Can the sheep model fully represent the human model for the functional evaluation of cervical interbody fusion cages?

Sheep model is the most favourable choice for animal study for functional evaluation of the cervical fusion prostheses before clinical application; however, significantly large differences between sheep and human existed in terms of morphological characteristics and daily-activity motions. Questions should be raised as whether the differences between the two species have influence on the reliability of sheep model. Finite element models (FEM) of the cervical spinal system were built to characterize the differences between the two species with respect to the range of motion (ROM) and biomechanical behaviour, and experimental cadaver tests on both species were employed for validation purposes. Results indicate that sheep model represents the worst-case scenario of the human model with exaggerated stresses (up to 3 times more) and ROM (up to 10 times more). Moreover, sheep model is very sensitive to the variation of prostheses design, whilst human model does not, which denotes that the sheep model provides a rather amplified effect of a certain design for its biomechanical performance. Therefore, caution needs to be taken when sheep models were used as the animal model for functional evaluation over various design, and the FEM built in this study can be employed as an effective methodology for performance evaluation of cage prostheses of cervical spine.

     

采用质粒DNA研究人结缔组织生长因子（hCTGF）对骨损伤修复作用的研究

摘要：目的 研究人结缔组织生长因子（hCTGF）对细胞的增殖作用及其骨损伤促愈合的生物学作用。方法 利用真核基因导入系统,转染具有分化潜能的成纤维细胞,并导入骨折实验动物模型,利用分子生物学和临床骨科技术检测分析,获得数据。结果 明确了hCTGF对细胞的增殖作用,表明了hCTGF以基因治疗为手段具有修复骨损伤的生物学活性,为该因子在临床上治疗骨损伤提供新的活性因子和新的治疗方法。     

Chromium-51 labeling of sheep red blood cells.

The failure of sheep red blood cells (RBCs) labeled with Chromium-51 (Cr-51) using the ascorbic acid technique to act as a suitable intravascular marker of blood volume in a septic sheep model prompted us to investigate the technique of radiolabeling sheep erythrocytes with this isotope. Consequently, we studied thirteen sheep in which the labeling efficiency of Cr-51 as sodium chromate and hemoglobin typing was determined for each animal. Mean Cr-51 labeling efficiency of sheep RBCs was 67.5% (n = 13). Although 5 of the 13 sheep were discovered to have two types of hemoglobin (Hb) as determined by electrophoresis, overall labeling efficiency of sheep RBCs was determined to be independent of the type of hemoglobin present. However, when two types of Hb were present (Hb-A and Hb-B), Cr-51 had a higher affinity for Hb-B (80%) than Hb-A (20%) even though both Hb types are present in similar proportions (Hb-A = 53%, Hb-B = 46%). The results of this study indicate that sheep RBCs express a lower labeling efficiency for Cr-51 than do human RBCs and that Cr-51 has a higher affinity for Hb-B than for Hb-A when both hemoglobin types are present. This difference is noteworthy when interpreting Cr-51 RBC data in experimental sheep models. Furthermore, caution should be exercised when extrapolating established human protocols to animal models.     

Selection of an animal model for implant fixation studies: anatomical aspects.

A number of different animal models have been employed by investigators to study the biology of the bone-cement interface as it relates to the problem of hip implant loosening in humans. This study compares to the human three species (baboon, dog, and sheep) currently under use as experimental animal models from an anatomical point of view. A number of parameters, important for the dimensional design of a femoral prosthesis, loads at the hip joint and its subsequent performance, were used for comparing external and internal femoral anatomy. The baboon and dog femora were found to be most similar to the human femur in their external anatomy. The quantification of cancellous bone distribution within the medullary canal revealed that, of the species studied, the sheep femur provided the least support to the prosthesis. The results suggest that the dog and baboon are anatomically appropriate for studying hip implant biomechanics experimentally. Thus, from an anatomical point of view, the current extensive use of the dog as an experimental animal appears appropriate.     

Morphometric comparison of the lumbar cancellous bone of sheep, deer, and humans

To investigate the feasibility of using deer and sheep as animal models for the human spine, we compared the microarchitectural dimensions of the deer and sheep spines and with human data. To this end, we adopted the traditional bone tissue morphometric method, using figure analysis software for quantitative analysis of 2D images of bone tissue. Compared with those of humans, the lumbar cancellous bone of deer and sheep has higher microarchitectural indices, more densely packed bone trabeculae, lower porosity, and higher bone mass. Despite specific differences in various morphologic indices, the anisotropy of lumbar cancellous bone in deer and sheep shows the same trend as that in humans.     

Inter-species investigation of the mechano-regulation of bone healing: comparison of secondary bone healing in sheep and rat

Inter-species differences in regeneration exist in various levels. One aspect is the dynamics of bone regeneration and healing, e.g. small animals show a faster healing response when compared to large animals. Mechanical as well as biological factors are known to play a key role in the process. However, it remains so far unknown whether different animals follow at all comparable mechano-biological rules during tissue regeneration, and in particular during bone healing. In this study, we investigated whether differences observed in vivo in the dynamics of bone healing between rat and sheep are only due to differences in the animal size or whether these animals have a different mechano-biological response during the healing process. Histological sections from in vivo experiments were compared to in silico predictions of a mechano-biological computer model for the simulation of bone healing. Investigations showed that the healing processes in both animal models occur under significantly different levels of mechanical stimuli within the callus region, which could explain histological observations of early intramembranous ossification at the endosteal side. A species-specific adaptation of a mechano-biological model allowed a qualitative match of model predictions with histological observations. Specifically, when keeping cell activity processes at the same rate, the amount of tissue straining defining favorable mechanical conditions for the formation of bone had to be increased in the large animal model, with respect to the small animal, to achieve a qualitative agreement of model predictions with histological data. These findings illustrate that geometrical (size) differences alone cannot explain the distinctions seen in the histological appearance of secondary bone healing in sheep and rat. It can be stated that significant differences in the mechano-biological regulation of the healing process exist between these species. Future investigations should aim towards understanding whether these differences are due to differences in cell behavior, material properties of the newly formed tissues within the callus and/or differences in response to the mechanical environment.     

Animal models of acute lung injury

Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury.     

Prediction of the Time Course of Callus Stiffness as a Function of Mechanical Parameters in Experimental Rat Fracture Healing Studies - A Numerical Study

Numerous experimental fracture healing studies are performed on rats, in which different experimental, mechanical parameters are applied, thereby prohibiting direct comparison between each other. Numerical fracture healing simulation models are able to predict courses of fracture healing and offer support for pre-planning animal experiments and for post-hoc comparison between outcomes of different in vivo studies. The aims of this study are to adapt a pre-existing fracture healing simulation algorithm for sheep and humans to the rat, to corroborate it using the data of numerous different rat experiments, and to provide healing predictions for future rat experiments. First, material properties of different tissue types involved were adjusted by comparing experimentally measured callus stiffness to respective simulated values obtained in three finite element (FE) models. This yielded values for Young’s moduli of cortical bone, woven bone, cartilage, and connective tissue of 15,750 MPa, 1,000 MPa, 5 MPa, and 1 MPa, respectively. Next, thresholds in the underlying mechanoregulatory tissue differentiation rules were calibrated by modifying model parameters so that predicted fracture callus stiffness matched experimental data from a study that used rigid and flexible fixators. This resulted in strain thresholds at higher magnitudes than in models for sheep and humans. The resulting numerical model was then used to simulate numerous fracture healing scenarios from literature, showing a considerable mismatch in only 6 of 21 cases. Based on this corroborated model, a fit curve function was derived which predicts the increase of callus stiffness dependent on bodyweight, fixation stiffness, and fracture gap size. By mathematically predicting the time course of the healing process prior to the animal studies, the data presented in this work provides support for planning new fracture healing experiments in rats. Furthermore, it allows one to transfer and compare new in vivo findings to previously performed studies with differing mechanical parameters.     

The spatio-temporal arrangement of different tissues during bone healing as a result of simple mechanobiological rules

During secondary bone healing, different tissue types are formed within the fracture callus depending on the local mechanical and biological environment. Our aim was to understand the temporal succession of these tissue patterns for a normal bone healing progression by means of a basic mechanobiological model. The experimental data stemmed from an extensive, previously published animal experiment on sheep with a 3?mm tibial osteotomy. Using recent experimental data, the development of the hard callus was modelled as a porous material with increasing stiffness and decreasing porosity. A basic phenomenological model was employed with a small number of simulation parameters, which allowed comprehensive parameter studies. The model distinguished between the formation of new bone via endochondral and intramembranous ossification. To evaluate the outcome of the computer simulations, the tissue images of the simulations were compared with experimentally derived tissue images for a normal healing progression in sheep. Parameter studies of the threshold values for the regulation of tissue formation were performed, and the source of the biological stimulation (comprising e.g. stem cells) was varied. It was found that the formation of the hard callus could be reproduced in silico for a wide range of threshold values. However, the bridging of the fracture gap by cartilage on the periosteal side was observed only (i) for a rather specific choice of the threshold values for tissue differentiation and (ii) when assuming a strong source of biological stimulation at the periosteum.     

Predicting risk of decompression sickness in humans from outcomes in sheep.

In animals, the response to decompression scales as a power of species body mass. Consequently, decompression sickness (DCS) risk in humans should be well predicted from an animal model with a body mass comparable to humans. No-stop decompression outcomes in compressed air and nitrogen-oxygen dives with sheep (n = 394 dives, 14.5% DCS) and humans (n = 463 dives, 4.5% DCS) were used with linear-exponential, probabilistic modeling to test this hypothesis. Scaling the response parameters of this model between species (without accounting for body mass), while estimating tissue-compartment kinetic parameters from combined human and sheep data, predicts combined risk better, based on log likelihood, than do separate sheep and human models, a combined model without scaling, and a kinetic-scaled model. These findings provide a practical tool for estimating DCS risk in humans from outcomes in sheep, especially in decompression profiles too risky to test with humans. This model supports the hypothesis that species of similar body mass have similar DCS risk.     

The critical size bony defect in a small animal for bone healing studies (I): Comparative anatomical study on rats' femur.

Laboratory rats are small animal models which are often used for scientific investigations in medicine. So far there are only few scientific data about the meaning of these small animal models for in vivo bone healing studies available in literature. Although the rat's femur with its cyclic loadings during gait is an appropriate model for investigations in the field of experimental orthopaedics and traumatology there is a lack of morphometric information with respect to its anatomy. The aim of this study is to evaluate the anatomy of rat femurs in two species, which are often performed in animal experimental medicine. These morphometric data should contribute to develope an appropriated osseous fragment fixation system in the rat's femur. The femurs of Wistar (WR) and Sprague Dawley (SDR) cadavers were prepared and analysed by x-rays in two standard planes. The results were compared with the corresponding data for humans by literature. It could be demonstrated that SDR showed a higher caput-collum-diaphyseal and antetorsion angle, but a lower transcondylar femur valgus angle compared to WR. Cortical thickness, bone marrow cavity diameter and femur length were higher in WR. Wistar rat's femur anatomy shows more similarities to human anatomy than Sprague Dawley rats.     

Hefting onto Place: Intersecting Lives of Humans and Sheep on Scottish Hills Landscape

This paper analyzes the phenomenon called hefting of sheep onto the landscape of hill sheep farms in the Scottish Borders. It is based upon data collected during extended periods of ethnographic fieldwork beginning in 1981 and continuing to the present. Hefting is the term used by sheep farmers for the natural tendency of hill sheep to graze, remain, and bond onto specific areas of the landscape without the need for fencing. The herding practices of hill sheep farms appropriate hefting in flock management and breeding. The analysis of hefting makes two contributions to understanding human–animal relations. First, because the of the centrality of territorial bonding, hefting makes explicit that we should always be ready to include a third dimension—place and emplacement—in understanding human–animal relations. Second, drawing on Haraway's concept of “becoming with,” hefting and herding demonstrate the fundamentally relational character of human–animal–place relations.     

人类疾病的动物模型

发展对人类疾病有效的预测、预防、诊断和治疗等途径,一直是人口健康领域关注的焦点.任何人类疾病似乎都可归咎于遗传背景和环境因素的共同作用,并影响到疾病的发生、病程、药物疗效和预后等.最有效的研究策略足直接针对患者的各方面临床研究,但这一策略常常会而临着同一临床症状却有不同病因(异质性)、个体差异显著(如治疗效果因人而异)以及难以回溯性地研究人类疾病的发生、发展(如发病以前的事件或经历)等问题,而且医学伦理学的要求使得大量医学研究和新药新疗法不能直接应用于人体,必须先有动物实验阐明其安全性和必要性.最佳的研究策略足创建人类疾病的动物模型,因为可严格地控制病因、遗传背景、环境因子等,也可跟踪性研究动物模型病症的发生、发展、治疗反应和结局等,但这一策略也常常面临着一系列问题和误解.对此,在<动物学研究>出版<灵长类动物与人类疾病模型>专刊之际,撰写此评述性论文,将系列问题和误解一一提出,并讨论其应对策略.     

Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance to the human condition

The prevalence of diabetes throughout the world has increased dramatically over the recent past, and the trend will continue for the foreseeable future. One of the major concerns associated with diabetes relates to the development of micro- and macrovascular complications, which contribute greatly to the morbidity and mortality associated with the disease. Progression of the disease from prediabetic state to overt diabetes and the development of complications occur over many years. Assessment of interventions designed to delay or prevent disease progression or complications in humans also takes years and requires tremendous resources. To better study both the pathogenesis and potential therapeutic agents, appropriate animal models of type 2 diabetes (T2D) mellitus are needed. However, for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. There appears to be no single animal model that encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of T2D in humans. Use of the appropriate animal model based on these similarities can provide much needed data on pathophysiological mechanisms operative in human T2D.     

Sheep-passaged bovine spongiform encephalopathy agent exhibits altered pathobiological properties in bovine-PrP transgenic mice

Sheep can be experimentally infected with bovine spongiform encephalopathy (BSE), and the ensuing disease is similar to scrapie in terms of pathogenesis and clinical signs. BSE infection in sheep is an animal and human health concern. In this study, the transmission in BoPrP-Tg110 mice of prions from BSE-infected sheep was examined and compared to the transmission of original cattle BSE in cattle and sheep scrapie prions. Our results indicate no transmission barrier for sheep BSE prions to infect BoPrP-Tg110 mice, but the course of the disease is accelerated compared to the effects of the original BSE isolate. The shortened incubation period of sheep BSE in the model was conserved in subsequent passage in BoPrP-Tg110 mice, indicating that it is not related to infectious titer differences. Biochemical signature, lesion profile, and PrP(Sc) deposition pattern of both cattle and sheep BSE were similar. In contrast, all three sheep scrapie isolates tested showed an evident transmission barrier and further adaptation in subsequent passage. Taken together, those data indicate that BSE agent can be altered by crossing a species barrier, raising concerns about the virulence of this new prion towards other species, including humans. The BoPrP-Tg110 mouse bioassay should be considered as a valuable tool for discriminating scrapie and BSE in sheep.     

The radial forearm flap: a biomechanical study of donor-site morbidity utilizing sheep tibia.

The use of vascularized bone grafts to reconstruct extremity and mandibular defects is now commonplace in reconstructive surgery. Fibula, scapula, iliac crest, rib, and metatarsal as well as the radial forearm osseocutaneous flaps have all been utilized for this purpose. Troublesome spiral fractures of the distal radius are the most common fractures associated with the use of the distal radius as a vascularized bone-graft donor site. This study was proposed to investigate the effect of donor-site bone loss on the strength of the radius under torsional (rotational) loading. Previous clinical series and experimental studies have not examined this aspect of distal radius loading after harvesting the bone graft. Fifty pairs of sheep tibiae were utilized in the experiment. Five pairs were used in a pilot study and 45 pairs were used in the main experiment. Five pairs of human radii were used for the control in the pilot study. The pilot study attempted to make a comparison between the human radius and the sheep tibia for experimental purposes. For the biomechanical study of donor-site defects, four study groups were examined with random assignment and matched pairs. The control group (group 1) had no alteration to the bone. Each test condition included five matched pairs of sheep tibiae. Experiment 1 compared the difference in the depth of the osteotomy defect. In doing this, one-third of the total length of the bone was removed in each of the following specimens to include (1a) 30 percent of the cross-sectional area of the total bone, (1b) 37 percent of the cross-sectional area of the total bone, and (1c) 50 percent of the cross-sectional area of the total bone. In experiment 2, the osteotomy shape was varied. Instead of the ends of the cuts being squared, the ends were beveled or rounded. Experiment 3 compared different lengths of bone removed in the osteotomy defect and included the following: In experiment 3a the diameter of the sheep tibia was measured at the incisura fibularis. This dimension was one diameter of bone, and a one-diameter length of bone was removed. In experiment 3b, a two-diameter length of bone was removed. In experiment 3c, a three-diameter length of bone was removed. In experiment 3d, a four-diameter length of bone was removed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Blood biochemistry values of sheep (Ovis aries ligeriensis)

1. Analysis of biochemical parameters were carried out on material pooled from 30 female sheep (Ovis aries ligeriensis). 2. The values determined were for the common metabolites and enzymes utilized for specific studies in general metabolism (urea, glucose, cholesterol, lipids, bilirubin, uric acid, creatinine, alkaline phosphatase, GOT, GPT, LDH, LAP, CGT, CK and amylase). 3. Results of these studies were compared with values from normal human adults. 4. The differences obtained in human and sheep ranges can be explained by the different physiology of the two species. 5. This study gives values for the sheep as an experimental animal in biomedical research.     

The pig: a model for human infectious diseases

An animal model to study human infectious diseases should accurately reproduce the various aspects of disease. Domestic pigs (Sus scrofa domesticus) are closely related to humans in terms of anatomy, genetics and physiology, and represent an excellent animal model to study various microbial infectious diseases. Indeed, experiments in pigs are much more likely to be predictive of therapeutic treatments in humans than experiments in rodents. In this review, we highlight the numerous advantages of the pig model for infectious disease research and vaccine development and document a few examples of human microbial infectious diseases for which the use of pigs as animal models has contributed to the acquisition of new knowledge to improve both animal and human health.     

Are allogenic or xenogenic screws and plates a reasonable alternative to alloplastic material for osteosynthesis—A histomorphological analysis in a dynamic system

Despite invention of titanium and resorbable screws and plates, still, one of the main challenges in bone fixation is the search for an ideal osteosynthetic material. Biomechanical properties, biocompatibility, and also cost effectiveness and clinical practicability are factors for the selection of a particular material. A promising alternative seems to be screws and plates made of bone. Recently, xenogenic bone pins and screws have been invented for use in joint surgery.In this study, screws made of allogenic sheep and xenogenic human bone were analyzed in a vital and dynamic sheep-model and compared to conventional titanium screws over a standard period of bone healing of 56 days with a constant applied extrusion force. Biomechanical analysis and histomorphological evaluation were performed.After 56 days of insertion xenogenic screws made of human bone showed significantly larger distance of extrusion of on average 173.8 μm compared to allogenic screws made of sheep bone of on average 27.8 and 29.95 μm of the titanium control group. Severe resorption processes with connective tissue interposition were found in the histomorphological analysis of the xenogenic screws in contrast to new bone formation and centripetal vascularization of the allogenic bone screw, as well as in processes of incorporation of the titanium control group.The study showed allogenic cortical bone screws as a substantial alternative to titanium screws with good biomechanical properties. In contrast to other reports a different result was shown for the xenogenic bone screws. They showed insufficient holding strength with confirmative histomorphological signs of degradation and insufficient osseointegration. Before common clinical use of xenogenic osteosynthetic material, further evaluation should be performed.