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New methods for the production of oral dosage forms
Get PDFThis thesis was previously held under moratorium from 18/11/19 to 18/11/21Oral drug delivery remains the preferred method of API administration, but Biopharmaceutical Classification System Class II drugs are not ideally suited to this due to their inherent poor solubility. The current study aims to utilise the innovative formulation technique of aerosol jet printing to increase the dissolution capability of poorly soluble drugs.Aerosol jet printing Class II drugs with an appropriate stabilising polymer reduces crystallinity, increasing drug solubility. Furthermore, in the presence of sufficient polymer content, fully amorphous products can be produced resulting in enhanced dissolution capabilities. The intrinsic dissolution rate of fenofibrate was found to increase by 10-fold on printing with PVP K30. A lesser increase was typically seen on printing the materials as separate layers, but a slight loss of crystallinity does suggest that there are some interactions happening at the interface. Printing with PVP K30 was also found to increase the intrinsic dissolution rate of ibuprofen, with 3-fold increase on formation of amorphous material.Aerosol jet printing also allows a high degree of precision, enabling control of drug location to the micrometre, production of scalable dosage forms and control of drug distribution within solid dispersions. This high degree of precision has also enabled design of more complex dosage forms with a view to generating a pulsatile release profile in an entirely novel manner. Scale up of printing was attempted to allow demonstration of high precision printing of a full-size tablet. Unfortunately, dissolution testing of the full-size tablet failed but it is hoped this technology could be developed further in the future.Overall this thesis demonstrates the ability of the aerosol jet technology to be applied to pharmaceutical manufacturing in a precise manner to increase dissolution of poorly soluble compounds. Future work could include development of the technique for use in production of more complex customisable dosage forms.Oral drug delivery remains the preferred method of API administration, but Biopharmaceutical Classification System Class II drugs are not ideally suited to this due to their inherent poor solubility. The current study aims to utilise the innovative formulation technique of aerosol jet printing to increase the dissolution capability of poorly soluble drugs.Aerosol jet printing Class II drugs with an appropriate stabilising polymer reduces crystallinity, increasing drug solubility. Furthermore, in the presence of sufficient polymer content, fully amorphous products can be produced resulting in enhanced dissolution capabilities. The intrinsic dissolution rate of fenofibrate was found to increase by 10-fold on printing with PVP K30. A lesser increase was typically seen on printing the materials as separate layers, but a slight loss of crystallinity does suggest that there are some interactions happening at the interface. Printing with PVP K30 was also found to increase the intrinsic dissolution rate of ibuprofen, with 3-fold increase on formation of amorphous material.Aerosol jet printing also allows a high degree of precision, enabling control of drug location to the micrometre, production of scalable dosage forms and control of drug distribution within solid dispersions. This high degree of precision has also enabled design of more complex dosage forms with a view to generating a pulsatile release profile in an entirely novel manner. Scale up of printing was attempted to allow demonstration of high precision printing of a full-size tablet. Unfortunately, dissolution testing of the full-size tablet failed but it is hoped this technology could be developed further in the future.Overall this thesis demonstrates the ability of the aerosol jet technology to be applied to pharmaceutical manufacturing in a precise manner to increase dissolution of poorly soluble compounds. Future work could include development of the technique for use in production of more complex customisable dosage forms
Investigating alternative delivery systems for self-Amplifying RNA vaccines
Get PDFThe rabies virus is an enveloped, single stranded, negative-sense RNA virus of the Lyssavirus genus, zoonotic pathogens within the family Rhabdoviridae. Although extensive effort has been made in the last decades to develop efficacious vaccines to prevent rabies spread, the virus is still responsible for the mortality of about 24,000 to 90,000 people per year especially in developing countries and it has been classified as one of the major causes of death from infectious diseases in humans.;Commercially available rabies vaccines for humans are considered effective, however the production costs are very high and multiple injections are required to achieve protection. Therefore, the development of new vaccines to reduce the toll of rabies disease in the developing world would be highly desirable. Within this project a nucleic acid based vaccine strategy - in particular self-amplifying RNA vaccine (SAM)- has been investigated since this platform was previously reported to elicit protective immune responses, particularly in the case of cell-mediated responses in a safe manner and for a variety of virus disease.;To enhance biological stability and cell internalisation, SAM was combined with four cationic delivery systems. Oil-in-water cationic nano emulsions (CNE), polymeric nanoparticles (NPs), lipid nanoparticles (SLNs) and liposomes were formulated in the absence of or in combination with a specific SAM vaccine. Despite the differences in formulation composition, all samples contained the same concentration of cationic lipid - 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP), or dimethyldioctadecylammonium (DDA) - known as immunostimulants.;In the preliminary studies, two different manufacturing processes such as Microfluidics and Microfluidisation were applied. As a proof of concept, anionic liposomes and solid lipid nanoparticles were formulated and ovalbumin was encapsulated within the delivery systems as model protein antigen. Resulting carriers were compared in terms of their physico-chemical properties. The purpose was to obtain homogeneous formulations with a diameter in the nanometres range with a given manufacturing method. Furthermore, dialysis, tangential flow filtration (TFF) and size exclusion chromatography (SEC) have been tested as purification methods and compared in terms of the ability to remove both residual organic solvent and unloaded protein from samples without altering physico-chemical attributes.;These process parameters and purification method optimisations were then applied to produce cationic CNE, NPs, SLNs and liposomes in combination with a specific SAM vaccine. In the preliminary studies and during formulations development optimisation, SAM encoding for green fluorescent protein (SAM-GFP) was used as a model SAM with a reporter function,given the ease of detection in in-vitro cell cultures. However, SAM encoding for rabies glycoprotein (SAM-Rabies) represented the actual antigen of interest, employed in this project for further in vivo analysis. Cationic SLNs, NPs and liposomes were produced using microfluidics, since this method required smaller volumes compared to the Microfluidisation, thus avoiding waste of reagents.;However, the Microfluidizer was used to reduce CNE size,due to incompatibility between CNE component and microfluidics chip. Moreover, particles were formulated with SAM encoding the antigen of interest and loaded into or adsorbed onto cationic carriers. All delivery systems were evaluated according to their physico-chemical properties: hydrodynamic radius, sample homogeneity (polydispersity index - PDI) and surface charge. Furthermore, in vitro activity was investigated using three different cell lines:bone marrow derived macrophages (BMDM), bone marrow derived dendritic cells (BMDC) and baby hamster kidney cells (BHK).;SAM uptake and antigen expression from each formulation in each cell line were used to discriminate and down-select formulations for invivo studies. In the in vivo studies, biodistribution of carriers alone or in combination with SAM were performed. Briefly the selected SAM-carriers were administered intramuscularly (i.m.) to BALB/c mice and their movement in the animal body was tracked using a radiolabelling technique thereby allowing measurement of formulations at chosen time-points and in specific organs. The aim of the study was to understand the pharmacokinetic profile of formulations in a mouse model and assess whether biodistribution might correlate with subsequent immunogenicity studies.;The initial attempt of these studies was to (i) find the antigen dose to induce high antibody and cellular responses in vivo and (ii) to compare the adjuvant properties of selected cationic candidates (i.e. SAM encapsulating DOTAP NPs, DOTAP liposomes and DDA liposomes) after i.m. injection. Formulations were selected according to the potency of inducing antigen expression in vitro. The commercial vaccine Rabipur, which is an inactivated virus rabies vaccine, was used as comparator. The aim was to find a valid and more cost-effective alternative formulation which induced an immune response comparable or superior to the commercial vaccine.;Data showed that DOTAP NPs were the most potent in triggering IgG titers among candidates and the antibody levels were equivalent to the ones induced by the commercial vaccine after a single dose. Interestingly, the GMT was well above the protective threshold despite the antigen dose used, thus meaning that elicited antibodies were functional against rabies glycoprotein G. In terms of cellular response all candidates were able to activate both CD4+ and CD8+ T cells in a comparable manner to the vaccine on the market.;Moreover, to evaluate if changing the route of administration might affect carriers' potency,SAM encapsulating candidates were also administered intradermally (i.d.) and intranasally (i.n.), and formulations immunogenicity was evaluated according to IgG titres and cellular response. To do so, DOTAP NPs and DOTAP SLNs were selected; NPs were tested considering the promising outcome from the first in vivo study, whereas SLNs were introduced although poor in vitro antigen expression. The aim was to understand the power of in vitro models to predict in vivo antigen immunogenicity.;Results highlighted that SLNs injected i.m.showed increased immunogenicity compared to both NPs and the licenced vaccine after a single dose. Moreover, the potency of SLNs was also seen after intradermal administration,where SLNs were as potent as Rabipur to elicit IgG titer in mice after two vaccinations, inducing comparable innate and adaptive immunity to the vaccine on the market. Herein it was also reported that two doses of SAM SLNs injected i.n. induced a humoral immunity which was higher than the one elicited by Rabipur.;Interestingly, intranasal administration of SLNs led to a higher percentage of IL-2 producing antigen specific CD4+ T cells compared to the licenced in both spleens and lungs. Although a significant difference was observed among formulations in the ability to enhance antigen-specific IgG titres, immunogenicity did not directly correlate with biodistribution, where carriers' pharmacokinetics were indeed similar. All together, these findings are encouraging and demonstrate that coformulation of SAM vaccine and solid lipid nanoparticles might be a valid and more advantageous alternative to produce rabies vaccines, with augmented patient' safety and compliance.The rabies virus is an enveloped, single stranded, negative-sense RNA virus of the Lyssavirus genus, zoonotic pathogens within the family Rhabdoviridae. Although extensive effort has been made in the last decades to develop efficacious vaccines to prevent rabies spread, the virus is still responsible for the mortality of about 24,000 to 90,000 people per year especially in developing countries and it has been classified as one of the major causes of death from infectious diseases in humans.;Commercially available rabies vaccines for humans are considered effective, however the production costs are very high and multiple injections are required to achieve protection. Therefore, the development of new vaccines to reduce the toll of rabies disease in the developing world would be highly desirable. Within this project a nucleic acid based vaccine strategy - in particular self-amplifying RNA vaccine (SAM)- has been investigated since this platform was previously reported to elicit protective immune responses, particularly in the case of cell-mediated responses in a safe manner and for a variety of virus disease.;To enhance biological stability and cell internalisation, SAM was combined with four cationic delivery systems. Oil-in-water cationic nano emulsions (CNE), polymeric nanoparticles (NPs), lipid nanoparticles (SLNs) and liposomes were formulated in the absence of or in combination with a specific SAM vaccine. Despite the differences in formulation composition, all samples contained the same concentration of cationic lipid - 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP), or dimethyldioctadecylammonium (DDA) - known as immunostimulants.;In the preliminary studies, two different manufacturing processes such as Microfluidics and Microfluidisation were applied. As a proof of concept, anionic liposomes and solid lipid nanoparticles were formulated and ovalbumin was encapsulated within the delivery systems as model protein antigen. Resulting carriers were compared in terms of their physico-chemical properties. The purpose was to obtain homogeneous formulations with a diameter in the nanometres range with a given manufacturing method. Furthermore, dialysis, tangential flow filtration (TFF) and size exclusion chromatography (SEC) have been tested as purification methods and compared in terms of the ability to remove both residual organic solvent and unloaded protein from samples without altering physico-chemical attributes.;These process parameters and purification method optimisations were then applied to produce cationic CNE, NPs, SLNs and liposomes in combination with a specific SAM vaccine. In the preliminary studies and during formulations development optimisation, SAM encoding for green fluorescent protein (SAM-GFP) was used as a model SAM with a reporter function,given the ease of detection in in-vitro cell cultures. However, SAM encoding for rabies glycoprotein (SAM-Rabies) represented the actual antigen of interest, employed in this project for further in vivo analysis. Cationic SLNs, NPs and liposomes were produced using microfluidics, since this method required smaller volumes compared to the Microfluidisation, thus avoiding waste of reagents.;However, the Microfluidizer was used to reduce CNE size,due to incompatibility between CNE component and microfluidics chip. Moreover, particles were formulated with SAM encoding the antigen of interest and loaded into or adsorbed onto cationic carriers. All delivery systems were evaluated according to their physico-chemical properties: hydrodynamic radius, sample homogeneity (polydispersity index - PDI) and surface charge. Furthermore, in vitro activity was investigated using three different cell lines:bone marrow derived macrophages (BMDM), bone marrow derived dendritic cells (BMDC) and baby hamster kidney cells (BHK).;SAM uptake and antigen expression from each formulation in each cell line were used to discriminate and down-select formulations for invivo studies. In the in vivo studies, biodistribution of carriers alone or in combination with SAM were performed. Briefly the selected SAM-carriers were administered intramuscularly (i.m.) to BALB/c mice and their movement in the animal body was tracked using a radiolabelling technique thereby allowing measurement of formulations at chosen time-points and in specific organs. The aim of the study was to understand the pharmacokinetic profile of formulations in a mouse model and assess whether biodistribution might correlate with subsequent immunogenicity studies.;The initial attempt of these studies was to (i) find the antigen dose to induce high antibody and cellular responses in vivo and (ii) to compare the adjuvant properties of selected cationic candidates (i.e. SAM encapsulating DOTAP NPs, DOTAP liposomes and DDA liposomes) after i.m. injection. Formulations were selected according to the potency of inducing antigen expression in vitro. The commercial vaccine Rabipur, which is an inactivated virus rabies vaccine, was used as comparator. The aim was to find a valid and more cost-effective alternative formulation which induced an immune response comparable or superior to the commercial vaccine.;Data showed that DOTAP NPs were the most potent in triggering IgG titers among candidates and the antibody levels were equivalent to the ones induced by the commercial vaccine after a single dose. Interestingly, the GMT was well above the protective threshold despite the antigen dose used, thus meaning that elicited antibodies were functional against rabies glycoprotein G. In terms of cellular response all candidates were able to activate both CD4+ and CD8+ T cells in a comparable manner to the vaccine on the market.;Moreover, to evaluate if changing the route of administration might affect carriers' potency,SAM encapsulating candidates were also administered intradermally (i.d.) and intranasally (i.n.), and formulations immunogenicity was evaluated according to IgG titres and cellular response. To do so, DOTAP NPs and DOTAP SLNs were selected; NPs were tested considering the promising outcome from the first in vivo study, whereas SLNs were introduced although poor in vitro antigen expression. The aim was to understand the power of in vitro models to predict in vivo antigen immunogenicity.;Results highlighted that SLNs injected i.m.showed increased immunogenicity compared to both NPs and the licenced vaccine after a single dose. Moreover, the potency of SLNs was also seen after intradermal administration,where SLNs were as potent as Rabipur to elicit IgG titer in mice after two vaccinations, inducing comparable innate and adaptive immunity to the vaccine on the market. Herein it was also reported that two doses of SAM SLNs injected i.n. induced a humoral immunity which was higher than the one elicited by Rabipur.;Interestingly, intranasal administration of SLNs led to a higher percentage of IL-2 producing antigen specific CD4+ T cells compared to the licenced in both spleens and lungs. Although a significant difference was observed among formulations in the ability to enhance antigen-specific IgG titres, immunogenicity did not directly correlate with biodistribution, where carriers' pharmacokinetics were indeed similar. All together, these findings are encouraging and demonstrate that coformulation of SAM vaccine and solid lipid nanoparticles might be a valid and more advantageous alternative to produce rabies vaccines, with augmented patient' safety and compliance
Parliamentary sovereignty : constitutional theory and practice from a Scottish perspective
Get PDFThe classic account of parliamentary sovereignty, captured in the work of A.V Dicey, has long been regarded as the fundamental doctrine of the UK constitution. The orthodox view is that the UK Parliament has unrestricted law making power which no other body can invalidate. However, overtime the relevance of the traditional doctrine has faced challenge from within the political, legal and common law constitution.;In this context, the focus of this thesis is to assess the impact that the Scottish constitutional trajectory has had on the orthodox understanding of sovereignty in the UK. This research has been prompted by the potential profound implications of the UK's pending exit from the European Union, which has intensified the debate around the understanding of sovereignty in the UK. Against this backdrop, the political and legal implications of the 2014 referendum on Scottish independence continue to develop, therefore this research will contribute to the sovereignty debate from a Scottish perspective.;Devolution in Scotland gives institutional expression to Scottish constitutional differences: differences that have existed within the Union since 1707. Arguably, the introduction and development of the settlement has entrenched constitutional distinctions between Scotland and UK. Indeed, the territorial dimensions of the UK constitution were fully tested when the question of Scottish independence was brought on to the political agenda.;Although Scotland voted to remain within the UK, the political response to the 'No' vote initiated the devolution of further power to Scotland. Consequently, the Scotland Act 2016 has introduced changes of potential constitutional significance. All of the above will be examined in great detail throughout this research, to reveal the pressure that the Scottish constitutional trajectory has placed on the classic account of parliamentary sovereignty. It will be concluded that the challenges to the doctrine continue to intensify overtime as the UK constitution evolves.The classic account of parliamentary sovereignty, captured in the work of A.V Dicey, has long been regarded as the fundamental doctrine of the UK constitution. The orthodox view is that the UK Parliament has unrestricted law making power which no other body can invalidate. However, overtime the relevance of the traditional doctrine has faced challenge from within the political, legal and common law constitution.;In this context, the focus of this thesis is to assess the impact that the Scottish constitutional trajectory has had on the orthodox understanding of sovereignty in the UK. This research has been prompted by the potential profound implications of the UK's pending exit from the European Union, which has intensified the debate around the understanding of sovereignty in the UK. Against this backdrop, the political and legal implications of the 2014 referendum on Scottish independence continue to develop, therefore this research will contribute to the sovereignty debate from a Scottish perspective.;Devolution in Scotland gives institutional expression to Scottish constitutional differences: differences that have existed within the Union since 1707. Arguably, the introduction and development of the settlement has entrenched constitutional distinctions between Scotland and UK. Indeed, the territorial dimensions of the UK constitution were fully tested when the question of Scottish independence was brought on to the political agenda.;Although Scotland voted to remain within the UK, the political response to the 'No' vote initiated the devolution of further power to Scotland. Consequently, the Scotland Act 2016 has introduced changes of potential constitutional significance. All of the above will be examined in great detail throughout this research, to reveal the pressure that the Scottish constitutional trajectory has placed on the classic account of parliamentary sovereignty. It will be concluded that the challenges to the doctrine continue to intensify overtime as the UK constitution evolves
Public library digital services : emergent issues of access and acceptable use
Get PDFThis research programme presented for consideration of the award of PhD by publication, presents a portfolio of 15 papers published between 2004 and 2018, and explores the transformation of public library digital services in a time of significant change. Initially exploring access issues from an organisational (policy) and architectural (design) perspective, ongoing work led to fundamental concerns over acceptable use from a user and ethical (behavioural) perspective. Significant access issues were initially discovered in relation to inconsistent digital service categorisation in architectural design, and restrictive policies and procedures.;Further studies identified acceptable use policies that were not fit for purpose, and Internet filtering systems blocking legitimate content. Issues were also identified around the use of third party service providers, and the impact on user privacy that results, as well as what constituted acceptable use from the point of view of library patrons. Issues of public awareness of appropriate ethical behaviours then led to a critical examination of approaches to character education in information literacy education, notably identifying a lack of explicit attention to important aspects of ethical education in information literacy frameworks and models, and establishing a research agenda for further work.;A range of research methods are utilised across the 15 papers that make up the submission, including literature reviews, surveys of library users and staff, heuristic evaluation of digital services, unobtrusive testing of access to public library services, content analysis of digital services, and content analysis of information literacy frameworks.This research programme presented for consideration of the award of PhD by publication, presents a portfolio of 15 papers published between 2004 and 2018, and explores the transformation of public library digital services in a time of significant change. Initially exploring access issues from an organisational (policy) and architectural (design) perspective, ongoing work led to fundamental concerns over acceptable use from a user and ethical (behavioural) perspective. Significant access issues were initially discovered in relation to inconsistent digital service categorisation in architectural design, and restrictive policies and procedures.;Further studies identified acceptable use policies that were not fit for purpose, and Internet filtering systems blocking legitimate content. Issues were also identified around the use of third party service providers, and the impact on user privacy that results, as well as what constituted acceptable use from the point of view of library patrons. Issues of public awareness of appropriate ethical behaviours then led to a critical examination of approaches to character education in information literacy education, notably identifying a lack of explicit attention to important aspects of ethical education in information literacy frameworks and models, and establishing a research agenda for further work.;A range of research methods are utilised across the 15 papers that make up the submission, including literature reviews, surveys of library users and staff, heuristic evaluation of digital services, unobtrusive testing of access to public library services, content analysis of digital services, and content analysis of information literacy frameworks
Performance-centred maintenance problem : modelling and heuristics
Get PDFThis study focuses on aligning the business functions of maintainers and operators in the manufacturing industry for better costs/profits. In practice, maintainers and operators undertake maintenance operations management and production operations management respectively; such two types of operations management are closely intertwined with each other and hence should not be considered independently. In the maintenance planning literature, however, the balance between machine utilisation and increased risk of failure is rarely thoroughly discussed. Motivated by the maintenance planning problem in a large scale British coal-fired power plant, this study aims at developing a theoretical framework which facilitates aligning the business functions of maintainers and operators for better costs/profits in a relatively generic manufacturing industrial setting. Initially we consider a generic multi-asset production system. In such system we investigate the fundamental trade-offs between the decision making of maintainers and operators, and we further analyse how such trade-offs are underpinned by the existence of contracted period for sales and the associated potentially high penalty cost; based on such problem structure elicitation, we then develop a maintenance approach which integrates the operators' decision making as part of the maintainers' decision making in a conceptual framework and then further mathematically formulates such integrated maintenance planning problem as a Markov decision process (MDP). Such maintenance approach not only facilitates maintenance planning optimisation given existing machine utilisation behaviours, but also facilitates machine utilisation behaviour improvement as researchers/practitioners can conduct what-if analysis by changing the integrated utilisation behaviours in the MDP model. Next we consider a multi-level hierarchical physical structure which involves multiple aforementioned multi-asset production systems; such hierarchical structure is shared by many industrial cases. We scale up the MDP model to capture such complex hierarchical structure, in the context of the coal-fired power plant case. The resulted mathematical problem is too complex to be solved by exact methods, and we therefore develop a set of heuristics to solve the problem: we select a simulation-based computation heuristic and a value function approximation method from literature, and we further combine them with our own designed decomposition method and parameters number bounding method. We further discuss how the scaled-up mathematical model and heuristics can be applied to other industrial cases of interest. Finally, we conduct numerical tests to demonstrate the practical value of our maintenance approach, mathematical model and heuristics.This study focuses on aligning the business functions of maintainers and operators in the manufacturing industry for better costs/profits. In practice, maintainers and operators undertake maintenance operations management and production operations management respectively; such two types of operations management are closely intertwined with each other and hence should not be considered independently. In the maintenance planning literature, however, the balance between machine utilisation and increased risk of failure is rarely thoroughly discussed. Motivated by the maintenance planning problem in a large scale British coal-fired power plant, this study aims at developing a theoretical framework which facilitates aligning the business functions of maintainers and operators for better costs/profits in a relatively generic manufacturing industrial setting. Initially we consider a generic multi-asset production system. In such system we investigate the fundamental trade-offs between the decision making of maintainers and operators, and we further analyse how such trade-offs are underpinned by the existence of contracted period for sales and the associated potentially high penalty cost; based on such problem structure elicitation, we then develop a maintenance approach which integrates the operators' decision making as part of the maintainers' decision making in a conceptual framework and then further mathematically formulates such integrated maintenance planning problem as a Markov decision process (MDP). Such maintenance approach not only facilitates maintenance planning optimisation given existing machine utilisation behaviours, but also facilitates machine utilisation behaviour improvement as researchers/practitioners can conduct what-if analysis by changing the integrated utilisation behaviours in the MDP model. Next we consider a multi-level hierarchical physical structure which involves multiple aforementioned multi-asset production systems; such hierarchical structure is shared by many industrial cases. We scale up the MDP model to capture such complex hierarchical structure, in the context of the coal-fired power plant case. The resulted mathematical problem is too complex to be solved by exact methods, and we therefore develop a set of heuristics to solve the problem: we select a simulation-based computation heuristic and a value function approximation method from literature, and we further combine them with our own designed decomposition method and parameters number bounding method. We further discuss how the scaled-up mathematical model and heuristics can be applied to other industrial cases of interest. Finally, we conduct numerical tests to demonstrate the practical value of our maintenance approach, mathematical model and heuristics
Investigation of cavitation influence on propeller-rudder-hull interaction
Get PDFComputational modelling of tip vortex cavitation of a ship propeller has its challenges particularly to extend the cavitating tip vortex trajectories in the propeller's slipstream for investigating their influence on the propeller-rudder-hull interaction. Although the prediction of sheet cavitation on the propeller blade surfaces has been tackled successfully by many researchers, the research to extend the prediction model for the tip vortex cavitation from all propeller blades simultaneously and throughout the rudder is rather scarce. This PhD study, therefore, aims to contribute in this area of research to investigate the cavitation influence on propeller-rudder-hull interaction, especially due to the tip vortex cavitation, by using a commercial Computational Fluid Dynamics (CFD) code.;To achieve the above aim, an investigation on the propeller-rudder-hull system is conducted in steps; first by modelling the propeller performance and cavitation in CFD for the isolated propeller case, and next to continue with the propeller-rudder system and finally by modelling the propeller-rudder-hull combination case to represent the ship system. The CFD modelling for these cases are conducted using the commercial CFD software STAR-CCM+ and validated by the available Experimental Fluid Dynamics (EFD) data for three benchmark propellers including the Potsdam Propeller Test Case (PPTC) VP1304, INSEAN E779A model propeller and The Princess Royal research vessel model propeller which are all tested in different experimental facilities.;The cavitation model used in the commercial software is the Schnerr-Sauer model based on the Rayleigh-Plesset equation. This model together with the new meshing technique called MARCS, which is developed by the Author as an advanced Mesh Adaption Refinement procedure for Cavitation Simulations, is applied successfully to simulate the cavitating tip vortices from all blades simultaneously in the propeller's slipstream beside other cavitation types. The cavitation simulations are conducted to test and validate the MARCS procedure to include the presence of the rudder and to study the interaction between the propeller and rudder including the effect of the hull wake in the model scale.;The simulation results are validated for two different types of propeller-rudder arrangements involving a typical container ship propeller-rudder arrangement and The Princess Royal propeller-rudder arrangement with an inclined shaft and flat rudder section tested in the Emerson Cavitation Tunnel.;Further cavitation simulations with the commercial code using the MARCS procedure are also conducted for the scaled full-model of The Princess Royal research vessel to simulate the model tests conducted in the depressurised large circulating water channel of CNR-INSEAN and to validate the simulation results with the EFD measurements available from this facility. Finally, the same computational tool and procedure are used for the cavitation simulations of The Princess Royal in full-scale, and the simulation results are compared with the cavitation observation images available from sea-trials with this vessel.;In spite of various shortcomings, which can be further improved, implementation of the new meshing procedure developed has proven that using a state-of-the-art commercial CFD code can be a practical and attractive analysis tool to investigate the influence of cavitation on propeller-rudder-hull interaction in the model and full-scale with confidence. Furthermore, it is feasible, and may be more attractive, to simulate the propeller cavitation directly in full-scale in order to save the additional time, effort and expense required for model tests. Due respect is given to the invaluable contributions made by the EFD in the validation stage of the CFD methods.Computational modelling of tip vortex cavitation of a ship propeller has its challenges particularly to extend the cavitating tip vortex trajectories in the propeller's slipstream for investigating their influence on the propeller-rudder-hull interaction. Although the prediction of sheet cavitation on the propeller blade surfaces has been tackled successfully by many researchers, the research to extend the prediction model for the tip vortex cavitation from all propeller blades simultaneously and throughout the rudder is rather scarce. This PhD study, therefore, aims to contribute in this area of research to investigate the cavitation influence on propeller-rudder-hull interaction, especially due to the tip vortex cavitation, by using a commercial Computational Fluid Dynamics (CFD) code.;To achieve the above aim, an investigation on the propeller-rudder-hull system is conducted in steps; first by modelling the propeller performance and cavitation in CFD for the isolated propeller case, and next to continue with the propeller-rudder system and finally by modelling the propeller-rudder-hull combination case to represent the ship system. The CFD modelling for these cases are conducted using the commercial CFD software STAR-CCM+ and validated by the available Experimental Fluid Dynamics (EFD) data for three benchmark propellers including the Potsdam Propeller Test Case (PPTC) VP1304, INSEAN E779A model propeller and The Princess Royal research vessel model propeller which are all tested in different experimental facilities.;The cavitation model used in the commercial software is the Schnerr-Sauer model based on the Rayleigh-Plesset equation. This model together with the new meshing technique called MARCS, which is developed by the Author as an advanced Mesh Adaption Refinement procedure for Cavitation Simulations, is applied successfully to simulate the cavitating tip vortices from all blades simultaneously in the propeller's slipstream beside other cavitation types. The cavitation simulations are conducted to test and validate the MARCS procedure to include the presence of the rudder and to study the interaction between the propeller and rudder including the effect of the hull wake in the model scale.;The simulation results are validated for two different types of propeller-rudder arrangements involving a typical container ship propeller-rudder arrangement and The Princess Royal propeller-rudder arrangement with an inclined shaft and flat rudder section tested in the Emerson Cavitation Tunnel.;Further cavitation simulations with the commercial code using the MARCS procedure are also conducted for the scaled full-model of The Princess Royal research vessel to simulate the model tests conducted in the depressurised large circulating water channel of CNR-INSEAN and to validate the simulation results with the EFD measurements available from this facility. Finally, the same computational tool and procedure are used for the cavitation simulations of The Princess Royal in full-scale, and the simulation results are compared with the cavitation observation images available from sea-trials with this vessel.;In spite of various shortcomings, which can be further improved, implementation of the new meshing procedure developed has proven that using a state-of-the-art commercial CFD code can be a practical and attractive analysis tool to investigate the influence of cavitation on propeller-rudder-hull interaction in the model and full-scale with confidence. Furthermore, it is feasible, and may be more attractive, to simulate the propeller cavitation directly in full-scale in order to save the additional time, effort and expense required for model tests. Due respect is given to the invaluable contributions made by the EFD in the validation stage of the CFD methods
Evaluation of the mechanisms of neurotoxcity using metabolomic strategies
Get PDFStrathclyde theses - ask staff. Thesis no. : T15211There are many neurotoxic substances that affect humans. Cobalt and mephedroneare examples of neurotoxic compounds with little known about their mode of action.Cobalt neurotoxicity was investigated in human astrocytoma and neuroblastoma cellsusing proliferation assays coupled with LC-MS based metabolomics and transcriptomics techniques. Cells were treated with a range of cobalt concentrations between 0 and 200 μM. The metabolism of mephedrone at 100 μM was first studied in primary rat hepatocytes and then the neurotoxicity of mephedrone at 100 μM was assessed in human neuroblastoma and astrocytoma cells using proliferation assays coupled with LC-MS based metabolomics.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assayr evealed that cobalt was cytotoxic and decreased cell metabolism and its effect was dose and time dependent in both cell lines. Metabolomic analysis revealed several altered metabolites particularly those related to DNA deamination and methylation pathways. One of the increased metabolites was uracil which can be generated from DNA deamination or from fragmentation of RNA. To investigate the origin of uracil genomic DNA was isolated and analysed by LC-MS. Interestingly, the source of uracil, which is uridine was increased significantly in the DNA of both cell lines.Additionally, the results of the qRT-PCR showed an increase in the production of five genes Mlh1, Sirt2, MeCP2, UNG and TDG in both cell lines. These genes are related to DNA strand breakage, hypoxia, methylation and base excision repair.;Cultured primary hepatocytes were able to metabolise mephedrone and produce many of the metabolites produced by previous research on freshly isolated hepatocytes. However, metabolic capacity was impaired in the cultured hepatocytes with lower quantities of metabolites being produced in comparison with freshly isolated hepatocytes. MTT and neutral red (NR) assays results showed no negative effect on cells metabolism or growth. There was an increase in cell metabolism at 100 μM of mephedrone. This concentration of mephedrone was used in the metabolomic experiments to further investigate metabolomics changes associated with this concentration. The metabolomic analysis of neuroblastoma revealed no strong pattern of effect of mephedrone on the cells. However, the analysis of the metabolome of astrocytoma revealed a marked effect after treatment with mephedrone. The predominant change was on lipids particularly ether lipids that play an important role in controlling membrane fluidity.Overall, metabolomic analysis was helpful in revealing the changes that both cobalt and mephedrone could induce in human neuronal derived cell lines. These findings could help in understanding the effect of these cytotoxic compounds on human brain.There are many neurotoxic substances that affect humans. Cobalt and mephedroneare examples of neurotoxic compounds with little known about their mode of action.Cobalt neurotoxicity was investigated in human astrocytoma and neuroblastoma cellsusing proliferation assays coupled with LC-MS based metabolomics and transcriptomics techniques. Cells were treated with a range of cobalt concentrations between 0 and 200 μM. The metabolism of mephedrone at 100 μM was first studied in primary rat hepatocytes and then the neurotoxicity of mephedrone at 100 μM was assessed in human neuroblastoma and astrocytoma cells using proliferation assays coupled with LC-MS based metabolomics.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assayr evealed that cobalt was cytotoxic and decreased cell metabolism and its effect was dose and time dependent in both cell lines. Metabolomic analysis revealed several altered metabolites particularly those related to DNA deamination and methylation pathways. One of the increased metabolites was uracil which can be generated from DNA deamination or from fragmentation of RNA. To investigate the origin of uracil genomic DNA was isolated and analysed by LC-MS. Interestingly, the source of uracil, which is uridine was increased significantly in the DNA of both cell lines.Additionally, the results of the qRT-PCR showed an increase in the production of five genes Mlh1, Sirt2, MeCP2, UNG and TDG in both cell lines. These genes are related to DNA strand breakage, hypoxia, methylation and base excision repair.;Cultured primary hepatocytes were able to metabolise mephedrone and produce many of the metabolites produced by previous research on freshly isolated hepatocytes. However, metabolic capacity was impaired in the cultured hepatocytes with lower quantities of metabolites being produced in comparison with freshly isolated hepatocytes. MTT and neutral red (NR) assays results showed no negative effect on cells metabolism or growth. There was an increase in cell metabolism at 100 μM of mephedrone. This concentration of mephedrone was used in the metabolomic experiments to further investigate metabolomics changes associated with this concentration. The metabolomic analysis of neuroblastoma revealed no strong pattern of effect of mephedrone on the cells. However, the analysis of the metabolome of astrocytoma revealed a marked effect after treatment with mephedrone. The predominant change was on lipids particularly ether lipids that play an important role in controlling membrane fluidity.Overall, metabolomic analysis was helpful in revealing the changes that both cobalt and mephedrone could induce in human neuronal derived cell lines. These findings could help in understanding the effect of these cytotoxic compounds on human brain
Understanding adherence to ankle-foot orthoses : an application of the theory of planned behaviour
Get PDFAnkle-foot orthoses (AFOs) are used to manage mobility disability in a wide range of conditions such as stroke, multiple sclerosis, arthritis, and trauma. However, sub-optimal adherence has been identified as a major concern. Poor adherence to AFOs may result in diminished physical and mental health outcomes, and is also an inefficient use of scarce resource. In addition, little is known about the extent of use of AFOs in the longer term. Therefore, this thesis set out to initially understand the prevalence of adherence to AFOs, and the relationship between adherence to AFOs and health and functioning outcomes.;The International Classification of Functioning Disability and Health (ICF, WHO, 2001) was used as a framework to define health outcomes. The first investigation was a cross-sectional survey, conducted with 157 participants from NHS Greater Glasgow and Clyde, who had been prescribed an AFO for a range of conditions. The adherence rate to use of AFOs as recommended was 56%. This study demonstrated that AFO use as recommended was associated with better physical and mental health outcomes.;Therefore, an understanding of potentially modifiable factors, which can improve adherence to AFOs, offers an alternative method of optimising outcomes of AFO use.;The Medical Research Council's framework for complex interventions (Craig et al., 2013) identifies the need for theory-driven research to inform interventions. Consequently, this thesis used a theoretical approach to attempt to understand adherence to orthoses. Firstly, the Theory of Planned Behaviour (TPB, Ajzen, 1991) was identified as a potentially appropriate model. Then, a meta-analysis was conducted, which drew on the wider health adherence literature, to review the efficacy of the TPB in understanding health adherence behaviours in conditions, which may give rise to an orthotic intervention.;This found that the TPB accounted for 28.3% of the variance in intentions and 14% of the variance in adherence behaviours. Attitudes and Perceived Behavioural Control (PBC) were significant predictors of intention, and intention was a significant predictor of behaviour. In line with the TPB, intention mediated the effects of attitude and PBC on behaviour. This suggested the TPB might offer a useful model to investigate adherence to AFOs.;This thesis then applied the TPB to modelling AFO use in people with stroke. Stroke was selected as the focus of this investigation, as it is the leading cause of acquired adult disability worldwide (McGrath, Canavan, & O'Donnell, 2018), and, in the first study, was identified as the most common condition for which an AFO is prescribed. In addition, Scotland has a high incidence of stroke, compared to other UK nations, and improving the treatment and care of stroke is a clinical priority (Scottish Government, 2014a).;In order to conduct a TPB investigation, firstly, a beliefs elicitation study was conducted with 13 participants who had been prescribed an AFO by NHS Lanarkshire following stroke. This study enabled elicitation of attitudinal, normative and control beliefs, in line with the TPB model.;Participants reported more advantages compared to disadvantages of using AFOs, suggesting that they had a generally positive attitude towards AFO use. The most commonly stated advantages were 'increased mobility' and 'supports the position of the leg or foot'. The most common disadvantage detailed was 'discomfort', followed by 'problems with footwear size' and 'problems with footwear style'. Participants also identified a far greater number of people who would approve of AFO use, compared to people who would disapprove of AFO use suggesting that support for use of AFOs from a wide range of normative groups is high.;Family and health professionals were the most frequently elicited supporting normative referents. However, participants identified far fewer enabling factors compared to factors which made AFO use difficult, suggesting that perceived control of AFO use may be low in people with stroke. The main barriers to AFO use highlighted by participants were: obstacles in the environment, needing help to put the AFO on and off, the AFO causing pain or discomfort, and low mood or tiredness.;Then, the efficacy of the TPB model in explaining adherence to use of AFOs in people with stroke was investigated. Attitude, subjective norm and PBC were measured at Time 1 and behaviour was measured one month later, at Time 2, using a prospective questionnaire design in 49 participants from NHS Lanarkshire. In this investigation, 63% of people used their AFO as recommended. The TPB accounted for 57% variance in intentions and 43% variance in use of AFOs as recommended. The significant amount of variance accounted for indicates the TPB is a useful model for understanding adherence to AFOs in people with stroke.;Attitude was the only significant predictor of intention, and intention was the only significant predictor of behaviour. These findings were broadly in line with the meta-analysis conducted, albeit, with a greater amount of variance explained. The higher level of variance found in the TPB study could potentially be explained by careful design of the questionnaire, and use of an elicitation investigation using participants with the same inclusion criteria, which ensured compatibility of measures.;The relationship between the underlying beliefs, the direct TPB constructs, and intention and behaviour, were analysed, enabling potential targets of a future intervention to be identified. Attitudinal beliefs, normative beliefs and control beliefs were significantly correlated with the direct constructs, demonstrating that the beliefs measured provided a good understanding of the cognitive foundations of attitude, subjective norms and PBC. Analysis of correlations between belief-based measures, intention, and behaviour enabled the identification of beliefs that could be targeted in a future intervention to increase adherence to AFO use.;These were positive attitudinal beliefs that AFOs can increase mobility, improve balance, and help a person to improve during rehabilitation, and also negative beliefs that AFOs may cause pain or discomfort, are heavy, and are effortful to use.;This thesis is the first body of work, which has applied a psychological model of behaviour to understanding AFO use in stroke, and therefore makes a significant contribution to the emerging cross-disciplinary field of psychology and physical rehabilitation for mobility disabilities. In addition, this work provides evidence of the efficacy of the TPB as a theoretical model for investigating other health behaviours, and specifically adherence behaviours in stroke.;Finally, this investigation has identified potential beliefs, which could be utilised in a future intervention to increase adherence to use of AFOs, by targeting the significant underlying attitudinal beliefs. More research is required to corroborate these findings, and important areas for future research have also been highlighted: there is the need for a stronger evidence base for recommendations for use of AFOs, and researchers should consider a broader range of outcome measures, which are more reflective of the patient experience of using an AFO in a real-world setting.Ankle-foot orthoses (AFOs) are used to manage mobility disability in a wide range of conditions such as stroke, multiple sclerosis, arthritis, and trauma. However, sub-optimal adherence has been identified as a major concern. Poor adherence to AFOs may result in diminished physical and mental health outcomes, and is also an inefficient use of scarce resource. In addition, little is known about the extent of use of AFOs in the longer term. Therefore, this thesis set out to initially understand the prevalence of adherence to AFOs, and the relationship between adherence to AFOs and health and functioning outcomes.;The International Classification of Functioning Disability and Health (ICF, WHO, 2001) was used as a framework to define health outcomes. The first investigation was a cross-sectional survey, conducted with 157 participants from NHS Greater Glasgow and Clyde, who had been prescribed an AFO for a range of conditions. The adherence rate to use of AFOs as recommended was 56%. This study demonstrated that AFO use as recommended was associated with better physical and mental health outcomes.;Therefore, an understanding of potentially modifiable factors, which can improve adherence to AFOs, offers an alternative method of optimising outcomes of AFO use.;The Medical Research Council's framework for complex interventions (Craig et al., 2013) identifies the need for theory-driven research to inform interventions. Consequently, this thesis used a theoretical approach to attempt to understand adherence to orthoses. Firstly, the Theory of Planned Behaviour (TPB, Ajzen, 1991) was identified as a potentially appropriate model. Then, a meta-analysis was conducted, which drew on the wider health adherence literature, to review the efficacy of the TPB in understanding health adherence behaviours in conditions, which may give rise to an orthotic intervention.;This found that the TPB accounted for 28.3% of the variance in intentions and 14% of the variance in adherence behaviours. Attitudes and Perceived Behavioural Control (PBC) were significant predictors of intention, and intention was a significant predictor of behaviour. In line with the TPB, intention mediated the effects of attitude and PBC on behaviour. This suggested the TPB might offer a useful model to investigate adherence to AFOs.;This thesis then applied the TPB to modelling AFO use in people with stroke. Stroke was selected as the focus of this investigation, as it is the leading cause of acquired adult disability worldwide (McGrath, Canavan, & O'Donnell, 2018), and, in the first study, was identified as the most common condition for which an AFO is prescribed. In addition, Scotland has a high incidence of stroke, compared to other UK nations, and improving the treatment and care of stroke is a clinical priority (Scottish Government, 2014a).;In order to conduct a TPB investigation, firstly, a beliefs elicitation study was conducted with 13 participants who had been prescribed an AFO by NHS Lanarkshire following stroke. This study enabled elicitation of attitudinal, normative and control beliefs, in line with the TPB model.;Participants reported more advantages compared to disadvantages of using AFOs, suggesting that they had a generally positive attitude towards AFO use. The most commonly stated advantages were 'increased mobility' and 'supports the position of the leg or foot'. The most common disadvantage detailed was 'discomfort', followed by 'problems with footwear size' and 'problems with footwear style'. Participants also identified a far greater number of people who would approve of AFO use, compared to people who would disapprove of AFO use suggesting that support for use of AFOs from a wide range of normative groups is high.;Family and health professionals were the most frequently elicited supporting normative referents. However, participants identified far fewer enabling factors compared to factors which made AFO use difficult, suggesting that perceived control of AFO use may be low in people with stroke. The main barriers to AFO use highlighted by participants were: obstacles in the environment, needing help to put the AFO on and off, the AFO causing pain or discomfort, and low mood or tiredness.;Then, the efficacy of the TPB model in explaining adherence to use of AFOs in people with stroke was investigated. Attitude, subjective norm and PBC were measured at Time 1 and behaviour was measured one month later, at Time 2, using a prospective questionnaire design in 49 participants from NHS Lanarkshire. In this investigation, 63% of people used their AFO as recommended. The TPB accounted for 57% variance in intentions and 43% variance in use of AFOs as recommended. The significant amount of variance accounted for indicates the TPB is a useful model for understanding adherence to AFOs in people with stroke.;Attitude was the only significant predictor of intention, and intention was the only significant predictor of behaviour. These findings were broadly in line with the meta-analysis conducted, albeit, with a greater amount of variance explained. The higher level of variance found in the TPB study could potentially be explained by careful design of the questionnaire, and use of an elicitation investigation using participants with the same inclusion criteria, which ensured compatibility of measures.;The relationship between the underlying beliefs, the direct TPB constructs, and intention and behaviour, were analysed, enabling potential targets of a future intervention to be identified. Attitudinal beliefs, normative beliefs and control beliefs were significantly correlated with the direct constructs, demonstrating that the beliefs measured provided a good understanding of the cognitive foundations of attitude, subjective norms and PBC. Analysis of correlations between belief-based measures, intention, and behaviour enabled the identification of beliefs that could be targeted in a future intervention to increase adherence to AFO use.;These were positive attitudinal beliefs that AFOs can increase mobility, improve balance, and help a person to improve during rehabilitation, and also negative beliefs that AFOs may cause pain or discomfort, are heavy, and are effortful to use.;This thesis is the first body of work, which has applied a psychological model of behaviour to understanding AFO use in stroke, and therefore makes a significant contribution to the emerging cross-disciplinary field of psychology and physical rehabilitation for mobility disabilities. In addition, this work provides evidence of the efficacy of the TPB as a theoretical model for investigating other health behaviours, and specifically adherence behaviours in stroke.;Finally, this investigation has identified potential beliefs, which could be utilised in a future intervention to increase adherence to use of AFOs, by targeting the significant underlying attitudinal beliefs. More research is required to corroborate these findings, and important areas for future research have also been highlighted: there is the need for a stronger evidence base for recommendations for use of AFOs, and researchers should consider a broader range of outcome measures, which are more reflective of the patient experience of using an AFO in a real-world setting
Towards improving the quantum coherence in Ion microtraps
No full textIon traps have a number of applications in optical atomic clocks, quantum metrology and quantum information processing. Quantum coherence is essential in these applications, yet motional decoherence of ions remains a significant limitation. Experiments towards improving the quantum coherence of ions confined in microfabricated traps are presented. Surface contamination, noise on DC sources and instabilities in magnetic field are all potential sources of decoherence that are investigated. Spectroscopy on a single ion aswell as a two ion string using 88Sr+ is then demonstrated. Hydrocarbon contamination on electrode surfaces is a possible sources of electric-field noise that may result in motional heating of the ion and therefore decoherence. A capacitively-coupled RF micro discharge was generated in situ with energies suited to selective removal of surface contamination. The plasma parameters needed for the calculation of the ion bombardment energy, namely the electron density and the gas temperature, were determined using optical emission spectroscopy. For the range of operating parameters tested, the mean ion energies between 0.3 eV and 4.1 eV were calculated. While these energies are below the sputtering threshold for hydrocarbon contamination (12 eV), calculations show that the high energy tail of the ion energy distribution should remove two adsorbate monolayers in as little as 1 min. Furthermore, calculations show that during this time, the distribution is insufficiently energetic to have a significant effect on the Au electrode surface. The results presented here suggest that the microplasma surface processing is suited to in situ selective removal of surface adsorbates from ion microtrap electrodes. If electrical noise present on the electrodes of the trap is resonant with the motion of the ion, ion motional heating can occur and result in a reduced ion coherence time. Therefore it is essential to minimise the electrical noise at the motional frequencies of the ion. A system was created for versatile control of the DC potentials on the ion electrodes.;Therefore it is essential to minimise the electrical noise at the motional frequencies of the ion. A system was created for versatile control of the DC potentials on the ion electrodes. Filtering of the DC signals such that the noise at the motional frequencies of the ion are attenuated, was implemented with a pair of interchangeable filter boards. For heating rate measurements a 2nd order RC filter board was designed with an attenuation of 192 dB at 1 MHz and a cut-off frequency of 6 Hz. A second filter board was made for ion shuttling; a 3rd order Butterworth filter with 59 dB attenuation at 1 MHz and a cut-off frequency of 100 kHz. Within this work the Δmj = -2 Zeeman component of the optical qubit transition in 88Sr+ is used. This transition is beneficial since, given the geometry of the experimental apparatus used here, it allows for a higher coupling strength relative to the other Zeeman components. However this transition also has a higher sensitivity to magnetic field fluctuations. The separation of the energy levels that need to be addressed are dependent on the magnetic field applied. Therefore magnetic field fluctuations lead to dampening of the phase relation between the states; i.e. decoherence. A high-precision stabilisation system was implemented for the control of the currents to the coils that generate the magnetic field the ion experiences. A derived stability of the current applied to the coils was expected to result in a magnetic field stability of 3 Δ10-7 G over 1000 s. However when measured directly, the magnetic field stability was limited by the drift of the ion pump magnet.;The characterisation of this drift and the methods for reducing it are presented. As atoms are evaporated towards the trap, the atomic flux can adsorb onto the electrode surfaces and, in a similar fashion to the hydrocarbon contamination, form sources of electric field-noise that can cause decoherence. Precise control of the heating of the atomic source enables efficient loading of the ions into the trap, while minimising the flux generated and therefore also maximises the lifetime of the device. An automated system is presented for improved control of the generated Sr atomic flux. This is anticipated to improve the lifetime of the atomic sources and reduce the potential for contamination of the electrode surfaces.Spectroscopy on a single ion and a two-ion string in the next generation of ion trap design is presented. The motional frequencies are measured in zero magnetic field and in the presence of a bias field. The measured motional frequencies were in-line with expectations.To investigate the effect of pulse-shaping, measurements with square pulses and Blackman shaped pulses were made. The excitation with Blackman-shaped pulses showed the suppression of Fourier components in the wings of the measured spectral line. The temporal control of the spectroscopy pulse is essential for minimising off-resonant excitation. The coherent control of a single ion was then further investigated and Rabi flopping on the carrier transition of the Δmj = -2 Zeeman component was observed. The coherent control of the ion was found to be intermittently affected by the presence of intensity noise on the spectroscopy pump laser. Methods for mitigating the effect of this noise are currently under investigation. The experimental procedures needed to implement a Molmer-Sorenson entanglement gate have been developed. This remains the next stage in the experimental investigation once stable coherent control of the ion has been established.Ion traps have a number of applications in optical atomic clocks, quantum metrology and quantum information processing. Quantum coherence is essential in these applications, yet motional decoherence of ions remains a significant limitation. Experiments towards improving the quantum coherence of ions confined in microfabricated traps are presented. Surface contamination, noise on DC sources and instabilities in magnetic field are all potential sources of decoherence that are investigated. Spectroscopy on a single ion aswell as a two ion string using 88Sr+ is then demonstrated. Hydrocarbon contamination on electrode surfaces is a possible sources of electric-field noise that may result in motional heating of the ion and therefore decoherence. A capacitively-coupled RF micro discharge was generated in situ with energies suited to selective removal of surface contamination. The plasma parameters needed for the calculation of the ion bombardment energy, namely the electron density and the gas temperature, were determined using optical emission spectroscopy. For the range of operating parameters tested, the mean ion energies between 0.3 eV and 4.1 eV were calculated. While these energies are below the sputtering threshold for hydrocarbon contamination (12 eV), calculations show that the high energy tail of the ion energy distribution should remove two adsorbate monolayers in as little as 1 min. Furthermore, calculations show that during this time, the distribution is insufficiently energetic to have a significant effect on the Au electrode surface. The results presented here suggest that the microplasma surface processing is suited to in situ selective removal of surface adsorbates from ion microtrap electrodes. If electrical noise present on the electrodes of the trap is resonant with the motion of the ion, ion motional heating can occur and result in a reduced ion coherence time. Therefore it is essential to minimise the electrical noise at the motional frequencies of the ion. A system was created for versatile control of the DC potentials on the ion electrodes.;Therefore it is essential to minimise the electrical noise at the motional frequencies of the ion. A system was created for versatile control of the DC potentials on the ion electrodes. Filtering of the DC signals such that the noise at the motional frequencies of the ion are attenuated, was implemented with a pair of interchangeable filter boards. For heating rate measurements a 2nd order RC filter board was designed with an attenuation of 192 dB at 1 MHz and a cut-off frequency of 6 Hz. A second filter board was made for ion shuttling; a 3rd order Butterworth filter with 59 dB attenuation at 1 MHz and a cut-off frequency of 100 kHz. Within this work the Δmj = -2 Zeeman component of the optical qubit transition in 88Sr+ is used. This transition is beneficial since, given the geometry of the experimental apparatus used here, it allows for a higher coupling strength relative to the other Zeeman components. However this transition also has a higher sensitivity to magnetic field fluctuations. The separation of the energy levels that need to be addressed are dependent on the magnetic field applied. Therefore magnetic field fluctuations lead to dampening of the phase relation between the states; i.e. decoherence. A high-precision stabilisation system was implemented for the control of the currents to the coils that generate the magnetic field the ion experiences. A derived stability of the current applied to the coils was expected to result in a magnetic field stability of 3 Δ10-7 G over 1000 s. However when measured directly, the magnetic field stability was limited by the drift of the ion pump magnet.;The characterisation of this drift and the methods for reducing it are presented. As atoms are evaporated towards the trap, the atomic flux can adsorb onto the electrode surfaces and, in a similar fashion to the hydrocarbon contamination, form sources of electric field-noise that can cause decoherence. Precise control of the heating of the atomic source enables efficient loading of the ions into the trap, while minimising the flux generated and therefore also maximises the lifetime of the device. An automated system is presented for improved control of the generated Sr atomic flux. This is anticipated to improve the lifetime of the atomic sources and reduce the potential for contamination of the electrode surfaces.Spectroscopy on a single ion and a two-ion string in the next generation of ion trap design is presented. The motional frequencies are measured in zero magnetic field and in the presence of a bias field. The measured motional frequencies were in-line with expectations.To investigate the effect of pulse-shaping, measurements with square pulses and Blackman shaped pulses were made. The excitation with Blackman-shaped pulses showed the suppression of Fourier components in the wings of the measured spectral line. The temporal control of the spectroscopy pulse is essential for minimising off-resonant excitation. The coherent control of a single ion was then further investigated and Rabi flopping on the carrier transition of the Δmj = -2 Zeeman component was observed. The coherent control of the ion was found to be intermittently affected by the presence of intensity noise on the spectroscopy pump laser. Methods for mitigating the effect of this noise are currently under investigation. The experimental procedures needed to implement a Molmer-Sorenson entanglement gate have been developed. This remains the next stage in the experimental investigation once stable coherent control of the ion has been established
Pore-scale dynamics of immiscible two-phase flow on porous and fractured media
Get PDFPore-scale investigations of immiscible two-phase flow displacement dynamics in porous media provides crucial information to natural and industrial processes such as nonaqueous phase liquid (NAPL) contamination of groundwater, carbon dioxide injection and storage, and enhanced oil recovery (EOR) operations. It has the potential to transform our understanding of multiphase flow processes, to improve oil and gas recovery efficiency, and to facilitate safe carbon dioxide storage. However, the modelled porespace geometry is naturally complex for these fields of application. For directly simulating multiphase flow within the complex structure, the most widely-used approach isthe lattice Boltzmann method (LBM).In this thesis, the implementation of the state-of-the-art colour gradient two-phase LBMhas been validated against the theoretical solution for capillary filling, and analytical solutions for relative permeabilities in a cocurrent flow in a 2D channel. Then it is employed to investigate the effects of interfacial tension, wettability, and the viscosity ratio on displacement of one fluid by another immiscible fluid in a two-dimensional(2D) Berea sandstone.;Through invasion of the wetting phase into the porous matrix,it is observed that the viscosity ratio plays an important role in the non-wetting phase recovery. At the viscosity ratio (λ) of unity, the saturation of the wetting fluid is highest,and linearly increases with time. The displacing fluid saturation reduces drastically when λ increases to 20; however, when λ is beyond 20, the reduction becomes less significant for both imbibition and drainage. The front of the bottom fingers is finally halted at a position near the inlet as the viscosity ratio increases to 10. Increasing the interfacial tension generally results in higher saturation of the wetting fluid. Finally,the contact angle is found to have a limited effect on the efficiency of displacement in the 2D Berea sandstone. In addition, it has also been utilized to provide a better understanding of spontaneous imbibition, a key oil recovery mechanism in the fractured reservoir rocks. A pore-scale computational study of the water imbibition into an articially generated dual-permeability porous matrix with a fracture attached on top is conducted. Several factors affecting the dynamic counter-current imbibition processes and the resulting oil recovery have been analysed, including the water injection velocity, the geometry configuration of the dual permeability zones, interfacial tension, viscosity ratio of water to oil phases, and fracture spacing if there are multiple fractures.;By examining different water injection velocities and interfacial tensions, it is identified for the first time that the three distinct imbibition regimes exist: the squeezing regime, the jetting regime and the dripping regime, and they can be distinguished with different expelled oil morphologies in the fracture (piston-like plug, elongated liquid thread or isolated drops).The geometry configuration of the high and low permeability zones affects the amount of oil that can be recovered by the counter-current imbibition in a fracture-matrix system through transition of the different regimes. In the squeezing regime, which occurs at low water injection velocity, it is interestingly found that the built-up squeezing pressure upstream in the fracture enables more water to imbibe into the permeability zone closerto the fracture inlet thus increasing the oil recovery factor. A larger interfacial tension or a lower water-to-oil viscosity ratio is favorable for enhancing oil recovery and new insights into the effect of viscosity ratio are provided. Introducing an extra parallel fracture can effectively increase the oil recovery factor and there is an optimal fracture spacing between the two adjacent horizontal fractures to maximize the oil recovery.These findings can aid the optimal design of water-injecting oil extraction in fractured rocks in reservoirs of low permeability like oil-bearing shale or tight sandstone.We conclude that the pore-scale modelling can act as a reliable tool to assess andpredict oil and gas resources and facilitate more efficient oil and gas recoveryPore-scale investigations of immiscible two-phase flow displacement dynamics in porous media provides crucial information to natural and industrial processes such as nonaqueous phase liquid (NAPL) contamination of groundwater, carbon dioxide injection and storage, and enhanced oil recovery (EOR) operations. It has the potential to transform our understanding of multiphase flow processes, to improve oil and gas recovery efficiency, and to facilitate safe carbon dioxide storage. However, the modelled porespace geometry is naturally complex for these fields of application. For directly simulating multiphase flow within the complex structure, the most widely-used approach isthe lattice Boltzmann method (LBM).In this thesis, the implementation of the state-of-the-art colour gradient two-phase LBMhas been validated against the theoretical solution for capillary filling, and analytical solutions for relative permeabilities in a cocurrent flow in a 2D channel. Then it is employed to investigate the effects of interfacial tension, wettability, and the viscosity ratio on displacement of one fluid by another immiscible fluid in a two-dimensional(2D) Berea sandstone.;Through invasion of the wetting phase into the porous matrix,it is observed that the viscosity ratio plays an important role in the non-wetting phase recovery. At the viscosity ratio (λ) of unity, the saturation of the wetting fluid is highest,and linearly increases with time. The displacing fluid saturation reduces drastically when λ increases to 20; however, when λ is beyond 20, the reduction becomes less significant for both imbibition and drainage. The front of the bottom fingers is finally halted at a position near the inlet as the viscosity ratio increases to 10. Increasing the interfacial tension generally results in higher saturation of the wetting fluid. Finally,the contact angle is found to have a limited effect on the efficiency of displacement in the 2D Berea sandstone. In addition, it has also been utilized to provide a better understanding of spontaneous imbibition, a key oil recovery mechanism in the fractured reservoir rocks. A pore-scale computational study of the water imbibition into an articially generated dual-permeability porous matrix with a fracture attached on top is conducted. Several factors affecting the dynamic counter-current imbibition processes and the resulting oil recovery have been analysed, including the water injection velocity, the geometry configuration of the dual permeability zones, interfacial tension, viscosity ratio of water to oil phases, and fracture spacing if there are multiple fractures.;By examining different water injection velocities and interfacial tensions, it is identified for the first time that the three distinct imbibition regimes exist: the squeezing regime, the jetting regime and the dripping regime, and they can be distinguished with different expelled oil morphologies in the fracture (piston-like plug, elongated liquid thread or isolated drops).The geometry configuration of the high and low permeability zones affects the amount of oil that can be recovered by the counter-current imbibition in a fracture-matrix system through transition of the different regimes. In the squeezing regime, which occurs at low water injection velocity, it is interestingly found that the built-up squeezing pressure upstream in the fracture enables more water to imbibe into the permeability zone closerto the fracture inlet thus increasing the oil recovery factor. A larger interfacial tension or a lower water-to-oil viscosity ratio is favorable for enhancing oil recovery and new insights into the effect of viscosity ratio are provided. Introducing an extra parallel fracture can effectively increase the oil recovery factor and there is an optimal fracture spacing between the two adjacent horizontal fractures to maximize the oil recovery.These findings can aid the optimal design of water-injecting oil extraction in fractured rocks in reservoirs of low permeability like oil-bearing shale or tight sandstone.We conclude that the pore-scale modelling can act as a reliable tool to assess andpredict oil and gas resources and facilitate more efficient oil and gas recover
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