Orban's Oral Histology and Embryology PDF

ORBAN’S ORAL HISTOLOGY AND EMBRYOLOGY FIFTEENTH EDITION G S Kumar, BDS, MDS (Oral Path) Principal, KSR Institute of Dental Science and Research, Tiruchengode, Tamil Nadu, INDIA https://t.me/DentalBooksWorld Table of Contents Cover image Title page Copyright Dedication List of contributors Preface to the fifteenth edition Preface to the fourteenth edition List of videos Brief contents 1. An overview of oral tissues Development of tooth https://t.me/DentalBooksWorld Enamel Dentin Pulp Cementum Periodontal ligament Alveolar bone Temporomandibular joint Maxillary sinus Eruption and shedding of teeth Oral mucosa Salivary glands Lymphoid tissue and lymphatics of orofacial region Age changes in oral tissues Study of oral tissues 2. Development of face and oral cavity Origin of facial tissues Development of facial prominences Final differentiation of facial tissues Clinical considerations https://t.me/DentalBooksWorld Summary Review questions References Suggested reading References 3. Development and growth of teeth Dental lamina Tooth development Developmental stages Histophysiology Molecular insights in tooth morphogenesis Clinical considerations Summary Review questions References Suggested reading References 4. Enamel Histology https://t.me/DentalBooksWorld Clinical considerations Development Clinical considerations Summary Review questions References Suggested reading References Structure Development 5. Dentin Physical and chemical properties Structure Primary dentin Secondary dentin Tertiary dentin Incremental lines Interglobular dentin Granular layer https://t.me/DentalBooksWorld Innervation of dentin Permeability of dentin Age and functional changes Development Clinical considerations Summary Review questions References Suggested reading References 6. Pulp Anatomy Structural features Functions Regressive changes (aging) Development Clinical considerations Summary Review questions https://t.me/DentalBooksWorld References Suggested reading References 7. Cementum Physical characteristics Chemical composition Cementogenesis Structure Cementodentinal junction Cementoenamel junction Functions Hypercementosis Clinical considerations Summary Review questions References Suggested reading References 8. Periodontal ligament https://t.me/DentalBooksWorld Introduction Development Periodontal ligament homeostasis Cells Extracellular substance Structures present in connective tissue Functions Age changes in periodontal ligament Unique features of periodontal ligament Clinical considerations Summary Review questions References Suggested reading References 9. Bone Classification of bones Composition of bone Bone histology https://t.me/DentalBooksWorld Bone cells Bone formation Bone resorption Bone remodeling Alveolar bone Development of alveolar process Structure of the alveolar bone Internal reconstruction of alveolar bone Age changes Clinical considerations Therapeutic considerations Summary Review questions References Suggested reading References 10. Oral mucous membrane Classification of oral mucosa Functions of oral mucosa Definitions and general considerations (flowchart 10.1) Structure of the oral epithelium Subdivisions of oral mucosa Gingival sulcus and dentogingival junction Development of oral mucosa Age changes in oral mucosa Clinical considerations Summary Review questions References Suggested reading References 11. Salivary glands Structure of terminal secretory units (acini) Classification and structure of human salivary glands Development and growth Control of secretion Composition of saliva Functions of saliva Clinical considerations Summary Review questions References Suggested reading References 12. Lymphoid tissue and lymphatics in orofacial region Introduction to lymphatic system Types of lymphoid tissues Development of lymph nodes and lymphatics Functions of the lymphatic system Lymph nodes Lymphatic vessels and capillaries Blood vessels of lymph nodes Clinical significance of lymph nodes Lymph Tonsils Lymphatic drainage of head and neck Summary Review questions References Suggested reading References 13. Tooth eruption Pattern of tooth movement Histology of tooth movement Mechanism of tooth movement (theories of tooth eruption) Clinical considerations Summary Review questions References Suggested reading References 14. Shedding of deciduous teeth Definition Pattern of shedding Histology of shedding Mechanism of resorption and shedding Clinical considerations Summary Review questions References Suggested reading References 15. Temporomandibular joint Gross anatomy Development of the joint Histology Clinical considerations Summary Review questions References Suggested reading References 16. Maxillary sinus Definition Developmental aspects Developmental anomalies Structure and variations Microscopic features (box 16.2) Functional importance Clinical considerations Summary Review questions References Suggested reading References 17. Age changes in oral tissues Theories of aging Age changes in enamel Age and functional changes in dentin Age changes in pulp Age changes in periodontium Changes in periodontal ligament Age changes in cementum Age changes in alveolar bone Change in dental arch shape Age changes in temporomandibular joint Age changes in oral mucosa Salivary gland function and aging Clinical considerations Summary Review questions References Suggested reading References 18. An Outline of histochemistry of oral tissues Special considerations in histochemical techniques Histochemical study of oral connective tissue Histochemical study of oral epithelial tissues and derivatives Important histochemical techniques Immunohistochemistry Clinical considerations Summary Review questions Suggested reading References 19. Preparation of specimens for histologic study Preparation of sections of paraffin-embedded specimens Preparation of sections of parlodion-embedded specimens Preparation of ground sections of teeth or bone Preparation of frozen sections Types of microscopy Summary Review questions References Suggested reading References Index Copyright RELX India Pvt. Ltd. Registered Office: 818, 8th floor, Indraprakash Building, 8th Floor, 21, Barakhamba Road, New Delhi-110001 Corporate Office: 14th Floor, Building No. 10B, DLF Cyber City, Phase II, Gurgaon-122 002, Haryana, India Orban’s Oral Histology and Embryology, 11e, S N Bhaskar Copyright © 1991 by Mosby Inc, Eleventh edition All rights reserved. ISBN: 978-0-8016-0239-9 This adaptation of Orban’s Oral Histology and Embryology, 11e by S N Bhaskar was undertaken by RELX India Private Limited and is published by arrangement with Elsevier Inc. Orban’s Oral Histology and Embryology, 15e Adaptation Editor: G S Kumar Copyright © 2019 by RELX India Pvt. Ltd. Adaptation ISBN: 978-81-312-5481-3 E ISBN: 978-81-312-5482-0 Package ISBN: 978-81-312-5475-2 Previous editions copyrighted, 2015, 2013, 2011, 2008 All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). 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Dedication To My Teachers Who Have Guided Me My Students Who Have Inspired Me My Family Who Have Encouraged Me My Associates Who Have Supported Me List of contributors Amsavardani S Tayaar, Formerly Professor and Head, Department of Oral Pathology and Microbiology, SDM College of Dental Sciences, Dharwad Chapters 3 and 18-online resource Arun V Kulkarni, Formerly Professor of Anatomy, SDM College of Dental Sciences, Dharwad Chapters 2, 15 and 16 Dinkar Desai, Professor and Head, Department of Oral Pathology and Microbiology, AJ Institute of Dental Sciences, Mangalore Chapter 4 Karen Boaz, Professor and Head, Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Mangalore, Manipal Academy of Higher Education Chapter 13 Pushparaja Shetty, Professor and Head, Department of Oral Pathology, AB Shetty Memorial Institute of Dental Sciences, Nitte University, Mangalore Chapter 10 Radhika Manoj Bavle, Professor and Head, Department of Oral and Maxillofacial Pathology, Krishnadevaraya College of Dental Sciences, Bangalore Chapters 7, 8, 11 and 12 A Ravi Prakash, Professor and Head, Department of Oral Pathology, G Pulla Reddy Dental College, Kurnool Chapter 5 Sharada P, Professor and Head, Department of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences, Bangalore Chapters 7, 8 and 9 Shreenivas Kallianpur, Professor and Head, Department of oral pathology and Microbiology, Century International Institute of Dental Sciences and Research Centre, Kasaragod Chapter 6 G Venkateswara Rao, Dean and Principal, Mamata Dental College, Khammam Chapter 3 Vinod Kumar R B, Principal, Malabar Dental college, Edappal Chapter 14 Manay Srinivas Muni Sekhar, Lecturer, Oral Pathology Division, Department of Preventive Dentistry, College of Dentistry, Sakaka, Jouf University, AlJouf Province, Kingdom of Saudi Arabia Chapter 17 G S Kumar, Principal and Professor of Oral Pathology, KSR Institute of Dental Science and Research, Tiruchengode Chapters 1, 18 and 19, Summary of all Chapters, & Multiple choice questions Preface to the fifteenth edition This edition has many features to meet the persistent demand of undergraduate students to make the subject easier for their comprehension. Audiovisual presentation of Oral Histology slides, which are usually shown in their practical classes, is attempted for a better correlation with the textual matter on microscopic appearance of the various structures. Clinical photographs of the oral cavity is another attempt to provide clinical correlation with histological appearances of oral structures. Subject matter is more simplified than in the previous edition. The chapter on Histochemistry is completely rewritten keeping in mind the requirements of undergraduate students. Additional text boxes, flowcharts and tables will be useful for a quick review before theory or viva- voce examinations. Multiple-choice questions based on difficulty index to test the learned concepts are provided, as a self- appraisal exercise. For students seeking more information on various aspects of oral histology, online resources provided with this text should be consulted. Detailed references are also available as online resource on www.medenact.com. Needless to say, our refinement in making this text relevant and useful to undergraduate students comes from the valuable feedback received, not only from undergraduate students but also as critical appraisal from the teachers of this subject. We eagerly look forward for your valuable suggestions to make this edition retain its popularity, as ever before. G S Kumar Preface to the fourteenth edition We, the editorial team, constantly strive to improve this book by incorporating not only additional information that we may have gathered, but also our readers’ valuable suggestions. Our contributors are dedicated to this cause and hence, within just three years, we have come up with the next edition of this book. A salient feature of this edition is the inclusion of Summary and Review Questions at the end of every chapter. ‘Appendix’ section has been removed and all chapters have been renumbered to give their due identity. The redrawn diagrams and change in the style and format of presentation are bound to be more appealing than before. However, the most important change is the addition of a new chapter ‘Lymphoid Tissue and Lymphatics in Orofacial Region’. We have included this chapter because we believe that this topic is not given enough importance in General Histology lectures. I hope to receive feedback from all our readers to aid further improvement of this book. G S Kumar List of videos Dev of tooth.mp4 Chapter 3- Page 30- s0105 subheading - Advanced bell stage Enamel full.mp4 Video for full Chapter 4 - Enamel Dentin full.mp4 Video for full Chapter 5 - Dentin Pulp and alveolar Video for full Chapter 6 - Pulp (same video file also to be used bone.mp4 for chapter 9) Cementum.mp4 Video for full Chapter 7 - Cementum Periodontal Chapter 8 - Page 148, s0165 subheading - Principal fibers of ligament.mp4 periodontal ligament Pulp and alveolar Video for full Chapter 9 - Bone (same video file as used for bone.mp4 chapter 6) Salivary glands.mp4 Video for full Chapter 11 - Salivary glands Oral mucous Video for full Chapter 10 - Oral mucous membrane membrane.mp4 Maxillary sinus.mp4 Video for full Chapter 16 - Maxillary sinus Brief contents List of Contributors vii Preface to the Fifteenth Edition ix Preface to the Fourteenth Edition xi List of Videos xiii 1 An Overview of Oral Tissues 1 2 Development of Face and Oral Cavity 5 3 Development and Growth of Teeth 21 4 Enamel 39 5 Dentin 73 6 Pulp 91 7 Cementum 113 8 Periodontal Ligament 133 9 Bone 163 10 Oral Mucous Membrane 191 11 Salivary Glands 235 12 Lymphoid Tissue and Lymphatics in Orofacial Region 259 13 Tooth Eruption 273 14 Shedding of Deciduous Teeth 287 15 Temporomandibular Joint 299 16 Maxillary Sinus 307 17 Age Changes in Oral Tissues 315 18 An Outline of Histochemistry of Oral Tissues 329 19 Preparation of Specimens for Histologic Study 337 Index CHAPTER 1 An overview of oral tissues CHAPTER OUTLINE Development of Tooth 1 Enamel 2 Dentin 2 Pulp 2 Cementum 2 Periodontal Ligament 2 Alveolar Bone 3 Temporomandibular Joint 3 Maxillary Sinus 3 Eruption and Shedding of Teeth 3 Oral Mucosa 3 Salivary Glands 3 Lymphoid Tissue and Lymphatics of Orofacial Region 4 Age Changes in Oral Tissues 4 Study of Oral Tissues 4 The oral cavity contains a variety of hard tissues and soft tissues. The hard tissues are the bones of the jaws and the teeth. The soft tissues include the lining mucosa of the mouth and the salivary glands. The tooth consists of crown and root. The visible part of the tooth in the mouth is called clinical crown, the extent of which increases with age and disease. The root portion of the tooth is not visible in the mouth of a person with healthy gums. The tooth is suspended in the sockets of the alveolar bone by the periodontal ligament. The anatomical crown is covered by enamel and the root by the cementum. Periodontium is the term given to supporting tissues of the tooth. They include the cementum, periodontal ligament, and the alveolar bone. The innermost portion of the crown and root is occupied by soft tissue, the pulp. The dentin occupies the region between the pulp and enamel in the crown, and between pulp and cementum in the root. Development of tooth The tooth is formed from the ectoderm and ectomesenchyme. The enamel is derived from the enamel organ which is differentiated from the primitive oral epithelium lining the stomodeum (primitive oral cavity). Epithelial mesenchymal interactions take place to determine the shape of the tooth and the differentiation of the formative cells of the tooth, and the timing of their secretion. The ectomesenchymal cells which are closer to the inner margins of the enamel organ differentiate into dental papilla and the ectomesenchymal cells closer to the outer margins of the enamel organ become dental follicles. Dentin and pulp are derivatives of dental papilla while cementum, periodontal ligament, and alveolar bone are all derivatives of dental follicle. The cells that form these tissues have their names ending with “blast.” Thus, ameloblast produces enamel, odontoblast produces dentin, cementoblast produces cementum, and osteoblast produces bone. These synthesizing cells have all the features of a protein-secreting cell —well-developed ribosomes and a rough endoplasmic reticulum (ER), Golgi apparatus, mitochondria, and a vesicular nucleus, which is often polarized. The cells that resorb the tissues have their names ending with “clast.” Thus, osteoclast resorbs bone, cementoclast resorbs cementum, and odontoclast resorbs all the dental tissues. The “clast” cells have a similar morphology in being multinucleated giant cells. Their ultrastructural features include numerous lysosomes and ingested vacuoles. Dentin is the first hard tissue of the tooth to form. Enamel starts its formation after the first layer of dentin has formed. The enamel formation is from its junction with dentin outward, first in the cuspal/incisal and later in the cervical regions. Dentin formation is similar, but from the dentinoenamel junction, the formation is toward the pulp. Cementum formation occurs after the form, size, shape and number of roots is outlined by the epithelial root sheath and dentin is laid down in these regions. Formation of enamel, dentin, and cementum takes place as a daily event in phases or in increments, and hence they show incremental lines. In dentin and cementum formation, a layer of uncalcified matrix forms first, followed by its mineralization. While in enamel formation, enamel matrix is calcified, its maturation or complete mineralization occurs as a secondary event. Mineralization occurs as a result of supersaturation of calcium and phosphorus in the tissue fluid. The formative cells concentrate the minerals from calcium phosphate (apatite) and secrete them into the organic matrix, in relation to specific substances like collagen, which act as attractants or nucleators for mineralization. The mechanism of mineralization is quite similar in all the hard tissues of tooth and in bone (Fig. 1.1). FIGURE 1.1 Diagrammatic representation of tooth in situ. Enamel The enamel is the hardest tissue in the human body. It is the only ectodermal derivative of the tooth. Inorganic constituents account for 96% by weight and they are mainly calcium phosphate in the form of hydroxyapatite crystals. These apatite crystals are arranged in the form of rods. All other hard tissues of the body, dentin, cementum, and bone also have hydroxyapatite as the principal inorganic constituent. Hydroxyapatite crystals differ in size and shape; those of the enamel are hexagonal and longest. Enamel is the only hard tissue which does not have collagen in its organic matrix. The enamel present in the fully formed crown has no viable cells, as the cells forming it—the ameloblast—degenerates, once enamel formation is over. Therefore, all the enamel is formed before eruption. This is of clinical importance as enamel lost, after tooth has erupted, due to wear and tear or due to dental caries, cannot be formed again. Enamel lacks not only formative cells but also blood vessels and nerves. Therefore, no blood oozes out or pain is felt when enamel is drilled while making a cavity for filling. Although enamel is not a viable tissue, it is permeable, so exchange of ions between tooth and saliva takes place. This property enables fluoride ions from a toothpaste to be incorporated in the enamel, making it harder and resistant to dental caries. Dentin The dentin forms the bulk of the tooth. It consists of dentinal tubules, which contains the cytoplasmic process of the odontoblasts. The tubules are laid in the calcified matrix—the walls of the tubules are more calcified than the region between the tubules. The apatite crystals in the matrix are plate like and shorter, when compared to enamel. The numbers of tubules near the pulp are broader and closer and they usually have a sinusoidal course, with branches, all along and at their terminus at the dentinoenamel or cementodentinal junction. The junction between enamel and dentin is scalloped to give mechanical retention to the enamel. Dentin is avascular. Nerves are present in the inner dentin only. Therefore, when dentin is exposed, by loss of enamel and stimulated, a pain-like sensation called sensitivity is experienced. The dentin forms throughout life without any stimulation or as a reaction to an irritant. The cells that form the dentin—the odontoblast lies in the pulp, near its border with dentin. Thus, dentin protects the pulp and the pulp nourishes the dentin. Though dentin and pulp are different tissues, they function as one unit. Pulp The pulp, the only soft tissue of the tooth, is a loose connective tissue enclosed by the dentin. The pulp responds to any stimuli by pain. Pulp contains the odontoblast. Odontoblasts are terminally differentiated cells, and in the event of their injury and death, they are replaced from the pool of undifferentiated ectomesenchymal cells in the pulp. The pulp is continuous with the periodontal ligament through the apical foramen or through the lateral canals in the root. Pulp also contains defense cells. The average volume of the pulp is about 0.02 cm3. Cementum The cementum is comparable to bone in its proportion of inorganic to organic constituents and to similarities in its structure. The cementum is thinnest at its junction with the enamel and thickest at the apex. The cementum gives attachment to the periodontal ligament fibers. Cementum forms throughout life to keep the tooth in functional position. Cementum also forms as a repair tissue and in excessive amounts due to low-grade irritants. The cells that form the cementum the cementoblasts, line the cemental surface. Uncalcified cementum is usually seen as the most superficial layer of cementum. The cells within the cementum, called the cementocytes are enclosed in a lacuna and its process in the canaliculi, similar to that seen in bone, but in a far less complex network. Cementocyte presence is limited to certain regions. The regions of cementum containing cells are called cellular cementum and the regions without it are known as the acellular cementum. The acellular cementum is concerned with the function of anchorage to the teeth and the cellular cementum is concerned with adaptation, i.e., to keep the tooth in the functional position. Like dentin, cementum forms throughout life, and is also avascular and noninnervated. Periodontal ligament The periodontal ligament is a fibrous connective tissue, which anchors the tooth to the alveolar bone. The collagen fibers of the periodontal ligament penetrate the alveolar bone and cementum. They have a wavy course. The periodontal ligament has the formative cells of bone and cementum, i.e., osteoblast and cementoblast in addition to fibroblast and resorptive cells—the osteoclast. Cementoclasts are very rarely seen, as cemental resorption is not seen in health. Fibroblast also functions as a resorptive cell. Thus, with the presence of both formative and resorptive cells of bone, cementum and connective tissue, and along with the wavy nature of the fibers, the periodontal ligament is able to adjust itself to the constant change in the position of teeth, and also maintains its width. The periodontal fibers connect all the teeth in the arch to keep them together and also attach the gingiva to the tooth. The periodontal ligament nourishes the cementum. The presence of proprioceptive nerve endings provides the tactile sensation to the tooth and excessive pressure on the tooth is prevented by pain originating from the pain receptors in the periodontal ligament. Alveolar bone Alveolar bone is the alveolar process of the jaws that forms and supports the sockets for the teeth. They develop during the eruption of the teeth and disappear after the tooth is extracted or lost. The basic structure of the alveolar bone is very similar to the bone found elsewhere, except for the presence of immature bundle bone amidst the compact bone lining the sockets for the teeth. The buccal and lingual plates of compact bone enclose the cancellous bone. The arrangement and the density of the cancellous bone vary in the upper and lower jaws and are related to the masticatory load the tooth receives. The ability of bone, but not cementum, to form under tension and resorb under pressure makes orthodontic treatment possible. Temporomandibular joint This only movable bilateral joint of the skull has a movable fibrous articular disk separating the joint cavity. The fibrous layer that lines the articular surface is continuous with the periosteum of the bones. The fibrous capsule, which covers the joint, is lined by the synovial membrane. The joint movement is intimately related to the presence or absence of teeth and to their function. Maxillary sinus The maxillary posterior teeth are related to the maxillary sinus in that they have a common nerve supply and that their roots are often separated by a thin plate of bone. Injuries to the lining and extension of infection from the apex of roots are often encountered in clinical practice. Developing maxillary canine teeth are found close to the sinus. Pseudostratified ciliated columnar epithelium lines the maxillary sinus. Eruption and shedding of teeth The eruption of teeth is a highly programed event. The teeth developing within the bony crypt initially undergo bodily and eccentric movements and finally by axial movement make its appearance in the oral cavity. At that time, the roots are about half to two-thirds complete. Just before the tooth makes its appearance in the oral cavity, the epithelium covering it fuses with the oral epithelium. The tooth then cuts through the degenerated fused epithelium, so that eruption of tooth is a bloodless event. Root growth, fluid pressure at the apex of the erupting teeth, and dental follicle cell contractile force are all shown to be involved in the eruption mechanism. The bony crypt forms and resorbs suitably to adjust to the growing tooth germ and later to its eruptive movements. The deciduous teeth are replaced by permanent successor teeth as an adaptation to the growth of jaws and due to the increased masticatory force of the masticatory muscles in the process of shedding. The permanent successor teeth during the eruptive movement cause pressure on the roots of deciduous teeth and induce resorption of the roots. The odontoclast, which has a similar morphology to osteoclast and participates in this event, has the capacity to resorb all dental hard tissues. Oral mucosa The mucosa lining the mouth is continuous anteriorly with the skin of the lip at the vermilion zone and with the pharyngeal mucosa posteriorly. Thus, the oral mucosa and GI tract mucosa are continuous. The integrity of the mucosa is interrupted by the teeth to which it is attached. The oral mucosa is attached to the underlying bone or muscle by a loose connective tissue called submucosa. The mucosa is firmly attached to the periosteum of hard palate and to the alveolar process (gingiva). The mucosa in these regions is a functional adaptation to mastication; hence, they are referred to as masticatory mucosa. Elsewhere, except in the dorsum of tongue, the mucosa is loosely attached as an adaptation to allow the mucosa to stretch. The mucosa in these regions is referred to as lining mucosa. The stratified squamous epithelium varies in thickness and is either keratinized as in masticatory mucosa or nonkeratinized as in lining mucosa. The submucosa is prominent in the lining and is nearly absent in the masticatory mucosa. The cells that have the ability to produce keratin, called keratinocytes, undergo maturational changes and finally desquamate. The nonkeratinocytes do not undergo these changes, and they are concerned either with immune function (Langerhans cells) or melanin production (melanocytes). The mucosa that attaches to the tooth is unique, thin, and permeable. The fluid that oozes through this lining into the crevice around the tooth is called gingival fluid. It aids in defense against entry of bacteria through this epithelium. The mucosa of the dorsum of tongue is called specialized mucosa because it has the taste buds in the papillae. Salivary glands The major salivary glands (parotid, submandibular, and sublingual) and the minor salivary glands, present in the submucosa, everywhere in the oral cavity, except in gingivae and anterior part of the hard palate secrete serous, mucous, or mixed salivary secretion into the oral cavity by a system of ducts. The connective tissue which contains nerves, blood vessels, and lymphatics divides the gland into compartments called lobes, and further into lobules. The acini, which are production centers of salivary secretion, are of two types—the serous and the mucous acini. They vary in size and shape and also in the mode of secretion. The composition and physical properties of saliva differ between mucous and serous secretions. The ducts not only act as passageways for saliva but also modify the salivary secretion with regard to quantity and electrolytes. The ducts which vary in their structure from having a simple epithelial lining to a stratified squamous epithelial lining show functional modifications. Lymphoid tissue and lymphatics of orofacial region The tissues of our body are bathed in the tissue fluid. The tissue fluid contains diffusible constituents of blood and waste products discarded by cells. Majority of the tissue fluid returns back to the circulation through veins. About 1⁄10th is carried by channels called lymphatic vessels. This fluid is called lymph and it passes through the lymph nodes. The lymph nodes are small bean-shaped organs occurring in groups. They function to filter the foreign substances called antigens. The tonsils are similar to lymph nodes and serve to guard the entrance to alimentary and respiratory tracts against antigens that come in contact with them during eating and breathing. The lymph nodes contain different zones. In it matures the lymphocytes, which are of two types: B and T lymphocytes. The lymph node contains a variety of defense cells. The lymphatic system consists of the primary lymphoid organs, namely the thymus and the bone marrow and the secondary lymphoid organs like the spleen and lymph nodes. Enlargements of lymph nodes is of clinical significance and occurs as a response to an invading organism or due to tumor cells entering from a draining area or due to tumors arising in the lymph nodes itself. Age changes in oral tissues The tissues of the body undergo certain changes in macroscopic and in their microscopic appearance and in their functions with time. These are called age changes. The oral tissues also undergo such changes. Some of the prominent age changes that have a clinical significance are dealt here. The enamel is lost due to physiological, mechanical, or chemical actions resulting in exposure of underlying dentin, causing pain-like sensation, called sensitivity of teeth. Deposition of calcium salts occurs in certain regions of the dentin making the root transparent in these regions. The pulp shows areas of calcified bodies, termed pulp stones. The cementum increases in thickness, especially in the apical third of the root. The periodontal ligament shows a decrease in number of cells and the alveolar bone shows bone loss. The oral mucosa becomes thin, the papillae of the tongue are lost, and mouth becomes dry due to decreased secretion from salivary glands. The person experiences a gradual loss of taste sensation. The attachment of the gingiva to the tooth shifts apically resulting in more exposure of the tooth clinically, i.e., the clinical crown becomes longer with age. Study of oral tissues For light microscopic examination, the tissues have to be made thin and stained, so that the structures can be appreciated. The teeth (and bone) can be ground or can be decalcified before making them into thin slices. In the first method, all hard tissues can be studied. In the second method, all the hard tissues, except enamel, pulp, and periodontal ligament can be studied. Soft tissues of the mouth require a similar preparation as soft tissues of other parts of the body for microscopic examination. For traditional light microscopic examination, the tissues have to be made into thin sections and differentially stained by utilizing the variations they exhibit in their biochemical and immunological properties. There are various histochemical, enzyme-histochemical, immunohistochemical, immunofluorescent techniques developed to enhance tissue characteristics. Apart from light microscopy, tissues can be examined using electron microscope, fluorescent microscope, confocal laser scanning microscope, and autoradiography techniques for better recognition of cellular details, functions, and the series of events that take place within them. CHAPTER 2 Development of face and oral cavity CHAPTER CONTENTS Origin of Facial Tissues 5 Development of Facial Prominences 9 Development of the frontonasal region: olfactory placode, primary palate, and nose 9 Development of maxillary prominences and secondary palate 11 Development of visceral arches and tongue 13 Final Differentiation of Facial Tissues 14 Clinical Considerations 16 Facial clefts 16 Hemifacial microsomia 17 Treacher Collins syndrome 18 Labial pits 18 Lingual anomalies 18 Developmental cysts 18 Summary 18 Review Questions 19 This chapter deals primarily with the development of the human face and oral cavity. Consideration is also given to information about underlying mechanisms which is derived from experimental studies conducted on developing subhuman embryos. Much of the experimental work has been conducted on amphibian and avian embryos. Evidence derived from these and more limited studies on other vertebrates including mammals indicates that the early facial development of all vertebrate embryos is similar. Many events occur, including cell migrations, interactions, differential growth, and differentiation, all of which lead to progressively maturing structures (Fig. 2.1). Progress has also been made with respect to abnormal developmental alterations that give rise to some of the most common human malformations. Further information on the topics discussed can be obtained by consulting the suggested readings at the end of the chapter. FIGURE 2.1 Emergence of facial structures during development of human embryos. Dorsal views of gestational day 19 and 22 embryos are depicted, while lateral aspects of older embryos are illustrated. At days 25 and 32, visceral arches are designated by Roman numerals. Embryos become recognizable as “human” by gestational day 50. Section planes for Fig. 2.2 are illustrated in the upper (days 19 and 22) diagrams. Origin of facial tissues After fertilization of the ovum, a series of cell divisions gives rise to an egg cell mass known as the morula in mammals (Fig. 2.2). In most vertebrates, including humans, the major portion of the egg cell mass forms the extraembryonic membranes and other supportive structures, such as the placenta. The inner cell mass (Fig. 2.2D) separates into two layers, the epiblast and hypoblast (Fig. 2.2E). Cell marking studies in chick and mouse embryos have shown that only the epiblast forms the embryo, with the hypoblast and other cells forming supporting tissues, such as the placenta. The anterior (rostral) end of the primitive streak forms the lower germ layer, the endoderm, in which are embedded the midline notochordal (and prechordal) plates (Figs 2.2F and 2.3A). Prospective mesodermal cells migrate from the epiblast through the primitive streak to form the middle germ layer, the mesoderm. FIGURE 2.2 Sketches summarizing development of embryos from fertilization through neural tube formation. (A) Ovum at the time of fertilization. (B) Two-celled embryo. Accumulation of fluid within egg cell mass (morula, C) leads to development of blastula (D). Inner cell mass (heavily stippled cells in D) will form two-layered embryonic disk in (E). It now appears that only epiblast (ep) will form embryo (see text), with hypoblast (hy) and other cell populations forming support tissues (e.g., placenta) of embryo. In (F), notochord (n) and its rostral (anterior) extension, prechordal plate (pp), as well as associated pharyngeal endoderm, form as a single layer. Prospective mesodermal cells migrate (arrows in F) through primitive streak (ps) and insert themselves between epiblast and endoderm. Epiblast cells remaining on surface become ectoderm. Cells of notochord (and prechordal plate) and adjacent mesoderm (together termed chorda mesoderm) induce overlying cells to form neural plate (neurectoderm). Only later does notochord separate from neural plate (G), while folding movements and differential growth (arrows in G and H) continue to shape embryo h, heart; b, buccal plate; op, olfactory placode; ef, eye field; nc, neural crest; so, somite; lp, lateral plate. (Source: Modified from Johnston MC and Sulik KK: Embryology of the head and neck. In Serafin D and Georgiade NG, editors: Pediatric plastic surgery, vol. 1, St Louis, 1984, The CV Mosby Co). Cells remaining in the epiblast form the ectoderm, completing formation of the three germ layers. Thus, at this stage, three distinct populations of embryonic cells have arisen largely through division and migration. They follow distinctly separate courses during later development. Migrations, such as those described above, create new associations between cells, which, in turn, allow unique possibilities for subsequent development through interactions between the cell populations. Such interactions have been studied experimentally by isolating the different cell populations or tissues and recombining them in different ways in culture or in transplants. From these studies it is known, for example, that a median strip of mesoderm cells (the chorda mesoderm) extending throughout the length of the embryo induces neural plate formation within the overlying ectoderm (Fig. 2.3). The prechordal plate is thought to have a similar role in the anterior neural plate region. The nature of such inductive stimuli is presently unknown. Sometimes cell-to-cell contact appears to be necessary, whereas in other cases (as in neural plate induction) the inductive influences appear to be able to act between cells separated by considerable distances and consist of diffusible substances. It is known that inductive influences need only be present for a short time, after which the responding tissue is capable of independent development. For example, an induced neural plate isolated in culture will roll up into a tube, which then differentiates into the brain, spinal cord, and other structures. In addition to inducing neural plate formation, the chorda mesoderm appears to be responsible for developing the organizational plan of the head. As noted previously, the notochord and prechordal plates arise initially within the endoderm (Fig. 2.3A), from which they eventually separate (Figs 2.2G and 2.3B). The mesodermal portion differentiates into well-organized blocks of cells, called somites, caudal to the developing ear and less organized somitomeres rostral to the ear (Figs 2.2 and 2.6). Later these structures form myoblasts and some of the skeletal and connective tissues of the head. Besides inducing the neural plate from overlying ectoderm, the chorda mesoderm organizes the positional relationships of various neural plate components, such as the initial primordium of the eye. A unique population of cells develops from the ectoderm along the lateral margins of the neural plate. These are the neural crest cells. They undergo extensive migrations, usually beginning at about the time of tube closure (Fig. 2.3), and give rise to a variety of different cells that form components of many tissues. The crest cells that migrate in the trunk region form mostly neural, endocrine, and pigment cells, whereas those that migrate in the head and neck also contribute extensively to skeletal and connective tissues (i.e., cartilage, bone, dentin, and dermis). In the trunk, all skeletal and connective tissues are formed by mesoderm. Of the skeletal or connective tissue of the facial region, it appears that tooth enamel is the only one not formed by crest cells. The enamel-forming cells are derived from ectoderm lining the oral cavity. FIGURE 2.3 Scheme of neural and gastrointestinal tube formation in higher vertebrate embryos (section planes illustrated in Fig. 2.1). (A) Cross-section through three-germ layer embryo. Similar structures are seen in both head and trunk regions. Neural crest cells (diamond pattern) are initially located between neural plate and surface ectoderm. Arrows indicate directions of folding processes. (B) Neural tube, which later forms major components of brain and spinal cord, and gastrointestinal tube will separate from embryo surface after fusions are completed. Arrows indicate directions of migration of crest cells, which are initiated at about 4th week in human embryo. (C) Scanning electron micrograph (SEM) of mouse embryo neural crest cells migrating over neural tube and under surface ectoderm near junction of brain and spinal cord following removal of piece of surface ectoderm as indicated in B. Such migrating cells are frequently bipolar (e.g., outlined cell at end of leading end) and oriented in path of migration (arrow). The migration routes that cephalic (head) neural crest cells follow are illustrated in Fig. 2.4. They move around the sides of the head beneath the surface ectoderm, en masse, as a sheet of cells. They form all the mesenchyme in the upper facial region, whereas in the lower facial region they surround mesodermal cores already present in the visceral arches. The pharyngeal region is then characterized by grooves (clefts and pouches) in the lateral pharyngeal wall endoderm and ectoderm that approach each other and appear to effectively segment the mesoderm into a number of bars that become surrounded by crest mesenchyme (Figs 2.4C, D and 2.7A). FIGURE 2.4 (A and B) Migratory and (C and D) postmigratory distributions of crest cells (stipple) and origins of cranial sensory ganglia. Initial ganglionic primordia (C and D) are formed by cords of neural crest cells that remain in contact with neural tube. Section planes in C and E pass through primordium of trigeminal ganglion. Ectodermal “thickenings,” termed placodes, form adjacent to distal ends of ganglionic primordia—for trigeminal (V) nerve as well as for cranial nerves VII, IX, and X. They contribute presumptive neuroblasts that migrate into previously purely crest cell ganglionic primordia. Distribution of crest and placodal neurons is illustrated in E and F. (Source: Adapted from Johnston MC and Hazelton RD: Embryonic origins of facial structures related to oral sensory and motor functions. From Bosma JB, editor: Third symposium on oral sensation and perception, Springfield, IL, 1972, Charles C Thomas Publisher). Toward the completion of migration, the trailing edge of the crest cell mass appears to attach itself to the neural tube at locations where sensory ganglia of the 5th, 7th, 9th, and 10th cranial nerves will form (Fig. 2.4C and D). In the trunk sensory ganglia, supporting (e.g., Schwann) cells and all neurons are derived from neural crest cells. On the other hand, many of the sensory neurons of the cranial sensory ganglia originate from placodes in the surface ectoderm (Fig. 2.4C and F). Eventually, capillary endothelial cells derived from mesoderm cells invade the crest cell mesenchyme, and it is from this mesenchyme that the supporting cells of the developing blood vessels are derived. Initially, these supporting cells include only pericytes, which are closely apposed to the outer surfaces of endothelial cells. Later, additional crest cells differentiate into the fibroblasts and smooth muscle cells that will form the vessel wall. The developing blood vessels become interconnected to form vascular networks. These networks undergo a series of modifications, examples of which are given in Fig. 2.5, before they eventually form the mature vascular system. The underlying mechanisms are not clearly understood. FIGURE 2.5 Development of arterial system serving facial region with emphasis on its relation to visceral arches. In 3-week human embryo, visceral arches are little more than conduits for blood traveling through aortic arch vessels (indicated by Roman numerals according to the visceral arch containing them) from heart to dorsal aorta. Other structures indicated are eye (broken circle) and ophthalmic artery. In 6- week embryo, first two aortic arch vessels have regressed almost entirely, and distal portions of arches have separated from heart. Portion of third aortic arch vessel adjacent to dorsal aorta persists and eventually forms stem of external carotid artery by fusing with stapedial artery. Stapedial artery, which develops from second aortic arch vessel, temporarily (in humans) provides arterial supply for embryonic face. After fusion with external carotid artery, proximal portion of stapedial artery regresses. Aortic arch vessel of fourth visceral arch persists as arch of aorta. By 9 weeks, primordium of definitive vascular system of face has been laid down (Source: From Ross RB, and Johnston MC: Cleft lip and palate, Baltimore, 1972, The Williams & Wilkins Co). Almost all the myoblasts that subsequently fuse with each other to form the multinucleated striated muscle fibers are derived from mesoderm. The myoblasts that form the hypoglossal (tongue) muscles are derived from somites located beside the developing hindbrain. Somites are condensed masses of cells derived from mesoderm located adjacent to the neural tube. The myoblasts of the extrinsic ocular muscles originate from the prechordal plate (Fig. 2.2F). They first migrate to poorly condensed blocks of mesoderm (somitomeres) located rostral to (in front of) the otocyst, from which they migrate to their final locations (Fig. 2.6). The supporting connective tissue found in facial muscles is derived from neural crest cells. Much of the development of the masticatory and other facial musculature is closely related to the final stages of visceral arch development and will be described later. FIGURE 2.6 Migration paths followed by prospective skeletal muscle cells. Somites, or comparable structures from which muscle cells are derived, give rise to most skeletal (voluntary) myoblasts (differentiating muscle cells). Condensed somites tend not to form in head region of higher vertebrates, and their position in lower forms is indicated by broken lines. It is from these locations that extrinsic ocular and “tongue” (hypoglossal cord) muscle contractile cells are derived from postoptic somites. Recent studies indicate that myoblasts which contribute to visceral arch musculature have similar origins and originate as indicated by Roman numerals according to their nerves of innervation. At this stage of development (approximately day 34), they are still migrating (arrowheads) into cores of each visceral arch. Information about fourth visceral arch is still inadequate, as indicated by question mark (?). Origin of extrinsic ocular myoblasts is complex (see text). A number of other structures in the facial region, such as the epithelial components or glands and the enamel organ of the tooth bud, are derived from epithelium that grows (invaginates) into underlying mesenchyme. Again, the connective tissue components in these structures (e.g., fibroblasts, odontoblasts, and the cells of tooth- supporting tissues) are derived from neural crest cells. Development of facial prominences On the completion of the initial crest cell migration and the vascularization of the derived mesenchyme, a series of outgrowths or swellings termed “facial prominences” initiates the next stages of facial development (Figs 2.7 and 2.8). The growth and fusion of upper facial prominences produce the primary and secondary palates. As will be described below, other prominences developing from the first two visceral arches considerably alter the nature of these arches. FIGURE 2.7 Scheme of development of facial prominences. After completion of crest cell migration. (A) Facial prominence development begins, with curling forward, lateral portion of nasal placode and is completed after fusion of prominences with each other or with other structures, C. (Details are given in text.) Heart and adjacent portions of visceral arches have been removed in A, and most of heart has been removed in B, and C. Arrows indicate direction of growth and/or movement. Mesenchymal cell process meshwork (CPM) is exposed after removal of epithelium (C) and is illustrated to right side of C. Single mesenchymal cell body is outlined by broken line. FIGURE 2.8 Schematic development of human face: maxillary prominence (stipple), lateral nasal prominence (oblique hatching), and medial nasal prominence (dark). (A) Embryo 4–6 mm in length, approximately 28 days. Prospective nasal and lateral nasal prominences are just beginning to form from mesenchyme surrounding olfactory placode. Maxillary prominence forming at proximal end of first (mandibular) arch under eye (compare to Fig. 2.3). (B) Embryo 8–11 mm in length, approximately 37 days. Medial nasal prominence is beginning to make contact with lateral nasal and maxillary prominences. (C) Embryo 16–18 mm in length, approximately 47 days. (D and E) Embryo 23–28 mm in length, approximately 54 days. (F) Adult face. Approximate derivatives of medial nasal prominence, lateral nasal prominence, and maxillary prominence are indicated. Development of the frontonasal region: Olfactory placode, primary palate, and nose After the crest cells arrive in the future location of the upper face and midface, this area often is referred to as the frontonasal region. The first structures to become evident are the olfactory placodes. These are thickenings of the ectoderm that appear to be derived at least partly from the anterior rim of the neural plate (Fig. 2.2F). Experimental evidence indicates that the lateral edges of the placodes actively curl forward, which enhance the initial development of the lateral nasal prominence (LNP, sometimes called the nasal wing—see Fig. 2.7A). This morphogenetic movement combined with persisting high rates of cell proliferation rapidly brings the LNP forward so that it catches up with the medial nasal prominence (MNP), which was situated in a more forward position at the beginning of its development (Fig. 2.7A and C). However, before that contact is made, the maxillary prominence (MxP) has already grown forward from its origin at the proximal end of the first visceral arch (Figs 2.7A and 2.13) to merge with the LNP and make early contact with the MNP (Fig. 2.7G). With development of the LNP–MNP contact, all the three prominences contribute to the initial separation of the developing oral cavity and nasal pit (Fig. 2.7C). This separation is usually called the primary palate (Fig. 2.9A–C). The combined right and left MxPs are sometimes called the intermaxillary segment. FIGURE 2.9 Some details of primary palate formation, here shown in mouse, are conveniently demonstrated by scanning electron micrographs (SEMs). Area encompassed by developing primary palate is outlined by broken lines. (A and B) Frontal and palatal views showing moderately advanced stage of primary palate formation. (C and D) In this more advanced stage, elimination of epithelial connection between anterior and posterior nasal pits is nearing completion. Area outlined by solid lines in C is given in (D), showing that last epithelial elements are regressing as nasal passage is now almost completely opened. The contacting epithelia form the epithelial seam. Before contact many of the surface epithelial (peridermal) cells are lost, and the underlying basal epithelial cells appear to actively participate in the contact phenomenon by forming processes that span the space between the contacting epithelia. During the 5th week of human embryonic development, a portion of the epithelial seam breaks down and the mesenchyme of the three prominences becomes confluent. Fluid accumulates between the cells of the persisting epithelium behind the point of epithelial breakdown. Eventually, these fluid- filled spaces coalesce to form the initial nasal passageway connecting the olfactory pit with the roof of the primitive oral cavity (Fig. 2.9). The tissue resulting from development and fusion of these prominences is termed the primary palate (outlined by broken lines in Fig. 2.9). It forms the roof of the anterior portion of the primitive oral cavity, as well as forming the initial separation between the oral and nasal cavities. In later development, derivatives of the primary palate form portions of the upper lip, anterior maxilla, and upper incisor teeth. The outlines of the developing external nose can be seen in Figure 2.8C. Although the nose is disproportionately large, the basic form is easily recognizable. Subsequent alterations in form lead to progressively more mature structure (Fig. 2.1, day 50 specimen). Figure 2.8 is a schematic illustration of the contribution of various facial prominences to the development of the external face. Development of maxillary prominences and secondary palate New outgrowths from the medial edges of the MxPs form the shelves of the secondary palate. These palatal shelves grow downward beside the tongue (Fig. 2.10), at which time the tongue partially fills the nasal cavities. At about the 9th gestational week, the shelves elevate, make contact, and fuse with each other above the tongue (Fig. 2.11). In the anterior region, the shelves are brought to the horizontal position by a rotational (hinge-like) movement. In the more posterior regions, the shelves appear to alter their position by changing shape (remodeling) as well as by rotation. Available evidence indicates that the shelves are incapable of elevation until the tongue is first withdrawn from between them. Although the motivating force for shelf elevation is not clearly defined, contractile elements may be involved. FIGURE 2.10 Scanning electron micrographs of developing human secondary palate. (A) Near completion of shelf elevation; (B) palatal shelves almost in contact; (C) contact between shelf edges has been made almost throughout entire length of hard and soft palate. Contacting epithelial seam rapidly disappears (see text). (Source: From Russell MM: Comparative Morphogenesis of the Secondary Palate in Murine and Human Embryos, PhD thesis, University of North Carolina, 1986). FIGURE 2.11 (A) Coronal section through secondary palates of 6- week-old human embryo with arrowheads denoting the dental lamina and arrows denoting the vestibular lamina. (B) Coronal section through 8-week-old human embryo showing contact of palatal shelves (a) and secondary nasal septum (b). Midline epithelial seam (c) and developing maxilla (d) are also seen (Masson trichrome X30). Fusion of palatal shelves requires alterations in the epithelium of the medial edges that begin prior to elevation. These alterations consist of cessation of cell division, which appears to be mediated through distinct underlying biochemical pathways, including a rise in cyclic AMP levels. There is also loss of some surface epithelial (peridermal) cells (Fig. 2.12) and production of extracellular surface substances, particularly glycoproteins, that appear to enhance adhesion between the shelf edges as well as between the shelves and inferior margin of the nasal septum (Fig. 2.11). FIGURE 2.12 Scanning and transmission electron micrographs of palatal shelf of human embryo at same stage of development as reconstruction in Fig. 2.9B. (A) Posterior region of palatal shelf viewed from below and from opposite side. Fusion will occur in “zone of alteration,” where surface epithelial (peridermal) cells have been lost (see text). Transmission electron micrographs of specimen in A. Surface cells of oral epithelium in B contain large amounts of glycogen, whereas those of zone of alteration in C are undergoing degenerative changes and many of them are presumably desquamated into oral cavity fluids. Asterisk in B indicates heavy metal deposited on embryo surfaces for scanning electron microscope. (Source: A to C from Waterman RE and Meller SM: Anat Rec 180:11, 1974). The ultimate fate of these remaining epithelial cells is controversial. Some of them appear to undergo cell death and eventually are phagocytized, but recent studies indicate that many undergo direct transformation in mesenchymal cells. The fate of cells in the epithelial seam of the primary palate described previously also is questionable. Some of the epithelial cells remain indefinitely in clusters (cell rests) along the fusion line. Eventually, most of the hard palate and all of the soft palate form from the secondary palate. Development of visceral arches and tongue The pituitary gland develops as a result of inductive interactions between the ventral forebrain and oral ectoderm and is derived in part from both tissues (Fig. 2.13). Following initial crest cell migration (Fig. 2.7A), these cells invade the area of the developing pituitary gland and are continuous with cells that will later form the MxP. Eventually, crest cells form the connective tissue components of the gland. FIGURE 2.13 Oropharyngeal development. (A) Diagram of sagittal section through head of 31/2- to 4-week-old human embryo. Oral fossa is separated from foregut by double layer of epithelium (buccopharyngeal membrane), which is in its early stages of breakdown. (B and C) Scanning electron micrographs (SEMs) of mouse head sectioned in plane indicated by broken line in A. More lateral view of specimen (B) while in (C), it is viewed from its posterior aspect. Rupturing buccopharyngeal membrane is outlined by rectangle in this figure. In humans, there is a total of six visceral arches, of which the fifth is rudimentary. These arches are also known as pharyngeal or branchial arches. The proximal portion of the first (mandibular) arch becomes the MxP (Fig. 2.1). As the heart recedes caudally, the mandibular and hyoid arches develop further at their distal portions to become consolidated in the ventral midline (Figs 2.7 and 2.13). As noted previously, the mesodermal core of each visceral arch (Fig. 2.7A) is concerned primarily with the formation of vascular endothelial cells. As noted below, these cells appear to be later replaced by cells that eventually form visceral arch myoblasts. The first (mandibular) and second (hyoid) visceral arches undergo further developmental changes. As the heart recedes caudally, both arches send out bilateral processes that merge with their opposite members in the ventral midline (Fig. 2.7). Nerve fibers from the 5th, 7th, 9th, and 10th cranial nerves extend into the mesoderm of the first four visceral arches. The mesoderm of the definitive mandibular and hyoid arches gives rise to the 5th and 7th nerve musculature, while mesoderm associated with the less well- developed 3rd and 4th arches forms the 9th and 10th nerve musculature. Recent studies show that myoblast cells in the visceral arches actually originate from mesoderm more closely associated with the neural tube (as do the cells that form the hypoglossal and extrinsic eye musculature; Fig. 2.6). They would then migrate into the visceral arches and replace the mesodermal cells that initiated blood vessel formation earlier. It therefore appears that myoblasts forming voluntary striated muscle fibers of the facial region would then originate from mesoderm adjacent to the neural tube. Groups of visceral arch myoblasts that are destined to form individual muscles each take a branch of the appropriate visceral arch nerve. Myoblasts from the second visceral arch, for example, take branches of the seventh cranial nerve and migrate very extensively throughout the head and neck to form the contractile components of the “muscles of facial expression.” Myoblasts from the first arch contribute mostly to the muscles of mastication, while those from the third and fourth arches contribute to the pharyngeal and soft palate musculature. As noted earlier, connective tissue components of each muscle in the facial region are provided by mesenchymal cells of crest origin. The crest mesenchymal cells of the visceral arches give rise to skeletal components such as the temporary visceral arch cartilages (e.g., Meckel’s cartilage; Fig. 2.11), middle ear cartilages, and mandibular bones. Also visceral arch crest cells form connective tissues such as dermis and the connective tissue components of the tongue. The tongue forms in the ventral floor of the pharynx after arrival of the hypoglossal muscle cells. The significance of the lateral lingual tubercles (Fig. 2.14) and other swellings in the forming tongue has not been carefully documented. It is known that the anterior two-thirds of the tongue is covered by ectoderm whereas endoderm covers the posterior one-third. The thyroid gland forms by invagination of the most anterior endoderm (thyroglossal duct). A residual pit (the foramen cecum; Fig. 2.14C) left in the epithelium at the site of invagination marks the junction between the anterior two-thirds and posterior one-third of the tongue, which are, respectively, covered by epithelia of ectodermal and endodermal origin. It is also known that the connective tissue components of the anterior two-thirds of the tongue are derived from first-arch mesenchyme, whereas those of the posterior one-third appear to be primarily derived from the third-arch mesenchyme. FIGURE 2.14 Scanning electron micrographs of developing visceral arches and tongue of mouse embryos. Planes of section illustrated in A and C (dorsal views of floor of pharynx) are shown in B and D. (A and B) Embryos whose developmental age is approximately equivalent to that of human 30-day-old embryos (see Fig. 2.1). Development of medial and lateral nasal prominences has yet to be initiated. Visceral arches are indicated by Roman numerals. First (mandibular) arch is almost separated from heart (h). Other structures indicated are eye (e), oral cavity (oc; compare to buccopharyngeal membrane in Fig. 2.15C), and neural tube (nt). (C and D) These are comparable to 35-day-old human embryos. The mandibular arch now has two distinct prominences, maxillary prominence (mp) and mandibular prominence (md). Second arch is called hyoid arch (hy). In D, blood vessel exiting from third arch is labeled (bv). Arrow indicates entry into lower pharynx. (E–G) Older specimens, prepared in a manner similar to B and D, illustrate development of tongue. Lingual swellings (I) presumably represent accumulations of myoblasts derived from hypoglossal cord. Tuberculum impar (ti) also contributes to anterior two-thirds of tongue. Foramen cecum (fc) is site of endodermal invagination that gives rise to epithelial components of thyroid gland. It lies at junction between anterior two-thirds and posterior one-third of tongue. Hypobranchial eminence (he) is primordium of epiglottis. (Source: From Johnston MC and Sulik KK: Embryology of the head and neck. In Serafin D, and Georgiade NG, editors: Pediatric plastic surgery, vol I, St Louis, 1984, The CV Mosby Co). The epithelial components of a number of glands are derived from the endodermal lining of the pharynx. In addition to the thyroid, these include the parathyroid and thymus. The epithelial components of the salivary and anterior pituitary glands are derived from oral ectoderm. Finally, a lateral extension from the inner groove between the first and second arch gives rise to the eustachian tube, which connects the pharynx with the ear. The external ear or pinna is formed at least partially from tissues of the first and second arches (Fig. 2.1, day 44) (Table 2.1). Table 2.1 Pharyngeal Arch Derivatives of First Three Arches From IV and VI arches, laryngeal cartilages develop. Note: Total of six arches, fifth disappears. Final differentiation of facial tissues The extensive cell migrations referred to above bring cell populations into new relationships and lead to further inductive interactions, which, in turn, lead to progressively more differentiated cell types. For example, some of the crest cells coming into contact with pharyngeal endoderm are induced by the endoderm to form visceral arch cartilages. Recent studies indicate that the early epithelial interactions are also involved in bone formation. The exact interactions involved in tooth formation are somewhat controversial. Mesenchymal cells of crest origin must be involved, and these cells form the dental papilla and the mesenchyme surrounding the epithelial enamel organ. Whether the epithelium or mesenchyme is initially responsible for determining which tooth (e.g., incisor or molar) forms from a tooth germ is controversial. Interestingly, epithelia from species that ceased forming teeth many centuries ago (e.g., the chick) can still form enamel under experimental conditions. In many instances, such as those cited above, only crest mesenchymal cells and not mesodermal mesenchymal cells will respond to inducing tissues such as pharyngeal endoderm. In other cases, as in the differentiation of dermis and meninges, it appears that the origin of the mesenchyme is of no consequence. In any case it is clear that one function, the formation of skeletal and connective tissues, ordinarily performed by mesodermal cells in other regions, has been usurped by neural crest cells in the facial region. The crest cells therefore play a very dominant role in facial development, since they form all nonepithelial components, except endothelial cells and the contractile elements of skeletal (voluntary) muscle. The onset of bone formation or the establishment of all the organ systems (about the 8th week of development) is considered as the termination of the embryonic period. Bone formation and other aspects of the final differentiation of facial tissues will be considered in detail elsewhere in this text. Clinical considerations Aberrations in embryonic facial development lead to a wide variety of defects. Although any step may be impaired, defects of primary and secondary palate development are most common. There is evidence that other developmental defects may be even more common but they are not compatible with completion of intrauterine life and are therefore not as well documented. Facial clefts Most cases of clefts of the lip with or without associated cleft palate (Fig. 2.15) appear to form a group etiologically different from clefts involving only the secondary palate. For example, when more than one child in a family has facial clefts, the clefts are almost always found to belong only to one group. FIGURE 2.15 Clefts of lip and palate in infants. Infant in photograph has complete unilateral cleft of lip and palate. (Source: From Ross RB, and Johnston MC: Cleft lip and palate, Baltimore, 1972, The Williams & Wilkins Co). Some evidence now indicates that there are two major etiologically and developmentally distinct types of cleft lips and palate. In the larger group, deficient MNPs appear to be the major developmental alteration, whereas in the smaller group the major developmental alteration appears to be underdevelopment of the MxP. Increases in clefting rates have been associated with children born to epileptic mothers undergoing phenytoin (Dilantin) therapy and to mothers who smoke cigarettes; in the latter case, the embryonic effects are thought to result from hypoxia. When pregnant mice are exposed to hypoxia, the portion of the olfactory placode undergoing morphogenetic movements (Fig. 2.1) break down, and this is associated with underdevelopment of the LNP. Reduction in the size of the LNP that is more severe than that of other facial prominences also has been observed in an animal model of phenytoin-induced cleft lip and palate. Combination of developmental alterations (e.g., placodal breakdown associated with MNP deficiency) may relate to the multifactorial etiology thought to be responsible for many human cleft cases. About two-thirds of patients with clefts of the primary palate also have clefts of the secondary palate. Studies of experimental animals suggest that excessive separation of jaw segments as a result of the primary palate cleft prevents the palatal shelves from contacting after elevation. The degree of clefting is highly variable. Clefts may be either bilateral or unilateral (Fig. 2.15) and complete or incomplete. Most of this variation results from differing degrees of fusion and may be explained by variable degrees of mesenchyme in the facial prominences. Some of the variations may represent different initiating events. Clefts involving only the secondary palate (cleft palate, Fig. 2.15) constitute, after clefts involving the primary palate, the second most frequent facial malformation in humans. Cleft palate can also be produced in experimental animals with a wide variety of chemical agents or other manipulations affecting the embryo. Usually, such agents retard or prevent shelf elevation. In other cases, however, it is shelf growth that is retarded so that, although elevation occurs, the shelves are too small to make contact. There is also some evidence that indicates that failure of the epithelial seam or failure of it to be replaced by mesenchyme occurs after the application of some environmental agents. Cleft formation could then result from rupture of the persisting seam, which would not have sufficient strength to prevent such rupture indefinitely. Less frequently, other types of facial clefting are observed. In most instances, they can be explained by failure of fusion or merging between facial prominences of reduced size, and similar clefts can be produced experimentally. Examples include failure of merging and fusion between the MxP and the LNP, leading to oblique facial clefts, or failure of merging of the MxP and mandibular arch, leading to lateral facial clefts (macrostomia). Many of the variations in the position or degree of these rare facial clefts may depend on the timing or position of arrest of growth of the MxP that normally merges and fuses with adjacent structures (Fig. 2.8). Other rare facial malformations (including oblique facial clefts) may also result from abnormal pressures or fusions with folds in the fetal (e.g., amniotic) membranes. Also new evidence regarding the apparent role of epithelial– mesenchymal interactions via the mesenchymal cell process meshwork (CPM) may help to explain the frequent association between facial abnormalities, especially clefts and limb defects. Genetic and/or environmental influences on this interaction might well affect both areas in the same individual. Hemifacial microsomia The term “hemifacial microsomia” is used to describe malformations involving underdevelopment and other abnormalities of the temporomandibular joint, the external and middle ear, and other structures in this region, such as the parotid gland and muscles of mastication. Substantial numbers of cases have associated malformations of the vertebrae and clefts of the lip and/or palate. The combination with vertebral anomalies is often considered to denote a distinct etiologic syndrome (oculoauriculovertebral syndrome, etc). Somewhat similar malformations have resulted from inadvertent use of the acne drug retinoic acid (Accutane) in pregnant women. Animal models using this drug have produced very similar malformations, many of which appear to result from major effects on neural crest cells. It now appears probable that at least some aspects of many hemifacial microsomia cases result from primary effects on crest cells. Malformations similar to hemifacial microsomia occurred in the fetuses of women who had taken the drug thalidomide. Treacher Collins syndrome Treacher Collins syndrome (mandibulofacial dysostosis) is an inherited disorder that results from the action of a dominant gene and may be almost as common as hemifacial microsomia. The syndrome consists of underdevelopment of the tissues derived from the maxillary, mandibular, and hyoid prominences. The external, middle, and inner ear are often defective, and clefts of the secondary palate are found in about one-third of the cases. The characteristic alterations in development appear to result effects on ganglionic placodal cells and the secondary effects on neural crest cells in this area. Labial pits Small pits may persist on either side of the midline of the lower lip. They are caused by the failure of the embryonic labial pits to disappear. Lingual anomalies Median rhomboid glossitis, an innocuous, red, rhomboidal smooth zone of the tongue in the midline in front of the foramen cecum, is considered the result of persistence of the tuberculum impar. Lack of fusion between the two lateral lingual prominences may produce a bifid tongue. Thyroid tissue may fail to descend and be present in the base of the tongue, giving rise to lingual thyroid nodule. Developmental cysts Epithelial rests in lines of union, of facial or oral prominences or from epithelial organs, (e.g., vestigial nasopalatine ducts) may give rise to cysts lined with epithelium. Branchial cleft (cervical) cysts or fistulas may arise from the rests of epithelium in the visceral arch area. They usually are seen laterally in the neck. Thyroglossal duct cysts may occur at any place along the course of the duct, usually at or near the midline. Cysts may arise from epithelial rests after the fusion of medial, maxillary, and LNPs. They are called globulomaxillary cysts.. They may, however, develop as primordial cysts from a supernumerary tooth germ. Nasolabial cysts, originate in the base of the wing of the nose and bulging into the nasal and oral vestibule and the root of the upper lip. Probably, they are retention cysts of vestibular nasal glands or that they develop from the epithelium of the nasolacrimal duct. The malformations in the development of head may indicate the defective formations in the heart as the spiral septum, which divides the conus cordis and truncus arteriosus, is derived from neural crest cells. Summary Early development of the fetus The cleavage or cell division is one of the effects of the fertilization of the ovum. Morula is formed following series of cell divisions. The outer cell mass (trophoblast cells) of the morula differentiates into the structures that nourish the embryo. Most of the inner cell mass (embryoblast) differentiates into the embryo. The initial, two-layered (epiblast and hypoblast) embryonic disk is converted into three- layered disk. This happens by the proliferation and migration of primitive streak cells into the region between ectoderm and endoderm, except over the region of prechordal plate that has only two layers. The primitive streak is the result of proliferation of the cells of epiblast (the later ectoderm). The cells from the cranial part of the primitive streak known as primitive knot migrate in the midline between ectoderm and endoderm up to the prechordal plate giving rise to the notochord. The notochordal cells induce the overlying ectoderm to form neural plate that forms neural groove with neural crest cells at its edges. Interaction between the cells causes the mesodermal cells to differentiate into paraxial, intermediate, and lateral plate of mesoderm. The paraxial mesodermal cells give rise to somites into which dermatome (dermis), myotome (muscles), and sclerotome (bones) are differentiated. Neural crest cells The neural crest cells are multipotent cells. They give rise to variety of cells like odontoblasts, melanocytes, ganglia, suprarenal medulla, parafollicular cells of thyroid gland, connective tissue, and blood vessels of head and neck region, conotruncal septum that results in the formation of ascending aorta and pulmonary trunk, etc. The enamel organ develops from the ectoderm. The ectomesenchyme consists of neural crest cells and mesodermal cells. The migration of sufficient number of neural crest cells is essential for the normal growth of head region. Development of pharyngeal arches The foldings of embryo, craniocaudal and lateral foldings, alter the positions of developing head such that it lies cranial to the cardiac bulge with stomodeum (primitive mouth) between them. The gradual appearance of pharyngeal (branchial) arches contributes to the development of the face and neck. In each arch, a skeletal element, artery, and muscles supplied by the nerve of that arch is formed. Ectodermal clefts and endodermal pouches thus formed between the arches give rise to various structures. Development of face The facial prominences, namely, frontonasal, maxillary, and mandibular, gives rise to the formation of the face. The olfactory placodes are formed in the frontonasal process as a result of ectodermal proliferation. Olfactory epithelium is derived from the placodes. MNP and LNP make the olfactory placodes to occupy the depth of the nasal pits which form nasal sacs. The fusion of the prominences bounding the stomodeum results in the formation of the face. Derivatives of pharyngeal arches Mesodermal proliferation adjoining the primitive pharynx gives rise to pharyngeal arches. Out of six arches found, the fifth one disappears soon. The first pharyngeal arch (mandibular arch) mesoderm gives rise to the muscles of mastication, mylohyoid, anterior belly of digastric, tensor veli palatini, and tensor tympani muscles. All these are supplied by the post-trematic nerve of the arch, the mandibular nerve. The pre-trematric nerve of this arch is the chorda tympani nerve. The Meckel’s cartilage of the arch gives rise to malleus, incus, anterior ligament of malleus, sphenomandibular ligament, and small part of mandible near the chin. The artery of the arch forms a part of maxillary artery. The second pharyngeal arch (hyoid arch) mesoderm gives rise to the muscles of facial expression, posterior belly of digastric, stylohyoid muscle, and stapedius muscle. These muscles are supplied by the nerve of the second arch, the facial nerve. The cartilage of this arch, the Reichert’s cartilage, gives rise to stapes, stylohyoid ligament, lesser cornu, and upper half of body of hyoid bone. The artery of this arch forms the stapedial artery. In the third pharyngeal arch mesoderm, stylopharyngeus muscle is formed and is supplied by the glossopharyngeal nerve. The lower part of body and greater horn of the hyoid bone are formed in the cartilage of this arch. The common carotid artery and parts of its terminal branches are formed from the artery of this arch. From the mesoderm of the fourth and sixth pharyngeal arches, cartilages of the larynx are formed. The superior laryngeal and recurrent laryngeal nerves are the nerves of these arches, respectively. Of the pharyngeal clefts (ectodermal), the first one gives rise to external acoustic meatus and the remaining get submerged deep to the caudally growing second arch. The cervical sinus found deep to the second arch may persist abnormally with its opening along the line of anterior border of the sternocleidomastoid muscle. From the first pharyngeal pouch, auditory tube and middle ear cavity are formed; the intra-tonsillar cleft is the remnant of the second pouch; the third pouch gives rise to the inferior parathyroid gland and the thymus; the fourth pouch gives rise to superior parathyroid gland. The parafollicular cells of the thyroid gland develop from the ultimobranchial body. Development of the tongue The tongue is the result of fusion of tuberculum impar, the lingual swellings (first arch) and cranial part of the hypobranchial eminence (third and fourth arches). This fusion is seen as “V”-shaped sulcus terminalis on the tongue. The sensory nerve supply thus can be correlated with its development. The muscles of the tongue are formed in the occipital myotomes with their hypoglossal nerve. Development of the palate The palate is formed by the union of primary and secondary palates, the former being formed by the frontonasal process and the latter by palatal process of MxPs. Clinical considerations Aberration in facial development leads to a wide variety of defects of which cleft lip and palate and anomalies of the tongue are more common than others. Cleft lip and palate may be due to a combination of genetic and environmental factors. These have been observed in pregnant mothers who smoke cigarettes and in those who take drugs like phenytoin. In experimental animals, deficient medial or lateral nasal process or underdevelopment of maxillary process causes clefting. Cleft lip may be unilateral or bilateral and may be associated with cleft palate. Rarely oblique facial cleft due to failure of fusion of maxillary process with lateral nasal process and lateral facial cleft due to failure of fusion of MxP and mandibular arch occurs. Experimentally retinoic acid affects neural crest cells leading to malformation of external and middle ear as seen in hemifacial microsomia. These anomalies in association with cleft palate are seen in Treacher Collins syndrome. Persistence of tuberculum impar is said to cause median rhomboid glossitis. Failure of fusion of lateral lingual prominence leads to bifid tongue. Thyroid tissue may persist at the base of the tongue. Rarely labial pits may be seen. Remnants of epithelial cells in the line of fusion of facial or oral prominence proliferate and give rise to cysts like branchial cleft cyst in the neck and nasolabial cyst. Review questions 1. What is the role of the notochord? 2. What are the derivatives of the neural crest cells? 3. What are the muscular, skeletal, nerve, and arterial elements formed in each pharyngeal arch? 4. What is the fate of pharyngeal clefts and pouches? 5. How can the correlation between the nerve supply and development of the tongue be made? References A complete list of references is available at www.mendenact.com Suggested reading 1. Berkovitz BK Holland GH, Moxham BJ. ed 4 Oral Anatomy, Histology and Embryology. St Louis: Mosby. 2009;278-282. 2. Nanci A. In Ten Cate’s Oral Histology Development, Structure and Function ed 1 Embryology of the Head, Face and Oral Cavity. South Asia, St Louis/New Delhi: Elsevier/Relx. 2018;23-40. References 1. Ardinger HH, Buetow KH, Bell GI. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet. 1989;45:348. 2. Bronsky PT, Johnston MC, Sulik KK. Morphogenesis of hypoxia-induced cleft lip in CL/Fr mice. J Craniofac Genet Dev Biol. 1986;2(suppl):113. 3. Chung CS Bixler D, Watanabe T. Segregation analysis of cleft lip with or without cleft palate: a comparison of Danish and Japanese data. Am J Hum Genet. 1986;39:603. 4. Couly GF Le Douarin NM. The fate map of the cephalic neural primordium at the presomitic to the 3-somite stage in the avian embryo. Development. 1988;103(Suppl):101- 113. 5. Eichele G Thaller C. Characterization of concentration gradients of a morphogenetically active retinoid in the chick limb bud. J Cell Biol. 1987;105:1917. 6. Erickson CA. vol 2 Browder LW Developmental biology a comprehensive synthesis Morphogenesis of the neural crest: New York: Plenum Press. 1986. 7. Fitchett JE Hay ED. Medial edge epithelium transforms to mesenchyme after embryonic palatal shelves fuse. Dev Biol. 1989;131:455. 8. Gasser RF. The development of the facial muscles in man. Am J Anat. 1967;120:357. 9. Goulding EH Pratt RM. Isotretinoin teratogenicity in mouse whole embryo culture. J Craniofac Genet Dev Biol. 1986;6:99. 10. Hall BK. The embryonic development of bone. Amer Scientist. 1988;76(2):174. 11. Hamilton WJ Mossman H. ed 4 Human embryology. Cambridge: W Heffer & Sons, Ltd. 1972. 12. Hay ED Meier S. Shaw JH Textbook of oral biology Tissue interactions in development. Philadelphia: WB Saunders Co. 1978. 13. Hazelton RB. A radioautographic analysis of the migration and fate of cells derived from the occipital somites of the chick embryo with specific reference to the hypoglossal musculature. J Embryol Exp Morphol. 1971;24:455. 14. Hinrichsen K. The early development of morphology and patterns of the face in the human embryo. Adv Anat Embryol Cell Biol. 1985;98:1. 15. Holtfreter JE. vol 5 Browder LW Developmental biology a comprehensive synthesis A new look at Spemann’s organizer: New York: Plenum Publishing Corp. 1988. 16. Jirásek JE. Atlas of human prenatal morphogenesis. Hingham, Mass: Martinus Nijhoff Publishers. 1983. 17. Embryology of the head and neck. In McCarthy J, editor: Plastic surgery. Philadelphia, WB Saunders Co (in press). 18. Johnston MC Bhakdinaronk A, Reid YC. Bosma JF Oral sensation and perception development in the fetus and infant An expanded role for the neural crest in oral and pharyngeal development: Washington, DC: US Government Printing Office. 1974. 19. Johnston MC Bronsky PT, Millicovsky G. Vol 4 McCarthy JG Plastic Surgery Embryology of the head and neck. Philadelphia: WB Saunders Co. 1990;2410-2495. 20. Johnston MC Bronsky PT, Millicovsky G. Vol. 4 McCarthy JG Plastic Surgery Embryogenesis of cleft lip and palate. Philadelphia: WB Saunders Co. 1990;2526-2530. 21. Johnston MC Listgarten MA. Slavkin HS Bavetta LA Developmental aspects of oral biology The migration interaction and early differentiation of oral-facial tissues. New York: Academic Press, Inc. 1972. 22. Johnston MC Noden DM, Hazelton RD. Origins of avian ocular and periocular tissues. Exp Eye Res. 1979;27-29. 23. Johnston MC Sulik KK. vol 1 Serafin D Georgiade NG Pediatric plastic surgery Embryology of the head and neck. St Louis: The CV Mosby Co. 1984. 24. Johnston MC Vig K, Ambrose L. Neurocristopathy as a unifying concept: clinical correlations. Adv Neurol. 1981;29:97. 25. Keels MA. The role of cigarette smoking during pregnancy in the etiology of cleft lip with or without cleft palate. PhD dissertation. Chapel Hill: University of North Carolina at Chapel Hill. 1991. 26. Kraus BS Kitamura H, Latham RA. Atlas of the developmental anatomy of the face. New York: Harper & Row Publishers. 1966. 27. LeLievre C LeDouarin NM. Mesenchymal derivatives of the neural crest: analysis of chimeric quail and chick embryos. J Embryol Exp Morphol. 1975;34:125. 28. Millicovsky G Johnston MC. Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice. Proc Natl Acad Sci USA. 1981;9:4723. 29. Minkoff R Kuntz AJ. Cell proliferation during morphogenetic changes: analysis of frontonasal morphogenesis in the chick embryo employing DNA labelling indices. J Embryol Exp Morphol. 1977;40:101. 30. Minkoff R Kuntz AJ. Cell proliferation and cell density of mesenchyme in the maxillary process on adjacent regions during facial development in the chick embryo. J Embryol Exp Morphol. 1978;65:46. 31. Moore KL. ed 4 The developing human. Philadelphia: WB Saunders Co. 1989. 32. Nishimura H. Eraser FC McKusick VA Congenital malformations Incidence of malformations in abortions. Amsterdam: ExcerptaMedica Press. 1969. 33. Nishimura H Semba R, Tanimura P. Prenatal development of humans with special reference to craniofacial structures: an atlas. Washington, DC: US Government Printing Office. 1977. 34. Noden DM. vol 5 Garrod DR Specificity of embryological interactions Interactions directing the migration and cytodifferentiation of avian neural crest cells. London: Chapman & Hall Ltd. 1978. 35. Noden DM. Embryonic origins of avian cephalic and cervical muscles and associated connective tissue. Am J Anat. 1983;168:257. 36. Noden DM. 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England: John Wright & Sons, Ltd. 1976. 45. Sulik KK Cook CS, Webster WS. Teratogens and craniofacial malformations: relationships to cell death. Development. 1988;103(Suppl):213-232. 46. Sulik KK Johnston MC. Sequence of developmental changes following ethanol exposure in mice: craniofacial features in the fetal alcohol syndrome (FAS). Am J Anat. 1983;166:257. 47. Sulik KK Johnston MC, Ambrose JLH. Phenytoin (Dilantin)-induced cleft lip, a scanning and transmission electron microscopic study. Anat Rec. 1979;195:243. 48. Sulik KK Johnston MC, Smiley SJ. Mandibulofacial dysostosis (Treacher Collins’ syndrome)a new proposal for its pathogenesis. Am J Med Genet. 1987;27:359. 49. Tam PPL Beddington RSP. The formation of mesodermal tissues in the mouse embryo during gastrulation and early organogenesis. Development. 1987;99:109. 50. Tam PPL Meier S. The establishment of a somitomeric pattern in the mesoderm of the gastrulating mouse embryo. J Anat. 1982;164:209. 51. Tamarin A Boyde A. 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CHAPTER 3 Development and growth of teeth CHAPTER CONTENTS Dental Lamina 21 Fate of dental lamina 21 Vestibular lamina 22 Tooth Development 22 Developmental Stages 24 Bud Stage 24 Cap Stage 24 Outer and inner enamel epithelium 24 Stellate reticulum 25 Dental papilla 26 Dental sac (dental follicle) 26 Bell Stage 26 Inner enamel epithelium 27 Stratum intermedium 27 Stellate reticulum 28 Outer enamel epithelium 28 Dental lamina 28 Dental papilla 28 Dental sac 28 Advanced Bell Stage 30 Hertwig’s epithelial root sheath and root formation 32 Histophysiology 33 Initiation 33 Proliferation 34 Histodifferentiation 34 Morphodifferentiation 35 Apposition 35 Molecular Insights in Tooth Morphogenesis 35 Clinical Considerations 35 Summary 36 Review Questions 37 The primitive oral cavity, or stomodeum, is lined by stratified squamous epithelium called the oral ectoderm or primitive oral epithelium. The oral ectoderm contacts the endoderm of the foregut to form the buccopharyngeal membrane. At about the 27th day of gestation, this membrane ruptures and the primitive oral cavity establishes a connection with the foregut. Most of the connective tissue cells underlying the oral ectoderm are of neural crest or ectomesenchyme in origin. These cells are thought to instruct or induce the overlying ectoderm to start tooth development, which begins in the anterior portion of what will be the future maxilla and mandible and proceeds posteriorly (see Chapter 2 for more details on embryonic induction). Dental lamina Two or three weeks after the rupture of the buccopharyngeal membrane, when the embryo is about 6 weeks old, certain areas of basal cells of the oral ectoderm proliferate more rapidly than do the cells of the adjacent areas. This leads to the

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