Selectively preventing development of third molars in rats using electrosurgical energy
ANTHONY R. SILVESTRI JR., D.M.D.,
RAYMOND J. CONNOLLY, Ph.D. and
MARK T. HIGGINS, B.S.
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ABSTRACT
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Background. Third molars are teeth with questionable value. People who never develop third molars avoid confronting the disease and pain these teeth often cause. Since third molars do not begin to develop until children are approximately five years of age, a window of opportunity exists to therapeutically prevent this tooth’s development. The dentition of neonate rats possess developmental stages of molars similar to that of five-year-old children. This pilot study tests the hypothesis that third molars can be selectively prevented from developing.
Methods. Thirty-three neonate rats received a momentary pulse of electrosurgical energy to one of their maxillary tuberosities. The tuberosities on the contralateral sides received no treatment. Intraoral and radiographic examinations of sacrificed animals occurred when they were between 47 and 52 days old. Several tuberosity areas from sacrificed animals underwent histologic examination.
Results. Ten rats showed no intraoral or radiographic evidence of third molar development, and six developed smaller-than-normal third molars. Development of the maxilla also was affected frequently. One treated tuberosity area that was missing a third molar showed no histologic evidence of tooth-forming tissues, cyst formation or other significant abnormal tissue changes.
Conclusions. Maxillary third molars can be selectively prevented from developing in rat pups at or near the time of tooth bud initiation; however, electrosurgical energy is too powerful and uncontrollable to reliably confine its damage to only the tooth-forming tissues.
Clinical Implications. Third molars may be able to be selectively prevented from developing in growing children near the time of tooth bud initiation if less-differentiated precursor tooth-forming tissues can be selectively targeted.
The third molar is a tooth of questionable value in 21st-century humans and one that causes pain, suffering and expense to millions of people worldwide every year.1 A clinical dilemma arises for dentists who are trying to manage the oral health of patients who develop third molars. If dentists recommend prophylactic extraction early in the patients’ lives before any signs or symptoms of disease are present, the patients face the physical and emotional trauma of surgical extraction, as well as the risks and morbidity associated with surgery. If dentists do not recommend prophylactic extraction, patients face an uncertain future, with the possibility of pain and disease from this tooth2–4 and the likelihood that if extraction becomes necessary, the surgical removal will occur with a greater morbidity.5,6 In spite of a 1979 National Institutes of Health, or NIH, conference that addressed the management of the third molar and the clinical dilemma that it poses to clinicians and their patients, evidence suggests clinicians have not reached a consensus of agreement on how best to manage this tooth.7,8
Maxillary third molars can be selectively prevented from developing in rat pups at or near the time of tooth bud initiation.
Few novel therapeutic solutions have been proposed to address the problems caused by third molars. Enucleating uncalcified third molars in children aged 7 to 9 years old was proposed in 1936 by Henry9 and was practiced for a period by Ricketts and colleagues10,11 in an attempt to reduce the surgical morbidity from extraction. In this procedure, the third molar is enucleated in a surgical procedure before calcification of the crown is complete and when the developing tooth is located in its crypt just below the surface of bone. Although evidence suggests that there may be reduced morbidity compared with extraction at later ages,12 the procedure still is surgically invasive, removes considerable tissue mass, has a moderate amount of surgical morbidity and can be traumatic for the patient. The 1979 NIH conference concluded that enucleating third molars is not considered an acceptable practice.13
Several authors have recognized that some teeth like third molars pose a problem for people and have conducted experiments on animals to inhibit tooth development using minimally invasive techniques with potential clinical application in mind. In 1966, Selinger and colleagues14 injected the sclerosing agent sodium tetradecyl sulfate into the developing premolars of 8- to 10-week-old mongrel dogs. In 1971 and 1972, Mehlisch and Tolman15,16 injected the same sclerosing agent into several developing dental follicles in rhesus monkeys. All of the treated teeth in each study were in developmental stages significantly beyond tooth bud initiation, were well below the bone surface and required the drilling of bone over the crypt to deliver the sclerosing agent. Each study successfully achieved varying degrees of tooth development inhibition.
Since third molars have no other molars developing distal to them, successfully stopping third molars from forming cannot interfere with the development of any tooth posterior to them.
In 1979, Gordon and Laskin17 recognized the potential benefits of avoiding the trauma associated with the surgical removal of impacted teeth and studied the effects of local hypothermia on odontogenesis in premolars of mongrel dogs. They used small 1.5 millimeter-diameter cryoprobes to deliver temperatures as low as –40 to –140 C to the developing teeth near the time when the hard tooth tissue was forming. Their work also targeted a tooth developmental stage at which significant tooth tissues already had formed and the follicle itself was well below the surface of bone.
In humans, third molar development occurs entirely after birth, with tooth bud initiation occurring at approximately 5 years of age.18 From birth to the time of third molar tooth bud initiation, children have no third molars. The epithelial and mesenchymal third molar anlage that is essential for third molar tooth bud initiation is microscopic, is located posteriorly in the mouth just several millimeters below the surface of the oral mucosa and is at or near the surface of bone.19 A permanent molar requires the distal backward extension of epithelial dental lamina emerging from the tissues of developing teeth mesial to it to begin tooth bud initiation.20 Since third molars have no other molars developing distal to them, successfully stopping third molars from forming cannot interfere with the development of any tooth posterior to them. In addition, since third molar tooth bud initiation does not occur until 4 to 5 years of age, the crowns of permanent second molars are nearly completely calcified and buried deep within their bony crypts.21 It is at this time in a child’s dental development that third molar tooth bud initiation begins. The dental laminae for third molars at this stage are located immediately occlusal and posterior to second molars just beneath the oral mucosa and at or near the surface of bone,22 awaiting the genetic signal to begin initiation of tooth bud formation. There is, therefore, an opportunity during the dentition’s development to intercept third molar development before the biomolecular signal for initiation is given and at the developmental time at which no third molar tooth tissue yet exists.
Rats have a molar developmental pattern that is similar to that of humans. Rats’ third molars begin tooth bud initiation shortly after birth, with early tooth bud initiation occurring within the first few days of life.23,24 Rats have three molars in each quadrant of their mouths that develop sequentially, with first molars developing first and third molars developing last. No molars develop distal to the third molars, and no molars develop at a later age. When third molar tooth bud initiation begins in the rat, the second molar is well on its way to forming and is located within its bony crypt with its crown nearly calcified (Figure 1
). Like in humans, rats’ second molars and third molars appear to develop from the distal extension of the dental lamina emerging from the tooth mesial to it. As a result of these developmental similarities, there is a tooth developmental stage seen in rats’ third molars near birth nearly parallel to that in 4- to 5-year-old children. For humans and rats at this dental developmental stage, the epithelial cells of the dental lamina and mesenchymal cells of developing bone lie in close proximity to the developing second molar just below the oral mucosa, awaiting the molecular signal to initiate tooth bud formation. Our study targeted only the maxillary third molar area since the maxillary tuberosity region is more readily accessible compared with the mandibular ramus region in the tiny rat pup mouth.
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Figure 1. Diagram of longitudinal section of rat pup jaws shortly after birth showing developmental stage of molars similar to that of a child at approximately 5 years of age. First molars, or M1, and second molars, or M2, have developmental stages in which their crowns are nearly fully formed within their bony crypts, while the third molar has yet to develop. The dental lamina for the initiation of the third molar, or M3 DL, is lying distal to the second molar, near the surface of the developing bone, just fractions of millimeters below the surface of the oral mucosa. Adapted with permission of the publisher from Byers and colleagues.24
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This study tested the hypothesis that third molars can be selectively prevented from developing in the rat animal model using electro-surgery at approximately the time when tooth bud initiation is occurring.
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MATERIALS AND METHODS
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Thirty-three edentulous neonate Sprague-Dawley rat pups received a single, unilateral, momentary pulse of monopolar electrosurgical energy to one of their maxillary tuberosity regions via a 30-gauge, stainless steel electrosurgical probe inserted into a custom-made, prefabricated, plastic intraoral positioning device. The contralateral sides of the pups’ mouths received no treatment and were the control. Sixteen 3-day-old, six 5-day-old and 11 10-day-old rat pups received treatment. We fabricated the insulating plastic positioning devices that housed the electrosurgical probes before actual treatment using the mouths of euthanized rat pups of the same age as the rats that were to be treated. The cutting tip of the electrosurgical probe extended beyond the insulated plastic positioning device to target only the most distal aspect of the tuberosity area of the maxilla. The stainless steel tip of the electrosurgical probe extended less than 1 mm beyond the plastic positioning device to ensure contact with the oral mucosa of the maxillary tuberosity. Clipping the grounding wire of the electrosurgical unit to gauze saturated with conduction fluid and laying the rat pups on the gauze during treatment grounded the animals. The rat pups received inhalation anesthesia until they were motionless via isolation in a closed vessel for approximately one minute. We placed the prefabricated positioning device into the animals’ mouths and secured it in place by gently holding the animals’ jaws together. The activated cutting tip of an electrosurgery unit momentarily touched the 30-gauge stainless steel probe of the positioning device extending outside the pups’ mouths to deliver a 90-watt pulse of energy to the tuberosity region. After treatment, the pups recovered on a heating pad and reunited with their nursing mother rats.
Thirty-three edentulous neonate rat pups received a single, unilateral, momentary pulse of monopolar electrosurgical energy to one of their maxillary tuberosity regions.
The pups received continuous care from their mother rats until they were weaned at approximately 30 days of age. The rats lived in standard caged housing using a 12-hour–light/12-hour–dark cycle with food and water provided ad lib throughout the experimental period. The animals received carbon dioxide inhalation euthanasia when they were between 47 and 52 days old, which is an age several weeks older than the date at which third molars normally erupt. After the rats were sacrificed, we dissected them for gross intraoral and radiographic examinations. If a third molar was present, we compared its size with the third molar on the same animal’s contralateral untreated control side.
We chose two euthanized rats with vastly differing maxillary development to evaluate histologically. One rat had no third molar on its treated side and a nearly normal tuberosity and maxillary development, while the other rat had no third molar and marked palatal asymmetry with accompanying facial deformity. We took tissue specimens of these rats from the tuberosity regions on their treated sides (in the area distal to the second molar in which no third molar development had occurred) and had these tissue specimens examined for evidence of third molar development and cyst formation. Additionally, we had these tissue samples of the treated sides compared histologically with a tissue sample taken from the tuberosity region distal to a third molar on a control side of one of the rats. Histologic sections were made through the frontal plane at 500-micrometer intervals, stained with hematoxylin and eosin, and evaluated by Pathology Associates, Advance, N.C.
Sixteen of 30 rats demonstrated clinical and radiographic differences in third molar development on their treated sides compared with their untreated sides.
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RESULTS
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Thirty of the 33 rat pups survived the experimental period. None died while under anesthesia, and all of the pups appeared healthy and to be nursing 24 hours after they returned to the mother rats. Three rats subsequently died for unknown reasons. Fourteen rats showed no apparent effects from the electrosurgery treatment (Figure 2). Sixteen rats demonstrated clinical and radiographic differences in third molar development on their treated sides compared with their untreated sides. Ten of these rats did not develop third molars on their treated sides (Figure 3), while the remaining six rats had noticeably smaller third molars on their treated sides (Figure 4, page 1402). The table shows the results of the clinical and radiographic examinations and the ages of the rats when they were treated.
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Figure 2. A. Intraoral view of adult rat with a normal-sized maxillary third molar on treated right side (arrow N). The untreated maxillary left side shows a normal-sized third molar (arrow U). B. Radiograph of adult rat with a normal-sized maxillary third molar on treated right side (arrow N). The untreated maxillary left side shows a normal-sized third molar (arrow U).
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Figure 3. A. Intraoral view of adult rat with missing maxillary third molar on treated right side (arrow M). The untreated left side shows a normal-sized maxillary third molar (arrow U). B. Radiograph of adult rat with missing maxillary third molar on treated right side (arrow M). The untreated left side shows a normal-sized maxillary third molar (arrow U).
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Figure 4. A. Intraoral view of adult rat with smaller maxillary third molar on treated right side (arrow S). Untreated left side shows a normal-sized maxillary third molar (arrow U). B. Radiograph of adult rat with smaller maxillary third molar on treated right side (arrow S). Untreated left side shows a normal-sized maxillary third molar (arrow U).
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The electrosurgical treatment also affected the rats’ palatal development. Only two rats missing third molars appeared to have nearly normal development of their palates (Figure 3
). We observed two general types of palatal developmental changes in the other rats. One type affected only the local topography of the tuberosity region. The other affected its overall symmetry, especially noticeable in the area of the rugae. The two types of palatal deformities often occurred independently of one another; some animals had changes only in the area of the tuberosity, while other animals had changes that were only reflected by the asymmetry of the rugae. Some animals possessed both types of palatal deformity.
Only two rats missing third molars appeared to have nearly normal development of their palates.
The histologic evaluation of the tissue specimen taken from the tuberosity region distal to the third molar on the untreated control side showed some local gingival inflammation, but otherwise it appeared normal (Figure 5, page 1403). The histologic evaluation of the tissue sample taken from the tuberosity region distal to the second molar of a treated side with a missing third molar and nearly normal maxillary development revealed no evidence of third molar tissues, cyst formation or abnormal tissue changes (Figure 6, page 1403). The histologic evaluation of the tissue sample taken from the tuberosity region distal to the second molar of the treated side of the animal that had severe maxillary growth disturbance, rugae asymmetry and facial deformity revealed no evidence of third molar tissues or cyst formation. It did, however, show other marked degenerative tissue changes (Figure 7, page 1404).
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Figure 5. Frontal section of tissue specimen taken 500 micrometers distal to a maxillary third molar on an untreated control side in the tuberosity region (hematoxylin and eosin stain, magnification x4). The appearance of the oral epithelium, or OE; connective tissue, or CT; and bone, or B, are normal.
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Figure 6. Frontal section of tissue specimen taken 500 micrometers distal to a maxillary right second molar on a treated side in the tuberosity region (hematoxylin and eosin stain, magnification x4). This animal possessed no clinically or radiographically apparent third molar development and had a nearly normal-appearing maxilla. No tooth tissues, cyst formation or other abnormal tissue changes were seen. The appearance of the oral epithelium, or OE; connective tissue, or CT; and bone, or B, are normal.
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Figure 7. Frontal section tissue specimen taken 500 micrometers distal to a maxillary right second molar on a treated side in the tuberosity region (hematoxylin and eosin stain, magnification x4). This animal possessed no clinically or radiographically apparent third molar development but had severe maxillary growth disturbance and facial asymmetry. Note the abnormal tissue changes and tissue topography compared with an untreated control side (Figure 5). OE: Oral epithelium. CT: Connective tissue. B: Bone. G: Glandular tissue. ND: Nasal duct.
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DISCUSSION
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Selectively preventing third molar development without detrimentally affecting other developing tissues such as the jawbone and nearby teeth is a challenging goal, especially in the tiny rat pup mouth where other critical developing tissues lie in close proximity to one another. The teratogenic agent must target selectively and specifically only the distally migrating dental lamina, the biomolecular events of the interaction between the dental lamina with highly specific jaw mesenchyme, or the earliest developing stages of tooth bud initiation. Otherwise, damage to other developing tissues will occur. When undesirable growth disturbances on the developing maxilla occurred, the electrosurgical energy likely had damaged developing bone. The wide range of developmental effects on the jaw most likely were due to the inability to control and limit the application of the electrosurgical energy specifically to the developing tissues of the third molar.
In a typical clinical setting, an electrosurgical unit is minimally invasive and highly controlled. Its effects are derived by damaging tissues with heat. The energy concentrated at the cutting tip causes an explosive rapid temperature rise in the cells closest to the tip, and a slower, lower temperature rise as its current passes deeper through the tissues.25 The cellular effects from the electrosurgical energy range from pyrolysis and vaporization at temperatures of more than 100 C to cell wall damage, DNA and RNA denaturation, and enzyme deactivation at temperatures closer to 60 C. When the tissue being removed is large enough to be seen by the operator and when the tissue is at a safe distance from other vulnerable tissues, the effects of electrosurgery can be very local and precise.
However, when electrosurgical energy is applied near the invisible tooth anlage in the tiny mouth of newborn rats, the effects of the electrosurgical energy cannot be nearly as local or precise. The embryonic tooth-forming tissues of the third molar lie fractions of a millimeter below the oral mucosa26 and cannot be seen. As a result, it was not possible to predictably protect and isolate the vulnerable developing bone from the energy and heat of the electrosurgical energy. The result was a relatively large, unpredictable area of tissue damage during treatment and a wide range of bony developmental effects seen after the rats were euthanized.
In the 14 treated rats that developed third molars and showed no effects from the treatment, the electrosurgical energy may have missed its intended third molar target and any developing tissues. In the two rats that developed no third molars and showed no apparent clinical or radiographic signs of damage to the maxilla, the treatment appears to have affected the intended tooth-forming tissues without damaging its bony surroundings significantly. In the six animals with smaller-than-normal third molars, electrosurgical energy may have caused partial ablation of tooth-forming tissues or may have acted as a thermal teratogen, altering normal embryologic tooth development by slightly elevating their temperatures. Temperature increases of as little as 1.5 to 2.5 C may cause teratogenic effects on developing tissues.27
The maxillary tuberosity is an active site for growth for the maxilla.28 Minor damage to this site during treatment could explain the local topographical changes observed in that region. The rats that displayed asymmetry of their palates, especially that evident in the area of the rugae, likely sustained more extensive damage to the developing bone during treatment. Unilateral electrosurgical treatment of these animals appears to have altered the degree of displacement growth of the treated side compared with the displacement growth of the untreated side.
Selectively prevented third molar development in the rats occurred with little to no observable collateral destructive tissue effects to the developing bone in several of the animals. The difficulty of targeting only the microscopic epithelial and mesenchymal anlage of the tooth-forming tissues without also detrimentally affecting surrounding developing tissues such as bone also was illustrated, as many of the animals that were missing third molars also possessed abnormal maxillary development to a greater or lesser extent. The key factor in selectively stopping third molar development is limiting teratogenic effects to only the developing tissues of the third molar, and the nonselective, invasive electrosurgical energy used in the study was not able to accomplish it predictably without frequent collateral damage.
For humans, a successful methodology to prevent third molar development near the time of tooth bud initiation must be not only highly selective but also minimally invasive or noninvasive, atraumatic and relatively easy to apply. That two test animals displayed a nearly ideal result—completely eliminating the third molar development without grossly disturbing the development of the maxilla—offers hope that selective agenesis might be achievable using a less invasive, more selective teratogen. However, the fact that only limited success occurred in some of the test animals—either a third molar merely reduced in size or a missing third molar accompanied by some degree of deformity of the maxilla—points out some of the difficulties that will be encountered in achieving a clinically acceptable therapeutic result in humans and some of the dangers associated with it.
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CONCLUSIONS
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A momentary pulse of electrosurgical energy can selectively stop the development of the third molars in neonate rat pups without cyst formation or other significant tissue changes. However, growth disturbances to the developing maxilla will occur if the energy is not confined to the anlage of the third molar or the developing tooth bud itself. In the rat animal model, electrosurgical energy is too powerful and indiscriminant in its tissue destruction to ablate tooth-forming tissues selectively without causing other unpredictable and undesirable collateral growth disturbances.
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FOOTNOTES
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Dr. Silvestri is a clinical professor and the director, Dental Anatomy, Tufts University School of Dental Medicine, Department of Restorative Dentistry, One Kneeland St., Boston, Mass. 02111, e-mail "anthony. silvestri_jr{at}tufts.edu". Address reprint requests to Dr. Silvestri.
Dr. Connolly is an associate professor, Tufts University School of Medicine, and the director, Surgical Research Laboratory, Tufts-New England Medical Center, Boston.
Mr. Higgins was a research assistant, Surgical Research Laboratory, Tufts-New England Medical Center, Boston, when this article was written. He now is specialty sales representative, Boehringer Ingelhein, Ridgefield, Conn.
This study was funded in part through a grant from the Kiwanis Pediatric Trauma Institute, Floating Hospital for Children, Tufts-New England Medical Center, Boston.
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ABSTRACT
MATERIALS AND METHODS
