DEVELOPMENT OF TOOTH

PRESENTED BY:
DR. MEGHA S 1
FIRST YEAR POST GRADUATE
CONTENTS

 Development of tooth
 Introduction
 Initiation of tooth development
 Molecular regulation of tooth formation
 Stages in tooth formation
 Hertwig’s epithelial root sheath and root formation
 Nerve and vascular supply during early development
 Amelogenesis and Dentinogenesis
 Developmental disturbances of teeth
2
 INTRODUCTION
 The primitive oral cavity, or stomodeum, is lined by stratified
squamous epithelium called the oral ectoderm or primitive oral
epithelium.
 Theoral ectoderm contacts the endoderm of the foregut to
form the buccopharyngeal membrane.
 Atabout 27th day of gestation this membrane ruptures and the
primitive oral cavity establishes a connection with foregut.
 Most of the connective tissue cells underlying the oral
ectoderm are of neural crest in origin.
 These cells are thought to induce the overlying ectoderm to 3
start tooth development.
 The
entire primary dentition is initiated between six and eight weeks of
embryonic development.

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DENTAL LAMINA
 Two or three weeks after the rupture of the buccopharyngeal membrane, certain areas
of basal cells of the oral ectoderm proliferate more rapidly than do the cells of the
adjacent areas.
 Thisleads to the formation of the Primary epithelial band-which is a band of
epithelium that has invaded the underlying ectomesenchyme along each of the
horseshoe-shaped future dental arches

Primary
epithelial band

At about 7th
week Outer (buccal)
Inner (lingual)
process called
process Dental
lamina
Vestibular
lamina. 5
 The dental lamina serve as the primordium for the ectodermal portion of the
deciduous teeth.
 Later,during the development of the jaws, the permanent molars arise directly
from a distal extension of the dental lamina.

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FATE OF DENTAL LAMINA

 Itis evident that the total activity of the dental lamina extends over a period of at
least 5 years.
 As the teeth continues to develop ,they loose their connection with dental lamina.
 Fragmentation of dental lamina progresses towards the formation of enamel
organ.

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 However, the dental lamina may still be active in the third molar region.
 As the teeth continue to develop, they lose their connection with the dental lamina.
 Remnants of the dental lamina persist as epithelial pearls or islands within the jaw as
well as in the gingiva. These are referred to as cell rest of Serres.

Derived from dental lamina (rests of Serres)

 Odontogenic keratocyst
 Gingival cyst of newborn
 Gingival cyst of adult
 Lateral periodontal cyst
 Glandular odontogenic cyst
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VESTIBULAR LAMINA

 Labial and buccal to the dental lamina in each dental

arch, another epithelial thickening develops
independently and somewhat later. It is the vestibular
lamina, also termed the lip furrow band
 It subsequently hollows and forms the oral vestibule
between the alveolar portion of the jaws and the lips
and cheeks.

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10
 DEVELOPMENT OF TOOTH
 At
certain points along the dental lamina, the ectodermal cells multiply still
more rapidly and form little knobs that grow into the underlying
mesenchyme.
 Eachof these little down growths represents the beginning of the enamel
organ of the tooth bud of a deciduous tooth, each representing one of 10
maxillary and 10 mandibular teeth.

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 As cell proliferation continues, each enamel organ
increases in size, sinks deeper into the
ectomesenchyme and due to differential growth
changes its shape.
 Inside the depression of the enamel organ, the
ectomesenchymal cells increase in number.
 The tissue appears more dense than the surrounding
mesenchyme and represents the beginning of the
dental papilla.
 The third part of the tooth bud surrounding enamel
organ and dental papilla is dental sac or dental
follicle consisting of ectomesenchymal cells and
fibers
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INITIATION AND MOLECULAR REGULATION
OF TOOTH DEVELOPMENT
 Development of tooth results from interaction of the epithelium
derived from the first arch and ectomesenchymal cells derived from
the neural crest cells.
 There are signalling molecules that mediate communication between
cell.
 Bone morphogenetic protein (BMP), Fibroblast growth factor (FgF),
Sonic hedgehog (Shh), Wingless-related integration site (Wnt),
Ectodysplasin A (Eda).
 These signals regulate tooth development all the way from initiation
to root formation.
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STAGES IN TOOTH
DEVELOPMENT

Cap stage
Bell stageAdvance bell stage

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BUD STAGE

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CAP STAGE

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• The outer enamel epithelium is separated from the dental sac, and the
inner enamel epithelium from the dental papilla, by a delicate basement
membrane.

• The enamel organ may be seen to have a double attachment of dental

lamina to the overlying oral epithelium enclosing ectomesenchyme called
enamel niche between them. This appearance is due to a funnel-shaped
depression of the dental lamina.

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 STELLATE RETICULUM
 Polygonal cells located in the center of the epithelial enamel organ, begin
to separate due to water being drawn into the enamel organ from the
surrounding dental papilla
 This is as a result of osmotic force exerted by glycosaminoglycans
contained in the ground substance.
 As a result the polygonal cells become star shaped but maintain contact
with each other by their cytoplasmic process.
 As these star-shaped cells form a cellular network, they are called the
stellate reticulum.
 This gives the stellate reticulum a cushion like consistency and acts as a
shock absorber that support and protect the delicate enamel-forming
cells.
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 The cells in the center of the enamel organ are densely packed and form the enamel knot.
 This knot projects in part toward the underlying dental papilla, so that the center of the
epithelial invagination shows a slightly knob-like enlargement that is bordered by the labial
and lingual enamel grooves.
 At the same time a vertical extension of the enamel knot, called the enamel cord occurs.

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Dental papilla
 It condenses to form the dental papilla, which is the formative organ of the dentin
and the primordium of the pulp.
 The dental papilla shows active budding of capillaries and mitotic figures, and its
peripheral cells adjacent to the inner enamel epithelium enlarge and later
differentiate into the odontoblasts.

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Dental sac (dental follicle)
 Concomitant with the development of the enamel organ and the dental papilla, there
is a marginal condensation in the ectomesenchyme surrounding the enamel organ and
dental papilla.
 Gradually, in this zone, a denser and more fibrous layer develops, which is the
primitive dental sac.

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 BELL STAGE

 As the invagination of the epithelium deepens and

its margins continue to grow, the enamel organ
assumes a bell shape.
 In the bell stage, crown shape is determined.
 It was thought that the shape of the crown is due to
the pressure exerted by the growing dental papilla
cells on the inner enamel epithelium.

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 Cells begin to differentiate only when cells cease to divide.
 The inner enamel epithelial cells lying near the future cusp tip or incisor
region begins to differentiate results in formation of cusp tip.
 Cell differentiation also proceeds gradually cervically, those at the cervix are
last to differentiate.

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Inner enamel epithelium
 Cells differentiate into tall columnar cells forming ameloblasts,
precursor for Amelogenesis.
 The cells of the inner enamel epithelium exert an organizing
influence on the underlying mesenchymal cells in the dental
papilla, which later differentiate into odontoblasts.

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Stratum intermedium
 The well-developed cytoplasmic organelles, acid mucopolysaccharides, and
glycogen deposits indicate a high degree of metabolic activity.
 The cells of stratum intermedium work synergistically with cells of inner enamel
epithelium as a single functional unit and form enamel.
 It is absent in the part of the tooth germ that outlines the root portions of the tooth
which does not form enamel.

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Stellate reticulum
 The stellate reticulum expands further, mainly by an increase in the amount of
intercellular fluid.
 Before enamel formation begins, the stellate reticulum collapses.
 This reduces the distance between the centrally situated ameloblasts and the
nutrient capillaries near the outer enamel epithelium.
 This change begins at the height of the cusp or the incisal edge and progresses
cervically.

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Outer enamel epithelium
 The cells of the outer enamel epithelium flatten to a low cuboidal form.
 Atthe end of the bell stage, preparatory to and during the formation of enamel,
the formerly smooth surface of the outer enamel epithelium is laid in folds.
 Between the folds the adjacent mesenchyme of the dental sac forms papillae
that contain capillary loops.
 Thisprovides a rich nutritional supply for the intense metabolic activity of the
avascular enamel organ.
 This would adequately compensate the loss of nutritional supply from dental
papilla owing to the formation of mineralized dentin.

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Dental lamina
 Extendslingually and is termed successional dental lamina as it gives rise to
enamel organs of permanent successors of deciduous teeth.
 The enamel organs of deciduous teeth in the bell stage show successional
lamina and their permanent successor teeth in the bud stage.

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Dental papilla
The dental papilla is enclosed in the invaginated portion of the enamel organ.
The dental papilla ultimately gives rise to dental pulp, once the dentin formation
begins at the cuspal tip of the bell stage tooth germ.
The basement membrane that separates the enamel organ and the dental papilla
just prior to dentin formation is called the membrana preformativa.

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Dental sac
 Before formation of dental tissues begins, the dental sac shows a circular arrangement
of its fibers and resembles a capsular structure.
 With the development of the root, the fibers of the dental sac differentiate into the
periodontal fibers that become embedded in the developing cementum and alveolar
bone.

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Advanced bell stage
 Thisstage is characterized by the commencement
of mineralization and root formation.
 During the advanced bell stage, the boundary
between inner enamel epithelium and
odontoblasts outlines the future dentino-enamel
junction.
 The formation of dentin occurs first as a layer
along the future dentino-enamel junction in the
region of future cusps and proceeds pulpally and
apically.
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 The enamel formation then proceeds coronally and cervically, in all regions from
the dentino enamel junction (DEJ) towards the surface.
 Enamel does not form in the absence of dentin, as demonstrated by the failure of
transplanted ameloblasts to form enamel when dentin is not present.
 The advanced bell stage marks not only active histodifferentiation but also an
important stage of morpho differentiation in the crown, outlining the future
dentino enamel junction
 In addition, the cervical portion of the enamel organ gives rise to the epithelial
root sheath of Hertwig.
 The Hertwig’s epithelial root sheath (HERS) outlines the future root and is thus
responsible for the shape, length, size, and number of roots.

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 HERTWIG’S EPITHELIAL ROOT SHEATH
AND ROOT FORMATION
 Thedevelopment of the roots begins after enamel and dentin
formation has reached the future cementoenamel junction.
 Thecells of the inner layer remain short and normally do not
produce enamel.
 These cells induce the differentiation of radicular dental
papilla cells into odontoblasts and the first layer of dentin has
been laid down.

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 Its remnants persist as an epithelial network of strands or clumps near the
external surface of the root.
 These epithelial remnants are found in the periodontal ligament of erupted
teeth and are called rests of Malassez.

Derived from rests of Malassez

 Periapical cyst
 Residual cyst

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 Thereis a pronounced difference in the development of HERS in teeth
with one root and in those with two or more roots.
 Theouter and inner enamel epithelia bend at the future cementoenamel
junction into a horizontal plane to form an epithelial diaphragm.
 This narrows the wide cervical opening of the tooth germ.
 The free end of the diaphragm does not grow into the connective tissue,
but the epithelium proliferates coronal to the epithelial diaphragm.
 Thedifferentiation of odontoblasts and the formation of dentin follow the
lengthening of the root sheath.

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 At the same time, the connective tissue of the dental sac surrounding the
root sheath proliferates and invades the continuous double epithelial layer
dividing it into a network of epithelial strands.
 The epithelium is moved away from the surface of the dentin so that
connective tissue cells come into contact with the outer surface of the
dentin and differentiate into cementoblasts
 A layer of cementum is deposited onto the surface of the dentin.
 The rapid sequence of proliferation and destruction of Hertwig’s root
sheath explains the fact that it cannot be seen as a continuous layer on the
surface of the developing root.

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 NERVE AND VASCULAR SUPPLY
DURING EARLY DEVELOPMENT

Vascular supply
 Clusters of blood vessels are found ramifying around the tooth germ in the
dental follicle and entering the dental papilla during the cap stage.
 Their number in the papilla increases, reaching a maximum during the bell
stage when the matrix deposition begins.

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 NERVE SUPPLY
 Pioneer nerve fibres approach the developing tooth during the bud cap stage of
development.
 They ramify and form a rich plexus around the tooth germ in the dental follicle.
 Not until dentinogenesis begins however do the fibres penetrate the dental papilla.
 Thus the initial innervation of the developing teeth is concerned with the sensory
innervation of the future periodontal ligament and pulp.

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 AMELOGENESIS

 It is the process of enamel formation

 Cells responsible for enamel formation are called as ameloblasts.

 Amelogenesis is a two step process

- Organic matrtix formation - secretion of enamel proteins
- produces partial mineralized enamel
- Mineralization - deposition of hydroxyapatite crystals
- organic matrix and water are lost and mineral is added to
attain greater than 96% mineral content

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AMELOBLASTS

 Secrete matrix proteins.

 Each ameloblast is approximately 4 micrometres in diameter, 40
micrometres in length and has hexagonal cross section.
 The secretory end of the ameloblasts end in a six sided pyramid like
projection known as tome’s process.

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LIFE CYCLE OF AMELOBLASTS

The life span of ameloblasts can be divided functionally into 3 stages and
again subdivided histologically as:
 PRESECRETORY STAGE
(1) Morphogenic phase
(2) Organizing phase
 SECRETORY STAGE
(1) Formative phase
 POST SECRETORY STAGE
(1) Maturative phase
(2) Protective phase 41
(3) Desmolytic phase
Morphogenic stage
 Early bell stage
 Before the ameloblasts are fully differentiated and produce enamel, they
interact with the adjacent mesenchymal cells, determining the shape of
the dentinoenamel junction and the crown.
 The inner enamel epithelium is separated from the connective tissue of
the dental papilla by a delicate basal lamina. The adjacent pulpal layer is
a cell-free.

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 This reversal of nutritional source is characterized by proliferation of capillaries
of the dental sac and by reduction and gradual disappearance of the stellate
reticulum.
 During the terminal phase of the organizing stage the formation of the predentin
by the odontoblasts happens.

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Maturative stage
 Enamel maturation (full mineralization) occurs after most of the
thickness of the enamel matrix has been formed in the occlusal or incisal
area.
 In the cervical parts of the crown, enamel matrix formation is still
progressing at this time.
 Reduction in height of ameloblasts ,decrease in the volume and
organelle content.
 Ameloblasts undergo programmed cell death ie apoptosis,25% die
during transitional phase and another 25% die as enamel maturation
proceeds.
 Ameloblasts show modulation, the cyclic creation loss and recreation of
a highly invaginated ruffle ended apical or a smooth surface.
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Protective stage
 When the enamel has completely developed and has fully calcified, the
ameloblasts cease to be arranged in a well-defined layer and can no longer
be differentiated from the cells of the stratum intermedium and outer
enamel epithelium.
 These cell layers then form a stratified epithelial covering of the enamel,
called reduced enamel epithelium.
 It protects the mature enamel by separating it from the connective tissue
until the tooth erupts.

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Desmolytic stage
 The reduced enamel epithelium proliferates and seems to induce atrophy of the
connective tissue separating it from the oral epithelium, so that fusion of the two
epithelia can occur.
 Premature degeneration of the reduced enamel epithelium may prevent the
eruption of a tooth.

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AMELOGENESIS
On the basis of ultrastructure and composition, two processes are involved
in the development of enamel: organic matrix formation and
mineralization.
Formation of the enamel matrix
 The ameloblasts begin their secretory activity when a small amount of
dentin has been laid down.
 The ameloblasts lose the projections that had penetrated the basal lamina
separating them from the predentin, and islands of enamel matrix are
deposited along the predentin.
 As enamel deposition proceeds, a thin, continuous layer of enamel is
formed along the dentin. 47
 Amelogenin is the major component of enamel matrix proteins.
 The genes coding for amelogenin is present in X and Y
chromosomes.
 Absence of amelogenin, resulted in the formation of hypoplastic
teeth.
 Ameloblastin and enamelin are the other important proteins of the
enamel matrix.
 Tuftelin,on the hand, is localized to DE junction and is suggested to
be involved in cell signaling.

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Mineralization and maturation of the enamel matrix
 In the first stage an immediate partial mineralization occurs in the matrix
segments and the interprismatic substance as they are laid down.
 The second stage, or maturation, is characterized by the gradual completion of
mineralization.
 The process of maturation starts from the height of the crown and progresses
cervically.

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DENTINOGENESIS

 Chemical composition of dentin is

-70% inorganic( calcium hydroxyapatite,calcium carbonate,sulfate salts,trace
elememts like cu,fe, f ,zn)
-20% organic( collagen mainly type 1 and traces of type 2,non collagenous matrix
proteins , enzymes and lipids )
-10% water

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 Dentinogenesis happens in 3 different stages

-Odontoblast differentiation
-Matrix formation
-Mineralization

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Matrix formation (collagen fibres + ground
substance)

 The odontoblasts differentiate in the pre existing

ground substance of the dental papilla to form
MANTLE DENTIN.

 The CIRCUMPULPAL DENTIN forms the bulk of

dentin which is parallel to DEJ.
 It is formed prior to root completion.
 More mineralized than mantle dentin.

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 INTERGLOBULAR DENTIN is the dentin that separate
mantle dentin and circumpulpal dentin which is
hypomineralized, calcospherites which is due to failed
fusion of homogenous mass with in mature dentin.

 PERITUBULAR DENTIN deposited on the walls of

dentinal tubules and is highly mineralized.

 INTERTUBULR DENTIN is located between dentinal

tubules, it is the end product od odontoblasts.

 ROOT DENTIN is initiated by HERS, it is deposited

parallel to CEJ.

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Mineralization
Histologically 2 patterns are seen:

Globular calcification
- Deposition of crystals in descrete areas of matrix by heterogenous capture in
collagen
- Globules enlarge and eventually fuse to form single calcified mass.
- eg: Mantle dentin

Linear calcification
- Rate of formation is slow
- Mineralization appears more uniform
- More linear
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- eg: Circumpulpal dentin
 DEVELOPMENT OF PULP

Begins at the 8th week of embryonic life

Inner enamel epithelium(singnaling molecules)
Dental papilla cells undergoes cytodifferenciation into a peripheral
layer of odontoblasts and central mass of fibroblasts

once odontoblasts have begun to lay down dentin

Dental papilla becomes dental pulp

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CLINICAL CONSIDERATIONS
The development of tooth is a complex process controlled by various factors.
Therefore this process may be disturbed by defect in genetic control, nutritional
or hormonal imbalances, infections or disturbances in local environment where
the tooth development occurs, resulting in various anomalies. Developmental
anomalies of teeth may be grouped into those affecting number, size, shape,
structure, location, etc.

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SUPERNUMERARY TEETH OR HYPERDONTIA
This may develop from an additional initiation of dental lamina near the
permanent tooth bud or by splitting of the permanent tooth bud itself. The most
common supernumerary tooth is ‘mesiodens’ occur as an extra small conical tooth
located between the two maxillary central incisors.
Other supernumerary teeth include:
• Distomolar situated distal to the third molar and
• paramolars located either buccal or palatal to the molars.

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ANODONTIA OR HYPODONTIA
Refers to absence of all teeth, i.e. total anodontia or some teeth, i.e. partial
anodontia. True anodontia is congenital absence of teeth which occur due to lack
of initiation. The absence of third molars is very common, followed by the second
premolar and lateral incisor. Anodontia or hypodontia is usually a feature of a
condition termed as hereditary ectodermal dysplasia.

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• Microdontia is a condition wherein the teeth are smaller

Pituitary dwarfism causes generalized microdontia

• Macrodontia is larger teeth than normal.

pituitary gigantism causes generalized macrodontia.

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• Rhizomicry : when the roots are smaller than normal

• Rhizomegaly : Refers to abnormally larger roots.

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DISTURBANCES AFFECTING THE SHAPE OF THE TEETH

Talon cusp
Is an anomalous cusp-like structure projecting from the lingual aspect, in the
region of cingulum of maxillary and mandibular incisors.

Taurodontism
Characterized by rectangular shaped tooth resembling that of a Bull’s tooth.

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Gemination
Is a condition that occur when a single tooth germ divide, by an invagination
resulting in incomplete formation of two teeth.

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 CONCRESCENCE
Concrescence is a condition of teeth where the cementum overlying
the roots of at least two teeth join together. The cause can
sometimes be attributed to trauma or crowding of teeth.

DENS EVAGINATUS
Characterized by the presence of a globule of enamel or an extra cusp
on the occlusal aspect between the buccal and lingual cusps of
premolars.

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DENS INVAGINATUS (DENS IN DENTE)

Occurs due to invagination of enamel organ into the dental papilla during
odontogenesis giving rise to a tooth within a tooth appearance.

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 DILACERATION
Dilaceration refers to an angulation or a sharp bend or curve anywhere along the
root portion of a tooth.
Condition probably occurs subsequent to trauma or any other defect of
development which alters the angulation of the tooth germ during root
formation.

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ENAMEL PEARL

During root formation, some of the remnants of Hertwig’s epithelial root sheath
remain attached to the root surface and may attain a capacity to form enamel
and deposit a globule enamel on surface of root near cemento-enamel junction
or close to furcation area, referred to as enamel pearl.

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 Developmental Disturbances In Structure of Teeth

Amelogenesis imperfecta
• Amelogenesis imperfect represents a group of hereditary defects of enamel.
• It is caused by alterations of genes involved in the process of formation and
maturation of enamel
• It may be differentiated into three main groups:
Hypoplastic
Hypomature
Hypocalcified

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RADIOGRAPHIC FEATURES
• Abnormally shaped tooth
• Enamel may be totally absent or may appear as a thin layer over
the cusps and interproximal surfaces.
• Calcification of enamel may be affected such that it appears to
have the same radiodensity of dentin.

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DENTINOGENESIS IMPERFECTA I
 Also known as opalescent dentin.
 Caused by mutation of DSPP gene.
 The teeth are blue gray or amber brown and opalescent.
 On radiograph the teeth have bulbous crowns, roots that are narrower than
normal, and pulp chambers and root canals that are smaller than normal or
obliterated.
 The enamel may split readily from the dentin when subjected to occlusal
stress.

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DENTINOGENESIS IMPERFECTA II
 The crowns of the deciduous and permanent teeth wear rapidly after eruption
and multiple pulp exposure may occur.
 The dentin is amber and smooth.
 Radiograph of deciduous teeth shows large pulp chambers and root canals
which reduces with age.
 The pulp spaces of the permanent teeth may be completely obliterated.
 Shell teeth appearance.

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 REGIONAL ODONTODYSPLASIA
• Also
known as ghost teeth.
• Maxillary teeth are involved more frequently.

CLINICAL FEATURES
 There is a delay or total failure of eruption.
 The shape is irregular.
 There is defect in mineralization

TREATMENT
 Extraction with restoration by prosthetic appliance is indicated.

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 Dentin Dysplasia
Dentin Dysplasia is an autosomal dominant disturbance in dentin formation
characterized by normal enamel but atypical dentin formation with abnormal
pulp morphology.

TYPES
 Radicular Dentin Dysplasia
 Coronal Dentin Dysplasia

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CLINICAL FEATURES

Type I
 Both dentitions are affected
 Slight amber translucency
 Teeth characteristically exhibit extreme mobility and are exfoliated
prematurely or after minor trauma as a result of abnormally short roots.

Type II
 Both dentitions are affected.
 Deciduous teeth are yellow, brown or bluish gray opalescent in appearance.

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Developmental Disturbances Of Growth (Eruption) Of Teeth

PREMATURE ERUPTION
• Deciduous teeth that have erupted into the oral cavity are
occasionally seen in infants.
• When teeth are present at birth it is known as natal teeth.
• Teeth which erupt prematurely in the first 30 days of life is known as
neonatal teeth.

CLINICAL FEATURES
 The teeth are usually well formed and normal.
 Most commonly seen premature teeth are mandibular central incisor.
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EMBEDDED TEETH
• Embedded Teeth are individual teeth which are unerupted due to lack
of eruptive force.

IMPACTED TEETH
• Impacted teeth are those prevented from erupting by some physical
barrier in the eruption path.
• Most commonly affected teeth are mandibular third molar and
maxillary cuspids.
• Impaction may be mesioangular, distoangular, vertical or horizontal

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ANKYLOSED TEETH
• Also known as submerged teeth.
• Mandibular second molars are most commonly affected.
• There is union of cementum with bone.
• This prevents exfoliation and subsequent replacement by permanent teeth.
• The ankylosed teeth appears submerged below the level of occlusion.
• The affected teeth lack mobility even though root resorption is far advance.
• Percussion results in solid sound.
• Radiograpically there is absence of periodontal ligament
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CONCLUSION

Since development of tooth forms the base of dentistry, a thorough

understanding and a sound knowledge is required by a dentist regarding
the developmental stages of tooth and the anomalies related to it to
diagnose and treat them in the correct way.

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REFERENCES

 Kumar GS. Orban's Oral Histology & Embryology-E-BOOK.

Elsevier Health Sciences; 2015 Jul 25.

 Neville BW, Damm DD, Allen CM, Chi AC. Oral and
maxillofacial pathology. Elsevier Health Sciences; 2015 May 13.

 Rajendran R. Shafer's textbook of oral pathology. Elsevier India;

2009.

 Jose M. Essentials of Oral Biology: Oral Anatomy, Histology,

Physiology & Embryology. CBS Publishers & Distributors;
2008. 78