). Blastemas in the experiments of de Giorgi, transplanted onto the back in the age-

Figure 15. Results of transplantation of the

[...] limb in place of the tail. (According to Guyénot and Ponse.) [...] grew up to 30 days, although they took root and increased slightly, they did not undergo differentiation. It is difficult to say what kind of conditions are significant here; in any case, the conclusion from the indicated facts can only be that for the presence of regeneration, a connection between the blastema and the remaining parts of the regenerate is necessary.

A number of authors tried to find out which part of the regenerating organ is specific, distinguishing one organ from another. Especially much attention was paid to the question of whether the material of the blastema is specific. Corresponding studies boiled down to transplanting blastemas of some organs onto others with the aim of finding out whether the specificity of the organ formed from the blastema would change in this case. Transplants of blastemas were performed on various species of animals.

It was discovered that a regenerate, transplanted before a certain age, develops in accordance with the area of the organism onto which it is transplanted. Thus, these experiments speak for the non-specificity of blastemas. However, all studies conducted so far are not sufficiently convincing.

Milosevic, when transplanting young regenerates of a hind limb to the place of a forelimb, in a number of cases obtained the formation of a forelimb at the new site, i.e., development according to the place of transplantation. However, these data are not conclusive due to the lack of a reliable criterion that the forming organ originates indeed from the tissue of the transplant, and not from the regenerating forelimb itself. In the experiment of Guyénot and Schotte, where the limb blastema, being transplanted onto the tail, gave rise to the formation of a tail, the authors themselves doubt the origin of the organ material. Finally, Weiss transplanted tail regenerates into the area of the forelimb and in three cases obtained the development of a limb. However, even in these experiments, there can be no certainty as to whether regeneration proceeds at the expense of the transplant tissues.

Thus, the question of the possibility of changing the path of development of a regenerate in amphibians, and at the same time the question of the specificity of the blastema, remains open. A similar situation exists for lower animals. The experiments of Gebhardt, who in two cases obtained the formation of a head from the regeneration bud of a tail in a planarian, can be interpreted as a result of the participation in regeneration of tissues of the head region, where the transplantation was performed. All that has been said concerns only young regenerates, since all authors agree that newly formed tissues taken at a relatively late age are already distinguished by specificity. Despite the insufficient evidence of experiments on the transplantation of young regenerates, the majority of authors consider not the blastema to be specific, but only the remaining part of the organ. The presence of mitogenetic radiation in the regenerate allowed the idea to be expressed about the possibility of the influence of radiation of some parts of the regenerate on others, especially mitogenetic rays arising during the resorption of tissues, on the multiplication of blastema cells (Blyakher and Bromley).

However, the significance of mitogenetic radiation during regeneration cannot yet be considered established. Nevertheless, it is undoubtedly possible to cause an acceleration of the process by acting on the regenerate with mitogenetic rays (Blyakher, Vorontsova, Irikhimovich, Liozner). The same authors showed the presence of stimulation of regenerative processes in cases where wound surfaces have the opportunity to influence each other (for example, with a triangular excision of a section of the tail). G. Processes occurring in the organism during regeneration. Regeneration is a process depending not only on the state of the given organ but also on the entire organism. Therefore, the processes occurring in the latter can have a decisive influence on the regenerative process.

In the experiments of Gecha, amputation of the head in a hydra did not lead to regeneration in the case when the hydra possessed a bud. Then only regulatory processes occurred, as a result of which the head of the increasing bud takes the place of the head of the polyp. If one head is amputated in a two-headed planarian, the latter does not regenerate (Steinmann). A change in the localization of the regenerating organ in relation to the organism may not, however, have an influence on the character of regeneration. Kurz transplanted an amputated limb onto the back, and a normal limb regenerated here. Weiss swapped the fore and hind limbs of a newt, and again, the regeneration of the transplanted limbs led to the development of that organ which would have formed in the case of leaving them in place. The same takes place when transplanting a section of the tail or the front part of the head. Thus, this or that place of development of the process is not specific during regeneration.

The influence of the organism on the regeneration of its parts can manifest itself not only in conditioning the very possibility of regeneration but also in the character of the regenerate, its form, position, and the course of the process. An example of such an influence can serve, for example, the significance of function for the regenerative process, when the use of the organ strongly affects the regenerate. The significance of other parts of the organism for the regeneration of a given area is revealed in experiments with endocrine glands; the removal of endocrine glands or the influence of their secretions can have an effect on the course of regeneration. It is undoubted that a whole series of processes occurring in the organism exerts an influence on the regenerative process. Among them, one can mention cases of the simultaneous presence in the organism of several regenerative processes. Whether stimulation or inhibition of regeneration will occur in this case depends on specific conditions, expressed in the size of these injuries, their location, etc. (Zeleny). The influence of the connections existing in the organism on regeneration is manifested in experiments of cutting out small sections from the body of hydras or planarians. In this case, a reversal of polarity can occur, when identical organs are formed on both sides of the regenerate (the formation of animals with two heads or two tails depending on the area from which the regenerating section was cut out).

resulting in the development of an entire organ (e.g., the head of an animal; Loeb, Child) (Fig. 17). The atypical course of regeneration can depend on the nature of the injury. Thus, when an amputated organ bifurcates, double formations arise. The position of the regenerate can also depend on how the amputation is performed, since the long axis of the emerging regenerate is usually perpendicular to the plane of amputation. Theories of regeneration. The phenomenon of regeneration has been known for a very long time. In a number of ancient scholars, one can find indications of familiarity with this phenomenon. However, systematic experiments dedicated to the study of regeneration were set up closer to modern times. Réaumur studied regeneration in the crayfish, attributing this phenomenon to the presence of additional "organ rudiments" (1721). Trembley's data on hydras, dating back to 1744, are known, which clearly established the pronounced regenerative capacity of this animal. The middle and end of the 18th century count a number of other studies on regeneration. These include the data of Bonnet and Spallanzani. These studies encompass not only lower but also a number of higher animals (vertebrates). In the years immediately following, the study of regeneration progressed very slowly. Only at the end of the 19th century did intensified research into regenerative phenomena begin, covering the most diverse types of animals. This study is characteristic not only for its systematic nature and detail but also for the fact that researchers were already penetrating much deeper into the essence of the phenomenon of regeneration. Researchers of the late 19th century devoted much attention to clarifying the connections of the regenerative process, its necessary conditions, and on this material built corresponding theories of regeneration. The principled approach of these authors to the study of the process received its justification in the works of W. Roux and can be called the causal-analytical method of research. Its characteristic features are the mechanistic and formal nature of the analysis of phenomena; the moments leading to the emergence of the phenomenon being studied are taken not in the process of development, but as static. By decomposing the process into individual components, they isolate a main component, which is taken as the starting point, and the phenomenon itself is viewed as the result of the influence of various conditions on this basis. On the other hand, since the direction of the process is viewed in isolation from its driving forces, a separate factor responsible for the direction of the process is also isolated on the basis of formal analysis. Thus, the sources of development and the direction of the phenomenon turn out to be external in relation to the individual components of the process. Since the source of development appears as external in relation to the other components of the process, the question of what causes the development of the source of development itself is inevitable. If some factor is isolated as the latter, the question of the source of development of this new factor will arise again. Proceeding in this way, we must either arrive at a divine prime mover or abandon the final resolution of the question. The entire incorrectness of the causal-analytical method clearly follows already from this description of it. The commonality of the method, however, does not prevent researchers of regeneration from disagreeing among themselves on a number of essential issues, thus forming different camps. A part of the scientists, closer to Roux himself, stood on a point of view that bore a preformist character. The development of the regenerate itself is caused, in their opinion, by the irritation inflicted by the amputation. The direction of regeneration is determined mainly under the influence of reserve hereditary rudiments, which thus represent the properties of the future organ and, upon further cell multiplication, entering various sections of the regenerate, prompt them to corresponding development. Most of these researchers simultaneously held the point of view that each tissue of the regenerating organ is formed at the expense of similar tissue of the organ remnant, and their development proceeds to a certain extent independently of each other (the theory of P. "Teil für Teil"). The preformist, causal-analytical theory of regeneration must be decisively rejected. It excludes the idea of a real process of new formation, treating the phenomenon as the realization of what already existed previously. Preformist ideas proceed from the assumption that we have in a hidden form, in the person of hereditary rudiments, a preformed structure of the future organ. All this assumption is of an extremely artificial nature and stands in contradiction with modern data. Also, a number of observations refuted the position on the independent development of individual tissues of the regenerate at the expense of the corresponding tissues of the stump. Along with the indicated idea, another one arises, the justification of which belongs to Driesch and is in sharp contradiction with the first idea. Driesch assumes that the regenerate is not preformed in the regenerating parts; otherwise, one would have to assume the presence in each part of countless mechanisms corresponding to different possibilities of development. This conclusion is based on the fact that at the most diverse levels of amputation, a normal organ arises; consequently, one and the same section of the regenerate can develop in one case one formation, in another—another. Driesch therefore believes that the regenerate is homogeneous in the sense of the regenerative capacity of its individual parts and is devoid of any structure predetermining future development. The differences between the parts of the future organ are conditioned not by the differences of the parts of the regenerate, but by the inequality of their position in the whole (the regenerate). Hence Driesch's well-known position that the fate of a part depends on its position in the whole. The character or essence of the considered differences is conditioned, however, not by the position in the whole, but by a certain non-material factor, called by Driesch entelechy. The strivings of entelechy are directed toward the regenerate developing in the direction necessary for the organism. Driesch arrives at the recognition of the non-materiality of the factor conditioning the direction of regeneration by way of excluding other explanations possible in his opinion, which reduce to crudely mechanistic ideas. Thus, according to Driesch, the picture of the regenerative process is drawn in such a way. The moment causing regeneration is an indefinable disturbance of the organism, resulting from the amputation and prompting the organism to correct the deficiency. The direction of regeneration is conditioned by entelechy, acting purposefully, and therefore depends on the final goal of regeneration, i.e., the form of that organ which must be formed. The undoubted idealism of Driesch's concepts does not prevent him from remaining a mechanist. It is easy to see that the method used by Driesch to explain the phenomena is the same causal-analytical method of Roux, but this time serving to justify vitalistic concepts. The source of development is also for Driesch external in relation to the developing object, and development is analyzed only in its formal conditioning. As a result of such an analysis, a purely formal position is obtained regarding the dependence of differences on the position of the part. Driesch thinks he can understand the essence of the process by isolating a special factor influencing the character of the phenomenon—entelechy. If in this part of Driesch's constructions he cannot be accused of a lack of even formal logic, the same cannot be said about his reasoning regarding the activity of entelechy. Here, the bias and far-fetched nature of Driesch's theory immediately strike the eye. Having broken the crudely mechanistic view and believing that this excludes any materialistic understanding of the process, Driesch attempts to explain the phenomenon of regeneration by introducing a non-material principle. Such a position, however, essentially means only the appearance of an explanation, and in reality, is a refusal of the latter; the activity of the imagination takes the place of actual study. Very soon, a number of studies showed the unsuitability of Driesch's theory for explaining regeneration and its direct contradiction with observed facts. It was shown that the regenerative process occurs regardless of whether it is purposeful. Transplanted organs regenerate in a place unusual for them, giving rise there to formations that disturb the harmony of the organism, which thus cannot be considered the goal toward which the regenerative process is directed. The triggering of the regenerative process in an unusual place by introducing a nerve shows that it is not at all the absence of an organ that is the driving moment of regeneration, and the direction of the latter is connected not with a purposeful, non-material principle, but with the entirely material properties of the regenerating region. Furthermore, since the forming organ is never entirely similar to the one that previously existed, and sometimes is not at all like it, the striving for the "restoration of the lost" can be disputed altogether. The unsatisfactoriness of Driesch's vitalistic constructions prompted researchers to seek another resolution to the regenerative problem. At the same time, the old preformist doctrine was also sufficiently compromised. This explains the attempts to construct theories of regeneration that would go in a different direction and be devoid of the shortcomings of the old ones.

The most developed theories in this regard belong to Guyénot and Weiss and date back to the 1920s. From the epigeneticists, these researchers borrow the concept of homogeneity in the sense of the potencies of the regeneration material, while at the same time they believe that the development of the blastema is determined by the tissues located immediately behind the regenerate. Thus, the direction of development, in the opinion of these authors, is introduced by a factor external to the regenerate; on the other hand, such a factor turns out to be the remainder of the amputated organ, that is, a quite concrete object of study, and not a mystical otherworldly factor, as is the case with Driesch. The possibility of such a construction is achieved by contrasting two different parts of the regenerate with each other: the newly formed tissues and the old ones lying behind them. The former are declared, on the basis of transplantation experiments, to be devoid of specificity up to a certain time. Conversely, the latter is characteristic of old tissues. The conclusion drawn from this is that the development of newly formed tissues occurs under the influence of the old ones; the former do not possess an independent, inherent direction of regeneration; it is induced in them by the tissues lying behind, which impart to the blastema the structure characteristic of them. This basic initial position receives one development or another and nuances depending on which view the author adheres to. Guyénot, closer to preformism, contrasts the old epigenetic point of view regarding the dependence of the direction of regeneration on the organism as a whole with the idea that the organism represents a mosaic of autonomous regions, each of which is capable of forming only the specific organ characteristic of it. Such isolated parts of the organism Guyénot calls "regeneration territories." Accepting that the specificity of development is imparted to the regenerate by the tissues lying behind, Guyénot attempts to continue the analysis and clarify which part of these tissues can be considered responsible for the direction of regeneration. Since none of the tissues used in the experiment (nerves, musculature, skeleton, skin) turns out to be a specific condition for regeneration, Guyénot comes to the conclusion that one must either attribute this property by the method of exclusion to connective tissue or link it to the territory as a whole. Either of these assertions would, from his point of view, be premature for now. Weiss, who leans more towards epigenetic concepts, formulates his views differently. He also accepts that newly formed tissues do not contain any tendency toward the development of one organ or another; they are "nullipotent," unorganized. Any organization, according to Weiss, can arise only under the influence of already organized material. The latter are the parts lying behind the regenerate. The influence of organized material on unorganized material does not occur in such a way that its parts influence each other independently—the organized material influences as a whole, it carries a "field." What a regeneration field is in essence, Weiss does not explain; he points only to some purely formal properties of it, e.g., the possibility of the fusion of two "fields" into one, etc. Each region of the organism possesses its own specific "field," thus the organism, according to Weiss as well, represents a mosaic of "fields." However, this mosaic is the result of embryonic development, the result of the division of a once homogeneous embryo into independent parts or the division of the general "field" of the embryo into several "fields." The resolution of the regeneration problem given by Guyénot and Weiss cannot in any way be considered satisfactory. Their error lies, again, in the mechanistic nature of the analysis, in the application of the causal-analytical method. The direction of regeneration is studied by them not in connection with the driving forces of the regeneration process, but independently of them; only its formal conditioning is studied. Only formal analysis allows one to draw from the position that the regenerate is non-specific up to a certain stage the conclusion about the introduction of the direction of regeneration from the outside, under the influence of the tissues lying behind. This is achieved by artificially contrasting the parts of the regenerating area, presenting them as external to each other. It is easy to show that the theories being examined do not resolve the contradiction between the epigenetic and preformist points of view. The idea of the source of development as a part of the organism external to the object under consideration is not directly discredited only as long as we are dealing with phenomena of regeneration. But if, logically continuing the authors' line of reasoning, one poses the question of what determines development at the initial moment of ontogenesis, when an as yet undifferentiated egg is present, then we must inevitably either admit the presence of some factor external to it or return to the insoluble contradictions of the former preformist point of view. The difficulties facing the theory under examination naturally manifest themselves in the fact that we still do not receive an explanation for the regeneration process. Guyénot refuses altogether to judge the essence of the action of the territory, while Weiss's "field," despite all the author's efforts to strip it of a mystical character, remains no clearer a concept than Driesch's entelechy, and undoubtedly points to Weiss's vitalistic tendencies. The theories mentioned so far are characterized by a purely morphological approach to the object being studied. The opposite of this point of view is represented by Child's theory of physiological gradients. Child places at the cornerstone of his theory the differences in the physiological properties of different regions of the organism. The latter can be revealed by various methods: by studying oxygen consumption, sensitivity to various reagents, etc. To the quantitative differences resulting from this, Child attributes decisive importance in the sense of influence on development. The degree of physiological activity determines the appearance of one formation or another. Child thus replaces the one-sidedness of the morphological point of view with a no less one-sided physiological, purely quantitative point of view. Such a resolution of the question is, of course, also unsatisfactory. Insofar as in regeneration it is a matter of the formation of qualitatively different organs, a purely quantitative view is condemned to sterility. And indeed, the connection between the presence of one gradient or another and the emergence of a specific organ remains unclear in Child's work. Furthermore, the differences in the physiological activity of various sections have, according to Child, their source in a specific region of the organism from which the necessary influence, having an energetic character, emanates. The emergence of such a "dominant" region is the result of the reaction of the protoplasm to a factor external to it. The view under consideration does not, in essence, answer the inevitably arising question of why the reaction has precisely this character. Child's theory bears the same stamp of mechanism and formal approach to the phenomenon as those previously examined, and therefore cannot provide a correct and non-contradictory understanding of the process. Thus, all the theories of regeneration we have examined cannot be recognized as corresponding to reality. They are incapable of revealing the driving forces of the phenomenon, the moments determining it, giving an incorrect understanding of the process. Due to the fact that researchers of regeneration were guided by an erroneous method, the results obtained by them have to be interpreted quite differently than they do. One must deny the determining role of the various factors highlighted as a result of the study of regeneration and recognize these factors only as conditions of the process. One cannot, however, limit oneself to this view; since the isolation of these conditions in most works proceeded from an incorrect point of view, the authors' conclusions can be disputed in a number of points. On the other hand, it is clear that one cannot rest on the position of conditionalism and must reveal those determining relations that lie at the basis of the regeneration process. Hence arises the necessity of developing a dialectical-materialist theory of regeneration, which alone can provide a deep knowledge of the phenomenon. At the present time, we do not yet have such a theory; however, it can be pointed out that its construction presupposes the consideration of the process in its self-movement, not a formal analysis, but the uncovering of the real driving forces of the process.

L. Liozner. Regeneration in humans, just as in all living beings in general, is of two types. A. Normological, or physiological regeneration takes place in the everyday normal life of a human and manifests itself in the continuously occurring replacement of dying tissue elements by newly formed cells. It is observed to one degree or another in all tissues; in particular, in the bone marrow, regenerative multiplication and maturation of erythrocytes are constantly occurring, replacing dying red blood cells; in the covering epithelium, in which there is a continuous detachment of keratinizing cells, there is a constant replacement of them by multiplying cells of the deep layers of the epithelial covering. -B. Pathological regeneration occurs as a result of pathological death of tissue elements. The process of regeneration in the latter type of cases, strictly speaking, is not a pathological process; pathological regeneration differs from normological regeneration not in its essence, but in its scale and other features related to the nature of the preceding loss of tissue elements. Since the death of tissue elements as a result of various pathological factors represents something quite different from the physiological dying off of cells in both quantitative and qualitative respects, pathological regeneration therefore differs quantitatively and qualitatively from normological regeneration. Manifestations of pathological regeneration are most often associated with the inflammatory process and are inseparable from the latter by a sharp boundary; it is often impossible to strictly delineate what belongs to inflammation and what to regeneration; in particular, the proliferative factor in the inflammatory reaction is very difficult to separate from the regenerative multiplication of cells. One way or another, every inflammation implies subsequent regeneration, although regeneration, as indicated, may not be associated with inflammation. The course of the regeneration process varies depending on the nature of the injury and the method of death of the tissue elements. If there was the action of a factor that caused an inflammatory reaction of the tissue along with the damage, then usually the manifestations of regeneration begin only after the acute period of inflammation, accompanied by a significant disturbance of tissue vital activity, subsides. If tissue necrosis occurred in connection with the injury or as a result of the developed inflammatory process, then regeneration is preceded by or combined with processes of resorption of dead material; the latter often proceed with the participation of an inflammatory reaction. In contrast to this, if cell death is a consequence of their degenerative and atrophic changes, then regeneration proceeds simultaneously with these necrobiotic processes and is not accompanied by inflammation; in particular, in the liver and kidneys, along with the degeneration of part of the parenchymal elements, one can see phenomena of regenerative multiplication of better-preserved cells; in the case of atrophy of one lobe of the liver from pressure, for example by an echinococcus, multiplication of cells occurs in the other lobe, often completely covering the occurring loss of liver tissue. At the basis of regeneration lies the multiplication of cells, corresponding to their normal division; in this, the main importance belongs to indirect, karyokinetic (mitotic) cell division, whereas direct, amitotic division is rarely observed. Besides the pictures of normal karyokinesis, in pathological regeneration there may occur pathological forms of mitotic division in the form of abortive, asymmetric, multipolar mitoses, etc. (see Karyokinesis). As a result of regenerative cell multiplication, young, immature cellular elements are formed, which subsequently mature and differentiate, reaching that degree of maturity which is characteristic of normal cells of the given type. If the regeneration process concerns individual cells, then morphologically it is expressed in the appearance of individual young cellular forms among the tissue. If, however, it is a matter of the regeneration of a more or less extensive tissue territory, then as a result of regenerative cell multiplication, the formation of immature, indifferent tissue of the embryonic type occurs; this tissue, consisting at first only of young cells and vessels, subsequently differentiates and matures. The period of the immature state of the regenerating tissue, depending on the pace of the process and various external conditions, can have a different duration. In some cases, the entire process of new tissue formation proceeds gradually, slowly, with new tissue elements being formed and maturing not simultaneously; under such conditions, as for example happens with the proliferation of interstitial tissue of parenchymal organs (liver, kidneys, heart muscle) depending on the atrophy of the parenchyma, the period of the immature state of the tissue is morphologically indefinable. Conversely, in other cases, specifically when the tissue of a given area undergoes energetic regenerative proliferation, morphologically obvious immature tissue is formed, which subsequently matures in one period of time or another; the most demonstrative in this sense is the proliferation of granulation tissue. In the majority of regenerative processes, the rule of preservation of specific tissue productivity is realized, i.e., the circumstance that cells multiplying during regeneration form the tissue from which this multiplication originates: multiplication of epithelium gives epithelial tissue, multiplication of connective tissue elements forms connective tissue. However, on the basis of data on regeneration in lower vertebrates, and in relation to humans - data concerning pathological regeneration, inflammatory proliferations, and tumors, one has to admit exceptions to this rule in the form of the possibility of the formation in some cases from multiplying and, so to speak, embryonicizing epithelium of tissues of a mesenchymal character (connective tissue, muscles, vessels), and from connective tissue - the development of muscle elements, vessels, blood elements. Furthermore, during regeneration in certain tissue groups (epithelium, connective tissue formations), a change in the type of tissue can occur, i.e., that which is termed metaplasia (see). It is conventionally accepted to distinguish between complete and incomplete regeneration. Complete regeneration, or restitution (restitutio ad integrum), is called that regeneration of tissues in which a new tissue is formed at the site of the dead tissue, corresponding to that which was lost, e.g., restoration of muscle tissue upon violation of the integrity of a muscle, restoration of the epithelial covering during the healing of a skin wound. Incomplete regeneration, or substitution, refers to those cases when the defect is not filled with tissue similar to that which was here before, but is replaced by the proliferation of connective tissue, which gradually turns into scar tissue; in connection with this, incomplete regeneration is also designated as healing by means of scarring. It very often happens that there are signs of regeneration of specific elements of a given tissue (e.g., in a damaged muscle, the formation of "muscle buds" from muscle fibers), however, regeneration does not go to the end and the defect is replaced predominantly by connective tissue. Incomplete regeneration takes place with more or less significant losses of tissue substance, as well as in those cases when, either due to the peculiarities of the organization of the damaged tissue (see below) or in connection with the presence of certain unfavorable conditions, the multiplication of specific elements of a given tissue does not occur at all or it proceeds too slowly; under such conditions, the proliferation of connective tissue gains predominance. It must be noted that in reality, complete regeneration in the sense of the restoration of tissue that is in no way different from the former, normal tissue of the given site is never observed. The newly formed tissue, corresponding in morphological and functional sense to the former tissue, is nevertheless always different from it to one degree or another. These differences are sometimes small (underdevelopment of individual elements, some irregularity of tissue architecture); in other cases, they are more substantial; for example, the formation of the same tissue, but of a simplified type (so-called hypotypia) or the development of tissue in a smaller volume. Also belonging here are cases of super-regeneration, manifesting in lower animals in the formation of extra organs, limbs (see above), and in humans in so-called overproduction of tissues; the latter consists in the fact that the regenerative proliferation of tissue goes beyond the boundaries of the defect and produces an excess of tissue. This is observed very often, e.g., in bone injuries, when excessively newly formed bone tissue appears in the form of thickenings, outgrowths, sometimes quite significant; during regeneration in epithelial coverings and glandular organs, when the multiplying epithelium forms quite significant proliferations, approaching manifestations of tumor growth, e.g., atypical proliferations of epithelium during regeneration of ulcers and wounds of the skin and mucous membranes, regenerative adenomas in the liver and kidneys during diseases of these organs accompanied by the death of part of their parenchyma. In the majority of cases, such excessively proliferated tissue is devoid of functional significance; sometimes (in bones) it subsequently undergoes loss by way of resorption. The conditions of regeneration in humans are very diverse and complex.

Among them, those very numerous factors with which the reactive capabilities of the organism in general are connected are of great importance; these include the hereditary-constitutional characteristics of the organism, age, the state of the blood and blood circulation, the state of nutrition and metabolism, the function of the endocrine and vegetative systems, as well as the living and working conditions of the individual. Depending on the settings of these factors, regeneration can proceed at one pace or another, with one degree of perfection or another; in different individuals, with damage of the same type, tissue regeneration can proceed normergically, hyperergically, anergically, or be absent altogether. Local conditions in the area where regeneration is occurring are also of great importance for regeneration: the state of blood circulation and lymph circulation in it; the absence or presence of inflammation, especially suppuration. It goes without saying that the formation of new cells can occur only with a sufficient supply of nutrient material by the blood; furthermore, the multiplication and maturation of cells cannot occur in tissues that are in a state of severe inflammation. The character of the regenerating tissue in the sense of its degree of organization and specific differentiation, as well as other features of the structure and existence of the tissue, is of very essential importance for regeneration. The higher the development of a tissue, the more complex its organization and differentiation, and the more specialized its function, the less the tissue is capable of regeneration; and, conversely, the less complexly constructed and differentiated a tissue is, the more it is characterized by regenerative manifestations. This rule of inverse proportionality between the ability of tissues to regenerate and the degree of their organization is, however, not absolute; besides the degree of differentiation, other biological and structural features of the tissue are always of importance; for example, cartilage cells are much less capable of regeneration than the more complexly organized epithelial cells. In general, however, it can be noted that, for example, poorly differentiated connective tissue cells and surface epithelial cells possess a great capacity for regeneration, whereas the possibility of regenerative multiplication of such highly differentiated elements as nerve cells of the brain and spinal cord, or heart muscle fibers, has not yet been proven and is doubtful. In the middle are the cells of the secretory epithelium of glandular organs and the fibers of voluntary musculature, which are characterized by regeneration, but not nearly as perfect as that of connective tissue and surface epithelium. The fact that regenerative multiplication is to a greater extent characteristic of less mature and developed cells is also manifested in the fact that in any tissue, regeneration proceeds from those of its zones in which less mature elements are preserved (in surface epithelium from the basal or germinative layer, in glands from the basal parts of the excretory ducts, in bone from the endosteum and periosteum); these zones are customarily called proliferation centers or growth centers. Regeneration of individual tissues. Regeneration of blood, for example after blood loss, occurs in such a way that first, through diffusion and osmosis through the vascular wall, blood plasma is restored, after which new red and white blood cells appear in the blood, which are regenerated in the bone marrow and in lymphadenoid tissue (see Hematopoiesis). Regeneration of blood vessels is of great importance because it accompanies the regeneration of any tissue. There are two types of formation of new vessels. A. Most often, budding of old vessels takes place, which consists in the fact that in the wall of a small vessel, swelling of an endothelial cell and karyokinetic division of its nucleus occurs; a bud-like protrusion forms outward (formation of the so-called angioblast), which subsequently, with the continuing division of endothelial nuclei, stretches into a long strand; in the latter, in the direction from the old vessel to the periphery, a lumen appears, thanks to which the strand, which was initially solid, turns into a tube that begins to allow blood to pass through. The new vascular branches formed in this way connect with each other, which results in the formation of vascular loops. B. The second type of new vessel formation is called autogenous development of vessels. It is based on the formation of vessels directly in the tissue without connection to previous vessels; directly among the cells, gaps appear into which capillaries open and blood pours, with the adjacent cells acquiring all the signs of endothelial elements. Such a method, similar to the embryonic development of vessels, can be observed in granulation tissue, in tumors, and apparently in organizing thrombi. Depending on the conditions of blood circulation, newly formed vessels, which initially had the character of capillaries, can subsequently acquire the character of arteries and veins; the formation of other elements of the vascular wall, in particular smooth muscle fibers, in such cases occurs at the expense of the multiplication and differentiation of the endothelium. The formation of new connective tissue takes place as a regenerative manifestation during damage to the connective tissue itself and, in addition, as an expression of incomplete regeneration (see above) of the most diverse other tissues (muscular, nervous, etc.). Furthermore, the new formation of connective tissue is observed in very diverse pathological processes: in so-called productive inflammations, in the disappearance of parenchymal elements in organs due to their atrophy, degeneration, and necrosis, in the healing of wounds, and in processes of organization (see) and encapsulation (see). Under all these conditions, the formation of young, immature granulation tissue (see) occurs first, which undergoes maturation to the degree of mature connective tissue. Regeneration of adipose tissue occurs from the nucleated remnants of the protoplasm of fat cells or by the transformation of ordinary connective tissue cells into fat cells. In both cases, round cells—lipoblasts—are formed first, the protoplasm of which is filled with a mass of small fat droplets; subsequently, these droplets merge into one large drop, pushing the nucleus to the periphery of the cell. Regeneration of bone tissue during bone damage is based on the multiplication of osteoblasts of the endosteum and the cambial layer of the periosteum, which, together with newly formed vessels, form osteoblastic granulation tissue. In bone fractures (see), this osteoblastic tissue forms the so-called provisional (preliminary) bone callus. Subsequently, a dense, homogeneous substance appears between the osteoblasts, thanks to which the newly formed tissue acquires the property of osteoid tissue; the latter, by petrifying, turns into bone tissue. In fractures, this coincides with the formation of a definitive (final) bone callus. Under functional load, a definite architecture of the newly formed bone tissue is established, which is accompanied by the resorption of excess parts and the formation of new ones (bone remodeling). Cartilage tissue is capable of regeneration to a comparatively weak degree, and cartilage cells do not take part in regenerative manifestations. With small damages to cartilage, multiplication of cells of the deep layer of the perichondrium, called chondroblasts, occurs; together with newly formed vessels, these cells form chondroblastic granulation tissue. Between the cells of the latter, the ground substance of cartilage is produced; part of the cells atrophies and disappears, another part turns into cartilage cells. Large defects of cartilage heal by scarring. Regeneration of muscle tissue—see Muscles. Epithelial tissue, especially the surface epithelium of the skin, mucous membranes, and serous membranes, is highly capable of regeneration. With defects in the stratified squamous epithelium of the skin and mucous membranes, new epithelial tissue is formed, which is a product of the karyokinetic division of cells of the germinal layer of the preserved epithelium. The young epithelial cells that are formed move onto the defect and cover it first with a single layer of low cells; subsequently, with the continuing multiplication of these cells, a multilayered covering is formed, in which the maturation and differentiation of cells occur, corresponding to the structure of ordinary stratified squamous epithelium. On mucous membranes covered with columnar epithelium, defects are replaced by advancing epithelial cells, which are products of the multiplication of cells of preserved glands (in the intestine—Lieberkühn's, in the uterus—uterine glands); here, just the same, the defect is first covered by low, immature cells, which subsequently mature and become tall and columnar. During the regeneration of the mucous membrane of the uterus and intestine, tubular glands are formed from such an epithelial covering through the continued multiplication of its cells.

The flat epithelial covering of serous membranes (peritoneum, pleura, pericardium) is restored through karyokinetic division of the surviving cells; at the same time, initially, the newly formed cells have larger dimensions and a cuboidal shape, and later they flatten. In relation to the regeneration of glandular organs, one must distinguish, on the one hand, the death and regeneration of only the glandular epithelium while preserving the basic structure of the organ, and on the other hand, damage with subsequent regeneration of the entire organ tissue as a whole. Regeneration of the epithelial parenchyma of glandular organs after its partial death due to necrosis and degeneration occurs quite perfectly. During various degenerations and necrosis, e.g., of the epithelium of the liver, kidneys, the surviving cells undergo karyokinetic (less often direct) division, thanks to which the replacement of lost elements with equivalent glandular cells occurs. Regeneration of parts of glandular organs as a whole is more complex and, in general, is very rarely perfect. In some glands, e.g., the thyroid gland and the lacrimal glands, one sometimes observes the formation of outgrowths from the surviving glandular tissue and the formation of new glandular cells. In other organs, regeneration is much weaker; often processes of hypertrophy and hyperplasia of the surviving epithelial elements predominate over it. In particular, in the liver, upon the death of its tissue, multiplication and simultaneous increase in the volume of hepatic cells occur only within the limits of the surviving lobules; on a cross-section of such a liver, to the naked eye, a larger pattern of the lobule structure is often noticeable in the corresponding places. In general, such processes of multiplication and increase in cell volume in the surviving hepatic tissue can reach a very high degree; there are observations indicating that with the gradual removal of ²/₃ of the parts of the liver, its surviving third can provide an increase in volume that covers the aforementioned loss. In contrast to this, the formation of new hepatic tissue as a whole, i.e., new lobules with their system of capillaries, etc., is never observed. Very often, the neoformation of bile ducts occurs, giving numerous new branches; at the ends of the latter, the cells often undergo an increase in volume and begin to resemble hepatic cells, but their development does not go further than this. In the kidneys, upon the death of their tissue, e.g., during the formation of an infarct, new renal tissue is not formed at all; only sometimes is the formation of small outgrowths from the tubules observed. At the same time, an increase in the volume of glomeruli and tubules can occur in the surviving sections of the kidney. During the regeneration of epithelial tissue, a significant restructuring of it often occurs, i.e., a change in the shape and interrelations of the structural parts. Sometimes metaplasia takes place; often there is an overproduction of tissue in the form of atypical epithelial growths (see above). In nervous tissue, regeneration concerns the actual nervous elements and neuroglia to a very different degree. The regeneration of dead nerve cells in the formed central nervous system of man apparently does not occur at all; only rarely have not entirely convincing pictures of what seemed to be the beginning of division of the nuclei of these cells been described. Ganglionic cells of the sympathetic nervous system in a young organism can multiply, however, this occurs very rarely. All losses of substance in the central nervous system heal by filling the defect with proliferating neuroglia tissue, which is highly capable of regenerative manifestations, especially the so-called mesoglia. Furthermore, large defects in brain tissue can be filled by connective tissue proliferating from the meninges or from the circumference of blood vessels. Regeneration of peripheral nerves—see Nerve fibers, regeneration of nerve fibers. A. Abrikosov.