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Chapter 2: The Craniofacial Complex

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The first line a child draws on a face is usually the mouth. The mouth is the center of communication and contact. Along with the eyes, ears, and nose, it is positioned near the brain, ensuring close integration and coordination. We use the craniofacial complex—the oral, dental, and the other craniofacial tissues that house the organs of taste, vision, hearing, and smell—to experience and interact with the world around us. These sense organs have evolved to serve as superb information processors and aids to survival. At the most elemental level, they enable us to sense our environment—from alerting us to predators or poisons to recognizing family, friends, or prospective mates.

Our ability to act on the nerve signals from these organs results from the abundant supply of paired cranial nerves that innervate the craniofacial tissues. No place in the body is as rich in both the number of sensory nerves and the ratio of motor nerves to muscle fibers as the face, and, within it, the mouth and teeth. The nerve circuits not only trigger protective reflexes to make us blink, gape, and start in surprise, but also enable us to perform countless functions we take for granted. We speak and taste and chew and swallow. We express our feelings through smiles and scowls; we grimace and cry out in pain; we murmur endearments and kiss our loved ones.

Beyond the special senses of vision, hearing, taste, and smell, the craniofacial complex includes nerve endings sensitive to the body's position in space and to touch, pressure, temperature, and pain. In sum, if the brain is the command-and-control center of the body, evolution has ensured that the staff reporting from the field and carrying out orders are stationed a strategic few inches away, in the craniofacial complex.

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CONTACT AND COMMUNICATION

Taste and Smell

The developmental process by which vital nerve centers came to be concentrated in the head, mouth, and teeth began early in evolution. Even paramecia have mouths, as do worms, bugs, and all more complex organisms. The mouth appears in the human embryo during the third week of development. By the thirteenth or fourteenth week, the fetal mouth can open in response to stimulation of the lower lip. During the next 2 months, the fetus will practice protruding and then pursing the lips, eventually achieving the ability to suck vigorously at 29 weeks. In the meantime, inspiratory gasps, tongue movements, lip curling, and swallowing responses will have been established (Wilentz 1968).

At birth, the taste buds are found on the roof of the mouth and in the throat, as well as on the tip, sides, and back of the tongue. Taste buds, such as those on the tip of the tongue, are particularly subject to wear and tear, and may be replaced every 2 weeks. The total number of buds diminishes over time, but there appears to be considerable reserve capacity, so there is normally little loss in the sense of taste as we age.

It has been said that taste is 90 percent smell, and to some extent that is true. The taste cells that line the buds respond to only five known qualities: sweet, sour, salty, bitter, and glutamate. The experience of taste is a complex mixture of smell, temperature, taste, and texture.

The day-old newborn responds to sweet stimuli. Suckling, the first oral function following the cry, is enhanced by the presence of lactose, the sugar in breast milk. Liquids sweetened with sugar or honey have been used widely after birth to stimulate appetite, and later to wean children from breast-feeding. The ability to recognize a sweet taste clearly has survival value, enabling the recognition and selection of carbohydrates—a vital source of energy.

The other taste modalities are also physiologically important. A sour taste, for example, can signal an unripe fruit. However, sour substances may be involved in more subtle biochemistry, such as maintaining the body's ion balance. They also satisfy thirst and promote digestion by stimulating the secretion of saliva. A bitter taste is sufficiently unpleasant to evoke aversion, a useful response given that many bitter-tasting plant alkaloids are toxic. A salty taste indicates the presence of sodium, which is essential to maintaining the fluid balance between cells and the extracellular compartment.

Humans probably began as herbivores before the advent of hunting and gathering and retained taste-discriminating ability as an evolutionary advantage. The combination of taste and smell remains important not only for the maintenance of an optimal diet (Young 1977), but also clearly for the pleasures of eating.

Unlike taste cells, olfactory cells can respond to many thousands of odorants, including ones that have been newly synthesized. Millions of olfactory receptors line a postage-stamp-sized area in the upper part of the nose, the olfactory epithelium. Although some smells may be judged universally as unpleasant or foul, others are subject to learning and cultural conditioning. For example, a ripe Roquefort cheese may delight some people, but repel others.

The primary receptor cells of the olfactory system are neurons with fine hairs at one end that project into the olfactory epithelium to pick up the olfactory stimulus. The cells translate the stimulus to nerve impulses transmitted to the brain along the two olfactory nerves—one from each nostril. Olfactory neurons have the unusual ability to regenerate (although recent studies suggest that neurons in other parts of the adult brain may also have this ability (Johansson et al. 1999). Olfactory pathways are widely distributed in the brain, relaying to emotional and cognitive centers in the cortex. These connections undoubtedly account for the ability of odors to stir old memories as well as stimulate a range of feelings, from fear to sexual arousal.

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Touch, Temperature, and Pain

The mouth also contains large numbers of nerve endings, similar to those found elsewhere in the body, that are sensitive to touch (mechanoreceptors), hot and cold temperatures (thermoreceptors), and pain (nociceptors). The dense concentration of these receptors in the facial skin, joints, muscle, and oral soft tissues, relayed to an image of the body mapped onto the sensory cortex of the brain, accounts for the finesse with which we can discriminate the qualities and precise location of these sensations. In particular, the periodontal ligament, which anchors the teeth in the jaws, is a tactilely sensitive tissue providing important feedback with regard to mastication (chewing) and dental occlusion (bite). As a test of this sensibility, a human hair placed between the tips of the fingers will rarely be sufficient to stimulate the nerve endings, but the same hair placed between the lips or incisors will instantly be felt.

Pain and thermal sensitivity in the teeth are transmitted through nerve endings in the pulp. Because the pulp is in a narrow canal composed of connective tissue, blood vessels, and nerves and surrounded by hard tissue, any infection or inflammation that would normally cause tissue to swell creates pressure on the pulpal nerves. That pressure, along with bacterial or immune system products that stimulate the nerve endings, produces the severe pain of pulpal infections.

Neuroscientists have long studied oral-facial pain, not only because of its importance in oral disease, but also because it provides an accessible model of pain elsewhere in the body. These investigations have greatly enriched our understanding of the basic mechanisms of pain perception and modulation. They have helped delineate the complex pathways and multiple transmitters that convey pain signals to the brain and spinal cord, as well as the mechanisms and molecules that can modulate and inhibit nociceptive input. These studies have also exploited new brain-imaging techniques to confirm the wide distribution of pain pathways and relay centers in the cerebral hemispheres and cerebellum.

This research has generated new approaches to the control of acute and chronic pain. These approaches include the use of nonsteroidal, anti-inflammatory drugs and long-acting local anesthetics for acute oral and dental pain, and the use of more potent drugs, drug combinations, and other kinds of therapies to treat chronic pain. Researchers have emphasized the importance of adequate pain control in patients with chronic pain conditions. Otherwise, the constant barrage of signals can effect long-term changes in the brain that actually worsen the pain (producing hyperalgesia) and cause normally nonpainful stimuli to be perceived as painful (a condition called allodynia). Unrelieved chronic pain may also suppress the immune system.

Recently, investigators discovered a link between certain taste sensations, pain, and temperature. Their findings indicate that capsaicin, the ingredient that makes hot peppers taste hot, binds to a receptor on the surface of nociceptors that also responds to noxious heat. The researchers have cloned the gene for the capsaicin receptor (called vanilloid receptor 1); they believe it is involved in several chronic pain conditions, especially those where inflammation plays a role, such as viral and diabetic neuropathy, rheumatoid arthritis, and oral mucositis pain caused by cancer chemotherapy or radiation (Caterina et al. 1997).

There is evidence that the prevalence of a number of pain conditions varies by gender and that men and women respond differently to different analgesic drugs. These findings have prompted studies aimed at determining whether there are sex differences in pain anatomy and neurochemistry and whether (and how) nociception is affected by sex hormones.

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Speech

Human speech and language are the faculties that most distinguish us from other higher primates; they are also the links that bind people together in diverse social groups and cultures.

Central to speech are laryngeal mechanisms involving the vocal cords. Equally critical are the respiratory system, the pharynx, and the nasal and oral cavities. The tongue is the most important structure of the peripheral speech mechanisms, working in conjunction with the lips, teeth, and palate to produce a rich repertoire of sounds. Abnormalities in oral structures, from missing or malformed teeth and malocclusion to cleft lip and palate, can seriously affect articulation. The movements of speech are orchestrated by brain centers that coordinate the muscles of mastication, facial expression, and jaw movements.

Hearing impairments can also affect speech. To learn to speak, children must be able to hear others and monitor the feedback from their own voices. Congenital deafness and the serious hearing defects associated with some craniofacial syndromes (see Chapter 3) can severely compromise speech acquisition.

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THE ORAL CAVITY

The mouth is the gateway to the body, performing dozens of functions that place high demands on its unique hard and soft tissues. The point of entry is the lips, which open into the oral cavity. The cheeks form the sides of the cavity, and the roof is formed by the palate, which separates the mouth from the nose above and the pharynx (throat) behind. The anterior palate is hard, formed by underlying bone, and serves as a shield against trauma to the face and head. The posterior palate is soft, composed of muscles and connective tissue that blend into the walls of the pharynx. Hanging from the rear of the soft palate is the uvula, a mass of muscle and connective tissue. Under the tongue is the floor of the mouth, composed primarily of muscle and salivary glands. The paired tonsils and adenoids, important components of the immune system, lie at the sides of the palate and within the nasopharynx, respectively.

The pharynx opens into channels leading either to the lungs for respiration or the esophagus for further digestion and passage to the stomach. This is a point of vulnerability: should food or some other obstruction lodge in the airway, it could lead to death by asphyxiation.

Externally, the oral cavity is bounded by the maxilla (the upper jaw bone), attached to the cranium, and the mandible (the lower jaw), attached to the temporal bone of the skull by the temporomandibular joint.

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The Oral Mucosa

Except for the teeth, the oral tissues are covered by a mucous membrane called the oral mucosa, which varies in color from pink to brownish purple, depending on an individual's skin color. Like skin, the oral mucosa acts as a major barrier against chemical irritants and mechanical forces; it can even withstand temperatures that would be painful to the skin. In areas subject to chewing forces and food movements, the surface layer is relatively hard, composed of epithelial cells filled with insoluble keratin, the fibrous protein found in skin, nails, hair, and animal horn. Elsewhere—in the mucosal lining of the cheeks, for example—the surface layers are softer and more flexible, enabling the mobility we need to speak, chew, and make facial expressions. To aid in their barrier function, surface mucosal cells are square-shaped and closely juxtaposed, with specialized organelles and cell products that promote cell-cell adherence. The cells can also secrete sticky molecules to plug gaps between them and further impede penetration by damaging chemicals or microorganisms. Still another type of oral mucosa forms the pebbly surface of the back and sides of the tongue. Lining the depths of these surface "papillae" are the taste buds.

Interestingly, the epithelium that lines the gingival surface completely lacks a keratin layer, yet this "naked" epithelium lies next to one of the most dense concentrations of bacteria to be found in the body. Thus there is an opportunity for infectious agents or their byproducts to penetrate the naked epithelial barrier and initiate an inflammatory response, as happens in gingival disease.

Special cells in the basal layer of the oral mucosa generate replacements for surface cells as they wear out. The painful oral ulcers and oral mucositis that may develop in patients undergoing radiation or chemotherapy for head and neck cancer occur because these cancer-killing agents attack all cells undergoing rapid turnover, whether healthy or cancerous.

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The Teeth

The most prominent features of the oral cavity are the teeth. The 20 primary, or deciduous, teeth erupt generally between 6 months and 2 to 3 years of age and are succeeded by the permanent teeth beginning at about age 6. The primary teeth enable infants to eat solid foods, aid speech development, and serve as placeholders for the permanent dentition. Keeping primary teeth healthy is important, not only in sparing an infant pain and disease, but also in preserving the dimensions of the dental arches and lessening the risk of dental caries in the permanent teeth. A period of mixed primary and permanent dentition occurs from about ages 6 to 13. There are 28 to 32 permanent teeth, depending on whether the 4 wisdom teeth (third molars), which are last to erupt, are present. Teeth are anchored in the jaws by the periodontal ligament. This ligament connects the cervix (neck) of the tooth, at the junction between the crown and root, to the gingiva. Below that, the ligament connects the outer layer of the tooth root, the cementum, to the adjacent alveolar bone (the part of the jaw bone that supports the tooth roots).

The evolutionary forces that shaped the human mouth designed an apparatus for optimal food intake. The front four upper and lower incisor teeth are chisel-shaped for biting, cutting, and tearing and exert forces of 30 to 50 pounds. The canines, or cuspids, are larger and stronger and have deeper roots than the incisors; their conical cusps are effective for ripping and tearing. The premolars, or bicuspids, and the molars are designed for heavy grinding and chewing, exerting forces as high as 200-plus pounds. The temporomandibular joint, the most complex synovial joint in the body, equips the human jaw with extraordinary mobility, enabling movements in three dimensions. Its range of motion is controlled by three sets of muscles of mastication—the masseter, temporalis, and pterygoid muscles (Oberg 1994). Chewing reduces food to small particles and mixes it with saliva to form a bolus for swallowing.

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The Salivary Glands

Saliva is the mixed product of multiple salivary glands that lie under the mucosa. The three major glands are the paired parotid, submandibular, and sublingual glands. The parotids, near the ears, secrete a watery saliva into the mouth via ducts in the cheeks. The walnut-sized submandibular glands lie in the floor of the mouth and secrete a mucous fluid. The secretions of the almond-shaped sublingual glands, also in the floor of the mouth but near the front, usually join with those of the submandibular glands. Tiny minor salivary glands are scattered within the inner surfaces of the lips, cheeks, and soft and hard palates; these secrete a mucinous saliva directly onto the soft tissue surfaces.

Saliva moistens food and provides mucinous proteins to lubricate the bolus for ease of swallowing. The combined movements of the tongue and cheeks move the bolus to the back of the mouth. Saliva also contains the enzyme amylase, which initiates the digestion of starch. By solubilizing food components and facilitating their interaction with the taste buds on the tongue and palate, saliva also contributes to taste enhancement.

Tissue Protection

The main function of saliva is not—as is commonly believed—to aid digestion, but to protect the integrity of the oral tissues. The moment a baby passes through the birth canal and takes its first breath, microbes begin to take up residence in its mouth. Later, as the teeth erupt, additional bacteria establish colonies on tooth surfaces (Mandel 1989). Nearly 500 species of microbes in all, most of which are not harmful, will colonize the oral cavity (Kroes et al. 1999). The microbes form a biofilm, in which their numbers greatly exceed the number of human inhabitants on Earth.

Millions of years before there were toothbrushes, dental floss, and water irrigators, evolutionary forces generated protective mechanisms to combat potentially harmful microbes. The physical flow of saliva helps to dislodge pathogens (viruses, bacteria, and yeast) from teeth and mucosal surfaces, just as tearing and blinking, sneezing, and coughing and expectorating clear the eye, nose, and throat. Saliva can also cause microbes to clump together so that they can be swallowed before they become firmly attached. Saliva can destroy orally shed infected white blood cells by virtue of its low salt content: the infected cells—of higher salt content—swell and burst when exposed to fluids of lower salinity (Baron et al. 1999).

Salivary secretions, like tears and other exocrine gland secretions, are rich in antimicrobial components. Certain molecules in saliva, such as lysozyme, lactoferrin, peroxidase, and histatins, can directly kill or inhibit a variety of microbes; the histatins are particularly potent antifungal agents (Xu et al. 1991). Several salivary proteins exhibit antiviral properties, including secretory leukocyte protease inhibitor (SLPI), recently discovered to have the ability to inhibit HIV from invading cells (Shugars and Wahl 1998).

The ability of saliva to limit the growth of pathogens, in some instances even preventing them from establishing a niche in the biofilm community in the first place, is a major determinant of general as well as of oral health. When salivary flow is compromised, the gateway to the body can open wide to local as well as to systemic pathogens.

Barrier and Buffering Properties

Salivary components protect oral tissues in other ways as well. Mucins have unique properties that enable them to concentrate on mucosal surfaces and provide an effective barrier against drying and physical and chemical irritants (Tabak 1995). They act as natural waterproofing, control the permeability of the tissue surfaces, and help limit penetration of potential irritants and toxins in foods and beverages, as well as toxic chemicals and potential carcinogens in tobacco and tobacco smoke and from other sources. This barrier function complements the barrier formed by the oral mucosa itself. The mucosa has a specific permeability coefficient that can change under various conditions of stress, nutritional status, and other challenges.

Saliva contains several effective buffering systems that can help maintain a normal pH when acidic foods and beverages are introduced, thereby protecting oral tissues against acidic attack. When swallowed, these buffers protect the esophagus, helping neutralize the reflux acids of conditions such as heartburn and hiatal hernia (Sarosiek et al. 1996).

Wound Healing

Saliva also contains molecules that nurture and preserve the oral tissues, even helping them to repair and regenerate (Mandel 1989, Tabak 1995, Zelles et al. 1995). Experimental studies have shown that wound healing is significantly enhanced by saliva, in part because of the presence of a potent molecule, epidermal growth factor (EGF) (Zelles et al. 1995). When swallowed, EGF can also protect the tissue surfaces of the esophagus (Sarosiek et al. 1996). Vascular endothelial growth factor (VEGF) has also been identified in saliva. VEGF stimulates blood vessels and may contribute to the remarkable healing capacity of oral tissues (Taichman et al. 1998, Zelles et al. 1995).

Caries Protection

Saliva also guards against dental caries (tooth decay), the disease that has been the greatest threat to teeth. Caries is caused by bacteria that generate acids that attack tooth mineral (see Chapter 3). The buffering systems in saliva, augmented by the neutralizing components urea and ammonium, counter the acid formation. The physical flow of saliva also helps flush out sugars and food particles that are the bacterial food source. Mineral salts in saliva—calcium and phosphate—can remineralize tooth enamel, effectively reversing the decay process. This regenerative function is greatly enhanced by the presence of fluoride in saliva. Finally, saliva forms a film on teeth made up of selectively adsorbed proteins that have a high affinity for tooth mineral. This acquired pellicle is insoluble and limits the diffusion of acids into the teeth and the dissolution of tooth mineral (Lamkin and Oppenheim 1993).

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The Immune System

The salivary glands and the oral mucosa, along with the body's other mucosal linings and the lymphatic circulation, constitute a major component of the body's defense system—the mucosal immune system (Mestecky 1987). When the area of the oral mucosa is combined with the areas of the mucosal linings and passageways of the respiratory, gastrointestinal, urinary, and genital tracts, the total represents the largest surface area of the body—nearly 400 square meters, or 200 times larger than the total skin area.

The great majority of infectious diseases affect, or are acquired through, mucosal surfaces. Immune cells that line the mucous membranes throughout the body secrete antibodies targeted to specific disease-causing microbes (Mandel and Ellison 1985). The mucosal immune system works in concert with the bloodborne immune system to detect and dispose of foreign substances and invading microbes.

The two components of the immune system consist of molecules and cells that provide both broad and specific defense mechanisms. In the broad group are some circulating white blood cells (monocytes and granulocytes) associated with the inflammatory response. These cells migrate to a site of injury or infection and move into damaged tissues manifesting the four signs of inflammation: swelling, heat, redness, and pain. The cells promote an increase in blood flow to begin the healing process, and they recruit other cells able to engulf and dispose of the offending organism.

The specific immune system is associated with two major classes of immune cells: T cells and B cells. T cells react to antigens (proteins associated with microbes or irritants) and can stimulate B cells to make antigen-specific antibodies. These are the Y-shaped molecules called immunoglobulins.

T cells are the instruments of cell-mediated immunity; they are able to detect telltale surface markers on diseased or foreign cells that distinguish them from normal body cells. Some T cells can kill infected cells and cancer cells directly. T cells are also involved in the rejection of organ transplants.

Certain T cells are memory cells, preserving the information from earlier encounters with specific pathogens. Thus they are able to initiate more rapid and effective responses in the event of a repeat encounter with the pathogen. Helper T cells assist in activating killer T and B cells. It is the loss of helper T cells that leads to the many infections that cause illness and death in HIV disease. Still another group of T cells, suppressor T cells, moderates the activities of both B and T lymphocytes.

Activated T cells generate and release cytokines—potent families of proteins, such as the interleukins, that can stimulate immune cells to divide, migrate, attack, and engulf invaders or participate in the inflammatory response. Other cytokines include varieties of tumor necrosis factor and adhesins (proteins that facilitate the binding of immune cells to each other or to blood vessel linings). Feedback mechanisms provide a system of checks and balances to regulate cytokine production.

The immune system interacts with the nervous and endocrine systems. For example, immune cytokines secreted into the brain can induce the fever associated with infection: the high temperature may help destroy the infectious agent. The brain's response to stress also has repercussions for the immune system. The hypothalamus-pituitary-adrenal axis is a major pathway activated in response to stress, which results in the secretion of cortisol, the stress hormone, from the adrenal glands. Cortisol promotes the body's fight-or-flight mechanisms, but via feedback loops, cortisol acts to depress immune reactions.

Much of what we know about the immune system has come from studies of serum factors, but research in the last two decades has generated much new information about mucosal immunity (McGhee and Kiyono 1999). The mucosal immune system can be divided into inductive and effector compartments. The nasal-associated lymphoreticular tissues (NALT) in the nasopharyngeal area (which includes the tonsils) and the gut-associated lymphoreticular tissues (GALT) in gut tissue are inductive regions, where foreign invaders are encountered. If, for example, infectious bacteria are swallowed, they can stimulate immune cells in GALT to circulate T and B cells through the lymph system to various effector sites in the gastrointestinal and upper respiratory tracts and in the salivary and other exocrine glands. The B cells in the gland produce antibodies, designated S-IgA, to which is attached a secretory component (Mestecky and Russell 1997). These antibodies are the dominant type found in saliva, tears, breast milk, and colostrum and in the gastrointestinal and genitourinary tracts.

The uses of the mucosal immune system extend beyond its normal surveillance and defense functions. The tissues can be used as routes for delivery of oral (swallowed) or nasal (inhaled) vaccines, as sites for gene transfer to augment host defenses, and as a means of invoking oral tolerance—the suppression of overactive or inappropriate immune responses that occur in chronic inflammatory and autoimmune diseases (Baum and O'Connell 1995, Hajishengallis and Michalek 1999).

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CRANIOFACIAL ORIGINS

The extraordinary successes of research in molecular genetics over the past decade, coupled with the National Institutes of Health's project to map and sequence the human genome, have proved to be a boon in understanding craniofacial development. The use of automated gene-sequencing equipment, the Internet availability of genome databases, and the ability to transfer genes or create "knockout" animals—in which a gene of interest has been eliminated—have greatly facilitated progress. The events that govern the transformation of a fertilized human egg cell into a healthy newborn with all organs and systems in place are being unfolded at the molecular level. Families of master and regulatory genes have been identified, and their role in controlling how the body's general shape and specialized tissues and organs are formed is coming to light.

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Early Development

The Three Germ Cell Layers

By the time the face and the mouth are ready to form, the human embryo is in the third week of development. The embryo has evolved from a sphere to an oval two-layered disk with a head-to-tail orientation. The outer layer is the epiblast and will become the ectodermal germ layer. A narrow groove, called the primitive streak, extends from the tail toward the center of the disk, where it ends in a spot surrounding a small depression called the primitive pit. Epiblast cells migrate toward the streak and pit, detach from the surface, and slip downward to form the two additional germ cell layers, the mesoderm and, below that, the endoderm.

The ectodermal layer gives rise to tissues that relate the body to the outside world: the nervous system; the sensory epithelium of the ears, nose, and eyes; skin, hair, nails, salivary glands, tonsils, and tooth enamel; and the pituitary, mammary, and sweat glands. At the head end, the mesodermal layer gives rise to a primitive connective tissue, called mesenchyme, which will interact with the ectoderm to form parts of the head and mouth. The remaining mesoderm develops into the muscle, cartilage, bone, and subcutaneous skin tissue of the rest of the body. The mesoderm is also the origin of the vascular and urogenital systems (except for the bladder), the spleen, and the adrenal cortex. The innermost, endodermal layer provides the linings of the gut, the respiratory system, bladder, liver, pancreas, thyroid and parathyroid glands, and parts of the middle ear.

Neural Tube and Neural Crest

Further migrations and descending movements of cells result in the formation of the notochord, a solid cord of cells along the midline that will become the backbone. The ectoderm above the notochord next thickens to form a neural plate. The sides of the plate curve up and inward to form a neural tube, beginning at the head, with fusion completed by the end of the fourth week. The tail end of the tube will form the spinal cord; the head end differentiates into the three parts of the primitive brain: the forebrain, midbrain, and hindbrain.

What happens next is of central importance to the craniofacial complex: cells that were at the edges of the neural plate break away to form neural crest cells, which migrate to the forebrain area and to the nearby branchial arches, a series of swellings on either side of the embryo, adjacent to the hindbrain. The hindbrain becomes organized into eight rhombomeres, segments of future nerve tissue arranged in an orderly fashion so that the first two rhombomeres innervate branchial arch 1, and so on.

During the formation of the midbrain and hindbrain, cranial neural crest cells migrate into the developing facial areas and differentiate into neuronal and nonneuronal tissues. The neuronal tissues include the clusters of nerve cells (ganglia) that lie adjacent to the spinal cord, parts of the ganglia of four cranial nerves, and two of the meningeal layers of the brain. The nonneuronal tissues include major bones, cartilage, the dentin and cementum of teeth, and the various types of connective tissues of the craniofacial complex, as well as the muscles of the eye. The branchial arches give rise to the bones, cartilage, nerves, muscles, and blood supply of successive segments of the head and neck.

The Face and Mouth

The branchial arches play a key role in the formation of the facial structures. Toward the end of the fourth week of gestation, a primitive mouth appears. This "stomadeum" is flanked by a series of swellings, or prominences, derived from the first pair of branchial arches. A single frontonasal prominence forms the upper border of the stomadeum. On either side of this prominence are two thickened regions of ectoderm—the nasal placodes. At the sides of the stomadeum and below it are pairs of maxillary and mandibular prominences.

In the course of the next 3 weeks, differential growth and movements of the various prominences and fusions of tissues that come together at the midline will sculpt the bridge, crest, sides, and tip of the nose, the upper and lower lips, and the upper and lower jaws (Bhaskar and Orban 1990, Sadler and Langman 1995).

The external merger at the midline of a pair of prominences that helps to form the nose occurs inside the mouth as well, resulting in an intermaxillary segment that will contribute to the formation of the four upper incisors and parts of a small triangular-shaped primary palate and the upper jaw. The bulk of the palate, the secondary palate, forms from shelflike outgrowths of the maxillary prominences. These growths appear in the sixth week, and in the following week fuse along the midline above the tongue. (The tongue appears at approximately 4 weeks, the front two-thirds forming from the first branchial arch, and the posterior third from parts of the second, third, and fourth branchial arches.) The palatal shelves also fuse with the primary palate along a triangular border called the incisive foramen. This border is considered the line of division among clefting abnormalities. Lateral cleft lip, cleft upper jaw, and clefts between the primary and secondary palates are associated with defects anterior to the incisive foramen. Cleft palate and cleft uvula occur because of defects affecting closure of the palatal shelves posterior to the foramen (Bhaskar and Orban 1990, Sadler and Langman 1995).

The Teeth

Tooth development begins in the sixth week with the appearance of an epithelial band lining the upper and lower jaws. A part of the band develops into a dental lamina, which forms a series of projections into the jaw. These are the tooth buds and correspond to the sites of deciduous teeth. The epithelial tissue of the bud develops into an enamel organ that forms a cap over tissue that is differentiating in the jaw to become the dental papilla. The two structures—the enamel organ, derived from the epithelium, and the dental papilla, derived from neural crest mesenchyme—constitute the tooth germ.

With further development, the tooth germ assumes a bell shape and separates from the oral epithelium. At the same time, the internal epithelial layer of the enamel organ undergoes a series of infoldings that will shape the future crown of the tooth.

Mineralization of the tooth begins at the late bell stage. The first mineralized tissue to form is dentin, which provides the foundation for the deposition of enamel. The differentiation of the odontoblasts (the dentin-producing cells) depends on organizing influences from enamel organ cells. Thus the development of these two different hard tissues is a mutually dependent process.

As dentin is laid down, the odontoblasts move toward the center of the papilla, trailing thin cellular processes, which become embedded in the mineralized matrix. When dentin formation is completed, dentin completely surrounds the pulp, protecting it from injury. The enamel layer of the tooth starts to form soon after the first dentin appears, synthesized by special enamel-forming cells, or ameloblasts, which develop from the enamel organ. The tooth root, and its outer layer of cementum, form only after the crown erupts.

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Genetic Controls

Only in the last decade have scientists begun to understand how certain genes and gene families control embryonic development. Their findings have come from detailed studies of species ranging from fruit flies, nematodes, and zebrafish to frog, chick, mouse, and human embryos. In many cases, the simpler organism has been the source of discoveries of genes or developmental processes that are highly conserved in the course of evolution (Alberts et al. 1994).

Research on the fruit fly, for example, has revealed that particular families of genes are responsible for the fundamental head to thorax to tail patterning of the fly's body. Another set of genes determines the back-to-front positioning of organs, and a third set subdivides this general body plan into a series of discrete segments. With further development, yet another family of genes confers a positional memory on the cells within a segment. These "homeotic selector" genes ensure that cells in one part of a particular segment "know" that they are destined to be wings and not legs, or to be eyes and not antennae. In flies the homeotic genes are known as Hom genes. Their arrangement on the fly chromosome is ordered with genes at one end of the chromosome specifying the developmental destiny of cells in the most anterior segments of the fly's body and genes at the other end specifying the fate of cells in the most posterior segments.

In the course of evolution, mammals have developed four overlapping sets of positional memory gene clusters homologous to the fly's single Hom complex. The four mammalian Hox gene families are ordered in a similar anterior-posterior fashion along four different chromosomes. The mammalian genes appear to operate like the Hom genes: they code for DNA-binding proteins that control gene expression. The similarity from fly to human is particularly evident when maps of the expression domains of Hom genes in anterior segments of the fly embryo are compared to maps of Hox gene expression as seen in the rhombomeres and branchial arches of mammals.

Molecular genetic studies of flies and other nonmammalian species show some variation in how and when the basic body patterns and repeating segments are formed. Sometimes the head-to-tail pattern is laid down in the egg cell before fertilization—dictated by egg polarity genes. Although egg polarity genes do not operate in humans, mutations have been found in a human gene homologous to the fly egg polarity gene and account for serious syndromes in which there are defects in anterior organs, such as the pituitary gland and heart.

None of these developmental controls work in isolation. Much remains to be understood about the genetic clock that determines when and where developmental genes act, how they interact, and what mechanisms are used to sustain as well as terminate their function. The systems that govern programmed cell death are also important: normal development depends as much on the elimination of cells as it does on the orderly movement, proliferation, and differentiation of cells.

When it comes to processes that control the development of particular tissues or organs—bones, skin, or heart—developmental biologists observe that there is often an "organizer," that is, a cell or set of cells that initiates the process. The organizer induces changes in the behavior of neighboring cells through cell-cell interactions, so that these cells develop into the specified type—bone or skin or heart muscle. The interaction with the neighboring cell is often in the form of a signaling molecule, such as a growth factor (e.g., transforming growth factor beta, epidermal growth factor, fibroblast growth factor) that attaches to a receptor on the surface membrane of the recipient cell. This interaction is translated to the interior of the cell, where a chain of molecular interactions eventually reaches the cell nucleus to effect gene expression. One of the more startling discoveries of the past decade has been the finding that a series of mutations, each associated with a change in only one nucleotide of the gene for the fibroblast growth factor receptor—a so-called point mutation—accounts for a range of organ defects seen in at least a half dozen craniofacial syndromes. Interestingly, all these syndromes include craniosynostosis, a premature closure of the bones that form the skull.

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THE AGING OF CRANIOFACIAL TISSUES

Normal aging describes the developmental processes that begin at conception, continue in childhood, and merge gradually into maturation and senescence. The milestones of development such as the age when children teethe, begin to walk, talk, enter puberty, attain their full height, and so on, are under genetic and hormonal controls, subject to important environmental factors such as nutrition and exercise. Despite the complexity and interrelationships of the variables involved, a reasonably accurate picture of normal age-related changes in the craniofacial complex is emerging (Ship 1999).

Barring major illness or injury, destructive behaviors, or severe or unusual environmental circumstances, the cells, tissues, and fluids of the face and mouth are hardy survivors, eminently durable and functional over a long life span. For any given individual the combination of life experience and lifestyle (including medical and dental history) creates a unique craniofacial portrait, one that inspired George Orwell to remark, "By the age of fifty, a man gets the face he deserves."

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The Teeth

One of the more dramatic discoveries in biomedical science in the twentieth century has been the realization that tooth loss is not an inevitable consequence of aging, but the result of disease or injury. Aging does produce a number of other dental changes, however. Teeth change in form and color with age. Wear and attrition alter the biting and chewing surfaces, as do food choices and oral habits. The altered surface structure produces a different pattern of light reflection in older teeth, resulting in some yellowing and a general loss of translucency (Mjor 1986). Fully formed enamel is acellular, hence there is no metabolic activity or turnover as occurs in skin, for example. Dentin and cementum have limited cellular activity. In contrast, tooth pulp and periodontal ligament undergo relatively high levels of tissue turnover.

Tooth surfaces can be eroded by chemical dissolution from fruit acids and from acids from sugars in foods such as soft drinks and candies. This destructive process can occur at any age, resulting in loss of translucency as well as some tissue loss from demineralization (Zero 1996). Countering the erosive forces are the natural components in saliva that help remineralize the enamel surface, a process that is enhanced when fluoride is present (see "Caries Protection" above).

The cementum increases in thickness with age. Gingival recession caused by normal aging exposes the cementum to the oral environment (and is the origin of the expression "long in the tooth"). The exposed cementum can often be worn away mechanically, exposing the underlying dentin, which can then become hypersensitive. Dentin responds through a series of protective changes that work to close off the connections between dentin and nerves in the pulp, reducing transmission of painful stimuli.

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The Jaws

The bones of the maxilla and mandible that support the teeth, called the alveolar processes, are, like bone elsewhere in the body, subject to cellular turnoverin a coordinated process of bone resorption and formation. Alveolar bone is well adapted to mechanical stresses, and changes continuously during facial growth, tooth eruption, tooth wear, and tooth loss. This lifelong adaptation makes orthodontic treatments to reposition teeth in adults possible.

Because the primary function of alveolar bone is to support the teeth, the loss of teeth will lead to bone atrophy, making prosthetic replacements difficult. The rate of bone loss is affected by both local disease such as periodontal disease and systemic conditions such as osteoporosis (Bhaskar 1991).

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The Oral Mucosa

The oral mucosa appears to age in much the same way as skin does. The oral epithelium thins and becomes less hydrated, increasing vulnerability to injury. The rate of cell division is slower, but the basic cell architecture and patterning of cell types throughout the oral cavity are maintained. It is not certain to what extent these changes are a natural consequence of aging; they may be due to altered protein synthesis or lowered responsiveness to regulatory molecules. They may also be an effect of diminished vascularity, which could limit cellular access to oxygen and nutrients (Mjor 1986).

Overall immune system function deteriorates with age, and it is likely that mucosal immunity does as well. Such a decline could result in an increased risk of transmission of infectious agents across the mucosa and probably contributes to delayed wound healing in oral tissues with aging.

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Sensory and Motor Functioning

The high density of sensory nerve endings in the craniofacial tissues and their functional abilities are well-preserved in aging. There may be minor increases in threshold detection levels or in judgments of intensity, but, for the most part, sensory cells can turn over or have a built-in reserve capacity that allows for near-optimal functioning in aging. The exception is olfaction, which declines in both men and women with age. This decrement in smell may lead to some dissatisfaction with how foods taste and increased use of flavor enhancers to compensate. But for most people, the ability to enjoy food is not appreciably diminished as time goes by. Any dramatic change in sensory function—complaints of a continued unpleasant taste or smell or the sudden complete loss of a sensory modality—should be taken seriously as a sign of possible oral or systemic disease or a side effect of medication and not dismissed as a natural by-product of aging.

The distribution of motor fibers in the craniofacial tissues is also abundant and sufficiently fine-tuned to allow for a full range of movement of the tongue, jaws, and oral-facial muscles. There is some loss of muscle tone in aging, along with changes in tongue shape and function in articulating specific speech sounds. Subtle changes may also occur in preparing food for swallowing. As with sensory changes, these developments do not seriously interfere with motor function in healthy older adults.

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The Salivary Glands

Studies of normative aging indicate that individuals vary in the quantity of "whole" saliva they produce. Whole saliva consists of the secretions of the various salivary glands plus other oral contents, such as cells shed from the mucosa. These individual patterns are consistent across the life span. In healthy adults, there is no diminution in the production of saliva from the major salivary glands in the course of aging.

This constancy may seem surprising given the morphological changes documented in aging salivary glands. Both the parotid and the submandibular glands lose between 20 and 30 percent of their essential tissue volume in the course of aging. The loss primarily affects the acinar components, the cells that secrete saliva. Increases in the number of ductal cells and in fat, vascular, and connective tissues compensate for this loss, however—evidence of the remarkable functional reserve capacity of the glands, which enables them to maintain a stable salivary output across the life span (Baum 1986).

In contrast, studies of age-related changes in the chemistry of salivary secretions suggest that there are significant reductions in the concentration of mucins from the submandibular gland (Navazesh et al. 1992), which could result in reduced lubrication and contribute to a sensation of mouth dryness. There are also subtle changes in the protective ability of salivary secretory IgA antibody (Smith et al. 1987).

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FINDINGS

Natural selection has served Homo sapiens well in evolving a craniofacial complex with remarkable functions and abilities to adapt, enabling the organism to meet the challenges of an ever-changing environment. An examination of the various tissues reveals elaborate designs that have evolved to serve the basic needs and functions of a complex mammal as well as those that are uniqely human, such as speech. The rich distribution of nerves, muscles, and blood vessels in the region as well as extensive endocrine and immune system connections is an indication of the vital role of the craniofacial complex in adaptation and survival over a long life span. In particular,

  • Genes controlling the basic patterning and segmental organization of human development, and specifically the craniofacial complex, are highly conserved in nature. Mutated genes affecting human development have counterparts in many simpler organisms.

  • There is considerable reserve capacity or redundancy in the cells and tissues of the craniofacial complex, so that if they are properly cared for, the structures should function well over a lifetime.

  • The salivary glands and saliva subserve tasting and digestive functions and also participate in the mucosal immune system, a main line of defense against pathogens, irritants, and toxins.

  • Salivary components protect and maintain oral tissues through antimicrobial components, buffering agents, and a process by which dental enamel can be remineralized.

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REFERENCES

 

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Bhaskar SN. Maxilla and mandible (alveolar process). In: Bhaskar SN, editor. Orban's oral histology and embryology. St. Louis (MO): Mosby Year Book; 1991. p. 239-59.

Bhaskar SN, Orban BJ. Orban's oral histology and embryology. 11th ed. St. Louis (MO): Mosby Year Book; 1990. Chapter 1, Development of the face and oral cavity.

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This page last updated: March 07, 2014