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=Chapter  11. The Development of the Circulatory System=  
=Chapter  12. The Histogenesis of Bone and the Development of the Skeletal System=  


==I. Histogenesis of Bone==


==I. The Interpretation of the Embryonic Circulation==
Histologically bone belongs to the group of tissues known as the connective and supporting tissues. In spite of their widely varying adult conditions these.tissues are all similar in that the secreted parts, rather than the cells themselves, carry out the functional role characteristic of the tissues. It is the secreted, fibrous portion of the binding connective tissues which ties together various other tissues and organs ; it is the secreted matrix of cartilage and of bone which affords rigid support and protection to soft parts and furnishes a lever system on which the muscles may be brought into play.


The embryonic circulation is difficult to understand only when
the meaning of its arrangement is overlooked. If one bears in mind
certain fundamental conceptions as to the significance of the circulatory system in organic economics, and the basic morphological
principle that any embryo must go through certain ancestral phases
of organization before it can arrive at its adult structure, the changes
in the arrangement of vascular channels during the course of development form a coherent and logical story.


In the embryo as in the adult the main vascular channels lead to
The cellular elements of these tissues must not be overlooked, however, in emphasizing the functional importance of the cell products. The cells are, so to speak, the power behind, in that they extract the appropriate raw materials from the circulation, elaborate them within their cytoplasm, and deposit the characteristic secretion as an end-product. Moreover after the fiber is formed or the matrix is laid down, it is dependent on the cells for maintenance in a healthy active conditidn.
and from the centers of metabolic activity. The circulating blood
carries food from the organs concerned with its absorption to parts of
the body remote from the source of supplies; oxygen to all the tissues
of the body from organs which are especially adapted to facilitate the  
taking of oxygen into the blood ; and waste materials from the places
of their liberation to the organs through which they are eliminated.  
One of the primary reasons the arrangement of the vessels in an
embryonic mammal differs so much from that in the adult, is the fact
that the emjbryo lives under conditions totally unlike those which
surround its parents. Its centers of metabolic activity are, therefore,
different; and, since the course of its main blood vessels is determined
by these centers, the vascular plan is different. No such profound
changes occur between the embryonic and the adult stages in the
circulation of a fish where embryo and adult are both living under
similar conditions.  


The organs which in the adult mammal carry out such functions
as digestion and absorption, respiration, and excretion are extremely
complex and highly differentiated structures. They are for this reason
slow to attain their definitive condition and are not ready to become
functional until toward the close of the embryonic period. Moreover
the conditions which surround certain of the developing organs during
intra-uterine life absolutely prevent their becoming functional even
were they suflSciently developed so to do. Suppose^ the lungs, for
example, were functionally competent at an early stage of development. The fact that the embryo is reliving ancestral conditions in its
private amniotic aquarium renders its lungs as incapable of functioning as those of a man under water. Likewise the developing digestive
organs of the embryo are inaccessible to raw food materials. Further
examples are not necessary to make it obvious that were the embryo
dependent on the same organs which carry on metabolism in the adult,
development would be at an impasse.


An embryo must, nevertheless, solve the problem of existence
Embryologically the entire connective-tissue group arises from mesenchymal cells. It is not surprising, in view of their closely related functions and their derivation from a common type of ancestral cell, that one type of connective tissue may be converted into or replaced by another. This facility for changing the type of specialization is sometimes referred to as plasticity.
during the protracted time in which it is building a set of organs
similar to those of its parents. In the absence of a dowry of stored
food in the form of yolk, the mammalian embryo draws upon the
uterine circulation of the mother. Utilization of this source of supplies
depends on the development of a special organ which serves through
fetal life and is then discarded. The embryo takes food not into its
slowly developing gastro-intestinal tract but into its chorion, a membrane projected outside its own body and applied to the uterine wall
to form, together with it, the placenta. The nutritive materials there
absorbed from the maternal blood must be transported to the body of
the growing embryo by its own blood stream.  


The use of food materials to produce the energy expressed in
growth depends on the presence of oxygen. For growth there must
be a means of securing oxygen and carrying it, as well as food, to all
parts of the body. Nor can continued growth go on unless the waste
products liberated by the developing tissues are eliminated. The blood
of the embryo cannot be relieved of its carbon dioxide and acquire a
fresh supply of oxygen in the primordial cell clusters which will later
become its lungs. It cannot excrete its nitrogenous waste products
through undeveloped kidneys. Its respiration and excretion, like its
absorption of food, are carried out in the rich plexus of small blood
vessels in the chorion. Here the fetal blood is separated from the
maternal, by tissues so thin that it can readily give up its waste materials to, and receive food and oxygen from, the maternal blood stream,
just as the mother’s own tissues constantly carry on this interchange
with the circulating blood. The placenta is thus the temporary
alimentary system, lung, and kidney of the mammalian embryo. The
large size of the umbilical blood vessels to the placenta is not a surprising thing — it is the entirely logical, the inevitable, expression of
the conditions under which the embryo develops.


The plasticity of the connective-tissue series is well exemplified in the development of bone. Bone does not form in vacant spaces. It is always laid down in an area already occupied by some less highly specialized member of the connective-tissue family. The formation of some bones begins in areas already occupied by connective tissue — such bones are said to be intramembranous in origin, or are spoken of as membrane bones. Other bones are laid down in areas already occupied by cartilage. In this case they are said to be pndochondral in origin, or, are called cartilage bones. It should be clearly borne in mind that these terms apply solely to the method by which a bone develops and do not imply any differences in histological structure, once the bone is fully formed.


The enormous chorionic blood supply during fetal life, with the
entire disappearance of this special arc of the circulation when the
organism assumes adult methods of living, is a striking example of the
determination of vascular channels by the location of functional
centers. We must not, however, overlook the fact that there are many
other centers of activity in the growing embryo less conspicuous but
equally important for its continued existence. Each developing organ
in the embryonic body is a center of intense metabolic activity.
During fetal life it must be supplied by vascular channels adequate to
care for its growth. But that is not all. Up to the time of birth each
organ has been drawing on blood furnished with food and freed of
waste materials by the activities of the maternal organism. At birth
all this must change. Each organ essential to metabolism must be
ready to assume its own active share in the process. Their vessels must
be adequate to take care not only of the needs of these organs themselves but also of the functions these organs must now take over in
maintaining the metabolism of the organism as a whole.


While the functional significance of the arrangement of the blood
Likewise we should know at the outset what histologists mean when they speak of cancellous bone and compact bone. These terms refer not to the method of origin of the bone but to its density when fully formed. Developmen tally all bone goes through the spongy or cancellous stage. Some bones later become compact, others remain cancellous. Most bones are compact in some areas and cancellous in others.
vessels is always of importance, especially in understanding the
progressive changes in vascular plan, there is another factor which we
cannot overlook. This factor is conservative, having to do with the  
things we inherit from our forebears. The goal of the embryonic
period is the attainment of a bodily structure similar to that of the
parents. Because it is so familiar, we accept with complaisance the  
remarkable fact that this goal is attained with absolute regularity.  
Accidents there may be, leading to defective development or malformation — but the fertilized ovum of a pig never gives rise to a cow.  
The new individual will show detailed differences from its parents,
differences which are capitalized in the slow march of evolution; but
in a single generation these differences are never radical. We say
that the offspring has inherited the structure of its parents. It does
more. It inherits the tendency to arrive at its adult condition by
passing through the same sort of changes which its ancestors underwent in the countless millions of years it took their present structure
to evolve.  


Applied to the development of the circulatory system of mammals
this means that the earliest form in which it appears will not be a
miniature of the adult circulation. The simple tubular heart pumping
blood out over aortic arches to be distributed over the body and
returned to the posterior part of the heart by a bilaterally symmetrical
venous system, in short the vascular plan which we see in young
mammalian embryos (Fig. 45), is essentially the plan of the circulation
in fishes. When we realize this, we are not puzzled either by the
appearance of a full complement of aortic arches, or by their subsequent disappearance to make way for a new respiratory circulation in
the lungs. We see the march of progress from a logical beginning in
ancestral conditions toward the consummation of fetal life with an
organization like that of the parent.


In addition to the fundamental ground plan of the circulation of
The subject of bone development can be presented more simply if we take up first the formation of primary cancellous bone intramembranously ; then the method by which this same type of spongy bone is formed within cartilage, and finally the changes by which cancellous bone, formed in either of the above ways, may become secondarily compact.
the mammalian embryo, recapitulations account for many transitory
peculiarities. The formation of a conspicuous though empty yolk-sac
with a complement of blood vessels almost as well developed as the  
vitelline vessels of animals well endowed with yolk, is clearly a recapitulation of ancestral conditions. So also is the highly developed
system of venous channels in the mesonephros. If the organ itself
appears it brings with it its quota of vessels, no matter whether or not
the organ is destined to degenerate later in development.  


Whatever peculiarities may be impressed on the course of the
===Intramembranous Formation of Primary Cancellous Bone===
circulation by the appearance of ancestral structures or by the  
In an area where intramembranous bone formation is about to begin we find an abundance of mesenchymal cells congregated and numerous small blood vessels present. The mesenchymal cells soon exhibit a tendency to cluster together in more or less elongated groups here and there throughout the area. If we study a group of this type which has been aggregated for a short time we can make out the beginning of a definite plan of organization. Near the axis of the cord delicate fibers appear, produced by the secretory activity of the cells. As this fibrous strand becomes more definite, the cells tend to become ranged against it (Fig. 151, A). In so doing they retract the cytoplasmic processes which are so characteristic of undifferentiated mesenchymal cells and become rounded. In this stage we have essentially a connective tissue in which the fibrous strands are for the most part rather widely separated from one another, and in which each strand has, lined up against it^ the cells responsible for its production.
development of special fetal organs such as the yolk-sac and the  
placenta, the main blood currents will at any time be found concentrated at the centers of activity. Changes of these main currents as one
center retrogresses and another becomes dominant, must take place
gradually. Large vessels become smaller, what was formerly an
irregular series of small vessels becomes excavated to form a new main
channel, but the circulation of blood to all parts of the body never
ceases. Even slight curtailment of the normal blood supply to any
region would stop its growth ; any marked local decrease in the circulation would result in local atrophy or malformation ; complete interruption of any important circulatory channel, even for a short time,
would inevitably mean the death of the embryo.  


II. The Arteries
The actual deposition of bone matrix begins very soon after the establishment of these primordial strands of mesenchymal cells and fibers. In fact one usually finds the formation of bone beginning on the older part of a strand while the strand itself is still being extended at one end by the aggregation of more mesenchymal cells (Fig. 151,


The Derivatives of the Aortic Arches. In vertebrate embryos
six pairs of aortic arches are formed connecting the ventral with the
dorsal aorta. The portions of the primitive paired aortae which bend
around the anterior part of the pharynx constitute the first (i.e., the
most anterior) of these aortic arches. In its course around the pharynx
the first aortic arch is embedded in the tissues of the mandibular arch
(Fig. 136, A). The other aortic arches develop later, in sequence, one
aortic arch in each branchial (gill) arch posterior to the mandibular


I'k;. 151, Formation of trabeculae of membrane bone. Projection drawings from the mandible of a pig embryo 130 mm. in length (cf. Fig. 182).


Abbreviations: Matrix cal., ossein matrix impregnated with calcium salts; Matrix oss., ossein matrix not yet impregnated with calcium salts.


Fig. 134. Ventral aspect of vessels in the branchial region of pig embryos
A). When the mesenchymal cells ranged against the fibrous axis of such a strand become active in the secretion of calcareous material they are spoken of as osteoblasts. We should not lose sight of the fact that they are the same cells which formed the fibrous axis of the original strands, given a new name in deference to their further specialization and altered internal chemistry.
of various ages. (After Heuser.) The drawings in this and the three following
figures were made directly from injected specimens rendered transparent by
treatment with wintergreen oil. A, 24 somites; B, 4.3 mm.; C, 6 mm.; D,
8 mm.; E, 12 mm.  




arches, leaves only the ventral and dorsal aortic roots and the third,  
In studying the deposition of bone matrix one must bear in mind its dual nature. The matrix consists of an organic fibrous framework which is impregnated by a subsequent deposit of inorganic calcium compounds. We may liken the matrix of bone to reinforced concrete* In the making of a road or a wall, a meshwork of steel is first placed in the forms and concrete is then poured in. The steel gives the finished structure tensile strength and a certain amount of elasticity, the concrete gives form and hardness. So in bone the organic fibers {ossein fibers) impart strength and resilience, while the calcium salts whh which the fibers are impregnated give to the completed matrix body and rigidity.
fourth, and sixth arches to play an important r61e in the formation
of adult vessels.  


In dealing with embryos of 9 to 12 mm. we have already seen
how the portions of the ventral aortic roots which formerly acted as
feeders to the first two arches were retained as the external carotid
arteries. These vessels, in part through the small channels left by the
disintegration of the aortic arches with which they were originally
associated, and in part through the formation of new branches to
subsequently formed structures, nourish the oral and cervical regions
(Figs. 67, 133 and 137, A, B).


The internal carotid arteries also, are, familiar as vessels which
The two steps in the deposition of bone matrix may be demonstrated readily in areas where active bone forma^tion is going on, owing to the fact that the presence of calcium compounds- in a tissue markedly increases its affinity for stains. Even after most of the calcium salts have been removed from the ossein framework by treatment of the tissue with acids (decalcification) to permit the making of sections, the staining reaction is still apparent. This indicates that the ossein fibers in which calcium has once been deposited are more or less permanently changed chemically even though all the calcium possible is subsequently removed.
arise as prolongations of the dorsal aortic roots and extend to the brain
(Fig. 67). When the portion of the dorsal aortic root which lies between arch 3 and arch 4 dwindles and drops out, the third arch is left
constituting the curved proximal part of the internal carotid artery
(Figs. 133, B, C, and 137, A~C). The part of the ventral aortic root
which, from the first, has fed the third aortic arch becomes somewhat
elongated and persists as the common carotid artery (Figs. 133, 137).  


The fourth aortic arch has a different fate on opposite sides of the
body. On the left it is greatly enlarged and persists as the arch of the
adult aorta (Figs. 133 and 134-137). On the right the fourth arch
forms the root of the subclavian artery. The short section of the right
ventral aortic root proximal to the fourth arch persists as the innominate (brachiocephalic) artery from which both the right subclavian and the right common carotid artery arise (Fig. 133, C).


The sixth aortic arch changes its original relationships somewhat
If we look at a strand on which the osteoblasts have been active for a time (Fig. 151, B) we see, next to the osteoblasts, a zone of bone matrix which takes very little stain. This is the newly deposited organic portion of the matrix as yet unimpregnated with calcium salts. It consists of a feltwork of minute fibers so delicate and so closely matted together that it is very difficult in ordinary preparations to see the individual fibers at all. Slightly farther from the osteoblasts the matrix is densely stained (Fig. 151, B). This part of the matrix has been impregnated with calcium salts, chiefly phosphates and carbonates, and has thereby been converted into true bone matrix. The calcium utilized by the osteoblasts in this process is brought to them by the blood stream where it is carried in soluble form, probably in organic linkage. It is interesting to note in this connection that the presence of calcium and of phosphates in the blood is not in itself all that is necessary for this process. There must be present also sufficient vitamin D, which in some way facilitates the extraction by the osteoblasts of these raw materials from the blood and their deposition in insoluble form as part of the bone matrix. The absence of vitamin D from the system results in the formation of bone matrix deficient in calcium salts and therefore lacking in rigidity — a cohdition not infrequent in pigs. Stock raisers have miscalled this condition rheumatism but it is really the same condition known medically as rickets.
more than the others. At an early stage of development branches
extend from its right and left limbs toward the lungs (Fig. 134, D, E).  
After these pulmonary vessels have been established^ the right side  of the sixth aortic arch loses communication with the dorsal aortic
root and disappears (Fig. 135, A, B). On the left, however, the sixth
arch retains its communication with the dorsal aortic root. The  
portion of it between the point where the pulmonary trunk is given
off and the dorsal aorta is called the ductus arteriosus (Figs. 133, C, and
138). During the fetal period when the lungs are not inflated the  
ductus arteriosus shunts the excess blood from the pulmonary circulation directly into the aorta. The functional importance of this channel
will be more fully appreciated when we have given it further consideration in connection with the development of the heart and the
changes which take place in the circulation at the time of birth.  


^ The details of the formation of the pulmonary arteries differ somewhat in
different mammals. In most of the forms which have been carefully studied (man,
cat, dog, sheep, cow, opossum) the pulmonary arteries maintain their original paired
condition throughout their entire length. In these forms part of the right sixth arch
is retained as the proximal portion of the adult right pulmonary artery (Fig, 133).
The pig is unusual in having its pulmonary branches fuse with each other proximally,
forming a median vessel ventral to the trachea (cf. Figs. 134, E, and 135, A). Distal
to this short median trunk the pulmonary vessels retain their original paired condition, each running to the lung on its own side of the body. Proximally the median
trunk becomes associated with the left sixth arch and the right sixth arch drops out
altogether.


In the deposition of the matrix, the fibrous core of the original strand serves as a sort of axis on which the first matrix is laid down. When such a strand is completely invested by bone matrix, it is called a trabecula (little beam). As the osteoblasts continue to secrete and thereby thicken the trabecula, the accumulation of their own product forces them farther and farther away from the axial strand about which the first of the matrix was formed. The new matrix added is not laid down uniformly. It is possible to make out in it markings which are suggestive of the growth rings of a tree. Apparently the osteoblasts work more or less in cycles, depositing a succession of thin layers of matrix. Each of these layers of the matrix is called a lamella (Fig. 152). As the row of osteoblasts is forced back with the deposit of each succeeding lamella, not all the cells free themselves from their secretion. Here and there a cell is left behind. As its former fellows continue to pile up new matrix, it becomes completely buried (Fig, 151, B). An osteoblast so caught and buried is called a bone cell {osteocyte)^ and the space in the matrix which it occupies is called a lacuna. The bone cells, thus entrapped, of necessity cease to be active bone formers, but they play a vital part in the maintenance of the bone already formed. They have delicate cytoplasmic processes radiating into the surrounding matrix through minute canalidhli. The processes of one cell come into communication with the processes of its neighbors (Fig. 152). Thus the bone cells nearer to blood vessels absorb and hand on materials to their more remote fellows which in turn utilize these materials in maintaining a healthy condition in the organic part of the bone matrix. It is the senescence of these cells with the consequent lowering of their efficiency and the resultant deterioration of the ossein component of the matrix which is in part responsible for the decreased resiliency of the bones in advanced age.






While these changes have been taking place in the more peripheral
part of the vascular channels which lead to the lungs, a fundamental
alteration has occurred in the main ventral aortic stem. Formerly a
single channel leading away from the undivided ventricle of the
primitive tubular heart, the ventral aorta now becomes divided
lengthwise into two separate channels. This division begins in the
aortic root just where the sixth arches come off, and progresses thence
toward the heart. Meanwhile, as wc shall see when we take up the
development of the heart, the ventricle has become divided into right
and left chambers. The final result of these two synchronous partitionings is the establishment of a channel leading from the right
ventricle to the lungs by way of the sixth aortic arches, and another
separate channel leading from the left ventricle to the dorsal aorta by
way of the left fourth aortic arch.


The Derivatives of the Intersegmental Branches of the Aorta.  
Fio. 152. A small area of bone and adjacent marrow as seen in highly magnified decalcified sections. The drawing has been schematized somewhat to emphasize the relations of the cytoplasmic processes of the osteoblasts* and the bone cells so important in nutrition. In the adjacent marrow developmental stages of various types ofiiiijioQd cells, have been
In dealing with the structure of 9-12 mm. embryos comment was
made on the importance of the small intersegmental branches from
the dorsal adrta (Figs. 67 and 136, F). At that time, too, we became
familiar with some of the vessels which are derived from these branches.
The anterior appendage bud first appears at the level of the seventh
cervical intersegmental, and it is this artery which becomes enlarged
to form the subclavian. With the enlargement of the left fourth aortic
arch to form the main channel leading from the heart to the dorsal
aorta, the dorsal aortic root on the right side becomes much reduced
(Fig. 135, A-D). Caudal to the level of the subclavian it drops out
entirely. It will be recalled that the sixth aortic arch also drops out
on this side. This leaves the right subclavian communicating with the
dorsal aorta by way of a considerable section of the old dorsal aortic
root and the fourth aortic arch. In the adult, both the distal part of




Fig. 153. Diagrams showing stages in establishing of a characteristic area of primary cancellous bone by extension and coalescence of originally separate trabeculae.


Fig. 136. Lateral aspect of vessels in the branchial region of pig embryos
of various ages. (After Heuser.) A, 10 somites; B, 19 somites; C, 26 somites;
D, 28 somites; E, 30 somites; F, 36 somites (6 mm.).


this vessel (formed by the intersegmental artery) and its proximal
As the various trabeculae in an area of developing bone grow, they inevitably come in contact with each other and fuse. Thus trabeculae, at first isolated, soon come to constitute a continuous system (Fig. 153). Because of its resemblance to a latticework (Latin — cancellus), bone in thb condition, where the trabeculae are slender and the spaces between them extensive, is known as cancellous bone. The spaces between the trabeculae are known as marrpw spaces.
portion (appropriated from the old aortic arch system) pass under the  
name subclavian. This accounts for the striking dissimilarities of
origin between the right and left subclavian arteries in the adult.  


===Endochondral Bone Formation===
As the term implies, endochondral bone formation goes on within cartilage. It cannot be stated too strongly that cartilage does not, in this process, become converted int# bone. Cartilage is destroyed and bone is formed where the cartilage used to be. The actual bone formation is essentially the same as in the case of membrane bone. The phenomena of special interest in connection with this type of bone development are those involved in the destruction of the cartilage preliminary to the formation of bone.


===Cartilage Formation===
To trace the process logically we must start back with the formation of cartilage. The first indication of impending chondrogenesis is the aggregation of an exceedingly dense mass of mesenchymal cells. This cell mass gradually takes on the shape of the cartilage to be formed. The histogenetic changes involved are not at first conspicuous. During the period of preliminary massing the cells have been migrating in from surrounding regions and also increasing the local congestion by rapid proliferation. As they are packed in together they lose their processes and become rounded (Fig. 154, A, 1). When it seems as if no more cells could possibly be crowded in, the course of events changes. The cells begin to separate from one another. This is due to the fact that they have become active in


Fig. 137. Continuation of the same series of lateral views of injected embryos.
A, 14 mm.; B, 17 mrn.; C, 19.3 mm.; D; 20.7 mm.


Fig. 154. Photomicrographs of developing cartilage. The areas photographed were from the margins of the paranasal cartilage of pig embryos between 25 and 30 mm. in length. For location of cartilage in head see figure 175.


Cephalic to the subclavian arteries, a series of longitudinal anastomoses appear connecting the cervical intersegmentals to form the
A, Early stage showing: at (1) the massing of mesenchymal cells which were about to be incorporated in the growing margin of the cartilage; and at (2) an area where matrix formation is already beginning.
vertebral arteries (Fig. 137). When the vertebral arteries are thus
established, all the intersegmental roots back to the subclavian drop
out, leaving the vertebral as a branch of the subclavian (Figs. 1 33, C,
and 137). The manner in which the vertebrals swing in to the mid-line
rostrally and become confluent with each other to form the basilar
artery, and the anastomosis between the internal carotids and the
basilar artery in the region of the hypophysis, are already familiar.  


Caudal to the subclavian, the internal mammary artery is formed
B, Slightly more advanced stage of the same cartilage showing: at (1) increase in the amount and density of the matrix in the center of the growing cartilage; at (2) concentration of the surrounding mesenchyme to form tire perichondrium; and at (3) the addition of new cartilage matrix peripherally secreting. It is the accumulation of the secretion of the cells which gradually forces them farther and farther apart unti^ they come to lie isolated from one another in the matrix they have produced (Fig. 1 54, A, 2). Such a method of increase in m^ss, where there are many scattered growth centers contributing independently to the increase in bulk of the whole, is known as interstitial growth. This interstitial growth of young cartilage stands in sharp contrast to the appositional growth of such rigid substances as bone or dentine or enamel where the matrix is laid down in successive layers one upon another. Obviously interstitial growth implies plasticity of the substance produced. Were the substance produced unyielding, the very activity of a number of growth centers within it would soon crowd those growth centers to obliteration.
by longitudinal anastomosing of the more cephalic of the thoracic
intersegmental arteries. Subsequent dropping out of the proximal
parts of the other intersegmentals leaves it arising from the subclavian.  
Thus the steps in its origin are strikingly similar to the processes by
which the vertebral artery was established cephalic to the subclavian
(Fig. 133). Still farther caudally in the body, the intersegmental
arteries retain their original independent condition as paired branches
extending from the aorta dorsad on either side of the neural tube and
the developing spinal column (Fig. 67). Even in the adult these vessels
appear with little change in their original relations.  


The Enteric Arteries. The first of the three enteric arteries to
As the cartilage matrix is increased in amount its affinity for basic stains becomes more marked, due probably to increase in concentration of the characteristic substance in it known chemically as chondrin. At the same time the matrix becomes more rigid with a resultant checking of interstitial growth. The cells continue to secrete to a certain extent, however, as evidenced by the fact that in mature cartilage the matrix immediately surrounding the cells becomes more dense than the rest of the matrix. This area of denser matrix around the lacuna in which the cell lies is known as the capsule. As the cartilage grows older the capsules become more conspicuous and many of them come to contain more than one cell. These nests of cells in a common capsule are the result of cell divisions, following which the daughter cells are held imprisoned in the original capsule of the mother cell — further evidence of the loss of plasticity in the matrix.
appear is the anterior {superior) mesenteric. We have already followed
its origin as a pair of arteries originally called the omphalomesentcrics
which, in young embryos, extended to the surface of the yolk-sac
(Fig. 45). When the yolk-sac degenerates and the ventral part of the
body closes in, these paired channels fuse with each other to form a  
median vessel situated in the mesentery and extending to the gut loop
in the belly-stalk (Fig. 66). This is now called the anterior mesenteric
artery. With the elongation and coiling of the intestine in the region
fed by it, the anterior mesenteric artery acquires many radiating
terminal branches. Its primary relations, however, remain unchanged.  


The celiac artery arises from the aorta in a manner basically similar
The formation of a matrix so rigid that interstitial growth is checked, takes place first centrally in an area of developing cartilage. When the center has become too rigid for interstitial growth to continue, appositional growth begins to take place peripherally. While the cartilage has been increasing in mass it has been acquiring a peripheral investment of compacted mesenchyme. This investing layer of mesenchyme soon becomes specialized into a connectivetissue covering called the perichondrium. The layer of the perichondrium next to the cartilage is less fibrous than the outer layer and the cells in it continue to proliferate rapidly and become active in the secretion of cartilage matrix. For this reason it is known as the chondrogenetic layer of the perichondrium. It is through the activity (rf the chondrogenetic layer that the cartilage continues to grow
to the origin of the anterior mesenteric artery, but at a slightly later
peripherally, by apposition, long after interstitial growth has ceased in the matrix first formed.
stage of development. The embryonic body has, therefore, become
more nearly closed ventrally and the primary dorsal mesentery has  
been established. As a result the primary paired condition we expect
to see in the early stages of the formation of all of the main enteric
arteries is greatly abbreviated in the case of the celiac artery, and
almost from its first appearance it is a median vessel extending in the
mesentery toward the gastric region of the gut (Fig. 67). As development progresses it becomes extensively branched, being the main
artery which feeds the gastro-hepato-pancreatic region of the digestive
system and also the spleen which arises in its territory (Fig. 111).  


The inferior mesenteric artery has an origin similar to that of the
celiac. It is established caudal to the anterior mesenteric artery slightly


Fig. 155. Drawing showing periosteal bud and an area of endochondral bone formation from the radius of a 125 mm. sheep embryo. The small sketch indicates the location of the area drawn in detail.


Fig. 138. Drawing (X 10) of parasagittal section of 15 mm. pig embryo.
Abbreviations: Cart, eros., area from which cartilage has recently been eroded; Cart, pre-eros., area with cartilage cells enlarged and arranged in rows presaging erosion; Cart, trab,, remnant of cartilage matrix which has become calcified and serves as an axis or core about which bone lamellae are deposited to form a bone trabecula; Mes., mesenchymal cell.
The section is in a plane slightly to the left of the mid-line and passes through
the ductus arteriosus, lung bud, stomach, gonad, and metanephros.  




later in development than the time at which the celiac appears and  
Cartilage Erosion. When a mass of cartilage is about to be replaced by bone, very striking changes in its structure take place. The cells which have hitherto been secreting cartilage matrix begin to destroy the matrix. The lacunae become enlarged and a curious arrangement of the cartilage cells becomes evident. The cells erode the cartilage in such a manner that they become lined up in rows (Fig. 155). This process of destruction continues until the cartilage is extensively honeycombed. Meanwhile the tissue of the perichondrium overlying the area of cartilage erosion becomes exceedingly active. There is rapid cell proliferation and the new cells, carrying blood vessels with them, begin to invade the honeycombed cartilage (Fig. 155).
is the main vessel to the posterior part of the intestinal tract (Fig. 111).  


The Renal Arteries. The mesonephros is suppliea by many small
===The Deposition of Bone===
arteries which arise ventro-laterally from the aorta. While the metanephroi or permanent kidneys are still very small, they lie in close
It is a striking fact that during its growth cartilage is devoid of blood vessels, the nearest vessels to it being those in the perichondrium. The invasion of cartilage by blood vessels definitely determines its disintegration as cartilage, and at the same time is the initial step in the formation of bone. For this reason the enveloping layer of connective tissue, up to this time called perichondrium because of its relation to the cartilage, is now called periosteum because of the relations it will directly acquire to the bone about to be formed. This change will not be confusing if we stop to think that both these terms are merely ones of relation, which translated mean, respectively, that tissue which surrounds cartilage, and that tissue which surrounds bone. The important fact to bear in mind is that this enveloping layer of tissue is of mesenchymal origin and therefore contains cells of the stock that may develop into any of the connectivetissue family to which bone as well as cartilage belongs. When, therefore, a mass of periosteal tissue {periosteal bud, Fig. 155) grows into an area of honeycombed cartilage it carries in potentially boneforming cells. These cells come to lie along the strand-like remnants of cartilage, just as in membrane bone formation osteoblasts ranged themselves along fibrous strands. The actual deposition of bone proceeds in the same manner endochondrally as it does intramembranously. The only difference is that in one case a strand-like remnant of cartilage serves as an axis for the trabecula, whereas in the other case deposition begins on a fibrous strand. Extensions and fusions of the growing trabeculae soon result in the establishment of typical cancellous bone similar to that formed intramembranously.
proximity to the mesonephroi and are fed by small arteries which  
arise from the aorta along with the mesonephric vessels (Fig. 127). The  
local vessels associated with the kidneys are progressively enlarged
as the kidneys themselves grow in bulk and become the renal arteries
of the adult (Fig. 128).  


The Arteries Arising from the Caudal End of the Aorta. The


main aortic trunk decreases abruptly in size where the large umbilical
===The Formation of Compact Bone from Primary Cancellous Bone===
(allantoic) arteries (Fig. 138) turn off into the belly-stalk. Beyond
The difference between cancellous bone and compact bone is architectural rather than histological. The fundamental composition of the bone matrix, its lamellation, and the relations of the bone cells to the matrix, are the same in both cases. It is the way in which the lamellae are arranged that distinguishes these two types of bone from each other. In cancellous bone the disposition of lamellae is such that it leaves large marrow spaces between the trabeculae. In compact bone there has been a secondary deposit of concentrically arranged lamellae in the marrow spaces which greatly increases the density of the bone as a whole.
this point the aorta is continued toward the tail as a slender median
vessel called the caudal artery (Fig. 67).  


The posterior appendage buds arise some time after the placental
The essential differences between the two, and the way in which cancellous bone may become converted into compact bone, can be illustrated by a simple schematic diagram. Figure 156, 1, shows the arrangement of lamellae and marrow spaces in primary cancellous bone. The osteoblasts which have formed the trabeculae still lie along them on the surface toward the marrow cavity. If such an area is to IxTome compact, these osteoblasts enter on a period of renewed activity and deposit a series of concentric lamellae in the marrow cavity. Frequently if the marrow spaces are irregular there is a preliminary rounding out of them by local resorption of the bone already formed (Fig. 156, 2). This is then followed by the deposition
circulation has been established. The umbilical arteries are consequently of considerable size, and the small vessels which branch off
from them to feed the appendage buds are by comparison quite
insignificant. As the appendage buds grow, these small vessels grow
with them to become the external iliac arteries. When, at birth, the  
placental circulation stops, the umbilical arteries are reduced to small
vessels nourishing the local tissues between their point of origin and  
the umbilicus. We then know their proximal portions as the internal
iliac^ or hypogastric arteries^ and the fibrous cords which still mark their
course along the wall of the bladder (the old allantoic stalk) as the
obliterated branches of the hypogastric arteries. Thus the tables are
turned between fetal and adult life. In the fetus the external iliac
artery to the leg appears as a branch of the dominating umbilical
artery. After birth the reduced umbilical arteries under their new
name of internal iliacs, or hypogastrics, appear as branches of the  
now larger external iliacs. The original umbilical root proximal to
the origin of the external iliac is called the common iliac (Fig. 150).  


III. The Veins


There is a natural grouping of the veins according to their relationships which it is convenient to follow in discussing their development.  
Fig. 156. Diagram showing transformation of cancellous to compact bone. The solid lines indicate the lamellae of primary cancellous bone; the dotted lines show the subsequently added concentric (Haversian) lamellae which nearly obliterate the marrow spaces of cancellous bone. The sequence of events is indicated by the numbers. Note that irregularly shaped spaces in the cancellous bone may be rounded out by absorption before the concentric lamellae are laid down.
Under the term systemic veins we can include all the vessels which  
collect the blood distributed to various parts of the body in the routine
of local metabolism. In young embryos these would be the cardinal
veins and their tributaries, that is, the return channels of the primitive
intra-embryonic circulatory arc. In older embryos and adults the  
systemic veins would include the anterior (superior) caval system
which is evolved from the anterior cardinals, and the posterior
(inferior) caval system which takes the place of the postcardinals and
their tributaries.  


We can set apart from the general systemic circulation three
special venous arcs: the umbilical, returning the blood from the
})lacenta; the pulmonary, returning the blood from the lungs; and
the hepatic portal, carrying blood from the intestinal tract to the liver.
I'he specialized nature of the placental and pulmonary circulations
is obvious. The peculiarities of the hepatic portal system call, perhaps, for a word of explanation. Ordinarily veins^ collect blood from
local capillaries and pass it on directly to the heart. Their blood stream
is away from the organ with which they arc associated ; once collected
within a vein the blood is not redistributed in capillaries until it has
again jiassed through the heart. The portal vein arises in typical
fashion by collecting the blood from capillaries in the digestive tube.
But then, contrary to the usual procedure, its blood flows, not directly
to the heart, but to the liver where it enters a second capillary bed
and is returned by a second set of collecting vessels to the heart. With
reference to the plexus of capillaries in the liver this vein is aflferent.
Hence its designation as a portal (translated = carrying to) vein,
setting it apart from other veins which carry blood only away from
the organ with which they are associated.


There is a tendency among those who have done but little work on the circulation to regard any vessel which carries oxygenated blood as an artery, and any vessel
of the concentrically arranged lamellae, sometimes called Haversian lamellae after the man who first described them in detail (Fig. 156, 3 ). In this process the original marrow spaces are reduced to small canals {Haversian canals^ into which have been crowded the blood vessels which formerly lay in the marrow cavities (Fig. 156, 4 ). These canals maintain intercommunication with each other in the substance of the bone, constituting a network of pathways over which the bone receives its vascular supply. As compared with the marrow spaces of cancellous bone, however, they are very small; and the gross appearance of a bone which has undergone this secondary deposit of concentric lamellae amply justifies characterizing it as ‘'compact.’’
which carries blood poor in oxygen and high in carbon dioxide content as a vein.
This is not entirely correct even for the circulation of adult mammals on which the  
( onception is based. In comparative anatomy and especially in embryology it is far
from being the .case. It is necessary, therefore, in dealing with the circulation of the
embryo, to eradicate this not uncommon misconception.  


The differentiation between arteries and veins which holds good for all forms,
==II. The Development of the Skeletal System==
both embryonic and adult, is based on the structure of their walls, and on the direction of their blood flow with reference to the heart. An artery is a vessel carrying
blood away from the heart under a relatively high, fluctuating pressure due to the
pumping of the heart. Correlated with the pressure conditions in it, its walls are
heavily reinforced by elastic tissue and smooth muscle. A vein is a vessel carrying
blood toward the heart under relatively low and constant pressure from the blood
welling into it from capillaries. Correlated with the pressure conditions characteristic for it, the walls of a vein have much less elastic and muscle tissue than artery
walls, and more non-elastic connective-tissue fibers.


In dealing with the development of the skeletal system we must recognize at the outset that the subject is far too extensive to be covered here with anything like completeness. It is not difficult, however, to become acquainted with the outstanding features in the development of two or three characteristic bones, as, for example: the sequence of events in the formation of a flat bone; the steps involved in the establishment and growth of a long bone; the way separate ossification centers appear in a common primordial cartilage mass and give rise to the various parts of a vertebra. Familiarity with such type processes gives one an understanding of the factors operative in the development of the skeleton as a whole and a background sufficient to permit ready and intelligent following up of developmental details in specific bones in which one may become interested.


Development of Flat Bones. The flat bones, such as the bones of the cranium and face, are for the most part of intramembranous origin. We are, therefore, already familiar with the early steps in their development from our study of the histogenesis of membrane bone (Figs. 151 and 153). After a mass of primary cancellous bone has been laid down in a configuration which suggests that of the adult bone being formed, there appears about this mass a peripheral concentration of mesenchyme (Fig. 157, A). This periosteal concentration of mesenchymal tissue contains potentially bone-forming cells which soon become active and lay down a dense layer of parallel lamellae about the spongy center of the growing bone (Fig. 157, B). Anatomically this dense peripheral portion is known as the outer table of the bone. The inner portion, which in the flat bones usually remains cancellous, is called the diploii. The original mesenchymal tissue which remains in the marrow spaces of the diploe develops into characteristic “red bone marrow” rich in blood-forming elements (Fig. 152).


Fig. 139. Diagrams illustrating stages in the development of the systemic
veins of the pig. (After Butler.) The cardinal and omphalomesenteric veins
are shown in black, the subcardinal system is stippled, the supracardinals are
horizontally hatched, and vessels arising independently of these three systems
are indicated by small crosses,


A, Ground plan of the veins of a young mammalian embryo (cf. Fig. 45).


B, Cross-section (at level of arrow in A) showing dorso-ventral relations
Fig. 157. Diagrams showing the manner in which the dense peripheral layer of a flat bone is formed by the deposition of subperiosteal lamellae about an area of primary cancellous bone.
of the various veins.  


C, Diagrammatic plot of veins of mm. pig embryos.


D, Arrangement of veins in 6“-7 ram. pig embryos.


The story of the growth of the mandible, a membrane bone which starts after the manner of flat bones but which later takes on a very elaborate shape and finally becomes largely compact, can be gleaned by a comparative study of figures 178, 180, and 184.


E, Cross-section (at level of arrow in D) showing dorso- ventral relations of  
Development of Long Bones. The long bones are characteristically of endochondral origin. The cartilage in which they are performed is a tempiorary miniature of the adult bone. Ordinarily there are several ossification centers involved in the formation of long bones. The first one to appiear is that in the shaft or diaphysis. The location of this center is shown schematically in figure 158, A, Such details as the cartilage erosion which preceded its appearance and the manner in which the deposit of bone was initiated have already been considered (Fig. 155). Our interest now is in the relation of such an endochondral ossification center to other centers, and to the bone as a whole.
vessels.  


F, Veins in 12—13 mm. embryos.


G, Veins in 16-19 mm. embryos.


H, Veins in 22-24 mm. embryos.  
Fig. 158, Diagrams showing liie progress of ossification in a long bone. The stippled areas represent cartilage; the black areas indicate bone.


I, Veins in 30-35 mm. embryos.  
A, Primary ossification center in shaft. B, Primary center plus shell of subperiosteal bone. C, Entire shaft ossified. D, Ossification centers have appeared in the epiphyses. E, Entire bone ossified except for the epiphyseal cartilage plates.


J, Cross-section of 17 mm, embryo at level of arrow in G.


K, Plan of veins in adult pig^
Almost coincidently with the beginning of bone formation within the cartilage the overlying periosteum begins to add bone externally (Fig. 158, B). In view of the fact that the bone-forming tissue carried into the eroded cartilage arose from the periosteum, this activity of the periosteum itself is not surprising. Moreover we have already encountered this same phenomenon of periosteal bone formation in the outer table of flat bones.


Changes in the Anterior Systemic Veins Resulting in the  
The formation of bone which starts at about the middle of the shaft soon extends toward either end until the entire shaft is involved (Fig. 158, C), leaving the two ends {epiphyses) still cartilage. Toward the end of fetal life ossification centers appear in the epiphyses. The number and location of these epiphyseal centers vary in different long bones. There is always at least one center in each epiphysis and there may be two or more. Not uncommonly there are two centers in one epiphysis and one in the other, as illustrated in figure 158, D.
Establishment of the Anterior (Superior) Vena <^va. The main
tributaries draining the anterior parts of the adult body are the
external and internal jugulars and the subclavians. In 12 mm. embryos we saw all these vessels laid down. The internal jugular is  
merely the original anterior cardinal under a new name. The external jugular develops from the small branch draining the mandibular region, and the subclavian as an enlargement of one of the segmental tributaries at the level of the anterior appendage bud (Fig. 68).  


When the appendage buds first appear, the heart lies far forward
Between the bone fojcmed in the diaphysis and that formed in the epiphysis there persists a mass of cartilage known as the epiphyseal plaie which is of vital importance in the growth in length of the bone.
in the body. As development progresses it is carried caudad. With
this change in the position of the heart, the common cardinal veins
(ducts of Cuvier) change their relative position in the body and come
to lie caudal to the anterior appendage buds. As a result of this
altered relation the subclavian veins from the anterior appendages,
which early in development drain into the posterior cardinals (Fig.
139, C) eventually empty into the anterior cardinals (Fig. 139, G).  


The outstanding characteristic of the systemic venous plan of a
young embryo is its bilateral symmetry. Paired vessels from the
anterior and from the posterior parts of the body become confluent
to enter the sinus region of a simple tubular heart (Figs. 1 39, A and
144, A-C). The rerouting of the blood to enter the right side of the
heart is the all-important end toward which the mammalian venous
system is progressing throughout its development. In dealing with
local changes this basic trend should never for a moment be forgotten.


In the anterior systemic channels this shift to the right is accomplished very simply and directly. A new vessel forms between the  
We should expect from the rigidity of bone matrix that interstitial growth could not account for its increase in length. This was long ago demonstrated experimentally by exposing a developing bone and driving into it three small silver pegs, two in the shaft and one in the epiphysis. The distance between the pegs being recorded, the incision was closed and development allowed to proceed until a marked increase had occurred in the length of the bone. On again exposing the pegs, the two in the shaft were found to be exactly the same distance apart as when they were driven in, but the distance between the pins in the shaft and that in the epiphysis had increased by an amount corresponding to the increase in length of the bone. This indicates clearly that the epiphyseal plates constitute a sort of temporary, plastic union between the parts of the growing bone. Continued increase in the length of the shaft is accomplished by the addition of new bone at the cartilage plate. These epiphyseal plates persist during the entire postnatal growth period. Only when the skeleton has acquired its adult size do they finally become eroded and replaced by bone which joins the epiphyses permanently to the diaphysis.
right and left anterior cardinals and shunts the left anterior cardinal
blood stream across to the right (Fig. 139, H). With the establishment
of this new channel, the part of the left anterior cardinal toward the  
heart drops out (Fig. 139, I). We have now but to apply the familiar
adult names (Fig. 139, K): the new connecting vessel is the left
innominate; the old anterior cardinal between the union of the subclavian with the jugulars and the new transverse connection is the  
right innominate ; from the confluence of the innominates to the heart
is the anterior vena cava. The anterior vena cava is thus composed of
the most proximal part of the right anterior cardinal and the right
common cardinal vein (duct of Cuvier). The small azygos (cervicothoracic) vein, which is the reduced posterior cardinal, indicates the  
old point of transition from anterior cardinal to common cardinal.  


As the bone increases in length there is a corresponding increase in its diameter. The manner in which this takes place is also susceptible of experimental demonstration. If madder leaves, or some of the alizarin compounds extracted from them, be fed to a growing animal, the bone formed during the time the feeding is continued is colored red. If the madder is discontinued, bone of normal color is again formed ; but the color still remains in the bone laid down while madder was being added to the diet. Thus it is possible, by keeping a record of alternate f>eriods of feeding and withholding madder and comparing these records with the resulting zones of coloration in a bone, to obtain very accurate information on the progress of bone growth and resorption. Applied to the development of long bones this method shows their increase in diameter to be due to continued appositional growth beneath the periosteum. As the bone is added to peripherally there is a corresponding resorption centrally. This central resorption results in the formation of a cavity in the axis of the long bone which is called the marrow canal (Fig. 158, C). With the further increase in the diameter of a bone, its marrow canal becomes correspondingly enlarged. A significant mechanical fact might be cited in this connection. 'Engineers have determined that the strongest rod which can be made from a given weight of steel is obtained by molding it into tubular form. The development of an essentially tubular shaft by progressive increase in the size of the marrow cavity gjivcs a long bone maximum strength with minimum weight.


The Formation of the Vertebrae. The development of the vertebrae is of interest to the student primarily because it exemplifies so excellently a fundamental embryological phenomenon — the origin of separate parts from an undifferentiated primordial tissue mass, and the subsequent association of these parts to form an organized structure. In studying young embryos we traced the history of the mesodermic somites through their early differentiation. It will be recalled that from the ventro-mesial face of each somite there arises a group of mesenchymal cells called collectively a sclerotome (Fig. 42). These cells migrate from either side toward the mid-line and become aggregated about the notochord. From these masses of cells the entire vertebral column is destined to arise.


Changes in the Posterior Systemic Veins Resulting in the  
The first significant change which takes place in these primordial masses is the clustering of sclerotomal cells derived in part from each of the two adjacent somites into groups which are located opposite the intervals between the myotomes. In studying series of transverse sections this arrangement is easy to overlook unless the density of the cells about the notochord is carefully noted in passing from section to section. It shows very clearly, however, in frontal sections (Fig. 159). Each of these cell clusters is the primordium of the centrum of a vertebra. Once formed they rapidly become more dense and more definitely circumscribed (Fig. 160). Soon after the centrum takes shape, paired mesenchymal concentrations extending dorsally and laterally from the centrum establish the primordia of the neural arches and of the ribs (Fig. 161).
Establishment of the Posterior (Inferior) Vena Cava. The changes
in the systemic veins of the posterior part of the body are much more  
radical than they are anteriorly. The posterior cardinal veins which
are the primitive systemic drainage channels are associated primarily
with the mesonephroi. When the mesonephroi degenerate, it is but
natural that the posterior cardinals should degenerate with them.
Hie posterior vena cava which replaces the cardinals is a composite
vessel which gradually takes shape by the enlargement and straightening of small local channels which are, as it were, pressed into service
as the posterior cardinals degenerate.  


The subcardinal veins initiate the diversion of the postcardinal
blood stream. The subcardinals arc established as vessels lying along
the ventro-mesial border of the mesonephros parallel with, and ventral
to, the postcardinals. Taking origin from an irregular plexus of small
vessels emptying from the mesonephroi into the posterior cardinals,
the subcardinals from their first appearance have many channels
connecting them with the postcardinals (Fig. 139, A-C). As the mesonephroi increase in size and bulge toward the mid -line the subcardinals are brought very close together. In the mid -mesonephric
region they anastomose with each other to form a large median vessel,
the subcardinal sinus, or intersubcardinal anastomosis (Figs. 60, 77,
and 139, D-F). When this sinus is established the small vessels connecting sub- and postcardinals drain into the capacious sinus rather than
toward the posterior cardinals. The result of this change very soon
becomes apparent in the disappearance of the posterior cardinals at
the level of this sinus. The blood from the posterior part of the body is
still collcctecl by the distal ends of the postcardinals but it returns to
the heart by way of the subcardinal sinus. Consequently the anterior
portions of the posterior cardinals, although they persist, are much
reduced in size (Fig. 139, F).


Meanwhile the increased volume of blood entering the subcardinal
Fig. 159. Semi-schematic coronal sections through the dorsal region of young embryos to show how the vertebrae became intermyotomal in position. Note that the primordium of a centrum is formed by cells originating from the sclerotomes of both the adjacent pairs of somites.
sinus is finding a new and more direct route to the heart. The cephalic
pole of the right mesonephros lies close to the liver. A fold of dorsal
body-wall tissue, just to the right of the primary dorsal mesentery,
early makes a sort of bridge between these two organs. This fold is  
known as the caval plica {caval mesentery) (Fig. 140). In it, as everywhere in the growing body, are numerous small vessels. Connection
of these small vessels with the plexus of channels in the liver cephalically (Fig. 140, A), and the mesonephros caudaliy (Fig. 140, B),




Fig. 160. Transverse section from pig cm])ryo of 17 mm. cut at the level of the lungs to show the structures in the dorsal body-wall. (After Minot.)


Fig. 140. Drawings of transverse sections of 5 mm. pig embryos showing
the relations of the caval fold of the mesentery (caval plica). A, Section at
level where cephalic end of caval plica merges with liver. Here the small
vessel which is the primordium of the mesenteric portion of the posterior
vena cava enters the sinusoidal circulation of the liver. B, Section showing
merging of caudal end of caval plica with right mesonephros. At this level
the developing mesenteric portion of the posterior vena cava anastomoses
with the right subcardinal vein (cf. Fig. 139, D).


Fig. 161 . Transverse section of 20 mm. pig embryo cut at the level of the lungs to show the developing vertebra and ribs. (After Minot.)


provides the entering wedge. Once a current of blood finds its way
from the mesonephros to the liver through these small vessels, enlargement of the channel proceeds with great rapidity. This new channel
becomes the mesenteric part of the inferior vena cava, (See relations of
posterior vena cava in figures 75 and 76, and portion of cava indicated
with small crosses in figure 139, D.)


Within the liver this new blood stream at first finds its way by
Fig. 162. Transverse section from 40 mm. pig embryo cut at the level of the lungs to show the developing vertebra and ribs.
devious small channels eventually entering the sinus venosus along
with the omphalomesenteric circulation. As its volume of blood
increases it excavates through the liver a main channel which gradually becomes walled in. As this new vessel becomes more and more
definitely organized it gradually crowds toward the surface and  
eventually appears as a great vein lying in a notch along the dorsal
side of the liver. This is the hepatic part of the inferior vena cava.  


From the subcardinal sinus the most direct route to this new outlet is by way of the right subcardinal vein. Thus in embryos as
young as 9 to 12 mm., the formation of the posterior vena cava is well
started with its proximal portion consisting of subcardinal sinus, a
portion of the right subcardinal vein, and the new channels through
the mesentery and through the liver. (Follow this part of the cava
through figure 139 from D to K.)


Posterior to the level of the subcardinal sinus still amother set of  
The Stage in which the various parts of the vertebrae arc sketched in mesenchymal concentrations, is frequently spoken of as the blastemal stage. It is rapidly followed by the cartilage stage. Conversion to cartilage begins in the blastemal mass first in the region of the centrum and then chondrification centers appear in each neural and each costal process (Fig. 161). These spread rapidly until all the centers fuse and the entire mass is involved (Fig. 162). The cartilage miniature of the vertebra thus formed is at first a single piece showing no lines of demarcation where the original centers of cartilage formation became confluent, and no foreshadowing of the separate parts of which it will be made up after the cartilage has been replaced by bone. Shortly before ossification begins the rib cartilage becomes separated from the vertebra, but the vertebra itself remains in one piece throughout the cartilage stage (Fig. 162).
veins enters into the formation of the post-cava. These are the supracardinal veins which appear, relatively late in development, as paired
channels draining the dorsal body-wall (Fig. 139, G, J).  


At the mid-mesonephric level, the supracardinals are diverted into
The locations of the endochondral ossification centers which appear in a vertebral cartilage are indicated schematically in figure 163. It readily can be seen how the spreading of these centers of bone formation will establish the conditions which exist in an adult vertebra. The median ossification center gives rise to the centrum. The centers in the neural processes extend dorsally to complete the neural arch. The spinous process in most of the vertebrae is formed by a prolongation of these same centers to meet dorsal to the neural canal.
the subcardinal sinus just as happened with the postcardinals earlier
in development. Cephalic to the sinus, parts of the supracardinals
persist as the azygos group draining in a somewhat variable manner
into the reduced proximal part of the postcardinals. Caudal to the  
anastomosis with the subcardinal sinus, the right supracardinal becomes the principal drainage channel of the region. Its appropriation
of the tributary vessels from the posterior appendages establishes it as
the postrenal portion of the inferior vena cava and is the last step in the
formation of that composite vessel (Fig. 139, G—K).  


The Coronary Sinus. The ultimate fate of the left common
cardinal vein (duct of Cuvier) is a result of the shift in the course of
the systemic blood so that it all enters the right side of the heart.
Formerly returning a full half of the systemic blood stream to the
heart, the left common cardinal vein is finally left almost without a
tributary from the body. In the pig a small amount of blood usually
does continue to enter it over the left azygos (Fig. 139, K). Occasionally in the pig, and normally in most other mammals, even this is cut
off and the azygos drainage is by way of the right side to the superior
cava (dotted line in Fig. 139, K). Nevertheless the proximal part of
the old left cardinal channel is utilized. Pulled around the heart in
the course of the migration of the sinus venosus toward the right, the
left common cardinal vein lies close against the heart wall for a considerable distance (Fig. 144, D). As the heart muscle grows in bulk it
demands a greater blood supply for its metabolism. The small returning veins of this circulation find their way into this conveniently
located main vessel (Fig. 144, E). Thus even when its peripheral
circulation is cut off the left common cardinal vein still persists as the
coronary sinus into which the vessels of the cardiac wall drain (Fig. 144, F).




Fig. 164. Diagram of four types of vertebrae indicating the parts derived from the different ossification centers shown in figure 163. The part formed by the median center in centrum is cdncentrically ringed; the parts arising from the costal centers are stippled; parts derived from the lateral centers in the neural arches are indicated in line-shading,




Fig. 141. Diagrams showing the development of the hepatic portal circulation from the omphalomesenteric veins, and the relations of the umbilical
In forms such as the pig the spinous processes of tl>e more anterior thoracic vertebrae are very long. In these vertebrae additional ossification centers appear in the spinous process and fuse with those in the neural processes. The transverse processes with which the tubercles of the ribs articulate are formed by the lateral extension of the primary ossification centers in the neural processes. These same centers extend ventrally also, and meet the centrum (cf. Figs. 163 and 164).
veins to the liver. (Adapted from several sources.)  


A is based on conditions in pig embryos of 3-4 mm.; B, on embryos of
about 6 mm.; C, on embryos of 8-9 mm.; D, on embryos of 20 mm. and
older.




The Pulmonary V eins. Phylogenetically the lungs are relatively
Fig. 165. Photograph (X 1/^ showing the ossification centers which have appeared in pig embryos of 35 mm. This and the two following figures were made by photographing in transmitted light embryos in which all the uncalcified tissues had been rendered transparent by treatment with potassium hydroxide and glycerine.
new structures. It is not surprising, therefore, that we find the pulmonary veins arising independently and not by the conversion of old
vascular channels. They originate as vessels which drain the various
branches of the lung buds and converge into a common trunk (Fig.
107), entering the left atrium dorsally. In the growth of the heart this
trunk vessel is gradually absorbed into the atrial wall and two or more
of its original branches open directly into the left atrium as the main
pulmonary veins of the adult (Fig. 144, D-F).  


The Portal Vein. The blood supply to the intestines is first
established through the omphalomesenteric arteries which later
become modified to form the anterior mesenteric artery. Likewise
the drainage of the intestinal tract is provided for by vessels which
were originally the return channels of the primitive omphalomesenteric circulatory arc (Fig. 45). In dealing with 9 to 12 mm. embryos
we have already seen the primary changes which occur in these vessels.
The growing cords of hepatic tissue break up the proximal portion
of the omphalomesenteric veins into a maze of small channels ramifying through the substance of the liver (Fig. 141, A, B). But the stubs
of the omphalomesenterics persist and drain this plexus. Distal to the
liver, the original veins are for a time retained, bringing blood from
the yolk-sac and intestines to the liver. With the disappearance of the
yolk-sac and the growth of the intestines, the omphalic (yolk-sac)
portions of these veins necessarily disappear, but the mesenteric
branches persist and become more extensive concomitantly with the
increased length and complexity of the intestinal tract.


The original omphalomesenteric trunks into which these tributaries converge become the unpaired portal vein by forming transverse
anastomoses and then abandoning one of the original channels. The
curious spiral course of the portal vein is due to the dropping out of
the original left channel cephalic to the middle anastomosis and the
original right channel caudal to the anastomosis (Fig. 141, D).


The Umbilical Veins. When they are first established the umbilical (allantoic) veins are embedded in the lateral body-walls
throughout their course from the belly-stalk to the sinus venosus
(Fig. 45). As the liver grows in bulk, it fuses with the lateral body-wall.
Where this fusion occurs vessels develop connecting the umbilical
veins with the plexus of vessels in the liver (Fig. 141, B). Once these
connections are established the umbilical stream tends more and more to pass by way of them to the liver, and the old channels to the sinus
venosus gradually degenerate (Fig. 141, C). ^


Meanwhile the umbilical veins distal to their entrance into the
Fic. 166. Photograph (X IM) showing the progress of ossification in the skeleton of a 65 mm. pig embryo.
body become fused with each other so that there comes to be but a
single vein in the umbilical cord (Fig. 141, C). Following this fusion
in the cord, the intra-embryonic part of the umbilical channel also
loses its original paired condition. The right umbilical vein is abandoned as a route to the liver and all the placental blood is returned
over the left umbilical vein. It is interesting to note that in spite of its
ceasing to be a through channel, part of the right umbilical vein
persists, draining the body-wall. The small blood stream it then carries
is reversed in direction, flowing back into the left umbilical (Fig. 141,
D).  


When first diverted into the liver, the umbilical blood stream
passes through by way of a mesh work of small anastomosing sinusoids.
As its volume increases it excavates a main channel through the
substance of the liver which is known as the ductus venosus (Figs. 138
and 141, B~D). Leaving the liver, the ductus venosus becomes confluent with the hepatic veins (omphalomesenteric stubs) which drain
the maze of small sinusoids in the liver. At this point, also, the vena
cava joins the others. Thus the blood streams from the posterior
systemic circulation, from the portal circulation, and from the placental circulation all enter the heart together. Embryologically this
great trunk vessel represents the fused proximal parts of the old
omphalomesenteric veins enlarged by the placental blood from the
ductus venosus and by the systemic blood from the vena cava (Fig.
141). During its early developmental phases it is often called the
common revehent hepatic vein. In the adult or in older fetuses it is more
convenient to regard it as a part of the vena cava because, with the
cessation of the placental circulation at the time of birth, the caval
blood stream becomes the dominant one.


IV. The Lymphatic System
Fig. 167. Photograph {X showing the extent of ossification in the skeleton of a 90 nun. pig embryo.


Important and interesting as the subject is, it has seemed expedient
The shaft of the rib is formed by extension of its primary ossification center (Fig. 163). After birth, secondary epiphyseal centers appear in the tubercle and head of the rib. These centers are separated from the shaft by persistent cartilage plates in the manner described in discussing the development of long bones. Fusion of the secondary epiphyseal centers with the shaft of the rib does not take place until the skeleton has acquired its adult dimensions.
to omit any account of the development of the lymphatic vessels.  
Those interested in this field will find that an unusual amount of
careful work has been done on the development of the lymphatics in
pig embryos. References to some of the more important recent papers
have been included in the bibliography appended at the end of the  
book.  


V. Blood Corpuscles
The foregoing discussion has been based on a thoracic vertebra in which the relations of the rib to the vertebra show most clearly. All the vertebrae have the costal element represented, although it is greatly reduced and modified in other regions than the thoracic. A study of figure 164, in which the components of vertebrae from the cervical, thoracic, lumbar, and sacral regions are schematically indicated, will make the homologies apparent. With these homologies in mind it is sufficiently evident, without going into further detail, how all these vertebrae arise by a process similar to that described for the thoracic vertebrae.


The first blood corpuscles which appear in the circulation are
The Progress of Ossification in the Skeleton as a Whole. It would carry us beyond the scope of this book to take up the development of specific bones. Each has its own story involving the formation of the connective tissue or the cartilage mass which precedes it ; local erosion centers if it be preformed in cartilage; number, location, and time of appearance of ossification centers; growth in length and diameter; development of epiphyses; time of fusion of epiphyses and diaphysis; and finally the development of muscle ridges and articular facets. Without entering into a discussion of details of this sort, it is possible nevertheless to follow the general progress of ossification in the skeletal system as a whole. Embryos which have been treated with potassium hydroxide and then cleared in glycerine clearly show the various ossification centers. In such preparations the areas where calcium salts have been deposited stand out white in reflected light and opaque in transmitted light. ^Figures 165-167, which are photographs of preparations of this type, can be used to trace the history of the more important bones. It should perhaps be stated explicitly that these figures arc included primarily to give a general view of the progress of ossification and secondarily to afford a readily available source of reference for following up points of interest that may arise. It is not a profitable use of the student’s time to attempt to memorize the ossification centers which have appeared in embryos of any given age.
produced extra-embryonically in the blood islands of the yolk-sac
(Fig. 48). Later in development there are many blood-forming centers
within the embryo. Concerning the establishment of these centers we
find the same controversy that was commented on in connection with
the origin of blood vessels. It is maintained by some authorities that  
these centers always arise from cells originally produced in the yolksac blood islands. According to this interpretation some of these blood
cells are believed to remain sufficiently undifferentiated to retain their
power of active proliferation. As such cells are carried by the circulation to various parts of the body they settle in favorable locations and
raise new families of blood corpuscles.  


According to the local origin idea it is not necessary to account
for all the centers of blood corpuscle formation on the basis of bloodmother-cells wandering in from the yolk-sac and settling down in new
locations within the embryo. It is maintained that mesodermal cells
arising in the body have the same capacity of becoming differentiated
into blood-mother-cells as mesodermal cells which arise in the yolksac. On this interpretation blood-forming centers arise in various
parts of the body from blood-mother-cells differentiated in situ from
local mesoderm. The recent experimental work tends to indicate that
such “local origin” does occur. That this same evidence proves that
the origin of blood-forming centers from migrating cells never occurs
is by no means so clear.


Whatever the source of the original blood-mother-cells may be
we always find them establishing their centers of proliferation in
places where the current of the circulation is sluggish. In very young
embryos the centers of corpuscle formation are located in the maze of
small channels in the yolk-sac and the allantois. When the yolk-sac
degenerates and the allantois becomes highly specialized as part of
the chorion, these centers cease to be active and new ones are established in connection with such rich vascular plexuses as those in the
mesonephros and the liver. Still later other centers appear in the
lymphoid organs, and last of all in the bone marrow (Fig. 152).


The histological details of the processes involved in the production
of red blood corpuscles and the various types of white blood corpuscles
are exceedingly complex. Moreover there is by no means agreement
as to the exact manner in which these processes occur, nor as to the genetic relations of one type of blood corpuscle to another. This whole
subject, other than the recognition of the multiplicity of blood-forming
centers and their shifting locations in the embryo at various phases of
development, is a special field of histogenesis entirely beyond the
scope of an elementary text.


VI. The Heart


To appreciate the significance of the changes which occur in
{{Historic Disclaimer}}
the growing heart one must have in mind the exigencies under which
it develops. Starting as a simple tube with the blood passing through
 
 
 
Fig. 142. Ventral aspect of the heart of the pig at various stages showing
the formation of the cardiac loop and the establishment of the primary
regional divisions of the heart. Drawn (A-E, X 30; F, X 20) from reconstructions made from series in the Carnegie Collection (A-D) and in the
Western Reserve University Collection (E, F).
 
A, 7 somites; B, 13 somites; C, 17 somites; D, 25 somites; E, 3.7 mm.
(after flexion); F, 6 mm.
 
Abbreviations: At., atrium (t., right; 1., left); Bui., aortic bulb (bulbus
arteriosus); Endc., endocardial tubes; Myc., cut edge of epi-myocardium;
S.V., sinus venosus; Tr. Art., truncus arteriosus; V. ao. r., ventral aortic
roots; Vent., ventricle (r., right; 1., left); V.O.M., omphalomesenteric veins.
 
 
it in an undivided stream, it must become converted into an elaborately valved, four-chambered organ, partitioned in the mid-line
and pumping from its right side a pulmonary stream which is returned to the left side and pumped out again as the systemic blood
stream. And the heart cannot cease work for alteration ; there can be
no interruption in the current of blood it pumps to the growing
embryo. This is but one phase of the matter. At the end of gestation
the vascular mechanism must be prepared to function under conditions radically different from those surrounding the embryo. In spite
of the impossibility of the developing lungs being effectively exercised
under air-breathing conditions, they themselves, their blood vessels,
 
 
 
Fig. 143. Sinistral aspect of reconstructions of the pig heart.
 
A, 13 somite embryo (cf. Fig. 142, B); B, 17 somite embryo (cf. Fig.
142, C); C, 25 somite embryo (cf. Fig. 142, D); D, 3.7 mm. embryo (cf.
Fig. 142, E); E, 6 mm. embryo (cf. Fig. 142, F).
 
Abbreviations: A.C.V., anterior cardinal veins; Al.V., allantoic (umbilical) vein; Ao., aorta; At., atrium; Bui., aortic bulb; Cav. P., posterior
vena cava; Cuv. d., duct of Cuvier (common cardinal vein); Myc., cut edge
of epi-myocardium; P.C.V.; posterior cardinal vein; S.V., sinus venosus;
Sin-at., sino-atrial region of heart; Tr. Art., truncus arteriosus; V. ao. r.,
ventral aortic roots; Vent., ventricle; V.O.M., omphalomesenteric veins.
 
 
and the right ventricle which pumps blood to them, must at the
moment of birth be ready to take over the entire r^esponsibility of
oxygenating the blood. And the systemic part of the circulation as
well as the pulmonary must be prepared. Throughout intra-uterine
development the left side of the heart receives less blood from the
pulmonary veins than the right side of the heart receives from the
venae cavae. Yet after birth the left ventricle is destined to carry a
greater load than the right ventricle. It must pump through the
myriad peripheral vessels of the systemic circulation,, sufficient blood
to care for the active metabolism and continued growth of the entire
body. These are some of the situations which must be faced before the
heart can arrive at its adult condition. The manner in which they are
met is doubly interesting because they seem at first sight so difficult.
 
The Formation of the Cardiac Loop and the Establishment of
the Regional Division of the Heart. In dealing with the establishment of the circulatory system in very young embryos we saw how
the tubular heart was formed by the fusion of paired primordia
(see Chap. 5 and especially Figs. 43 and 44). The primary factor
which brings about its regional differentiation is the rapid elongation
of this primitive cardiac tube. The heart increases in length so much
faster than the chamber in which it lies that it is first bent to the right
and then twisted into a loop. Since the anterior end of the heart is
anchored in the body by the aortic roots, and the posterior end by
the great veins, it is the mid-portion of the heart-tube which, in this
process, undergoes the most extensive changes in position. This is
facilitated by the early disappearance of the dorsal mesocardium
which leaves the heart entirely free in its mid-region.
 
During the period in which the cardiac loop is being formed, the
primary regional divisions of the heart become clearly differentiated.
The sinus venosus is the thin-walled chamber in which the great veins
become confluent to enter the heart at its primary posterior end
(Fig. 144). The atrial region is established by transverse dilation of
the heart-tube just cephalic to the sinus venosus (Fig. 144).
 
The ventricle is formed by the bent mid-portion of the original
cardiac tube. As this ventricular loop becomes progressively more
extensive, it at first projects ventrally beneath the attached aortic
and sinus ends of the heart (Fig. 143, A-C). Later it is bent caudally
so that the ventricle, formerly situated cephalic to the atrium, is
brought into its characteristic adult position caudal to the atrium
(Fig. 143, D, E). Between the atrium and ventricle the heart remains
 
 
Fig. 144. Six stages in the development of the heart, drawn in dorsal
aspect to show the changing relations of the sinus venosus and great veins
entering heart. (Patten: ‘‘Human Embryology,” The Blakiston Company.)
 
relatively undilated. This narrow connecting portion is the atrioventricular canal.
 
The most cephalic part of the cardiac tube undergoes least change
in appearance, persisting as the truncus arteriosus connecting the ventricle with the ventral aortic roots (Fig. 142). In very young embryos
there is a conspicuous bulge where the truncus arteriosus swings
toward the mid-line to break up in the aortic arches. This sharply
bent and somewhat dilated region is called the aortic bulb (Fig. 142,
B, C). Its location is of interest as being the place at which the paired
endocardial primordia first fused with each other (Figs. 43 and 44)
and the place at which, later in development, the division of the
truncus arteriosus into separate aortic and pulmonary roots will first
become apparent. The bulge itself soon merges into the rest of the
truncus arteriosus without giving rise to any special structure.
 
Almost from their earliest appearance the atrium and the ventricle
show external indications of the impending division of the heart into
right and left sides. A distinct median furrow appears at the apex of
the ventricular loop (Figs. 142, E, F, and 144, U, E). The atrium
meanwhile has undergone rapid dilation and bulges out on either
side of the mid-line (Fig. 144). Its bilobed configuration is emphasized by the manner in which the truncus arteriosus compresses it
mid-ventrally (Fig. 142, E, F).
 
The Partitioning of the Heart. These superficial features suggest
the more important changes going on internally. As the wall of the
ventricle increases in thickness it develops on its internal face a meshwork of interlacing muscular bands, the trabeculae carneae. Opposite
the external furrow in the ventricle these muscular bands become
consolidated as a partition which appears to grow from the apex of
the ventricle toward the atrium. This is the interventricular septum
(Fig. 147).
 
Meanwhile two conspicuous masses of peculiar, loosely organized
mesenchyme (called endocardial-cushion tissue) develop in the walls
of the narrowed portion of the heart between the atrium and the
ventricle. One of these so-called endocardial cushions of the atrio-ventricular
canal is formed in its dorsal wall (Fig. 147, A) and the other is formed
opposite, on the ventral wall. These two masses nearly occlude the
central part of the canal and thus initiate its separation into right and
left channels.
 
At the same time a median partition appears in the cephalic
wall of the atrium. Because another closely related partition is destined to form here later, this one is called the first interatrial septum or
septum primum. In shape it is crescentic with its concavity directed
toward the ventricle and the apices of the crescent extending, one
along the dorsal wall, and one along the ventral wall of the atrium,
all the way to the atrio-ventricular canal where they merge, respectively, with the dorsal and ventral endocardial cushions (Fig. 147).
This leaves the atria separated from each other except for an opening
called the interatrial foramen primum.
 
While these changes have been occurring, the sinus venosus has
been shifted out of the mid-line so that it opens into the atrium to
the right of the interatrial septum (Fig. 147). The heart is now in a
critical stage of development. Its simple tubular form has been
altered so that the four chambers characteristic of the adult heart
are clearly recognizable. Partitioning of the heart into right and left
sides is well under way. But there is as yet no division of the blood
stream because there are still open communications from the right to
 
 
Fio. 145. Reconstruction of the heart of a 9.4 mm. pig embryo cut
open somewhat to the right of the mid-line to show its internal structure
(cf. Fig. 146).
 
the left side in both atrium and ventricle. A little further progress in
the growth of the partitions, however, and the two si^cs of the heart
would be completely separated. Were this to occur now, the left side
 
 
 
Fig. 146. Section (X 45) through the heart of a 9.4 mm. pig
embryo, at the level of the atrio-ventricular canals. (From the
series used in making the reconstruction appearing as figure 145.
This section may be oriented as passing horizontally through Fig.
145 at the level of the most caudal portion of the interventricular foramen.)
 
 
of the heart would become almost literally dry. For the sinus venosus,
into which systemic, portal, and placental currents all enter, opens
on the right of the interatrial septum, and not until much later do
the lungs, and their vessels develop sufficiently to return any considerable volume of blood to the left atrium. The partitions in the
ventricle and in the atrio-ventricular canal do progress rapidly to
completion (Figs. 147, 148, and 149), but an interesting series of
events takes place at the interatrial partition which assures an adequate supply of blood reaching the left atrium and thence the left
ventricle.
 
Just when it appears that the septum primum is going to fuse with
the endocardial cushions of the atrio-ventricular canals, closing the
interatrial foramen primum and isolating the left atrium, a new
opening is established. The more cephalic part of the septum primum
ruptures to form the interatrial for amen secundum, thus keeping a route
open from the right to the left atrium (Fig. 148).
 
At about this time the second interatrial partition makes its
appearance just to the right of the first. Also crescentic in form, this
septum secundum extends its apices along the dorsal and ventral walls
of the atrium to fuse with the septum primum near the endocardial
cushion mass which now completely divides the atrio-ventricular
 
 
 
Fig. 147. Drawings showing the initial steps in the partitioning of the
heart.
 
A, Slightly schematized drawing from reconstruction of heart of 3.7 mm.
pig embryo. The heart has been opened by a diagonally frontal cut in the
plane which can be indicated by drawing a line through the labels At. and
Vent, in figure 143, D. The dorsal portion of the heart is shown viewed from
the ventral side.
 
B, Slightly schematized drawing from a reconstruction of the heart of a
6 mm. pig embryo. The heart has been opened in a plane which can be
indicated by drawing a line through the labels At, and Vent, in figure 143, E.
The dorsal portion of the heart is shown viewed from the ventral side.
 
 
 
Fig, 148. Slightly schematized drawing from a reconstruction of the heart
of a 9.4 mm. pig embryo. Dorsal part of heart, interior view. The plane in
which the heart is opened can be indicated by drawing a line through the
center of the interatrial and the interventricular foramina in figure 145.
 
 
canals. But the septum secundum never becomes a complete partition.
An oval opening of considerable size persists in its center. This is the
foramen ovale (Fig. 149).
 
The newly established septum secundum and the flap-like remains
of the septum primum constitute an efficient valvular mechanism
between the two atria. When the atria are filling, some of the blood
discharged from the venae cavae into the right atrium can pass freely
through the foramen ovale by merely pushing aside the flap of the
septum primum. The inferior caval entrance lies adjacent to, and
is directed straight into, the orifice of the foramen ovale (Fig. 149).
Consequently it is primarily — some think exclusively — blood from
the inferior vena cava which passes through the foramen ovale into
the left atrium. When the atria start to contract, pressure of the blood
within the left atrium forces the flap of the septum primum against the
foramen ovale, effectively closing it against return flow into the right
atrium. Without some such mechanism affording a supply of blood
 
septum
 
 
Fig. 149. Schematic drawing based on dissected heart of pig fetus shortly
before birth. Interior aspect of dorsal part of heart to show valvular mechanism at foramen ovale.
 
 
to its left side, the developing heart could not be partitioned in the
mid-line ready to assume its adult function of pumping two separate
blood streams.^
 
While alf these changes have been going on in the main part of
the heart, the truncus arteriosus has been divided into two separate
channels. Reference has already been made to the start of this process
in the aortic root between the fourth and sixth arches (Fig. 133).
Continuing toward the ventricle, the division is effected by the formation of longitudinal ridges of plastic young connective tissue of the
same type as that making up the endocardial cushions of the atrioventricular canal. These ridges, called truncus ridges^ bulge progressively farther into the lumen of the truncus arteriosus and finally meet
to separate it into aortic and pulmonary channels. ^ (Note shape of
lumen in Figs. 142, F, and 145.) The semilunar valves of the aorta,
and of the main pulmonary trunk (Fig. 138), develop as local specializations of these truncus ridges. Toward the ventricles from the site
of formation of the semilunar valves the same ridges are continued
into the conus of the ventricles. The fact that proximal to the valves
these ridges are, for descriptive purposes, called conus ridges should not
be allowed to obscure their developmental and functional continuity
with the truncus ridges. The truncus and conus ridges follow a spiral
course such that where the conus ridges extend down into the ventricles they meet and become continuous with the interventricular
septum. The right ventricle then leads into the pulmonary channel
and the left into the aorta. With this condition established the heart
is completely divided into right and left sides except for the interatrial
valve which must remain open throughout fetal life, until, after birth,
the lungs attain their full functional capacity and the full volume of
the pulmonary stream passes through them to be returned to the left
atrium.
 
^ There are on record a few cases of a peculiar cardiac malformation in which
this valvular communication was prematurely closed and the left atrium thereby
shut off from the right. In all these cases the left side of the heart has not been sufficiently developed to support life for any length of time after birth.
 
 
 
 
This leaves but one of the exigencies of heart development still to
be accounted for. If, during early fetal life, before the lungs were well
developed, the pulmonary channel were the only exit from the right
side of the heart, the right ventricle would have an outlet inadequate
to develop its pumping power. For it is only late in fetal life that the
lungs and their vessels develop to a degree which prepares them for
assuming their postnatal activity, and the power of the heart muscle
must be built up gradually by continued functional activity. This
situation is met by the ductus arteriosus leading from the pulmonary
trunk to the aorta (Fig. 138). The right ventricle is not unprepared
for its adult function because it pumps its full share of the blood
throughout fetal life. Instead of all going to the lungs, however, part
of the blood pumped by the right ventricle passes by way of the ductus
arteriosus into the aorta (Fig. 150). As the lungs increase in size,
relatively more blood goes to them and relatively less goes through
the ductus arteriosus. By the time of birth enough blood is passing
through the lungs to support life, and within a short time after birth,
under the stimulus of functional activity, the lungs are able to take all
the blood from the right side of the heart and the ductus arteriosus is
gradually obliterated. The ductus arteriosus, therefore, serves during
intra-uterine life as what might be called a ‘‘compensated exercising
channel” for the right ventricle.
 
 
Changes in the Sinus Region. In following the story of the
development of the heart from the functional standpoint, many things
of less striking significance have been passed over. Some of these
should have a word of comment. Cephalic to the sinus orifice the
valvulae venosae which guard it against return flow fuse and are prolonged onto the dorsal wall of the atrium in the form of a ridge called
the septum spurium (false septum). This septum is, for a time, too
conspicuous to ignore, but it is of little importance in the partitioning
of the heart and soon undergoes retrogression.
 
As the heart grows it absorbs the sinus venosus into its walls so
that eventually the anterior and posterior venae cavae and the
coronary sinus all open separately into the right atrium (cf. Figs. 147,
148, and 149). Portions of the right valvula venosa are retained as the
valves of the caval and coronary orifices. In the adult heart a small
external sulcus can usually be found between the entrance of the
anterior and the posterior vena cava which records the old line of
demarcation between sinus venosus and atrium.
 
The Atrio-ventricular Valves and the Papillary Muscles. At
the point where the atrio-ventricular canals open into the ventricles
there are early indications of the establishment of valves. From the
partition in the atrio-ventricular canal and from the outer walls on
either side, masses of tissue in the shape of thick, blunt flaps project
toward the ventricle (Figs. 146 and 148). It is these masses of a primitive type of connective tissue, similar to that in the endocardial
cushions of the canal, which later become differentiated into the flaps
of the adult valves (Fig. 149). The papillary muscles and tendinous
cords which, in the adult, act as stays to these valves, arise by modification of soine of the related trabeculae carneae (cf. Figs. 146, 148,
and 149).
 
The Aortic and Pulmonary Valves. The valves which guard
the orifices of the aorta and of the pulmonary artery arise from
mesenchymal pads (Fig. 138) already mentioned as developing in
connection with the truncus septum. In early histological appearance
and in the manner in which this loose tissue gradually becomes
organized into the exceedingly dense fibrous tissue characteristic of
adult valves, they are similar to the atrio-ventricular valves. They
do not, however, develop any supporting strands comparable to the
papillary muscles and tendinous cords.
 
Course and Balance of Blood Flow in the Fetal Heart. All the
steps in the partitioning of the embryonic heart lead gradually toward
the final adult condition in which the heart is completely divided into
right and left sides. Yet from the nature of its living conditions it is
not possible for the tetus in utero fully to attain the adult type of
circulation. The plan of the completely divided circulation is predicated on lung breathing. In the adult the right side of the heart
receives the blood returning from a circuit of the body and pumps
it to the lungs where it is relieved of carbon dioxide and acquires a
fresh supply of oxygen. The left side of the heart receives the blood
that has just passed through the lungs and pumps it again through
ramifying channels to all the tissues of the body. In the fetus the
function of respiration is carried out in the placenta by interchange
with the maternal blood circulating through the uterus. The lungs,
although in the last part of fetal life they are fully formed and ready
to function, cannot actually begin their work until after birth. The
radical change which must inevitably take place immediately following birth in the manner in which the blood is oxygenated has led to a
widespread belief that there must be revolutionary changes in the
routing of blood through the heart and great vessels. However, as the
embryology of the circulatory system has been studied more closely
from a functional angle it is becoming increasingly clear that the
heart and the major vascular channels develop in such a manner that
the pumping load on the different parts of the heart remains balanced
at all times during fetal life. Moreover, the very mechanisms which
maintain this cardiac balance during intra-uterine life are perfectly
adapted to rebalance the circulatory load on the new postnatal basis
without involving any sudden overloading of previously inactive
parts of the vascular system.
 
To understand the changes in circulation which are so smoothly
accomplished at the time of birth it is necessary to have clearly in
mind the manner in which the way for them has been prepared
during intra-uterine life. In the foregoing account of the development
of the interatrial septal complex, emphasis was laid upon the fact
that at no time were the atria completely separated from each other.
This permits the left atrium, throughout prenatal life, to receive a
contribution of blood from the inferior cava and the right atrium by
a transseptal flow which compensates for the relatively small amount
of blood entering the left atrium of the young embryo by way of the
pulmonary circuit, and maintains an approximate balance of intake
into the right and left sides of the heart.
 
The precise manner in which this transseptal flow occurs, and
where, and to what extent the various blood streams of the fetal circulation are mixed has long been a controversial subject. The recent
brilliant work of Barcroft and Barron and their co-workers has gone
far toward putting some of these old controversies into proper perspective. Their first approach was through the quantitative analysis
of blood samples drawn from various critical parts of the fetal circulation. The oxygen content of such samples has given important
evidence as to what mixing of the currents is actually taking place in
the living fetus. Later work involving the collaboration of Barclay
and Franklin utilized serial x-ray photography following the injection
of opaque material into the blood stream at various points. This
method has given further direct evidence as to the course followed by
some of the important blood currents. Synthesizing the most significant of the anatomical evidence with the newer experimental evidence, the course followed by the blood in passing through the fetal
heart may be summarized somewhat as follows. The inferior caval
entrance is so directed with reference to the foramen ovale that a considerable portion of its stream passes directly into the left atrium
(Figs. 149 and 150). Under fluctuating pressure conditions — say
following uterine contractions which send a surge of placental blood
through the umbilical vein — the placental flow may temporarily
hold back any blood from entering the circuit by way of either the
portal vein or the inferior caval tributaries (Fig. 150). For a time,
under these conditions, the left atrium would be charged almost
completely with fully oxygenated blood. Such conditions, however,
would be but temporary and would be counterbalanced 6y periods
when the portal and systemic veins poured enough blood into the
common channels to load the heart for a time with mixed or depleted
blood. The ipiportant thing physiologically is not the fluctuations,
but the maintenance of the average oxygen content of the blood at
adequate levels.
 
Compared with conditions in adult mammals, the mixing of
oxygenated blood freshly returned from the placenta with depleted
blood returning from a circuit of the body may seem inefficient. But
this is a one-sided comparison. The fetus is an organism in transition.
Starting with a simple ancestral plan of structure and living an aquatic
life, it attains its full heritage but slowly. It must be viewed as much
in the light of the primitive conditions from which it is emerging as in
comparison with the definitive conditions toward which it is progressing. Below the bird-mammal level circulatory mechanisms with
partially divided and undivided hearts and correspondingly unseparated blood streams meet all the needs of metabolism and
growth. Maintenance of food, oxygen, and waste products at an
average level which successfully supports life does not depend on
''pure currents,” although such separated currents undoubtedly
make for higher efficiency in the rate of interchange of materials.
From a comparative viewpoint, the fact that the mammalian fetus is
supported by a mixed circulation seems but natural.
 
Another significant fact is that careful measurements have shown
that the interatrial communication in the heart of the fetus at term
is considerably smaller than the inferior caval inlet. This would mean
that the portion of the inferior caval stream which could not pass
through this opening into the left atrium would eddy back and mix
with the rest of the blood in the right atrium.
 
One of the most important inferences as to the fetal circulation
based on vessel size is that the circulation through the lungs in a fetus
which is sufficiently mature to be viable is of considerable volume.
This too has now been supported by experimental work. From the
standpoint of smooth postnatal circulatory readjustments, the larger
the fetal pulmonary return becomes the less will be the balancing
transatrial flow, and the less will be the change entailed by the assumption of lung breathing. Very early in development, before the lungs
have been formed, the pulmonary return is negligible and the flow
from the right atrium through the interatrial ostium primum constitutes practically the entire intake of the left atrium. After the
ostium primum is closed and while the lungs are but little developed,
flow through the interatrial ostium secundum must still be the major
part of the blood entering the left atrium. During the latter part of
fetal life the foramen ovale in septum secundum becomes the transseptal route. As the lungs grow and the pulmonary circulation
increases in volume, a progressively smaller proportion of the left
atrial intake comes by way of the foramen ovale and a progressively
larger amount from the vessels of the growing lungs.
 
The balanced atrial intake thus maintained implies a balanced
ventricular intake, and this in turn implies a balanced ventricular
output. Although not in the heart itself, we have seen that there is in
the closely associated great vessels a mechanism which affords an
adequate outlet from the right ventricle during the period when the
pulmonary circuit is developing. When the pulmonary arteries are
formed from the sixth pair of aortic arches, the right sixth arch soon
loses its original connection with the dorsal aorta. On the left, however, a portion of the sixth arch persists as a large vessel connecting
the pulmonary artery with the dorsal aorta (Fig^. 138 and 150).
This vessel, already familiar to us as the ductus arteriosus, remains
open throughout fetal life and acts as a .shunt, carrying over to the
aorta whatever excess of blood the pulmonary vessels at any particular
phase of their development are not prepared to receive from the right
ventricle. As has already been pointed out, the ductus arteriosus can
be called the “exercising channel” of the right ventricle because it
makes it possible for the right ventricle to carry its full share of work
throughout development and thus to be prepared for pumping all the
blood through the lungs at the time of birth.
 
VII. The Changes in the Circulation Following Birth
 
The two most obvious changes which occur in the circulation at
the time of birth are the abrupt cutting off of the placental blood
stream and the immediate assumption by the pulmonary circulation
of the function of oxygenating blood. One of the most impressive
things in embryology is the perfect preparedness for this event which
has been built into the very architecture of the circulatory system
during its development. The shunt at the ductus arteriosus, whic ii
has been one of the factors in balancing ventricular loads throughout
development, and the valvular mechanism at the foramen ovale,
which has at the same time been balancing atrial intakes, are perfectly adapted to effect the postnatal rebalancing of the circulation.
The closure of the ductus arteriosus is the primary event and the
closure of the foramen ovale follows as a logical sequel.
 
It has long been known that the lumen of the ductus arteriosus is
gradually occluded postnatally by an overgrowth of its intimal tissue.
This process in the wall of the ductus is as characteristic and regular
a feature of the development of the circulatory system as the formation of the cardiac septa. Its earliest phases begin to be recognizable
in the fetus as the time of birth approaches, and postnatally the
process continues at an accelerated rate to terminate in complete
anatomical occlusion of the lumen of the ductus about six to eight
weeks after birth,
 
Barcroft, Barclay, and Barron have conducted an extensive series
of experiments on animals delivered by Cesarean section which,
indicate that the ductus arteriosus closes functionally far sooner than
it does anatomically. Following birth there appears to be a contraction of the circularly disposed smooth muscle in the wall of the ductus
which promptly reduces the flow of blood through it. This reduction
in the shunt from the pulmonary circuit to the aorta, acting together
with the newly assumed respiratory activity of the lungs themselves,
aids in raising the pulmonary circulation promptly to full functional
level. At the same time the functional closure of the ductus by muscular contraction paves the way for the ultimate anatomical obliteration
of its lumen by overgrowth of intimal connective tissue. This concept
of the immediate functional closure of the ductus is so appealing on
theoretical grounds that a little extra caution in evaluating the evidence is indicated. It should be borne in mind that an initial tendency
on the part of the circular smooth muscle of the ductus to contract
does not necessarily imply a contraction sufficiently strongly and
steadily maintained to shut off all blood flow during the six to eight
weeks occupied by morphological closure. The dramatic quality of an
immediate muscular response should not cause us to forget the importance of the slower but more positive structural closure.
 
The results of increased pulmonary circulation with the concomitant increase in the direct intake of the left atrium are manifested secondarily at the foramen ovale. Following birth, as the
pulmonary return increases, compensatory blood flow from the right
atrium to the left decreases correspondingly, and finally ceases
altogether. This is indicated anatomically by a progressive reduction
in the looseness of the valvula foraminis ovalis and the consequent
diminution of the interatrial communication to a progressively narrower slit between the valvula and the septum. When equalization
of atrial intakes has occurred, the compensating one-way valve at the
foramen ovale falls into disuse, and the foramen ovale may be regarded as functionally closed.


Anatomical obliteration of the foramen ovale follows leisurely in
{{Patten1951 TOC}}
the wake of its functional abandonment. There is a considerable
interval following birth before the septum primum fuses with the
septum secundum to seal the foramen ovale. This delay is, however,
of no import because as long as the pulmonary circuit is normal and
pressure in the left atrium does not fall below that in the right, the
orifice between them is functionally inoperative. It is not uncommon
to find the fusion of these two septa incomplete in the hearts of individuals who have, as far as circulatory disturbances are concerned,
lived uneventfully to maturity. Such a condition can be characterized
as ‘‘probe potency’’ of the foramen ovale. When, in such hearts, one
inserts a probe under the margin of the fossa ovalis and pushes it
toward the left atrium one is, so to speak, prying behind the no longer
used, but still unfastened, interatrial door. ,


With birth and the interruption of the placental circuit there
follows the gradual fibrous involution of the umbilical vein and the
umbilical arteries. The flow of blood in these vessels, of course, ceases
immediately with the severing of the umbilical cord, but obliteration
of the lumen is likejy to take from three to , five weeks, and isolated
portions of these vessels may retain a vestigial lumen for much longer.
Ultimately these vessels are reduced to fibrous cords. The old course
of the umbilical vein is represented in the adult by the round ligament of the liver extending from the umbilicus through the falciform
ligament, and by the ligamentum venosus within the substance of the
liver. The proximal portions of the umbilical arteries are retained in
reduced relative size as the hypogastric or internal iliac arteries. The
fibrous cords extending from these arteries on either side of the urachus
toward the umbilicus represent the remains of the more distal portions
of the old umbilical arteries. They are known in the adult as the
obliterated branches of the hypogastric arteries, or as the lateral
umbilical ligaments.
Much yet remains to be learned as to the more precise physiology
of the fetal circulation and as to the interaction of various factors
during the transition from intra-uterine to postnatal conditions.
Nevertheless, with our present knowledge it is quite apparent that the
changes in the circulation which occur following birth involve no
revolutionary disturbances of the load carried by different parts of
the heart. The fact that the pulmonary circulation is already so well
developed before birth means that the changes which must occur
following birth are far less profound than was formerly believed ; and
the compensatory mechanisms at the foramen ovale and the ductus
arteriosus which have been functioning all during fetal life are entirely
competent to effect the final postnatal rebalancing of the circulation
with a minimum of functional disturbance. It is still true that as
individuals we crowd into a few crucial moments the change from
water living to air living that in phylogeny must have been spread
over eons of transitional amphibious existence. But as we learn more
about this change in manner of living, it becomes apparent that we
should marvel more at the completeness and the perfection of the
preparations for its smooth accomplishment, and dwell less on the
old theme of the revolutionary character of the changes involved.
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Patten BM. Embryology of the Pig. (1951) The Blakiston Company, Toronto.

Patten 1951: 1 Foreword to the Student | 2 Reproductive Organs - Gametogenesis | 3 Sexual Cycle | 4 Cleavage and Germ Layers | 5 Body Form and Organs | 6 Extra-Embryonic Membranes | 7 Embryos 9-12 mm | 8 Nervous System | 9 Digestive - Respiratory and Body Cavities | 10 Urogenital | 11 Circulatory System | 12 Bone and Skeletal System | 13 Face and Jaws | Bibliography
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This historic 1951 embryology of the pig textbook by Patten was designed as an introduction to the topic. Currently only the text has been made available online, figures will be added at a later date. My thanks to the Internet Archive for making the original scanned book available.


By the same author: Patten BM. The Early Embryology of the Chick. (1920) Philadelphia: P. Blakiston's Son and Co.

Patten BM. Developmental defects at the foramen ovale. (1938) Am J Pathol. 14(2):135-162. PMID 19970381


Modern Notes

pig

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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Chapter 12. The Histogenesis of Bone and the Development of the Skeletal System

I. Histogenesis of Bone

Histologically bone belongs to the group of tissues known as the connective and supporting tissues. In spite of their widely varying adult conditions these.tissues are all similar in that the secreted parts, rather than the cells themselves, carry out the functional role characteristic of the tissues. It is the secreted, fibrous portion of the binding connective tissues which ties together various other tissues and organs ; it is the secreted matrix of cartilage and of bone which affords rigid support and protection to soft parts and furnishes a lever system on which the muscles may be brought into play.


The cellular elements of these tissues must not be overlooked, however, in emphasizing the functional importance of the cell products. The cells are, so to speak, the power behind, in that they extract the appropriate raw materials from the circulation, elaborate them within their cytoplasm, and deposit the characteristic secretion as an end-product. Moreover after the fiber is formed or the matrix is laid down, it is dependent on the cells for maintenance in a healthy active conditidn.


Embryologically the entire connective-tissue group arises from mesenchymal cells. It is not surprising, in view of their closely related functions and their derivation from a common type of ancestral cell, that one type of connective tissue may be converted into or replaced by another. This facility for changing the type of specialization is sometimes referred to as plasticity.


The plasticity of the connective-tissue series is well exemplified in the development of bone. Bone does not form in vacant spaces. It is always laid down in an area already occupied by some less highly specialized member of the connective-tissue family. The formation of some bones begins in areas already occupied by connective tissue — such bones are said to be intramembranous in origin, or are spoken of as membrane bones. Other bones are laid down in areas already occupied by cartilage. In this case they are said to be pndochondral in origin, or, are called cartilage bones. It should be clearly borne in mind that these terms apply solely to the method by which a bone develops and do not imply any differences in histological structure, once the bone is fully formed.


Likewise we should know at the outset what histologists mean when they speak of cancellous bone and compact bone. These terms refer not to the method of origin of the bone but to its density when fully formed. Developmen tally all bone goes through the spongy or cancellous stage. Some bones later become compact, others remain cancellous. Most bones are compact in some areas and cancellous in others.


The subject of bone development can be presented more simply if we take up first the formation of primary cancellous bone intramembranously ; then the method by which this same type of spongy bone is formed within cartilage, and finally the changes by which cancellous bone, formed in either of the above ways, may become secondarily compact.

Intramembranous Formation of Primary Cancellous Bone

In an area where intramembranous bone formation is about to begin we find an abundance of mesenchymal cells congregated and numerous small blood vessels present. The mesenchymal cells soon exhibit a tendency to cluster together in more or less elongated groups here and there throughout the area. If we study a group of this type which has been aggregated for a short time we can make out the beginning of a definite plan of organization. Near the axis of the cord delicate fibers appear, produced by the secretory activity of the cells. As this fibrous strand becomes more definite, the cells tend to become ranged against it (Fig. 151, A). In so doing they retract the cytoplasmic processes which are so characteristic of undifferentiated mesenchymal cells and become rounded. In this stage we have essentially a connective tissue in which the fibrous strands are for the most part rather widely separated from one another, and in which each strand has, lined up against it^ the cells responsible for its production.

The actual deposition of bone matrix begins very soon after the establishment of these primordial strands of mesenchymal cells and fibers. In fact one usually finds the formation of bone beginning on the older part of a strand while the strand itself is still being extended at one end by the aggregation of more mesenchymal cells (Fig. 151,


I'k;. 151, Formation of trabeculae of membrane bone. Projection drawings from the mandible of a pig embryo 130 mm. in length (cf. Fig. 182).

Abbreviations: Matrix cal., ossein matrix impregnated with calcium salts; Matrix oss., ossein matrix not yet impregnated with calcium salts.

A). When the mesenchymal cells ranged against the fibrous axis of such a strand become active in the secretion of calcareous material they are spoken of as osteoblasts. We should not lose sight of the fact that they are the same cells which formed the fibrous axis of the original strands, given a new name in deference to their further specialization and altered internal chemistry.


In studying the deposition of bone matrix one must bear in mind its dual nature. The matrix consists of an organic fibrous framework which is impregnated by a subsequent deposit of inorganic calcium compounds. We may liken the matrix of bone to reinforced concrete* In the making of a road or a wall, a meshwork of steel is first placed in the forms and concrete is then poured in. The steel gives the finished structure tensile strength and a certain amount of elasticity, the concrete gives form and hardness. So in bone the organic fibers {ossein fibers) impart strength and resilience, while the calcium salts whh which the fibers are impregnated give to the completed matrix body and rigidity.


The two steps in the deposition of bone matrix may be demonstrated readily in areas where active bone forma^tion is going on, owing to the fact that the presence of calcium compounds- in a tissue markedly increases its affinity for stains. Even after most of the calcium salts have been removed from the ossein framework by treatment of the tissue with acids (decalcification) to permit the making of sections, the staining reaction is still apparent. This indicates that the ossein fibers in which calcium has once been deposited are more or less permanently changed chemically even though all the calcium possible is subsequently removed.


If we look at a strand on which the osteoblasts have been active for a time (Fig. 151, B) we see, next to the osteoblasts, a zone of bone matrix which takes very little stain. This is the newly deposited organic portion of the matrix as yet unimpregnated with calcium salts. It consists of a feltwork of minute fibers so delicate and so closely matted together that it is very difficult in ordinary preparations to see the individual fibers at all. Slightly farther from the osteoblasts the matrix is densely stained (Fig. 151, B). This part of the matrix has been impregnated with calcium salts, chiefly phosphates and carbonates, and has thereby been converted into true bone matrix. The calcium utilized by the osteoblasts in this process is brought to them by the blood stream where it is carried in soluble form, probably in organic linkage. It is interesting to note in this connection that the presence of calcium and of phosphates in the blood is not in itself all that is necessary for this process. There must be present also sufficient vitamin D, which in some way facilitates the extraction by the osteoblasts of these raw materials from the blood and their deposition in insoluble form as part of the bone matrix. The absence of vitamin D from the system results in the formation of bone matrix deficient in calcium salts and therefore lacking in rigidity — a cohdition not infrequent in pigs. Stock raisers have miscalled this condition rheumatism but it is really the same condition known medically as rickets.


In the deposition of the matrix, the fibrous core of the original strand serves as a sort of axis on which the first matrix is laid down. When such a strand is completely invested by bone matrix, it is called a trabecula (little beam). As the osteoblasts continue to secrete and thereby thicken the trabecula, the accumulation of their own product forces them farther and farther away from the axial strand about which the first of the matrix was formed. The new matrix added is not laid down uniformly. It is possible to make out in it markings which are suggestive of the growth rings of a tree. Apparently the osteoblasts work more or less in cycles, depositing a succession of thin layers of matrix. Each of these layers of the matrix is called a lamella (Fig. 152). As the row of osteoblasts is forced back with the deposit of each succeeding lamella, not all the cells free themselves from their secretion. Here and there a cell is left behind. As its former fellows continue to pile up new matrix, it becomes completely buried (Fig, 151, B). An osteoblast so caught and buried is called a bone cell {osteocyte)^ and the space in the matrix which it occupies is called a lacuna. The bone cells, thus entrapped, of necessity cease to be active bone formers, but they play a vital part in the maintenance of the bone already formed. They have delicate cytoplasmic processes radiating into the surrounding matrix through minute canalidhli. The processes of one cell come into communication with the processes of its neighbors (Fig. 152). Thus the bone cells nearer to blood vessels absorb and hand on materials to their more remote fellows which in turn utilize these materials in maintaining a healthy condition in the organic part of the bone matrix. It is the senescence of these cells with the consequent lowering of their efficiency and the resultant deterioration of the ossein component of the matrix which is in part responsible for the decreased resiliency of the bones in advanced age.



Fio. 152. A small area of bone and adjacent marrow as seen in highly magnified decalcified sections. The drawing has been schematized somewhat to emphasize the relations of the cytoplasmic processes of the osteoblasts* and the bone cells so important in nutrition. In the adjacent marrow developmental stages of various types ofiiiijioQd cells, have been


Fig. 153. Diagrams showing stages in establishing of a characteristic area of primary cancellous bone by extension and coalescence of originally separate trabeculae.


As the various trabeculae in an area of developing bone grow, they inevitably come in contact with each other and fuse. Thus trabeculae, at first isolated, soon come to constitute a continuous system (Fig. 153). Because of its resemblance to a latticework (Latin — cancellus), bone in thb condition, where the trabeculae are slender and the spaces between them extensive, is known as cancellous bone. The spaces between the trabeculae are known as marrpw spaces.

Endochondral Bone Formation

As the term implies, endochondral bone formation goes on within cartilage. It cannot be stated too strongly that cartilage does not, in this process, become converted int# bone. Cartilage is destroyed and bone is formed where the cartilage used to be. The actual bone formation is essentially the same as in the case of membrane bone. The phenomena of special interest in connection with this type of bone development are those involved in the destruction of the cartilage preliminary to the formation of bone.

Cartilage Formation

To trace the process logically we must start back with the formation of cartilage. The first indication of impending chondrogenesis is the aggregation of an exceedingly dense mass of mesenchymal cells. This cell mass gradually takes on the shape of the cartilage to be formed. The histogenetic changes involved are not at first conspicuous. During the period of preliminary massing the cells have been migrating in from surrounding regions and also increasing the local congestion by rapid proliferation. As they are packed in together they lose their processes and become rounded (Fig. 154, A, 1). When it seems as if no more cells could possibly be crowded in, the course of events changes. The cells begin to separate from one another. This is due to the fact that they have become active in


Fig. 154. Photomicrographs of developing cartilage. The areas photographed were from the margins of the paranasal cartilage of pig embryos between 25 and 30 mm. in length. For location of cartilage in head see figure 175.

A, Early stage showing: at (1) the massing of mesenchymal cells which were about to be incorporated in the growing margin of the cartilage; and at (2) an area where matrix formation is already beginning.

B, Slightly more advanced stage of the same cartilage showing: at (1) increase in the amount and density of the matrix in the center of the growing cartilage; at (2) concentration of the surrounding mesenchyme to form tire perichondrium; and at (3) the addition of new cartilage matrix peripherally secreting. It is the accumulation of the secretion of the cells which gradually forces them farther and farther apart unti^ they come to lie isolated from one another in the matrix they have produced (Fig. 1 54, A, 2). Such a method of increase in m^ss, where there are many scattered growth centers contributing independently to the increase in bulk of the whole, is known as interstitial growth. This interstitial growth of young cartilage stands in sharp contrast to the appositional growth of such rigid substances as bone or dentine or enamel where the matrix is laid down in successive layers one upon another. Obviously interstitial growth implies plasticity of the substance produced. Were the substance produced unyielding, the very activity of a number of growth centers within it would soon crowd those growth centers to obliteration.

As the cartilage matrix is increased in amount its affinity for basic stains becomes more marked, due probably to increase in concentration of the characteristic substance in it known chemically as chondrin. At the same time the matrix becomes more rigid with a resultant checking of interstitial growth. The cells continue to secrete to a certain extent, however, as evidenced by the fact that in mature cartilage the matrix immediately surrounding the cells becomes more dense than the rest of the matrix. This area of denser matrix around the lacuna in which the cell lies is known as the capsule. As the cartilage grows older the capsules become more conspicuous and many of them come to contain more than one cell. These nests of cells in a common capsule are the result of cell divisions, following which the daughter cells are held imprisoned in the original capsule of the mother cell — further evidence of the loss of plasticity in the matrix.

The formation of a matrix so rigid that interstitial growth is checked, takes place first centrally in an area of developing cartilage. When the center has become too rigid for interstitial growth to continue, appositional growth begins to take place peripherally. While the cartilage has been increasing in mass it has been acquiring a peripheral investment of compacted mesenchyme. This investing layer of mesenchyme soon becomes specialized into a connectivetissue covering called the perichondrium. The layer of the perichondrium next to the cartilage is less fibrous than the outer layer and the cells in it continue to proliferate rapidly and become active in the secretion of cartilage matrix. For this reason it is known as the chondrogenetic layer of the perichondrium. It is through the activity (rf the chondrogenetic layer that the cartilage continues to grow peripherally, by apposition, long after interstitial growth has ceased in the matrix first formed.


Fig. 155. Drawing showing periosteal bud and an area of endochondral bone formation from the radius of a 125 mm. sheep embryo. The small sketch indicates the location of the area drawn in detail.

Abbreviations: Cart, eros., area from which cartilage has recently been eroded; Cart, pre-eros., area with cartilage cells enlarged and arranged in rows presaging erosion; Cart, trab,, remnant of cartilage matrix which has become calcified and serves as an axis or core about which bone lamellae are deposited to form a bone trabecula; Mes., mesenchymal cell.


Cartilage Erosion. When a mass of cartilage is about to be replaced by bone, very striking changes in its structure take place. The cells which have hitherto been secreting cartilage matrix begin to destroy the matrix. The lacunae become enlarged and a curious arrangement of the cartilage cells becomes evident. The cells erode the cartilage in such a manner that they become lined up in rows (Fig. 155). This process of destruction continues until the cartilage is extensively honeycombed. Meanwhile the tissue of the perichondrium overlying the area of cartilage erosion becomes exceedingly active. There is rapid cell proliferation and the new cells, carrying blood vessels with them, begin to invade the honeycombed cartilage (Fig. 155).

The Deposition of Bone

It is a striking fact that during its growth cartilage is devoid of blood vessels, the nearest vessels to it being those in the perichondrium. The invasion of cartilage by blood vessels definitely determines its disintegration as cartilage, and at the same time is the initial step in the formation of bone. For this reason the enveloping layer of connective tissue, up to this time called perichondrium because of its relation to the cartilage, is now called periosteum because of the relations it will directly acquire to the bone about to be formed. This change will not be confusing if we stop to think that both these terms are merely ones of relation, which translated mean, respectively, that tissue which surrounds cartilage, and that tissue which surrounds bone. The important fact to bear in mind is that this enveloping layer of tissue is of mesenchymal origin and therefore contains cells of the stock that may develop into any of the connectivetissue family to which bone as well as cartilage belongs. When, therefore, a mass of periosteal tissue {periosteal bud, Fig. 155) grows into an area of honeycombed cartilage it carries in potentially boneforming cells. These cells come to lie along the strand-like remnants of cartilage, just as in membrane bone formation osteoblasts ranged themselves along fibrous strands. The actual deposition of bone proceeds in the same manner endochondrally as it does intramembranously. The only difference is that in one case a strand-like remnant of cartilage serves as an axis for the trabecula, whereas in the other case deposition begins on a fibrous strand. Extensions and fusions of the growing trabeculae soon result in the establishment of typical cancellous bone similar to that formed intramembranously.


The Formation of Compact Bone from Primary Cancellous Bone

The difference between cancellous bone and compact bone is architectural rather than histological. The fundamental composition of the bone matrix, its lamellation, and the relations of the bone cells to the matrix, are the same in both cases. It is the way in which the lamellae are arranged that distinguishes these two types of bone from each other. In cancellous bone the disposition of lamellae is such that it leaves large marrow spaces between the trabeculae. In compact bone there has been a secondary deposit of concentrically arranged lamellae in the marrow spaces which greatly increases the density of the bone as a whole.

The essential differences between the two, and the way in which cancellous bone may become converted into compact bone, can be illustrated by a simple schematic diagram. Figure 156, 1, shows the arrangement of lamellae and marrow spaces in primary cancellous bone. The osteoblasts which have formed the trabeculae still lie along them on the surface toward the marrow cavity. If such an area is to IxTome compact, these osteoblasts enter on a period of renewed activity and deposit a series of concentric lamellae in the marrow cavity. Frequently if the marrow spaces are irregular there is a preliminary rounding out of them by local resorption of the bone already formed (Fig. 156, 2). This is then followed by the deposition


Fig. 156. Diagram showing transformation of cancellous to compact bone. The solid lines indicate the lamellae of primary cancellous bone; the dotted lines show the subsequently added concentric (Haversian) lamellae which nearly obliterate the marrow spaces of cancellous bone. The sequence of events is indicated by the numbers. Note that irregularly shaped spaces in the cancellous bone may be rounded out by absorption before the concentric lamellae are laid down.


of the concentrically arranged lamellae, sometimes called Haversian lamellae after the man who first described them in detail (Fig. 156, 3 ). In this process the original marrow spaces are reduced to small canals {Haversian canals^ into which have been crowded the blood vessels which formerly lay in the marrow cavities (Fig. 156, 4 ). These canals maintain intercommunication with each other in the substance of the bone, constituting a network of pathways over which the bone receives its vascular supply. As compared with the marrow spaces of cancellous bone, however, they are very small; and the gross appearance of a bone which has undergone this secondary deposit of concentric lamellae amply justifies characterizing it as ‘'compact.’’

II. The Development of the Skeletal System

In dealing with the development of the skeletal system we must recognize at the outset that the subject is far too extensive to be covered here with anything like completeness. It is not difficult, however, to become acquainted with the outstanding features in the development of two or three characteristic bones, as, for example: the sequence of events in the formation of a flat bone; the steps involved in the establishment and growth of a long bone; the way separate ossification centers appear in a common primordial cartilage mass and give rise to the various parts of a vertebra. Familiarity with such type processes gives one an understanding of the factors operative in the development of the skeleton as a whole and a background sufficient to permit ready and intelligent following up of developmental details in specific bones in which one may become interested.

Development of Flat Bones. The flat bones, such as the bones of the cranium and face, are for the most part of intramembranous origin. We are, therefore, already familiar with the early steps in their development from our study of the histogenesis of membrane bone (Figs. 151 and 153). After a mass of primary cancellous bone has been laid down in a configuration which suggests that of the adult bone being formed, there appears about this mass a peripheral concentration of mesenchyme (Fig. 157, A). This periosteal concentration of mesenchymal tissue contains potentially bone-forming cells which soon become active and lay down a dense layer of parallel lamellae about the spongy center of the growing bone (Fig. 157, B). Anatomically this dense peripheral portion is known as the outer table of the bone. The inner portion, which in the flat bones usually remains cancellous, is called the diploii. The original mesenchymal tissue which remains in the marrow spaces of the diploe develops into characteristic “red bone marrow” rich in blood-forming elements (Fig. 152).


Fig. 157. Diagrams showing the manner in which the dense peripheral layer of a flat bone is formed by the deposition of subperiosteal lamellae about an area of primary cancellous bone.


The story of the growth of the mandible, a membrane bone which starts after the manner of flat bones but which later takes on a very elaborate shape and finally becomes largely compact, can be gleaned by a comparative study of figures 178, 180, and 184.

Development of Long Bones. The long bones are characteristically of endochondral origin. The cartilage in which they are performed is a tempiorary miniature of the adult bone. Ordinarily there are several ossification centers involved in the formation of long bones. The first one to appiear is that in the shaft or diaphysis. The location of this center is shown schematically in figure 158, A, Such details as the cartilage erosion which preceded its appearance and the manner in which the deposit of bone was initiated have already been considered (Fig. 155). Our interest now is in the relation of such an endochondral ossification center to other centers, and to the bone as a whole.


Fig. 158, Diagrams showing liie progress of ossification in a long bone. The stippled areas represent cartilage; the black areas indicate bone.

A, Primary ossification center in shaft. B, Primary center plus shell of subperiosteal bone. C, Entire shaft ossified. D, Ossification centers have appeared in the epiphyses. E, Entire bone ossified except for the epiphyseal cartilage plates.


Almost coincidently with the beginning of bone formation within the cartilage the overlying periosteum begins to add bone externally (Fig. 158, B). In view of the fact that the bone-forming tissue carried into the eroded cartilage arose from the periosteum, this activity of the periosteum itself is not surprising. Moreover we have already encountered this same phenomenon of periosteal bone formation in the outer table of flat bones.

The formation of bone which starts at about the middle of the shaft soon extends toward either end until the entire shaft is involved (Fig. 158, C), leaving the two ends {epiphyses) still cartilage. Toward the end of fetal life ossification centers appear in the epiphyses. The number and location of these epiphyseal centers vary in different long bones. There is always at least one center in each epiphysis and there may be two or more. Not uncommonly there are two centers in one epiphysis and one in the other, as illustrated in figure 158, D.

Between the bone fojcmed in the diaphysis and that formed in the epiphysis there persists a mass of cartilage known as the epiphyseal plaie which is of vital importance in the growth in length of the bone.


We should expect from the rigidity of bone matrix that interstitial growth could not account for its increase in length. This was long ago demonstrated experimentally by exposing a developing bone and driving into it three small silver pegs, two in the shaft and one in the epiphysis. The distance between the pegs being recorded, the incision was closed and development allowed to proceed until a marked increase had occurred in the length of the bone. On again exposing the pegs, the two in the shaft were found to be exactly the same distance apart as when they were driven in, but the distance between the pins in the shaft and that in the epiphysis had increased by an amount corresponding to the increase in length of the bone. This indicates clearly that the epiphyseal plates constitute a sort of temporary, plastic union between the parts of the growing bone. Continued increase in the length of the shaft is accomplished by the addition of new bone at the cartilage plate. These epiphyseal plates persist during the entire postnatal growth period. Only when the skeleton has acquired its adult size do they finally become eroded and replaced by bone which joins the epiphyses permanently to the diaphysis.

As the bone increases in length there is a corresponding increase in its diameter. The manner in which this takes place is also susceptible of experimental demonstration. If madder leaves, or some of the alizarin compounds extracted from them, be fed to a growing animal, the bone formed during the time the feeding is continued is colored red. If the madder is discontinued, bone of normal color is again formed ; but the color still remains in the bone laid down while madder was being added to the diet. Thus it is possible, by keeping a record of alternate f>eriods of feeding and withholding madder and comparing these records with the resulting zones of coloration in a bone, to obtain very accurate information on the progress of bone growth and resorption. Applied to the development of long bones this method shows their increase in diameter to be due to continued appositional growth beneath the periosteum. As the bone is added to peripherally there is a corresponding resorption centrally. This central resorption results in the formation of a cavity in the axis of the long bone which is called the marrow canal (Fig. 158, C). With the further increase in the diameter of a bone, its marrow canal becomes correspondingly enlarged. A significant mechanical fact might be cited in this connection. 'Engineers have determined that the strongest rod which can be made from a given weight of steel is obtained by molding it into tubular form. The development of an essentially tubular shaft by progressive increase in the size of the marrow cavity gjivcs a long bone maximum strength with minimum weight.

The Formation of the Vertebrae. The development of the vertebrae is of interest to the student primarily because it exemplifies so excellently a fundamental embryological phenomenon — the origin of separate parts from an undifferentiated primordial tissue mass, and the subsequent association of these parts to form an organized structure. In studying young embryos we traced the history of the mesodermic somites through their early differentiation. It will be recalled that from the ventro-mesial face of each somite there arises a group of mesenchymal cells called collectively a sclerotome (Fig. 42). These cells migrate from either side toward the mid-line and become aggregated about the notochord. From these masses of cells the entire vertebral column is destined to arise.

The first significant change which takes place in these primordial masses is the clustering of sclerotomal cells derived in part from each of the two adjacent somites into groups which are located opposite the intervals between the myotomes. In studying series of transverse sections this arrangement is easy to overlook unless the density of the cells about the notochord is carefully noted in passing from section to section. It shows very clearly, however, in frontal sections (Fig. 159). Each of these cell clusters is the primordium of the centrum of a vertebra. Once formed they rapidly become more dense and more definitely circumscribed (Fig. 160). Soon after the centrum takes shape, paired mesenchymal concentrations extending dorsally and laterally from the centrum establish the primordia of the neural arches and of the ribs (Fig. 161).


Fig. 159. Semi-schematic coronal sections through the dorsal region of young embryos to show how the vertebrae became intermyotomal in position. Note that the primordium of a centrum is formed by cells originating from the sclerotomes of both the adjacent pairs of somites.


Fig. 160. Transverse section from pig cm])ryo of 17 mm. cut at the level of the lungs to show the structures in the dorsal body-wall. (After Minot.)


Fig. 161 . Transverse section of 20 mm. pig embryo cut at the level of the lungs to show the developing vertebra and ribs. (After Minot.)


Fig. 162. Transverse section from 40 mm. pig embryo cut at the level of the lungs to show the developing vertebra and ribs.


The Stage in which the various parts of the vertebrae arc sketched in mesenchymal concentrations, is frequently spoken of as the blastemal stage. It is rapidly followed by the cartilage stage. Conversion to cartilage begins in the blastemal mass first in the region of the centrum and then chondrification centers appear in each neural and each costal process (Fig. 161). These spread rapidly until all the centers fuse and the entire mass is involved (Fig. 162). The cartilage miniature of the vertebra thus formed is at first a single piece showing no lines of demarcation where the original centers of cartilage formation became confluent, and no foreshadowing of the separate parts of which it will be made up after the cartilage has been replaced by bone. Shortly before ossification begins the rib cartilage becomes separated from the vertebra, but the vertebra itself remains in one piece throughout the cartilage stage (Fig. 162).

The locations of the endochondral ossification centers which appear in a vertebral cartilage are indicated schematically in figure 163. It readily can be seen how the spreading of these centers of bone formation will establish the conditions which exist in an adult vertebra. The median ossification center gives rise to the centrum. The centers in the neural processes extend dorsally to complete the neural arch. The spinous process in most of the vertebrae is formed by a prolongation of these same centers to meet dorsal to the neural canal.


Fig. 164. Diagram of four types of vertebrae indicating the parts derived from the different ossification centers shown in figure 163. The part formed by the median center in centrum is cdncentrically ringed; the parts arising from the costal centers are stippled; parts derived from the lateral centers in the neural arches are indicated in line-shading,


In forms such as the pig the spinous processes of tl>e more anterior thoracic vertebrae are very long. In these vertebrae additional ossification centers appear in the spinous process and fuse with those in the neural processes. The transverse processes with which the tubercles of the ribs articulate are formed by the lateral extension of the primary ossification centers in the neural processes. These same centers extend ventrally also, and meet the centrum (cf. Figs. 163 and 164).


Fig. 165. Photograph (X 1/^ showing the ossification centers which have appeared in pig embryos of 35 mm. This and the two following figures were made by photographing in transmitted light embryos in which all the uncalcified tissues had been rendered transparent by treatment with potassium hydroxide and glycerine.



Fic. 166. Photograph (X IM) showing the progress of ossification in the skeleton of a 65 mm. pig embryo.


Fig. 167. Photograph {X showing the extent of ossification in the skeleton of a 90 nun. pig embryo.

The shaft of the rib is formed by extension of its primary ossification center (Fig. 163). After birth, secondary epiphyseal centers appear in the tubercle and head of the rib. These centers are separated from the shaft by persistent cartilage plates in the manner described in discussing the development of long bones. Fusion of the secondary epiphyseal centers with the shaft of the rib does not take place until the skeleton has acquired its adult dimensions.

The foregoing discussion has been based on a thoracic vertebra in which the relations of the rib to the vertebra show most clearly. All the vertebrae have the costal element represented, although it is greatly reduced and modified in other regions than the thoracic. A study of figure 164, in which the components of vertebrae from the cervical, thoracic, lumbar, and sacral regions are schematically indicated, will make the homologies apparent. With these homologies in mind it is sufficiently evident, without going into further detail, how all these vertebrae arise by a process similar to that described for the thoracic vertebrae.

The Progress of Ossification in the Skeleton as a Whole. It would carry us beyond the scope of this book to take up the development of specific bones. Each has its own story involving the formation of the connective tissue or the cartilage mass which precedes it ; local erosion centers if it be preformed in cartilage; number, location, and time of appearance of ossification centers; growth in length and diameter; development of epiphyses; time of fusion of epiphyses and diaphysis; and finally the development of muscle ridges and articular facets. Without entering into a discussion of details of this sort, it is possible nevertheless to follow the general progress of ossification in the skeletal system as a whole. Embryos which have been treated with potassium hydroxide and then cleared in glycerine clearly show the various ossification centers. In such preparations the areas where calcium salts have been deposited stand out white in reflected light and opaque in transmitted light. ^Figures 165-167, which are photographs of preparations of this type, can be used to trace the history of the more important bones. It should perhaps be stated explicitly that these figures arc included primarily to give a general view of the progress of ossification and secondarily to afford a readily available source of reference for following up points of interest that may arise. It is not a profitable use of the student’s time to attempt to memorize the ossification centers which have appeared in embryos of any given age.



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Patten 1951: 1 Foreword to the Student | 2 Reproductive Organs - Gametogenesis | 3 Sexual Cycle | 4 Cleavage and Germ Layers | 5 Body Form and Organs | 6 Extra-Embryonic Membranes | 7 Embryos 9-12 mm | 8 Nervous System | 9 Digestive - Respiratory and Body Cavities | 10 Urogenital | 11 Circulatory System | 12 Bone and Skeletal System | 13 Face and Jaws | Bibliography

Cite this page: Hill, M.A. (2024, May 17) Embryology Book - Embryology of the Pig 12. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Embryology_of_the_Pig_12

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