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Simulating academic entrepreneurship and inter-organisational collaboration in university ecosystems, a hybrid system dynamics agent-based simulation
Get PDFPreviously held under moratorium from 28th October 2024 until 28th October 2025.Universities are increasingly expected to actively contribute to socio-economic development. Academic entrepreneurship and the evolution of the entrepreneurial
university within ecosystems have received increasing attention from both policy
makers and academic communities over the last decades. However, most studies
on universities’ external engagement have focused on individual activities and
single universities, hereby neglecting the feedback effects between different activities and how universities are linked through an overlap of their ecosystems.
The result is an incomplete understanding of how universities interact with their
ecosystem and the resulting inter- and intra-organisational dynamics. This research addresses this issue by developing a hybrid system dynamics agent-based
model, which captures feedback structure and the internal decision-making of
universities and companies. Both the conceptual and simulation model are based
on a triangulation of the literature, interviews with representatives of Scottish
universities, and secondary data for Scottish universities and UK businesses.
This research makes several theoretical, methodological, and empirical contributions. From a theoretical perspective, it contributes in two distinct ways
to the field of entrepreneurship by defining university ecosystems in new way
that provides a basis for future research and developing a multi-modal simulation
model that can be applied in tested in different contexts. The methodological
contributions to the field of modelling and simulation in management science
include a modelling process for hybrid simulations, new practices for modelling
the size of agent populations through different designs of stocks and flows in the
system dynamics module in hybrid simulations, and complex events for recognising emergent behaviour. Lastly, this research makes two empirical contributions
to the field of entrepreneurship. This research shines a light on the dynamics
of academic entrepreneurship and how universities can partially overcome a low
research prestige to increase academic entrepreneurship. Implications for policy and practice are outlined and opportunities for future research conclude this
thesis.Universities are increasingly expected to actively contribute to socio-economic development. Academic entrepreneurship and the evolution of the entrepreneurial
university within ecosystems have received increasing attention from both policy
makers and academic communities over the last decades. However, most studies
on universities’ external engagement have focused on individual activities and
single universities, hereby neglecting the feedback effects between different activities and how universities are linked through an overlap of their ecosystems.
The result is an incomplete understanding of how universities interact with their
ecosystem and the resulting inter- and intra-organisational dynamics. This research addresses this issue by developing a hybrid system dynamics agent-based
model, which captures feedback structure and the internal decision-making of
universities and companies. Both the conceptual and simulation model are based
on a triangulation of the literature, interviews with representatives of Scottish
universities, and secondary data for Scottish universities and UK businesses.
This research makes several theoretical, methodological, and empirical contributions. From a theoretical perspective, it contributes in two distinct ways
to the field of entrepreneurship by defining university ecosystems in new way
that provides a basis for future research and developing a multi-modal simulation
model that can be applied in tested in different contexts. The methodological
contributions to the field of modelling and simulation in management science
include a modelling process for hybrid simulations, new practices for modelling
the size of agent populations through different designs of stocks and flows in the
system dynamics module in hybrid simulations, and complex events for recognising emergent behaviour. Lastly, this research makes two empirical contributions
to the field of entrepreneurship. This research shines a light on the dynamics
of academic entrepreneurship and how universities can partially overcome a low
research prestige to increase academic entrepreneurship. Implications for policy and practice are outlined and opportunities for future research conclude this
thesis
Biomechanical study of rigid ankle-foot orthoses in the treatment of stroke patients
Get PDFRigid Ankle-Foot Orthoses (AFOs) are commonly prescribed for stroke patients who exhibit equinovarus deformity as an orthotic intervention. The main purpose of prescribing a rigid AFO is to provide appropriate control of unwanted ankle and foot motions in any plane. To achieve the optimal effects of the AFO, appropriate stiffness and alignment optimisation (tuning) should be considered. The AFO provides moments (referred to as the orthotic moments) to control ankle motion. Orthotic moments are different from the moments generated by ground reaction forces, the later are known as total ankle moments. Reviewing the literature showed limited research in this area. The aims of this study are to investigate the biomechanical effects of using rigid AFO (before and after tuning) and to investigate the orthotic moment during walking in stroke patients.Gait data were collected from six stroke participants (2 females, 4 males) and six healthy participants (3 females, 3 males) using a Motekforce Link dual belt instrumented treadmill and a Vicon 3-dimensional motion analysis system. Each participant was fitted with a custom made rigid AFO instrumented using four strain gauges. Walking at a self-selected speed was investigated while wearing: (1) Standard shoes only (2) Rigid AFO with standard shoes (3) Rigid Tuned-AFO with standard shoes. Lower limb temporal-spatial, kinetic and kinematic parameters, and electromyographic activity (Delsys TrignoTM) of the knee muscles were compared among the test conditions. The orthotic moments were also quantified using the strain gauges data combined with gait analysis. Repeated measures ANOVA and Friedman’s ANOVA were used for statistical analysis.The rigid AFO showed immediate improvement in the temporal-spatial parameters and the kinematics and the kinetics of post stroke gait. Greater improvement in knee kinematics and kinetics was achieved when tuning the rigid AFO. The rigid AFO (before and after tuning) increased quadriceps muscle activity and reduced hamstring muscle activity compared to walking with standard shoes only. Tuning a rigid AFO further increased quadriceps muscle activity and reduced hamstring muscle activity compared to AFO before tuning. Strain gauges data combined with gait analysis can be used in evaluating the orthotic moment around the ankle in sagittal and frontal planes. Tuning a rigid AFO had no clear changes in the orthotic moment, and it did not alter the anatomical moments at the ankle joint in sagittal and at the subtalar joint in frontal plane.Rigid Ankle-Foot Orthoses (AFOs) are commonly prescribed for stroke patients who exhibit equinovarus deformity as an orthotic intervention. The main purpose of prescribing a rigid AFO is to provide appropriate control of unwanted ankle and foot motions in any plane. To achieve the optimal effects of the AFO, appropriate stiffness and alignment optimisation (tuning) should be considered. The AFO provides moments (referred to as the orthotic moments) to control ankle motion. Orthotic moments are different from the moments generated by ground reaction forces, the later are known as total ankle moments. Reviewing the literature showed limited research in this area. The aims of this study are to investigate the biomechanical effects of using rigid AFO (before and after tuning) and to investigate the orthotic moment during walking in stroke patients.Gait data were collected from six stroke participants (2 females, 4 males) and six healthy participants (3 females, 3 males) using a Motekforce Link dual belt instrumented treadmill and a Vicon 3-dimensional motion analysis system. Each participant was fitted with a custom made rigid AFO instrumented using four strain gauges. Walking at a self-selected speed was investigated while wearing: (1) Standard shoes only (2) Rigid AFO with standard shoes (3) Rigid Tuned-AFO with standard shoes. Lower limb temporal-spatial, kinetic and kinematic parameters, and electromyographic activity (Delsys TrignoTM) of the knee muscles were compared among the test conditions. The orthotic moments were also quantified using the strain gauges data combined with gait analysis. Repeated measures ANOVA and Friedman’s ANOVA were used for statistical analysis.The rigid AFO showed immediate improvement in the temporal-spatial parameters and the kinematics and the kinetics of post stroke gait. Greater improvement in knee kinematics and kinetics was achieved when tuning the rigid AFO. The rigid AFO (before and after tuning) increased quadriceps muscle activity and reduced hamstring muscle activity compared to walking with standard shoes only. Tuning a rigid AFO further increased quadriceps muscle activity and reduced hamstring muscle activity compared to AFO before tuning. Strain gauges data combined with gait analysis can be used in evaluating the orthotic moment around the ankle in sagittal and frontal planes. Tuning a rigid AFO had no clear changes in the orthotic moment, and it did not alter the anatomical moments at the ankle joint in sagittal and at the subtalar joint in frontal plane
Studies of alkali metal compounds in diesel fuel and small molecule activation chemistry
Get PDFThis thesis was previously held under moratorium from 7/07/2020 to 7/07/2021The study of internal diesel engine deposits is a field that has recently begun to be explored in more depth from a chemistry perspective. The many issues caused within diesel engines related to the formation of insoluble, carboxylate-based deposits demanded insight be gained into the chemical make-up and composition of such deposits in the crystalline state. Such insight is challenging as the long chain nature of these deposits complicates the ability to render them crystalline, hence why no detailed studies had previously been carried out onto such species.Of related interest is the expanding field of small molecule activation chemistry, with CO2 being a prime example of an environmentally damaging small molecule produced by diesel engines. Despite the worldwide activity in both small molecule activation and alkali metal-based chemistry, no previous studies had sought to combine these two strands of research as undertaken here.The first part of this project develops the field of diesel deposits in terms of accessing suitable crystals in order to determine the solid-state structures of long chain alkali metal carboxylates, of the type commonly found within diesel engines. The products obtained were characterised by X-ray crystallography and multinuclear NMR spectroscopy. This revealed a remarkable set of structures, ranging from dimeric arrangements in polar solvents to polymeric arrangements in non-coordinating solvents. A highlight is the structure of the long chain sodium 2-ethylhexanoate, 3, which to the best of our knowledge represents the longest chain solvent-free and donor-free alkali metal carboxylate characterised using single crystal diffraction, showing a novel arrangement composed of a central hydrophobic core, with the long alkyl chains arranged around the periphery of this central core, rather than a simple layering arrangement.In the second part of this project the activation of the globally important small molecule CO2 was probed using common alkali metal based reagents. Three novel structures were crystallographically characterised, collectively exhibiting a higher degree of complexity post CO2 addition than would otherwise be anticipated. For example, addition of CO2 to LDA was antici[pated to occur between the reactive Li-N bond to form a molecular lithium carbamate, however in actual fact addition of CO2 furnished a more complex dodecameric structure, composed of two open cubanes linked by planar four-membered (LiO)2 ringsExtension to small isocyanate molecules and NacNac alkali metal reagents revealed a common series of transformations, leading to products containing new dual imine and amide functionality at the backbone γ-carbon position. The mechanism leading to this dual functionality was explored via multinuclear NMR spectroscopic studies. Finally, extension to carbodiimides and phosphine oxide molecules revealed attack at the front of the alkali metal NacNac complex, contrasting with the backbone γ-carbon attack seen with isocyanates and CO2.The study of internal diesel engine deposits is a field that has recently begun to be explored in more depth from a chemistry perspective. The many issues caused within diesel engines related to the formation of insoluble, carboxylate-based deposits demanded insight be gained into the chemical make-up and composition of such deposits in the crystalline state. Such insight is challenging as the long chain nature of these deposits complicates the ability to render them crystalline, hence why no detailed studies had previously been carried out onto such species.Of related interest is the expanding field of small molecule activation chemistry, with CO2 being a prime example of an environmentally damaging small molecule produced by diesel engines. Despite the worldwide activity in both small molecule activation and alkali metal-based chemistry, no previous studies had sought to combine these two strands of research as undertaken here.The first part of this project develops the field of diesel deposits in terms of accessing suitable crystals in order to determine the solid-state structures of long chain alkali metal carboxylates, of the type commonly found within diesel engines. The products obtained were characterised by X-ray crystallography and multinuclear NMR spectroscopy. This revealed a remarkable set of structures, ranging from dimeric arrangements in polar solvents to polymeric arrangements in non-coordinating solvents. A highlight is the structure of the long chain sodium 2-ethylhexanoate, 3, which to the best of our knowledge represents the longest chain solvent-free and donor-free alkali metal carboxylate characterised using single crystal diffraction, showing a novel arrangement composed of a central hydrophobic core, with the long alkyl chains arranged around the periphery of this central core, rather than a simple layering arrangement.In the second part of this project the activation of the globally important small molecule CO2 was probed using common alkali metal based reagents. Three novel structures were crystallographically characterised, collectively exhibiting a higher degree of complexity post CO2 addition than would otherwise be anticipated. For example, addition of CO2 to LDA was antici[pated to occur between the reactive Li-N bond to form a molecular lithium carbamate, however in actual fact addition of CO2 furnished a more complex dodecameric structure, composed of two open cubanes linked by planar four-membered (LiO)2 ringsExtension to small isocyanate molecules and NacNac alkali metal reagents revealed a common series of transformations, leading to products containing new dual imine and amide functionality at the backbone γ-carbon position. The mechanism leading to this dual functionality was explored via multinuclear NMR spectroscopic studies. Finally, extension to carbodiimides and phosphine oxide molecules revealed attack at the front of the alkali metal NacNac complex, contrasting with the backbone γ-carbon attack seen with isocyanates and CO2
Improved seismic design of structures using risk-targeting and cost-minimization considerations
Get PDFThis thesis was previously held under moratorium from 28th August 2020 until 30th August 2021.This thesis addresses various topics in the context of seismic design of structures with risk and loss considerations. Three design philosophies are investigated: the one based on uniform-hazard spectra, the risk-targeting technique, and an approach that minimizes the life-cycle costs. While the “uniform-hazard” approach is embedded in most of seismic design regulations, many studies have highlighted the need for a more rigorous and explicit control of the structural performance and of the consequences of seismic damage, not only at the assessment but also at the design stage. Thus, in this context, the risk targeting philosophy has emerged and has been implemented in US regulations. This approach is thoroughly reviewed herein, together with alternative risk-targeting techniques. Various case studies and European-wide investigations are performed to compare the results obtained with the risk-targeting and the uniform hazard approaches, evaluate the strengths and limitations of the techniques, and show possible steps forward. Acknowledging the significant financial implications of earthquakes, more advanced frameworks have been developed to account also for losses from future earthquake events in the design. A life-cycle cost optimization technique that considers the initial construction costs and the expected losses is studied in this work. A benchmark building is designed and analysed for different seismic levels and the results are compared against those obtained with the uniform-hazard and the risk-targeting approaches. Subsequently, an investigation is carried out on how the epistemic uncertainty inherent in seismic hazard models influences the structural design and the attained risk and loss estimates. The topic is investigated through different case studies, while a simplified approach for modelling hazard uncertainty is introduced and applied across Europe.In addition to constructing frameworks that mitigate losses, earthquake engineering can provide guidance to help manage the incurred loss levels. Thus, the last part of this thesis looks at the seismic risk management via the mechanism of transfer of financial risk. A method to define loss-informed insurance premiums is presented and various investigations across Europe are performed to explore efficient insurance strategies.This thesis addresses various topics in the context of seismic design of structures with risk and loss considerations. Three design philosophies are investigated: the one based on uniform-hazard spectra, the risk-targeting technique, and an approach that minimizes the life-cycle costs. While the “uniform-hazard” approach is embedded in most of seismic design regulations, many studies have highlighted the need for a more rigorous and explicit control of the structural performance and of the consequences of seismic damage, not only at the assessment but also at the design stage. Thus, in this context, the risk targeting philosophy has emerged and has been implemented in US regulations. This approach is thoroughly reviewed herein, together with alternative risk-targeting techniques. Various case studies and European-wide investigations are performed to compare the results obtained with the risk-targeting and the uniform hazard approaches, evaluate the strengths and limitations of the techniques, and show possible steps forward. Acknowledging the significant financial implications of earthquakes, more advanced frameworks have been developed to account also for losses from future earthquake events in the design. A life-cycle cost optimization technique that considers the initial construction costs and the expected losses is studied in this work. A benchmark building is designed and analysed for different seismic levels and the results are compared against those obtained with the uniform-hazard and the risk-targeting approaches. Subsequently, an investigation is carried out on how the epistemic uncertainty inherent in seismic hazard models influences the structural design and the attained risk and loss estimates. The topic is investigated through different case studies, while a simplified approach for modelling hazard uncertainty is introduced and applied across Europe.In addition to constructing frameworks that mitigate losses, earthquake engineering can provide guidance to help manage the incurred loss levels. Thus, the last part of this thesis looks at the seismic risk management via the mechanism of transfer of financial risk. A method to define loss-informed insurance premiums is presented and various investigations across Europe are performed to explore efficient insurance strategies
Investigating novel inhibitors of essential Leishmania mexicana kinases GSK3β and MPK4
No full textThe superfamily of protein kinases are emerging as valid therapeutic targets for anti-leishmanial drug development. The essential kinase GSK3β regulates cell proliferation, motility, glycogen metabolism and apoptosis. A peptide sequence derived from ubiquitin hydrolase (UBH5) is one of many substrates of GSK3β and was obtained from a strain of Leishmania Mexicana for recombinant expression and affinity purification. Radiometric kinase assays were then used to screen 320 small-molecule chemical inhibitors designed by Lifearc for their ability to inhibit recombinant GSK3β phosphorylation of UBH5. Three chemical small-molecule inhibitors were identified G18, J16 and J22 which inhibited UBH5 peptide substrate phosphorylation in a concentration- dependent manner with IC50 values of 3.0 µM, 1.4 µM and 3.2 µM, respectively. Two compounds Malabaricone B and Malabricone C were extracted from a plant called Myristica malabarica, previously identified as having anti-leishmanial properties, and investigated for their ability to inhibit GSK3β enzymatic activity. Both plant compounds induced concentration-dependent inhibition of GSK3β auto-phosphorylation and UBH5 peptide substrate phosphorylation. Malabaricone B showed an IC50 of 1.5 µM for auto-phosphorylation and an IC50 of 3.8 µM for substrate phosphorylation. Malabaricone C had IC50's of 1.6 µM and 4.2 µM, respectively. Both Malabaricones were type 1 ATP-competitive inhibitors. Leishmania MPK4 is an essential kinase involved in lesion formation and life cyclestage conversion. Recombinant MPK4 was not well expressed in bacteria therefore two expression plasmids were generated in order to express MPK4 in Leishmania for later purification and screening of inhibitors. The plasmids were constructed expressing C-terminal green fluorescent protein (GFP)-tagged LmxMPK4 or N-terminal GFP-tagged and His-tagged LmxMPK4 both containing the selective marker gene conferring blasticidin resistance. The expression plasmids were used for transfection with wild type Leishmania Mexicana promastigotes and a mutant form which contained no genomic copy of LmxMPK4 but instead carried a plasmid containing the LmxMPK4 gene. Appearance of the GFP during fluorescence microscopy suggested the LmxMPK4-GFP fusion protein was expressed. However, an attempt to replace the plasmid containing LmxMPK4 from the mutant form with a GFP-tagged version was unsuccessful indicating the fusion protein was inactive.The superfamily of protein kinases are emerging as valid therapeutic targets for anti-leishmanial drug development. The essential kinase GSK3β regulates cell proliferation, motility, glycogen metabolism and apoptosis. A peptide sequence derived from ubiquitin hydrolase (UBH5) is one of many substrates of GSK3β and was obtained from a strain of Leishmania Mexicana for recombinant expression and affinity purification. Radiometric kinase assays were then used to screen 320 small-molecule chemical inhibitors designed by Lifearc for their ability to inhibit recombinant GSK3β phosphorylation of UBH5. Three chemical small-molecule inhibitors were identified G18, J16 and J22 which inhibited UBH5 peptide substrate phosphorylation in a concentration- dependent manner with IC50 values of 3.0 µM, 1.4 µM and 3.2 µM, respectively. Two compounds Malabaricone B and Malabricone C were extracted from a plant called Myristica malabarica, previously identified as having anti-leishmanial properties, and investigated for their ability to inhibit GSK3β enzymatic activity. Both plant compounds induced concentration-dependent inhibition of GSK3β auto-phosphorylation and UBH5 peptide substrate phosphorylation. Malabaricone B showed an IC50 of 1.5 µM for auto-phosphorylation and an IC50 of 3.8 µM for substrate phosphorylation. Malabaricone C had IC50's of 1.6 µM and 4.2 µM, respectively. Both Malabaricones were type 1 ATP-competitive inhibitors. Leishmania MPK4 is an essential kinase involved in lesion formation and life cyclestage conversion. Recombinant MPK4 was not well expressed in bacteria therefore two expression plasmids were generated in order to express MPK4 in Leishmania for later purification and screening of inhibitors. The plasmids were constructed expressing C-terminal green fluorescent protein (GFP)-tagged LmxMPK4 or N-terminal GFP-tagged and His-tagged LmxMPK4 both containing the selective marker gene conferring blasticidin resistance. The expression plasmids were used for transfection with wild type Leishmania Mexicana promastigotes and a mutant form which contained no genomic copy of LmxMPK4 but instead carried a plasmid containing the LmxMPK4 gene. Appearance of the GFP during fluorescence microscopy suggested the LmxMPK4-GFP fusion protein was expressed. However, an attempt to replace the plasmid containing LmxMPK4 from the mutant form with a GFP-tagged version was unsuccessful indicating the fusion protein was inactive
Self-assembling silk hydrogels for mesenchymal stem cell and drug delivery
No full textThis thesis was previously held under moratorium from 11th January 2020 until 11th January 2021.Silk fibroin has been commonly used as sutures and surgical meshes in humans. Additionally, silk fibroin had been used for a wide range of biomedical uses including as a coating for polymer scaffolds produced for tissue engineering and silk fibroin hydrogels containing silk nanoparticles have previously been studied for the controlled delivery of model drugs. The aims of this thesis was to characterise silk hydrogels by both FT-IR analysis and using compression testing. Next, the effect of loading drugs into silk hydrogels with different physicochemical properties. The final aim of the project was to investigate the trophic factors released from MSCs cultured on top (i.e. 2D) and in (i.e. 3D) a silk hydrogel. From the sol-gel transition experiments the ideal silk hydrogel to be used for incorporated MSCs is a 5% or 4% w/v 60 minute degummed silk hydrogel diluted with PBS due to a fast sol-gel transition allowing enough time for the addition of MSCs ensuring they were homogenously distributed throughout the silk hydrogel. Protease XIV increases the degradation in the 3% w/v silk hydrogel compared to the 5% w/v silk hydrogel. This is likely caused by the higher the silk concentration the higher the cross-linking density. This results in a stronger hydrogel structure. SDS-PAGE analysis showed that the 60 minute degummed silk hydrogel supernatants had smearing in the range 70 to 130 kDa. The 60 minute degummed silk hydrogel supernatants have a smaller average molecular weight. Mechanical testing of silk hydrogels revealed that the stress required to reach the yield point in hydrogels in their natural state and suspended in DMEM for 24 hours is ~35 KPa and ~32KPa respectively. MSCs grown in 2D secrete higher concentrations of cytokines. For example, there is a 2.3 fold higher concentration of VEGF in 2D in comparison to 3D environment. VEGF improves cardiac performance by enhancing angiogenesis. The obtained excretory profiles of MSCs would be beneficial in regenerative medicine and are promising for future in vitro studies. Overall, this thesis demonstrates that silk hydrogels can be used in MSC delivery in vitro and the nature of cell culture can affect the secretion of cytokines. This is promising for future studies using silk hydrogels to deliver MSCs where excretory profiles should be evaluated more rigorously using 3 independent replicates to validate the findings in this thesis. In addition, this thesis has shown that the degradation rate of silk hydrogels can be tuned in vivo by altering the silk content. This is an encouraging prospect for the use of silk hydrogels in drug and cell delivery which provides a foundation for further in vitro and in vivo studies.Silk fibroin has been commonly used as sutures and surgical meshes in humans. Additionally, silk fibroin had been used for a wide range of biomedical uses including as a coating for polymer scaffolds produced for tissue engineering and silk fibroin hydrogels containing silk nanoparticles have previously been studied for the controlled delivery of model drugs. The aims of this thesis was to characterise silk hydrogels by both FT-IR analysis and using compression testing. Next, the effect of loading drugs into silk hydrogels with different physicochemical properties. The final aim of the project was to investigate the trophic factors released from MSCs cultured on top (i.e. 2D) and in (i.e. 3D) a silk hydrogel. From the sol-gel transition experiments the ideal silk hydrogel to be used for incorporated MSCs is a 5% or 4% w/v 60 minute degummed silk hydrogel diluted with PBS due to a fast sol-gel transition allowing enough time for the addition of MSCs ensuring they were homogenously distributed throughout the silk hydrogel. Protease XIV increases the degradation in the 3% w/v silk hydrogel compared to the 5% w/v silk hydrogel. This is likely caused by the higher the silk concentration the higher the cross-linking density. This results in a stronger hydrogel structure. SDS-PAGE analysis showed that the 60 minute degummed silk hydrogel supernatants had smearing in the range 70 to 130 kDa. The 60 minute degummed silk hydrogel supernatants have a smaller average molecular weight. Mechanical testing of silk hydrogels revealed that the stress required to reach the yield point in hydrogels in their natural state and suspended in DMEM for 24 hours is ~35 KPa and ~32KPa respectively. MSCs grown in 2D secrete higher concentrations of cytokines. For example, there is a 2.3 fold higher concentration of VEGF in 2D in comparison to 3D environment. VEGF improves cardiac performance by enhancing angiogenesis. The obtained excretory profiles of MSCs would be beneficial in regenerative medicine and are promising for future in vitro studies. Overall, this thesis demonstrates that silk hydrogels can be used in MSC delivery in vitro and the nature of cell culture can affect the secretion of cytokines. This is promising for future studies using silk hydrogels to deliver MSCs where excretory profiles should be evaluated more rigorously using 3 independent replicates to validate the findings in this thesis. In addition, this thesis has shown that the degradation rate of silk hydrogels can be tuned in vivo by altering the silk content. This is an encouraging prospect for the use of silk hydrogels in drug and cell delivery which provides a foundation for further in vitro and in vivo studies
Development of a prosthetic heart valve with inbuilt sensing technology, to aid in continuous monitoring of function under various stenotic conditions
Get PDFIn spite of technological advances in the design of prosthetic heart valves, they are still often subject to complications after implantation. One of the common complications is valve stenosis, which involves the obstruction of the valve orifice caused by biological processes. The greatest challenge in diagnosing the development of valve failure and complications is related to the fact that the valve is implanted and isolated. To continuously monitor the state of the valve and its performance would be of great benefit but practically can only be achieved by instrumenting the implanted valve. In this thesis, we explore the development of a prosthetic valve with inbuilt sensing technology to aid in continuous monitoring of valve function under various stenotic conditions. 22mm polyurethane valves were designed via dipcoating. A custom made mock circulatory system was designed and hydrodynamic testing of the polyurethane valves under different flow rates were performed with Effective orifice area (EOA) and Transvalvular Pressure Gradient (TVPG) being the parameters of interest. Valves were subjected to varying levels of obstruction to investigate the effect obstruction has on the pressure gradient across the valves. Similar tests were performed on a Carpentier Edwards SAV 2650 model bioprosthetic valve for comparison. Polyurethane valves were then instrumented with strain gauges to measure peak to peak strain difference, in response to varying levels of obstructions. All the polyurethane valves exhibited good hydrodynamic performance with EOA (>1cm2) under baseline physiological conditions. It was also discovered that pressure difference across the valves was directly proportional to the flow rate. The pressure difference also demonstrated a slow increase during the initial stages of simulated stenosis and a sudden increase as the obstruction became severe. This provides further evidence to support the ideal that stenosis is a slow progressive disease which may not present symptoms until severe. The peak to peak strain differences also tend to decrease as the severity of the obstruction was increased. The peak to peak strain difference is indicative of the pressures within the valve (intravalvular pressure). The results suggest that directly monitoring the pressures within the valve could be a useful diagnostic tool for detecting valve stenosis. Future works involves miniaturisation of the sensors and also the incorporation of telemetry into the sensor design.In spite of technological advances in the design of prosthetic heart valves, they are still often subject to complications after implantation. One of the common complications is valve stenosis, which involves the obstruction of the valve orifice caused by biological processes. The greatest challenge in diagnosing the development of valve failure and complications is related to the fact that the valve is implanted and isolated. To continuously monitor the state of the valve and its performance would be of great benefit but practically can only be achieved by instrumenting the implanted valve. In this thesis, we explore the development of a prosthetic valve with inbuilt sensing technology to aid in continuous monitoring of valve function under various stenotic conditions. 22mm polyurethane valves were designed via dipcoating. A custom made mock circulatory system was designed and hydrodynamic testing of the polyurethane valves under different flow rates were performed with Effective orifice area (EOA) and Transvalvular Pressure Gradient (TVPG) being the parameters of interest. Valves were subjected to varying levels of obstruction to investigate the effect obstruction has on the pressure gradient across the valves. Similar tests were performed on a Carpentier Edwards SAV 2650 model bioprosthetic valve for comparison. Polyurethane valves were then instrumented with strain gauges to measure peak to peak strain difference, in response to varying levels of obstructions. All the polyurethane valves exhibited good hydrodynamic performance with EOA (>1cm2) under baseline physiological conditions. It was also discovered that pressure difference across the valves was directly proportional to the flow rate. The pressure difference also demonstrated a slow increase during the initial stages of simulated stenosis and a sudden increase as the obstruction became severe. This provides further evidence to support the ideal that stenosis is a slow progressive disease which may not present symptoms until severe. The peak to peak strain differences also tend to decrease as the severity of the obstruction was increased. The peak to peak strain difference is indicative of the pressures within the valve (intravalvular pressure). The results suggest that directly monitoring the pressures within the valve could be a useful diagnostic tool for detecting valve stenosis. Future works involves miniaturisation of the sensors and also the incorporation of telemetry into the sensor design
This dying machine
Get PDFPreviously held under moratorium from 18th March 2020 until 18th March 2025.The following Creative Writing PhD thesis consists of two parts: the original novel
‘This Dying Machine’ and a critical exegesis. The novel “This Dying Machine” is set
in Glasgow in 1922. Having returned to Scotland from First World War France and
suffering from neurasthenia, the protagonist, Robert Grant, struggles to reintegrate
into Glasgow life. Amidst a backdrop of strange events that plague the city, Rob
learns that his brother-in-arms Victor has gone missing. Resolving to search for his
friend, Rob uncovers an uncanny and sinister force that threatens not only Victor but
also humanity itself. The exegesis that follows the novel provides a critical
commentary and exploration of the Creative Writing PhD dissertation, focusing on
the development of the novel and its emergent poetics, its intertextuality and place in
the literary canon, and how it contributes to the field of Creative Writing.The following Creative Writing PhD thesis consists of two parts: the original novel
‘This Dying Machine’ and a critical exegesis. The novel “This Dying Machine” is set
in Glasgow in 1922. Having returned to Scotland from First World War France and
suffering from neurasthenia, the protagonist, Robert Grant, struggles to reintegrate
into Glasgow life. Amidst a backdrop of strange events that plague the city, Rob
learns that his brother-in-arms Victor has gone missing. Resolving to search for his
friend, Rob uncovers an uncanny and sinister force that threatens not only Victor but
also humanity itself. The exegesis that follows the novel provides a critical
commentary and exploration of the Creative Writing PhD dissertation, focusing on
the development of the novel and its emergent poetics, its intertextuality and place in
the literary canon, and how it contributes to the field of Creative Writing
Multi-scale metrology for automated non-destructive testing systems
Get PDFThis thesis was previously held under moratorium from 5/05/2020 to 5/05/2022The use of lightweight composite structures in the aerospace industry is now commonplace. Unlike conventional materials, these parts can be moulded into complex aerodynamic shapes, which are diffcult to inspect rapidly using conventional Non-Destructive Testing (NDT) techniques. Industrial robots provide a means of automating the inspection process due to their high dexterity and improved path planning methods.This thesis concerns using industrial robots as a method for assessing the quality of components with complex geometries. The focus of the investigations in this thesis is on improving the overall system performance through the use of concepts from the field of metrology, specifically calibration and traceability. The use of computer vision is investigated as a way to increase automation levels by identifying a component's type and approximate position through comparison with CAD models.The challenges identified through this research include developing novel calibration techniques for optimising sensor integration, verifying system performance using laser trackers, and improving automation levels through optical sensing. The developed calibration techniques are evaluated experimentally using standard reference samples. A 70% increase in absolute accuracy was achieved in comparison to manual calibration techniques. Inspections were improved as verified by a 30% improvement in ultrasonic signal response.A new approach to automatically identify and estimate the pose of a component was developed specifically for automated NDT applications. The method uses 2D and 3D camera measurements along with CAD models to extract and match shape information. It was found that optical large volume measurements could provide suffciently high accuracy measurements to allow ultrasonic alignment methods to work, establishing a multi-scale metrology approach to increasing automation levels. A classification framework based on shape outlines extracted from images was shown to provide over 88% accuracy on a limited number of samples.The use of lightweight composite structures in the aerospace industry is now commonplace. Unlike conventional materials, these parts can be moulded into complex aerodynamic shapes, which are diffcult to inspect rapidly using conventional Non-Destructive Testing (NDT) techniques. Industrial robots provide a means of automating the inspection process due to their high dexterity and improved path planning methods.This thesis concerns using industrial robots as a method for assessing the quality of components with complex geometries. The focus of the investigations in this thesis is on improving the overall system performance through the use of concepts from the field of metrology, specifically calibration and traceability. The use of computer vision is investigated as a way to increase automation levels by identifying a component's type and approximate position through comparison with CAD models.The challenges identified through this research include developing novel calibration techniques for optimising sensor integration, verifying system performance using laser trackers, and improving automation levels through optical sensing. The developed calibration techniques are evaluated experimentally using standard reference samples. A 70% increase in absolute accuracy was achieved in comparison to manual calibration techniques. Inspections were improved as verified by a 30% improvement in ultrasonic signal response.A new approach to automatically identify and estimate the pose of a component was developed specifically for automated NDT applications. The method uses 2D and 3D camera measurements along with CAD models to extract and match shape information. It was found that optical large volume measurements could provide suffciently high accuracy measurements to allow ultrasonic alignment methods to work, establishing a multi-scale metrology approach to increasing automation levels. A classification framework based on shape outlines extracted from images was shown to provide over 88% accuracy on a limited number of samples
Measurement, optimisation and control of particle properties in pharmaceutical manufacturing processes
Get PDFPreviously held under moratorium from 2 June 2020 until 6 June 2022.The understanding and optimisation of particle properties connected to their structure and morphology is a common objective for particle engineering applications either to improve materialhandling in the manufacturing process or to influence Critical Quality Attributes (CQAs) linkedto product performance. This work aims to demonstrate experimental means to support a rational development approach for pharmaceutical particulate systems with a specific focus ondroplet drying platforms such as spray drying.Micro-X-ray tomography (micro-XRT) is widely applied in areas such as geo- and biomedicalsciences to enable a three dimensional investigation of the specimens. Chapter 4 elaborateson practical aspects of micro-XRT for a quantitative analysis of pharmaceutical solid productswith an emphasis on implemented image processing and analysis methodologies. Potentialapplications of micro-XRT in the pharmaceutical manufacturing process can range from thecharacterisation of single crystals to fully formulated oral dosage forms. Extracted quantitativeinformation can be utilised to directly inform product design and production for process development or optimisation. The non-destructive nature of the micro-XRT analysis can be furtheremployed to investigate structure-performance relationships which might provide valuable insights for modelling approaches.Chapter 5 further demonstrates the applicability of micro-XRT for the analysis of ibuprofen capsules as a multi-particulate system each with a population of approximately 300 pellets. Thein-depth analysis of collected micro-XRT image data allowed the extraction of more than 200features quantifying aspects of the pellets’ size, shape, porosity, surface and orientation. Employed feature selection and machine learning methods enabled the detection of broken pelletswithin a classification model. The classification model has an accuracy of more than 99.55%and a minimum precision of 86.20% validated with a test dataset of 886 pellets from three capsules.The combination of single droplet drying (SDD) experiments with a subsequent micro-XRTanalysis was used for a quantitative investigation of the particle design space and is describedin Chapter 6. The implemented platform was applied to investigate the solidification of formulated metformin hydrochloride particles using D-mannitol and hydroxypropyl methylcellulosewithin a selected, pragmatic particle design space. The results indicate a significant impact ofhydroxypropyl methylcellulose reducing liquid evaporation rates and particle drying kinetics.The morphology and internal structure of the formulated particles after drying are dominatedby a crystalline core of D-mannitol partially suppressed with increasing hydroxypropyl methylcellulose additions. The characterisation of formulated metformin hydrochloride particles withincreasing polymer content demonstrated the importance of an early-stage quantitative assessment of formulation-related particle properties.A reliable and rational spray drying development approach needs to assess parameters of thecompound system as well as of the process itself in order to define a well-controlled and robustoperational design space. Chapter 7 presents strategies for process implementation to producepeptide-based formulations via spray drying demonstrated using s-glucagon as a model peptide.The process implementation was supported by an initial characterisation of the lab-scale spraydryer assessing a range of relevant independent process variables including drying temperatureand feed rate. The platform response was captured with available and in-house developed Process Analytical Technology. A B-290 Mini-Spray Dryer was used to verify the developmentapproach and to implement the pre-designed spray drying process. Information on the particleformation mechanism observed in SDD experiments were utilised to interpret the characteristics of the spray dried material.The understanding and optimisation of particle properties connected to their structure and morphology is a common objective for particle engineering applications either to improve materialhandling in the manufacturing process or to influence Critical Quality Attributes (CQAs) linkedto product performance. This work aims to demonstrate experimental means to support a rational development approach for pharmaceutical particulate systems with a specific focus ondroplet drying platforms such as spray drying.Micro-X-ray tomography (micro-XRT) is widely applied in areas such as geo- and biomedicalsciences to enable a three dimensional investigation of the specimens. Chapter 4 elaborateson practical aspects of micro-XRT for a quantitative analysis of pharmaceutical solid productswith an emphasis on implemented image processing and analysis methodologies. Potentialapplications of micro-XRT in the pharmaceutical manufacturing process can range from thecharacterisation of single crystals to fully formulated oral dosage forms. Extracted quantitativeinformation can be utilised to directly inform product design and production for process development or optimisation. The non-destructive nature of the micro-XRT analysis can be furtheremployed to investigate structure-performance relationships which might provide valuable insights for modelling approaches.Chapter 5 further demonstrates the applicability of micro-XRT for the analysis of ibuprofen capsules as a multi-particulate system each with a population of approximately 300 pellets. Thein-depth analysis of collected micro-XRT image data allowed the extraction of more than 200features quantifying aspects of the pellets’ size, shape, porosity, surface and orientation. Employed feature selection and machine learning methods enabled the detection of broken pelletswithin a classification model. The classification model has an accuracy of more than 99.55%and a minimum precision of 86.20% validated with a test dataset of 886 pellets from three capsules.The combination of single droplet drying (SDD) experiments with a subsequent micro-XRTanalysis was used for a quantitative investigation of the particle design space and is describedin Chapter 6. The implemented platform was applied to investigate the solidification of formulated metformin hydrochloride particles using D-mannitol and hydroxypropyl methylcellulosewithin a selected, pragmatic particle design space. The results indicate a significant impact ofhydroxypropyl methylcellulose reducing liquid evaporation rates and particle drying kinetics.The morphology and internal structure of the formulated particles after drying are dominatedby a crystalline core of D-mannitol partially suppressed with increasing hydroxypropyl methylcellulose additions. The characterisation of formulated metformin hydrochloride particles withincreasing polymer content demonstrated the importance of an early-stage quantitative assessment of formulation-related particle properties.A reliable and rational spray drying development approach needs to assess parameters of thecompound system as well as of the process itself in order to define a well-controlled and robustoperational design space. Chapter 7 presents strategies for process implementation to producepeptide-based formulations via spray drying demonstrated using s-glucagon as a model peptide.The process implementation was supported by an initial characterisation of the lab-scale spraydryer assessing a range of relevant independent process variables including drying temperatureand feed rate. The platform response was captured with available and in-house developed Process Analytical Technology. A B-290 Mini-Spray Dryer was used to verify the developmentapproach and to implement the pre-designed spray drying process. Information on the particleformation mechanism observed in SDD experiments were utilised to interpret the characteristics of the spray dried material
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