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Liu Kin Hung. / "May, 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 153-193). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

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L'imagerie par résonance magnétique (IRM) est largement utilisée dans le milieu médical pour l'imagerie des tissus mous. Afin d'obtenir des images de meilleures qualité, les hôpitaux s'équipent d'IRM avec des champs de plus en plus intenses. Les agents de contraste à base de nanoparticules de fer sont très prometteurs pour l'imagerie à haut champ. En effet, au contraire des agents de contraste à base de gadolinium, ils ne perdent pas leur efficacité à haut champ. Plusieurs paramètres sont à prendre en compte afin d'obtenir des agents de contrastes plus efficaces en IRM : tout d'abord, les propriétés magnétiques des nanoparticules d'oxydes de fer. Celles-ci doivent avoir des aimantations importantes. Ensuite, les nanoparticules agrégées sont plus efficaces que les nanoparticules individuelles. Pour finir, la présence d'une couche plus ou moins imperméable à l'eau ainsi que son épaisseur vont influencer l'efficacité de l'agent de contraste. Ce mémoire de thèse présente la conception de nouveaux agents de contraste à base de nanoparticules d'oxyde de fer, depuis l'optimisation de la synthèse afin d'obtenir les nanoparticules ayant les propriétés magnétiques les plus intéressantes pour l'IRM, jusqu'à l'assemblage de ces nanoparticules afin d'améliorer leur efficacité en IRM. La première partie de ce travail est donc consacrée à la synthèse de nanoparticules d'oxyde de fer. Une approche organométallique a été choisit car elle permet d'obtenir des nanoparticules de taille contrôlée. Nous montrons dans cette partie que les conditions de synthèse ont une grande influence sur la structure cristalline des nanoparticules synthétisées ainsi que sur leurs propriétés magnétiques. La deuxième partie de ce travail est consacrée à la réalisation d'agrégats de nanoparticules de taille contrôlée. L'agrégation des nanoparticules est réalisée par effet solvophobe en ajoutant de l'eau sur une solution de nanoparticules hydrophobes dans le THF. Nous montrons dans cette partie que la cinétique d'agrégation dépend de la quantité d'eau ajoutée. Les agrégats sont ensuite stabilisés par l'ajout d'un polymère et nous montrons que la morphologie et la taille des agrégats après leur transfert dans l'eau dépendent de la masse molaire et de la nature du polymère utilisé. La troisième partie de ce travail est consacrée à l'évaluation de l'efficacité des agrégats de nanoparticules en tant qu'agent de contraste. Les agrégats testés se sont révélés prometteurs, et des efficacités supérieures à celles d'agents de contraste commerciaux ont été obtenues. / The magnetic resonance imaging (MRI) is widely used in the medical field for soft tissue imaging. In order to obtain images of better quality, hospitals equip themselves with MRI of higher fields. Iron-based nanoparticle contrast agents are very promising for imaging at high field. Indeed, unlike the gadolinium contrast agents, they do not lose their effeciency at high field. Several parameters must be taken into account to achieve more effective contrast agents in MRI: first, the magnetic properties of iron oxide nanoparticles. They must have significant magnetization. Then, aggregated nanoparticles are more effective than individual nanoparticles. Finally, the presence of a more or less hydrophylic layer and its thickness will influence the effeciencys of the contrast agent.This thesis presents the design of new contrast agents based on iron oxide nanoparticles assembly, since the optimization of the synthesis to obtain nanoparticles with the most interesting magnetic properties for MRI up assembly of nanoparticles to improve their effectiveness in MRI.The first part of this work is devoted to the synthesis of iron oxide nanoparticles. An organometallic approach was chosen because it allows to obtain nanoparticles of controlled size. We show in this part of the synthesis conditions have a great influence on the crystal structure of the synthesized nanoparticles and their magnetic properties.The second part of this work is dedicated to the production of controlled size aggregates of nanoparticles. The aggregation of nanoparticles is performed by solvophobic effect by adding water to a solution of hydrophobic nanoparticles in THF. We show in this section that the kinetics of aggregation depends on the amount of water added. The aggregates are then stabilized by the addition of a polymer and show that the morphology and size of the aggregates after transfer into the water depend on the molecular weight and nature of the polymer used.The third part of this work is devoted to the evaluation of the efficiency of nanoparticle aggregates as a contrast agent. The aggregates tested have shown promise, and efficiencies higher than commercial contrast agents were obtained.

The steady-state free precession (SSFP) is one type of the fast scanning technique in MRI. So far most of its analysis are concentrated on the gradient echo SSFP (GR SSFP), very few paper~discuss the spin echo (SSFP (SE SSFP), and they are usually based on the simplified the hard pulse assumption. The advantage of the SE SSFP is that it can refocus the dephasing caused by the magnetic field inhomogeniety, which is the disadvantage of the GR SSFP. Also the hard pulse model can provide very limited information. The purpose of this paper is to establish the soft pulse model for both GR SSFP and SE SSFP. By using the spinor method to describe the interaction between the RF pulse, magnetic field, and the spin's magnetization, we create the steady state equations of the GR SSFP and SE SSFP, and give their analytical solutions. Because the SE SSFP's mathematical model is very complicated, we introduce a new concept, the linked-pulse, to simplify the problem, and provide the valuable results. Based on both traditional hard pulse model and our soft pulse model, we did a series of simulations, and compared both results. First of all, the soft pulse model can provide the slice profile and gradient effects, which is impossible for the hard pulse model. Second, in both models, the signal intensities are all depended on the Tl/T2 ratio, which is the characterization of the SSFP image. Third, we also observed how the pulse shape and the flip angles affect the slice profile and the signal intensity. In conclusion, the soft pulse model can give more information than hard pulse model can, such as slice profile and gradient effects, etc., provide more aspects for analyzing the SSFP image.

It has been suggested that simulating physiological loading of the knee during magnetic resonance imaging (MRI) is a promising technique for assessing soft and hard tissues in the knee joint. We have developed a novel MRI-compatible lower limb loading and positioning device to assess knee biomechanics in a physiologically relevant environment using MRI. The objectives of this study were (1) to evaluate inter- and intra-examiner reliability for using our custom-built loading system to maintain a desired load magnitude and direction during each loading trial and over repeated subject visits and (2) to determine the effect of the applied load on motion of the subject's knee over the duration of a loading trial. The pneumatic-controlled loading system was tested on ten subjects at a compression load of 50% of the subject's bodyweight. Two examiners separately positioned and loaded each subject for three loading trials per visit, repeated for three visits. The primary outcome measure was the magnitude of the primary axial load (proximal/distal force) applied to the subject's foot over a loading trial. Secondary outcome measures included average magnitude of medial/lateral and anterior/posterior forces as well as valgus/varus, flexion/extension, and external/internal moments applied to the subject's foot during a loading trial. Location of center of loading at the foot was also recorded. Primary axial load was found to be maintained to within 44-47% of subject bodyweight. Following load-application, the subject's knee exhibited movement throughout the duration of each loading trial. We found that 61.0% of proximal/distal knee displacement occurred within the first 2 minutes following loading. Between minutes 4 and 12, knee positioning was maintained to within 0.92 mm in the medial/lateral direction and 1.24 mm in the proximal/distal direction. We conclude that our loading device can apply controllable and reproducible loading over repeated trials as well as limit subject motion throughout each trial.

Four new potential MR imaging contrast agents were synthesised. Gadolinium-hematoporphyrin (Gd-H) was produced by inserting gadolinium into the naturally occurring porphyrin,hematoporphyrin.Gadolinium-tetra-carboranylmethoxyphenyl-porphyrin acetate (Gd-TCP)was similarly synthesised by gadolinium insertion into the synthetic porphyrin, 1, 6, 11, 16-tetra-[3-(carboranylmethoxy)phenyl] porphyrin. The monoclonal antibodies, 9.2.27 against melanoma and WM53 against leukaemia cell lines, were conjugated with cyclic anhydride gadolinium-diethylenetriaminepenta-acetic acid (Gd-cDTPAa), yielding the attachment of chelate DTPA to the antibodies. Gadolinium ion was inserted into the chelate DTPA, thus labelled both these antibodies with Gd-DTPA. Overall, with the satisfactory low levels of gadolinium in the liver, kidneys, and spleen, and good tumour uptake, gadolinium antibody conjugates has considerable potential for further diagnostic applications of MR imaging. / Doctor of Philosophy (PhD)

Aim To determine the neural correlates of Bipolar Disorder (BD) using functional Magnetic Resonance Imaging (fMRI) in different phases of the illness. Methods Five fMRI studies were conducted in adult female BD patients and healthy matched comparison subjects. The first two studies examined patients with bipolar depression and hypomania using captioned-pictures to characterize mood-state related patterns of activation. The subsequent three studies investigated BD euthymia using emotional words and faces to identify a potential trait-marker. Results During depression, bipolar patients demonstrated additional subcortical activation in the thalamus, amygdala, hypothalamus and medial globus pallidus. In hypomania, patients again had additional subcortical activation involving the caudate and the thalamus. In both studies patients had prefrontal cortex activation, but the pattern differed from that in healthy subjects. These studies suggested a pattern of mood-state related subcortical recruitment for emotional processing in BD. The next set of studies examined euthymic BD patients to partition trait and state-markers. The first study used implicit positive and negative word-associated affect and found diminished responses to positive and negative affective words as compared to healthy subjects in both cortical and subcortical brain regions, in particular the cingulate, thalamus and caudate. The second study used the emotional Stroop task to elicit implicit affective processing and euthymic patients had less cortical and subcortical activation in response to affect, in particular decreased left ventral prefrontal cortex (BA47) activation. The final study used explicit emotional processing of fear and disgust to examine affective responses, and showed that patients were generally less responsive to disgust, but had comparatively greater activations to fear. Conclusions BD patients have a likely deficit in the ventral prefrontal cortex that is evident in euthymia. Prefrontal cognitive appraisal of emotions is constrained in euthymic, depressed and hypomanic phases, reflected in subcortical changes that suggest additional processing. The likely cause for this is a functional prefrontal cortex deficit that results in compensatory changes in emotional processing systems. Treatment probably stabilizes these systems without normalizing them. Our studies demonstrate the benefits of examining BD in its different phases, and future studies should attempt to emulate this in medication-free patients.

The interactions of biomolecules and cells at solid-liquid interfaces play a pivotal role in a range of biomedical applications and have hence been studied in detail. An improved understanding of these interactions results in the ability to manipulate biomolecules and concurrently cells spatially and temporally at surfaces with high precision. Spatial control can be achieved using patterned surface chemistries whilst temporal control is achieved by switchable surfaces. The combination of these two surface properties offers unprecedented control over the behaviour of biomolecules and cells at the solid-liquid interface. This is particularly relevant for cell microarray applications, where a range of biological processes must be duly controlled in order to maximise the efficiency and throughput of these devices. Of particular interest are transfected cell microarrays (TCMs), which significantly widen the scope of microarray genomic analysis by enabling the high-throughput analysis of gene function within living cells Initially, this thesis focuses on the spatially controlled, electro-stimulated adsorption and desorption of DNA. Surface modification of a silicon chip with an allylamine plasma polymer (ALAPP) layer resulted in a surface that supported DNA adsorption and sustained cell attachment. Subsequent high density grafting of poly(ethylene glycol) (PEG) formed a layer resistant to biomolecule adsorption and cell attachment. PEG grafted surfaces also showed significantly reduced attachment of DNA with an equilibrium binding constant of 23 ml/mg as compared with 1600 ml/mg for ALAPP modified surfaces. Moreover, both hydrophobic and electrostatic interactions were shown to contribute to the binding of DNA to ALAPP. Spatial control over the surface chemistry was achieved using excimer laser ablation of the PEG coating which enabled the production of patterns of re-exposed ALAPP with high resolution. Preferential electro-stimulated adsorption of DNA to the ALAPP regions and subsequent desorption by the application of a negative bias was observed. Furthermore, this approach was investigated for TCM applications. Cell culture experiments demonstrated efficient and controlled transfection of cells. Electro-stimulated desorption of DNA was shown to yield enhanced solid phase transfection efficiencies with values of up to 30%. The ability to spatially control DNA adsorption combined with the ability to control the binding and release of DNA by application of a controlled voltage enables an advanced level of control over DNA bioactivity on solid substrates and lends itself to biochip applications. As an alternative approach to surface patterning, the fabrication and characterisation of chemical patterns using a technique that can be readily integrated with methods currently used for the formation of microarrays is also presented. Here, phenylazide modified polymers were printed onto low fouling ALAPP-PEG modified surfaces. UV irradiation of these polymer arrays resulted in the crosslinking of the polymer spots and their covalent attachment to the surface. Cell attachment was shown to follow the patterned surface chemistry. Due to the use of a microarray contact printer it was easily possible to deposit DNA on top of the polymer microarray spots. A transfected cell microarray was generated in this way, demonstrating the ability to limit cell attachment to specific regions and the suitability of this approach for high density cell assays. In order to allow for the high-throughput characterisation of the resultant polymer microarrays, surface plasmon resonance imaging was utilised to study the adsorption and desorption of bovine serum albumin, collagen and fibronectin. This analysis enabled insights into the underlying mechanisms of cell attachment to the polymers studied. For the system analysed here, electrostatic interactions were shown to dominate cellular behaviour.

Defining language lateralisation is important to minimise morbidity in patients treated surgically for temporal lobe epilepsy (TLE). Functional magnetic resonance imaging (fMRI) offers a promising, non-invasive, alternative strategy to the Wada test. Here, fMRI has been used to study healthy controls and patients with TLE in order (i) to define language-related activation patterns and their reproducibility; (ii) to compare lateralisation determined by fMRI with that from the Wada test; and (iii) to explore the usefulness of multiple fMRI language paradigms. 18 healthy controls (12 right-handed and 6 left-handed) and 24 pre-operative TLE patients (19 right-handed: 12 left-TLE, 7 right-TLE; 5 left-handed: 2 right-TLE, 3 left-TLE) were studied using fMRI. Four fMRI language paradigms used: phonetic and semantic fluency, and the naming of living and non-living things. The data for all 4 tasks were acquired during a single scanning session on two occasions. All patients also underwent Wada testing. In patients and controls, phonetic and semantic fluency tasks were robustly activating and strongly lateralising. Quantified language-related lateralisation from fMRI verbal fluency data was highly reproducible and concordant with the lateralisation of the Wada test. Both fluency tasks identified patients with atypical language lateralisation, including 4/12 right-handed patients with left-TLE and 4/5 left-handed TLE patients, regardless of the side of epileptic focus. In comparison, the two confrontational naming tasks were not strongly lateralising and did not reliably agree with Wada lateralisation in either 12 right-handed controls or 19 right-handed patients with TLE. However, there was a difference in the pattern of fMRI activation in right-handed pat ients with left-TLE. Left-TLE patients had a more right lateralised network of activation when naming living things relative to non-living things, suggesting that some patients may be at risk of a category specific naming decline for non-living things after left anterior temporal lobectomy. These results demonstrate that non-invasive fMRI measures of languagerelated lateralisation may provide a practical and reliable alternative to invasive testing for pre-surgical language lateralisation in patients with TLE. The high proportion of TLE patients showing atypical language lateralisation suggests considerable plasticity of language representation in the brains of patients with intractable TLE.