Skip to main content
Download PDF

Role of animal models in biomedical research: a review

Laboratory Animal Research volume 38, Article number: 18 (2022) Cite this article

Abstract

The animal model deals with the species other than the human, as it can imitate the disease progression, its’ diagnosis as well as a treatment similar to human. Discovery of a drug and/or component, equipment, their toxicological studies, dose, side effects are in vivo studied for future use in humans considering its’ ethical issues. Here lies the importance of the animal model for its enormous use in biomedical research. Animal models have many facets that mimic various disease conditions in humans like systemic autoimmune diseases, rheumatoid arthritis, epilepsy, Alzheimer’s disease, cardiovascular diseases, Atherosclerosis, diabetes, etc., and many more. Besides, the model has tremendous importance in drug development, development of medical devices, tissue engineering, wound healing, and bone and cartilage regeneration studies, as a model in vascular surgeries as well as the model for vertebral disc regeneration surgery. Though, all the models have some advantages as well as challenges, but, present review has emphasized the importance of various small and large animal models in pharmaceutical drug development, transgenic animal models, models for medical device developments, studies for various human diseases, bone and cartilage regeneration model, diabetic and burn wound model as well as surgical models like vascular surgeries and surgeries for intervertebral disc degeneration considering all the ethical issues of that specific animal model. Despite, the process of using the animal model has facilitated researchers to carry out the researches that would have been impossible to accomplish in human considering the ethical prohibitions.

Background

The animals used in various studies and investigations are related to the evolution of human history. Though there are many shreds of evidence that Aristotle in ancient Greece successfully used animals in understanding the human body, the main breakthrough in animal models happened in the eighteenth and nineteenth centuries with the scientists like Jean Baptiste Van Helmont, Francesco Redi, John Needham, Lazzaro Spallanzani, Lavoisier and Pasteur who studied the origin of life using animal models [1]. At the same time, human physiology, anatomy, pathology as well as pharmacology were also studied using animal models. With the remarkable advancements in drug development, biomedicine and pre-clinical trials, the importance of animal models has increased many folds in the last decades, as the therapeutic outcome and drug safety are the foremost important criteria for a drug and medical device considered to be used in the human model [2]. The scientific apply of animal models in the arena of biological research and drug development is an age-old practice because of the notable resemblance in physiology and anatomy between humans and animals, especially mammals [3]. One must consider that the physiological processes of humans, as well as mammals, are complex in terms of circulatory factors, hormones, cellular structures, and tissue systems. Hence, investigation of various aspects such as molecular structures, cellular and organ functions in physiological and pathological conditions must be taken into consideration.

The process of selection of an animal model for biomedical research is a very intricate part, as all models are not acceptable due to various limitations. Many factors should be taken into consideration during the selection of an ideal animal model for biomedical trials. The most important criteria are the proper selection of models in terms of resemblance between animal species and humans in terms of physiological and/or pathophysiological aspects. Detailed evaluation during the application of certain drugs/molecules/devices and their capacity to reproduce the disease or pathology at the same level as that of humans. Availability and the size of animal species under consideration. Long life duration of the animal species under study. A Large animal population in a model facilitates the availability of multiple sub-species.

Many animal species such as Drosophila (insects), Danio rerio, or zebrafish (fish), Caenorhabditis elegans (nematodes), Xenopus (frogs), and mammals such as mice, rabbits, rats, cats, dogs, pigs, and monkeys have been accepted worldwide for their phylogenetic resemblance to humans [4].

Choice of an appropriate animal model is most of the time a tedious job and sometimes depends on assumptions and convenience of the study and researchers without considering whether the model will be appropriate or not. Irrational selection of an inappropriate animal model for scientific investigations will yield incorrect findings, as well as fetch misusage of resources and lives. Moreover, it results in erroneous, duplicative, and inappropriate experiments [5]. To minimize these problems, recently researchers have advanced their researches to produce animal models that are very specific to the research under consideration. They produced custom-made transgenic animal models by incorporating genetic information directly into the embryo either by injecting foreign DNA or through retroviral vectors [6]. Through the incorporation of human cells into the recipient animals, researchers can study the effects of pathogens similar to the way in the human body [7]. Proper selection of animal models is mainly related to the nature of the drug or medical devices under study. In many instances, a single animal model is not able to signify a human disease alone, in that case, the combination of several models can potentially signify the procedure [8].

Main text

The significance and challenges of animals in biomedical research

There has always been a debate among the researchers about the significance of animal models, as many experiments yield promising results, whereas, others couldn’t produce desired outcomes, so, that model could be translated to humans too. Owing to their close phylogenetic closeness to humans, non-human primates are proved to be the most potential candidate. They have genetic, biochemical, and psychological activities similar to humans. In this context, the necessity of non-human primates continues to grow in several areas of research of human diseases viz. AIDS, Parkinson’s disease, hepatitis, dentistry, orthopaedic surgical techniques, cardiovascular surgeries, psychological disorders, toxicological studies, drug development, toxicological studies as well as vaccine development [4]. The discovery of vaccines and diagnostic modalities with the animal model does not only benefit humans but also enhances the lifespan of animals and prevents many zoonotic diseases, with the production of many vaccines and drugs like rabies, tetanus, parvo virus, feline leukemia, etc (Table 1).

Table 1 Significance and challenges of different animal models
Full size table

Ethical matters on the use of animals

Animal research adheres to a few dimensions like government legislation, public opinion, moral stand, and search for appropriate alternatives for the research. Mahatma Gandhi opined that to judge the greatness and moral progress of a nation, one should judge the way its animals are being treated. Government legislation restricts the researchers and institutes from likely injury, pain, or suffering that may arise during animal research [33]. On the contrary, many modern countries ruled that before human administration, vaccine testing, lethal dose testing should be done on animals [34]. Social acceptance has also an influential role in animal experiments as it utilizes public money [33]. In their moral view, many people think that dog has more moral impact than pig, rat, fishes, mouse, etc.

Ethical issues on animal experimentation started in 1959, where the emphasis has been given on principles of 3Rs, reduction, refinement, and replacement of animal use [35]. According to this principle, minimum necessary numbers of animals are to be used for scientific experiments i.e. reduction. Pain or distress of the animals during experiments has to be minimized, i.e. refinement. Wherever applicable replacements of the animals are to be done with other non-animal alternatives, i.e. replacement. Though these principles are considered as the cornerstone of animal experimentations, but there are questions regarding the implementation of these regulations [36].

Laboratory (small) and large animal models for human diseases

The importance of rat and mouse models has proved their outstanding importance in biomedical research. Besides, other mammalian and non-mammalian small domestic animals like the guinea pig, hamster, rabbit, ferrets, birds, amphibians, fishes, flies, worms have equal importance in terms of anatomical and physiological resemblance with humans. Large animal models also proved their uniqueness due to specific anatomical and physiological characteristics pertinent to those specific researches (Table 2).

Table 2 Biomedical significances and limitations of small animal models
Full size table

Transgenic animal models in biomedical research

The gene rule and role in the biological system of human diseases has improved many folds with the introduction of the transgenic animal model in biomedical research within the last three decades. The early example of most unique biological research started, when structural gene coding for the human growth hormone (GH) was initiated into mice after fusion with the regulatory region of mouse metallothionein-I gene, as a result, transgenic mouse produced and showed excess GH production [157].

Linking of the genotype with disease phenotype has been expedited with the genome editing with the introduction of the CRISPR–Cas9 system by which disease-causing mutations are done in animal models [158]. Moreover, the production of transgenic animals has been radically changed by the introduction of the CRISPR–Cas9 system. Through the successful use of this model accurate human disease models in animals have been produced and possible therapies have been potentiated. Recapitulation of various disease-causing single nucleotide polymorphisms (SNPs) in animal models is achieved by the introduction of gRNA with the combination of Cas9 and donor template DNA [159], viz. mouse model has enormous importance in carrying human genetic traits, developmental similarities as well as disease translation [158, 160,161,162]. Zhang and Sharp labs at MIT/Broad Institute used CRISPR–Cas9 through AAV and lentivirus [163] both in vivo and ex vivo in neurons as well as endothelial cells of mice for the production of lung cancer model in mice where lung causing genes namely Kras, Tp53, and Lkb1 were mutated. On the other hand, an MIT-Harvard team [164] disrupted the tumor suppressor genes Pten and Tp53, and consequently liver cancer was produced in mice.

Animal models in pharmaceutical drug development

In recent advancements, animal models are the most practical tools for pre-clinical drug screening before application into clinical trials. Animal models are considered as most important in vivo models in terms of basic pharmacokinetic parameters like drug efficiency, safety, toxicological studies, as these pre-clinical data are required before translating into humans. Toxicological tests are performed on a large number of animals like general toxicity, mutagenicity, carcinogenicity, and teratogenicity and to evaluate whether the drugs are irritant to eyes and skin. In most instances, both in vitro and in vivo models are corroborated before proceeding to medical trials. In vivo models are mostly conducted in mice, rats, and rabbits [2]. Certain stages are involved in pre-clinical trials with animal models: firstly, if the trial drug shows desirable efficacy then only further studies are carried out; secondly, if a drug in pre-clinical trials on animals proved to be safe, then it is administered in small human volunteer groups, at the same time, the animal trial will go on to evaluate the effect of the drug when administered for an extended period [8, 165]. Mostly, rodents are used for these trials as they have similar biological properties to humans and are easy to handle and rear in laboratories. In new regulations, it is mandatory to carry on the trials on non-rodents such as rabbits, dogs, cats, or primates simultaneously with rodents [166].

Animal models in orthopedic research

There are many conditions involving bone pathologies such as osteomyelitis, osteosarcoma, osteoporosis, etc. Being a complex organ, the treatment of bone needs special care and extensive researches that involves specialized techniques as well as specific animal models for the studies of specific diseases. Herein, the animal models emphasize mostly related to fracture healing (critical size defect), osteoporosis, osteomyelitis, and osteosarcoma (Table 3).

Table 3 Different animal models in orthopaedic research
Full size table

Animal models in diabetic and burn wound healing

Type 2 diabetes and associated foot ulcer have turned into an epidemic worldwide in recent years causing severe socio-economic trouble to the patients as well as the health care system of the nation as a whole [208]. Various researches depicted that chance of developing an ulcer in diabetic patients varies between 15–25% [209, 210] and the chance of recurrence is about 20–58% among the patients within a year after recovery [211]. Hence, many researchers studied different materials or drugs to treat diabetic wounds. Similarly, burn wounds occur due to exposure to flames, hot surfaces, liquids, chemicals, or even cold exposure [212]. Though with the recent modalities like skin grafting prognosis has improved however, the mortality rate is high [213,214,215].

Diabetic wound rat model

For developing this model, clinically healthy male Wistar rats (150 ~ 250 g body weight) are used. To induce hyperglycemia, injection nicotinamide (NAD)@ 150 mg/kg BW intraperitoneally, after 15 min injection Streptozotocin (STZ) @ 65 mg/kg BW intraperitoneally [216] are to be injected. The same procedure has to be repeated after 24 h. Blood is to be collected from the tail after 72 h to check hyperglycemia. Rats having high blood glucose levels (≥ 10 mmol/L) are considered to be diabetic [217]. For wound creation, rats are to be anesthetized with a combination of xylazine @10 mg/kg (intramuscular injection) and ketamine @90 mg/kg (intramuscular injection) [218]. After marking the dorsal back area with methylene blue, the site is to be prepared aseptically after shaving [219]. Full-thickness wound creation is to be done with a sterile 6 mm biopsy punch measuring 6 mm diameter and 2 mm depth and left open [218] (Fig. 1c).

Fig. 1
figure 1

a. Bone defect model and implantation of implant b. Vascular graft mode c. Diabetic wound model d. Osteomyelitis model development e. Creation of burn wound model f. Cartilage graft model—All in rabbit

Full size image

Burn wound models

Because of the severity and types of cause, the management of burn injuries poses a significant challenge to plastic surgeons in humans. In general, primary and secondary burn wounds heal by the primary healing process, but, third-degree burn injuries with the destruction of all the skin layers are resistant to the normal healing process and necessitate the added surgical procedures, such as skin grafting, and the relevance of advanced wound dressing [220]. Several researchers used the albino Winstar male rats (Rattus norvegicus) model weighing 250 ± 50 g for the study of burn wounds. Anesthesia was achieved with intramuscular administration of atropine sulfate (0.04 mg/kg BW) and after 10 min a combination of 10% ketamine (90 mg/kg) and 2% xylazine (10 mg/kg) intramuscularly produced adequate anesthesia [221]. After aseptic preparation of the dorsal back area, thermal injury has to be made with a 10 mm aluminium rod previously heated with 100 °C boiling water. The aluminium rod has to be kept in situ for 15 s. Immediately after the procedure analgesic is to be provided and to be continued for at least 3 days [222,223,224]. A hot air blower has been used to produce a 6% third-degree burn injury in a mouse model [225]. In pig, a partial-thickness burn model in the skin was produced by placing a glass bottle having heated water at 92 °C for 14 s [226] In other studies, a homemade heating device was placed over the skin for 35 s to create burn wound [227]. In rabbits, it was demonstrated to use a dry-heated brass rod for 10 and 20 s at 90 °C to create a deep partial-thickness burn wound in the ear [228]. In mice, a full-thickness burn was created under 3–5% isoflurane anesthesia and intraperitoneal caprofen 5 mg/kg as analgesia. Here, a 4 cm2 brass rod attached to a temperature probe was first heated to 260 °C and then cool to 230 °C and finally placed on the dorsum skin for 9 s [229] (Fig. 1e).

Animal models in cartilage repair

Animal models have enormous importance in the study of cartilage repair. Though in vitro models have been reported, it could not replace the necessity of using animal models prior to clinical implementation [230,231,232,233,234,235,236] (Table 4).

Table 4 Different animal models for cartilage rejuvenation or repair
Full size table

Animal models in vascular grafting

With the increase of cardiovascular complications, there is a need for surgical intervention using vascular grafts. Vascular grafting and cardiac valve repair have become important issues to the clinicians for the replacement of damaged vessels [249, 250], hence there is an increased demand for tissue-engineered blood vessel substitute [250, 251]. The main prosthetic options are synthetic grafts such as polytetrafluoroethylene, polyethylene terephthalate, and polyurethane [252], and autologous conduits. Although these types of synthetic grafts provide reasonable outcomes in large-diameter vascular applications, long-term patency is questionable as compared to autologous conduits in small-diameter (< 6 mm) applications due to their inclination to various complications [253]. Despite the superior outcome of autologous grafts, it has some disadvantages such as limited availability and prior use. Moreover, the determination of a suitable animal model needs considerations of various factors. The factors for the selection of animal species depend on diameter and length of conduits, period of implantation, anastomotic site, price, accessibility, reaction to anesthesia and surgery, and flow of blood at sites of graft implantation. Animal applications of these tissue-engineered vessels are, therefore, an utmost necessity as pre-clinical studies before use in humans (Fig. 1b, Table 5).

Table 5 In vivo animal studies of different vascular grafts
Full size table

Animal models in disc degeneration

Intervertebral disc degeneration (IVDD) and herniation manifested as lower back pain cause a massive socio-economic burden to the patient and society as a whole [264,265,266,267]. But there is a lack of treatment modalities to cure mildly to moderate degeneration as well as complications associated with surgical interventions associated with the advanced stage; hence, researchers are enormously trying to reinforce regenerative strategies and to lower the suffering by controlling the pain with the injection of stem cells, growth factors hydrogels for replacement of the disc [268]. Diverse animal models have been reported as a pre-clinical trial to translate the procedure in humans (Table 6).

Table 6 Different animal models for the study of IVDD
Full size table

Conclusions

The importance of animal models is unquestionable in terms of in vivo study for the implementation of any biomedical research to humans. It serves not only the human race but also well being of veterinary patients. Animal models have not only important roles in drug development, toxicity studies, pharmacokinetic studies of a drug, but also the pre-clinical study of medical and tissue engineering devices that are intended to be used in humans. Laboratory animal models are more cost-effective and agreeable to high throughput testing as compared to large animal models. Yet, to obtain preclinical data and to ascertain the clinical potential of vascular graft as well as orthopedic bone plates and implants, large animal models that mimic human anatomy and physiology are to be developed. Whatever may be the modes of using animal models for biomedical researches, it should abide by the principles of 3Rs, i.e., reduction, refinement, and replacement of animals.

Availability of data and materials

The data in the present manuscript were collected by searching of literatures as well as involving authors own materials.

Abbreviations

BW:

Body weight

Cfu:

Colony forming unit

ESC:

Embryonic stem cell

IVDD:

Intervertebral disc degeneration

PCL:

Polycaprolactone

STZ:

Streptozotocin

VEGF:

Vascular endothelial growth factor

References

  1. Oparin AI. The origin of life on the earth. 3rd ed. New York: Academic Press Inc.; 1957. p. XViii+495.

    Google Scholar 

  2. Pehlivanovic B, Dina F, Emina A, Ziga Smajic N, Fahir B. Animal models in modern biomedical research. Eur J Pharm Med Res. 2019;6(7):35–8.

    Google Scholar 

  3. Barré-Sinoussi F, Montagutelli X. Animal models are essential to biological research: issues and perspectives. Future Sci OA. 2015;1(4):FSO63.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Andersen ML, Winter LMF. Animal models in biological and biomedical research - experimental and ethical concerns. An Acad Bras Ciênc. 2017;91(suppl 1):e20170238.

    Article  PubMed  Google Scholar 

  5. Gad SC. Animal models in toxicology. In: Wexler P, editor. Encyclopedia of toxicology. Boca Raton: CRC/Taylor & Francis; 2005. p. 138–40.

    Chapter  Google Scholar 

  6. Simmons D. The use of animal models in studying genetic disease: transgenesis and induced mutation. Nat Educ. 2008;1(1):70.

    Google Scholar 

  7. Ernst W. Humanized mice in infectious diseases. Comp Immunol Microbiol Infect Dis. 2016;49:29–38.

    Article  CAS  PubMed  Google Scholar 

  8. Dam DV, Deyn PPD. Animal models in the drug discovery pipeline for Alzheimer’s disease. Br J Pharmacol. 2011;164(4):1285–300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Simon F, Oberhuber A, Schelzig H. Advantages and disadvantages of different animal models for studying ischemia/reperfusion injury of the spinal cord. Eur J Vasc Endovasc Surg. 2015;49(6):744.

    Article  Google Scholar 

  10. Moran CJ, Ramesh A, Brama PAJ, O’Byrne JM, O’Brien FJ, Levingstone TJ. The benefits and limitations of animal models for translational research in cartilage repair. J Exp Orthop. 2016;3(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Loisel S, Ohresser M, Pallardy M, Daydé D, Berthou C, Cartron G, et al. Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment. Crit Rev Oncol Hematol. 2007;62(1):34–42.

    Article  PubMed  Google Scholar 

  12. French V. Leg regeneration in the cockroach, Blatella germanica: II. Regeneration from a non-congruent tibial graft/host junction. J Embryol Exp Morphol. 1976;35(2):267–301.

    CAS  PubMed  Google Scholar 

  13. Olsen AS, Sarras MP, Intine RV. Limb regeneration is impaired in an adult zebrafish model of diabetes mellitus. Wound Repair Regen. 2010;18(5):532–42.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pfefferli C, Jaźwińska A. The art of fin regeneration in zebrafish. Regeneration. 2015;2(2):72–83.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gutpell KM, Hrinivich WT, Hoffman LM. Skeletal muscle fibrosis in the mdx/utrn+/- mouse validates its suitability as a murine model of Duchenne muscular dystrophy. PLoS ONE. 2015;10(1):e0117306.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Heber-Katz E, Leferovich JM, Bedelbaeva K, Gourevitch D. Spallanzani’s mouse: a model of restoration and regeneration. In: Heber-Katz E, editor. Regeneration: stem cells and beyond. Berlin: Springer; 2004. p. 165–89.

    Chapter  Google Scholar 

  17. Zaccagnini G, Palmisano A, Canu T, Maimone B, Russo FML, Ambrogi F, et al. Magnetic resonance imaging allows the evaluation of tissue damage and regeneration in a mouse model of critical limb ischemia. PLoS ONE. 2015;10(11): e0142111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Cheng L, Liu Y, Zhao H, Zhang W, Guo Y-J, Nie L. Lentiviral-mediated transfer of CDNF promotes nerve regeneration and functional recovery after sciatic nerve injury in adult rats. Biochem Biophys Res Commun. 2013;440(2):330–5.

    Article  CAS  PubMed  Google Scholar 

  19. Leppik LP, Froemel D, Slavici A, Ovadia ZN, Hudak L, Henrich D, et al. Effects of electrical stimulation on rat limb regeneration, a new look at an old model. Sci Rep. 2015;5(1):18353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Oliveira KMC, Barker JH, Berezikov E, Pindur L, Kynigopoulos S, Eischen-Loges M, et al. Electrical stimulation shifts healing/scarring towards regeneration in a rat limb amputation model. Sci Rep. 2019;9(1):11433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zaccagnini G, Gaetano C, Della Pietra L, Nanni S, Grasselli A, Mangoni A, et al. Telomerase mediates vascular endothelial growth factor-dependent responsiveness in a rat model of hind limb ischemia. J Biol Chem. 2005;280(15):14790–8.

    Article  CAS  PubMed  Google Scholar 

  22. Barraza-Flores P, Fontelonga TM, Wuebbles RD, Hermann HJ, Nunes AM, Kornegay JN, et al. Laminin-111 protein therapy enhances muscle regeneration and repair in the GRMD dog model of Duchenne muscular dystrophy. Hum Mol Genet. 2019;28(16):2686–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cook J, Fox D, Malaviya P, Tomlinson J, Farr J, Kuroki K, et al. Evaluation of small intestinal submucosa grafts for meniscal regeneration in a clinically relevant posterior meniscectomy model in dogs. J Knee Surg. 2006;19(3):159–67.

    Article  PubMed  Google Scholar 

  24. Farah Z, Fan H, Liu Z, He J-Q. A concise review of common animal models for the study of limb regeneration. Organogenesis. 2016;12(3):109–18.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Fitzpatrick N, Smith TJ, Pendegrass CJ, Yeadon R, Ring M, Goodship AE, et al. Intraosseous transcutaneous amputation prosthesis (ITAP) for limb salvage in 4 Dogs. Vet Surg. 2011;40(8):909–25.

    PubMed  Google Scholar 

  26. Raske M, McClaran JK, Mariano A. Short-term wound complications and predictive variables for complication after limb amputation in dogs and cats. J Small Anim Pract. 2015;56(4):247–52.

    Article  CAS  PubMed  Google Scholar 

  27. Fortier LA, Smith RKW. Regenerative Medicine for tendinous and ligamentous injuries of sport horses. Vet Clin North Am Equine Pract. 2008;24(1):191–201.

    Article  PubMed  Google Scholar 

  28. Kon E, Mutini A, Arcangeli E, Delcogliano M, Filardo G, Aldini NN, et al. Novel nanostructured scaffold for osteochondral regeneration: pilot study in horses. J Tissue Eng Regen Med. 2010;4(4):300–8.

    Article  CAS  PubMed  Google Scholar 

  29. Parnell LKS, Volk SW. The evolution of animal models in wound healing research: 1993–2017. Adv Wound Care. 2019;8(12):692–702.

    Article  Google Scholar 

  30. Smith RK, Garvican ER, Fortier LA. The current ‘state of play’ of regenerative medicine in horses: what the horse can tell the human. Regen Med. 2014;9(5):673–85.

    Article  CAS  PubMed  Google Scholar 

  31. Greek R, Hansen L. The strengths and limits of animal models as illustrated by the discovery and development of antibacterials. Biol Syst Open Access. 2013;2(2):109.

    Google Scholar 

  32. Goyal SN, Reddy NM, Patil KR, Nakhate KT, Ojha S, Patil CR, et al. Challenges and issues with streptozotocin-induced diabetes – a clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact. 2016;244:49–63.

    Article  CAS  PubMed  Google Scholar 

  33. VandeWoude S, Rollin BE. Practical considerations in regenerative medicine research: IACUCs, ethics, and the use of animals in stem cell studies. ILAR J. 2010;51(1):82–4. https://doi.org/10.1093/ilar.51.1.82.

    Article  CAS  Google Scholar 

  34. Kooijman M. Why animal studies are still being used in drug development. Altern Lab Anim. 2013;41(6):P79-81.

    Article  CAS  PubMed  Google Scholar 

  35. Russell WMS, Burch RL. The principles of humane experimental technique. Princ hum exp tech. London: Methuen & Co. Limited; 1960, p. 252.

  36. Liguori GR, Jeronimus BF, de Aquinas Liguori TT, Moreira LFP, Harmsen MC. Ethical issues in the use of animal models for tissue engineering: reflections on legal aspects, moral theory, three Rs strategies, and harm-benefit analysis. Tissue Eng Part C Methods. 2017;23(12):850–62.

    Article  PubMed  Google Scholar 

  37. Antony JJ, Sithika MAA, Joseph TA, Suriyakalaa U, Sankarganesh A, Siva D, et al. In vivo antitumor activity of biosynthesized silver nanoparticles using Ficus religiosa as a nanofactory in DAL induced mice model. Colloids Surf B Biointerfaces. 2013;108:185–90.

    Article  CAS  PubMed  Google Scholar 

  38. Liu X, Manzano G, Kim HT, Feeley BT. A rat model of massive rotator cuff tears. J Orthop Res. 2011;29(4):588–95.

    Article  PubMed  Google Scholar 

  39. Shurey S, Akelina Y, Legagneux J, Malzone G, Jiga L, Ghanem AM. The rat model in microsurgery education: classical exercises and new horizons. Arch Plast Surg. 2014;41(3):201–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Soares E, Prediger RD, Nunes S, Castro AA, Viana SD, Lemos C, et al. Spatial memory impairments in a prediabetic rat model. Neuroscience. 2013;250:565–77.

    Article  CAS  PubMed  Google Scholar 

  41. von Scheidt M, Zhao Y, Kurt Z, Pan C, Zeng L, Yang X, et al. Applications and limitations of mouse models for understanding human atherosclerosis. Cell Metab. 2017;25(2):248–61.

    Article  CAS  Google Scholar 

  42. Mequanint W, Makonnen E, Urga K. In vivo anti-inflammatory activities of leaf extracts of Ocimum lamiifolium in mice model. J Ethnopharmacol. 2011;134(1):32–6.

    Article  Google Scholar 

  43. Antwi AO, Obiri DD, Osafo N. Stigmasterol modulates allergic airway inflammation in guinea pig model of ovalbumin-induced asthma. Mediators Inflamm. 2017;2017:2953930.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bates K, Vink R, Martins R, Harvey A. Aging, cortical injury and Alzheimer’s disease-like pathology in the guinea pig brain. Neurobiol Aging. 2014;35(6):1345–51.

    Article  PubMed  Google Scholar 

  45. Buels KS, Jacoby DB, Fryer AD. Non-bronchodilating mechanisms of tiotropium prevent airway hyperreactivity in a guinea-pig model of allergic asthma. Br J Pharmacol. 2012;165(5):1501–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cashman KA, Broderick KE, Wilkinson ER, Shaia CI, Bell TM, Shurtleff AC, et al. Enhanced efficacy of a codon-optimized DNA vaccine encoding the glycoprotein precursor gene of lassa virus in a guinea pig disease model when delivered by dermal electroporation. Vaccines. 2013;1(3):262–77.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Clark S, Hall Y, Williams A. Animal models of tuberculosis: guinea pigs. Cold Spring Harb Perspect Med. 2015;5(5):a018572.

    Article  PubMed Central  CAS  Google Scholar 

  48. deOgburn R, Leite JO, Ratliff J, Volek JS, McGrane MM, Fernandez ML. Effects of increased dietary cholesterol with carbohydrate restriction on hepatic lipid metabolism in guinea pigs. Comp Med. 2012;62(2):109–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Espinoza J, Montaño LM, Perusquía M. Nongenomic bronchodilating action elicited by dehydroepiandrosterone (DHEA) in a guinea pig asthma model. J Steroid Biochem Mol Biol. 2013;138:174–82.

    Article  CAS  PubMed  Google Scholar 

  50. Grover A, Troudt J, Arnett K, Izzo L, Lucas M, Strain K, et al. Assessment of vaccine testing at three laboratories using the guinea pig model of tuberculosis. Tuberculosis. 2012;92(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  51. Kondo M, Tsuji M, Hara K, Arimura K, Yagi O, Tagaya E, et al. Chloride ion transport and overexpression of TMEM16A in a guinea-pig asthma model. Clin Exp Allergy. 2017;47(6):795–804.

    Article  CAS  PubMed  Google Scholar 

  52. Larrouy-Maumus G, Layre E, Clark S, Prandi J, Rayner E, Lepore M, et al. Protective efficacy of a lipid antigen vaccine in a guinea pig model of tuberculosis. Vaccine. 2017;35(10):1395–402.

    Article  CAS  PubMed  Google Scholar 

  53. Maghdessian R, Côté F, Rouleau T, Ouadda ABD, Levy É, Lavoie J-C. Ascorbylperoxide contaminating parenteral nutrition perturbs the lipid metabolism in newborn guinea pig. J Pharmacol Exp Ther. 2010;334(1):278–84.

    Article  CAS  PubMed  Google Scholar 

  54. Mahajan SG, Mehta AA. Suppression of ovalbumin-induced Th2-driven airway inflammation by β-sitosterol in a guinea pig model of asthma. Eur J Pharmacol. 2011;650(1):458–64.

    Article  CAS  PubMed  Google Scholar 

  55. Ordway DJ, Shanley CA, Caraway ML, Orme EA, Bucy DS, Hascall-Dove L, et al. Evaluation of standard chemotherapy in the guinea pig model of tuberculosis. Antimicrob Agents Chemother. 2010;54(5):1820–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Orme IM, Ordway DJ. Mouse and guinea pig models of tuberculosis. In: Jacobs WR Jr, McShane H, Mizrahi V, Orme IM, editors. Tuberculosis and the tubercle bacillus. John Wiley & Sons, Ltd; 2017. p. 143–62.

    Chapter  Google Scholar 

  57. Pohanka M, Zemek F, Bandouchova H, Pikula J. Toxicological scoring of Alzheimer’s disease drug huperzine in a guinea pig model. Toxicol Mech Methods. 2012;22(3):231–5.

    Article  CAS  PubMed  Google Scholar 

  58. Ryan VE, Bailey TW, Liu D, Vemulapalli T, Cooper B, Cox AD, et al. Listeria adhesion protein-expressing bioengineered probiotics prevent fetoplacental transmission of Listeria monocytogenes in a pregnant guinea pig model. Microb Pathog. 2021;151:104752.

    Article  CAS  PubMed  Google Scholar 

  59. Salazar C, Valdivia G, Ardiles ÁO, Ewer J, Palacios AG. Genetic variants associated with neurodegenerative Alzheimer disease in natural models. Biol Res. 2016;49(1):14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Sharman MJ, Nik SHM, Chen MM, Ong D, Wijaya L, Laws SM, et al. The guinea pig as a model for sporadic alzheimer’s disease (AD): the impact of cholesterol intake on expression of AD-related genes. PLoS ONE. 2013;8(6):e66235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Valdés G, Acuña S, Schneider D, Ortíz R, Padilla O. Bradykinin exerts independent effects on trophoblast invasion and blood pressure in pregnant guinea pigs. Reprod Sci. 2020;27(8):1648–55.

    Article  PubMed  Google Scholar 

  62. Veselenak RL, Shlapobersky M, Pyles RB, Wei Q, Sullivan SM, Bourne N. A Vaxfectin®-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes. Vaccine. 2012;30(49):7046–51.

    Article  CAS  PubMed  Google Scholar 

  63. Yang R, Guo P, Song X, Liu F, Gao N. Hyperlipidemic guinea pig model: mechanisms of triglyceride metabolism disorder and comparison to rat. Biol Pharm Bull. 2011;34(7):1046–51.

    Article  CAS  PubMed  Google Scholar 

  64. Barbosa MDCL, Bouskela E, Cyrino FZ, Azevedo APS, Costa MCP, de Souza MDGC, et al. Effects of babassu nut oil on ischemia/reperfusion-induced leukocyte adhesion and macromolecular leakage in the microcirculation: observation in the hamster cheek pouch. Lipids Health Dis. 2012;11(1):158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Camarozano AC, de Garcia ACFZ, Bottino DA, Bouskela E. Effects of microbubbles and ultrasound on the microcirculation: observation on the hamster cheek pouch. J Am Soc Echocardiogr. 2010;23(12):1323–30.

    Article  PubMed  Google Scholar 

  66. Chanut FJA, Williams AM. The syrian golden hamster estrous cycle: unique characteristics, visual guide to staging, and comparison with the rat. Toxicol Pathol. 2016;44(1):43–50.

    Article  PubMed  Google Scholar 

  67. Cruz ISS, Garabalino MA, Trivillin VA, Itoiz ME, Pozzi ECC, Thorp S, et al. Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy. Oral Dis. 2020;26(6):1175–84.

    Article  Google Scholar 

  68. Evangelista KV, Lourdault K, Matsunaga J, Haake DA. Immunoprotective properties of recombinant LigA and LigB in a hamster model of acute leptospirosis. PLoS ONE. 2017;12(7): e0180004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Ford J, Carnes K, Hess RA. Ductuli efferentes of the male golden Syrian hamster reproductive tract. Andrology. 2014;2(4):510–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tsai AG, Intaglietta M, Sakai H, Delpy E, Rochelle CDL, Rousselot M, Zal F. Microcirculation and NO-CO Studies of a natural extracellular hemoglobin developed for an oxygen therapeutic carrier. Curr Drug Discov Technol. 2012;9(3):166–72. https://doi.org/10.2174/157016312802650814.

    Article  CAS  PubMed  Google Scholar 

  71. Gomes-Solecki M, Santecchia I, Werts C. Animal models of leptospirosis: of mice and hamsters. Front Immunol. 2017;8:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Hirose M, Ogura A. The golden (Syrian) hamster as a model for the study of reproductive biology: past, present, and future. Reprod Med Biol. 2019;18(1):34–9.

    Article  PubMed  Google Scholar 

  73. Julander JG, Trent DW, Monath TP. Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model. Vaccine. 2011;29(35):6008–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Krötz F, Hellwig N, Bürkle MA, Lehrer S, Riexinger T, Mannell H, et al. A sulfaphenazole-sensitive EDHF opposes platelet–endothelium interactions in vitro and in the hamster microcirculation in vivo. Cardiovasc Res. 2010;85(3):542–50.

    Article  PubMed  CAS  Google Scholar 

  75. Miao J, Chard LS, Wang Z, Wang Y. Syrian hamster as an animal model for the study on infectious diseases. Front Immunol. 2019;10:2329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Molinari AJ, Aromando RF, Itoiz ME, Garabalino MA, Hughes AM, Heber EM, et al. Blood vessel normalization in the hamster oral cancer model for experimental cancer therapy studies. Anticancer Res. 2012;32(7):2703–9.

    CAS  PubMed  Google Scholar 

  77. Molinari AJ, Pozzi ECC, Hughes AM, Heber EM, Garabalino MA, Thorp SI, et al. “Sequential” boron neutron capture therapy (BNCT): A novel approach to BNCT for the treatment of oral cancer in the hamster cheek pouch model. Radiat Res. 2011;175(4):463–72.

    Article  CAS  PubMed  Google Scholar 

  78. Vernel-Pauillac F, Goarant C. Differential Cytokine gene expression according to outcome in a hamster model of leptospirosis. PLoS Negl Trop Dis. 2010;4(1): e582.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Walpita P, Cong Y, Jahrling PB, Rojas O, Postnikova E, Yu S, et al. A VLP-based vaccine provides complete protection against Nipah virus challenge following multiple-dose or single-dose vaccination schedules in a hamster model. Npj Vaccines. 2017;2:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Ye H, Yang K, Tan X-M, Fu X-J, Li H-X. Daily rhythm variations of the clock gene PER1 and cancer-related genes during various stages of carcinogenesis in a golden hamster model of buccal mucosa carcinoma. Onco Targets Ther. 2015;8:1419–26.

    PubMed  PubMed Central  Google Scholar 

  81. Zhang W, Xie X, Wang J, Song N, Lv T, Wu D, et al. Increased inflammation with crude E. coli LPS protects against acute leptospirosis in hamsters. Emerg Microbes Infect. 2020;9(1):140–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bajpayee AG, Scheu M, Grodzinsky AJ, Porter RM. A rabbit model demonstrates the influence of cartilage thickness on intra-articular drug delivery and retention within cartilage. J Orthop Res. 2015;33(5):660–7.

    Article  CAS  PubMed  Google Scholar 

  83. Brunner AM, Henn CM, Drewniak EI, Lesieur-Brooks A, Machan J, Crisco JJ, et al. High dietary fat and the development of osteoarthritis in a rabbit model. Osteoarthr Cartil. 2012;20(6):584–92.

    Article  CAS  Google Scholar 

  84. Camacho P, Fan H, Liu Z, He J-Q. Small mammalian animal models of heart disease. Am J Cardiovasc Dis. 2016;6(3):70–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Dos Santos RA, Südy R, Peták F, Habre W. Physiologically variable ventilation in a rabbit model of asthma exacerbation. Br J Anaesth. 2020;125(6):1107–16.

    Article  Google Scholar 

  86. Elmorsy S, Funakoshi T, Sasazawa F, Todoh M, Tadano S, Iwasaki N. Chondroprotective effects of high-molecular-weight cross-linked hyaluronic acid in a rabbit knee osteoarthritis model. Osteoarthritis Cartilage. 2014;22(1):121–7.

    Article  CAS  PubMed  Google Scholar 

  87. Fan J, Kitajima S, Watanabe T, Xu J, Zhang J, Liu E, et al. Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther. 2015;146:104–19.

    Article  CAS  PubMed  Google Scholar 

  88. Hu C-H, Tseng Y-W, Chiou C-Y, Lan K-C, Chou C-H, Tai C-S, et al. Bone marrow concentrate-induced mesenchymal stem cell conditioned medium facilitates wound healing and prevents hypertrophic scar formation in a rabbit ear model. Stem Cell Res Ther. 2019;10(1):275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kamaruzaman NA, Sulaiman SA, Kaur G, Yahaya B. Inhalation of honey reduces airway inflammation and histopathological changes in a rabbit model of ovalbumin-induced chronic asthma. BMC Complement Altern Med. 2014;14(1):176.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kobayashi T, Ito T, Shiomi M. Roles of the WHHL rabbit in translational research on hypercholesterolemia and cardiovascular diseases. J Biomed Biotechnol. 2011;2011: 406473.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Laverty S, Girard CA, Williams JM, Hunziker EB, Pritzker KPH. The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the rabbit. Osteoarthr Cartil. 2010;18:S53-65.

    Article  Google Scholar 

  92. Liang H, Baudouin C, Daull P, Garrigue J-S, Brignole-Baudouin F. Ocular safety of cationic emulsion of cyclosporine in an in vitro corneal wound-healing model and an acute in vivo rabbit model. Mol Vis. 2012;18:2195–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Liu QY, Koukiekolo R, Zhang DL, Smith B, Ly D, Lei JX, et al. Molecular events linking cholesterol to Alzheimer’s disease and inclusion body myositis in a rabbit model. Am J Neurodegener Dis. 2016;5(1):74–84.

    PubMed  PubMed Central  Google Scholar 

  94. Ludwig JM, Xing M, Gai Y, Sun L, Zeng D, Kim HS. Targeted yttrium 89-doxorubicin drug-eluting bead—a safety and feasibility pilot study in a rabbit liver cancer model. Mol Pharm. 2017;14(8):2824–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schoenberg ED, Blake DA, Swann FB, Parlin AW, Zurakowski D, Margo CE, et al. Effect of two novel sustained-release drug delivery systems on bleb fibrosis: an in vivo glaucoma drainage device study in a rabbit model. Transl Vis Sci Technol. 2015;4(3):4.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Schreurs BG, Smith-Bell CA, Lemieux SK. Dietary cholesterol increases ventricular volume and narrows cerebrovascular diameter in a rabbit model of Alzheimer’s disease. Neuroscience. 2013;254:61–9.

    Article  CAS  PubMed  Google Scholar 

  97. Shirai T, Kobayashi M, Nishitani K, Satake T, Kuroki H, Nakagawa Y, et al. Chondroprotective effect of alendronate in a rabbit model of osteoarthritis. J Orthop Res. 2011;29(10):1572–7.

    Article  CAS  PubMed  Google Scholar 

  98. Colbath AC, Frisbie DD, Dow SW, Kisiday JD, McIlwraith CW, Goodrich LR. Equine models for the investigation of mesenchymal stem cell therapies in orthopaedic disease. Oper Tech Sports Med. 2017;25(1):41–9.

    Article  Google Scholar 

  99. Gastal EL, de Gastal MO, Wischral Á, Davis J. The equine model to study the influence of obesity and insulin resistance in human ovarian function. Acta Sci Vet. 2011;39(Suppl 1):s57-70.

    Google Scholar 

  100. Kajabi AW, Casula V, Sarin JK, Ketola JH, Nykänen O, Te Moller NCR, et al. Evaluation of articular cartilage with quantitative MRI in an equine model of post-traumatic osteoarthritis. J Orthop Res. 2021;39(1):63–73.

    Article  CAS  PubMed  Google Scholar 

  101. Nixon AJ, Begum L, Mohammed HO, Huibregtse B, O’Callaghan MM, Matthews GL. Autologous chondrocyte implantation drives early chondrogenesis and organized repair in extensive full- and partial-thickness cartilage defects in an equine model. J Orthop Res. 2011;29(7):1121–30.

    Article  CAS  PubMed  Google Scholar 

  102. Vargas A, Boivin R, Cano P, Murcia Y, Bazin I, Lavoie JP. Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma. Respir Res. 2017;18(1):207.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Brooks-Pollock E, Wood JLN. Eliminating bovine tuberculosis in cattle and badgers: insight from a dynamic model. Proc Biol Sci. 1808;2015(282):20150374.

    Google Scholar 

  104. Chen Z, Robbins KM, Wells KD, Rivera RM. Large offspring syndrome. Epigenetics. 2013;8(6):591–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hoeck VV, Sturmey RG, Bermejo-Alvarez P, Rizos D, Gutierrez-Adan A, Leese HJ, et al. Elevated non-esterified fatty acid concentrations during bovine oocyte maturation compromise early embryo physiology. PLoS ONE. 2011;6(8): e23183.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Villarreal-Ramos B, Berg S, Chamberlain L, McShane H, Hewinson RG, Clifford D, et al. Development of a BCG challenge model for the testing of vaccine candidates against tuberculosis in cattle. Vaccine. 2014;32(43):5645–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Waters WR, Palmer MV, Thacker TC, Davis WC, Sreevatsan S, Coussens P, et al. Tuberculosis immunity: opportunities from studies with cattle. Clin Dev Immunol. 2010;2011: e768542.

    Google Scholar 

  108. Csepe TA, Kilic A. Advancements in mechanical circulatory support for patients in acute and chronic heart failure. J Thorac Dis. 2017;9(10):4070–83.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Elzaiat M, Jouneau L, Thépot D, Klopp C, Allais-Bonnet A, Cabau C, et al. High-throughput sequencing analyses of XX genital ridges lacking FOXL2 reveal DMRT1 Up-regulation before SOX9 expression during the sex-reversal process in goats. Biol Reprod. 2014;91(6):153.

    Article  PubMed  CAS  Google Scholar 

  110. Guan Y, Karkhanis T, Wang S, Rider A, Koenig SC, Slaughter MS, et al. Physiologic benefits of pulsatile perfusion during mechanical circulatory support for the treatment of acute and chronic heart failure in adults. Artif Organs. 2010;34(7):529–36.

    Article  PubMed  Google Scholar 

  111. Howarth WR, Brochard K, Campbell SE, Grogan BF. Effect of microfracture on meniscal tear healing in a goat (Capra hircus) model. Orthopedics. 2016;39(2):105–10. https://doi.org/10.3928/01477447-20160119-04.

    Article  PubMed  Google Scholar 

  112. Miyamoto T, Karimov JH, Xanthopoulos A, Starling RC, Fukamachi K. Large animal models to test mechanical circulatory support devices. Drug Discov Today Dis Models. 2017;24:47–53.

    Article  Google Scholar 

  113. Pannetier M, Elzaiat M, Thépot D, Pailhoux E. Telling the story of XX sex reversal in the goat: highlighting the sex-crossroad in domestic mammals. Sex Dev. 2012;6(1–3):33–45.

    Article  CAS  PubMed  Google Scholar 

  114. Hongli W, Fan Z, Feizhou Lv, Jianyuan J, Dayong L, Xinlei X. Osteoinductive activity of ErhBMP-2 after anterior cervical diskectomy and fusion with a ß-TCP interbody cage in a goat model. Orthopedics. 2014;37(2):e123–31.

    Google Scholar 

  115. Wang JL, Xu JK, Hopkins C, Chow DH, Qin L. Biodegradable magnesium-based implants in orthopedics—a general review and perspectives. Adv Sci. 2020;7(8):1902443.

    Article  CAS  Google Scholar 

  116. Wang Z, Zhai C, Fei H, Hu J, Cui W, Wang Z, et al. Intraarticular injection autologous platelet-rich plasma and bone marrow concentrate in a goat osteoarthritis model. J Orthop Res. 2018;36(8):2140–6.

    Article  CAS  Google Scholar 

  117. Clifton VL, McDonald M, Morrison JL, Holman SL, Lock MC, Saif Z, et al. Placental glucocorticoid receptor isoforms in a sheep model of maternal allergic asthma. Placenta. 2019;83:33–6.

    Article  CAS  PubMed  Google Scholar 

  118. Emmert MY, Schmitt BA, Loerakker S, Sanders B, Spriestersbach H, Fioretta ES, et al. Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model. Sci Transl Med. 2018;10(440):eaan4587.

    Article  PubMed  CAS  Google Scholar 

  119. Faburay B, Gaudreault NN, Liu Q, Davis AS, Shivanna V, Sunwoo SY, et al. Development of a sheep challenge model for Rift Valley fever. Virology. 2016;489:128–40.

    Article  CAS  PubMed  Google Scholar 

  120. Gerdts V, Wilson HL, Meurens F, van Drunen Littel S, van den Hurk S, Wilson D, Walker S, Wheler C, Townsend H, Potter AA. Large animal models for vaccine development and testing. ILAR J. 2015;56(1):53–62. https://doi.org/10.1093/ilar/ilv009.

    Article  CAS  PubMed  Google Scholar 

  121. Gouveris H, Nousia C, Giatromanolaki A, Riga M, Katotomichelakis M, Ypsilantis P, et al. Inferior nasal turbinate wound healing after submucosal radiofrequency tissue ablation and monopolar electrocautery: histologic study in a sheep model. Laryngoscope. 2010;120(7):1453–9.

    Article  PubMed  Google Scholar 

  122. Hosper NA, Eggink AJ, Roelofs LAJ, Wijnen RMH, van Luyn MJA, Bank RA, et al. Intra-uterine tissue engineering of full-thickness skin defects in a fetal sheep model. Biomaterials. 2010;31(14):3910–9.

    Article  CAS  PubMed  Google Scholar 

  123. Jäger M, Ott C-E, Grünhagen J, Hecht J, Schell H, Mundlos S, et al. Composite transcriptome assembly of RNA-seq data in a sheep model for delayed bone healing. BMC Genomics. 2011;12(1):158.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Lienau J, Schmidt-Bleek K, Peters A, Weber H, Bail HJ, Duda GN, et al. Insight into the molecular pathophysiology of delayed bone healing in a sheep model. Tissue Eng Part A. 2009;16(1):191–9.

    Article  CAS  Google Scholar 

  125. Malhotra A, Pelletier MH, Yu Y, Christou C, Walsh WR. A sheep model for cancellous bone healing. Front Surg. 2014;1:37.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Martinello T, Gomiero C, Perazzi A, Iacopetti I, Gemignani F, DeBenedictis GM, et al. Allogeneic mesenchymal stem cells improve the wound healing process of sheep skin. BMC Vet Res. 2018;14(1):202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Swibel-Rosenthal LH, Benninger MS, Stone CH, Zacharek MA. Wound healing in the paranasal sinuses after coblation, part II: evaluation for endoscopic sinus surgery using a sheep model. Am J Rhinol Allergy. 2010;24(6):464–6.

    Article  PubMed  Google Scholar 

  128. Theodoridis K, Tudorache I, Calistru A, Cebotari S, Meyer T, Sarikouch S, et al. Successful matrix guided tissue regeneration of decellularized pulmonary heart valve allografts in elderly sheep. Biomaterials. 2015;52:221–8.

    Article  CAS  PubMed  Google Scholar 

  129. Van der Velden J, Harkness LM, Barker DM, Barcham GJ, Ugalde CL, Koumoundouros E, et al. The effects of tumstatin on vascularity, airway inflammation and lung function in an experimental sheep Model of chronic asthma. Sci Rep. 2016;6(1):26309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Asquith CRM, Sil BC, Laitinen T, Tizzard GJ, Coles SJ, Poso A, et al. Novel epidithiodiketopiperazines as anti-viral zinc ejectors of the feline immunodeficiency virus (FIV) nucleocapsid protein as a model for HIV infection. Bioorg Med Chem. 2019;27(18):4174–84.

    Article  CAS  PubMed  Google Scholar 

  131. Aun MV, Bonamichi-Santos R, Arantes-Costa FM, Kalil J, Giavina-Bianchi P. Animal models of asthma: utility and limitations. J Asthma Allergy. 2017;10:293–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Clowry GJ, Basuodan R, Chan F. What are the best animal models for testing early intervention in cerebral palsy? Front Neurol. 2014;5:258.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Cohn LA, DeClue AE, Cohen RL, Reinero CR. Effects of fluticasone propionate dosage in an experimental model of feline asthma. J Feline Med Surg. 2010;12(2):91–6.

    Article  PubMed  Google Scholar 

  134. Hoenig M. The cat as a model for human obesity and diabetes. J Diabetes Sci Technol. 2012;6(3):525–33.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Lee-Fowler TM, Guntur V, Dodam J, Cohn LA, DeClue AE, Reinero CR. The tyrosine kinase inhibitor masitinib blunts airway inflammation and improves associated lung mechanics in a feline Model of chronic allergic asthma. Int Arch Allergy Immunol. 2012;158(4):369–74.

    Article  CAS  PubMed  Google Scholar 

  136. Martin JH, Chakrabarty S, Friel KM. Harnessing activity-dependent plasticity to repair the damaged corticospinal tract in an animal model of cerebral palsy. Dev Med Child Neurol. 2011;53(s4):9–13.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Meeker RB, Hudson L. Feline immunodeficiency virus neuropathogenesis: a model for HIV-induced Cns inflammation and neurodegeneration. Vet Sci. 2017;4(1):14.

    Article  PubMed Central  Google Scholar 

  138. Thoms F, Jennings GT, Maudrich M, Vogel M, Haas S, Zeltins A, et al. Immunization of cats to induce neutralizing antibodies against Fel d 1, the major feline allergen in human subjects. J Allergy Clin Immunol. 2019;144(1):193–203.

    Article  CAS  PubMed  Google Scholar 

  139. Trzil JE, Masseau I, Webb TL, Chang C-H, Dodam JR, Cohn LA, et al. Long-term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma. Clin Exp Allergy. 2014;44(12):1546–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Yamamoto JK, Sanou MP, Abbott JR, Coleman JK. Feline immunodeficiency virus model for designing HIV/AIDS vaccines. Curr HIV Res. 2010;8(1):14–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Brown DC, Agnello K, Iadarola MJ. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain. 2015;156(6):1018–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cantore A, Ranzani M, Bartholomae CC, Volpin M, Valle PD, Sanvito F, et al. Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med. 2015;7(277):277ra28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Correard S, Plassais J, Lagoutte L, Botherel N, Thibaud J-L, Hédan B, et al. Canine neuropathies: powerful spontaneous models for human hereditary sensory neuropathies. Hum Genet. 2019;138(5):455–66.

    Article  CAS  PubMed  Google Scholar 

  144. Elbadawy M, Usui T, Mori T, Tsunedomi R, Hazama S, Nabeta R, et al. Establishment of a novel experimental model for muscle-invasive bladder cancer using a dog bladder cancer organoid culture. Cancer Sci. 2019;110(9):2806–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. French RA, Samelson-Jones BJ, Niemeyer GP, Lothrop CD Jr, Merricks EP, Nichols TC, et al. Complete correction of hemophilia B phenotype by FIX-Padua skeletal muscle gene therapy in an inhibitor-prone dog model. Blood Adv. 2018;2(5):505–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. John J, Thannickal TC, McGregor R, Ramanathan L, Ohtsu H, Nishino S, et al. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann Neurol. 2013;74(6):786–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mohammed SI, Utturkar S, Lee M, Yang HH, Cui Z, Atallah Lanman N, et al. Ductal carcinoma in situ progression in dog model of breast cancer. Cancers. 2020;12(2):418.

    Article  CAS  Google Scholar 

  148. Stark H, Fischer MS, Hunt A, Young F, Quinn R, Andrada E. A three-dimensional musculoskeletal model of the dog. Sci Rep. 2021;11(1):11335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Story BD, Miller ME, Bradbury AM, Million ED, Duan D, Taghian T, et al. Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci. 2020;7:80.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Switonski M. Dog as a model in studies on human hereditary diseases and their gene therapy. Reprod Biol. 2014;14(1):44–50.

    Article  PubMed  Google Scholar 

  151. Acharya NK, Qi X, Goldwaser EL, Godsey GA, Wu H, Kosciuk MC, et al. Retinal pathology is associated with increased blood–retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2 inhibitor Darapladib. Diab Vasc Dis Res. 2017;14(3):200–13.

    Article  CAS  PubMed  Google Scholar 

  152. Bassols A, Costa C, Eckersall PD, Osada J, Sabrià J, Tibau J. The pig as an animal model for human pathologies: a proteomics perspective. Proteomics Clin Appl. 2014;8(9–10):715–31.

    Article  CAS  PubMed  Google Scholar 

  153. Bolli R, Tang X-L, Sanganalmath SK, Rimoldi O, Mosna F, Abdel-Latif A, et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation. 2013;128(2):122–31.

    Article  CAS  PubMed  Google Scholar 

  154. Luo Y, Li J, Liu Y, Lin L, Du Y, Li S, et al. High efficiency of BRCA1 knockout using rAAV-mediated gene targeting: developing a pig model for breast cancer. Transgenic Res. 2011;20(5):975–88.

    Article  CAS  PubMed  Google Scholar 

  155. van Hout GPJ, Bosch L, Ellenbroek GHJM, de Haan JJ, van Solinge WW, Cooper MA, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. 2017;38(11):828–36.

    PubMed  Google Scholar 

  156. Wahlberg LU, Lind G, Almqvist PM, Kusk P, Tornøe J, Juliusson B, et al. Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery: clinical article. J Neurosurg. 2012;117(2):340–7.

    Article  PubMed  Google Scholar 

  157. Palmiter RD, Norstedt G, Gelinas RE, Hammer RE, Brinster RL. Metallothionein-human GH fusion genes stimulate growth of mice. Science. 1983;222(4625):809–14.

    Article  CAS  PubMed  Google Scholar 

  158. Kato T, Takada S. In vivo and in vitro disease modeling with CRISPR/Cas9. Brief Funct Genomics. 2017;16(1):13–24.

    Article  CAS  PubMed  Google Scholar 

  159. Yang L, Guell M, Byrne S, Yang JL, De Los AA, Mali P, et al. Optimization of scarless human stem cell genome editing. Nucleic Acids Res. 2013;41(19):9049–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Seruggia D, Fernández A, Cantero M, Pelczar P, Montoliu L. Functional validation of mouse tyrosinase non-coding regulatory DNA elements by CRISPR–Cas9-mediated mutagenesis. Nucleic Acids Res. 2015;43(10):4855–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Mei Y, Wang Y, Chen H, Sun ZS, Ju X-D. Recent progress in CRISPR/Cas9 technology. J Genet Genomics. 2016;43(2):63–75.

    Article  PubMed  Google Scholar 

  162. Dow LE. Modeling disease in vivo with CRISPR/Cas9. Trends Mol Med. 2015;21(10):609–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, et al. CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell. 2014;159(2):440–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Xue W, Chen S, Yin H, Tammela T, Papagiannakopoulos T, Joshi NS, et al. CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature. 2014;514(7522):380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Badyal DK, Desai C. Animal use in pharmacology education and research: the changing scenario. Indian J Pharmacol. 2014;46(3):257–65.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Fox JG, Barthold SW, Davisson MT, Newcomer CE, Quimby FW, Smith AL. The mouse in biomedical research. Elsevier Inc.; 2007.

    Google Scholar 

  167. Lee DJ, Diachina S, Lee YT, Zhao L, Zou R, Tang N, et al. Decellularized bone matrix grafts for calvaria regeneration. J Tissue Eng. 2016;7:2041731416680306.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Liu M, Lv Y. Reconstructing bone with natural bone graft: a review of in vivo studies in bone defect animal model. Nanomaterials. 2018;8(12):999.

    Article  PubMed Central  CAS  Google Scholar 

  169. Spicer PP, Kretlow JD, Young S, Jansen JA, Kasper FK, Mikos AG. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc. 2012;7(10):1918–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ball AN, Donahue SW, Wojda SJ, McIlwraith CW, Kawcak CE, Ehrhart N, et al. The challenges of promoting osteogenesis in segmental bone defects and osteoporosis. J Orthop Res. 2018;36(6):1559–72.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Liebschner MAK. Biomechanical considerations of animal models used in tissue engineering of bone. Biomaterials. 2004;25(9):1697–714.

    Article  CAS  PubMed  Google Scholar 

  172. Bagi CM, Berryman E, Moalli MR. Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery. Comp Med. 2011;61(1):76–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Peric M, Dumic-Cule I, Grcevic D, Matijasic M, Verbanac D, Paul R, et al. The rational use of animal models in the evaluation of novel bone regenerative therapies. Bone. 2015;70:73–86.

    Article  CAS  PubMed  Google Scholar 

  174. Begam H, Nandi SK, Chanda A, Kundu B. Effect of bone morphogenetic protein on Zn-HAp and Zn-HAp/collagen composite: a systematic in vivo study. Res Vet Sci. 2017;115:1–9.

    Article  CAS  PubMed  Google Scholar 

  175. Dasgupta S, Maji K, Nandi SK. Investigating the mechanical, physiochemical and osteogenic properties in gelatin-chitosan-bioactive nanoceramic composite scaffolds for bone tissue regeneration: in vitro and in vivo. Mater Sci Eng C Mater Biol Appl. 2019;94:713–28.

    Article  CAS  PubMed  Google Scholar 

  176. Kasten P, Vogel J, Geiger F, Niemeyer P, Luginbühl R, Szalay K. The effect of platelet-rich plasma on healing in critical-size long-bone defects. Biomaterials. 2008;29(29):3983–92.

    Article  CAS  PubMed  Google Scholar 

  177. Khan PK, Mahato A, Kundu B, Nandi SK, Mukherjee P, Datta S, et al. Influence of single and binary doping of strontium and lithium on in vivo biological properties of bioactive glass scaffolds. Sci Rep. 2016;6(1):32964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mukherjee S, Nandi SK, Kundu B, Chanda A, Sen S, Das PK. Enhanced bone regeneration with carbon nanotube reinforced hydroxyapatite in animal model. J Mech Behav Biomed Mater. 2016;60:243–55.

    Article  CAS  PubMed  Google Scholar 

  179. Mapara M, Thomas BS, Bhat KM. Rabbit as an animal model for experimental research. Dent Res J. 2012;9(1):111–8.

    Article  Google Scholar 

  180. Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007;13:1–10.

    Article  CAS  PubMed  Google Scholar 

  181. Ewing KK. Anesthesia techniques in sheep and goats. Vet Clin North Am Food Anim Pract. 1990;6(3):759–78.

    Article  CAS  PubMed  Google Scholar 

  182. Liu G, Zhao L, Zhang W, Cui L, Liu W, Cao Y. Repair of goat tibial defects with bone marrow stromal cells and β-tricalcium phosphate. J Mater Sci Mater Med. 2008;19(6):2367–76.

    Article  CAS  PubMed  Google Scholar 

  183. Nandi SK, Kundu B, Datta S, De DK, Basu D. The repair of segmental bone defects with porous bioglass: an experimental study in goat. Res Vet Sci. 2009;86(1):162–73.

    Article  CAS  PubMed  Google Scholar 

  184. Nandi SK, Kundu B, Ghosh SK, De DK, Basu D. Efficacy of nano-hydroxyapatite prepared by an aqueous solution combustion technique in healing bone defects of goat. J Vet Sci. 2008;9(2):183–91.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Wang L, Fan H, Zhang Z-Y, Lou A-J, Pei G-X, Jiang S, et al. Osteogenesis and angiogenesis of tissue-engineered bone constructed by prevascularized β-tricalcium phosphate scaffold and mesenchymal stem cells. Biomaterials. 2010;31(36):9452–61.

    Article  CAS  PubMed  Google Scholar 

  186. Aerssens J, Boonen S, Lowet G, Dequeker J. Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology. 1998;139(2):663–70.

    Article  CAS  PubMed  Google Scholar 

  187. Kundu B, Nandi SK, Roy S, Dandapat N, Soundrapandian C, Datta S, et al. Systematic approach to treat chronic osteomyelitis through ceftriaxone–sulbactam impregnated porous β-tri calcium phosphate localized delivery system. Ceram Int. 2012;38(2):1533–48.

    Article  CAS  Google Scholar 

  188. Nandi SK, Shivaram A, Bose S, Bandyopadhyay A. Silver nanoparticle deposited implants to treat osteomyelitis. J Biomed Mater Res B Appl Biomater. 2018;106(3):1073–83.

    Article  CAS  PubMed  Google Scholar 

  189. Nandi SK, Kundu B, Mukherjee P, Mandal TK, Datta S, De DK, et al. In vitro and in vivo release of cefuroxime axetil from bioactive glass as an implantable delivery system in experimental osteomyelitis. Ceram Int. 2009;35(8):3207–16.

    Article  CAS  Google Scholar 

  190. Nandi SK, Kundu B, Ghosh SK, Mandal TK, Datta S, De DK, et al. Cefuroxime-impregnated calcium phosphates as an implantable delivery system in experimental osteomyelitis. Ceram Int. 2009;35(4):1367–76.

    Article  CAS  Google Scholar 

  191. Patel M, Rojavin Y, Jamali AA, Wasielewski SJ, Salgado CJ. Animal models for the study of osteomyelitis. Semin Plast Surg. 2009;23(2):148–54.

    Article  PubMed  PubMed Central  Google Scholar 

  192. Schulz S, Steinhart H, Mutters R. Chronic osteomyelitis in a new rabbit model. J Invest Surg. 2001;14(2):121–31.

    Article  CAS  PubMed  Google Scholar 

  193. Reizner W, Hunter JG, O’Malley NT, Southgate RD, Schwarz EM, Kates SL. A systematic review of animal models for Staphylococcus aureus osteomyelitis. Eur Cell Mater. 2014;27:196–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Lucke M, Schmidmaier G, Sadoni S, Wildemann B, Schiller R, Stemberger A, et al. A new model of implant-related osteomyelitis in rats. J Biomed Mater Res B Appl Biomater. 2003;67(1):593–602.

    Article  CAS  PubMed  Google Scholar 

  195. Wenke JC, Owens BD, Svoboda SJ, Brooks DE. Effectiveness of commercially-available antibiotic-impregnated implants. J Bone Joint Surg Br. 2006;88(8):1102–4.

    Article  CAS  PubMed  Google Scholar 

  196. Baofeng L, Zhi Y, Bei C, Guolin M, Qingshui Y, Jian L. Characterization of a rabbit osteoporosis model induced by ovariectomy and glucocorticoid. Acta Orthop. 2010;81(3):396–401.

    Article  PubMed  PubMed Central  Google Scholar 

  197. Kaveh K, Ibrahim R, AbuBakar MZ, Ibrahim TA. Osteoporosis induction in animal model. Am J Anim Vet Sci. 2010;5(2):139–45.

    Article  Google Scholar 

  198. Oue H, Doi K, Oki Y, Makihara Y, Kubo T, Perrotti V, et al. Influence of implant surface topography on primary stability in a standardized osteoporosis rabbit model study. J Funct Biomater. 2015;6(1):143–52.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Wanderman NR, Mallet C, Giambini H, Bao N, Zhao C, An K-N, et al. An ovariectomy-induced rabbit osteoporotic model: a new perspective. Asian Spine J. 2018;12(1):12–7.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Permuy M, López-Peña M, Muñoz F, González-Cantalapiedra A. Rabbit as model for osteoporosis research. J Bone Miner Metab. 2019;37(4):573–83.

    Article  PubMed  Google Scholar 

  201. Lill CA, Hesseln J, Schlegel U, Eckhardt C, Goldhahn J, Schneider E. Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res. 2003;21(5):836–42.

    Article  CAS  PubMed  Google Scholar 

  202. Zarrinkalam MR, Beard H, Schultz CG, Moore RJ. Validation of the sheep as a large animal model for the study of vertebral osteoporosis. Eur Spine J. 2009;18(2):244–53.

    Article  CAS  PubMed  Google Scholar 

  203. Egermann M, Goldhahn J, Schneider E. Animal models for fracture treatment in osteoporosis. Osteoporos Int. 2005;16(2):S129–38.

    Article  PubMed  Google Scholar 

  204. Turner AS. The sheep as a model for osteoporosis in humans. Vet J. 2002;163(3):232–9.

    Article  CAS  PubMed  Google Scholar 

  205. Blattmann C, Thiemann M, Stenzinger A, Roth EK, Dittmar A, Witt H, et al. Establishment of a patient-derived orthotopic osteosarcoma mouse model. J Transl Med. 2015;13(1):136.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  206. Uluçkan Ö, Segaliny A, Botter S, Santiago JM, Mutsaers AJ. Preclinical mouse models of osteosarcoma. BoneKEy Rep. 2015;4:670.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Ek ETH, Dass CR, Choong PFM. Commonly used mouse models of osteosarcoma. Crit Rev Oncol Hematol. 2006;60(1):1–8.

    Article  PubMed  Google Scholar 

  208. Sriyani KA, Wasalathanthri S, Hettiarachchi P, Prathapan S. Predictors of diabetic foot and leg ulcers in a developing country with a rapid increase in the prevalence of diabetes mellitus. PLoS ONE. 2013;8(11): e80856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Haji Zaine N, Burns J, Vicaretti M, Fletcher JP, Begg L, Hitos K. Characteristics of diabetic foot ulcers in Western Sydney, Australia. J Foot Ankle Res. 2014;7(1):39.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217–28.

    Article  CAS  PubMed  Google Scholar 

  211. Wu S, Armstrong DG. Risk assessment of the diabetic foot and wound. Int Wound J. 2005;2(1):17–24.

    Article  PubMed  PubMed Central  Google Scholar 

  212. Jorge SA, Dantas SRPE. Abordagem multiprofissional do tratamento de feridas. 2003;378. São Paulo; Atheneu; 2005. p 378.

  213. Barret JP, Herndon DN. Modulation of inflammatory and catabolic responses in severely burned children by early burn wound excision in the first 24 hours. Arch Surg. 2003;138(2):127–32.

    Article  PubMed  Google Scholar 

  214. Ramos-e-Silva M, de Castro MCR. New dressings, including tissue-engineered living skin. Clin Dermatol. 2002;20(6):715–23.

    Article  PubMed  Google Scholar 

  215. Sheridan RL, Hinson MI, Liang MH, Nackel AF, Schoenfeld DA, Ryan CM, et al. Long-term Outcome of children surviving massive burns. JAMA. 2000;283(1):69–73.

    Article  CAS  PubMed  Google Scholar 

  216. Pimple B, Kadam P, Patil MJ. Ulcer healing properties of different extracts of Origanum majorana in streptozotocin-nicotinamide induced diabetic rats. Asian Pac J Trop Dis. 2012;2(4):312–8.

    Article  Google Scholar 

  217. Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D, et al. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes. 1998;47(2):224–9.

    Article  CAS  PubMed  Google Scholar 

  218. Muhammad AA, Arulselvan P, Cheah PS, Abas F, Fakurazi S. Evaluation of wound healing properties of bioactive aqueous fraction from Moringa oleifera Lam on experimentally induced diabetic animal model. Drug Des Devel Ther. 2016;10:1715–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Khorshid F, Ali Abdulhadi S, Alsufyani T, Albar H. Plectranthus tenuiflorus (Shara) promotes wound healing: in vitro and in vivo studies. Int J Bot. 2010;6(2):69–80.

    Article  CAS  Google Scholar 

  220. Wang Y, Beekman J, Hew J, Jackson S, Issler-Fisher AC, Parungao R, et al. Burn injury: challenges and advances in burn wound healing, infection, pain and scarring. Adv Drug Deliv Rev. 2018;123:3–17.

    Article  CAS  PubMed  Google Scholar 

  221. Massone F. Anestesiologia veterinária: farmacologia e técnicas. In: Anestesiol Veterinária Farmacol E Téc., Rio de Janeiro: Guanabara; 1988. p 235.

  222. Campelo APBS, Campelo MWS, de Britto GAC, Ayala AP, Guimarães SB, de Vasconcelos PRL. An optimized animal model for partial and total skin thickness burns studies. Acta Cirúrgica Bras. 2011;26:38–42.

    Article  Google Scholar 

  223. Shukla SK, Sharma AK, Shaw P, Kalonia A, Yashavarddhan MH, Singh S. Creation of rapid and reproducible burn in animal model with a newly developed burn device. Burns. 2020;46(5):1142–9.

    Article  PubMed  Google Scholar 

  224. dos Tavares Pereira DS, Lima-Ribeiro MHM, de Pontes-Filho NT, dos Carneiro-Leão AMA, dos Correia MTS. Development of animal model for studying deep second-degree thermal burns. J Biomed Biotechnol. 2012;2012:e460841.

    Article  Google Scholar 

  225. Calum H, Høiby N, Moser C. Burn mouse models. Methods Mol Biol Clifton NJ. 2014;1149:793–802.

    Article  Google Scholar 

  226. Cuttle L, Kempf M, Phillips GE, Mill J, Hayes MT, Fraser JF, et al. A porcine deep dermal partial thickness burn model with hypertrophic scarring. Burns. 2006;32(7):806–20.

    Article  PubMed  Google Scholar 

  227. Deng X, Chen Q, Qiang L, Chi M, Xie N, Wu Y, et al. Development of a porcine full-thickness burn hypertrophic scar model and investigation of the effects of shikonin on hypertrophic scar remediation. Front Pharmacol. 2018;9:590.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Friedrich EE, Niknam-Bienia S, Xie P, Jia S-X, Hong SJ, Mustoe TA, et al. Thermal injury model in the rabbit ear with quantifiable burn progression and hypertrophic scar. Wound Repair Regen. 2017;25(2):327–37.

    Article  PubMed  Google Scholar 

  229. Hew JJ, Parungao RJ, Shi H, Tsai KH-Y, Kim S, Ma D, Malcolm J, Li Z, Maitz PK, Wang Y. Mouse models in burns research: characterisation of the hypermetabolic response to burn injury. Burns. 2020;46(3):663–74. https://doi.org/10.1016/j.burns.2019.09.014.

    Article  PubMed  Google Scholar 

  230. Chu CR, Szczodry M, Bruno S. Animal Models for cartilage regeneration and repair. Tissue Eng Part B Rev. 2010;16(1):105–15.

    Article  PubMed  PubMed Central  Google Scholar 

  231. Chung JY, Song M, Ha C-W, Kim J-A, Lee C-H, Park Y-B. Comparison of articular cartilage repair with different hydrogel-human umbilical cord blood-derived mesenchymal stem cell composites in a rat model. Stem Cell Res Ther. 2014;5(2):39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Gregory MH, Capito N, Kuroki K, Stoker AM, Cook JL, Sherman SL. A review of translational animal models for knee osteoarthritis. Arthritis. 2012;2012:e764621.

    Article  Google Scholar 

  233. Hurtig MB, Buschmann MD, Fortier LA, Hoemann CD, Hunziker EB, Jurvelin JS, et al. Preclinical studies for cartilage repair: recommendations from the international cartilage repair society. Cartilage. 2011;2(2):137–52.

    Article  PubMed  PubMed Central  Google Scholar 

  234. McGowan KB, Stiegman G. Regulatory challenges for cartilage repair technologies. Cartilage. 2013;4(1):4–11.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Mithoefer K, Saris DBF, Farr J, Kon E, Zaslav K, Cole BJ, et al. Guidelines for the design and conduct of clinical studies in knee articular cartilage repair: international cartilage repair society recommendations based on current scientific evidence and standards of clinical care. Cartilage. 2011;2(2):100–21.

    Article  PubMed  PubMed Central  Google Scholar 

  236. Moyer HR, Wang Y, Farooque T, Wick T, Singh KA, Xie L, et al. A new animal model for assessing cartilage repair and regeneration at a nonarticular site. Tissue Eng Part A. 2010;16(7):2321–30.

    Article  CAS  PubMed  Google Scholar 

  237. Das P, Mishra R, Devi B, Rajesh K, Basak P, Roy M, et al. Decellularized xenogenic cartilage extracellular matrix (ECM) scaffolds for the reconstruction of osteochondral defects in rabbits. J Mater Chem B. 2021;9(24):4873–94.

    Article  CAS  PubMed  Google Scholar 

  238. Orth P, Zurakowski D, Wincheringer D, Madry H. Reliability, reproducibility, and validation of five major histological scoring systems for experimental articular cartilage repair in the rabbit model. Tissue Eng Part C Methods. 2012;18(5):329–39.

    Article  CAS  PubMed  Google Scholar 

  239. Qi Y, Du Y, Li W, Dai X, Zhao T, Yan W. Cartilage repair using mesenchymal stem cell (MSC) sheet and MSCs-loaded bilayer PLGA scaffold in a rabbit model. Knee Surg Sports Traumatol Arthrosc. 2014;22(6):1424–33.

    Article  PubMed  Google Scholar 

  240. Desando G, Giavaresi G, Cavallo C, Bartolotti I, Sartoni F, Nicoli Aldini N, et al. Autologous bone marrow concentrate in a sheep model of osteoarthritis: new perspectives for cartilage and meniscus repair. Tissue Eng Part C Methods. 2016;22(6):608–19.

    Article  CAS  PubMed  Google Scholar 

  241. Marmotti A, Bruzzone M, Bonasia DE, Castoldi F, Degerfeld MMV, Bignardi C, et al. Autologous cartilage fragments in a composite scaffold for one stage osteochondral repair in a goat model. Eur Cell Mater. 2013;26:15–32.

    Article  CAS  PubMed  Google Scholar 

  242. Miot S, Brehm W, Dickinson S, Sims T, Wixmerten A, Longinotti C, et al. Influence of in vitro maturation of engineered cartilage on the outcome of osteochondral repair in a goat model. Eur Cell Mater. 2012;23:222–36.

    Article  CAS  PubMed  Google Scholar 

  243. Ude CC, Sulaiman SB, Min-Hwei N, Hui-Cheng C, Ahmad J, Yahaya NM, et al. Cartilage regeneration by chondrogenic induced Adult stem cells in osteoarthritic sheep model. PLoS ONE. 2014;9(6): e98770.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Proffen BL, McElfresh M, Fleming BC, Murray MM. A comparative anatomical study of the human knee and six animal species. Knee. 2012;19(4):493–9.

    Article  PubMed  Google Scholar 

  245. LaPrade RF, Kimber KA, Wentorf FA, Olson EJ. Anatomy of the posterolateral aspect of the goat knee. J Orthop Res. 2006;24(2):141–8.

    Article  PubMed  Google Scholar 

  246. Cook JL, Hung CT, Kuroki K, Stoker AM, Cook CR, Pfeiffer FM, et al. Animal models of cartilage repair. Bone Jt Res. 2014;3(4):89–94.

    Article  CAS  Google Scholar 

  247. Sasaki A, Mizuno M, Mochizuki M, Sekiya I. Mesenchymal stem cells for cartilage regeneration in dogs. World J Stem Cells. 2019;11(5):254–69.

    Article  PubMed  PubMed Central  Google Scholar 

  248. Ahern BJ, Parvizi J, Boston R, Schaer TP. Preclinical animal models in single site cartilage defect testing: a systematic review. Osteoarthr Cartil. 2009;17(6):705–13.

    Article  CAS  Google Scholar 

  249. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Executive summary: heart disease and stroke statistics—2014 update. Circulation. 2014;129(3):399–410.

    Article  PubMed  Google Scholar 

  250. Li S, Sengupta D, Chien S. Vascular tissue engineering: from in vitro to in situ. WIREs Syst Biol Med. 2014;6(1):61–76.

    Article  CAS  Google Scholar 

  251. Nerem RM, Seliktar D. Vascular tissue engineering. Annu Rev Biomed Eng. 2001;3(1):225–43.

    Article  CAS  PubMed  Google Scholar 

  252. Kannan RY, Salacinski HJ, Butler PE, Hamilton G, Seifalian AM. Current status of prosthetic bypass grafts: a review. J Biomed Mater Res B Appl Biomater. 2005;74B(1):570–81.

    Article  CAS  Google Scholar 

  253. Ziegler KR, Muto A, Eghbalieh SDD, Dardik A. Basic data related to surgical infrainguinal revascularization procedures: a twenty year update. Ann Vasc Surg. 2011;25(3):413–22.

    Article  PubMed  PubMed Central  Google Scholar 

  254. Tillman BW, Yazdani SK, Neff LP, Corriere MA, Christ GJ, Soker S, et al. Bioengineered vascular access maintains structural integrity in response to arteriovenous flow and repeated needle puncture. J Vasc Surg. 2012;56(3):783–93.

    Article  PubMed  Google Scholar 

  255. Ye L, Wu X, Mu Q, Chen B, Duan Y, Geng X, et al. Heparin-conjugated pcl scaffolds fabricated by electrospinning and loaded with fibroblast growth factor 2. J Biomater Sci Polym Ed. 2011;22(1–3):389–406.

    Article  CAS  PubMed  Google Scholar 

  256. Wang S, Mo XM, Jiang BJ, Gao CJ, Wang HS, Zhuang YG, et al. Fabrication of small-diameter vascular scaffolds by heparin-bonded P(LLA-CL) composite nanofibers to improve graft patency. Int J Nanomedicine. 2013;8:2131–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  257. Huang C, Wang S, Qiu L, Ke Q, Zhai W, Mo X. Heparin loading and pre-endothelialization in enhancing the patency rate of electrospun small-diameter vascular grafts in a canine model. ACS Appl Mater Interfaces. 2013;5(6):2220–6.

    Article  CAS  PubMed  Google Scholar 

  258. Syedain ZH, Meier LA, Lahti MT, Johnson SL, Tranquillo RT. Implantation of completely biological engineered grafts following decellularization into the sheep femoral artery. Tissue Eng Part A. 2014;20(11–12):1726–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Koobatian MT, Row S, Smith RJ Jr, Koenigsknecht C, Andreadis ST, Swartz DD. Successful endothelialization and remodeling of a cell-free small-diameter arterial graft in a large animal model. Biomaterials. 2016;76:344–58.

    Article  CAS  PubMed  Google Scholar 

  260. Chan AHP, Tan RP, Michael PL, Lee BSL, Vanags LZ, Ng MKC, et al. Evaluation of synthetic vascular grafts in a mouse carotid grafting model. PLoS ONE. 2017;12(3): e0174773.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Hu Y-T, Pan X-D, Zheng J, Ma W-G, Sun L-Z. In vitro and in vivo evaluation of a small-caliber coaxial electrospun vascular graft loaded with heparin and VEGF. Int J Surg. 2017;44:244–9.

    Article  PubMed  Google Scholar 

  262. Matsuzaki Y, Miyamoto S, Miyachi H, Iwaki R, Shoji T, Blum K, et al. Improvement of a novel small-diameter tissue-engineered arterial graft with heparin conjugation. Ann Thorac Surg. 2021;111(4):1234–41.

    Article  PubMed  Google Scholar 

  263. Antonova LV, Mironov AV, Yuzhalin AE, Krivkina EO, Shabaev AR, Rezvova MA, et al. A brief report on an implantation of small-caliber biodegradable vascular grafts in a carotid artery of the sheep. Pharmaceuticals. 2020;13(5):101.

    Article  CAS  PubMed Central  Google Scholar 

  264. Cappello R, Bird JLE, Pfeiffer D, Bayliss MT, Dudhia J. Notochordal cell produce and assemble extracellular matrix in a distinct manner, which may be responsible for the maintenance of healthy nucleus pulposus. Spine. 2006;31(8):873–82. https://doi.org/10.1097/01.brs.0000209302.00820.fd.

    Article  PubMed  Google Scholar 

  265. Centers for Disease Control and Prevention (CDC). Prevalence and most common causes of disability among adults–United States 2005. MMWR Morb Mortal Wkly Rep. 2009;58(16):421–6.

    Google Scholar 

  266. Webb AA. Potential sources of neck and back pain in clinical conditions of dogs and cats: a review. Vet J Lond Engl 1997. 2003;165(3):193–213.

    Google Scholar 

  267. Yelin E, Weinstein S, King T. The burden of musculoskeletal diseases in the United States. Semin Arthritis Rheum. 2016;46(3):259–60.

    Article  PubMed  Google Scholar 

  268. Gullbrand SE, Malhotra NR, Schaer TP, Zawacki Z, Martin JT, Bendigo JR, et al. A large animal model that recapitulates the spectrum of human intervertebral disc degeneration. Osteoarthritis Cartilage. 2017;25(1):146–56.

    Article  CAS  PubMed  Google Scholar 

  269. Zhang C, Gullbrand SE, Schaer TP, Lau YK, Jiang Z, Dodge GR, et al. Inflammatory cytokine and catabolic enzyme expression in a goat model of intervertebral disc degeneration. J Orthop Res. 2020;38(11):2521–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Zhang Y, Drapeau S, An HS, Markova D, Lenart BA, Anderson DG. Histological features of the degenerating intervertebral disc in a goat disc-injury model. Spine. 2011;36(19):1519–27.

    Article  PubMed  PubMed Central  Google Scholar 

  271. Patel SA, Kepler CK, Schaer TP, Anderson DG. Large animal models of disc degeneration. In: Shapiro IM, Risbud MV, editors. The Intervertebral Disc: molecular and structural studies of the disc in health and disease. Vienna: Springer; 2014. p. 291–303.

    Chapter  Google Scholar 

  272. Malli SE, Kumbhkarn P, Dewle A, Srivastava A. Evaluation of tissue engineering approaches for intervertebral disc regeneration in relevant animal models. ACS Appl Bio Mater. 2021;4(11):7721–37.

    Article  CAS  PubMed  Google Scholar 

  273. Ashinsky BG, Gullbrand SE, Bonnevie ED, Mandalapu SA, Wang C, Elliott DM, et al. Multiscale and multimodal structure–function analysis of intervertebral disc degeneration in a rabbit model. Osteoarthr Cartil. 2019;27(12):1860–9.

    Article  CAS  Google Scholar 

  274. Kroeber MW, Unglaub F, Wang H, Schmid C, Thomsen M, Nerlich A, et al. New in vivo animal model to create intervertebral disc degeneration and to investigate the effects of therapeutic strategies to stimulate disc regeneration. Spine. 2002;27(23):2684–90.

    Article  PubMed  Google Scholar 

  275. Leckie SK, Bechara BP, Hartman RA, Sowa GA, Woods BI, Coelho JP, et al. Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J. 2012;12(1):7–20.

    Article  PubMed  Google Scholar 

  276. Mwale F, Masuda K, Pichika R, Epure LM, Yoshikawa T, Hemmad A, et al. The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. Arthritis Res Ther. 2011;13(4):R120.

    Article  PubMed  PubMed Central  Google Scholar 

  277. Kong MH, Do DH, Miyazaki M, Wei F, Yoon S-H, Wang JC. Rabbit Model for in vivo Study of intervertebral disc degeneration and regeneration. J Korean Neurosurg Soc. 2008;44(5):327–33.

    Article  PubMed  PubMed Central  Google Scholar 

  278. Masuda K, Aota Y, Muehleman C, Imai Y, Okuma M, Thonar EJ, et al. A novel rabbit model of mild, reproducible disc degeneration by an anulus needle puncture: correlation between the degree of disc injury and radiological and histological appearances of disc degeneration. Spine. 2005;30(1):5–14.

    Article  PubMed  Google Scholar 

  279. Lipson SJ, Muir H. Proteoglycans in experimental intervertebral disc degeneration. Spine. 1981;6(3):194–210. https://doi.org/10.1097/00007632-198105000-00002.

    Article  CAS  PubMed  Google Scholar 

  280. Sobajima S, Kompel JF, Kim JS, Wallach CJ, Robertson DD, Vogt MT, et al. A slowly progressive and reproducible animal model of intervertebral disc degeneration characterized by MRI, X-ray, and histology. Spine. 2005;30(1):15–24.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the kind support of Vice-Chancellor, West Bengal University of Animal and Fishery Sciences, Kolkata, India.

Funding

There was no funding support for this study.

Author information

Author notes

  1. P. Mukherjee and S. Roy equally contributed and joint first author

Authors and Affiliations

  1. Department of Veterinary Clinical Complex, West Bengal University of Animal and Fishery Sciences, Mohanpur, Nadia, India

    P. Mukherjee & S. Roy

  2. Department of Veterinary Surgery and Radiology, West Bengal University of Animal and Fishery Sciences, Kolkata, India

    D. Ghosh & S. K. Nandi

Authors
  1. P. Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. K. Nandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SKN: Conceptualization, Methodology, Supervision and final correction of draft. PM and SR: Data curation, Writing-Original draft preparation. DG: Editing. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to S. K. Nandi.

Ethics declarations

Competing interests

The authors declare that there is no competing of interest in this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mukherjee, P., Roy, S., Ghosh, D. et al. Role of animal models in biomedical research: a review. Lab Anim Res 38, 18 (2022). https://doi.org/10.1186/s42826-022-00128-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s42826-022-00128-1

Keywords

Laboratory Animal Research

ISSN: 2233-7660