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Animal Models in Periodontal Research: Insights into Disease Pathogenesis and Therapeutic Strategies
1Senior Lecturer, Department of Periodontology, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, Karnataka, India.
2Department of Periodontology, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, Karnataka, India
3Department of Periodontology, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, Karnataka, India
4Department of Periodontology, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, Karnataka, India
5Department of Prosthodontics, JSS Dental College and Hospital, Sri Shivarathreeshwara Nagara, Mysore, Karnataka, India
6Department of Prosthodontics, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, Karnataka, India
*Corresponding Author:
Senior Lecturer, Department of Periodontology, Dayananda Sagar College of Dental Sciences, Shavige Malleshwara Hills, Kumaraswamy Layout, Bangalore, Karnataka, India., Email: sravanikodur@dscds.edu.in
Abstract
Periodontitis is a chronic inflammatory disease initiated by microbial accumulation on tooth surfaces, leading to the destruction of root cementum, periodontal ligament, gingiva, and alveolar bone, resulting in various intraosseous defects. It is influenced not only by microbial infection but also by host susceptibility. Clinical manifestations include gingival inflammation, tooth-supporting structure breakdown, tooth mobility, and ultimately tooth loss. Moreover, periodontitis is associated with systemic conditions such as cardiovascular disease, rheumatoid arthritis, and adverse pregnancy outcomes. Control measures include scaling, root planing, and rigorous oral hygiene practices. The primary goal of periodontal treatment is to regenerate lost periodontal tissues through non-surgical or surgical methods, local drug delivery, guided tissue regeneration using biomaterials, bone substitutes, and advanced techniques. Animal models play a critical role in testing these treatments for safety and efficacy before human application. Various species including rats, hamsters, ferrets, pigs, dogs, and rabbits are used to induce periodontal disease and evaluate therapeutic strategies. Each species presents distinct advantages and challenges, offering valuable insights into periodontal pathogenesis and treatment efficacy. This article provides a comprehensive review of animal models in periodontal research, emphasizing their anatomical resemblances to humans, genetic and physiological characteristics, ease of handling, and ethical considerations. These models facilitate controlled experiments that yield valuable insights into periodontal health and disease mechanisms. However, differences in physiology and ethical concerns necessitate careful interpretation and application of findings to clinical practice.
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Introduction
Periodontitis is an inflammatory disease elicited by microbial accumulations on tooth surfaces and characterized by destruction of root cementum, periodontal ligament, gingiva and alveolar bone, resulting in a variety of intraosseous defects of various architectures.1 Periodontitis is induced not only by microbial infection but could also be linked to the host’s susceptibility to the opposing effects of periodontal disease.2 The clinical signs of periodontal disease include inflammation of gingival tissues, breakdown of the tooth-supporting structures, loosening of teeth and finally loss of tooth. Furthermore, periodontitis has been associated with systemic conditions, like cardiovascular complications, rheumatoid arthritis, and unfavourable pregnancy outcomes.3,4,5 To halt the progression of periodontal disease, scaling and root planing are typically performed in conjunction with strict adherence to oral hygiene practices. The ultimate goal of periodontal therapy is to regenerate the lost periodontal tissues through non-surgical or surgical approaches, local drug delivery systems, guided tissue regeneration using biomaterials, bone substitutes, or other advanced techniques.⁶ Before being approved for use in humans, all drugs and treatment methods must undergo thorough safety testing. Animal models play a crucial role in this process, serving as a valuable platform for evaluating the safety and efficacy of new treatments.⁷ They have been instrumental in advancing our understanding of biological sciences, particularly in the field of periodontology.8,9
The most frequently used animals for inducing and treating periodontal diseases are rats, hamsters, ferrets, pigs, dogs and rabbits. First, animals are intentionally induced with the disease, after which the new treatments are tested on them to observe their effects. Nonetheless, it is crucial to handle these models with great care due to ethical considerations.10,11
Types of Animal Models Used in Periodontal Research
Animal models have significantly contributed to advancing knowledge in biological sciences, including the field of periodontology. In these models, periodontal disease may arise spontaneously or be experimentally induced to replicate human disease conditions. A range of animal species has been utilized to explore periodontitis's pathogenesis and assess the efficacy of various therapeutic interventions.12
Non-human primates
The smallest non-human primate species, like marmo-sets, typically weigh between 300 and 355 grams, while the largest species, such as chimps and gorillas, can weigh up to 1,000 kilograms. All of these species are diphyodont, meaning they have two sets of teeth. Their teeth and roots share similar anatomy with humans, albeit scaled down in size in marmosets. Canines are elongated and prehensile in many non-human primates. Gorillas and baboons possess premolars with multiple roots. Monkeys share phylogenetic similarities with humans, which gives them a unique advantage. However, certain species of non-human primates develop periodontal disease upon reaching adulthood.13 Spontaneous perio-dontal disease presents considerable risks to rhesus monkeys, cynomolgus monkeys, and baboons. The histological structure of the periodontium clearly demonstrates these effects.14
Dogs
Periodontal diseases in dogs closely resemble those in humans, with gingival recession being a prominent feature in dogs affected by periodontitis.15 There are notable differences in the microbiota between humans and dogs. In beagle dogs, the subgingival microbiota is mainly composed of a high proportion of gram-negative bacteria. Unlike humans, there is an increase in catalase-positive Prevotella species during disease.16 Dog models, especially beagles, are widely used in dental research to conduct clinical surgical trials in periodontology. Over a hundred studies have utilized canine models to inves-tigate periodontal healing, focusing on the use of various biomaterials, membranes, and enamel matrix derivatives. A notable surgical model introduced by Wikesjö in 1994 involved creating critical-sized supra-alveolar defects each 6 mm in size at the mandibular premolar region. These class III furcation defects allowed researchers to evaluate different regenerative procedures, both with and without the use of grafting materials.¹⁷⁻²¹
Rats
The gingival structure of rats bears close resemblance to that of humans.22 Despite these similarities, differences exist, including variations in crevicular epithelium keratinization and the association between gingival and junctional epithelia, characterized by desmosome contacts between superficial cells of the gingival epithelium and non-keratinized cells in the junctional epithelium.23 During tooth eruption in rats, several changes occur that cause molars to move in a three-dimensional space, resulting in occlusal, distal, and buccal shifts, which differ from the occluso-mesial shift seen in human teeth. The cementoenamel junction shifts occlusally at a faster rate than alveolar bone deposition. Age-related factors and changes significantly impact research on periodontal health and experiments. Rats typically exhibit good health under natural conditions, necessitating the induction of disease for research purposes. Periodontal diseases are induced in rats by injecting pathogens such as Porphyromonas gingivalis, Streptococ-cus sobrinus, Aggregatibacter actinomycetemcomitans, Actinomyces viscosus, Fusobacterium nucleatum, Capnocytophaga, and Eikenella corrodens.24
Disease-resistant strains in periodontics are developed through methods such as ligating silk around molars, utilizing strains like Sprague-Dawley or white Lobund, or by inoculating specific bacteria.25 In the initial stages, inflammation is localized to the junctional epithelium, characterized by high activity of phagocytes and neutrophils, which serve as a defensive barrier. Acute interdental inflammation manifests as ulcerations in the junctional epithelium and neutrophil infiltration into the supraalveolar connective tissue, along with increased osteoclastic activity in 10% of animals by hundred days of age.26,27
Hamsters
Researchers have successfully demonstrated that periodontal disease can be transmitted through plaque-associated microbes in hamsters, with the golden Syrian hamster being the most commonly used species. While the histological structure of the hamster periodontium is similar to that of rats, their interdental septum is thinner due to their smaller size. Spontaneous periodontal disease has been induced in hamsters by administering a high-carbohydrate, sucrose-rich diet. This diet promotes plaque accumulation through formic acid-producing bacteria mixed with food debris, predominantly affecting the palatal surfaces rather than the buccal.28 Although hamsters exhibit a relatively limited inflammatory response that differs significantly from that in humans, the periodontal lesions and alveolar bone resorption caused by gram-positive bacteria in rats closely mirror human pathology.29 As close relatives of mice, hamsters are widely used in periodontal and cariogenic research, particularly for studying disease transmission and progression. They are especially valuable in caries research due to their susceptibility to cariogenic bacteria, which produce extensive plaque and rapidly induce carious lesions.30,31
Miniature pigs
Pigs share notable similarities with humans in terms of disease progression, anatomical structure, and physiological processes.32 The Minnesota miniature pig, in particular, has been widely employed in biomedical research.33 Typically, minipigs begin to show signs of gingivitis after six months of age, presenting with gingival inflammation, bleeding on probing, and accumulation of plaque and calculus. Experimental periodontitis can be reliably induced in minipigs within 4 to 8 weeks using bacterial inoculation combined with ligature placement.33
Ferrets
The domestic ferret is thought to have descended from the wild European polecat. Ferrets are particularly suitable for studying calculus because their calculus closely resembles human calculus and is not influenced by diet, unlike mice and hamsters. They are commonly employed in evaluating periodontal abnormalities.30,34 Ferrets possess mixed dentition.35
Rabbits
Various microorganisms have been identified in the oral cavity of rabbits, including Arcanobacteriumhaemolyticum, F.nucleatum, Prevotella species, Streptococcus milleri group, Peptostreptococcus micros, Actinomyces israelii, and Prevotella hepari-nolytica, a microbial profile that closely resembles the flora associated with periodontal disease in humans.36 To study periodontal regeneration, surgically induced periodontal defects have been created in rabbits. However, these models have shown limited suitability for replicating periodontal ligament regeneration.11,37 Periodontitis in humans typically results from local factors such as plaque and calculus, which trigger progressive inflammation and subsequent bone loss.38,39 Surgically induced defects, however, may not accurately represent the natural progression of the disease.
Advantages of animal experiments32,40
- Maintaining consistent environmental conditions in research is highly advantageous for studying genetic defects.
- Sequential induction of various environmental conditions allows for the characterization of genetic-environmental interactions.
- Animal models facilitate the generation of complex pedigrees that enhance the power of genetic analysis.
- Selective mating enables the prospective testing of genetic hypotheses.
- Animal experiments allow for the conduct of essential invasive and terminal experiments.
Limitations of animal studies32,40
- Ethical concerns regarding animal welfare and rights.
- Differences between animal and human physiology, limiting direct applicability to humans.
- High costs and time intensiveness associated with maintaining animal facilities and conducting experiments.
- Complexity in replicating genetic-environmental interactions observed in humans.
- Limited generalizability of findings due to variations in genetic backgrounds and environmental conditions.
- Potential for misinterpretation of results if experimental conditions are not rigorously controlled.
- Invasive procedures and ethical considerations related to terminal experiments.
- Regulatory constraints and compliance with animal welfare laws.
Criteria to Select Animal Models in Periodontal Research
1. Anatomical and physiological similarity: The chosen animal model should exhibit anatomical and physiological characteristics of the periodontium (gums, periodontal ligament, alveolar bone) similar to humans. This similarity ensures that experimental results can be extrapolated to human conditions.
2. Genetic and immunological characteristics: Gen-etic and immunological similarities to humans are important for understanding the underlying mechanisms of periodontal diseases and their treatment responses.
3. Ease of handling and husbandry: Practical considerations such as ease of handling, availability, and cost-effectiveness of maintaining the animals should be taken into account.
4. Ability to develop periodontal disease: The animal model should be susceptible to developing periodontal diseases spontaneously or through induction methods that mimic human conditions.
5. Compatibility with experimental methods: Compa-tibility with experimental techniques and tools used in periodontal research, such as imaging modalities, histological analysis, and biochemical assays.
6. Ethical considerations: Compliance with ethical standards for animal research, including minimizing pain and distress through appropriate anaesthesia and euthanasia protocols.
These criteria help researchers select animal models that best mimic human periodontal conditions, thereby enhancing the translational relevance of their findings to clinical practice.41,42
The article provides an extensive overview of the role of animal models in periodontal research, emphasizing their importance in understanding the pathogenesis of periodontitis and evaluating therapeutic interventions. Various animal species, including non-human primates, dogs, rats, hamsters, miniature pigs, ferrets, and rabbits, are discussed in terms of their anatomical similarities to humans and their suitability for inducing periodontal disease. Each species offers unique advantages and challenges, such as genetic and physiological similarities, ease of handling, and ethical considerations. These models enable controlled experiments that contribute valuable insights into periodontal health and disease mechanisms. However, ethical considerations and physiological differences between animals and humans highlight the need for cautious interpretation and application of findings to clinical practice.
Conflicts of interest
Nil
Funding
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Supporting File
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