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Requirements and selection of an animal model
Abstract
There are two broad classes of models: those based on analogy (similar structures imply similar functions), and those based on homology (structures derived from the same evolutionary precursor have the same or similar functions). There are four main categories of animal models: 1) induced or experimental models, that attempt to reproduce conditions found in the original species, 2) spontaneous or natural models, that are recognized as being similar to some condition in the original species, 3) negative or nonreactive models, that are the normal counterparts of a disease model, and 4) orphan models, that are animal diseases for which no human or animal counterpart is known. The selection of any model, but particularly animal models, for research should be based on the following considerations: 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. The criteria for selection or rejection of particular animal models also include customary practice within a particular discipline, the existence of diseases or conditions that might complicate results, the existing body of knowledge on the problem under consideration, and special features of the animal, such as unique responses or microflora, that may make a particular species useful.
... Again the animals basically can be classified as: small animal models and large animal models [9] ( Fig. 1) According to Davidson et al. 1987, animal models are classified into four categories: [10] Experimental model, Negative model, Spontaneous model, orphan model. (Fig. 2) ...
... Animal models selected for the research is based on various factors like the type of study, conditions unique to the animal that might complicate study, existing knowledge about condition or knowledge about unique response of the animal to study conditions. Laboratory constraints such as housing of large or non standard animals are also to be considered [10]. The selection or rejection of animal model should be based on the following criteria: Appropriateness as an analog, Transferability of information, Genetic uniformity of organisms, where applicable, Background knowledge of biological properties, Cost and availability, Generalizability of the results, Ease of and adaptability to experimental manipulation, Ecological consequences and the Ethical implications [10] (Table 1). ...
... Laboratory constraints such as housing of large or non standard animals are also to be considered [10]. The selection or rejection of animal model should be based on the following criteria: Appropriateness as an analog, Transferability of information, Genetic uniformity of organisms, where applicable, Background knowledge of biological properties, Cost and availability, Generalizability of the results, Ease of and adaptability to experimental manipulation, Ecological consequences and the Ethical implications [10] (Table 1). ...
... Conventional methods for pre-clinical modelling of human vasculature, and screening for therapeutics efficacy use animal models and 2D in vitro cell culture systems [4,10,11]. Advances in microfabrication technologies, as well as ever-present concerns regarding model organism to human translatability, and ethical considerations for in vivo animal experimentation has generated demand for sophisticated and higher throughput in vitro biomimetic test platforms [6,10,[12][13][14][15][16][17][18][19][20][21][22]. ...
... MPS models for angiogenesis, the sprouting of new blood vessels from pre-existing large vessels, and vasculogenesis, the development of nascent blood vessels from disorganized endothelial cells, are sought-after tools in vascular biological research [5,10,11,16,24]. Conventional in vivo and ex vivo assays like the retinal whole mount, and zebrafish models have served in experimental niches similar to that of in vitro MPS based vessel formation assays, as a means of functionally assaying vessel morphologies at a tissue level, but with the same limitations of in vivo experimentation [4,[12][13][14]25]. Given the foundational role of vasculature in the human body, models can range broadly from simple endothelial cell network formation assays to sophisticated models of cancer metastasis in perfusable vascularized tissues [26][27][28][29][30]. Vascular MPS models see potential applications incorporating high throughput in "pre-preclinical" drug testing, pathology modelling, vascular bio mechanistic studies, and more [10,31,32]. ...
Microfluidic organ-on-a-chip technologies have enabled construction of biomimetic physiologically and pathologically relevant models. This paper describes an injection molded microfluidic platform that utilizes a novel sequential edge-guided patterning method based on spontaneous capillary flow to realize three-dimensional co-culture models and form an array of micro-vascularized tissues (28 per 1 × 2-inch slide format). The MicroVascular Injection-Molded Plastic Array 3D Culture (MV-IMPACT) platform is fabricated by injection molding, resulting in devices that are reliable and easy to use. By patterning hydrogels containing human umbilical endothelial cells and fibroblasts in close proximity and allowing them to form vasculogenic networks, an array of perfusable vascularized micro-tissues can be formed in a highly efficient manner. The high-throughput generation of angiogenic sprouts was quantified and their uniformity was characterized. Due to its compact design (half the size of a 96-well microtiter plate), it requires small amount of reagents and cells per device. In addition, the device design is compatible with a high content imaging machine such as Yokogawa CQ-1. Furthermore, we demonstrated the potential of our platform for high-throughput phenotypic screening by testing the effect of DAPT, a chemical known to affect angiogenesis. The MV-IMPACT represent a significant improvement over our previous PDMS-based devices in terms of molding 3D co-culture conditions at much higher throughput with added reliability and robustness in obtaining vascular micro-tissues and will provide a platform for developing applications in drug screening and development.
... D614G is related to increased infectivity of cells, E484Q has been shown to increase neutralization resistance, and N501 Y has been shown to cause enhanced viral transmission. criteria (Davidson et al., 1987): They must be able to: 1) replicate life cycle of the pathogen (i.e. incubation period similar to humans); 2) Demonstrate similar symptoms as seen in humans when infected with SARS-CoV-2; 3) recapitulate the illness brought on by physiological viral dosing as seen in humans. ...
... Transduction infection of mouse with Adenovirus with hACE-2 gene (Goh et al., 2020;Hartman et al., 2020;Qiu et al., 2020) Mouse Hepatitis Virus Model* MHV virus (Coronavirus family) produces identical SARS-CoV-2/COVID19 tissue pathology and clinical symptoms compared to humans (Bailey et al., 1949;Barthold and Smith, 1983;Davidson et al., 1987;Barthold et al., 1988;Rempel et al., 2004a;Kim et al., 2020;McMahan et al., 2021;Nejat et al., 2021;Rees-Spear et al., 2021;Singh et al., 2021) Cat seroconversion is proportional to that seen in human studies and most importantly the MHV-1 model is able to be used at low cost, is highly practical, and most importantly can be studied in a Biosafety Level-2 lab setting, and provides acceptable ecological, as well as ethical consequences during experimentation. Balancing safety, mimicking human COVID-19 and robustness of the animal model, the Murine Hepatitis Virus-1 model currently represents the most suitable model for SARS-CoV-2/COVID19 research. ...
COVID-19 is the most consequential pandemic of the 21 st century. Since the earliest stage of the 2019-2020 epidemic, animal models have been useful in understanding the etiopathogenesis of SARS-CoV-2 infection and rapid development of vaccines/drugs to prevent, treat or eradicate SARS-CoV-2 infection. Early SARS-CoV-1 research using immortalized in-vitro cell lines have aided in understanding different cells and receptors needed for SARS-CoV-2 infection and, due to their ability to be easily manipulated, continue to broaden our understanding of COVID-19 disease in in-vivo models. The scientific community determined animal models as the most useful models which could demonstrate viral infection, replication, transmission, and spectrum of illness as seen in human populations. Until now, there have not been well-described animal models of SARS-CoV-2 infection although transgenic mouse models (i.e. mice with humanized ACE2 receptors with humanized receptors) have been proposed. Additionally, there are only limited facilities (Biosafety level 3 laboratories) available to contribute research to aid in eventually exterminating SARS-CoV-2 infection around the world. This review summarizes the most successful animal models of SARS-CoV-2 infection including studies in Non-Human Primates (NHPs) which were found to be susceptible to infection and transmitted the virus similarly to humans (e.g., Rhesus macaques, Cynomolgus, and African Green Monkeys), and animal models that do not require Biosafety level 3 laboratories (e.g., Mouse Hepatitis Virus models of COVID-19, Ferret model, Syrian Hamster model). Balancing safety, mimicking human COVID-19 and robustness of the animal model, the Murine Hepatitis Virus-1 Murine model currently represents the most optimal model for SARS-CoV-2/COVID19 research. Exploring future animal models will aid researchers/scientists in discovering the mechanisms of SARS-CoV-2 infection and in identifying therapies to prevent or treat COVID-19.
... Translational medicine will need to continue to rely on a fit-for-purpose selection of animal models to approximate the human condition, based on the essential characteristics that must be mimicked for a particular research question 19 . Peculiarities, strengths, and weaknesses of the model species need to be accounted for in the study design, analysis and interpretation 19,128,129 . Data from multiple animal models should be combined to optimize translational predictive validity. ...
... Inflammatory stimulation. Gene expression, proliferation and migration of tenocytes of all five species were compared under standard culture conditions (healthy control) as well as under transient (24 h) and constant exposure to inflammatory stimuli (10 ng/ml IL1β (Immuno Tools, Friesoythe, Germany) and 10 ng/ ml TNFα (Immuno Tools, Friesoythe, Germany)) as previously described 28,89,90,93,115,129 . Successful induction of inflammation was confirmed by upregulation of inflammatory markers (COX2, IL6, see results). ...
For research on tendon injury, many different animal models are utilized; however, the extent to which these species simulate the clinical condition and disease pathophysiology has not yet been critically evaluated. Considering the importance of inflammation in tendon disease, this study compared the cellular and molecular features of inflammation in tenocytes of humans and four common model species (mouse, rat, sheep, and horse). While mouse and rat tenocytes most closely equalled human tenocytes’ low proliferation capacity and the negligible effect of inflammation on proliferation, the wound closure speed of humans was best approximated by rats and horses. The overall gene expression of human tenocytes was most similar to mice under healthy, to horses under transient and to sheep under constant inflammatory conditions. Humans were best matched by mice and horses in their tendon marker and collagen expression, by horses in extracellular matrix remodelling genes, and by rats in inflammatory mediators. As no single animal model perfectly replicates the clinical condition and sufficiently emulates human tenocytes, fit-for-purpose selection of the model species for each specific research question and combination of data from multiple species will be essential to optimize translational predictive validity.
... With the advance of genetics, a significant increase in the knowledge of genomes, especially of nonhuman mammals that are genetically close to humans, has allowed the development of animal organs, tissues, and even animal species that express human diseases. Therefore, these approaches have provided more robust animal models for human diseases, i.e., 1 Experimental -They are used in an attempt to reproduce the conditions detected in the original wild species Hughes and Lang (1978); Davidson et al. (1987) 2 Spontaneous -They are known to exhibit some conditions similar to those of the original species 3 Negative -They behave as the normal counterparts of disease models 4 Orphan -They are disease models with no known animal or human counterparts Page 11 of 17 285 models with characteristics that are more similar to those of humans, both in phenotypic (e.g., signs and symptoms) and etiological (e.g., cause mechanism) aspects. Complex human diseases can commonly be better understood in less complex or manipulated simplified animal systems where individual parts of the disease process can be isolated stepwise by silencing or knock-down. ...
... The selection of an animal model for research should, therefore, be based on the following considerations: appropriateness as an analog, transferability of information, genetic uniformity of organisms, basic information on biological properties, availability, cost, and generalizability of the results. Adaptability to experimental manipulation, ecological consequences, and ethical implications should also be carefully considered (Davidson et al., 1987). Furthermore, much information on physiological and biochemical mechanisms was obtained from research on human relatives and was useful in understanding how disease mechanisms arise, with subsequent increasing use in medicine (Saraf & Kumaraswamy, 2013). ...
Safeguarding the environment is one of the most serious modern challenges, as increasing amounts of chemical compounds are produced and released into the environment, causing a serious threat to the future health of the Earth as well as organisms and humans on a global scale. Ecotoxicology is an integrative science involving different physical, chemical, biological, and social aspects concerned with the study of toxic effects caused by natural or synthetic pollutants on any constituents of ecosystems, including animals (including humans), plants, or microorganisms, in an integral context. In recent decades, this science has undergone considerable development by addressing environmental risk assessments through the biomonitoring of indicator species using biomarkers, model organisms, and nanocompounds in toxicological assays. Since a single taxon cannot be representative of complex ecotoxicological effects and mechanisms of action of a chemical, the use of test batteries is widely accepted in ecotoxicology. Test batteries include properly chosen organisms that are easy to breed, adapt easily to laboratory conditions, and are representative of the environmental compartment under consideration. One of the main issues of toxicological and ecotoxicological research is to gain a deeper understanding of how data should be obtained through laboratory and field approaches using experimental models and how they could be extrapolated to humans. There is a tendency to replace animal tests with in vitro systems and to perform them according to standardized analytical methods and the rules of the so-called good laboratory practice (GLP). This paper aims to review this topic to stimulate both efforts to understand the toxicological and ecotoxicological properties of natural and synthetic chemicals and the possible use of such data for application to humans.
... Ethical approval (IRB/21/038) for this study was sought and obtained in accordance with Nigerian animal welfare law and experimental protocols, compliance with "Guide for Care and Use of Laboratory Animals" summarized by Davidson et al [23] from Institutional Review Board (IRB) of the Nigerian Institute of Medical Research (NIMR), Yaba Lagos, Nigeria. ...
The harmless potential of gadolinium-based contrast agent (GBCA) used in MRI studies was remarkable until when gadolinium was detected in the brain, bones, and skin. This study aimed to evaluate the effect of four GBCAs on the liver, heart, and kidney of Wistar rats. Twenty-five (25) male Wistar rats weighing 165-239 g were divided into 4 experimental and control groups after obtaining ethical approval from the Institutional Review Board (IRB) of the Nigerian Institute of Medical Research (NIMR). Specimens in the experimental groups received 2.5 mls / day of one GBCA and the control same normal saline through the lateral tail for 5 days consecutively / week. The Livers, Hearts and Kidneys were harvested 4 weeks following last injection. Pathohistology showed all kidney tissues exposed to Gadopentetate, 80 % to Gadodiamide, and 40 % to Dotarem and Cyclolux were inflamed. Sixty percent Gadodiamide and Doterem to the liver tissue, 50 % and 20 % to Gadopentetate and Cyclolux also inflamed. Samples exposed to Gadopentetate and Dotarem had 50 and 40 % of their heart tissue inflamed. Only those to Gadodiamide and Cyclolux were not affected. Injuries like necrosis, degeneration, and hypertrophy were also noted in all the tissues. All GBCAs were statistically significant in all tissue studied. Gadolinium-based contrast agents had a weak negative correlation with inflamed and degenerated tissues, also a weak positive correlation with hypertrophied tissue, but a moderate positive correlation with necrosis tissues of the kidney, liver, and heart. Keywords: Contrast agents, Heart, Histopathology, Kidney, Liver, Magnetic resonance imaging.
... All methods adopted in this study were conventionally in line with Nigerian animal welfare law and experimental protocols, compliance with the "Guide for Care and Use of Laboratory Animals" summarized by [16]. The experiments were conducted after an ethical approval (IRB/21/038) was obtained from the Institutional Review Board (IRB) of the Nigerian Institute of Medical Research (NIMR), Yaba Lagos, Nigeria. ...
Magnetic resonance imaging (MRI) is an established non-invasive and non-destructive medical imaging modality for the assessment of various organ systems in the human body. Gadolinium-Based Contrast Agent (GBCA) enhanced and improved images from MRI and was believed to be entirely excreted through urine in normal kidney function within 24 hours after injection. Previous studies identified gadolinium accumulations in the brain, bones, and skin of animals. This study evaluated gadolinium retention in normal kidneys, Liver, and heart of Wistar rats after administration of GBCAs in male Wistar rats. Twenty-five male Wistar rats of ages ≥ 5 weeks or ≤ 6 weeks in 4 experimental and 1 control groups were studied. Ethical considerations were obtained from the Institutional Review Board (IRB) of the Nigerian Institute of Medical Research (NIMR), Nigeria. Samples in experimental groups each administered 2.5 mls of 4 different GBCAs, and the control group same per day of saline intravenously through the lateral tail for five days a week and continued for 4 weeks. The kidney, Liver, and Heart tissues of these samples were harvested 4 weeks after the last injection and sent for spectrometry evaluation. Samples in the control group had no gadolinium accumulation. Groups administered gadopentetate dimeglumine, and gadodiamide had greater cardiac metrics (0.397 and 0.390). The higher renal metric was experienced by samples that received dotarem and cyclolux (0.397 and 0.377), though the sample exposed to cyclolux reported more Liver metric (0.407) than other concentrations. Wistar rats’ Kidneys, Liver, and Heart retained gadolinium weeks after injection of GBCAs. Keywords: Dotarem and Cyclolux, Gadolinium, Gadodiamide, Gadopentetate dimenglumine, Magnetic resonance imaging.
This chapter details testing in living systems as a continuation of laboratory and bench testing presented in the preceding chapter. Both in vitro (cell and tissue) and in vivo (animal and human) testing are shown. In an industry design project, testing in living systems is usually required to provide evidence of safety and efficacy for regulatory bodies, hospitals, and some insurance companies. It is used to support the marketing and sales of the new device. In an academic design project, the primary aim of testing in living systems is to generate data that will help demonstrate that one of more design specifications has been met or that a prototype has been validated. Animal testing requires approval from the Institutional Animal Care and Use Committee (ACUC). Human testing requires approval from the Institutional Review Board (IRB). Application guidance is provided for living system testing, as well for biocompatibility and biodurability testing. Clinical trials are the ultimate test of the safety and efficacy of a device before becoming commercially available. Formal validation testing is a form of human testing that requires IRB approval to perform.
The olfactory bulbectomized rodent has long been one of the preferred animal models of depression and certain other neuropsychiatric diseases. In fact, it is considered unparalleled, by some, in the search for antidepressant medication and the literature generated about the model is prodigious. We have revisited the "syndrome" of behavioral sequela following bulbectomy choosing ecologically valid tests likely to be underpinned with evolutionarily preserved neural circuits. Our test battery included measurements of activity, intermale aggression, pleasure seeking, stress/fear and non-spatial memory. The emphasis was on the timetable of syndrome emergence, since this has been understudied and bears on the widely held belief that non-olfactory effects dominate. Our results largely agree with previous reports describing the behavioral syndrome in that we document bulbectomized mice as hyperactive, non-aggressive and fearless. However, we did not find deficits in memory as have frequently been reported in previous studies. Notably, our results revealed that some syndrome behaviors-including the hallmark of hyperactivity-appear immediately or soon after surgery. This rapid appearance casts doubt on the widely held view that compensatory reorganization of limbic and prefrontal cortical areas following bulbectomy underlies the syndrome. Rather, hyperactivity, non-aggressiveness, reduced fear and diminished sucrose preference in the olfactory bulbectomized mouse find ready explanations in the loss of smell that is the immediate and irreversible outcome of bulbectomy. Finally, after a critical consideration of the literature and our results, we conclude that the olfactory bulbectomy model lacks the validity and simplicity previously credited to it. Indeed, we deem this lesion unsuitable as a model of most neuropsychiatric diseases since its effects are at least as complex and misunderstood as the disorders it is purported to model.
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