Animal models

Presented by:
Shashwati Paul
II Year PG
Dept. of Periodontology

 Introduction
 Definition
 History
 Need for animal models
 Categories of animal models
 Classification
 Model selection
 Species selection
 Animal models used in periodontal research
 Advantages in periodontal research
 Limitations in periodontal studies
 Controversies
 The 3R Principle
 Arrive guidelines
 Criteria for humane death
 Conclusion
 References
CONTENTS


INTRODUCTION
 In the 1920s, “experimental epidemiology” meant the study of
epidemics among colonies of experimental animals such as rats and
mice.
 In modern usage, experimental epidemiology is often equated with
randomized controlled trials.

The aims of experimental studies may be stated as follows :
 a) to provide “scientific proof” of etiological (or risk) factors which may
permit the modification or control of those diseases
 b) to provide a method of measuring the effectiveness and efficiency of
health services for the prevention, control and treatment of disease and to
improve the health of the community.

1.In Vitro study-Lab specimens.
2.In Vivo study -Animal models
-Human beings
 Throughout history animals have played an important role in men’s quest
for knowledge about himself and the environment.
 Animal studies have contributed to our knowledge of anatomy, physiology,
pathology, microbiology, immunology, genetics, chemotherapy and so
many others.

 Weggler in 1983 defined an animal model as a living organism with an
inherited, naturally acquired, or induced pathological process that in one or
more respects closely resembles the same phenomenon in men.
 The institute of laboratory animal resources(ILAR) of the NationalAcademy
of Sciences adopted and modified Weggler’s definition as follows:
An animal model is a living organism in which normative biology or behaviour
can be studied, or in which a spontaneous or induced pathological process can
be investigated, and in which the phenomenon in one or more respects
resembles the same phenomenon in humans or other species of animal.
DEFINITION


History:
 Earliest reference.. Greeks (2nd /4th centuries BC)
 Galen (2nd century Rome)..father of vivisection.
 Insulin..from dogs (1922), revolutionized the treatment of diabetes.
 1957, Laika..
 Dolly …1996..cloned adult cell..
 Thalidomide tragedy.. toxicology studies


Major advances in basic research that
depended on animal experiments
1600's - Function of the lungs, Measurement of blood pressure.
1800's – Vaccination, Understanding of infectious diseases
1900's - Antibodies, hormones
1930's - Mechanism of nerve impulses, tumor viruses.
1940's - Embryonic development


1960's - Monoclonal antibodies, liver functions
1970's - Transplantation antigens, brain functions, Discovery of prostaglandins
1980's - Development of transgenic animals
1990's - Understanding auto-immune disorders, In vitro fertilization, cloning
Major advances in basic research that
depended on animal experiments


 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.
 Inability to examine initiation and progression of periodontal diseases 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.
NEED FOR THE ANIMAL MODELS

 Periodontal diseases 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.
 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

 Though, 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.
 It is important to be able to test 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.


 INDUCED / EXPERIMENTAL MODELS
 SPONTANEOUS / NATURAL MODELS
 NEGATIVE / NON REACTIVE MODELS
 ORPHAN MODELS
(Davidson et al 1987)
CATEGORIES OF ANIMAL MODELS


CLASSIFICATION
(Page &Schroeder 1982)
I] Small rodents
E. g: Mice, Rats, Hamsters, Minks.
II] Larger animals
E. g: Dogs and sheep.
III] Non-Human primates
E. g: Baboon, Macaca, Chimpanzee and Gorilla
IV] Others
E. g: Apes, Cats, Horses, Guinea pigs, Mongooses, Wolves, Foxes,
Rabbits, Ferret etc.


 1) appropriateness as an analog,
 2) transferability of information,
 3) genetic uniformity of organisms, where applicable,
 4) background knowledge of biological properties,
 5) cost and availability,
 6) generalizability of the results,
 7) ease of and adaptability to experimental manipulation,
 8) ecological consequences, and
 9) ethical implications
CRITERIA FOR SELECTION OF ANIMAL
MODELS


CONSIDERATIONS FOR SPECIES
SELECTION:
 Availability of laboratory facilities
 Presence of a breeding colony
 Cost
 Ease of handling
 Ease of housing
 Relatedness to humans
 Limitations imposed by the size of oral structures
 Availability of appropriately sized periodontal instrument


ANIMAL MODELS USED IN
PERIODONTAL RESEARCH


RATS
 Physiological changes in the dentition occur throughout the life span of the rodent.
 Rats have 1 set of teeth consisting of 1 incisor that is rootless and 3 molars in each
quadrant (Navia 1977).
 There is rapid wear of the occlusal surfaces with continuous eruption of the teeth
and apposition of cementum and bone.
 This causes progressive changes in tooth position, especially the molars which
continuously move in an occlusal-distal-buccal direction.
 Most histologic features of the epithelium and connective tissue in the rat are
similar to humans except for the sulcular epithelium which is keratinized
(Listgarten 1975).

 When gnotobiotic rats were infected with a gram-negative anaerobic
rod(A. actinomycetemcomitans) isolated from a localized juvenile
periodontitis patient (Irving et al.1975) or Eikenella corrodens
(Listgarten et al. 1978), plaque adhering to the tooth surface was not
formed.
 Once initiated, bone resorption occurred continuously rather than
sporadically as in humans.
 Lesions induced by gram-negative bacteria showed minimal
inflammation.


 Gnotobiotic rats of the Spraque-Dawley strain have been used to
demonstrate the ability of various filamentous bacteria to form plaque and
induce periodontal disease in the absence of other bacteria (Socransky et al.
1970).
 Several gram-positive species isolated from the human oral cavity were used
as mono contaminants in rats, causing periodontal destruction.
 These species included Actinomyces viscosus, Actinomyces israelii,
Streptococcus mutans (Klausen et al. 1986, Crawford et al. 1978) and
Actinomyces naeslundii (Garant 1976).

 The connective tissue infiltrate contained primarily neutrophils, few lymphocytes, no plasma
cells.
 Thus, the destructive process in response to gram negative bacteria can occur in absence of a
cell-mediated immune response (Irving & Socransky 1974), which is not similar to humans.
 Calculus formation can be studied in different strains of rats where diet seems to be the most
consistent factor (Baer et al. 1961).
 Rats fed on a sucrose-rich diet developed a rapid proliferation and overgrowth of bacteria
plaque, mainly gram-positive, covering the molar fissures, the interdental spaces and the
marginal gingiva. This ultimately resulted in gingival pockets.

 Lab rat, although an acceptable model for studying calculus and caries, has
limitations as a model for periodontal disease.
 Periodontal disease in rats is different from that of humans.
 After inoculation of micro-organisms into germ-free rats, periodontal
destruction occurs very rapidly, so there is no need for inducing disease with
ligatures.
 The rat is relatively resistant to periodontal disease .

Rat Ligature Model
 This has been used as a model of experimental periodontitis for over 40
years. (Rovin S et al, J Periodontal Res 1966; Kenworthy R et al, J Clin
Periodontol 1981; Weiner GS et al, J Periodontol 1979; Samejima Y et al, J
Periodontal Res 1990; Bezerra MM et al, J Periodontol 2000; Liu R et al, J
Dent Res. 2006).
 The placement of a silk or cotton ligature around the tooth facilitates
plaque accumulation. In germ free rats placement of the ligatures does not
induce significant gingival inflammation or periodontal bone loss.


 Topical treatment with chlorhexidine reduces bone resorption and
antibiotics reduce both loss of attachment and loss of bone, supporting the
role of bacteria in initiating destruction in this model.
 In contrast, increasing Gram-negative bacterial burden enhances
osteoclastogenesis and bone resorption and inhibitors of a host
inflammatory response decrease periodontal destruction.


ADVANTAGES
 This model can be adapted to study bone formation and
resorption separately.
 The tissue is well adapted for histologic analysis although the
area of analysis is restricted to the mesial aspect of interdental
bone due to slow but continuous distal drift of the maxillary
molars.

LIMITATIONS
 Isolation of bone is difficult, limiting the use of the model.
 The number of genetically modified rats is limited. The delivery of etiologic agents to
initiate the disease process cannot be precisely controlled. While one can control the
challenge, the difficulty in quantifying the infection has limited the use of this model.
 This model has limited usefulness in studying bacterial colonization and natural
mechanisms of infectivity since infection is facilitated by the ligature.


Oral Infection Model
 In this model, normal rats are orally infected on multiple occasions
to establish colonization. This has been accomplished with a range
of human oral bacteria, principally P gingivalis and Aa.
 Depending upon the specific model and questions being asked,
evaluation can take place from 1-3 months after oral infection.
(Sasaki et al, J Periodontal Res. 2004; Kawai et al, Oral Microbiol
Immunol 2007 In press; Kesavalu et al, Infect. Immun. 2007).

ADVANTAGES
 This infection model allows study of immune cell responses, local
gingival tissue responses, and bone resorption. There is markedly
increased periodontal bone resorption in infected rats.
 This model may be adapted to study colonization or infectivity. However,
the results need to be interpreted with caution since the impact of
introducing a bacterium to the normal flora may not be simple and one
cannot assume that the introduced bacterium is responsible for the
pathologic changes i.e. the introduced bacterium could indirectly cause
pathogenesis by modifying the biofilm.

This model may be used to study host-bacteria interactions in the periodontium
and bone resorption.
LIMITATIONS
 This model does not allow isolation of the immune components. There is
limited ability to isolate the individual immune cell contributions to
periodontal bone resorption compared to the murine models.


LPS-induced alveolar bone resorption
 This model has been recently employed in the laboratory of Dr. Keith
Kirkwood (Kirkwood et al, J Pharmacol Exp Ther 2007; Rogers et al,
J Perio, 2007).
 They have established a model of aggressive inflammatory alveolar
bone loss in rats using LPS derived from a periodontal pathogen Aa
delivered orally three times a week.
 Bone resorption has been quantitivately measured. The bone loss is
observed within 8 weeks.


 This model is easily reproducible.
 Controlled delivery of LPS results in readily demonstrable bone loss and
exhibits many features of human periodontal pathology e.g. bone
resorption
 The model is useful in studying LPS-host interactions in the periodontium
and bone resorption.


LIMITATIONS
 This is not an infectious, chronic model but an inflammatory induced
bone loss model. At this point only Aa LPS has been tested in this
model.


MICE
 Mice have been studied but periodontal disease is very different to that
observed in humans.
 The dental formula of mice is typical rodent dentition: I 1/1, C 0/0, Pm 0/0,
M 3/3.
 Incisors have continuous growth and molars present complex physiological
modifications with ageing. There is occlusal wear, bucco-occlusal motion
and hypercementosis at the apical part of each root.
 Cementum is deposited on the apical third of the root. 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.


 Gilmore and Glickman (1959) suggested, that with age, the rate of bone
apposition at the alveolar crest does not keep pace with occlusal
eruption of the tooth.
 The healthy and diseased periodontium of the mouse has been studied
in a large number of strains, most of which were highly inbred.
 Out of the many strains populating the natural habitat, only two strains
of the mouse (Peromyscus maniculatus and Peromyscus Oreas) have
been examined, and used only briefly.
 Furthermore, Baer and Bernick (1957) and Baer and Lieberman (1959)
demonstrated clearly the occlusal wear and the elongation of the
maxillary molar roots, due to marked apposition of cellular cementum.


 Periodontal alterations are characterized by bone loss which is more severe at
the lingual and palatal sides of the molars than at the buccal sides. There is also
the presence of crater-like defects at the interdental and interradicular spaces.
 However, periodontal disease does not appear in mice younger than one year.
The inflammatory response is relatively poor.
 The extensive physiological alterations in molar position in the alveolar socket
over time mean that mice are not the best model for studying natural or
induced periodontal disease.


HAMSTERS
 Hamsters have the same teeth formula as rats with a continuously erupting
incisor and can open their mouths almost 180 degrees wide (Navia 1977).
 Hamsters have been used to demonstrate the transmissibility of periodontal
disease with plaque bacteria (Jordan & Keyes 1964).
 The type of periodontal disease hamsters 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 in humans.
 Albino hamsters remain essentially disease-free while the golden and cream-
colored hamsters develop spontaneous periodontal disease when fed a high
carbohydrate diet (King & Rowles 1955).


 The disease can be induced in non-infected albinos by
inoculating subgingival plaque from affected hamsters, and can
be transmitted from generation to generation (Keyes & Jordan
1964).
 Subepithelial inflammatory response characteristic of human
gingivitis, has not been identified for periodontal disease in the
hamster.


 When a cariogenic streptococci strain was inoculated with a plaque-
producing filament, the hamsters developed both caries and extensive
periodontal disease.
 This is of special interest because the 2 diseases, caries and periodontal
disease, could be evaluated in vivo at the same time (Jordan & Keyes 1964)

 Miniature pigs have oral and maxillofacial structures similar to those of
humans in terms of anatomy, physiology, and disease development.
 The Minnesota miniature pig (minipig) was developed about 60 years
ago and has been used extensively in biomedical research.
 After the age of 6 months, minipigs usually develop gingivitis,
manifested by inflamed gingival tissue, accumulated plaque and calculus,
and bleeding when probed.
.
MINIATURE PIGS


 There is infiltration of inflammatory cells in the gingival tissue that
results in progression to severe periodontal inflammation at 16 months
of age with identical histopathology to that seen in humans.
 Periodontitis in minipigs is promoted in about 4–8 weeks using
ligatures, and in association with bacterial inoculations of P.gingivalis,
S. mutans, and A. actinomycetemcomitans.
 Minipigs can be suitable for periodontal as well as orofacial
investigations.
 However, minipigs are relatively expensive, with husbandry issues
and few studies to support their use


DOGS
 Permanent teeth of the dog consists of 3 incisors, 1 canine, 4 premolars and 3
molars in the mandible and 2 molars in the maxilla (Navia 1977).
 In view of their natural susceptibility to periodontal disease, dogs, particularly
beagles, are used in dental research for the study of periodontal disease
progression, guided tissue regeneration, tissue wound healing, and dental
implants.

 Dogs maintained plaque free by repeated scalings and meticulous
plaque control can develop clinically healthy gingiva.
 The etiologic factors of periodontal disease seem to be identical in
humans and dogs (Attstrőm et al. 1975, Ericsson et al. 1975, Gad 1968).
 Dogs may therefore be of value as a model for experimental gingivitis.
 The fact that it is possible to maintain periodontal health in sites where
plaque accumulation was prevented confirms similar reports in humans
(Lindhe & Nyman 1975, Theilade & Attström 1985).

 Originally, it was reported that periodontal disease began slowly in
young dogs and increased with age (Gad 1968), progressing about 5x
faster in dogs than humans (Ericsson et al. 1975).
 Later, it was documented that the range and severity of gingivitis and
periodontitis varied in both young and older dogs and that gingivitis in
younger dogs did not necessarily progress into periodontitis (Hull 1974).
 Gingival recession is an outstanding feature in dogs with periodontitis
(Ericsson et al. 1975).

 Differences exist between dog and man in the location of the inflammatory
infiltrate in early gingivitis.
 In the dog, the initial infiltrate located in the marginal part of the gingiva,
proceeds along the junctional epithelium leaving the connective tissue in a
relatively normal state.
 In healthy dogs kept plaque free for prolonged periods of time, a gingival
sulcus is not evident, but a pocket develops with the onset of gingivitis
(Lindhe & Rylander 1975).
 Gingivitis did not necessarily progress into periodontitis. (Lindhe et al.
1975).

 It has been demonstrated that induced gingivitis in young beagle dogs can
progress into periodontitis, simply by allowing additional plaque to accumulate
(Soames & Davies 1980).
 This process can be accelerated by the placement of ligatures (Lindhe &
Ericsson 1978).
 Histologic features are characteristic of an advanced lesion, with the majority of
tissue destruction occurring within the 1st 4 weeks following ligature placement
(Schroeder & Lindhe 1975).
 Class II and III furcations may be found in the beagle dog.
 Wikesjo et al. (1994) was able to create the same ligature-induced intrabony
defects demonstrated in monkeys by Caton et al. 1976, 1994.

 This was done by surgically removing alveolar bone around the
circumference of mandibular premolars Wikesjő et al. 1994.
 Variations in attachment loss between adjacent surfaces make it difficult
to document the presurgical size of the defect and to evaluate the
postsurgical healing response (Selvig, 1994).
 A much faster bone turnover rate, and a different architecture and
thickness of bone limit the suitability of dogs for regenerative studies
(Giannobile et al. 1994).

 Early implant research utilized dogs, as well as rats, hamster, guinea pigs,
rabbits and cats to explore the pathophysiology of tissue injury and repair.
 Osseointegration was demonstrated in various parts of the animal skeleton
when titanium fixtures were placed Branemark 1983.
 Even though dogs have been used most frequently due to their size and the
simple morphology of the roots, there are differences in the distances of the
anterior and posterior teeth relative to the point of mandibular articulation.
 Furthermore, eating movements consisting of biting and grasping plays
different functional demands on the bone (Navia 1977).

 Although the features of gingivitis and periodontitis lesions in dogs closely
resemble those in humans, there are still differences.
 Inflammatory lesions in dogs begin in the most coronal portion of the
connective tissue at the gingival margin, rather than lateral and apical to the
base of the gingival sulcus as in humans.
 With increasing severity of gingivitis, the entire thickness of the marginal
gingiva is involved and not just the tissue lateral to the gingival pocket wall
(Matsson & Attstrőm 1979).
 Limitations of the use of a canine model includes great inter-animal variability,
expense, limited number of bony defects available and faster bone formation
(Giannobile et al. 1994).


FERRETS
 Ferrets were thought to be first domesticated by the Egyptians to
control rodents around 1300 B.C.
 The dentition, wear patterns, calculus formation, salivary glands, and
periodontal lesion of the ferret have been studied, although not to the
extent of the previously-discussed species.
 The domestic ferret (Mustela putorius furo) is believed to have been
derived from the wild (European) polecat (Fox 1988).

 Use of the domestic ferret as an animal study model in periodontics
was originally described in the 1940s by King et al., who documented
that the occurrence of periodontal disease in ferrets was similar to
that occurring in humans (King 1954).
 The ferret has both a deciduous and a permanent dentition. The
permanent dentition consists of incisors, canine, 2nd, 3rd and 4th
premolar and first and 2nd molar (Berkovitz & Silverstone 1969).


 Ferrets have been used as a medical and dental model. Harper et al.
(1990) and Mann et al. (1990) have found ferrets to be a suitable
model for the study of calculus.
 Calculus in ferrets has a physical structure similar to hydroxyapatite.
 The main difference between the ferret and human calculus is a
lesser degree of calcification in the ferret deposits.
 Diet did influence the rate of formation, but not as much as in rats.
 Calculus in ferrets can be scored while the animal is alive, whereas
this is not possible in rats (Harper et al. 1990).


 The course of the periodontal lesion follows a similar path as in humans.
 The tissues responded by characteristic inflammatory reactions, which are
identical in all respects to those found in human gingivitis (King & Gimson
1947).
 Ferrets can develop periodontitis in ligature induced sites and lost 50-75% of
attachment, and lesions exhibited large populations of PMNs adjacent to the
ligatures.


 Plasma cells and lymphocytes were observed apical to the lesions.
 The ferret is a suitable model for the study of calculus because of its
resemblance to human calculus and the fact that formation of calculus
is not diet dependent as in the rat and hamster.
 Further research is still needed to ascertain the role of ferrets as a
model in the pathogenesis of periodontal disease.


 Rabbits have been used in periodontal tissue regeneration studies for
the testing of biomaterials (El-Bokle et al., 1993) or for evaluating the
treatment of peri-implantitis (Struillou et al., 2010).
 Rabbits do not exhibit the spontaneous form of PD, so the disease has
to be induced.
 Moreover, this is a poorly standardized model with respect to relevant
aspects of PD pathogenesis (Hasturk et al., 2007).
RABBITS


 Sheep present a natural form of periodontitis called ‘broken mouth’
(Duncan et al., 2003).
 The periodontium, oral microflora associated with PD and the bone
metabolism in sheep are similar to those of humans (Genco et al.,
1998).
 The publications using this model describe it as a suitable model for
training surgical methods and for guided tissue regeneration research
(Danesh-Meyer et al., 1997; Al-Qareer et al., 2004).
 However, its size, cost and handling demands, as well as the
challenging diagnosis of PD as a result of poor access to posterior
teeth, are disadvantages (Genco et al., 1998; Duncan et al., 2003).
SHEEP


NON-HUMAN PRIMATES
 In designing any medical or dental animal study, it is often advantageous to
select an animal that is phylogenetically similar to humans.
 The wide range of non-human primate species allows appropriate selection
for different investigations.
 Each species has unique similarities and dissimilarities to humans.


 Non-human primates have similar oral structures to humans and have
naturally occurring dental plaque, calculus and gingivitis, but small
increase in pocket depths.
 The majority of non-human primates have similar deciduous and
permanent dental formulas as man with closely related dental anatomy,
although the size of teeth are dramatically smaller.

 Clinically, healthy monkey gingiva is histologically indistinguishable from human gingiva.
 A shift in the composition of plaque flora from an early gingivitis to a later stage is also
comparable to humans (Krygier et al. 1973,Schou et al. 1993).
 The inflammatory infiltrate associated with periodontal disease is microscopically similar to
humans in some species such as the cynomolgus monkeys (Macaca fascicularis), but the
squirrel monkeys (Saimiri sciureus) and marmosets have limited numbers of lymphocytes and
plasma cells, making them inappropriate models for studying pathogenesis of periodontitis.
(Shou et al. 1993, Brecx et al. 1985, Kornman et al. 1981a,Listgarten & Ellegaard 1973, Page &
Schroeder 1982, Page et al. 1972).


 Monkeys have been used widely as an animal model for studying
periodontal surgical procedures.
 Large non-human primates have a naturally occurring periodontitis, but
it occurs later in life and the lesions are asymmetrical (Caton et al. 1994).
 Therefore, if osseous lesions are needed for clinical studies, they are
usually experimentally induced.

 Similar dental anatomy, periodontal wound healing (Caton & Kowalski 1976), suitability
of furcation sites (Giannoble et al. 1994) and experimentally induced defects that do not
spontaneously regenerate, make mature adult rhesus (Macaca mulatta) species good
models for studying ligature-induced periodontitis.
 Periodontal lesions in these animals are also suitable for evaluating periodontal
regenerative procedures (Shou et al.1993), especially since histometric analysis needed to
quantify the amount of new cementum, periodontal ligament and alveolar bone formed as
the result of regenerative periodontal surgery (Caton et al. 1994), can only be done with
animals, usually monkeys or dogs.

 In the original non-human primate model described by Caton & Kowalski (1976),
experimentally-induced periodontal disease was created with elastic ligatures that
were removed after 3–6 months. Thereafter, Caton et al.(1994) described 3 types of
experimentally-induced periodontal lesions.
 The acute defect model required surgical removal of bone, cementum and
periodontal ligament to create the defect where spontaneous regeneration of the
defects occurs.
 The chronic defect model, required the placement of orthodontic elastics around the
circumference of teeth to create defects which may take up to 6 months to produce,
with deep defects found more likely in proximal sites than on the facial and lingual
surfaces.

 The acute/chronic defect model also creates defects surgically. These defects
enter a chronic inflammatory state by placement of stainless steel bands into
the defects and plaque retentive ligatures.
 Due to the possibility of obtaining block biopsies, the rhesus monkey, and
baboons have been used to study osseointegrated oral implants.
 A study (Fritz et al.1997) suggested that ligature-induced periodontitis around
teeth and ligature-induced peri-implantitis follow similar destructive patterns

 Although various species of non-human primates are adequate for studying
different aspects of periodontal diseases, monkeys are expensive to purchase
and maintain and are ferocious.
 Wild captured monkeys can be disease carriers.
 Monkeys are also prone to systemic infections and diseases, and pose
difficulties in controlling post-surgical infections and trauma.


MACACA
 Johnson and his co-workers have assessed the nature of the inflammatory cell
infiltrate in connective tissues at various stages of spontaneously developing
gingivitis in M.fascicularis as well as in animals whose teeth were cleaned and
chlorhexidine applied for 3 weeks and then left to accumulate plaque.
 The composition of the inflammatory infiltrate in the gingival tissues of young
M.fascicularis allowed to accumulate plaque was assessed (Johnson and Hopps,
1975).
 Biopsy specimens were harvested at various times for upto 243 days after the
beginning of plaque accumulation and from older animals allowed to collect
plaque for 3 years.

 The clinical and histopathologic features of plaque induced gingivitis in
M.mulatta were studied by Listgarten and Ellegaard (1973).
 In the animals on the tooth cleaning regimen, inflammatory cells
continued to be present in most of the biopsy specimens, although their
numbers fluctuated.
 Leukocytes in the area of the infiltrate and neutrophils in the junctional
epithelium both increase in number.


MARMOSETS
 Gingivitis and periodontitis have been studied extensively in wild caught and
colony maintained marmosets.
 Early reports indicated that marmosets do get chronic periodontitis.
 That the prevalence is high and that the lesions closely resemble those seen in
humans.
 More extensive studies were later done on wild caught and colony maintained
animals (Page et al, 1971, 1972; Levy 1971).


CHIMPANZEES
 Gingivitis closely resembled that seen in humans, with neutrophils present in the
junctional epithelium and the gingival vessels, along with an infiltrate comprising
mostly plasma cells and lymphocytes (Arnold and Baram, 1973).
 Pathologically altered fibroblasts were present within the infiltrated connective
tissue. In an animal of 8 years of age, severe periodontitis resulting in tooth
exfoliation and confined to the first molars and incisors was observed (Page et al
1975).


 Unlike chronic periodontitis in humans, which takes more time, in the
rats the disease progresses to a chronic destruction of soft and hard
tissue within a few weeks.
 Transcortical drilled holes creating tibial or radial critical-sized
femoral defects are traditionally the most commonly used models in
rabbits
ADVANTAGES OF ANIMAL MODELS IN


 Rats and mice are useful for understanding some aspects of the host-
microbe interaction and therapies. The rat model has been utilized by
numerous investigators to study bone healing and consequently, the
healing response under a variety of conditions is well documented.
 The dogs is susceptible to periodontal disease and the jaws are large
enough for the use of standard type of implants in designated areas.


 The frequent lack of gingival sulci and crevicular fluid, a different
composition of periodontal plaque and calculus are important
differences between dog and humans.
 Though periodontitis in in primates most closely resembles the human
disease, the expense of and special husbandry requirements limit their
use in periodontal studies.
LIMITATIONS OF ANIMAL MODELS IN


 Minipigs can be suitable for investigation, but are relatively
expensive, and few studies for their support for use.
 The extent and localization of periodontal lesions are not always
synchronized in dogs.


 The use of animals for research and testing purposes has decreased substantially
during the last two decades but is now increasing again, mainly because of the
increased use of transgenic animal models.
 Presently, 10-12 millions of vertebrate animals are used per year within EU
Member States.
 Scientists who are using animals in research are frequently criticized by animal
protection groups and blamed that they do not respect the integrity of an animal's
life.
 A study of 20 reviews of animal tests’ accuracy found that only two concluded
that the animal tests were consistent with the human findings or had contributed
significantly to developing new treatments.
 The animal activists do not appreciate the use of animals in biological studies.
They are equating cruelty to animals committed by animal experiments
conducted for scientific investigations.
CONTROVERSIES


 REPLACEMENT
 REDUCTION
 REFINEMENT
(RUSSEL AND BURCH,1959)
THE “3 Rs” OF ANIMAL RESEARCH


 Death without signs of panic, pain or distress.
 Minimum time to loss of consciousness.
 Safety for personnel involved
 Minimal undesirable physiological and psychological effect on animal
 Minimal or no emotional effects on the observer and the operator
 A location remote from animal rooms
CRITERIA FOR A HUMANE DEATH


 No genuine analogue of the various forms of human periodontitis
exists in animals.
 A gold standard animal model in periodontology does not exist since
every application requires a model that fills specific needs.
 Experimental models for periodontal diseases are essential for
understanding the origin and evolution of the pathology in humans.
 The use of animal models in periodontal research is a necessary step
prior to entering into clinical trials with new biomaterials and
treatments.
 The anatomy, physiology and pathogenicity of experimental models
should relate as much as possible to those of patients in order to
demonstrate the safety and efficacy of new biomaterials or treatments
in periodontal regeneration.
CONCLUSION


 Amit Bhardwaj, Shalu V. Bhardwaj Contribution of Animal Models in
Periodontal Research IJAVMS, Vol. 6, Issue 3, 2012: 150-157
 Xavier Struillou, Hervé Boutigny, Assem Soueidan, and Pierre
Layrolle,E xperimental Animal Models in Periodontology: A Review
The Open Dentistry Journal, 2010, 4, 37-47
 Carlos Albuquerque, Francisco Morinha, João Requicha,Teresa
Martins, Isabel Dias Canine periodontitis: The dog as an important
model for periodontal studiesique .
 Guedes-Pinto , Estela Bastos, Carlos Viegas The Veterinary Journal
191 (2012) 299–305
REFERENCES


 Ashwini Ashok Apine and Shiva Prasad BM. Current Status of Animal
Experimentation in the Study of Periodontal Diseases and Therapeutics.
Research and Reviews: Journal of Dental Sciences
 George Hajishengallisa, Richard J Lamontb & Dana T Graves The enduring
importance of animal models in understanding periodontal disease
 The ARRIVE guidelines Animal Research: Reporting In Vivo Experiments
Carol Kilkenny, William J Browne, Innes C Cuthill, Michael Emerson4 and
Douglas G Altman
 Helieh S. Oz and David A. Puleo Animal Models for Periodontal Disease
 Amit Arvind Agrawal Considerations For Use Of Experimental Animals In
Biomedical And Periodontal Research

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