Animal Models of Human Pathology: Revision, Relevance and Refinements 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 11964

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Guest Editor
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Interests: challenges in animal model research; translation; unbiased reporting of animal model characteristics and results; ethical justification
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Special Issue Information

Dear Colleagues,

Use of animal models of human pathology is accepted on the assumption that it benefits humans. However, recent publications have shown that research on animals faces serious challenges. The increasing number of potential targets, molecular pathways or treatment strategies, which have been recognized as promising in animal models, have failed when translated into human trials. We have reached the point where the clinical relevance of animal models needs urgent clarification.

Multiple methodological problems in animal research have already been exposed, such as poor experimental design, inadequate use of fundamental statistical principles (i.e., randomization, blinding, inadequate power, inadequate sample size, pseudo-replication, etc.), and nontransparent reporting, which results in low scientific validity and irreproducibility of results. However, research on animal models also requires comprehensive knowledge about the model, as well as an understanding of the complex pathogenesis of diseases, which involves both local and systemic effects in the body. Every animal model has its own characteristics, advantages, and limitations. There are factors specific to the disease or animal model that can influence not only the severity of the disease but also underlying mechanisms, and, when these factors are not taken into account, research may result in the discovery of new targets and disease pathways that are of no scientific or clinical value. There are also animal-model-specific factors that can seriously affect the results and lead to false conclusions and failed translation. Although overall animal health and welfare issues—such as animal clinical state, morbidity, mortality, humane endpoints and humane interventions, whole body necropsy findings, sampling principles, pathohistological diagnosis—are of vital importance in the interpretation of the molecular mechanisms or treatment strategies in an organism, this information is usually lacking or rarely properly addressed in animal model studies.

The purpose of this Special issue is thus to promote submissions of high-quality papers of basic research using animal models to understand diseases and underlying mechanisms or to investigate new treatment strategies in various human diseases such as cancer, bowel diseases, kidney injury, Parkinson’s disease, etc. New approaches towards the use of animal models or refinements of particular animal models of human pathology as well as methodological and welfare principles (such as experimental design and welfare or supportive measures in animal models) are also welcome.

Dr. Martina Perše
Guest Editor

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Keywords

  • animal models
  • biomarkers
  • human disease
  • pathology
  • translation
  • mechanisms
  • nephrology
  • gastroenterology
  • urology
  • neuroscience
  • cancer
  • experimental design
  • reproducibility
  • refinements

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Published Papers (10 papers)

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Research

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12 pages, 2470 KiB  
Article
Refinement in Post-Operative Care for Orthopaedic Models: Implementing a Sheep Walking Cast (SWC) for Effective Tibial Fracture Management
by Ivonne Jeanette Knorr, Leonie Tix, Wenjia Liu, Steven R. Talbot, Mareike Schulz, Laura Bell, Babette Kögel, Rene Tolba and Lisa Ernst
Biomedicines 2024, 12(2), 343; https://doi.org/10.3390/biomedicines12020343 - 01 Feb 2024
Viewed by 724
Abstract
In the healthcare system, lower leg fractures remain relevant, incurring costs related to surgical treatment, hospitalization, and rehabilitation. The duration of treatment may vary depending on the individual case and its severity. Casting as a post-surgical fracture treatment is a common method in [...] Read more.
In the healthcare system, lower leg fractures remain relevant, incurring costs related to surgical treatment, hospitalization, and rehabilitation. The duration of treatment may vary depending on the individual case and its severity. Casting as a post-surgical fracture treatment is a common method in human and experimental veterinary medicine. Despite the high importance of sheep in preclinical testing materials for osteosynthesis, there is no standardised cast system ensuring proper stabilisation and functionality of hind limbs during the healing of tibia fractures or defects. Existing treatment approaches for tibial osteosynthesis in laboratory animal science include sling hanging, external fixators, or former Achilles tendon incision. These methods restrict animal movement for 4–6 weeks, limit species-typical behaviour, and impact social interactions. Our pilot study introduces a Standardised Walking Cast (SWC) for sheep, enabling immediate physiological movement post surgery. Seven Rhone sheep (female, 63.5 kg ± 6.45 kg) each with a single tibia defect (6 mm mechanical drilled defect) underwent SWC application for 4 weeks after plate osteosynthesis. The animals bore weight on their operated leg from day one, exhibiting slight lameness (grade 1–2 out of 5). Individual step lengths showed good uniformity (average deviation: 0.89 cm). Group housing successfully started on day three after surgery. Weekly X-rays and cast changes ensured proper placement, depicting the healing process. This study demonstrates the feasibility of using an SWC for up to 72 kg of body weight without sling hanging via ceiling mounting or external fixation techniques. Allowing species-typical movement and social behaviour can significantly improve the physiological behaviour of sheep in experiments, contributing to refinement. Full article
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16 pages, 33308 KiB  
Article
Epoxy- versus Glutaraldehyde-Treated Bovine Jugular Vein Conduit for Pulmonary Valve Replacement: A Comparison of Morphological Changes in a Pig Model
by Nataliya R. Nichay, Anna A. Dokuchaeva, Yuriy Yu. Kulyabin, Evgeniy V. Boyarkin, Elena V. Kuznetsova, Yanina L. Rusakova, Ivan S. Murashov, Andrey A. Vaver, Alexander V. Bogachev-Prokophiev and Irina Yu. Zhuravleva
Biomedicines 2023, 11(11), 3101; https://doi.org/10.3390/biomedicines11113101 - 20 Nov 2023
Viewed by 828
Abstract
Valved conduits are often required to replace pulmonary arteries (PA). A widely used Contegra device is made of bovine jugular vein (BJV), preserved with glutaraldehyde (GA) and iso-propanol. However, it has several drawbacks that may be attributed to its chemical treatment. We hypothesized [...] Read more.
Valved conduits are often required to replace pulmonary arteries (PA). A widely used Contegra device is made of bovine jugular vein (BJV), preserved with glutaraldehyde (GA) and iso-propanol. However, it has several drawbacks that may be attributed to its chemical treatment. We hypothesized that the use of an alternative preservation compound may significantly improve BJV conduit performance. This study aimed to compare the macroscopic and microscopic properties of the BJV treated with diepoxide (DE) and GA in a porcine model. Twelve DE-BJVs and four Contegra conduits were used for PA replacement in minipigs. To assess the isolated influence of GA, we included an additional control group—BJV treated with 0.625% GA (n = 4). The animals were withdrawn after 6 months of follow-up and the conduits were examined. Explanted DE-BJV had a soft elastic wall with no signs of thrombosis or calcification and good conduit integration, including myofibroblast germination, an ingrowth of soft connective tissue formations and remarkable neoangiogenesis. The inner surface of DE-BJVs was covered by a thin neointimal layer with a solid endothelium. Contegra grafts had a stiffer wall with thrombosis on the leaflets. Calcified foci, chondroid metaplasia, and hyalinosis were observed within the wall. The distal anastomotic sites had hyperplastic neointima, partially covered with the endothelium. The wall of GA-BJV was stiff and rigid with degenerative changes, a substantial amount of calcium deposits and dense fibrotic formations in adventitia. An irregular neointimal layer was presented in the anastomotic sites without endothelial cover in the GA BJV wall. These results demonstrate that DE treatment improves conduit integration and the endothelialization of the inner surface while preventing the mineralization of the BJV, which may reduce the risk of early conduit dysfunction. Full article
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13 pages, 2262 KiB  
Article
Effects of Prolonged Serum Calcium Suppression during Extracorporeal Cardiopulmonary Resuscitation in Pigs
by Jan-Steffen Pooth, Yechi Liu, Ralf Petzold, Christian Scherer, Leo Benning, Maximilian Kreibich, Martin Czerny, Friedhelm Beyersdorf, Christoph Benk, Georg Trummer and Sam Joé Brixius
Biomedicines 2023, 11(10), 2612; https://doi.org/10.3390/biomedicines11102612 - 23 Sep 2023
Viewed by 684
Abstract
Controlled reperfusion by monitoring the blood pressure, blood flow, and specific blood parameters during extracorporeal reperfusion after cardiac arrest has the potential to limit ischemia–reperfusion injury. The intracellular calcium overload as part of the ischemia–reperfusion injury provides the possibility for the injury to [...] Read more.
Controlled reperfusion by monitoring the blood pressure, blood flow, and specific blood parameters during extracorporeal reperfusion after cardiac arrest has the potential to limit ischemia–reperfusion injury. The intracellular calcium overload as part of the ischemia–reperfusion injury provides the possibility for the injury to be counteracted by the early suppression of serum calcium with the aim of improving survival and the neurological outcome. We investigated the effects of prolonged serum calcium suppression via sodium citrate during extracorporeal resuscitation using the CARL protocol (CARL—controlled automated reperfusion of the whole body) compared to a single-dose approach in a porcine model after prolonged cardiac arrest. A control group (N = 10) was resuscitated after a 20 min cardiac arrest, initially lowering the intravascular calcium with the help of a single dose of sodium citrate as part of the priming solution. Animals in the intervention group (N = 13) received additional sodium citrate for the first 15 min of reperfusion. In the control group, 9/10 (90.0%) animals survived until day 7 and 7/13 (53.8%) survived in the intervention group (p = 0.09). A favorable neurological outcome on day 7 after the cardiac arrest was observed in all the surviving animals using a species-specific neurological deficit score. The coronary perfusion pressure was significantly lower with a tendency towards more cardiac arrhythmias in the intervention group. In conclusion, a prolonged reduction in serum calcium levels over the first 15 min of reperfusion after prolonged cardiac arrest tended to be unfavorable regarding survival and hemodynamic variables compared to a single-dose approach in this animal model. Full article
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13 pages, 6004 KiB  
Article
Evaluation of Five Mammalian Models for Human Disease Research Using Genomic and Bioinformatic Approaches
by Sankarasubramanian Jagadesan, Pinaki Mondal, Mark A. Carlson and Chittibabu Guda
Biomedicines 2023, 11(8), 2197; https://doi.org/10.3390/biomedicines11082197 - 04 Aug 2023
Viewed by 1252
Abstract
The suitability of an animal model for use in studying human diseases relies heavily on the similarities between the two species at the genetic, epigenetic, and metabolic levels. However, there is a lack of consistent data from different animal models at each level [...] Read more.
The suitability of an animal model for use in studying human diseases relies heavily on the similarities between the two species at the genetic, epigenetic, and metabolic levels. However, there is a lack of consistent data from different animal models at each level to evaluate this suitability. With the availability of genome sequences for many mammalian species, it is now possible to compare animal models based on genomic similarities. Herein, we compare the coding sequences (CDSs) of five mammalian models, including rhesus macaque, marmoset, pig, mouse, and rat models, with human coding sequences. We identified 10,316 conserved CDSs across the five organisms and the human genome based on sequence similarity. Mapping the human-disease-associated single-nucleotide polymorphisms (SNPs) from these conserved CDSs in each species has identified species-specific associations with various human diseases. While associations with a disease such as colon cancer were prevalent in multiple model species, the rhesus macaque showed the most model-specific human disease associations. Based on the percentage of disease-associated SNP-containing genes, marmoset models are well suited to study many human ailments, including behavioral and cardiovascular diseases. This study demonstrates a genomic similarity evaluation of five animal models against human CDSs that could help investigators select a suitable animal model for studying their target disease. Full article
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27 pages, 8698 KiB  
Article
Comprehensive Grading System for Experimental Autoimmune Uveitis in Mice
by Avik Shome, Odunayo O. Mugisho, Rachael L. Niederer and Ilva D. Rupenthal
Biomedicines 2023, 11(7), 2022; https://doi.org/10.3390/biomedicines11072022 - 18 Jul 2023
Viewed by 1228
Abstract
Experimental autoimmune uveitis (EAU) is the most commonly used animal model to study the progression of chronic uveitis and to test various therapies to treat the disease. However, to accurately evaluate the effectiveness of such treatments, a grading system that combines the latest [...] Read more.
Experimental autoimmune uveitis (EAU) is the most commonly used animal model to study the progression of chronic uveitis and to test various therapies to treat the disease. However, to accurately evaluate the effectiveness of such treatments, a grading system that combines the latest imaging techniques with definitive quantitative grading thresholds is required. This study aimed to develop a comprehensive grading system that objectively evaluates EAU progression in C57BL/6J mice. EAU was induced following immunisation with interphotoreceptor retinoid-binding protein (IRBP) and pertussis toxin. Weekly fundus and optical coherence tomography (OCT) images were acquired over 12 weeks using a Micron IV imaging system. Each mouse was graded (between 0 to 4) based on changes seen on both the fundus (optic disc, retinal blood vessels and retinal tissue) and OCT (vitreous and retinal layers) images. A total EAU response (with a maximum score of 48) was calculated for each mouse based on the sum of the individual scores each week. Analysis of the clinical scores depicted a gradual increase in inflammatory signs including optic disc and vascular swelling, leukocyte infiltration in the vitreous, lesions in the retina and formation of granulomas and hyper-reflective foci in the retinal layers in EAU mice, with most signs reaching a plateau towards the end of the study period. Development of these signs into sight-threatening complications such as optic disc atrophy, structural damage to the retina and subretinal oedema were noted in 80–90% of mice suggesting consistent disease induction. Overall, a comprehensive and objective grading system encompassing all pathologies occurring in EAU mice was developed to enhance the preclinical evaluation of novel uveitis treatments. Full article
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18 pages, 8249 KiB  
Article
A Pig Model to Assess Skin Lesions after Apomorphine Application
by Vera Martin, Christian Knecht, Sophie Duerlinger, Barbara Richter and Andrea Ladinig
Biomedicines 2023, 11(5), 1244; https://doi.org/10.3390/biomedicines11051244 - 23 Apr 2023
Viewed by 1448
Abstract
Owing to their similarities, pigs are often used as experimental models for humans. In particular, the similarity of the skin allows them to be a good dermatological model. The aim of the study was to develop an animal model in conventional domestic pigs [...] Read more.
Owing to their similarities, pigs are often used as experimental models for humans. In particular, the similarity of the skin allows them to be a good dermatological model. The aim of the study was to develop an animal model in conventional domestic pigs to evaluate skin lesions macroscopically and histologically after a continuous subcutaneous apomorphine application. A total of 16 pigs from two different age groups were injected with four different apomorphine formulations for 12 h daily over a period of 28 days into the subcutis, which was then evaluated macroscopically for nodules and erythema, as well as histologically. Differences in skin lesions between the formulations were found, with formulation 1 leading to the fewest nodules, least skin lesions, no lymph follicles, least necrosis, and best skin tolerance. Older pigs were easier to handle and, because of the thicker skin and subcutis of these animals, drug application with the appropriate needle length was safer. The experimental setup worked well and an animal model to assess skin lesions after a continuous subcutaneous application of drugs could be successfully established. Full article
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16 pages, 1688 KiB  
Article
Oleic Acid-Containing Phosphatidylinositol Is a Blood Biomarker Candidate for SPG28
by Takuya Morikawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Kosei Moriyama, Gohsuke Hattori, Ryuta Fujioka, Shiroh Miura and Hiroki Shibata
Biomedicines 2023, 11(4), 1092; https://doi.org/10.3390/biomedicines11041092 - 04 Apr 2023
Viewed by 1343
Abstract
Hereditary spastic paraplegia is a genetic neurological disorder characterized by spasticity of the lower limbs, and spastic paraplegia type 28 is one of its subtypes. Spastic paraplegia type 28 is a hereditary neurogenerative disorder with an autosomal recessive inheritance caused by loss of [...] Read more.
Hereditary spastic paraplegia is a genetic neurological disorder characterized by spasticity of the lower limbs, and spastic paraplegia type 28 is one of its subtypes. Spastic paraplegia type 28 is a hereditary neurogenerative disorder with an autosomal recessive inheritance caused by loss of function of DDHD1. DDHD1 encodes phospholipase A1, which catalyzes phospholipids to lysophospholipids such as phosphatidic acids and phosphatidylinositols to lysophosphatidic acids and lysophoshatidylinositols. Quantitative changes in these phospholipids can be key to the pathogenesis of SPG28, even at subclinical levels. By lipidome analysis using plasma from mice, we globally examined phospholipids to identify molecules showing significant quantitative changes in Ddhd1 knockout mice. We then examined reproducibility of the quantitative changes in human sera including SPG28 patients. We identified nine kinds of phosphatidylinositols that show significant increases in Ddhd1 knockout mice. Of these, four kinds of phosphatidylinositols replicated the highest level in the SPG28 patient serum. All four kinds of phosphatidylinositols contained oleic acid. This observation suggests that the amount of oleic acid-containing PI was affected by loss of function of DDHD1. Our results also propose the possibility of using oleic acid-containing PI as a blood biomarker for SPG28. Full article
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Review

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24 pages, 2738 KiB  
Review
Advantages and Limitations of Diabetic Bone Healing in Mouse Models: A Narrative Review
by Tanja C. Maisenbacher, Sabrina Ehnert, Tina Histing, Andreas K. Nüssler and Maximilian M. Menger
Biomedicines 2023, 11(12), 3302; https://doi.org/10.3390/biomedicines11123302 - 13 Dec 2023
Viewed by 894
Abstract
Diabetes represents a major risk factor for impaired fracture healing. Type 2 diabetes mellitus is a growing epidemic worldwide, hence an increase in diabetes-related complications in fracture healing can be expected. However, the underlying mechanisms are not yet completely understood. Different mouse models [...] Read more.
Diabetes represents a major risk factor for impaired fracture healing. Type 2 diabetes mellitus is a growing epidemic worldwide, hence an increase in diabetes-related complications in fracture healing can be expected. However, the underlying mechanisms are not yet completely understood. Different mouse models are used in preclinical trauma research for fracture healing under diabetic conditions. The present review elucidates and evaluates the characteristics of state-of-the-art murine diabetic fracture healing models. Three major categories of murine models were identified: Streptozotocin-induced diabetes models, diet-induced diabetes models, and transgenic diabetes models. They all have specific advantages and limitations and affect bone physiology and fracture healing differently. The studies differed widely in their diabetic and fracture healing models and the chosen models were evaluated and discussed, raising concerns in the comparability of the current literature. Researchers should be aware of the presented advantages and limitations when choosing a murine diabetes model. Given the rapid increase in type II diabetics worldwide, our review found that there are a lack of models that sufficiently mimic the development of type II diabetes in adult patients over the years. We suggest that a model with a high-fat diet that accounts for 60% of the daily calorie intake over a period of at least 12 weeks provides the most accurate representation. Full article
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24 pages, 2040 KiB  
Review
Back to the Basics: Usefulness of Naturally Aged Mouse Models and Immunohistochemical and Quantitative Morphologic Methods in Studying Mechanisms of Lung Aging and Associated Diseases
by Gilberto Jaramillo-Rangel, María-de-Lourdes Chávez-Briones, Adriana Ancer-Arellano, Ivett Miranda-Maldonado and Marta Ortega-Martínez
Biomedicines 2023, 11(7), 2075; https://doi.org/10.3390/biomedicines11072075 - 24 Jul 2023
Viewed by 1294
Abstract
Aging-related molecular and cellular alterations in the lung contribute to an increased susceptibility of the elderly to devastating diseases. Although the study of the aging process in the lung may benefit from the use of genetically modified mouse models and omics techniques, these [...] Read more.
Aging-related molecular and cellular alterations in the lung contribute to an increased susceptibility of the elderly to devastating diseases. Although the study of the aging process in the lung may benefit from the use of genetically modified mouse models and omics techniques, these approaches are still not available to most researchers and produce complex results. In this article, we review works that used naturally aged mouse models, together with immunohistochemistry (IHC) and quantitative morphologic (QM) methods in the study of the mechanisms of the aging process in the lung and its most commonly associated disorders: cancer, chronic obstructive pulmonary disease (COPD), and infectious diseases. The advantage of using naturally aged mice is that they present characteristics similar to those observed in human aging. The advantage of using IHC and QM methods lies in their simplicity, economic accessibility, and easy interpretation, in addition to the fact that they provide extremely important information. The study of the aging process in the lung and its associated diseases could allow the design of appropriate therapeutic strategies, which is extremely important considering that life expectancy and the number of elderly people continue to increase considerably worldwide. Full article
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21 pages, 1143 KiB  
Review
Animal Models of Hypertension (ISIAH Rats), Catatonia (GC Rats), and Audiogenic Epilepsy (PM Rats) Developed by Breeding
by Marina A. Ryazanova, Vladislava S. Plekanchuk, Olga I. Prokudina, Yulia V. Makovka, Tatiana A. Alekhina, Olga E. Redina and Arcady L. Markel
Biomedicines 2023, 11(7), 1814; https://doi.org/10.3390/biomedicines11071814 - 24 Jun 2023
Cited by 1 | Viewed by 1317
Abstract
Research into genetic and physiological mechanisms of widespread disorders such as arterial hypertension as well as neuropsychiatric and other human diseases is urgently needed in academic and practical medicine and in the field of biology. Nevertheless, such studies have many limitations and pose [...] Read more.
Research into genetic and physiological mechanisms of widespread disorders such as arterial hypertension as well as neuropsychiatric and other human diseases is urgently needed in academic and practical medicine and in the field of biology. Nevertheless, such studies have many limitations and pose difficulties that can be overcome by using animal models. To date, for the purposes of creating animal models of human pathologies, several approaches have been used: pharmacological/chemical intervention; surgical procedures; genetic technologies for creating transgenic animals, knockouts, or knockdowns; and breeding. Although some of these approaches are good for certain research aims, they have many drawbacks, the greatest being a strong perturbation (in a biological system) that, along with the expected effect, exerts side effects in the study. Therefore, for investigating the pathogenesis of a disease, models obtained using genetic selection for a target trait are of high value as this approach allows for the creation of a model with a “natural” manifestation of the pathology. In this review, three rat models are described: ISIAH rats (arterial hypertension), GC rats (catatonia), and PM rats (audiogenic epilepsy), which are developed by breeding in the Laboratory of Evolutionary Genetics at the Institute of Cytology and Genetics (the Siberian Branch of the Russian Academy of Sciences). Full article
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