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Keibel F. and Mall FP. Manual of Human Embryology I. (1910) J. B. Lippincott Company, Philadelphia.

Manual of Human Embryology I: The Germ Cells | Fertilization | Segmentation | First Primitive Segment | Gastrulation | External Form | Placenta | Human Embryo and Fetus Age | Ovum Pathology | Integument | Skeleton and Connective Tissues | Muscular System | Coelom and Diaphragm | Figures | Manual of Human Embryology 1 | Manual of Human Embryology 2 | Franz Keibel | Franklin Mall | Embryology History

Bardeen CR. XI. Development of the Skeleton and of the Connective Tissues in Keibel F. and Mall FP. Manual of Human Embryology I. (1910) J. B. Lippincott Company, Philadelphia.

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XI. Development of the Skeleton and of the Connective Tissues

Charles Bardeen
Charles Russell Bardeen (1871 – 1935)

By Charles R Bardeen, Madison, Wis.

Skeleton and Connective Tissues: Connective Tissue Histogenesis | Skeletal Morphogenesis | Chorda Dorsalis | Vertebral Column and Thorax | Limb Skeleton | Skull Hyoid Bone Larynx

General Features

In the bodies of most living things certain tissues are differentiated for the purpose of passively supporting or protecting the physiologically more active structures. These tissues are characterized in the higher vertebrates by the predominant amount of extracellular substance, usually fibrous in nature, which, in large part at least, is differentiated during embryonic development from the peripheral portions of branched anastomosing cells. according to the nature of the intercellular substance the supporting tissues are subdivided into white fibrous and yellow elastic tissues, reticulum, cartilage, and bone.

In early embryonic stages the branched anastomosing cells which compose the supporting tissue or mesenchyme, form an extensive continuous framework. Certain parts of this framework are differentiated into the definitive skeleton and other parts into connective-tissue structures which protect and support the parenchyme of the various organs of the body and attach these organs to the skeleton.

The development of the various connective-tissue structures may be considered from two aspects, that of histogenesis and that of organogenesis. The histogenesis of the connective tissues has been most carefully studied in the lower vertebrates, in which the cells are large and the conditions are relatively simple. Organogenesis has been more carefully studied in man than in any of the lower forms. The histogenesis pf the connective tissues is apparently similar in the different vertebrates. Study of the histogenesis of these tissues in man and the higher mammals in general serves to confirm the results found in the lower vertebrates. Organogenesis is peculiar for each species, although there are fundamental similarities to be observed in related forms. We shall first give a brief account of the histogenesis of the connective tissues with especial reference to man and then treat with more detail the morphogenesis of the human skeleton. The specific development of the intrinsic supporting connective-tissue framework of the various organs is most conveniently taken up in connection with each of these organs, and will therefore not be attempted liere.

PART I. Histogenesis of the Connective Tissues

(a) Early Mesodermic Syncytium

In the youngest human embryos which have been described there is present a well-developed layer of tissue composed of branched anastomosing cells. This tissue layer surrounds the amniotic and yolk-sacs and lines the chorionic vesicle (Fig. 219, A). It forms a continuous sheet between the epithelium lining the amniotic cavity and that lining the yolk sac. The origin of the tissue is imeertain. It evidently is homologous with the mesoderm which in many of the mammals is known to arise from the primitive streak and head process.

In man the primitive mesoderm is apparently formed before the appearance of the medullary plate, the neurenteric canal, and the primitive streak. After these structures appear the mesoderm disappears in the mid-axial line anterior to the primitive streak, and a chordal plate is differentiated in the entoderm. (See Fig. 219.)

Keibel Mall 219.jpg

Fig. 219. — Diagrammatic section through two young human embryos described by Oral Spee. A. IV. Sp«. ArFh. f. Anat. u. Fliysiol., Anal. Abt., 1S96. Taf. I. Fig. 3.1 llalf-acheniBtic xagiiul B«lJon through Graf Spec's embryo v. H. B. (Kbcnda. Ts(. I. Fig. I.) [laLf-xchematio sugittiJ necuon (hrough Gnf [jpee-s embryo die. C. <Ebenda. 1SB9, Taf. XI, Fig. 14.) Tmnsvene i<ectioa through (he eDibo'onic C chorda aniage; f^,. chorion; en., caoalii neurentericus; cf., yolk^E p, blood ialBads; h., lieert; kp,, region of primitive etrcak; M.,

(b) Formation of the Mesodermic Somites

In Graf Spee's embryo Gle (Fig. 219, B and C) the mesoderm extends on each side of the neurenteric canal and of the medullary groove (Fig. 219, C) to the anterior extremity of the embryonic anlage where the mesodermic sheets of both sides become united (Fig. 219, B, h). Posterior to the neurenteric canal the mesoderm is intimately united to the tissue of the primitive streak, a region of active production of mesenchymal tissue. At the outer margin of the embryonic anlage the mesoderm is continuous posteriorly with the mesenchymal lining of the chorion, laterally and anteriorly with the mesodermic covering of the yolk sac and amnion (Fig. 219, B and C).

At a slightly later period the sheet of mesoderm on each side of the neural tube becomes longitudinally separated from the more laterally situated mesoderm (Fig. 220, A and C) and at the same time divided into a series of segments (mesoblastic somites). In the chick the first somites formed are the occipital somites (J. T. Patterson, Biological Bulletin, 1907, vol. xiii, p. 121), then follow in turn the cervical, thoracic, lumbar, sacral, and coccygeal. It is probable that the first somites formed in the human embryo belong to the occipital region. In the latter half of the first month of development in the human embryo there are found anterior to the cersdcal myotomes three incomplete occipital myotomes. The relations of these myotomes to the first somites differentiated have not yet been definitely determined. Etemod (Anat. Anz., 1899, p. 131) has described an embryo with eight somites, Kollmann (Anat. Anz., 1890, Arch. f. Anat. u. Physiol., Anat. Abt., 1891) one with fourteen (Fig. 220, A), and Mall (Journ. Morphol., 1897) likewise one with fourteen. Mall considers the first three somites in his embryo to be occipital somites. They probably correspond with the first three somites in the embryo described by Kollmann and possibly with the first three in the embryo described by Eternod.

The occipital somites are probably not completely divided off either from one another or from the lateral mesoderm (Figs. 229, 230, A).* The cervical somites, at least the more distal ones, on the other hand, become completely separated, and the tissue in

' Kollman states that in his embryo Biille, with fourteen somites, the segmentation externally appears well marked in the post-otic re^rion, but intemally^ is apparently incomplete. (Pei'sonal communication to the author.)

Keibel Mall 220.jpg

Fig. 220.— A. (After Kollmann) Human embryo with fourU«a Homitt section througli the region behind t^ Arch, f. Anat. u, Phy><ii>1.. Anst. Abt. o( MmiteB ot the embryo Bhowu in F.

", 2.5 mm. long. Mogn. 1891. Piste III, Fit. 3.1

ituogiienihichte des Mensthen, Fis. It9.) 30 t I. B. (Ebnula, Fig. 5S.) Transvene lOWQ in Fig. 220. A. C. (After Kollmann. Tiwuvene MCtion (hroujh the tenlh pair each assumes an epithelial character and becomes arranged about a central cavity or myoccel (Fig. 230, d). At the posterior end of the cervical region a solid column of cells marks for a short period the remains of the neurenteric canal. Bevond this in the axial region lies the tissue of the primitive streak which is continued into the mesenchyme of the allantoic stalk. In subsequent development mesoderm is differentiated from the anterior end of the primitive streak on each side of the posterior end of the neural groove. In this mesoderm successive somites are formed. Finally, as the differentiation of the body extends posteriorly, a definite primitive streak gradually gives way to a mass of mesenchymal cells situated between the ectoderm and entoderm, and then, in the caudal process, to a mass of cells entirely surrounded by ectoderm. From this mass of cells are successively differentiated the more caudal mesodermic somites.

(c) Axial Mesenchyme

As the chorda dorsalis becomes differentiated (see below) marked changes take place in the somites. For a time these consist of epithelial tissue which surrounds a central cavity or myoccel (Fig. 220, C). Toward the end of the third week the cervical and thoracic myocceles become gradually filled with branched spindleshaped mesenchyme cells which come from the surrounding epithelium. The medial wall of the somite opens, and the mesenchyme cells wander out toward the neural tube and the chorda, and give rise to a tissue which ensheathes these organs (Fig. 221). The mass of mesenchyme derived from each somite represents a sclerotome. The successive sclerotomes soon fuse so as to give rise to a continuous mass of mesenchyme. The mesenchyme of the two sides becomes fused. Alter gi\'ing rise to the sclerotomes the somites become converted into myotomes, the further fate of which is described in the section on the development of the muscular system. In many of the lower vertebrates the lateral layer of the myotomes gives rise to dermis, but in mammals the dermis comes chiefly, if not wholly, from axial mesenchjTne. (Bardeen, Johns Hopkins Hospital Eeports, vol. ix, 1900.)

(d) Parietal and Visceral Layers of the Mesoderm

During the formation of the embryonic coelom, the lateral tmsegmented mesoderm plates become divided into two layers, a parietal layer and a visceral layer (Figs. 220, C, and 221). The cells facing the coelom assume an epithelial character. The deep strata of the parietal layer give rise to scleroblastema, from which some of the skeletal apparatus and connective tissues of the trunk and limbs are derived. The deeper strata of the visceral layer give rise to the connective tissues as well as to the musculature of the thoracic and abdominal viscera.

(e) Mesenchyme of the Head

The axial mesoderm of the trunk is continued forward on each side of the chorda dorsalia to the region of the base of the midbrain. From it arises a large part of the mesenchyme of the head, including most of that which gives rise to the skeletal structures of the cranium and the upper part of the face. The transformation of mesoderm into definitive skeletal structures is more direct in the cranial than in the spinal region. The formation of somites for the axial region of the head is restricted to the postotlc region, and even here it is, as mentioned above, less complete than

Keibel Mall 221.jpg

Fig. 221.— (AftiT Kollnmnn, Arch. f. AnM, 0. Pni-jiol.. Anal. Abt.. 1891, Plata III. FL(. 8.) Tran-veres

in the trunk. The cranial mesoderm apparently is largely converted into mesenchyme without going through that process of division into somites characteristic of the spinal mesoderm. The mesenchyme near the chorda in the occipital region shows no segmentation in the latter half of the first month. More laterally segmentation is indicated by the formation of myotomes from the dorso-lateral portion of the mesoderm. Near the myosepta the mesoderm may show a slight condensation.

In the prechordal mesenchyme of the head there are differentiated in many vertebrates vesicular cavities, "head cavities," lined by epithelium, from which musculature and mesenchyme arise. There are four such cavities in selachians and in reptiles. Their relation to the somites is undetermined. In man very transitory structures of this nature have been reported (Zimmermann, Ueber Kopfhohlenrudimente beim Menschen, Arch. f. mikr. Anat., 1898, vol. liii), but they are rare and play no essential part in development. The dorsal portion of the lateral mesoderm plate of the trunk is continued anteriorly into the branchial region, where it gives rise to the mesenchjTne of the branchial arches and partly also to that of the head. Ventral to the branchial arches the lateral mesoderm of the trunk is continued into the pericardial mesoderm. The coelom does not extend into the branchial region of the lateral mesoderm of the head.

(f) Origin of the Connective Tissues

From the mesenchyme, derived in part directly from the primitive embryonic mesodermic tissue, in part from somites differentiated from this primitive tissue, and in part from the primitve streak, there arses a syncytial tissue which in turn gives origin to the various connective tissues and skeletal structures of the body as well as to some other structures, for instance, muscles and blood-vessels.

In the adult connective tissues the bulk of the tissue substance is usually described as extracellular.^ The chief problem for those who have studied the histogenesis of the connective tissues has been to determine whether the substances which are intercellular in the differentiated tissues have an intracellular or an intercellular origin. The weight of evidence seems at present to be decidedly in favor of the intracellular origin (Fleming, 1891, 1897, 1902, Retterer, 1892-1906, Spuler, 1897, Mall, 1902, and Spalteholz, 1906). Among recent investigators who believe that the connectivetissue fibres have an intercellular origin may be mentioned E. Laguesse (1903) and Fr. Merkel (1895, 1909).^ Golowinski, while contending that the fibres appear between the cells, admits that they rise close to the cell body. according to him, most investigators have described essentially the same phenomena, but some consider the mother substance in which the fibres arise as ectoplasm, while others consider it an intercellular substance. The majority of those who adopt the view that the ** intercellular" portions of the adult connective tissues are intracellular in origin describe the primitive mesenchymal cells as becoming differentiated into endoplasmic and ectoplasmic portions. In the ectoplasm the intercellular elements characteristic of each of the various kinds of connective tissue are differentiated while the endoplasm becomes <5onverted into the cells of the adult tissue. Retterer (1892-1906) gives a different description of the process. according to him the primitive tissue from which the various kinds of connective tissue are differentiated consists of a homogeneous syncytium in which nuclei are scattered about. This homogeneous syncytium becomes differentiated into two parts, a hyaloplasm and a granular chromophilic portion. The granular chromophilic portion surrounds the nuclei and gives rise to branching processes which anastomose so as ultimately to form an extensive network. The hyaloplasm lies in the meshes of this network. The fibres of recticulum, elastic fibres, and the branched anastomosing processes which fill the canaliculi of bone arise from the chromophilic network, while white fibrous tissue and the chief part of the ground substance of cartilage and of bone are differentiated from the hyaloplasm.

  • Spalteholz (Anat. Anz., 1906) has, however, shown tliat even in the adult many, if not all, of the fibrils have an intracellular position.

Recently still another view of the origin of the fibrils of the c'onnective tissues has been advanced. It has been known for some time that in the vitreous humor before the entrance of blood-vessels and mesenchyme cells there exists a fibrillar structure the components of which may be looked upon as branched anastomosing processes of cells of the retina and lens. From this fibrillar network the fibrils of the adult vitreous humor are probably derived. Aurel V. Szily (1908) has described a fibrous network filling in spaces throughout the embryonic body before the origin of the mesenchyme. The fibrils of the network are branched anastomosing processes of the epithelial layers bounding the various cavities. Szily thinks that when the mesenchyme cells arise they wander into meshes of this fibrillar network and enter into intimate relations with the component fibrils. The fibrils subsequently lose connections with the epithelial cells from which they arise. according to Szily the fibrils of the early embryonic syncytium are thus of epithelial origin, while the cell protoplasm is of the mesenchymal origin. Although the early connective-tissue fibrils are thus according to this view of epithelial origin, at a later stage connective-tissue fibrils are also differentiated in the ectoplasm of cells derived from the mesenchyme. according to Retterer (1904 and 1906) the syncytium of the cutis arises partly from the epidermis.

The following account of the origin of the connective tissues is based chiefly on the paper of Mall, who has taken up the problem in connection with the pig and man.

At an early stage there appear to be many individual cells in the mesenchyme which multiply rapidly, so that in certain regions the nuclei are closely packed together. Then the cells unite to form a syncytium and the protoplasm of the syncytium increases more rapidly in amount than the nuclei, so that the latter appear more widely separated from one another than at first. The nuclei at an early stage lie within the protoplasm of the syncytium, but gradually differentiation takes place. Immediately about the nuclei the protoplasm becomes granular and forms an endoplasm which is distinct from the rest of the syncytium or ectoplasm. From the granular endoplasm about the nuclei processes may extend into the surrounding ectoplasm. In the ectoplasm fibrillation becomes more and more distinct. The nuclei surrounded by the endoplasm come to lie in certain of the meshes of the network formed by the ectoplasm. In other of the meshes merely a fluid substance is seen. From this embryonic syncytium the various types of connective tissue are differentiated.


Reticulum seems to be the least highly differentiated form of tissue which arises from the embryonic connective-tissue syncytium. The reticulum develops directly in the syncytial ectoplasm, while the nuclei and endoplasm are converted into cells which lie upon the reticulum fibres. In the liver the origin of the reticulum differs from that in other parts of the body in that it arises from Kupffer's endothelial cells instead of from mesenchyme. The endothelial cells form a syncytium in which the reticulum fibres are differentiated. according to Retterer the reticulum fibres arise from chromophilic processes of the perinuclear protoplasm.

White Fibrous Tissue

In the development of white fibrous tissue from the embryonic syncytium Mall distinguishes two stages. In the first or prefibrous stage a tissue much resembling reticulum is differentiated, in the second or fibrous stage true white fibrous tissue appears. (Fig. 222, A and B.) In the first stage the syncytium grows very rapidly. The ectoplasm increases in amount much more rapidly than the endoplasm. The nuclei, however, multiply, and the endoplasm about each nucleus becomes drawn out spindle-like, giving rise to the well-known embryonic bipolar cells. The tips of these cells are extended into the ectoplasm, and here the endoplasm appears constantly to contribute to the ectoplasm. The ectoplasm becomes steadily more fibrillated. The strands of ectoplasm become more and more drawn out, in tendons and fascia? into parallel, in areolar tissue into interweaving bundles of fibres. In the fibrous stage the embryonic fibres are converted into true white fibrous tissue, their chemical nature meanwhile changing. The fibres at first occasionally anastomose, but during further development the anastomosing bridges begin to break down. according to Mall the larger fibres become split into the individual fibrils of white fibrous tissue. The embryonic spindle-shaped cells become converted into the adult connective tissue corpuscles. according to Retterer the fibres in the prefibrous stage belong to the chroraophilic processes of the perinuclear protoplasm. On the other hand, the collagenous fibres arise from the hyaloplasm {ectoplasm).

The body of the cornea is composed of a tissue the origin of which is similar to that of white fibrous tissue. It retains more features characteristic of the embryonic connective tissue than does the ordinary white fibrous tissue. It contains no elastic fibres.

Keibel Mall 222.jpg

(Fig. 12. Mail.) Section thraugh the skin of (

k plK 5 cm. long. White Gbrag

C. (Fig.

E. {Fig

Elastic Tissue

With the exception of the tissue of the cornea probably all white fibrous tissue contains a greater or less number of elastic fibres intermingled with the bundles of white fibrils. The elastic-tissue fibres apparently are differentiated . directly in the same syncytial ectoplasm in which the bundles of white fibrils develop (Fig. 222, C). The youngest pigs in which Mall found elastic fibres were four centimetres long. these fibres were found in the aorta and neighboring arteries. Fenestrated membranes are formed by the coalescence of neighboring fibres. Spalteholz (1906) has found elastic fibres in the truncus arteriosus of pig embryos 9.2 mm. long. Ranvier held that elastic fibres arise from the fusion of rows of elastic granules. according to Mall, elastic fibres are never formed by the fusion of rows of such granules. Spalteholz has likewise found that the elastic fibres are directly differentiated. according to Eetterer, the elastic fibres arise in the perinuclear chroraophilic protoplasm and from the chromophilic processes which spring from it.

Adipose Tissue

Adipose tissue appears in the fourth month in the human embrj^o. In the regions where the adipose tissue is formed the embryonic mesenchymal tissue becomes differentiated on the one hand into blood-vessels and a supporting fibrous-tissue framework, on the other into cells in the protoplasm of which granules of fat appear. The granules of fat in each cell gradually become consolidated, so that finally there arises a single large globule of fat which greatly distends the cell. The protoplasm of the cell now forms a thin covering for the globule of fat. The nucleus surrounded by a small amount of granular protoplasm lies at one side. The fat cells are arranged more or less definitely with relation to the blood-vessels and frequently form well-marked clusters. (See Bell, 1909.)


In the formation of cartilage the ectoplasm of the syncytium becomes more and more dense. The nuclei surrounded by endoplasm come to lie in spaces in the ectoplasm, thus forming precartilage cells which in turn become converted into cartilage cells (Fig. 222, D). The syncytial ectoplasm undergoes chemical changes which make it exhibit the reactions characteristic of hyaline ground substance. Not infrequently the ectoplasm before becoming converted into hyaline ground substance becomes marked out into cell territories by the appearance of membranes between the cell units. These membranes appear as fine lines in cross section and have staining reactions similar to hyaline cartilage. When this condition is found, the cartilage has an epithelioid appearance (cellular cartilage).

The endoplasmic units or cartilage cells exhibit a differentiation into perinuclear and peripheral portions. From the peripheral portion hyaline substance is differentiated so as to form a capsule (Max Schultze). The capsule appears lighter than the surrounding tissue and has slightly different staining reactions. Meanwhile the endoplasm increases in amount, the nuclei multiply, and from time to time cell division takes place in the endoplasmic units, but this division does not extend into the surrounding ectoplasm. When cell division takes place, the line of separation between the two daughter cells usually becomes marked by a fine septal membrane composed of a substance that has some of the staining qualities of the cell capsules. This septum then becomes divided into two lamellae, each of which together with half of the old capsule surrounds a daughter cell. Sometimes the capsules of several successive generations of cells remain distinct for a considerable period, so that a capsule which first surrounded a single cell comes to surround several groups of daughter cells, each group and each daughter cell having in turn a capsule of its own. Usually, however, the primitive capsules become indistinguishably fused with the surrounding matrix, so that capsules about single cells or pairs of cells alone remain distinct. Growth of cartilage is in part interstitial, in part perichondral. The interstitial growth is due (1) to the direct increase in amount of the ectoplasm or ground substance, (2) to the formation of cell capsules at the periphery of the cells and the fusion of these capsules with the matrix, and (3) to cell multiplication. Perichondral chondrification is due to the formation of new cartilage beneath the perichondrium. The ground substance increases in amount faster than the cells multiply.^

In white-fibrous cartilage bundles of fibrils develop in the syncytium while the hyaline substance is being deposited. In elastic cartilage, according to Mall, elastic fibres are formed after the hyaline substance has been differentiated. according to Spalteholz (1906), however, elastic fibres appear before the hyaline ground substance in the ear cartilage of the pig. In the arytenoid cartilage clumps of elastic granules are deposited. While Eanvier held that elastic fibres arise from the fusion of rows of these granules. Mall, as mentioned above, believes that neither here nor elsewhere are the elastic granules fused to form elastic fibres.


The histological structure of bone is still a matter of dispute. Most investigators seem to consider the ground substance to be composed of bundles of fibrils resembling those of white fibrous connective tissue embedded in a homogeneous ** cement" substance. V. Kolliker, who considered the cement substance to be slight in amount, believed the calcium salts to be embedded both in this and in the fibrils. V. Ebner, 1875, believed the calcium salts to be embedded chiefly in the cement substance. Eetterer, 1905 and 1906, believes the ground substance of bone to be composed of a chromophilic reticulum embedded in a hyaloplasm impregnated with calcium salts. It is well known that the ground substance of bone contains a collagenous substance similar to that of white fibrous tissue.

Bone, like other connective tissues, is formed from a blastemal syncytium. Ectoplasm becomes distinct from nucleated endoplasmic cell units. In the ectoplasm calcium salts are deposited. Two stages may thus be distinguished, — a pre-osseous, previous to the deposition of calcium salts, and an osseous, after these salts have been deposited. During ossification about two parts of inorganic salts combine with one part of organic matter. The cells which give rise to bone may appear similar to ordinary immature connective tissue cells or they may pass through a stage in which they appear epithelioid in character. Cells of the latter type are frequently found in regions where layers of bone are being applied to pre-existing bone or to calcified cartilage. The epithelioid cells, which Gegenbaur called osteoblasts, form a layer from the deep surface of which certain cells branch, anastomose, and give rise to an osteogenetic syncytium which becomes converted into bone (Fig. 223, A).

according to v. Kolliker (Gewebelehre) and to many other investigators, the osteoblasts secrete the ground substance, which, therefore, is to be looked upon rather as intercellular than as intracellular. To Waldeyer (1865) we are indebted for the first clear description of the differentiation of the ground substance of bone in the peripheral protoplasm of the osteoblasts.

  • For details concerning the development of cartilage see Retterer (1900).

The endoplasmic units, or bone corpuscles, have branched processes which anastomose freely through the canaliculi with those of neighboring cells. Before birth (Neumann) the periphery of the bone corpuscles becomes differentiated into a resistant cuticle which has staining reactions similar to elastic tissue (Retterer) and which is resistant to strong acids and alkalies. Brosike (1885) considered this cuticle (bone-cell capsule) to be composed of keratin, but Kolliker has shown it to be soluble in boiling water. according to Eetterer the protoplasm of the branching processes which lie in the canaliculi is converted into a similar substance.

In the human embryo bone arises chiefly in connection with a transitory cartilaginous skeleton which it gradually in large part replaces. Thus the vertebrae, ribs, sternum, the skeleton of the extremities, and most of the base of the skull are first formed of cartilage, and the cartilage is later replaced by bone (substitution bone). Centres of ossification may appear within the cartilage (endochondral ossification) or beneath the perichondrium (subperiosteal ossification). On the other hand, most of the bones of the face and the flat bones of the skull are formed directly in membranous tissue (intramembranous bone).

When bone is first formed in the embryo, it consists of a eoarse plexiform or spongy framework, in the meshes of which lies a vascular embryonic marrow. To the walls of the spaces in this primitive spongy bone successive layers of bone are added by osteoblasts, so that the spaces come to have lamellated walls. Similarly beneath the periosteum lamellae of bone are laid down, so that the surface of the bone comes to consist of a series of successive lamellae. The formation of definite lamellae of compact bone is not, however, well marked until after birth. Previous to this period the vascular spaces in the bone are relatively large, so that the coarse spongy structure mentioned above is long retained. In long bones Schwalbe found compact lamellar bone formed about the marrow cavity and in the Haversian canals in the sixth month after birth, but beneath the periosteum not until the fourth year. Kolliker (Gewebelehre) found lamellar subperiosteal bone as early as in the first year after birth.

During the period of the growth of bone new bony tissue is being constantly added in some regions, while in other regions the bone already formed is absorbed to make way for new vascular marrow cavities. In this process of bone absorption large cells, osteoclasts, containing, according to v. Kolliker who first described them, from one to sixty nuclei, play a chief part (Fig. 223, B). These osteoclasts vary in size, being from 43 to 91 /* long, 30 to 40 M wide, and 16 to 17 fi thick. They apparently have the power of dissolving bone or calcified cartilage. The depressions which they cause in bone are called Howship's lacunae. according to Kolliker, they arise from osteoblasts, and may again divide up into osteoblasts or after remaining for a greater or less length of time in the bone marrow they may disappear. The nuclei within the cell multiply by direct division. The changes of form which bones undergo through the process of growth by apposition of new layers of bone to pre-existing layers and the absorption of bone previously laid down are well illustrated by comparing the jaw of the infant with that of the adult (Fig. 224, C).

Under the term Sharpey's fibres, according to Eetterer (1906), several distinct structures have been described: (a) prolongation of the periosteum into the bone; (b) granular elastic protoplasmic processes of the lamellar system; (c) portions of the bone in which calcium salts have disappeared from the hyaloplasm and fibrous tissue has been differentiated. The true Sharpey's fibres are probably prolongations of the periosteum left behind as successive layers of bone are differentiated beneath the periosteum. To this brief description of the general nature of the process of ossification we may add a short account of the special features which characterize intramembranous, subperiosteal, and endochondral types of ossification.

Intramembranous Ossification (Fig. 222, E, Fig. 224). — ^In this type of ossification bone first appears in the form of a network of spicules interwoven with a network of blood-vessels. Ossification begins at a centre from which it radiates peripherally. As one passes from the centre towards the periphery in the early period of ossification, one finds all stages from fully formed bone to an undifferentiated embryonic connectivetissue syncytium. In ossification in very young embryos the connectivetissue syncytium appears to be directly transformed into bone. The transformation is marked first by the fibrils of the ectoplasm becoming more clearly marked, and then by the appearance of a basophilic substance in the ectoplasm. In older embryos the ectoplasm is, according to Mall (1906), transformed into prefibrous tissue and the latter is transformed into bone. The diameter of the embryonic bone corpuscles, according to v. Kolliker, varies from 13 to 22 f^.

The primitive plexiform bone is thickened by deposit of osseous substance beneath the periosteum. The latter appears soon after bone-formation has commenced. The spaces in the plexiform network of bone at an early stage become converted into canals containing blood-vessels and primitive marrow. In bone of membranous origin cartilage may subsequently be developed beneath the periosteum. Examples of this are to be found in the temporomandibular joint.

Keibel Mall 224.jpg

Fig. 224.— A.

Keibel Mall 225A.jpgKeibel Mall 225B.jpg

Fig. 225. A.— (After Siymonowici, Text-book ol Histology, translated by MiwCum, Fig. 103.) From B longitudinal section of * faigrr of & tlirBe-and-«-halt-montlia human fetus. Two-thirds oJ the second phftlbox are repreeeuted. At X a periosteal bud is to be seen. Magn. about 85 : I

Subperiosteal Ossification (Fig. 225, A and B). — Bone is formed in the deep layer of the periosteum (perichondrium) essentially as bone is formed in membrane which is not closely applied to cartilage. The bone formed beneath the periosteum has at first a coarse plexiform structure. The meshes of the osseous framework enclose vascular embryonic marrow. As mentioned above, dense subperiosteal lamellst are formed in human long bones in the first year after birth, according to Kolliker (Gewebelehre), while according to Schwalbe they are not formed until the fourth year. Subperiosteal ossification is the sole method of substitutioa of osseous for cartilaginous tissue in some of the bones (in the ribs, for example), while in others it is closely associated with endochondral ossification (diaphyses of the long bones). When it is the sole method of ossification, the underlying cartilage frequently undergoes changes similar to those preceding endochondral ossification (see below).

Keibel Mall 226-228.jpg

Fig. 226, B. — (Afor Siymonowic., Teit-book of HinWlogy, tmoJiliWd by MMC»llum. Fig. 196.) From » lonsitiidiaal nection of a tinger of a four-moDths huioBD fitiu. Only tbfl diaphysis of the saccnd phalanx is rtpreMnt«d. Mien, about 86 : 1.

Endochondral Ossification

In endochondral ossification processes from the osteogenic layer of the perichondrium, or periosteum, extend into the substance of the cartilage, and these give rise on the one hand to destructive activities which break down the cartilage and on the other to constructive activities which result in the formation of bone. Endochondral ossification is preceded by well-marked changes in the cartilage (Fig. 225). The cartilage cells first multiply rapidly in number and then enlarge so that the matrix becomes relatively reduced in amount. Neighboring cartilage cells may so expand that the matrix between them disappears. Meanwhile calcium salts are deposited in the matrix in the form of granules which may become confluent. The processes from the periosteum break into the cavities occupied by the cartilage cells, enlarge them, and thus give rise to primary marrow cavities. In the phalanges and other long bones of limited size, the cartilage at the centre of the shaft may be completely absorbed before the endochondral ossification begins. The primitive marrow is vascular and contains an embryonic syncytium not highly differentiated. Osteoblasts and osteoclasts and embryonic connective tissue, however, appear in it at an early stage, fat and marrow cells at a later period. About the primitive marrow cavities bone is quickly laid down and there thus arises spongy endochondral bone. The bone first laid down is later again absorbed during development of the larger central marrow cavities. From the cavities into which the marrow first penetrates it gradually extends into neighboring cartilage-cell spaces. As the osteogenic tissue spreads, the surrounding cartilage undergoes changes similar to those which took place at the primary centre of ossification. Thus, so long as the process of ossification continues, the cartilage farthest removed from the centre of ossification shows the least modification from the type of primitive hyaline cartilage, while as one passes toward the centre of ossification one finds the successive changes of cell multiplication, cell expansion, and calcification of the matrix. In long bones these successive stages are especially well marked. The multiplication of cartilage cells gives rise to groups which become arranged in long columns which are parallel to the long axis of the bone. The boundary between the zone of ossification and that of the highly modified cartilage is usually fairly sharp (Fig. 225, B). Capillary loops extend close to the limit of the advancing ossification. The extremities of these loops are often dilated.

The fate of the cartilage cells in the calcified matrix is still in dispute. Most modem investigators, including Kolliker ( Gewebelehre, 1889), seem to follow Sharpey and Loven in con<;luding that the cartilage cells are destroyed as osteogenic tissue derived indirectly from the periosteum enters the cell spaces. Numerous accurate observers, however, among who may be mentioned H. Muller (1859), Ranvier (1865), and Retterer (1900), T)elieve that the cartilage cells become converted into osteogenic tissue, each cartilage cell giving rise to several smaller cells and to reticular tissue. The old view, that cartilage may become directly converted into bone, seems to have few modern adherents.*

  • according to Strelzoff (1873), this metaplasia is constant in some regions, for example, in the lower jaw of human embryos.

In epiphyses centres of ossification arise at a comparatively late period. Blood-vessels, which spring from the periosteum and from the bone marrow, penetrate into the epiphyseal cartilage long before ossification begins. Friedlander (1904) gives good pictures of the blood-vessels in the epiphyseal cartilages of the long bones. In some cartilages the blood-vessels appear in the third fetal month. In the seventh all the larger cartilaginous areas show rich vascular plexuses.

Growth of Bone. — The question as to whether or not there is an interstitial growth of bone has given rise to extensive investigations. The evidence is fairly conclusive that there is no wellmarked interstitial growth in bone. Hales, Duhamel, John Hunter, and others showed, during the eighteenth century, that two pegs driven into a bone do not move apart during development unless there is a non-ossified region between the two pegs. Z. G. StrelzoflF (1873), however, brought forward a certain amount of evidence to show that under some circumstances there may be a slight interstitial growth of bone.^ Experiments made with madder go to show that growth of bone takes place entirely by apposition. Madder stains newly forming bone, and by feeding it to young animals the successive applications of layers of bone may be followed. Experiments along this line were first performed by Duhamel and J. Hunter. Duhamel also showed that a ring placed on the outside of a long bone of a young animal may eventually be found in the marrow cavity.

Regeneration. — In case of fractures union is effected by osteoblasts which give rise to new bone which unites the broken ends. These osteoblasts in young animals may apparently be derived either from the marrow or from the periosteum, but in the adult chiefly, if not wholly, from the periosteum. Bonome (1885) has, however, brought forward evidence to show that the bone corpuscles in certain conditions where they are supplied with abundant nutrient blood may give rise to osteoblasts. Not infrequently temporary cartilage is produced in places at the site of the fracture. In man fibrous tissue is often produced if the broken ends of the fractured bone are not closely approximated. The experiments of Oilier and others have shown that the bone-forming power of the periosteum may be exercised even when this is transplanted into the tissues at some distance removed from any bone. If the periosteum is preserved it has the power of restoring in nearly normal form large parts of bone.

See also Egger (1885) and J. Wolff (1885).


Since the preceding section on the development of the connective tissues was written, there have appeared several important articles on the development of the connective tissues in mammals. Fr, Merkel (1909) brings forth new evidence in favor of the intercellular origin of the connective-tissue fibrils. He pays particular attention to the development of limiting membranes which in places sharply mark off epithelium from the underlying connective tissue. These membranes, according to Merkel, arise from the connective-tissue matrix independently of the connective-tissue cells. They may become fibrillated. Similar non-cellular connective-tissue substances are formed at an early stage in the septa between myotomes, and later between muscle cells of various types and in lamellated connective tissues. The sarcolemma of striated muscle cells has a similar origin, according to Merkel. Disse (1909), on the other hand, describes the osteogenetic tissue as arising from the cell protoplasm. Each osteoblast becomes divided into two parts, a perinuclear granular portion and a peripheral, usually basilar, hyaline portion. The hyaline substance derived from osteoblasts fuses to form a mass in which fibrils differentiate after the hyaline substance is separated from the perinuclear protoplasm. Bell (1909) gives a clear description of the development of adipose tissue. He supports the view of the histogenesis of the connective tissues adopted by Mall.


(On the development of the connective tissues, with especial reference to man.)

Aeby, C. L. : Uber die Symphysis ossium des Menschen nebst Beitragen zur Lehre vom hyalinen Knorpel und seiner Verknocherung. Zeitschr. f. rat. Med. Bd. 4. 1858.

AsKANAZY, M. : Uber das basophile Protoplasma der Osteoblasten, Osteoklasten und anderer Gewebszellen. Centralbl. f. allg. Pathol, usw. Bd. 13, S. 369378. 1902.

Bardeen, C. R., and Lewis, W. H. : Development of the Limbs, Bodywall, and Back in Man. Amer. Joum. of Anat. Vol. 1. 1901.

B^clard: Uber die Osteose, oder die Bildung, das Wachstum und die Altersabnahme der Knochen des Menschen. Meckel's Arch. Bd. 6, S. 405-446. 1820.

Bell, E. T. : I. On the occurrence of Fat in the Epithelium, Cartilage, and Muscle Fibres of the Ox. II. On the Histogenesis of the Adipose Tissue of the Ox. Amer. Joum. of Anat. Vol. 9, p. 401. 1909.

Bidder, Alf. : Osteobiologie. Arch, f . mikr. Anat. Bd. 68, S. 137-213. 1906.

Bolk: Die Segmentaldifferenzierung des menschlichen Rumpfes und seiner Extremitaten. III. Beitrage zur Anatomic und Morphogenese des menschlichen Korpers. Morphol. Jahrb. .Bd. 27. 1899. IV. Ebenda, Bd. 28. 1899.

Boll: Untersuchungen iiber den Bau und die Entwicklung der Gewebe. Zweite Abteilung: Die Entwicklung des fibrillaren Bindegewebes. Arch. f. mikr. Anat. Bd. 8, S 28. 1872.

BoNOME, A.: Zur Histogenese der Knochenregeneration. Virchow's Arch. Bd. 100. 1885.

Brosike, G. : Uber die sogenannten Grenzscheiden des Elnochenkanalsystems, nebst Bemerkungen uber die Keratinsubstanzen. Arch. f. mikr. Anat. Bd. 26. 1885.

Bruning, Fr. : Uber das Auftreten des Fettes im Knochenmark in den ersten Lebensjahren. Diss. Freiburg i. Br. 1903.

Coca, Arth. F. : Die Bedeutung der Fibroglia-Fibrillen. Eine embryologische Studie. Virchow's Arch. Bd. 186. 1906.

Disse, J.: Die Entstehung des Knochengewebes und des Zahnbeines. Arch. f. mikr. Anat. Bd. 73, S. 563-606. 1909.

Ebner, v.: Uber den feineren Bau der Knochensubstanz. Sitzungsberichte der Kais. Akademie der Wissensehaften. Wien. Bd. 72, S. 49. 1875. Sind die Fibrillen des Knochengewebes verkalkt oder nichtf Arch. f. mikr. Anat. Bd. 29. 1887.

Egger, G. : Experimentelle Beitrage zur Lehre vom interstitiellen Knochenwachstum. Virchow's Arch. Bd. 99. 1885.

FiBiCH, R. : Beitrag zur Kenntnis der Histologie des hyalinen Knorpels. Anat. Anz. Bd. 24, S. 209-214. 1904.

Flemming, W. : Zur Entwicklungsgeschichte der Bindegewebesfibrillen. Intemat, Beitrage zur wissensch. Medizin. Virchow's Festschrift, Berlin, 1891. Uber die Entwicklung der collagenen Bindegewebesfibrillen bei Amphibien und Saugetieren. Archiv. f. Anat. u. Physiol. S. 171. 1897. Die Histogenese der Stiitzsubstanzen dor Bindegewebsgruppe. Hertwig's Handb. d. vgl. Entwicklungsgesch. 1906, erschienen 1902. Friedlander, Friedr. v.: Beitrag zur Kenntnis der Architektur spongioser Knochen. Anat. Hefte. Bd. 23, Heft. 72. 1904.

Fromm, Wald. : Beitrag zur Kasuistik der kongenitalen Knorpelreste am Halse. Diss. Munchen 1904. (Literatur. 63 Fiille.)

Froriep, a. : Kopf teil der Chorda dorsalis bei menschlichen Embryonen. Festschr. f. Henle. 1882.

Garmaschew, W. p. : Veranderungen des Knochenmarks wahrend des WachstumS. Diss. St. Petersburg, 1902. (Russiseh.)

Gegenbaur, C. : Uber die Bildung des Knochengewebes. Jen. Zeitschr, f . Med. u. Naturw. Bd. 1, S. 343-369. 1864; Bd. 3, S. 206-246. 1867.

Geipel, p.: Ll)er elastisches Gewebe beim Embryo und in Geschwiilsten. Centralbl. f. allg. Pathol, usw. Bd. 17, Nr. 14. 31. Juli 1906. Of. Nakai^ Virchow's Arch. Bd. 182. 1906. (Man and fowl.)

GrOLOwiNSKi, J.: Zur Kenntnis der Histogenese der Bindegewebsfibrillen. Anat. Hefte. 1. Abt. Bd. 33. 1907.

Grandis e Copello : Studi sulla composizione chimica delle ceneri delle cartilagini in relazione col process© di ossiiicazione. Arch. Sc. Med., p. 175-183. Vol. 26. 1902.

Grekow, a. W. : Uber die morphologischen Veranderungen bei Rohrenknochen im Verlaufe des Kindesalters. Diss. St. Petersburg. 1903. (Russian.)

Hammar, J. A. : Zur Kenntniss des Fettgewebes. Arch, f . mikr. Anat. Vol. 45. 1895.

Hansen, C. C. : Uber die Genese einiger Bindegewebsgrundsubstanzen. Anat. Anz. Bd. 16, S. 147. 1899.

Heller, G. : Beitrage zur Histogenese der elastischen Fasem im Netzknorpel und Ligamentum nuchae. Monatsschr. f. prakt. Dermat. Bd. 14, S. 217-237. 1892.

Hertwig, 0.: Uber die Entwicklung und den Bau des elastischen Gewebes im Netzknorpel. Arch. f. mikr. Anat. Bd. 9, S. 80. 1873.

HoRWiTZ, K. : Uber die Histologie des embryonalen Knochenmarkes. Wien. med. Wochenschr. Jg. 54, S. 1449-1453, 1499-1503, 1544-1547, 1582-1584, 1631 bis 1634. 1904.

HuGONNENQ : Sur la fixation des bases alcalines dans le squelette mineral du foetus pendant les cinq demiers mois de la grossesse. C. R. Acad. Sc. Paris. T. 130, p. 941. 1900.

Kassowitz, M. : Die normale Ossifikation usw. Strieker's med. Jahrb. 1879-1880.

KoLLiKER, A.: Die normale Resorption des Knochengewebes und ihre Bedeutung fur die Entstehung der typischen Knochenformen. Leipzig 1873. Zur Entwicklung des Fettgewebes. Anat. Anz. Bd. 1, S. 206-208. 1886.

KoLLER, H. : 1st der bindegewebig vorgebildete Knochen imstande, Knorpel zu bilden? Arch. f. Entwicklungsmechanik. Bd. 3. 1892.

KoLLMANN, J. : Die Entwicklung der Chorda dorsalis beim Menschen. Anat. Anz. Bd. 5. 1890. Die Rurapfsegmente menschlicher Einbryonen von 13-35 Unvirbelu. Arch. f. Anat. u. Physiol., Anat. Abt. 1891.

Korff: Uber die Entwicklung der Zahnbeinund Knochengrundsubstanz der Saugetiere. Anat. Anz. Ergh. S. 132. 1906.

KuSKOw, N. : Beitrage zur Kenutnis der Entwicklung des elastischen Gewebes. Arch. f. mikr. Anat. Bd. 30, S. 32-38. 1887. Laguesse, E :. Sur Thistogenese de la fibre collag^ne et de la substance fondamentale dans la capsule de la rate chez les selaciens. Arch, d* Anatomic microscop. Vol. 6, p. 99. 1903.

Landois, L. : Untersuchungen iiber die Bindesubstanz und den Verknocherungsprozess derselben. Zeitschrift f. Zool. Bd. 16, S. 1-26. 1866.

Leboucq, H. : Etudes sur I'ossification. Evolution du Cartilage embryonnaire chez les mammiferes. Bull. Acad. Roy. Belg. Vol. 14, p. 457-459. 1877.

Leser, E. : Uber histologische Vorgange an der Ossificationsgrenze, mit besondei-er Beriicksichtigung des Verhaltens der Knorpelzellen. Arch. f. mikr. Anat. Bd. 32, S. 214-222. 1888.

LoiSEL, G. : Formation et evolution des elements du tissu elastique. These de Paris 1896.

Lowe, L. : Uber die Umwandlung der Osteoklasten im Knochenmark, nebst Bemerkungen iiber Knochenwachstum. Arch. f. mikr. Anat. Bd. 36, S. 618-626. 1879. Lwoff: Uber die Entwicklung der Fibrillen des Bindegewebes. Sitz.-Ber. d. Wiener Akad. d. Wiss. M.-X. Kl. Bd. 98, Abt. 3, S. 184. 1889.

Mall, F. : Das retikulierte Gewebe und seine Beziehungen zu den Bindegewebesfibrillen. Abhandl. d. K. Sachs. Gesellsch. d. Wiss. Bd. 17. 1891. The Development of the Connective Tissues from the Connective Tissue Syncytium. Amer. Joum. Anat. 1902. ALisuoka: Die Regeneration des Knorpelgewebes. Virchow's Arch. Bd. 175. 1904.

Merkel: Zur Histogenese des Bindegewebes. Verhandl. d. anatom. GeselLschaft, Basel. S. 45. 1895. Betrachtungen iiber die Entwicklung des Bindegewebes. Anat. Hefte, Bd. 38, S. 321. 1909.

MiJLLER, Heinr. : Uber die Entwicklung der Knochensubstanz nebst Bemerkungen iiber den Bau rachitischer Knochen. Zeitschr. f. wiss. Zool. Bd. 9, S. 147 233. ia59. Uber Verknocherung. Eine Erwiderung an N. Lieberkiihn. Wiirzburger naturw. Zeitschr. Bd. 4. 1863.

Nakai, Motokichi: Uber die Entwicklung der elastischen Fasem im Organismus und ihre Beziehungen zu der Gewebsfunktion. 1 Taf. Virchow's Arch. Bd. 182, S. 153. 1905. Neumann : Beitrage zur Kenntnis des normalen Zahnbeinund Knochengewebes. Leipzig 1863.

Nicolas, A. : Developpement et structure des os. Traite d'Anatomie humaine par Poirier et Charpy. I. Paris 1899. Ollier: Du Perioste, 1865. Traits de la regeneration des os. 2 volumes. Paris 1867.

Pacchioni, D. : Untersuchungen iiber die normale Ossifikation des Knorpels. Jahrb. f. Kinderheilk. Bd. 26, S. 327-340. 1902.

Pommer, G. : Uber die Osteoklastentheorie. Virchow's Arch. Bd. 92. 1883. Rabl, C. : Theorie des Mesoderms. Morph. Jahrb. Bd. 15. 1889. Rambaud et Renault: Origine et developpement des os. Paris 1864.

Ranvier, L. : De quelques points relatifs a preparation et aiix proprietes des cellules du cartilage. Journal de la physiol. T. 6, p. 577. 1865. Quelques faits relatifs au developpement du tissu osseux. C. R. Acad. Sc. Paris. Vol. 77, p. 1105-1109. 1873. Nouvelles recherches sur la structure et le developpement des tendons. Arch. de Physiol. Vol. 6, p. 181-202. 1874. Developpement du tissu conjunctif. Traite technique d'Histologie, p. 405 409. 1875.

Renaut, J. : Sur la formation cloisonnante du cartilage hyalin foetal. C. R. Acad. Sc. Palis. T. 104, p. 1452-1455. 1887. Sur la tramule du tissue conjunctive. Arch. Anat. Microsc. T. 6, p. 1. 1903.

Retterer, Ed.: Les dCoouvertes recentes relatives au developpement du tissu conjunctif. Joum. de TAnat. et de la Physiol. Annee 28, 1892, p. 211. Sur le developpement des cavites closes tendineuses et des bourses muqueuses. C. R. de la Soc. de Biol., Ser. 10. T. 2. 1895. Sur le developpement morphologique et histologique des bourses muqueuses et des cavites peritendineuses. Joum. de TAnat. et de la Physiol. Annee 22, p. 256. 1896. Similitude des processus histogenetiques chez Tembryon et Tadulte. Joum. de TAnat. et de la Physiol. Annee 36, p. 358. 1900*. Evolution du cartilage transitoire. Joum. de TAiiat, et de la Physiol. Annee 36, p. 467-565. 1900. Structure et evolution du tegument exteme. Journ. de TAnat. et de la Physiol. Annee 30, p. 337. 1904. Structure et histogen^e de Vos. Joum. de TAnat. et de la Physiol. Annee 41. 1905. Histogenese des tissus fibreux et fibrocartilaerineux. C. R. Soc. Biol. Paris. T. 58, p. 240-243. 1905. Evolution du tissu osseux. Journ. de PAnat. et de la Physiol. Annee 42, p. 193 bis 238. 1906. Des Elements qui servent k la croissance et k la renovation du derme, etc. Joum. de TAnat. et de la Physiol. Annee 42, 1906. De Fosteogenese et du developpement variable des elements de la substance osseuse. Compt. rend. Soc. Biol. Vol. 64. 1908. De Tossification infracartilagineuse ou enchondrale. Compt. rend. Soc. Biol. Vol. 64. 1908.

RoLLETT, A.: Entwicklung des Bindegewebes. Strieker's Handbuch. Bd. 1, S. 61, 1871. Uber die Entwicklung des fibrillaren Bindegewebes. Unters. Inst. f. Phys. u. Histolog. Graz. S. 257-265. 1873.

Salvioli, I.: Contributo alio studio deir accrescimento del tessuto connettivo. Arch, per le Sc. Med. Torino. Vol. 13, p. 281-290. 1889.

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