Assessment of cancellous bone mechanical properties from micro-FE models based on micro-CT, pQCT and MR images.

Recently, new micro-finite element (micro-FE) techniques have been introduced to calculate cancellous bone mechanical properties directly from high-resolution images of its internal architecture. Also recently, new peripheral quantitative computed tomography (pQCT) and magnetic resonance (MR) imaging techniques have been developed that can create images of whole bones in vivo with enough detail to visualize the internal cancellous bone architecture. In this study we aim to investigate if the calculation of cancellous bone mechanical properties from micro-FE models based on such new pQCT and MR images is feasible. Three bone specimens were imaged with the pQCT scanning system and the MR-imaging system. The specimens were scanned a second time using a micro-CT scanner with a much higher resolution. Digitized reconstructions were made based on each set of images and converted to micro-FE models from which the bone elastic properties were calculated. It was found that the results of both the pQCT and the MR-based FE-models compared well to those of the more accurate micro-CT based models in a qualitative sense, but correction factors will be needed to get accurate values.     

Applications of ultrasmall superparamagnetic iron oxide contrast agents in the MR study of animal models

Ultrasmall superparamagnetic iron oxide nanoparticles have been widely used during the past decade as MR intravascular contrast agents in the study of animal models. Such agents enhance both T1 and T2/T2* relaxation, although for animal studies it is the later type of enhancement that is most commonly exploited. Their strong microscopic intravascular susceptibility effect enables the local blood volume distribution to be mapped in various organs. High spatial resolution and sensitivity can be achieved, because the long half-life of these agents in blood, combined with anesthetization, permits steady-state measurements over extended periods. This capability has been utilized to study the cerebrovascular blood volume distributions and their changes in normal, activated, pathologic and pharmacologically or genetically modified states, particularly in rodent animal models. It has also been applied to study blood volume changes in other tissues, such as the myocardium. The relaxation rate shifts Delta R2 and Delta R2* induced by iron oxide agents may differ depending on certain morphological characteristics of the microvascular network, and sensitive Delta R2 and Delta R2* mapping can potentially provide, in addition to blood volume, measurement of other important microvascular parameters such as blood vessel density and size. This work aims to review the applications of ultrasmall superparamagnetic iron oxide contrast agents in MR animal studies, with an emphasis on the investigation of microvascular parameters.     

Imaging techniques for small animal models of pulmonary disease: MR microscopy

In vivo magnetic resonance microscopy (MRM) of the small animal lung has become a valuable research tool, especially for preclinical studies. MRM offers a noninvasive and nondestructive tool for imaging small animals longitudinally and at high spatial resolution. We summarize some of the technical and biologic problems and solutions associated with imaging the small animal lung and describe several important pulmonary disease applications. A major advantage of MR is direct imaging of the gas spaces of the lung using breathable gases such as helium and xenon. When polarized, these gases become rich MR signal sources. In animals breathing hyperpolarized helium, the dynamics of gas distribution can be followed and airway constrictions and obstructions can be detected. Diffusion coefficients of helium can be calculated from diffusion-sensitive images, which can reveal micro-structural changes in the lungs associated with pathologies such as emphysema and fibrosis. Unlike helium, xenon in the lung is absorbed by blood and exhibits different frequencies in gas, tissue, or erythrocytes. Thus, with MR imaging, the movement of xenon gas can be tracked through pulmonary compartments to detect defects of gas transfer. MRM has become a valuable tool for studying morphologic and functional changes in small animal models of lung diseases.     

Applications of electron microscopy to diagnostic pulmonary pathology

Viruses and other possible causative agents should be sought light and electron microscopically in all cases of ill-defined diseases including "sarcoid." Ideally, tissue should be prepared for electron microscopic examination as soon as a specimen is obtained; however, when this has not been done, tissue preserved in formalin solution can be used. Viruses, some bacteria, and other agents suspected on the basis of light microscopic findings can be verified electron microscopically by reprocessing paraffin-embedded tissue from areas that show smudge cells, focal necrosis with atypical cellular proliferation, and nuclear inclusions. Electron microscopically, all dying cells show swelling and rupture of cellular organelles and membranes; reactive changes include proliferation of branching tubules and paracrystalline and other types of proteinaceous precipitates (inclusions) in both the nucleus and cytoplasm. Qualitative and quantitative changes of cellular organelles, fibrils, microvilli, and intercellular junctions reflect hyperplasia, metaplasia, or dysplasia of the cell and may enable identification of the diseases, e.g., desquamative interstitial pneumonia. In various conditions, basal laminae become irregular, disruptive, or reduplicated following epithelial necrosis and regeneration. Electron microscopic evidence of immunologic damage to basal lamina and cells and immuno-electron-microscopic features of the lung in general require further studies. Electron microscopic features of transbronchial biopsy specimens may be diagnostic in cases of alveolar proteinosis, histiocytosis X, and amyloidosis. Ultrastructural abnormalities of cilia are common; primary ciliary defects are rare. Finally, light microscopic, scanning electron microscopic, and x-ray energy-dispersive spectrometric examinations of paraffin-embedded sections appear most practical for the pathologic evaluation of cases of pneumoconiosis.     

Influence of circadian phase and test illumination on pre-clinical models of anxiety

Pre-clinical models of anxiety, particularly the elevated plus-maze (EPM), have been shown to be sensitive to a variety of methodological variations. Recent research has implicated circadian phase of testing in influencing the behavioural profile of 5-HT(1A) ligands on the EPM. The present study investigated the effects of testing animals during the dark and light phases and in light and subjective dark test conditions on baseline behaviour in animal models of anxiety. Eighty singly housed male Sprague-Dawley rats were exposed to a battery of unconditioned, exploratory tests (EPM, open field arena, holeboard) and a new model of extreme anxiety, the unstable elevated exposed plus-maze (UEEPM). Circadian phase of testing failed to consistently alter behaviour on any model. Level of test illumination had no effect on subjects' response to the open field arena, holeboard or UEEPM. Dark testing increased locomotor activity on the EPM (total arm entries, closed arm entries and distance moved) without decreasing open-arm avoidance. The construct of anxiety as measured by a number of different paradigms withstood major intra-laboratory manipulation of circadian phase of testing and illumination of apparatus. It is suggested that the effects of circadian rhythmicity may be confined to the behavioural profiles of serotonergic, particularly 5-HT(1A), ligands on the EPM.     

Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.     

骨关节炎的转基因动物模型

背景：近年来随着转基因技术的发展,出现了骨关节炎的转基因动物模型,表明不同基因的缺失与突变都可能导致骨关节炎,这将为骨关节炎的药物筛选试验和治疗提供新方案。 目的：对骨关节炎的转基因动物模型的构建及其相关机制进行概述,为防治骨关节炎奠定理论基础。 方法：第一作者应用计算机检索1995/2010 PubMed数据库相关文章,检索词为“transgenic animal models,Osteoarthritis”,并限定文章语言种类为English。同时计算机检索2000/2010 中国知网数据库相关文章,检索词为“转基因动物模型,骨关节炎”并限定文章语言种类为中文。共检索到文章158 篇,最终纳入22篇。 结果与结论：骨关节炎转基因动物模型在研究骨关节炎起始机制、关节软骨生化改变和防治效果的比较等方面具有明显优势;排除了手术创伤及炎症对骨关节炎模型软骨、滑膜的生化代谢的影响;同时也减轻了模型动物的痛苦。为药物筛选试验和治疗提供新方案。     

骨代谢指标与骨关节炎及绝经后骨质疏松症的关系

背景：研究显示,在绝经后骨质疏松症及骨关节炎状态下,原本正常的骨转换平衡状态被破坏,血清、尿液中一些特异性指标可以较敏感地反映出骨转换的具体变化过程。 目的：测量绝经后原发性膝骨关节炎及绝经后骨质疏松症患者的骨密度及骨代谢指标,分析两疾病骨密度及骨代谢指标的变化特点。 方法：选取248例绝经女性受试者,行骨密度、膝关节X射线片检查,最终选出180例进入试验,分为骨关节炎组、骨质疏松组及对照组。对比分析各组观察对象的骨代谢指标：骨碱性磷酸酶、骨钙素、Ⅰ型胶原交联C末端肽、血清抗酒石酸酸性磷酸酶5b。通过二元Logistic回归分析判断两疾病发病与各项指标间的相关性。 结果与结论：与对照组比较,骨关节炎组腰椎骨密度升高,Ⅰ型胶原交联C末端肽值降低;骨质疏松组腰椎及全髋部骨密度降低,骨钙素、Ⅰ型胶原交联C末端肽、血清抗酒石酸酸性磷酸酶5b升高。血清Ⅰ型胶原交联C末端肽水平的降低与骨关节炎发病具有显著相关性;血清骨钙素、Ⅰ型胶原交联C末端肽、血清抗酒石酸酸性磷酸酶5b水平的升高与骨质疏松发病具有显著相关性。提示绝经女性骨关节炎患者骨吸收速率减低,骨质疏松患者骨转换率加快,骨代谢水平的差异导致两疾病患者骨密度呈现出负相关趋势。监测Ⅰ型胶原交联C末端肽、血清抗酒石酸酸性磷酸酶5b、骨钙素,特别是Ⅰ型胶原交联C末端肽血清水平对骨关节炎及骨质疏松的早期诊断及治疗有一定的参考价值。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

骨质疏松与骨关节炎患者松质骨的显微结构

目的:通过显微计算机断层扫描(micro-computed tomography,Micro-CT)检测股骨头松质骨显微结构,研究骨质疏松与骨关节炎的关系。方法:绝经后妇女骨质疏松性股骨颈骨折和原发性髋关节骨关节炎患者各20名,以Micro-CT扫描检测股骨头软骨下松质骨标本,对2组患者的松质骨显微结构参数进行比较。结果:骨质疏松与骨关节炎松质骨显微结构参数:骨体积分数(bone volume fraction,BV/TV)、骨表面积体积比(bone surface/bone volume,BS/BV)、骨小梁厚度(trabecular thickness,Tb.Th)、骨小梁间距(trabecular separation,Tb.Sp)、结构模型指数(structure model index,SMI)、连接密度(connectivity density,Conn.D)比较差异有统计学意义,BV/TV,SMI与Tb.N,TbTh,BS/BV,Tb.Sp呈相关关系。结论:骨质疏松与骨关节炎的显微结构存在差异,这些差异可能导致相反的骨缺陷;BV/TV,SMI是评价显微结构参数的2个重要指标。     

Novel micro-MRI approach for subchondral trabecular bone analysis in patients with hip osteoarthritis is comparable to micro-CT approach

AimTo test the agreement between a newly developed micro-magnetic resonance imaging (MRI) analysis of the subchondral bone and the micro-computed tomography (CT) approach.MethodsSamples obtained from 10 patients with osteoarthritis undergoing total hip arthroplasty were scanned with a 7.0 T micro-MRI. Proton density-weighted images and proton density-weighted images with fat suppression were obtained. The results were validated with a micro-CT device. Micro-MRI and micro-CT scans of the same sample were aligned, and regions of interest were delineated on equal areas of the sample. Bone volume fraction was calculated by using in-house plugins. The agreement between the methods was tested with Bland-Altman analysis.ResultsThe agreement between the methods was good, with average difference of 2.167%. The differences between the methods were not significant (P = 0.272, t test).ConclusionThe novel micro-MRI approach could be used for subchondral bone analysis. With further optimization for clinical MRI machines, the approach can be also used in the diagnostics of hip osteoarthritis.

Osteoarthritis (OA) is a progressive disorder that affects articular cartilage and subchondral bone. It is characterized by the development of subchondral cysts, bone marrow lesions, osteophytes, and a variety of other degenerative changes (1). The disorder is one of the leading causes of disability. Its prevalence is growing with obesity and age (2) – OA affects more than 60% of the population older than 60. However, it also affects younger people (3,4). It is a major economic burden, with a yearly cost of hip and knee replacements of £850 million in the United States alone (5). Although the available surgical treatments significantly improve the quality of life, no therapies are able to repair damaged joint tissue and to considerably postpone the need for surgical replacement. Recently, some progress has been made in terms of gene therapy and tissue engineering.The increase in OA prevalence highlights the need for an effective therapy. If we want to understand OA progression we need to apply a holistic approach. Only by studying cartilage, the underlying subchondral bone, and the synovial membrane together can we gain a detailed insight into the triggers of degenerative changes. This insight can improve OA diagnostics and lead to the development of an effective OA therapy (1-4,6,7).When it comes to OA studies, the main focus so far has been on cartilaginous tissue. Since articular cartilage has a high water content, magnetic resonance imaging (MRI) is the radiological method of choice for studying cartilage changes (8). Compositional MRI techniques, which visualize and quantify biochemical changes of the cartilage and other joint tissues, have revolutionized the imaging of articular joints. As MRI is able to detect biochemical changes before their morphological manifestation, it has markedly improved OA diagnostics and helped us to better understand the molecular background of OA (9-13). The degenerative changes of the subchondral bone induced by OA, on the other hand, are best visualized by computed tomography (CT) (14-17). Even though changes of subchondral bone play an important role in OA progression, they have not yet been studied in much detail. Researchers who prioritize MRI-based cartilage analysis over bone research mainly do so due to the overall emphasis on degenerative changes of cartilage in OA. Besides MRI, contrast-enhanced CT is also used to evaluate cartilage and provide information on collagen structure, proteoglycan content, and the severity of OA (18-21).Although CT has some advantages over MRI, such as being cheaper and faster, its main disadvantages are exposure to ionizing radiation and lack of soft-tissue contrast. MRI, on the other hand, offers excellent soft-tissue contrast and is the method of choice for studying structural changes of articular cartilage (22). Given the MRI’s superior ability to visualize soft tissues, it is a better choice than CT for the whole-joint tissue analysis. Currently available MRI-based methods are mostly used for the analysis of bone marrow fat content and visualization of bone marrow lesions. These methods do not provide quantitative information on bone structure, such as bone volume fraction, which is often used in OA grading. Moreover, their reliance on complex sequences makes them not easily accessible (23-27).A novel approach to trabecular bone structure analysis by micro-MRI allowed us to compare for the first time micro-MRI and micro-CT scans using ImageJ software. Our newly-developed ImageJ plugins can be used to acquire valuable quantitative information about trabecular bone structure, ie, bone volume percentage, as well as information about bone marrow fat composition. The validity of our new approach was tested by comparison with micro-CT – the gold standard in bone analysis. In addition to conventional MRI-based protocols used for studying cartilaginous tissue, by utilizing our novel approach the whole osteochondral unit can be studied using only one scanning method.     

Applications of magnetic resonance microscopy

Magnetic resonance imaging (MRI) has enjoyed enormous clinical success since the first demonstration of the method more than 30 years ago. An increasing number of pharmaceutical manufacturers seeking new biomarkers for assessing drug efficacy and toxicity are turning to MRI. A specific application of MRI promises to revolutionize pathology for the basic scientist in the same way MRI has forever altered the standard of care in the clinical domain. More specifically, this application is the use of magnetic resonance microscopy (MRM) in conjunction with new staining methodologies that now make MRM routinely available to the widest range of investigators.     

Mouse models for studies of HLA-G functions in basic science and pre-clinical research

HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response.This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.     

Imaging techniques for small animal imaging models of pulmonary disease: micro-CT

Microcomputed tomography (micro-CT) is ideal for quantifying pulmonary disease because of the inherent contrast between tissue and air that exists in the lungs. Both in vivo and in vitro studies can be performed using micro-CT. Live animal studies show function, while fixed specimen studies show structure. Through the use of image processing techniques, both acute and chronic lung diseases can be quantified. The information provided by micro-CT is complementary to histological evaluation, since CT is nondestructive. This paper discusses two examples, in vivo and in vitro, of how micro-CT can be used to assess pulmonary diseases in small animal models. With the use of micro-CT, we were able to quantify pulmonary fibrosis in the live rat and investigate the microstructure of the airway in fixed mouse lungs.     

骨关节炎动物模型的选择

背景:目前骨关节炎的发病原因尚不清楚,而且也没有有效的治疗手段。选择合适的动物模型会给骨关节炎的动物实验创造一个良好的条件。目的:对骨关节炎的不同实验动物及不同造模方式作一综述。方法:检索中国期刊全文数据库(CNKI)、万方数据库、维普数据库和PubMed数据库2013年1月至2018年7月的相关文章,以“骨关节炎、模型动物、大鼠、小鼠、豚鼠、兔、狗、羊”,英文检索词为“Osteoarthritis、Models、Animals、Mice、Rats、Rabbits、Dogs、Goats、guinea pigs、sheep”进行检索,剔除重复文献,选取与骨关节炎动物模型相关的文章,进行整理和分析。结果与结论:小鼠、大鼠、豚鼠、兔、狗、羊等动物都可作为骨关节炎研究的动物模型。而在研究骨关节炎动物实验的时候,正确选择动物模型和造模方式是很重要的。非手术模型避免了手术对于关节其他部位的损伤,更符合骨关节炎的病理过程,但是对于造模方法难以掌控,容易造成误差,且不能模拟创伤改变。手术模型通过手术破坏组织而造成关节损伤,进展快,效果明显,是短期研究的最佳选择。不同的实验动物和造模方案各有其优缺点,需要根据实验的需求合理选择。     

Exercise protects against insulin-dependent diabetes-induced osteoarthritis in rats: A scanning electron microscopy study

We tested the hypothesis that swim exercise can protect the articular cartilage from damages induced secondary to insulin-dependent diabetes mellitus in rats using the scanning electron microscopy and to monitor the blood levels of oxidative and antioxidative stress biomarkers that are known to be modulated in osteoarthritis (OA). A profound damage to the cartilage was observed in the diabetic rats. Our findings also show that swim exercise protects the knee joints from damage induced by diabetes as well as significantly inhibiting OA-induced upregulation of thiobarbituric acid reactive substances (TBARS) and tumor necrosis factor alpha (TNF-α) and augmented superoxide dismutase (SOD) inhibition by OA. Thus, we demonstrated an effective protection by swim exercise against diabetes-induced OA in a rat model of the disease.     

骨质疏松动物模型的研究现状

背景：骨质疏松的发病机制十分复杂,但又不能直接在人体上进行实验,需要复制类似人类骨质疏松的动物模型进行研究。 目的：全面分析各种骨质疏松动物模型的造模方法及优缺点,为今后研究骨质疏松症,在模型选择上提供参考。 方法：电子检索中国知识资源总库(CNKI)系列数据库和ESBCO Medline数据库1990-01/2010-07收录的骨质疏松模型的相关综述和论文报告。中文检索词为“骨质疏松,动物模型”;英文检索词为“osteoporosis,animal models”。共检索到469篇相关文献,对文章进行初审,纳入文献主题内容与此文联系紧密;原创、论点论据可靠的试验文章;观点明确,分析全面的文章。排除内容陈旧或重复文献及试验设计中不是采用随机对照试验的文章。 结果与结论：共纳入符合标准的38篇文献。目前用于骨质疏松症研究的动物模型主要有诱发性动物模型和转基因动物模型。各种骨质疏松动物模型可能只侧重于表现该疾病的某种病因、某一阶段、某些主要症状及某些病理生理变化,必须根据研究目的,选择合适的造模方法和实验动物。     

去势雌性山羊骨质疏松模型的特点

背景：加强骨质疏松模型的研究,对骨质疏松性骨折的防治非常必要。 目的：综述现有的山羊骨质疏松模型的特点,为骨质疏松和骨质疏松性骨折的防治提供帮助。 方法：应用计算机检索中国知网和PubMed数据库中2005-06/2011-02关于去势雌性山羊骨质疏松模型的文章,在标题和摘要中以“骨质疏松症、动物模型、山羊、卵巢切除”或“osteoporosis, animal model, goats, ovariectomy”为检索词进行检索。选择文章内容与建立骨质疏松模型的方法、评价标准,骨质变化等有关的研究,排除重复研究及建立雄性动物骨质疏松模型的研究。 结果与结论：初检得到48 篇文献,根据纳入标准选择21篇文章进行综述。山羊来源方便,容易处置,具有自动排卵和与成年妇女相似的排卵周期,是理想的实验动物材料;能获取大量血、尿和骨骼标本,是理想的制备骨质疏松模型的实验动物。去势法是建立骨质疏松模型常用的方法,山羊骨质疏松模型的建立将为骨质疏松和骨质疏松性骨折防治药物的开发、改进内置物设计等提供研究的基础。 关键词：卵巢切除术;骨质疏松;模型;雌激素;骨代谢;山羊 doi:10.3969/j.issn.1673-8225.2012.07.038