Table 4.
Summary of the available sheep models of major physiological systems.
| Body System | Disease or Syndrome Model | Strain/ Sex |
Age/ Body Weight |
Description/Observation | Reference |
|---|---|---|---|---|---|
| Cardiovascular | Ovine endo-toxemic shock (macrocirculation) | Sheep/F | Adult | The macro- and microvascular effects of selective and nonselective potassium channel inhibitors studied in ovine endotoxemic shock. | [78] |
| Angiography of the cardiac coronary venous system | Lacaune/M | 68 ± 5.3 kg | The general organization of the coronary venous circulation evaluated from clinical angiographic studies. | [54] | |
| Tissue-Engineered(TE) heart valves replacement | Swifter/F | 1 y | Immunological markers and expression of proteins specific to sheep validated for the immunohistochemical analysis of tissue-engineered heart valve after implantation in a sheep model. | [79] | |
| Beating heart sheep model | Sheep | 42 ± 5 kg | Structural and functional outcomes of trans-ventricular implantation of a modified stented bovine pulmonary valve assessed. | [80] | |
| Atrioventricular block model | Castrated, merino cross/M | 1 y/ 63.1 ± 5.6 kg |
Atrioventricular block by radiofrequency ablation of the His bundle and implantation of the pacemaker into the right ventricular apex developed, characterized and validated in adult sheep. | [81] | |
| Extarterectomy model | Sheep/M | 11/2 y/ 39–48 kg |
Tumor removal by extarterectomy technique and its long term effect of on the vascular wall and arterial blood flow investigated in male sheep. | [82] | |
| Chronic heart failure | Sheep | NA | Testing and optimizing of surgical therapies for chronic heart failure. | [28] | |
| Endocrine | Polycystic ovarian syndrome | Scottish Greyface/F | Adult | Prenatal testosterone (T)-treated female sheep showed reproductive deficits comparable to women with polycystic ovarian syndrome (PCOS). | [83,84] |
| Maternal-Fetal sheep model | Dorse/F | Adult pregnant | a maternal-fetal pharmacokinetic model of propofol in pregnant ewes successfully developed. | [85] | |
| Pregnancy model | sheep | Adult pregnant | Placental development, oxygen and nutrient transfer between maternal-fetal interaction are similar to human pregnancy. | [86] | |
| Immune | Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) | Spanish castrated lamb/M | 3 months | Repetitive inoculation of aluminium-containing adjuvants through vaccination showed acute and chronic neurological episode resulting in ASIA syndrome that can be used to model similar disease affecting both human and animals. | [87] |
| Nervous | Peripheral nerve regeneration | Sheep | NA | Similar size and regeneration behavior of nerves supports the use of sheep as a model for studying peripheral nerve regeneration following nerve injury. | [88] |
| Neurogenesis | Sheep | NA | Distinctive feature of hypothalamic, olfactory and hippocampal neurogenesis in adult sheep and its contribution to reproduction, odour processing and maternal behavioral revealed. | [89] | |
| Neurogenesis | Romney/ Suffolk |
3–6 y/ 53.1–59.8 |
Cell proliferation in the subventricular and subgranular zone of adult sheep is comparable with human and has the same distinct layers. | [90] | |
| Transient stroke | Merino/ M and F |
18–36 months/ 65 ± 7 kg |
A survival model of sheep transient middle cerebral artery occlusion and the temporal profile of intracranial pressure change following transient stroke developed in sheep. | [53,76] | |
| Occlusion (permanent middle cerebral artery) stroke model | Outbreed adult hornless merino /M | Adult/ 42–65 kg |
The permanent middle cerebral artery (MCA) occlusion results into cerebral ischemia and produces reproducible neurologic dysfunctions and can be modified by altering the occlusions in MCA. | [91] | |
| Acute proximal middle cerebral artery ischemic stroke | Merino/M and F | 18–24 months/50.1 ± 5.8 kg | A surgical model of permanent and transient MCA stroke in the sheep developed. | [92] | |
| Spina bifida | Lamb | NA | The congenital anomaly of CNS (spina bifida phenotype) with and without myelotomy comprehensively and reliably characterised in fetal lamb. | [93] | |
| Axonal injury | Merino/F | 2 y | The physiological and pathological changes resulting from traumatic injury using immunostaining as a marker of early axonal injury developed to established a head impact model of axonal injury in sheep. | [94] | |
| Transgenic Huntington’s disease | Sheep/F | 1 and 7 months | Six transgenic founder sheep generated, expressing full length human HTT with a poly- glutamine region of 73 residues. | [75] | |
| Alzheimer’s disease | Sheep | 8–14 y | The processing of amyloid protein, total tau and neurofilament markers in the aged sheep comparable to those found in sheep. | [95] | |
| Parkinson’s diseases | Columbia-Suffolk cross bred/F | 1–3 y/ 40–70 kg |
Infusion of MPTP and MPP+ through jugular cannula produces parkinsonian-like behavior in sheep. | [96] | |
| Parkinson’s diseases | Rambouilette, ranch bred/F | 1–3 y/ 40–55 kg |
Unilateral acute (over 30 min) and chronic (over 1 week) intracarotid injection of MPTP (0.4–5.0 mg/kg) via slow continuous infusion produces Parkinsonian-like behavior in sheep. | [74] | |
| Sleep and neurological dysfunction | Borderdale | 14.3 ± 0.5 months | Electroencephalography study performed in CLN5 batten disease-affected sheep to characterize the sleep and neurological dysfunction. | [97] |
|
| Motor neuron syndrome | Border Leicester dominant cross/ | 18 months/ 34–45 kg |
Molybdenum deprivation, purine ingestion and an astrocyte-associated motor neurone syndrome produced 18–27 months later in sheep. | [98] | |
| CLN5 Batten disease | Borderdale | 2 to 3 months | Efficacy of CLN5 gene therapy on the CNS monitored in a sheep model of CLN5 batten disease. | [99] | |
| Focal epilepsy | Merino/F | Adult | Focal epilepsy in sheep generated with injection of penicillin into the right prefrontal cortex and studied with the use of fMRI and iEEG. | [100] | |
| Neuropathic pain model | Polypay sheep/F | 75 kg | A neuropathic pain model established by tight ligation and axotomy of the common peroneal nerve and analgesic effect of morphine studied in sheep. | [101] | |
| Ovine ceroid lipofuscinosis (CLN6) | South Hampshire lamb/M and F | 9–12 month | Linkage between ovine ceroid lipofuscinoses (CLN6) and microsatellite markers OAR 7 q13–15 established. | [102] | |
| Spinal cord injury | Suffolk | 2 y | A model of spinal cord injury established by hemi sectioning of the spinal cord (left side) and injury quantified by a gait analysis of pre an post injury in ovine. | [103] | |
| Fetal Alcohol Spectrum Disorder | Sheep/F | NA | Pregnant sheep were exposed to binge alcohol consumption for a three-trimester period and plasma MiRNA profile was assessed from pregnant and from newborn. | [104] | |
| Acute neuronopathic Gaucher disease | Lamb | 2 h after birth | Acute neuronopathic Gaucher disease model developed in lamb by mutation in the β-glucocerebrosidase gene C381Y, which is equivalent to human C342Y. | [105] | |
| Non-accidental head injury | Lamb | 5–9 days old/ 5–12 kg |
Axonal injury, neuronal reaction, and albumin extravasation examined in the hemispheric white matter, brainstem and at the intracranio cervical junction after manual shaking of head in lamb. | [106] | |
| Gastro-intestinal | Colorectal Mucosal Injury | Yearling virginal/F | NA | Due to similar gross and microscopic between sheep and human rectum Optical coherence tomography imaging and colonoscopy used to visualize morphological abnormalities and scoring of microbicide-induced injury in sheep model. | [107] |
| Intestinal loop model (gut cannulation) | Canadian Arcott/F | 8–10 months | Surgical method of catherization of intestinal loops without affecting health or loop function developed to elucidate the host response to various treatments within the small intestine of ruminants. | [108] | |
| Respiratory | Fetal lung inflammation | Merino/F | NA | Acute systemic inflammatory response of the 10 mg e.coli LPS into amniotic fluid showed three major fetal surfaces exposed to inflammatory mediators in pregnancy (the lung, gastro-intestinal tract and skin/amnion). | [109] |
| Ovine pulmonary adenocarcinoma | Sheep/F | 39–65 kg | Sheep model of naturally occurring lung cancer, ovine pulmonary adenocarcinoma caused by jaagsiekte sheep retrovirus has similar histological characteristics of human lung adenocarcinomas. | [110] | |
| Ocular | Ophthalmic model | Coopworth × Texel/M | 10–12 months/ 50–60 kg |
The anatomical and clinical characteristics of sheep such as ocular response, central corneal thickness, topographic maps, intraocular pressure, corneal hysteresis, and corneal resistance factor confirmed the suitability of sheep as a model for ophthalmic experiments. | [111] |
| Opthalmic surgery training | Afshar | 1 y | Sheep eye for ophthalmic surgery training in skills laboratory found similar ultrasonic graphic and physical biometric description. | [112] | |
| Vision prosthesis model | NA | Development and surgical implantation of a vision prosthesis model into the ovine eye. | [113] | ||
| Corneal transplantation | Merino | Adult/44–68 kg | Corneal graft rejection in the sheep is macroscopically and histologically similar to human corneal graft rejection. | [114] | |
| Musculoskeletal | Collagen-induced arthritis | Merino (F) | 2 y | Bovine collagen type II injected into the hock joint and the histopathological scoring system was developed to established a collagen induced arthritis model in sheep. | [115] |
| Nociceptive withdrawal reflex | Swiss alpine | 2–3 y/ 63.1 ± 6.1 kg |
Nociceptive withdrawal reflex induced by electrical stimulation in the thoracic and pelvic limb used as a tool to evaluate nociception in conscious non-medicated sheep. | [116] | |
| Osteoporosis | Corriedale/F | 2 y | Osteoporosis induced by hypothalamic-pituitary disconnection in sheep model to determine sustainability of bone loss and its biomechanical relevance. | [117] | |
| Spinal orthopedic model | Merino/F | 2 y/62.5 ± 5.3 kg | CT scan from sheep L1 to L6 showed similar vertebral endplates and spinal canal to humans supporting sheep as a model for human orthopedic spinal research. | [118] | |
| Hypophosphatasia | Sheep | NA | Using CRISPR/Cas9,a single point mutation in the tissue nonspecific alkaline phosphatase (TNSALP) gene (ALPL) made to generated hypophosphatasia- rare human bone disease. | [119] | |
| Cancellous bone healing | Sheep | 18 months and 5 y | A sheep model for cancellous bone healing surgically created to assess early healing and biological changes of the medial distal femoral and proximal tibial epipheses bilaterally. | [120] | |
| Artificial bone substitute | Mecklenburg | 63 kg | Artificial bone substitute (Nanobone) used in bone defect model of ovine tibial metaphysis appears to be highly potent bone substitute with osteoconductive properties. | [121] | |
| Skin | Skin wound healing model | Sheep/M | 6 months/ 20–25 kg |
Topical administration of platelet-rich plasma improved skin wound healing process in sheep making a good model for regenerative medicine research. | [122] |
| Second intention healing model | Bergamasca/F | NA | Peripheral blood-derived MSCs improve the quality of wound healing by accelerating granulation, reepithelization and neovascularization both for superficial injuries and deep lesions. | [123] | |
| Urinary | Renal ischaemia–reperfusion injury | Sheep/F | 35–40 kg | The reno-protective effects of zinc preconditioning in renal ischaemia reperfusion injury was assessed in a sheep model and found to be beneficial for human applications. | [20] |
| Uterine transplantation | Biparous (Prealpes and Romane)/F | 35–70 months/ 57–91 kg |
Uterine transplantation method set-up using end to end anastomosis of external iliac vessels in sheep and complications were highlighted. | [124] | |
| Renal function | Segurena/M and F | 2–6 y/50 kg | Simplified Iohexol-based method was developed to measure renal function using glomerular filtration rate as a model of renal diseases in sheep. | [125] | |
| Haemodialysis treatment | Merino/M | 16–18 months | The two-step bilateral nephrectomy was conducted to develop ovine model of haemodialysis treatment to measure dialysis adequacy and urea reduction ratio for each haemodialysis treatment. | [126] |