| 4521. |
- Häbel, Henrike, 1987
(author)
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Characterization of Micro-Structures in Materials
- 2015
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Licentiate thesis (other academic/artistic)abstract
- On developing the next generation sustainable soft materials, it is often crucial to understand and control their properties and function. Whereas a characterization of three-dimensional data is desirable in corresponding studies, often two-dimensional data are less time consuming to obtain. Consequently, characterizing the three-dimensional micro-structure of a material from two-dimensional data would enable efficient screening of its properties. In this work, the challenge of characterizing two different materials from two-dimensional images obtained by scanning (transmission) electron microscopy is overcome by using tools from image analysis and spatial statistics. The two different materials are a colloidal nanoparticle gel and a polymer blended film. The characterization of the micro-structures in the materials is conducted in two main steps. First, the microscopy images are processed in order to identify the objects of interest. Second, the structures are characterized according to the objects of interest. In particular, the spatial arrangement of nanoparticles is evaluated by summary functions from spatial statistics. One such function based on the size of a cluster of particles has been developed in this project. For the pore space analysis of a polymer blended film, tools from image analysis are applied to measure and compare the shapes of pores in a statistical analysis. The results obtained in this work, may be useful for reconstructions of the micro-structure in materials in three dimensions. Such reconstructions can be used to analyze materials, which may not yet have even been synthesized, in simulation studies without experiments involving valuable resources. In that way, new sustainable high quality products may be developed.
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| 4522. |
- Häbel, Henrike, 1987, et al.
(author)
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Characterization of pore structure of polymer blended films used for controlled drug release
- 2016
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 222, s. 151-158
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Journal article (peer-reviewed)abstract
- The characterization of the pore structure in pharmaceutical coatings is crucial for understanding and controlling mass transport properties and function in controlled drug release. Since the drug release rate can be associated with the film permeability, the effect of the pore structure on the permeability is important to study. In this paper, a new approach for characterizing the pore structure in polymer blended films was developed based on an image processing procedure for given two-dimensional scanning electron microscopy images of film cross-sections. The focus was on different measures for characterizing the complexity of the shape of a pore. The pore characterization developed was applied to ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) blended films, often used as pharmaceutical coatings, where HPC acts as the pore former. It was studied how two different HPC viscosity grades influence the pore structure and, hence, mass transport through the respective films. The film with higher HPC viscosity grade had been observed to be more permeable than the other in a previous study; however, experiments had failed to show a difference between their pore structures. By instead characterizing the pore structures using tools from image analysis, statistically significant differences in pore area fraction and pore shape were identified. More specifically, it was found that the more permeable film with higher HPC viscosity grade seemed to have more extended and complex pore shapes than the film with lower HPC viscosity grade. This result indicates a greater degree of connectivity in the film with higher permeability and statistically confirms hypotheses on permeability from related experimental studies.
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| 4523. |
- Häbel, Henrike, 1987, et al.
(author)
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Colloidal particle aggregation in three dimensions
- 2019
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In: Journal of Microscopy. - : Wiley. - 0022-2720 .- 1365-2818. ; 275:3, s. 149-158
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Journal article (peer-reviewed)abstract
- Colloidal systems are of importance not only for everyday products, but also for the development of new advanced materials. In many applications, it is crucial to understand and control colloidal interaction. In this paper, we study colloidal particle aggregation of silica nanoparticles, where the data are given in a three-dimensional micrograph obtained by high-angle annular dark field scanning transmission electron microscopy tomography. We investigate whether dynamic models for particle aggregation, namely the diffusion limited cluster aggregation and the reaction limited cluster aggregation models, can be used to construct structures present in the scanning transmission electron microscopy data. We compare the experimentally obtained silica aggregate to the simulated postaggregated structures obtained by the dynamic models. In addition, we fit static Gibbs point process models, which are commonly used models for point patterns with interactions, to the silica data. We were able to simulate structures similar to the silica structures by using Gibbs point process models. By fitting Gibbs models to the simulated cluster aggregation patterns, we saw that a smaller probability of aggregation would be needed to construct structures similar to the observed silica particle structure.
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| 4524. |
- Häbel, Henrike, 1987
(author)
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From experiments with images to 3D models
- 2017
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Doctoral thesis (other academic/artistic)abstract
- For developing the next generation sustainable materials, it is often crucial to understand and control their properties and function. This work presents cross-disciplinary research starting with experimentally fabricated porous soft biomaterials and images of their micro-structure obtained by electron or laser microscopy. It is investigated how much information on the three-dimensional material structure can be extracted from two-dimensional images and how conclusions compare to three-dimensional image analysis. Based on the image data, spatial statistical models are constructed and fitted to two different materials: a colloidal nanoparticle gel and a porous polymer blended film. Colloidal systems are everywhere in our everyday life and of high interest for the development of new advanced materials. Polymer films are popular for pharmaceutical coatings which control the release of a drug to obtain important therapeutic benefits. Besides presenting image analysis routines, three-dimensional finite Gibbs point processes with inhomogeneous and anisotropic pair-potential functions are introduced. Observed point patterns are formed by silica particle positions or pore branching points located at intersections of at least three pore channels. Due to physical chemical forces between particles and polymers, it is assumed that the points interact with each other. The pairwise interaction is described in the pair-potential function of a Gibbs process. In this way, there is a link between static Gibbs point process models and dynamic physical chemical processes like colloidal particle aggregation and polymer phase separation. Furthermore, a new spatial statistical summary function is suggested for the cluster size analysis on different length scales in aggregated structures. This function is a useful tool for comparing two regimes for particle aggregation resulting in different size and shape distributions of particle clusters. More precisely, it is used to study the diffusion limited and the reaction limited cluster aggregation. The methods introduced in this work can be applied to point processes in general and are important contributions to the point process literature. The results are useful for setting up a virtual design framework for the study of properties of various materials, which may not yet have even been synthesized, in simulation studies instead of experiments involving valuable resources.
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| 4525. |
- Häbel, Henrike, 1987, et al.
(author)
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From static micrographs to particle aggregation dynamics in three dimensions
- 2016
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In: Journal of Microscopy. - : Wiley. - 1365-2818 .- 0022-2720. ; 262:1, s. 102-111
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Journal article (peer-reviewed)abstract
- Studies on colloidal aggregation have brought forth theories on stability of colloidal gels and models for aggregation dynamics. Still, a complete link between developed frameworks and obtained laboratory observations has to be found. In this work, aggregates of silica nanoparticles (20 nm) are studied using diffusion limited cluster aggregation (DLCA) and reaction limited cluster aggregation (RLCA) models. These processes are driven by the probability of particles to aggregate upon collision. This probability of aggregation is one in the DLCA and close to zero in the RLCA process. We show how to study the probability of aggregation from static micrographs on the example of a silica nanoparticle gel at 9 wt%. The analysis includes common summary functions from spatial statistics, namely the empty space function and Ripley's K-function, as well as two newly developed summary functions for cluster analysis based on graph theory. One of the new cluster analysis functions is related to the clustering coefficient in communication networks and the other to the size of a cluster. All four topological summary statistics are used to quantitatively compare in plots and in a least-square approach experimental data to cluster aggregation simulations with decreasing probabilities of aggregation. We study scanning transmission electron micrographs and utilize the intensity - mass thickness relation present in such images to create comparable micrographs from three-dimensional simulations. Finally, a characterization of colloidal silica aggregates and simulated structures is obtained, which allows for an evaluation of the cluster aggregation process for different aggregation scenarios. As a result, we find that the RLCA process fits the experimental data better than the DLCA process.
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| 4526. |
- Hägg, Daniel, 1974, et al.
(author)
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Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop?
- 2007
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In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 190:2, s. 291-7
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Journal article (peer-reviewed)abstract
- The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n=15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n=15) (P=0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P=0.012) with enhanced macrophage IL-6 secretion (3.13+/-2.5 pg/mL versus 0.32+/-0.16 pg/mL in controls, P=0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8+/-0.7 pg/mL versus 14.3+/-0.7 pg/mL; P=0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P=0.038) and 48 h (P=0.015). Taken together, our data show an IL-6-CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.
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| 4527. |
- Hägg, Daniel, 1974, et al.
(author)
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Expression of chemokine (C-C motif) ligand 18 in human macrophages and atherosclerotic plaques
- 2009
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 204:2, s. e15-20
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Using gene expression profiling, we aimed to identify genes that are predominantly expressed in human carotid atherosclerotic plaques. Such genes may be important in atherogenesis and pathophysiology of the plaque, and genes that encode for secreted proteins may be potential biomarkers for atherosclerosis and cardiovascular disease. METHODS: DNA microarray generated expression profiles of human carotid atherosclerotic plaques were compared to expression profiles of 80 different human tissues and cell types, to identify plaque-specific genes. RESULTS: We identified the chemokine (C-C motif) ligand 18 (CCL18) as predominantly expressed in human carotid plaque. Immunohistochemistry showed that CCL18 protein was localized to a subset of macrophages in carotid plaques. Monocyte-derived macrophages from subjects with atherosclerosis had threefold higher expression of CCL18 than macrophages from control subjects (p=0.012). Subjects with A/G genotype of the rs2015086 SNP in the promoter region of the CCL18 gene had threefold higher macrophage expression of CCL18 than subjects with A/A genotype (p=0.049), but we found no association of this SNP with an increased risk of coronary heart disease. We also compared serum levels of CCL18 from subjects with symptomatic carotid artery disease with control subjects. There were no differences in serum levels of CCL18 between the two groups, however CCL18 correlated with measurements of adiposity. CONCLUSION: CCL18 is predominantly expressed in human atherosclerotic plaques and may participate in the atherosclerotic plaque formation.
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| 4528. |
- Hägg, Daniel, 1974
(author)
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Expression profiling of human macrophages and atherosclerotic plaques to identify genes and mechanisms that modulate the development of atherosclerosis
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Macrophages play an important role in atherosclerosis, a disease that affects large and medium size arteries and causes clinical manifestations such as myocardial infarction or stroke. The aim of this thesis was to identify genes that are important in the development of atherosclerosis. Genes that have their major site of expression in macrophages or in atherosclerotic plaques, or are differently expressed in macrophages from subjects with atherosclerosis compared with macrophages from control subjects may affect atherogenesis. By comparing DNA microarray expression profiles of macrophages and atherosclerotic plaques with expression profiles from major tissues and cell types, macrophage and plaque specific genes were identified. The macrophage specific anti-inflammatory cytokine interleukin 1 receptor antagonist (IL1RN) was down regulated by oxidized low-density lipoprotein (LDL), suggesting a novel pro-inflammatory role of oxidized LDL. Immunohistochemistry showed that the plaque specific gene chemokine CC motif ligand 18 (CCL18) co-localized with macrophages in the plaques. In addition, macrophages from subjects with atherosclerosis had more than two-fold higher gene expression of CCL18 than macrophages from subjects without atherosclerosis. CCL18 is chemotactic for leukocytes and may therefore contribute to plaque inflammation. A promoter region polymorphism of the CCL18 gene was associated with increased macrophage CCL18 gene expression, but not with an increased risk of coronary heart disease (CHD). Comparison of macrophage expression profiles from subjects with atherosclerosis and control subjects identified 27 genes with an altered expression. Among these genes, CD44 and insulin receptor substrate 2 (IRS2) were both expressed at higher levels in macrophages from subjects with atherosclerosis compared with macrophages from control subjects. Immunohistochemistry showed that IRS2, an intracellular signaling molecule important in metabolism, was expressed in macrophages and endothelial cells in human carotid plaques. The C allele of the -765C→T SNP in the promoter region of the IRS2 gene was associated with increased macrophage expression of IRS2, and subjects homozygous for the C allele had 40% increased risk of coronary heart disease. The receptor CD44 mediates adhesion of monocytes to the vascular wall, a crucial step in atherosclerosis. CD44 expression correlated with secretion of interleukin 6 (IL-6) in macrophages, and IL-6 augmented CD44 expression in macrophages. In addition, CD44 deficient mice had lower circulating IL-6 than wild type mice. This suggests a positive feed-back loop between IL-6 and CD44, and that CD44 may affect atherosclerosis progression by modulating the inflammatory response. In conclusion, IRS2 might be a new susceptibility gene for atherosclerosis and CHD. CCL18, IL1RN and CD44 may play important roles in the development of atherosclerosis.
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| 4529. |
- Hägg, Daniel, 1974, et al.
(author)
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Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
- 2008
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In: International journal of molecular medicine. - 1107-3756. ; 21:6, s. 697-704
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Journal article (peer-reviewed)abstract
- Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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| 4530. |
- Hägg, Daniel, 1974, et al.
(author)
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Oxidized LDL induces a coordinated up-regulation of the glutathione and thioredoxin systems in human macrophages.
- 2006
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In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 185:2, s. 282-9
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Journal article (peer-reviewed)abstract
- Using DNA microarray analysis, we found that human macrophages respond to oxidized low-density lipoprotein (oxLDL) by activating the antioxidative glutathione and thioredoxin systems. Several genes of the glutathione and thioredoxin systems were expressed at high levels in macrophages when compared to 80 other human tissues and cell types, indicating that these systems may be of particular importance in macrophages. The up-regulation of three genes in these systems, thioredoxin (P < 0.005), thioredoxin reductase 1 (P < 0.001) and glutathione reductase (P < 0.001) was verified with real-time RT-PCR, using human macrophages from 10 healthy donors. To investigate the possible role of these antioxidative systems in the development of atherosclerosis, expression levels in macrophages from 15 subjects with atherosclerosis (12 men, 3 women) and 15 matched controls (12 men, 3 women) were analyzed using DNA microarrays. Two genes in the glutathione system Mn superoxide dismutase (P < 0.05) and catalase (P < 0.05) differed in expression between the groups. We conclude that macrophage uptake of oxidized LDL induces a coordinated up-regulation of genes of the glutathione and thioredoxin systems, suggesting that these systems may participate in the cellular defense against oxidized LDL and possibly modulate the development of atherosclerosis.
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