Animal models in periodontics

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1. ANIMAL MODELS IN PERIODONTICS ã INTRODUCTION ã NEED FOR THE ANIMAL MODELS ã LIMITATIONS OF ANIMAL MODELS ã CLASSIFICATION ã VARIOUS ANIMAL MODELS ã…
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  • 1. ANIMAL MODELS IN PERIODONTICS • INTRODUCTION • NEED FOR THE ANIMAL MODELS • LIMITATIONS OF ANIMAL MODELS • CLASSIFICATION • VARIOUS ANIMAL MODELS • CONCLUSION • REFERENCES INRODUCTION To achieve an understandining of the life process, animals are experimented since long. This may be about the animals themselves, their physiology, their diseases and their treatment or behavior. Much of the knowledge is sought in the hope that it may be applicable to humans. In the field of periodontics, the first report appears to be that of Talbott (1899), who described periodontitis in mongrel dogs. For over hundred years, periodontal diseases have been studied in many species and a wealth of dependable data about periodontitis in species other than human exists. NEED FOR THE ANIMAL MODELS 1. For ethical reasons, initiation and progression of periodontal disease as well as certain types of periodontal treatment cannot be studied in humans. Animal data can provide us with models of biologic trends before proceeding to human application. 2. Human periodontal disease is extremely difficult to study. The number of cultivable bacterial species in subgingival plaque exceeds 300, and the technical and conceptual problems involved in finding the etiologic agents among these 1
  • 2. species are enormous. This inability to examine initiation and progression of Periodontal Disease has led to a great interest in the use of animal models in periodontal research. Human longitudinal studies of periodontal disease pose many problems such as determining the level of disease activity, individuals at risk, and susceptibility of disease progression. 3. Furthermore, periodontal disease can only be studied retrospectively in man, since reliable clinical markers for ongoing tissue destruction (disease activity) are not available. Therefore, an animal model in which selected microbiological and immunological parameters can be studied prospectively is desirable. 4. Animal models have been used to evaluate various periodontal treatment modalities like regenerative procedures like bone grafts and GTR, and implant surgical procedures to study their safety and efficacy. 5. Eventhough, there are computer models and cell cultures, as well as other adjunct research methods, these methods are used to screen and determine the toxic potential of a substance in the early stages of investigation. The final test, however, has to be done in a whole, living system. Even the most sophisticated technology cannot mimic the complicated interactions among cells, tissues and organs that occur in humans and animals. Scientists must understand these interactions before introducing a new treatment or substance into humans. 6. There are striking similarities between the physiological systems of humans and various species of animals. For example, much of what we know about the immune system has come from studies with mice, and much of what we know about the cardiovascular system has come from studies with dogs. 7. Research results from animals also provide the information necessary to design human trials that must be completed for legal approval of new devices, drugs or procedures. It is important to be able to gauge how a new drug or procedure will affect a whole biological system before using it on humans. This is critical for scientific as well as ethical reasons. Laboratory animals are an integral part of the research process. In fact, virtually every major medical advance of the last century is due, in part, to research with animals. LIMITATIONS OF ANIMAL MODELS 2
  • 3. 1. Animal research and its value to human experience remain controversial. Regardless of how much data can be presented, it is, a priorly, impossible to expect different species to respond identically or even similarly to the same challenge except within very narrow limits. 2. There are very strong economic incentives to replace animals with computers or other adjunct methods. Research animals are very expensive to acquire and care for and are only used because no alternatives currently exist. 3. Features of periodontal diseases in humans and animals vary greatly depending upon which form of the disease is present and the stage of the development. 4. Genetic background of many of the animals has not been established. 5. Animals used in research are often wild-captured animals, with heterogeneity in age, body weight and oral and general health conditions. CLASSIFICATION I] Small and inexpensive rodents Eg: Mice, Rats, Hamsters, Minks. II] Larger animals Eg: Dogs and sheep. III] Non-Human primates- Eg: Baboon, Macaque, Chimpanzee and Gorilla IV] Various other species include Apes, Cats, Horses, Guinea pigs, Hogs, Mongooses, Wolves, Foxes, Rabbits, Ferret etc. ANIMAL MODELS The most convincing animal model would be one in which all aspects of the disease are analogous to periodontitis in human. The data make abundantly clear that while many of the manifestations of periodontal diseases in humans are observed to some degree in other species and no analog of human diseases exists. Varieties of mammals have been studied in the search for satisfactory animal models. MICE 3
  • 4. Mice represent the primary species used in research, comprising 67% of all animals used in biomedical research and testing. Today, the laboratory mouse is recognized as the preeminent model for modern genetic research. Advantages 1. Small size and short life span. 2. Proclivity for reproduction 3. Known age and genetic background. 4. Controllable microflora, resistance to other diseases. 5. Minimal expense for purchase and maintenance has made them a desirable animal model.  They have typical rodent dentition with the formula I 1/1, C 0/0, Pm 0/0, M 3/3.  The periodontal tissues of the continuously growing incisors are rarely affected by periodontitis. Only the molar tissues are commonly affected, bone loss, and abundant amounts of microbial plaque, including filamentous organisms were seen at about 10 weeks of age.  As soon as functional occlusion is attained, the crown is being worn down with relative rapidity because of the enamel free areas on the cusps. To compensate for the occlusal wear, there is a gradual deposition of cellular cementum at the apical end of each tooth, which keeps the teeth in occlusion. The formation of cellular cementum is so pronounced in the mature molar, that there is a distinct hypercementosis at each root tip.  The direction of eruption is bucco-occlusal. Accommodating this eruption, the buccal plate undergoes resorption along the periodontal surface, and opposition along the periosteal surface of lingual plate and along the fundus of the alveolus. Also, the junctional epithelium shifts apically onto the root surface with age. Consequently, the distance between the crest of the alveolus and the CEJ increases, particularly at the lingual and palatal aspects of the mouse molars. Bear et al 1964 using periodontal disease resistant germ free mice and found that above mentioned bone changes are due to physiologic changes and not due to periodontal disease. The distance between the CEJ and the alveolar bone crest, while increasing with age, was always about twice as long on the lingual aspects of the molars as on the buccal. It is apparent that periodontitis had not developed upto 1 year. It was only in very old animals, 365-450 days, that periodontitis appeared and even then with only moderate bone loss and irregular, shallow pocketing. 4
  • 5.  Some strains are relatively resistant to periodontitis DBA/2JN, C57L/ HeN and Swis albino BNL mouse is highly resistant to periodontitis.  In some strain A/LN, A/HeN the periodontal lesions were related to massive hair impaction in to the sulcus  Only two strains STR/N, BRSUNT/N developed periodontitis regularly.  Grey lethal mouse strain seems to have genetic susceptibility to periodontal disease. RATS (Rattus norveigicus): Normal oral structure and physiology and pathogenesis of periodontal diseases have been studied more extensively in rat than in any other rodent. PERIODONTAL FEATURES OF THE RAT Periodontal Anatomy and Physiology Rats have 1 set of teeth consisting of 1 incisor that is rootless and 3 molars in each quadrant (I 1/1, C 0/0, Pm 0/0, M 3/3). The incisors are rootless, continuously growing teeth and, therefore, unsuitable as models for human periodontal disease. In contrast, the structure and organization of the periodontal tissues of the molars (oral gingival epithelium, oral sulcular epithelium, junctional epithelium, periodontal collagen fibres, acellular and cellular cementum, and alveolar bone) are very similar in rats and humans. The only major difference is that the gingival sulcular epithelium of the rat is keratinized. Theoretically, this tissue structure could interfere with the movement of bacterial metabolites into the gingival connective tissue, thereby preventing the initiation of an inflammatory response. However, recent studies have shown that material placed in the gingival sulcus swiftly enters the connective tissue via the junctional epithelium. Thus, there is no reason to believe that the gingival barrier function is fundamentally different in rat and man, although the extent of the affected area may be greater in man. Keratinization could also affect the adhesion of certain bacteria to the epithelium, but experiments have shown that a substantial number of periodontal pathogens are able to colonize the dentogingival area of rats as well as humans. Therefore, it seems unwarranted to discard the rat model because of the keratinized sulcular epithelium. Usually, all molars are fully erupted when the rats are 5 weeks old. After that time a slow passive eruption is reported in relation to attrition of the occlusal surfaces of the teeth. With age, as interproximal attrition proceeds, the molars also drift occlusal-distal- buccal direction and the junctional epithelium in the apical direction, which in the normal course of aging covers coronal portions of the root cementum in germ free as 5
  • 6. well as in conventional rats. Concurrently the interdental bone is narrowed. Along with this migration of the teeth, the alveolar bone is continuously being remodeled. The distance between the cemento-enamel junction (CEJ) and alveolar bone crest (ABC) remains constant on buccal surfaces in rats without periodontal disease, whereas an age- dependent physiological increase in the distance can be observed in some lingual and palatal sites. In order to avoid confounding of the results by such physiological bone remodeling processes, it is crucial that all rats in a periodontitis experiment are of similar age. Pathogenesis of Periodontal Disease The most frequently used inbred strains of rats include the Wistar albino, Lewis, Norwegian grey, Rice, Wistar, CD and CDF- Fisher 344 (fairly disease resistant) and several strains of Sprague-Dawley rat. The most frequently used rat strain in periodontitis studies is the Sprague-Dawley strain, but other strains have also been used successfully. It seems probable that rat strains may differ with respect to susceptibility to periodontitis, but no experimental data are available on the subject. Periodontal disease may develop in rats in relation to indigenous plaque, to experimentally introduced microorganisms, or to experimentally introduced bacterial products. In rats, however, periodontal destruction occurs rapidly without ligatures, and there is no reason to add a traumatic lesion to the bacterially induced lesion in the rat model. The immunological status of the host at the time of introduction of periodontal pathogens is important for the development of periodontitis. The clinical and histological findings in experimental periodontal disease in rats are similar to findings in man. Clinically, gingival bleeding upon gentle probing can be seen in rats a few days after the introduction of periodontal pathogens. Histologically, the junctional epithelium gradually undergoes pathologic changes, including rete peg formation, ulceration, and apical migration of epithelial attachment. An inflammatory cell infiltrate containing T and B-lymphocytes, macrophages, and polymorphonuclear leukocytes (PMN) appears in the connective tissue, and PMNs migrate through the epithelium into the gingival sulcus. Plasma cells can be inconspicuous in early stages of the disease, but with time they become very prominent. Damage to collagen fibers and fibroblast also occurs. Periodontal bone loss occurs rapidly in rats. Significant bone destruction has been reported 42 days after inoculation, and the lesions progress considerably between 60 and 90 days after infection; experiments are rarely extended 6
  • 7. beyond 100 days. Occasionally, bone loss may occur without apical migration of junctional epithelium and loss of connective tissue attachment. One of the most striking characteristics of the rat periodontium is the heavy impaction of hair and feeding material that may occur in both germ-free and infected rats. Impaction of foreign material seems closely related to loss of bone and attachment. It may be local contributing factor; they act as a syringe effect providing direct pathway for bacteria and their metabolites to reach deep portions of the soft periodontal tissues. A higher frequency and greater severity of abnormality was noted in mandible than in maxilla HAMSTERS  Hamsters account for 0.6% (approximately 500,000 used per year) of the total number of animals used in research annually. There are more than 15 species of hamsters, but the one used most frequently in biomedical research is the Syrian (golden) hamster, Mesocricetus auratus.  Hamsters have the same teeth formula as rats (I 1/1, C 0/0, Pm 0/0, M 3/3) with a continuously erupting incisor and can open their mouths almost 180 degrees wide (Navia 1977).  The molars differ form those of rats and mice in that their crowns are completely covered by enamel and the apical half of the molar roots has more dentin core and less cellular cementum than in the rat. These differences imply that hamster molars are less subject to occlusal wear and may continue their eruption to a lesser degree that does the rat molars.  Hamsters there is molar shifting similar to that occurring in rats and mice, resulting in an age-related change of the topographical relationship between the teeth and their sockets, i.e., an increasing distance between the teeth and their sockets, i.e., an increasing distance between the CEJ and the alveolar bone crest, particularly on the palatal and lingual side of the molars.  Hamsters have been used to demonstrate the transmissibility of periodontal disease with plaque develop is similar to rats in that there is primarily gingival retraction with horizontal bone loss, the interdental septum being too narrow to induce infrabony defects. Inflammation is not a prominent feature, as it is seen in humans.  In the hamster, periodontal disease is a result of experimental and highly artificial conditions and, in general, it does not seem to occur in animals living in a natural habitat. Albino hamsters remain essentially disease-free while the golden and cream- 7
  • 8. colored hamsters develop spontaneous periodontal disease when fed a high carbohydrate diet (King & Rowles 1955). They naturally harbor an infectious agent capable of inducing the disease when experimental conditions are favorable. The disease can be induced in non-infected albinos by inoculating subgingival plaque from affected hamsters, and can be transmitted from generation to generation (Keys & Jordan 1964). Subepithelial inflammatory response characteristic of human gingivitis has not been identified for periodontal disease in the hamster.  Hamsters have been used primarily for caries research due to the capability of the cariogenic microorganisms to form profuse amount of plaque and quickly develop carious lesions. Actinomyces viscosus is prominent bacteria in diseased hamsters.  Hamsters do not exhibit the wide spectrum of spontaneous overt and latent diseases common to rats and mice. Their good general health, their susceptibility to induced disease conditions, the low cost of production and maintenance, and literature available on the biology and physiology of these species make them useful animal models. In conclusion, periodontal disease in the hamster resembles in type, features, and pathogenicity very much what has been observed in the rat. MINKS  The dentition of the adult mink is typical of the order Carnivora and is represented by the formula I 3/3, C 1/1, Pm 3/3, M 1/2. Characteristic dental features of mink include the presence of diastema distal to the maxillary third incisors, which accommodate the mandibular canines when the jaws are closed and unusually large maxillary third premolars and mandibular first molars. The vestibule of the upper jaw is deep and has a wide band of attached gingival anteriorly which gradually narrows posteriorly; the upper lip is flexible. The lower lip is firmly attached near the gingival margins at the mandibular incisors, canines and premolars, so that there is a very shallow vestibule and the band of gingiva is less than 1mm wide. However, the vestibular depth and the zone of attached gingival in the third premolar and molar regions are comparable to those of the upper jaw. Severe abrasion and numerous tooth fractures, probably associated with cage chewing, are often noted. Frequently, the palatal surface of the maxillary canines and the occlusal surfaces of the maxillary and mandibular first and second premolars are worn away to the gingival margin. Exposing the pulps. 8
  • 9.  The alveolar crest around the posterior teeth is almost level with the closely approximates the CEJs. The interdental contour of the alveolar crest in the posterior segment of the maxilla is usually flat, while in the mandible the crest rises to a slight peak between the premolars and molars. The alveolar margin of the mandibular canines and third incisors is slightly scalloped, but towards the midline it tapers to create a V-shaped groove between the central incisors. The pulp chambers come very close to the occlusal surfaces of the teeth and slight amounts of tooth wear result in exposure, pulpal death and periapical lesions.  Minks exhibit variety of periodontal alterations extending from a clinically normal appearance to one of massive inflammation of the marginal and attached gingiva with tooth exfoliation. Minks many times carry Chediak Higashi Syndrome (C-HS), a genetically transmitted autosomal trait. Minks with C-HS develop early-onset periodontitis at approximately the age of sexual maturity and the disease progresses rapidly to tooth exfoliation. Some C-HS minks present clinical manifestations of disease so extensive that they cannot be quantitatively assessed. Occasionally, the animals lose all of their teeth except for a few root tips.  Only very mild manifestations of PDS disease are seen in normal animals even at 5-6 years of age, whereas advanced lesions with tooth exfoliation are observed in the animals with C-HS even at young age.  In both normal and affected minks, bone resorption seems to be age-related. There is no evidence of bone loss in either group at age 6 months, and the normal animals generally remain free of manifestations of bone loss at 18 months. There is a considerable inter-animal and inter-tooth variation in the extent of bone loss in normal animals. In both groups of animals, the debris and inflammation scores are highest for the maxillary premolars and lowest for the incisors, canines, and molars. In normal animals, there is a strong and positive correlation between debris scores and inflammation scores (r = 0.95), whereas these values do not correlate for animals in the C-HS group (r = 0.45). These data indicate that factors other than plaque accu
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