Articulated statistical shape models for the analysis of bone destruction in mouse models of rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease that affects approximately 1% of the population, where chronic inflammation of the synovial joints can lead to active destruction of cartilage and bone. New therapeutic targets are discovered by investigating genes or processes that exacerbate or ameliorate disease progression. Mouse models of inflammatory arthritis are commonly employed for this purpose, in conjunction with biomedical imaging techniques and suitable measures of disease severity. This thesis investigated the hypothesis that a statistical model of non-pathological bone shape variation could be used to quantify bone destruction present in micro-CT images. A framework for constructing statistical shape models of the hind paw was developed, based on articulated registration of a manually segmented reference image. Successful registration of the reference towards ten healthy hind paw samples was followed by statistical shape analysis. Mouse models of inflammatory arthritis were then investigated and compared by identifying bone abnormalities as deviations from the model statistics. Validation of the model against digital phantoms and clinical scores indicates that the method is largely successful in this effort. Application of the method in a novel study of macrophage-mediated inflammation shows promising results that are supportive of previous findings

Detection and characterisation of bone destruction in murine rheumatoid arthritis using statistical shape models

Rheumatoid arthritis (RA) is an autoimmune disease in which chronic inflammation of the synovial joints can lead to destruction of cartilage and bone. Pre-clinical studies attempt to uncover the underlying causes by emulating the disease in genetically different mouse strains and characterising the nature and severity of bone shape changes as indicators of pathology. This paper presents a fully automated method for obtaining quantitative measurements of bone destruction from volumetric micro-CT images of a mouse hind paw. A statistical model of normal bone morphology derived from a training set of healthy examples serves as a template against which a given pathological sample is compared. Abnormalities in bone shapes are identified as deviations from the model statistics, characterised in terms of type (erosion / formation) and quantified in terms of severity (percentage affected bone area). The colour-coded magnitudes of the deviations superimposed on a three-dimensional rendering of the paw show at a glance the severity of malformations for the individual bones and joints. With quantitative data it is possible to derive population statistics characterising differences in bone malformations for different mouse strains and in different anatomical regions. The method was applied to data acquired from three different mouse strains. The derived quantitative indicators of bone destruction have shown agreement both with the subjective visual scores and with the previous biological findings. This suggests that pathological bone shape changes can be usefully and objectively identified as deviations from the model statistics

Visualizing and Predicting the Effects of Rheumatoid Arthritis on Hands

This dissertation was inspired by difficult decisions patients of chronic diseases have to make about about treatment options in light of uncertainty. We look at rheumatoid arthritis (RA), a chronic, autoimmune disease that primarily affects the synovial joints of the hands and causes pain and deformities. In this work, we focus on several parts of a computer-based decision tool that patients can interact with using gestures, ask questions about the disease, and visualize possible futures. We propose a hand gesture based interaction method that is easily setup in a doctor\u27s office and can be trained using a custom set of gestures that are least painful. Our system is versatile and can be used for operations like simple selections to navigating a 3D world. We propose a point distribution model (PDM) that is capable of modeling hand deformities that occur due to RA and a generalized fitting method for use on radiographs of hands. Using our shape model, we show novel visualization of disease progression. Using expertly staged radiographs, we propose a novel distance metric learning and embedding technique that can be used to automatically stage an unlabeled radiograph. Given a large set of expertly labeled radiographs, our data-driven approach can be used to extract different modes of deformation specific to a disease

Imaging in pre-clinical cancer research : applied to bone metastases

The aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In order to do this, normalized methods to analyse MicroCT scans and perform quantitative measurements within these datasets are described in this thesis. These techniques were combined with a biological angiogenesis assay and used as research tools in a study comparing various different combination treatments of bone metastases.KWF KankerbestrijdingUBL - phd migration 201

Development and characterisation of mechanical and enzymatic models of cartilage degeneration

Currently, there is a gap between pharmacological treatment and joint replacement for the management of cartilage degradation diseases, such as osteoarthritis. It may be possible to use cartilage substitution materials to treat small defects in cartilage tissues, delaying the need for joint replacements, which have a limited lifetime in vivo, so are not suitable for many patients. A major barrier to the use of cartilage substitution materials is suitable in vitro testing of cartilage materials. Therefore mechanical and enzymatic models of cartilage degeneration were developed, which may be used to assess novel cartilage substitution materials. A single station pin-on-plate rig with a variable load was used to degrade the cartilage tissue of osteochondral pins and plates to produce two mechanical models of degradation denoted “mild” and “moderate”. A Ringer’s solution and serum based lubricant were chosen to hydrate cartilage tissues during articulation. The lubricants used during mechanical degradation were collected and analysed quantitatively for glycosaminoglycan (GAG) and collagen content. In addition, a method for isolating and imaging the cartilage wear particles in the lubricant was developed. A chondroitinase ABC enzyme was used to enzymatically degrade cartilage tissues. The mechanical and enzymatic degradation in the models was characterised using a broad range of mechanical and biological assessment techniques. The mechanical degradation and wear of the tissues created using the pin-on-plate rig was evaluated using cartilage height measurements, friction measurements, surface profilometry, histological and immunohistological staining, and quantitative biochemical assays. The wear on the surface of the tissue was observed using environmental scanning electron microscopy and the tissue ultrastructure was observed using transmission electron microscopy. The tissues degraded using chondroitinase ABC were analysed using indentation testing, histological and immunohistological staining, quantitative biochemical assays, and transmission electron microscopy. It was determined that an increased load used during pin-on-plate testing resulted in an increase in tissue degradation. Mechanical degradation under the “moderate” loading condition caused the surface of the cartilage tissue to become fibrillated and areas of tissue loss were observed. Under the mild condition the cartilage surface remained relatively smooth however, several small fissures were observed in some specimens. The surface of the tissue degraded under moderate conditions was significantly rougher than that degraded under the mild condition. There was a small loss of GAGs in the mild condition whereas a large volume of GAGs were lost from the tissue under the moderate condition, and the aggrecan network in the tissue was heavily disrupted. There was no significant difference between the friction measurements or the height measurements recorded for the specimens under the two variable loading conditions. Immunohistochemical staining for minor tissue components showed that collagen VI and cartilage oligomeric matrix protein (COMP) were not altered by the mechanical degradation, whereas a loss in biglycan was observed in specimens loaded under the moderate condition. It was observed that the serum lubricant may protect the cartilage tissue from degradation during articulation. An increased number of wear particles were observed in the lubricants recovered from the moderate loading condition tests. Digestion of tissues with chondroitinase ABC led to an increase in tissue deformation during indentation. The level of GAGs in the tissues was reduced and the GAGs associated with the aggrecan network in the tissue were no longer visible. Collagen VI and COMP were not significantly affected by chondroitinase ABC digestion, however biglycan staining was reduced at the superficial to middle zone of the tissue. The models produced have potential to be used in the assessment of novel cartilage substitution materials. The parameters used in this study will also be useful in the development of in vitro whole joint simulators