| 1. |
- 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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| 2. |
- Andersson, Helene, 1983
(författare)
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Mass Transport through Phase Separated Films - Effects of Ethyl Cellulose Molecular Weight on Cellulose Derivative Blends for Pharmaceutical Coatings
- 2012
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polymer blends are utilized for a variety of applications, not least in pharmaceutical coatings for controlled release of drugs. For instance, blends of ethyl cellulose (EC) and the water-soluble hydroxypropyl cellulose (HPC) can be used to coat drug pellets for oral extendedrelease formulations. Although EC and HPC can be co-dissolved in ethanol, they tend to phase separate during solvent evaporation in the coating process. If a substantial amount of HPC is present in the coating, pores form when the coating is subjected to water. The HPC-rich phase may then serve as a template for the pore geometries that transport the drug. Phase separated microstructures can have a variety of morphological features. However, polymer phase separation is a complex process and much is still left to be understood regardingthe underlying mechanisms that drive structure evolution. A range of physical and chemical parameters are known to affect phase separation, including the molecular weight (MW) of polymers. If the morphology of phase separated structures is affected by the MW, then drugrelease through a phase separated coating is likely to be affected as well. The major aims of this work were to study the effects of the MW of EC, on the mass transport and microstructure in films made of 70% EC and 30% HPC, and to understand the underlying mechanisms behind different release profiles from coated pharmaceutical pellets. A wide range of batches of EC were investigated, with weight average MWs from 19·10^3 to 68·10^3. Overall, the effects on solvent cast films, sprayed films and spray coated pellets were investigated. The MW showed substantial influence on the phase separated morphology, as well as effects on the pore structures in sprayed freestanding films. A decrease in mass transfer ratewith increasing MW of EC was found by permeability measurements on free films and drug release from coated pellets. The observed trend in permeability was mainly affected by the geometries of pores, while drug release was affected by both HPC-leakage and the film structure.As a result, it was concluded that the MW of EC affects the phase separated structure of EC/HPC-films, which has profound effects on diffusion mediated release from coated pellets.
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| 3. |
- Boge, Lukas, 1987
(författare)
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Lipid-based liquid crystals as drug delivery vehicles for antimicrobial peptides
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The development of antimicrobial resistance is a great challenge within the health sector around the world. The demand for new efficient treatments is alarming in order to treat various bacterial infections in the near future. Antimicrobial peptides (AMPs) are a group of novel antibiotics that have gain more and more attraction the past decade. However, AMPs suffers from relatively low stability due to proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are highly needed for achieving efficient treatments. In this thesis, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for three AMPs (AP114, DPK-060 and LL-37). Both bulk gels and discrete dispersed structures, i.e. cubosomes and hexosomes have been studied. Moreover, two different peptide loading approaches for the cubosomes were tested and compared; pre- and post-loading. Characterization of the LC structures was performed using small-angle x-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by liquid chromatography. The antimicrobial effect of the AMP loaded LC nanoparticles (LCNPs) was studied in vitro using minimum inhibitory concentration (MIC) and time-kill assays. Proteolytic protection was investigated by incubating the formulations with two elastases and the antimicrobial effect after proteolysis was studied using radial diffusion assay (RDA). Results showed that the most hydrophobic peptide (AP114) was prone to induce an increase in negative curvature of the bulk cubic LC gel, hence pushing the system towards a hexagonal structure. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. The cubic pre- and post-loaded LCNPs displayed promising antimicrobial activity, and sometimes could a synergetic effect be observed, resulting in a slightly better activity than the unformulated AMP. The hexagonal LCNPs were found to be very efficient in encapsulating the AMPs, but did not display any antimicrobial effect, indicating insufficient delivery of peptide to the bacteria. Moreover, cubosomes post-loaded with LL-37 was found to protect the peptide from proteolytic degradation, resulting in a significant better bactericidal effect after proteolysis.
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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. |
- Ponnandai Schanmugavel, Kumaravel, 1991
(författare)
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Development of a Yeast Model for Functional Analysis of Human Copper Transport Proteins
- 2018
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACT Copper (Cu) is an important trace element that plays a vital role in several biological processes. It mediates numerous biochemical functions to maintain cellular homeostasis making it an essential metal for sustaining life. Many proteins or enzymes that are involved in various biochemical pathways require copper as a cofactor (also a regulator). In human cells, the Cu uptake is mediated by high-affinity copper uptake protein (Ctr1), followed by cytoplasmic chaperone Atox1 that shuttles Cu from the plasma membrane to Wilson’s disease protein ATP7B (P-type ATPase), a membrane-bound protein located at the Golgi apparatus. ATP7B incorporates Cu to various Cu-dependent enzymes in the secretory pathway. The main biological role of ATP7B (or Wilson Disease Protein) is to maintain the copper balance inside the human cell. Genetic defects in ATP7B often leads to a nonfunctional protein where copper balance is impaired and this condition results in Wilson’s disease (WD). ATP7B is a large multi-domain membrane transport protein that shows typical characteristics of a P1b type ATPase. In contrast to its bacterial (CopA) or yeast (Ccc2) counterparts which have one or two metal binding domains (MBD) respectively, the human ATP7B has six cytosolic MBDs in the N-terminal region. The reason for the presence of these six MBDs in ATP7B is not completely understood, and neither is the ATP7B mediated copper release in the Golgi. In this thesis, the development of a novel yeast model system for investigating the functional role of ATP7B in copper transport is described. The system probes shuttling of copper via human Atox1 to ATP7B proteins when expressed in a yeast humanized model. Using this system, we investigated the roles of six metal binding domains (MBDs) in ATP7B (Paper 1) and examined the Cu release (paper II). The results address the importance of the yeast model for studying human Cu transport proteins, the role of MBDs in ATP7B mediated Cu transport, the role of Atox1 in shuttling Cu and the significance of the luminal loop in ATP7B for Cu release function. Overall, the yeast model system developed in this thesis has great future potential for studying human copper transport proteins, which are involved in genetic diseases such as WD. The designed system can be expanded by using system biology approaches, to gain further understanding on human copper transport as well as copper transport related disorders.
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| 6. |
- 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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| 7. |
- Cardilin, Tim, 1989
(författare)
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Data-driven modeling of combination therapy in oncology
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis contains two manuscripts: Tumor Static Concentration Curves in Combination Therapy and Extending the Tumor Static Concentration Curve to Exposure - A Combination Therapy Example with Radiation Therapy. There is also an introductory chapter presenting some basic facts necessary to understand the appended manuscripts. The manuscripts share the common goal of developing model-based data-driven tools and techniques to quantitatively assess the effectiveness of anticancer combinations. The first paper presents a dynamical systems model for combination therapy with the anticancer drugs cetuximab and cisplatin. Using a mixed-effects approach the model is shown to adequately describe a preclinical dataset. The model is then analyzed by introducing the Tumor Static Concentration (TSC) curve, a curve of cetuximab-cisplatin concentration pairs all of which, if maintained, result in tumor stasis. The TSC analysis reveals a modest gain from combining the compounds. The variability of the TSC curve across the population is also explored. In the second paper we develop a dynamical systems model for combination therapy with ionizing radiation and a test compound. For this combination we introduce an extension of the TSC curve called the (average) Tumor Static Exposure (TSE) curve based on average, as opposed to pointwise, tumor stasis. The TSE analysis for combinations of radiation and the test compound demonstrates a large synergistic effect.
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| 8. |
- Tapani, Sofia, 1982
(författare)
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Three dimensional mathematical modelling of pronuclei migration for the mouse
- 2009
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main question addressed in this thesis is what happens between the moment when the sperm enters the egg and the fusion of the male and the female pronuclei. Orientation of the apposing pronuclei most likely plays a decisive role in the polarity of the developing embryo. The migration and the dependence between the pronuclei have been investigated through three different measures of correlation. It was concluded that a measure based on the projection of the movement onto the axis between the pronuclei’s centres was preferred. Two mathematical models that describe the pronuclei dynamics have been constructed in the form of stochastic differential equations. The models concern pronuclei migration from the time of the sperm entry to the fusion and spatial orientation of this fusion. First, a basic model was created. This was then developed into a refined model. The methodology consists of using stacks of confocal microscopy time-lapse images of the pronuclei migration together with statistical methods to identify realistic parameters in the models. Given different angles between the sperm entry and the position of the second polar body, the final models are then used to produce distributions of orientations of the meeting positions between the pronuclei. However, the main result is the suggested models themselves which describe the main features of the migration. The basic fitted model is based on two forces of attraction. Migration is directed towards the centre but also towards the other pronucleus. Parameter values corresponding to the size of these forces are estimated from data of both eggs treated with a microtubule inhibitor and untreated eggs. The refined model is also based on centring and attraction to the other pronucleus, but the centring is modelled into two mechanisms of pushing and pulling of the microtubule exerted forces. Simulated distributions from the models could for instance be used as initial value distributions for future models of egg cleavage.
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| 9. |
- Tyagi, Nisha
(författare)
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Live Biotherapeutics : importance of formulation and lyophilization parametersand an example of a clinical application
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, probiotics have expanded from their traditional classification as “health promoting food” to the development of live biotherapeutic products (LBP). Traditional probiotics are marketed as food/dietary supplements while LBPs are drug products intended for treatment or prevention of diseases. This type of products offers several advantages over traditional drugs, but also entail potential challenges with development, manufacturing, and demonstration of clinical safety. To obtain a sufficient quality, LBPs are typically produced by cultivation in a bioreactor, followed by formulation and lyophilization.In the first part of the project, the impact of lyophilization parameters on physicochemical and biological properties of Limosilactobacillus reuteri R2LC was evaluated. Using sucrose as a lyoprotectant gave a better freeze-drying survival, vitality and storage stability than using trehalose. A high concentration (20%) of sucrose sometimes resulted in a collapsed structure and 15% gave the overall best properties of the lyophilized bacteria. Interestingly, vitality was positively affected by using a higher concentration (1010 cfu/ml) of bacteria. Another observation was that introducing an annealing step in the process was positive when using sucrose as lyoprotectant, but no effect was seen when using trehalose.The second part of the project describes evaluation of the genetically modified L. reuteri R2LC expressing the human chemokine CXCL12 (ILP100-Topical) in a phase 1 trial on wound healing. The product was safe and well-tolerated. In addition, it gave a larger proportion of healed wounds (76 %) on Day 32 when compared to saline/placebo (59 %) (p=0.020) and the time of wound healing was reduced by 6 days on average and by 10 days at highest dose. Also, ILP100-Topical increased the density of CXCL12+ cells in the wounds and local wound blood perfusion.
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| 10. |
- 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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