| 1. |
- Deyhle Jr, Richard
(författare)
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Cross-modal Imaging in Lung Research: From µCT dosimetry to synchrotron phase contrast microtomography biomechanical insights in preclinical lung injury models
- 2024
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung diseases continue to present a large burden to public health, especially in industrialized countries. For abetter understanding of the underlying patho-mechanisms in lung related diseases as well as for testing theefficacy of novel therapies, preclinical studies in animal models are indispensable. The significance of preclinical X-ray based micro-computed tomography (µCT) research lies in its ability to provide high-resolution, non-invasive lung imaging of small animals as the air inside the lung acts as a natural contrast and to image the lung parenchyma longitudinally to assess functional and morphological alterations and test efficacy of therapeutic interventions. This often requires requires imaging protocols that balance between sufficient image quality and clinically relevant radiation absorbed doses. A reproducible method for evaluation of absorbed radiation absorbed doses is desirable. Absorbed radiation absorbed doses were measured in a polymethyl methacrylate (PMMA) phantom using standard TLD and a novel type of OSLD made form household salt. Four imaging protocols from MILabs “xUHR-µCT” scanner were tested. A large discrepancy was observed from results compared to vendor-provided values. The results indicate a need for thorough empirical dose measurements prior to performing longitudinal studies. Four-dimensional imaging, allows for investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. It is of significant interest to have direct visualization and quantification of interstitial lung diseases at spatial resolutions beyond the capabilities of clinical and conventional absorption-based only CT. Thus far, the high intensity of synchrotron X-ray light sources offer a tool to investigate dynamic morphological and mechanistic features, enabling dynamic in-vivo microscopy. This investigation elucidates the direct effects of interventions targeting the pathophysiology of Acute Respiratory Distress Syndrome (ARDS) and Ventilator-Induced Lung Injury (VILI) on the terminal airways and alveolar microstructure within intact lungs. In such conditions, the relationship between microscopic strain within the mechanics of the alveolar structure and the broader mechanical characteristics and viscoelastic properties of the lungs remains poorly understood. A time-resolved synchrotron phase-contrast micro-computed tomography imaging acquisition protocol based on the synchronization between the mechanical ventilation and the cardiac activity was used to resolve the lung parenchyma motion with an effective isotropic voxel size of 6 µm. Quantitative maps of microscopic local lung tissue strain within aerated lung alveolar tissue under protective mechanical ventilation in anesthetized rats were obtained. This approach was used to assess the effect of alterations in lung tissue biomechanics induced by lung injury at 7 days after single-dose, intratracheal bleomycin instillation in combination with short-term high-tidal volume (VT) mechanical ventilation. Overall, this work address the aspects of radiation exposure to in experimental imaging of small animals and lays a foundation for a more nuanced understanding of lung injury and mechanical ventilation. In the future, it may result in a more effective and less injurious respiratory support for patients with acute lung injury or chronic lung diseases.
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| 2. |
- Mastinu, Enzo, 1987
(författare)
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Embedded Controller for Artificial Limbs
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Promising developments are currently ongoing worldwide in the field of neuroprosthetics and artificial limb control. It is now possible to chronically connect a robotic limb to bone, nerves and muscles of a human being, and use the signals sourced from these connections to enable movements in the artificial limb. It is also possible to surgically redirect a nerve, deprived from its original target muscle due to amputation, to a new target in order to restore the original motor functionality. Intelligent signal processing algorithms can now utilize the bioelectric signals gathered from remaining muscles on the stump to decode the motor intention of the amputee, providing an intuitive control interface. Unfortunately for patients, clinical implementations still lag behind the advancements of research, and the conventional solutions for amputees remained basically unchanged since decades. More efforts are therefore needed from researchers to close the gap between scientific publications and hospital practices.The ultimate focus of this thesis is set on the intuitive control of a prosthetic upper limb. It was developed an embedded system capable of prosthetic control via the processing of bioelectric signals and pattern recognition algorithms. It includes a neurostimulator to provide direct neural feedback modulated by sensory information from artificial sensors. The system was designed towards clinical implementation and its functionality was proven by amputee subjects in daily life. It also constitutes a research platform to monitor prosthesis usage and training, machine learning based control algorithms, and neural stimulation paradigms.
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| 3. |
- Holmboe, Michael
(författare)
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The bentonite barrier : microstructural aspects on colloid filtration and radiation effects on bentonite colloid stability
- 2009
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In many countries a multi-barrier concept in a deep geological repository is planned for final disposal of nuclear waste. Many of these different concepts, for example the Swedish KBS-3 model, include an engineered barrier consisting of compacted bentonite. The compacted bentonite barrier will be positioned around copper canisters holding the nuclear waste and act as a transport barrier for various radioactive species. This is due to the compact microstructure as well as the large sorption capacity of compacted water saturated bentonite. During its required lifetime (> 100000 years) a deep geological repository and the bentonite barrier itself will be subjected to changing groundwater composition and flow, geochemistry, temperature, and large doses of ionizing irradiation. The long lifetime and significance of a deep geologic repository mean that it must be regarded as a thermodynamically open system and be assessed in terms of worst case scenarios. In case of water bearing fractures, formed by future movements in the granitic host bedrock, low ionic strength groundwater can endanger the stability of the bentonite barrier. Prolonged erosion of the bentonite barrier might cause significant loss of buffer material and jeopardize its overall functionality. This thesis deals with the microstructure of the water saturated compacted bentonite as a function of compaction, as well as effects of γ-radiation on bentonite dispersions. The microstructure was investigated both indirectly through colloid filtration experiments, as well as using low-angle XRD. Effects of γ-irradiation were investigated in terms of colloid stability and sediment behavior of bentonite (and Na-montmorillonite) dispersions. The colloid filtration experiments, using small gold colloids of different sizes as tracers, shows that the microstructural constraints of bentonite effectively filter even extremely small inorganic colloids. Colloid transport was only observed at very low compactions (i.e. dry density g/cm3) where the average interlayer distances of montmorillonite exceeded the colloid size, indicating interlayer rather than interparticle transport. From the low-angle XRD experiments the free porosity of water saturated compacted bentonite was determined by comparing its basal spacings (interlayer distances + 1 nm) with the hypothetical basal spacings assuming no free porosity. Irrespective of compaction, the maximum free porosity proved to be very low, in line with the colloid filtration experiments. The results showed that existing microstructural models sometimes exaggerate the importance of interparticle voids. The γ-irradiation experiments showed a radiation induced increase in colloid stability. This radiation induced effect also changed the sedimentation behavior of irradiated bentonite dispersions compared to unirradiated samples. The effect is attributed to an increase in surface potential of the bentonite colloids, due to reactions with the short-lived radicals formed upon water radiolysis.
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| 4. |
- Larsson, Mikael, 1982
(författare)
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Heterogeneities in polymer gels: Effects on swelling and mechanical properties
- 2010
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polymeric hydrogels is a class of scientifically interesting materials that are being extensively studied. They are found in numerous applications within; drug delivery, hygiene products, food industry, analytical chemistry, etc. In addition, polymeric hydrogels have promising future applications as; cell scaffolds, implants, sensors, etc.One of the critical parameters for the performance of hydrogels in different applications is their structure. One such structural feature is the heterogeneity of the material, where the term heterogeneity applies to many different types of structural variations.The aim of this thesis was to investigate how different kinds of heterogeneities can be introduced into hydrogels, and how the presence of the different heterogeneities can be related to swelling and mechanical properties of such materials. The materials investigated were; polyacrylic acid neutralized with calcium hydroxide, polysodium acrylate superabsorbents with microfibrillated cellulose utilized as a filler and hydroxypropyl methylcellulose with heterogeneous distribution of the substituents.It was found that the presence of calcium ions during the synthesis of crosslinked polyacrylic acid introduces heterogeneities, both in network structure and in the form of phase separation, with dramatic impact on gel properties. Microfibrillated cellulose was found to even in small amounts cause significant changes to the swelling and shear modulus of crosslinked polysodium acrylate superabsorbents. The effect of the microfibrillated cellulose was similar as if an equivalent mass of covalent crosslinker had been used, but with improved resistance to fracture. For hydroxypropyl methylcellulose it was found that a heterogeneous distribution of the substituents causes increased interactions within the material, as determined from the glass transition temperature. Those increased interactions are coherent with earlier reports on solution behaviour for heterogeneously substituted hydroxypropyl methylcellulose.Hopefully the results presented in this thesis can contribute to the field of gel science, and in particular to the design of new multi-component soft materials.
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| 5. |
- Åström, Johan, 1977
(författare)
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Wastewater discharges and microbial variability in a surface water source
- 2008
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Planning for drinking-water safety in surface waters includes a systematic assessment of hazards in the catchment, and microbial contamination is considered a major health risk. The aim of this thesis was to identify and characterize microbial hazardous events reported for River Göta älv, Sweden. Moreover, the magnitude and variability of the microbial load from municipal sewer systems was determined for varying weather conditions.The raw water intake to Göteborg at River Göta älv, regularly closed to avoid contaminants in the raw water, act as a barrier against various hazardous substances. Occasionally, bacterial peak concentrations penetrate the raw water intake, as not registered in time. Present results show that data on upstream precipitation, turbidity and real-time reporting of wastewater discharges may give valuable guidance to predict high microbial concentrations at the raw water intake.Wastewater treatment plants and sewer networks with about 110,000 persons connected give a substantial pathogen load to the river. Monte Carlo simulations showed that wastewater treatment plants dominated the pathogen load to River Göta älv during dry weather conditions. During wet weather conditions, including sewer overflows and emergency discharges, total microbial loads from the municipal sewer systems were for E. coli about 13 log10 CFU/day and for Cryptosporidium about 8 log10 oocysts/day.Microbial river water concentrations due to municipal wastewater discharges were approximated by simulations. Wastewater contaminations may explain the magnitude and variability of river water sample concentrations of indicator bacteria (E. coli, clostridia and somatic coliphages) and Giardia. Risk reduction options are discussed based on sensitivity analyses for dry and wet weather conditions.
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| 6. |
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| 7. |
- Blissing, Annica
(författare)
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Thiopurine S-methyltransferase - characterization of variants and ligand binding
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thiopurine S-methyltransferase (TPMT) belongs to the Class I S-adenosylmethionine-dependent methyltransferase (SAM-MT) super family of structurally related proteins. Common to the members of this large protein family is the catalysis of methylation reactions using S-adenosylmethionine (SAM) as a methyl group donor, although SAM-MTs act on a wide range of different substrates and carry out numerous biologically important functions. While the natural function of TPMT is unknown, this enzyme is involved in the metabolism of thiopurines, a class of pharmaceutical substances administered in treatment of immune-related disorders. Specifically, methylation by TPMT inactivates thiopurines and their metabolic intermediates, which reduces the efficacy of clinical treatment and increases the risk of adverse side effects. To further complicate matters, TPMT is a polymorphic enzyme with over 40 naturally occurring variants known to date, most of which exhibit lowered methylation activity towards thiopurines. Consequently, there are individual variations in TPMTmediated thiopurine inactivation, and the administered dose has to be adjusted prior to clinical treatment to avoid harmful side effects.Although the clinical relevance of TPMT is well established, few studies have investigated the molecular causes of the reduced methylation activity of variant proteins. In this thesis, the results of biophysical characterization of two variant proteins, TPMT*6 (Y180F) and TPMT*8 (R215H), are presented. While the properties of TPMT*8 were indistinguishable from those of the wild-type protein, TPMT*6 was found to be somewhat destabilized. Interestingly, the TPMT*6 amino acid substitution did not affect the functionality or folding pattern of the variant protein. Therefore, the decreased in vivo functionality reported for TPMT*6 is probably caused by increased proteolytic degradation in response to the reduced stability of this protein variant, rather than loss of function.Also presented herein are novel methodological approaches for studies of TPMT and its variants. Firstly, the advantages of using 8-anilinonaphthalene-1-sulfonic acid (ANS) to probe TPMT tertiary structure and active site integrity are presented. ANS binds exclusively to the native state of TPMT with high affinity (KD ~ 0.2 μm) and a 1:1 ratio. The stability of TPMT was dramatically increased by binding of ANS, which was shown to co-localize with the structurally similar adenine moiety of the cofactor SAM. Secondly, an enzyme activity assay based on isothermal titration calorimetry (ITC) is presented. Using this approach, the kinetics of 6-MP and 6-TG methylation by TPMT has been characterized.
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| 8. |
- Löfhede, Johan, 1978
(författare)
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Classification of Burst and Suppression in the Neonatal EEG
- 2007
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The brain requires a continuous supply of oxygen and even a short period of reduced oxygen supply risks severe and lifelong consequences for the affected individual. The delivery is a vulnerable period for a baby who may experience for example hypoxia (lack of oxygen) that can damage the brain. Babies who experience problems are placed in an intensive care unit where their vital signs are monitored, but there is no reliable way to monitor the brain directly. Monitoring the brain would provide valuable information about the processes going on in it and could influence the treatment and help to improve the quality of neonatal care. The scope of this project is to develop methods that eventually can be put together to form a monitoring system for the brain that can function as decision-support for the physician in charge of treating the patient.The specific technical problem that is the topic of this thesis is detection of burst and suppression in the electroencephalogram (EEG) signal. The thesis starts with a brief description of the brain, with a focus on where the EEG originates, what types of activity can be found in this signal and what they mean. The data that have been available for the project are described, followed by the signal processing methods that have been used for pre-processing, and the feature functions that can be used for extracting certain types of characteristics from the data are defined. The next section describes classification methodology and how it can be used for making decisions based on combinations of several features extracted from a signal. The classification methods Fisher’s Linear Discriminant, Neural Networks and Support Vector Machines are described and are finally compared with respect to their ability to discriminate between burst and suppression. An experiment with different combinations of features in the classification has also been carried out. The results show similar results for the three methods but it can be seen that the SVM is the best method with respect to handling multiple features.
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| 9. |
- Pfister, Anna, 1984-
(författare)
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Outcomes of Myosin 1C Gene Expression Depletion on Cancer-related Pathways, in Vitro and in Clinical Samples
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The unconventional myosin IC has previously been suggested to be a haploinsufficient tumour suppressor. The mechanism for this action has hitherto been unknown, however, and hence we decided to attempt to elucidate the genes involved. The first study involved knock-down of MYO1C using siRNA technology followed by whole transcriptiome microarray analysis performed on samples taken at different time points post transfection. This revealed a cornucopia of differential expressions compared to the negative control, among them we found an early up-regulation of the PI3K/AKT pathway and the pathway for prostate cancer. Among the down regulated pathways we found endometrial-, colorectal cancer and small cell lung cancer as well as the cell cycle pathway which was a little counter intuitive to the hypothesis that MYO1C suppresses cancer. For the next study six different genes (CCND1, CCND2, CDKN2B, CDKN2C, MYC, RBL1) important for the transitions into S-phase of the cell cycle were therefore chosen for validation using qPCR. These six genes and MYO1C were analysed on both the original time series and a new biological replicate as well as a well stratified set of endometrial carcinoma samples. We were able to verify the significant down-regulation of CCND2 in both time series indicating that this is caused by the depletion of MYO1C. In the tumour samples we saw a negative correlation between the expression of MYO1C and FIGO grade corroborating results previously found by our group when looking at protein expression.
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| 10. |
- Carlberg, Björn, 1983
(författare)
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Integration of Electrospun Materials in Microelectronic and Biomedical Applications
- 2009
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis demonstrates the use of electrospinning and the novel properties of electrospunmaterials in two fields.The microelectronics industry has identified thermal interface materials as one of themajor bottlenecks hindering further integration at packaging level. New concepts basedon metal-polymer composite architectures are needed to fulfill current and future thermaland thermomechanical requirements on thermal interface materials at maintained costefficiency. In this thesis, an interpenetrating phase polymer-metal composite for thermalinterface material applications has been developed and characterized. Both fabricationand metrology equipment has been developed for the purpose at hand. The composite isbased on a porous electrospun polymer carrier infiltrated with a high thermal conductivitymetal phase. The two phases form two fully interpenetrating networks in the composite.Efficient heat transfer is achieved through the continuous metal phase, while the polymericphase defines geometry and phase composition. The devised composite architecture is believedto be a step towards meeting current and future demands on thermal performanceand thermomechanical reliability in microelectronic products.Furthermore, the thesis presents initial results of human embryonic stem cell proliferationand neural differentiation in co-culture with electrospun scaffolds, of interestin future regenerative medicine based on stem cells. Results indicate that physical cuesemanating from cell-scaffold interactions affect cells towards a neuronal fate during differentiation,a phenomenon consistent with reports in literature on physical cues influencingstem cell fate. To allow for deeper analysis on cell-scaffold interactions of thetype described above, a microfabricated platform was developed for the purpose. A novelmethod for direct photolithographic micropatterning of electrospun polyurethane fibrousfilms over large surfaces has been devised. The method allows for assembly of complexelectrospun microstructures on single substrates via a multilayer approach involving multiplephotolithographic exposures, analogous to conventional photolithography in microfabricationof solid state devices. Indeed, this technique can find application in a variety ofapplications where it is beneficial to integrate micropatterned electrospun structures intomicrofabricated devices, in particular within biomedical engineering applications.
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