lisa mayo, rdh, bsdh concorde career college dh227 board review oral histology & embryology
TRANSCRIPT
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LISA MAYO, RDH, BSDHCONCORDE CAREER COLLEGE
DH227 Board ReviewOral Histology & Embryology
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General Embryology
23 chromosomes in each germ cell (haploid)46 chromosomes after fertilization (diploid)Zygote: mitotic divisions
1. Morula2. Blastocele3. Blastocyst
3 periods of development1. Period of ovum (1st week)2. Embryonic Period (2-8 weeks): most congenital
malformations occur3. Fetal Period (3-9mo)
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Gen Embryology
Facial & Oral structures dependent on grp of neural crest cells derived from ectoderm as neural tube develops Facial skeleton: Meckel’s cartilage Neck skeleton: hyoid bone Connective tissue components Tooth development
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Gen Embryology
Neural crest cells migrate into each brachial arches and surrounds existing mesoderm1. Cartilage rod: 1st brachial arch2. Muscular component: 2nd, facial muscles3. Vasculature component4. Nerve component: 1st, trigeminal nerve
Internal brachial arches – corresponding pharyngeal pouches that give rise to1. External auditory meatus2. Pharyngotympanic tube3. Palatine tonsils4. Parathyroid glands
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Five Pharyngeal (Branchial) arches develop below the oral pit
Each pharyngeal arch is associated with a specific Cranial Nerve 1st Pharyngeal Arch: Mandibular 2nd Pharyngeal Arch: Hyoid 3rd, 4th, and 5th Pharyngeal Arches are located
respectively below the other two arches and are separated down the middle by the pericardial cavity (heart).
5 Brachial Arches
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Developing Pharyngeal Arches
3 ½ Weeks
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Pharyngeal (Branchial) Arches
The cores of these arches will differentiate into the blood vessels, muscles, nerves, cartilages, and bones that will form the human face
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Mandibular Arch: (1st Pharyngeal Arch)
Gives rise to the Maxillary Process which forms the cheeks
Eventually forms the: Mandible Muscles of Mastication
Innervated by V Cranial Nerve(Trigeminal Nerve)
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Hyoid: 2nd Pharyngeal Arch)
Forms the: Facial muscles Vessels Hyoid bone
Innervated by the VII Cranial Nerve
(Facial Nerve)
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3rd and 4th Pharyngeal Arches
Become the constrictor muscles of the throat
Innervated by other Cranial Nerves of the muscles of the neck
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Question
Which of the following tissues derive from ectoderm?a. Boneb. Nervous tissuec. Dentin and pulpd. Chewing muscles
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Answer
Which of the following tissues derive from ectoderm?a. Boneb. Nervous tissuec. Dentin and pulpd. Chewing muscles
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NBQ
The first brachial arch gives rise to the mandible, and it innervated by the trigeminal nerve
a. Both statement are TRUEb. Both statements are FALSEc. The first statement is TRUE, the second
statement is FALSEd. The first statement is FALSE, the second
statement is TRUE
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NBQ
The first brachial arch gives rise to the mandible, and it innervated by the trigeminal nerve
a. Both statement are TRUEb. Both statements are FALSEc. The first statement is TRUE, the second
statement is FALSEd. The first statement is FALSE, the second
statement is TRUE
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NBQ
With the exception of the ____, the oral and nasal cavities develop from the first brachial arch and the frontal process
a. Lower lipb. Lower border of the cheeksc. Anterior portion of the hard palated. Base of tonguee. Base of the nasal septum
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NBQ
With the exception of the ____, the oral and nasal cavities develop from the first brachial arch and the frontal process
a. Lower lipb. Lower border of the cheeksc. Anterior portion of the hard palated. Base of tonguee. Base of the nasal septum
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Pharyngeal Grooves and
Pharyngeal Pouches
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Development of Pharyngeal Arches
Each arch is separatedInternally by
Pharyngeal pouchesExternally by
Branchial clefts/grooves
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Gill-like slits (pharyngeal arches) smooth to form Neck
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Disappearing “Gills”
Tissues of the 2nd and 5th pharyngeal arches grow over the other arch grooves and make contact with each other
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Pharyngeal Grooves & Pharyngeal Pouches
The 1st Pharyngeal Groove (covered by ectoderm) deepens to form the external auditory canal.
The 1st Pharyngeal pouch forms into the middle ear and Eustachian tube.
The membrane at the deepest part of this tube becomes the tympanic membrane.
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2’nd Pharyngeal Pouch BecomesPalatine Tonsils
3’rd Pharyngeal Pouch BecomesParathyroid GlandsThymus
4’th Pharyngeal Pouch BecomesUltimobranchial Body
Pharyngeal Grooves & Pharyngeal Pouches
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Prenatal Development
Pre-implantation: 1-7 days Embryonic: 2-8 weeksFetal: 9-38+ weeksMajor developmental malformation occur in
the embryonic period
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NBQ
The olfactory (nasal) pits appear on the lateral sides of these
a. Maxillary processb. Olfactory processc. Mandibular processd. Frontal processe. Globular process
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NBQ
The olfactory (nasal) pits appear on the lateral sides of these
a. Maxillary processb. Olfactory processc. Mandibular processd. Frontal processe. Globular process
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Prenatal Development
3 primitive tissue precursors form1. Ectoderm: Form outer covering of body. Lining of
oral cavity. epithelium, salivary glands, nervous system, ameloblasts (enamel)
2. Endoderm: Epithelial linings of internal organs: GI tract, resp system, urinary tract
3. Mesoderm: connective tissues of skeletal, vascular, muscle, dermis, dental pulp, periodontal attachment, cementum, dentin
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Derivatives of Ectoderm, Mesoderm, and Endoderm layers
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The embryo is covered by a single layer of ectodermal cells which differentiate into multiple layers
Epidermal and dermal cells develop and differentiate into hair, teeth, nails and mammary, sebaceous, and salivary glands
Ectoderm
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Medial somites in the mesoderm form the skeleton that will surround the neural tube.
Intermediate mesoderm forms the striated/voluntary muscle of the body.
Lateral mesoderm forms the dermis of the epithelium of the body and the GI tract. All peristaltic musculature is derived from mesoderm.
Mesoderm
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The endoderm forms into the gastrointestinal tract, which elongates and develops “outpouchings” that form the pharyngeal pouches, lung buds, liver, gall bladder, pancreas, and urinary bladder.
Endoderm
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Neural crest cells form the sensory system of the dorsal root ganglia of the cranial and spinal nerves
Ectoderm forms Neural Crest
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Neural Tube Development: Week 3 - 9Neural Tube Development: Week 3 - 9
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Closing of Neural Tube(3rd week of development)
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Head and Neck Development
Folding of the embryo at 3-4 weeks forms a space (stomodeum) limited by a temporary barrier (oropharyngeal membrane). It will become the oral cavity
Pouches form called brachial arches FIRST MANDIBULAR ARCH: forms mandible, muscles
of mastication, nerve and blood supplies, Merkel’s cartilage which is the precursor of the mandible
SECOND ARCH (HYOID): forms facial muscles and vessels, hyoid bone
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Head & Neck Development
Face forms week 4-7 w/ formation of stomodeum Tooth enamel forms from ectoderm lining the stomodeum
Upper Lip: complete within 6-8 weeks: Fusion of the median nasal process and RT/LF maxillary processes
Palate forms week 5-12 Failure of components to fuse during these periods results in cleft lip,
palate or both. Unilateral or bilateral Fusion of globular process with the LF/RT palatal shelves Separates the stomodeum into an upper (nasal) and lower (oral) cavity
Tongue forms weeks 4-8 Body from tuberculum impar and lateral tissues, and base from copula
form and fuse at the sulcus terminalis Post 1/3 and hyoid bone develops from the 2nd and 3rd brachial arches Know the nerve and blood supplies for the tongue, other oral soft tissues,
facial skeleton, teeth
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NBQ
The buccopharyngeal membrane at what week in development?
a. 2 weeksb. 3 weeksc. 4 weeksd. 6 weeks
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NBQ
The buccopharyngeal membrane at what week in development?
a. 2 weeksb. 3 weeksc. 4 weeksd. 6 weeks
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NBQ
A cleft lip occurs when maxillary process fails to fuse with the
a. Palatine processb. Globular processc. Lateral nasal processd. Mandibular processe. Opposing maxillary process
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NBQ
A cleft lip occurs when maxillary process fails to fuse with the
a. Palatine processb. Globular processc. Lateral nasal processd. Mandibular processe. Opposing maxillary process
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NBQ
Palatal closure occurs during which week in embryonic development?
a. 2b. 4c. 8-12d. 16
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NBQ
Palatal closure occurs during which week in embryonic development?
a. 2b. 4c. 8-12d. 16
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Head & Neck
Most structures of oral cavity develop from 2 embryonic processes Frontal process
Forehead, frontal bone Median nasal process: center and tip nose, nasal septum,
globular process (philtrum, premaxillary palate) Lateral nasal process: sides of nose, infraorbital area
1st brachial arch Maxillary process: lateral palatine processes (palatal
shelves), upper parts of cheek, sides of upper lip Mand process: lower jaw, lower parts of the face and
lower lip, ant 2/3 of tongue
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Salivary Glands
Major and minor, serous and mucous components, major from 1st brachial arch
PAROTID: Stenson’s duct, serous saliva, most common site for tumors
SUBMANDIBULAR: Wharton’s duct, serous mucous
SUBLINGUAL: anterior floor of mouth, mucous, several ducts along sublingual folds
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Question
The embryological origin of the face is largely from thea. Second brachial archb. Second and third brachial archesc. Frontal process and first brachial archd. Frontal process and second brachial arch
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Answer
The embryological origin of the face is largely from thea. Second brachial archb. Second and third brachial archesc. Frontal process and first brachial archd. Frontal process and second brachial arch
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Tongue Development
Pharyngeal Arches:1st forms the anterior (moveable)2nd , 3rd forms the immovable base
The tongue is innervated by the V, VII, IX, X, and XII Cranial nerves for various functions.
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Tissues of the Tongue
3 Parts: Tuberculum impar (central) Both lateral lingual swellings (sides)
As they grow, a U-shaped sulcus forms around the anterior of the tongue to separate it from the jaw tissues
This allows free movement of the anterior tongue
The 3 parts fuse completely to form the tongue body
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Tongue formation: 1st Pharyngeal Arch
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Tongue Development
The body and the base of the tongue are separated by the terminal sulcus
Behind the terminal sulcus the lingual tonsil develops from the base on the dorsal side
Waldeyer’s Ring: (ring of tonsils in pharynx) Lingual tonsil Palatine tonsils Pharyngeal tonsils
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Body and Base of the Tongue
Lateral lingual swellings and tuberculum impar have completely merged and fused to form the body and base of the tongue.
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Question
What is the origin of “Rests of Malassez”? Junctional epithelium Reduced enamel epithelium Hertwig’s epithelial root sheath Cementoblasts in the PDL
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Answer
What is the origin of “Rests of Malassez”? Junctional epithelium Reduced enamel epithelium Hertwig’s epithelial root sheath Cementoblasts in the PDL
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Question
Rests of Malassez are composed of Calcified PDL Calcifications n the dental pulp Groups of epithelial cells attached t the enamel Groups of epithelial cells in the PDL
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Answer
Rests of Malassez are composed of Calcified PDL Calcifications n the dental pulp Groups of epithelial cells attached t the enamel Groups of epithelial cells in the PDL
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Question
Which structure marks the embryonic origin of the thyroid gland?a. Tonsillar pillarb. Stenson’s ductc. Foramen ovaled. Foramen cecum
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Answer
Which structure marks the embryonic origin of the thyroid gland?a. Tonsillar pillarb. Stenson’s ductc. Foramen ovaled. Foramen cecum
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NBQ
What anatomic feature separates the root and the body of the tongue?
a. The lingual frenumb. The fungifofrm papillaec. The median grooved. The third brachial arche. The circumvallate papillae
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NBQ
What anatomic feature separates the root and the body of the tongue?
a. The lingual frenumb. The fungifofrm papillaec. The median grooved. The third brachial arche. The circumvallate papillae
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NBQ
Remnants of Hertwig’s epithelial root sheath sound in the PDL of a functional tooth are called:
a. Enamel pearlsb. Denticlesc. Rests of Malassezd. Cementiclese. Intermediate plexus
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NBQ
Remnants of Hertwig’s epithelial root sheath sound in the PDL of a functional tooth are called:
a. Enamel pearlsb. Denticlesc. Rests of Malassezd. Cementiclese. Intermediate plexus
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HISTOLOGY
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Histology
Cells parts reviewed during A&P lectureTissues
Epithelium Connective Tissue Muscle Nervous Tissue
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Histology: Epithelium Tissues
Simple and stratified (layered)Named by cell shapeAvascularBasement membrane separates from
underlying connective tissueReview locations of different typesStratified squamous epithelium lines oral
cavity
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Histology: Connective Tissues
Collagen fibersLoose and denseCalcified and non-calcifiedCartilage: hyaline remodels into boneElastic is flexibleFibrous lines boney surfacesBone: form skeletal systemBlasts: buildClasts: consumeCytes: just hang around different hard CT
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Histology: Muscle Tissues
Skeletal (voluntary)Smooth(GI and blood vessels)Cardiac (heart muscle)
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Histology: Nervous Tissues
Ectodermal originCentral: brain and spinal cordPeripheral componentsAfferent (sensory) signals to CNSEfferent (motor) signals from CNS to muscle and
glandsSomatic system carries signals to voluntary musclesAutonomic system carries signals from CNS to
involuntary muscles and glands Sympathetic: causes activity, fight-or-flight Parasympathetic: maintain status quo, decrease activity
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Tooth Development
Begins 7th weeks of embryonic life with 20 primary teeth
Continue development until late teensEnamel forms from ectoderm lining the
sotmoduemDentin/pulp form from ectomesenchyme
(derived from embryonic ectoderm adjacent to the underlying mesenchymal tissue
Each tooth is product of 2 tissues 1. Mesenchymal: derived from neural crest cells2. Epithelium: oral epithelium derived from ectoderm
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NBQ
What type of primitive tissue gives rise to the enamel of a tooth?
a. Ectodermb. Mesodermc. Endodermd. None of the above
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NBQ
What type of primitive tissue gives rise to the enamel of a tooth?
a. Ectodermb. Mesodermc. Endodermd. None of the above
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NBQ
The embryonic origin of all connective tissue is
a. Mesenchymeb. Endodermc. Fasciad. Ectoderm
e. Epithelium
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NBQ
The embryonic origin of all connective tissue is
a. Mesenchymeb. Endodermc. Fasciad. Ectoderm
e. Epithelium
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NBQ
Rathke’s pouch if the embryonic origin of thea. Thyroid glandb. Palatec. Globular processd. Pituitary glande. Nasal septum
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NBQ
Rathke’s pouch if the embryonic origin of thea. Thyroid glandb. Palatec. Globular processd. Pituitary glande. Nasal septum
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Tooth Development: 2 Events
Morphodifferentiation Shaping of teeth Stages: Bud, Cap, Bell, Apposition
Cytodifferentiation Epithelial
Outer Inner Stratum Stellate reticulum
Mesenchymal Dental sac: alveolar bone, PDL, Cementum Dental papilla: odontoblasts Pulp
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Tooth Development
1. Initiation (Bud) stage Dental lamina (ectodermal thickening) grows into the
underlying mesenchymal (conncective) tissue at 20 places to form the primary teetj
2. Proliferation (Cap) Stage Enamel organ develops from the dental lamina, and
will produce enamel Dental papilla arises and produces pulp/dentin The dental sac surrounds the developing tooth, and
becomes cementum, the PDL and alveolar bone
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Tooth Development
3. Differentiation (Bell) Stage Enamel organ develops 4 distinct layers
1) Outer enamel epithelium 2) Stellate reticulum3) Stratum intermedium4) Inner enamel epithelium: becomes enamel.
IEE becomes amelobasts which produce enamel, odontoblasts from the dental papillae produce dentin
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Tooth Development
Tooth structure is produced layer by layer (appositional growth)
Tooth matrix is initially soft, then mineralizes (hydroxyapatite is crystalized calcium phosphate)
Root formation begins after the crown if complete, and ends 1-4yrs after eruption
Enamel organ layers condense to form the reduced enamel epithelium
Hertwig’s epithelial root sheath (HERS), which develops from the internal and external enamel epithelium, helps determine outline of the root and dissolves
Remnants of HERS (knows as rests of Malassez) have the potential to form cysts
Remnants of the dental lamina are known as Rests of Serres
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Teeth: Enamel
96% mineralized (hydroxyapatite)Composed of enamel rods perpendicular to surfaceEctodermal origin from inner enamel epitheliumSecreted by ameloblasts after dentin formation
beginsInner and outer enamel epithelial areas combine to
form the Reduced Enamel Epithelium as enamel formation is completed
Hertwig’s root sheath formsREE combines with surface epithelium at eruption
and cervical area becomes junctional epitheliumAmeloblasts have disappeared as formative cells
appear
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Teeth: Dentin
70% mineralized Composed of dentinal tubules extending from DEJ to
pulp chamberMesodermal origin and formed by odontoblasts
(precedes enamel formation initially) Odontoblasts remain viable and capable of forming
dentin after tooth formation is completedPrimary dentition forms before completion of the root
apexSecondary dentin forms after apex is completedTertiary (reparative) dentin forms in response to
injury or some irritations
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Teeth: Dentin
Peritubular dentin forms tubule wallsIntertubular dentin forms between tubulesOuterdentinal layer nearest DEJ formed 1st and is
called mantle dentinCicrumpulpal dentin forms inner dentinal layer
nearest pulp chamberTubules narrow with age
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NBQ
The layer of dentin found adjacent to the pulp in young teeth is called
a. Tome’s granular layerb. Predentinc. Interglobular dentind. Dead tractse. Sclerotic dentin
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NBQ
The layer of dentin found adjacent to the pulp in young teeth is called
a. Tome’s granular layerb. Predentinc. Interglobular dentind. Dead tractse. Sclerotic dentin
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The last visible layer in Nonkeratinized stratified squamous epithelium is the
a. Basal cell layerb. Prickle cell layerc. Granular layerd. Corneum layer
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The last visible layer in Nonkeratinized stratified squamous epithelium is the
a. Basal cell layerb. Prickle cell layerc. Granular layerd. Corneum layer
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NBQ
Dentin is the product ofa. Dental laminab. Dental organc. Dental papillad. Dental cuticlee. Dental sac
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NBQ
Dentin is the product ofa. Dental laminab. Dental organc. Dental papillad. Dental cuticlee. Dental sac
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Teeth: Cementum
Cementicles Calcified ovoid or round nodule found in the PDL May be found in grps or near the surface of the
cementum More prevalent along the root in an aging person May be found at the site of trauma
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Teeth: Cementum
Mature Cementum: 3 grps fibers1. Grp I: collagen fibers produced by
cementoblasts, parallel to long axis of root
2. Grp II: fibers from cells of dental sac, form fibers PDL
3. Grp III (external): coarser than internal, Sharpey’s fibers
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Teeth: Pulp
Vascular tissue within pulp chamberContains connective tissue, nerves, blood
vessels, odontoblasts at peripheryNerves only respond with pain to stimulationDerived from dental papilla
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Pulp & Dentin Comparisons
Closely related developmentally and functionally
Pulp = loose, non-calcified ct, vascularDentin=calcified ct, avascularDevelopment
Odontobasts = form dentin Dental papilla = form pulp
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Bone: Alveolar
Formed during development & eruption of teeth
Located in boney crypts of jaw boneSame histology as other bones in bodyAnatomy
Each tooth in own alveolus (socket), inner cortical plate, spongiosa
Each socket has 3 parts: Outer cortical plate Alveolar bone proper: part of bone facing root of
tooth, follows outline of roots, sometimes called cribiform plate/lamina dura
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Question
The cells that produce enamel derive from the
a. Stellate recticulumb. Junctional epitheliumc. Inner enamel epitheliumd. Outer enamel epithelium
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Answer
The cells that produce enamel derive from the
a. Stellate recticulumb. Junctional epitheliumc. Inner enamel epitheliumd. Outer enamel epithelium
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Question
Which of the following is a likely reaction to destruction of a focal area of odontoblasts by injury?
a. New odontoblasts will differentiate from epithelial rests of Malassez
b. New odontoblasts will form by division of vital odontoblasts adjacent to the zone of injury
c. New odontoblasts will form by differentiation from cells in the cell rich layer of the pulp
d. None of the above
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Answer
Which of the following is a likely reaction to destruction of a focal area of odontoblasts by injury?
a. New odontoblasts will differentiate from epithelial rests of Malassez
b. New odontoblasts will form by division of vital odontoblasts adjacent to the zone of injury
c. New odontoblasts will form by differentiation from cells in the cell rich layer of the pulp
d. None of the above
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PDL
Specialized form of ctDerived from dental sacMade of fiber bundles
1. Gingival: dentogingival, dentoperiosteal, transeptal, circumfrential
2. Principal: alveolar crest, horizontal, oblique, apical, interradicular
Fast turnover rateFibrous Matrix
Fibers are collagen & oxytalan with few elastic fibers assoc with blood vessels
Sharepy’s Fibers: terminal portion of PDL that is embedded in bone
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PDL
Rich blood supply2 types nerves
1. Autonomic2. Afferent sensory
2 types nerve endings1. Free, un-myelinated2. Encapsulated
Width varies Wider in younger adults than older Greater near cervical/apical areas Greatest movements occur apical/cervical Related to amt of function
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Oral Mucosa
Composed of stratified squamous epithelial layer and a ct lamina propria, separated by a basement membrane
It includes the masticatory, lining, and specialized mucosal tissues
Masticatory mucosal tissue is keratinized and protects the gingiva and hard palate. The keratinization of the attached gingiva ends at the free gingival margin
Lining mucosa is not keratinized and includes the alveolar, vestibular and buccal mucosa, floor of the mouth
Specialized mucosa refers to the papillae of the tongue
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NBQ
In the oral cavity, one way in which lining mucosa differs from masticatory mucosa is that
a. Lining mucosa contains more muscle fibersb. Masticatory mucosa contains glandsc. Lining mucosa has no submucosa
d. Lining mucosa is not keratinized
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NBQ
In the oral cavity, one way in which lining mucosa differs from masticatory mucosa is that
a. Lining mucosa contains more muscle fibersb. Masticatory mucosa contains glandsc. Lining mucosa has no submucosa
d. Lining mucosa is not keratinized
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Anatomy of Gingiva
Stratified squamous epithelium with a basement membrane between the epithelium and connective tissue
Stratum corneum outside layerKeratinized=no nuclei, tough
Attached GingivaNon-Keratinized=have nuclei, more flexible,
lining mucosa Sulcular & Junctional Epithelium
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Anatomy of Gingiva
No blood vesselsNutrients from connective tissue vasculatureDesmosomes connect epithelial cells to each otherHemidesmosomes connect epithelial cells to
connective tissueGingival Fibers: 9 groups based on orientation,
insertions, structures, involvedGingival connective tissue
Lots collagen matrix Few cells: fibroblasts, macrophages, lymphocytes,
neutrophils
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3 Gingival Epithelium Areas
1. Oral Epithelium Outer surface of free and attached gingiva
from gingival margin to mucogingival junction
Keratinized or partially keratinized Orthokeratinized= thicker granular layer
Rete pegs connect to connective tissue inside2. Sulcular Epithelium
Lining of gingival sulcus Nonkeratinized=allows for crevicular fluid in
and out No Rete pegs, just smooth interface
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3 Gingival Epithelium Areas
3. Junctional Epithelium Seals and protects Forms base of sulcus and attaches to tooth
surface 0.75-1.35mm long Nonkeratinized Attached by hemidesmosomes to enamel or an
implant surface in health, dentin or cementum in disease
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Oral Epithelium
MelanocytesLangerhans cellsMerkle cellsInflammatory cellsStratified squamous (3 types)
1. Orthokeratinizeda. Less commonb. Cell layers: Basal (deepest), Prickle, Granular, Keratinized
outer layer
2. Nonkeratinizeda. Cell layers: Basal, prickle, nonker. outer layer
3. Parakeratinized: between #1&2a. Cell layers: Basal, prickle, keratinized outer layers
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Oral Epithelium
Connective Tissues: Lamina Propria Layers: Papillary & Reticular
Submucosa: between lamina propria & musclesInterface
Area between oral epithelium & ct Rete Pegs: epithelial extension into lamina propria
Basement Membrane 2 layers: Basal lamina (densa) & Reticular lamina
(lucida) Epithelial cells for hemidesmosome attachments to basal
lamina
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Question
Where are Von Ebner’s glands located? In submucosa of the pharynx In the submucosa of the cheek Beneath the floor of the mouth Beneath circumvallate papillae in the tongue
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Answer
Where are Von Ebner’s glands located? In submucosa of the pharynx In the submucosa of the cheek Beneath the floor of the mouth Beneath circumvallate papillae in the tongue
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Question
During which time of fetal development will cleft palate form?a. Second trimesterb. Week 1-3c. Weeks 6-11d. Early in the 3rd trimester
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Answer
During which time of fetal development will cleft palate form?a. Second trimesterb. Week 1-3c. Weeks 6-11d. Early in the 3rd trimester