| 1. |
- Eriksson Barman, Sandra, 1985, et al.
(författare)
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New characterization measures of pore shape and connectivity applied to coatings used for controlled drug release
- 2021
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1520-6017 .- 0022-3549. ; 110:7, s. 2753-2764
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Tidskriftsartikel (refereegranskat)abstract
- Pore geometry characterization-methods are important tools for understanding how pore structure influences properties such as transport through a porous material. Bottlenecks can have a large influence on transport and related properties. However, existing methods only catch certain types of bottleneck effects caused by variations in pore size. We here introduce a new measure, geodesic channel strength, which captures a different type of bottleneck effect caused by many paths coinciding in the same pore. We further develop new variants of pore size measures and propose a new way of visualizing 3-D characterization results using layered images. The new measures together with existing measures were used to characterize and visualize properties of 3-D FIB-SEM images of three leached ethyl-cellulose/hydroxypropyl-cellulose films. All films were shown to be anisotropic, and the strongest anisotropy was found in the film with lowest porosity. This film had very tortuous paths and strong geodesic channel-bottlenecks, while the paths through the other two films were relatively straight with well-connected pore networks. The geodesic channel strength was shown to give important new visual and quantitative insights about connectivity, and the new pore size measures provided useful information about anisotropies and inhomogeneities in the pore structures. The methods have been implemented in the freely available software MIST.
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| 2. |
- Fager, Cecilia, 1990, et al.
(författare)
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3D high spatial resolution visualisation and quantification of interconnectivity in polymer films
- 2020
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Ingår i: International Journal of Pharmaceutics. - : Elsevier B.V.. - 0378-5173 .- 1873-3476. ; 587
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Tidskriftsartikel (refereegranskat)abstract
- A porous network acts as transport paths for drugs through films for controlled drug release. The interconnectivity of the network strongly influences the transport properties. It is therefore important to quantify the interconnectivity and correlate it to transport properties for control and design of new films. This work presents a novel method for 3D visualisation and analysis of interconnectivity. High spatial resolution 3D data on porous polymer films for controlled drug release has been acquired using a focused ion beam (FIB) combined with a scanning electron microscope (SEM). The data analysis method enables visualisation of pore paths starting at a chosen inlet pore, dividing them into groups by length, enabling a more detailed quantification and visualisation. The method also enables identification of central features of the porous network by quantification of channels where pore paths coincide. The method was applied to FIB-SEM data of three leached ethyl cellulose (EC)/hydroxypropyl cellulose (HPC) films with different weight percentages. The results from the analysis were consistent with the experimentally measured release properties of the films. The interconnectivity and porosity increase with increasing amount of HPC. The bottleneck effect was strong in the leached film with lowest porosity.
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| 3. |
- Fager, Cecilia, 1990
(författare)
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3D Reconstruction of Porous and Poorly Conductive Soft Materials using FIB-SEM Tomography
- 2018
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Focused ion beam combined with scanning electron microscope (FIB-SEM) is a powerful tool that can be utilised to reveal the internal microstructure of materials. It basically uses ions to make cross-sections with high precision and electrons to image the cross-section surface with high spatial resolution. In addition to revealing the internal microstructure, FIB-SEM can be used to perform a sequential slice and image procedure which, after some data processing, can result in a 3D reconstruction of the microstructure, also denoted as FIB-SEM tomography. Focused ion beam tomography is a well-established procedure since 1987. It has been successfully applied to a variety of well conductive materials. However, to perform FIB-SEM tomography on ion and electron beam sensitive as well as poorly conductive soft materials is still challenging. Some of the common challenges are cross-sectioning artefacts, shadowing-effects and charging. The presence of pores adds additional challenges. Fully dense materials provide a planar cross-section while pores expose surface area beneath the planar cross-section surface as well. The sub-surface pore information and the varying intensity from the sub-surface areas give rise to intensity overlaps which complicates the data processing. Several solutions to overcome these challenges have been reported. Examples are milling and imaging at low beam energies and specimen preparations. However, the ultimate aim is to examine porous and poorly conductive soft materials as close to their original state to avoid introduction of artefacts. The aim of this work was to develop a general protocol for optimisation of FIB-SEM tomography parameters for porous and poorly conductive soft materials.The optimised parameters include the energies and currents of the ion and electron beams, reduction of shadowing-effects, choice of electron detector and selection of method for charge neutralisation. In addition, a new self-learning binarisation algorithm is introduced to enable an automatic separation between pores and matrix. The binary data have been used to visualise the interconnectivity in 3D of individual pore paths through phase separated polymer films. The optimised protocol for FIB-SEM tomography is applicable to a variety of porous and poorly conductive soft materials. The porous and poorly conductive soft materials in these studies were leached phase separated polymer films intended for controlled drug release coatings in pharmaceuticals. The porous microstructure within the films acts as transport path for the drug. In this work, the complex microstructure has been visualised in 3D. In addition, 3D visualisation of the shortest, intermediate and longest paths through the films, based upon tortuosity calculations, have been performed as well.
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| 4. |
- Fager, Cecilia, 1990, et al.
(författare)
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Correlating 3D porous structure in polymer films with mass transport properties using FIB-SEM tomography
- 2021
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Ingår i: Chemical Engineering Science: X. - : Elsevier BV. - 2590-1400. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Porous polymer coatings are used to control drug release from pharmaceutical products. The coating covers a drug core and depending on the porous structure, different drug release rates are obtained. This work presents mass transport simulations performed on porous ethyl cellulose films with different porosities. The simulations were performed on high spatial resolution 3D data obtained using a focused ion beam scanning electron microscope. The effective diffusion coefficient of water was determined using a diffusion chamber. Lattice Boltzmann simulations were used to simulate water diffusion in the 3D data. The simulated coefficient was in good agreement with the measured coefficient. From the results it was concluded that the tortuosity and constrictivity of the porous network increase with decreasing amount of added hydroxypropyl cellulose, resulting in a sharp decrease in effective diffusion. This work shows that high spatial resolution 3D data is necessary, and that 2D data is insufficient, in order to predict diffusion through the porous structure with high accuracy.
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| 5. |
- Fager, Cecilia, 1990, et al.
(författare)
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Optimization of FIB-SEM Tomography and Reconstruction for Soft, Porous, and Poorly Conducting Materials
- 2020
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Ingår i: Microscopy and Microanalysis. - 1431-9276 .- 1435-8115. ; 26:4, s. 837-845
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Tidskriftsartikel (refereegranskat)abstract
- Tomography using a focused ion beam (FIB) combined with a scanning electron microscope (SEM) is well-established for a wide range of conducting materials. However, performing FIB-SEM tomography on ion- and electron-beam-sensitive materials as well as poorly conducting soft materials remains challenging. Some common challenges include cross-sectioning artifacts, shadowing effects, and charging. Fully dense materials provide a planar cross section, whereas pores also expose subsurface areas of the planar cross-section surface. The image intensity of the subsurface areas gives rise to overlap between the grayscale intensity levels of the solid and pore areas, which complicates image processing and segmentation for three-dimensional (3D) reconstruction. To avoid the introduction of artifacts, the goal is to examine porous and poorly conducting soft materials as close as possible to their original state. This work presents a protocol for the optimization of FIB-SEM tomography parameters for porous and poorly conducting soft materials. The protocol reduces cross-sectioning artifacts, charging, and eliminates shadowing effects. In addition, it handles the subsurface and grayscale intensity overlap problems in image segmentation. The protocol was evaluated on porous polymer films which have both poor conductivity and pores. 3D reconstructions, with automated data segmentation, from three films with different porosities were successfully obtained.
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| 6. |
- Fager, Cecilia, 1990
(författare)
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Quantitative 3D reconstruction of porous polymers using FIB-SEM tomography -correlating materials structures to properties of coatings for controlled drug release
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Porous networks are found in a wide range of different advanced and technologically important materials and influence the materials properties. The networks are active components in for example batteries, food and pharmaceuticals. The interconnectivity of a network strongly influences the transport properties. One example is polymer film coatings for controlled drug release where the porous network acts as a transport path for drugs. The correlation between the detailed structure of the network and the transport properties illustrates the importance of quantifying the interconnectivity in 3D. One approach to image material in 3D is sequential imaging (tomography). Examples of tomography techniques are confocal laser scanning microscopy, x-ray and neutron tomography where the spatial resolution is limited to the micrometre length scale. Transmission electron microscopy tomography and focused ion beam (FIB) combined scanning electron microscope (SEM) tomography are examples of techniques with higher spatial resolution ranging from micrometre to sub-nanometre. In this work the focus is on the understanding of the correlation between the structure and materials properties of phase-separated polymer film coatings used for controlled drug release. We acquired high spatial 3D resolution data on microporous ethyl cellulose and hydroxypropyl cellulose film coatings using FIB-SEM tomography. The tomography was performed after the water soluble hydroxypropyl cellulose phase had been removed leaving a porous network providing a transport path for the drug. We optimised the FIB-SEM parameters and established a generic protocol for porous and poorly conducting materials in order to overcome challenges such as redeposition, curtaining, shadowing effects, charging and sub-surface information due to the pores. In addition, a new self-learning segmentation algorithm was introduced to enable an automatic separation between pores and matrix. The quantification of the porous network was carried out by determining the pore size distribution, tortuosity and interconnectivity. As a final step, diffusion simulations were performed on the FIB-SEM data and correlated with experimentally measured permeability.
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| 7. |
- Malekian, Bita, 1986, et al.
(författare)
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Fabrication and Characterization of Plasmonic Nanopores with Cavities in the Solid Support
- 2017
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Ingår i: Sensors. - : MDPI AG. - 1424-8220. ; 17:6, s. Article no. 1444 -
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Tidskriftsartikel (refereegranskat)abstract
- Plasmonic nanostructures are widely used for various sensing applications by monitoring changes in refractive index through optical spectroscopy or as substrates for surface enhanced Raman spectroscopy. However, in most practical situations conventional surface plasmon resonance is preferred for biomolecular interaction analysis because of its high resolution in surface coverage and the simple single-material planar interface. Still, plasmonic nanostructures may find unique sensing applications, for instance when the nanoscale geometry itself is of interest. This calls for new methods to prepare nanoscale particles and cavities with controllable dimensions and curvature. In this work, we present two types of plasmonic nanopores where the solid support underneath a nanohole array has been etched, thereby creating cavities denoted as 'nanowells' or 'nanocaves' depending on the degree of anisotropy (dry or wet etch). The refractometric sensitivity is shown to be enhanced upon removing the solid support because of an increased probing volume and a shift of the asymmetric plasmonic field towards the liquid side of the finite gold film. Furthermore, the structures exhibit different spectral changes upon binding inside the cavities compared to the gold surface, which means that the structures can be used for location-specific detection. Other sensing applications are also suggested.
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| 8. |
- Megido, Loerto, et al.
(författare)
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Understanding and utilizing the biomolecule/nanosystems interface: Soft materials and coatings for controlled drug release
- 2017
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Ingår i: Nanotechnologies in Preventive and Regenerative Medicine: An Emerging Big Picture. - 9780323480642 ; , s. 244-260
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Combining biomolecules with materials used in medicine allows for local control of the biological response and can be used for modulating the host immune response, a major challenge in the efficacy of many medical devices. In Subchapter 3.1, we will review different methods used to attach biomolecules to materials, focusing on protein conjugation methods. We will begin by describing noncovalent immobilization strategies, including encapsulation within biomaterials and adsorption to material surfaces. We will then discuss strategies to covalently attach biomolecules to materials via the use of specific functional groups, thus enhancing the stability of the interaction. Finally, we will describe emerging methods to site specifically immobilize biomolecules to materials such that proteins are presented in an oriented manner, improving their overall functionality. Throughout the subchapter, we will emphasize the advantages and disadvantages of each technique, successes achieved, as well as the challenges remaining in this growing field.During last years, increasing development of nanoparticles as targeted drug delivery agents, has led to a wide amount of studies involving their characterization to the application as novel therapeutic agents. Hence, the nanoparticles interact with biological environments when they enter in the human body, and then proteins bind to the nanomaterial surface forming the protein corona. Protein corona has a great relevance in the interaction and function of the nanoparticle-drug conjugates. In fact, its characterization is one of the main challenges for nanoscience development. Herein, it is reviewed the main proteomic methods described for quantify and qualify the protein corona formed around nanoparticles to better understand the process of interaction with the biological media, and to decipher key parameters to control the effects of the protein corona.In Subchapter 3.3, the structure and working principles of coatings for controlled drug release in oral drug administration are presented. The release mechanisms, including diffusion, dissolution, osmotic pumping, and swelling are described. The soft materials used in the majority of controlled drug release formulations are natural and synthetic polymers. They are presented here and examples of specific polymers applied in controlled release formulations are provided. There is also a section containing characterization of soft materials using in situ electron microscopy for studying water transport through coatings at high-spatial resolution. The reason for this is that the detailed properties and release mechanisms of the controlled release depend on the material nanostructure. The in situ characterization gives access not only the information about the nanostructure but also the direct correlation between structure and properties on different length scales. Finally, an overview of the present major challenges and future possibilities concerning controlled drug release formulations is presented.Targeting cancer cells with functional nanoprobes possessing a targeting drug unit and an imaging moiety carries great potential for early detection, accurate diagnosis, and targeted therapy of various diseases. Given their nanoscopic dimensions, ultrasmall particles ( < 100nm) are in general well suited for interactions with the cells; however, the current challenge of the nanomedicine is to transform inorganic nanoparticles of metals (e.g., gold) or metal oxide (e.g., magnetite) into signal-generating vectors. Engineered nanostructures can act as vehicles for a large number of signaling centers and/or targeting units thereby offering unique opportunity to enhance the sensitivity by locally enhancing the density of signal groups. For this purpose, creation of surface groups enabling chemical attachment of antibodies or other targeting biomolecules are essential that will allow the delivery of therapeutic payloads to the diseased sites. Multimodal nanoprobes functionalized with different diagnostic and therapeutic options within a single nanoparticle followed by their functionalization with organic ligands and biomolecules can provide specific uptake and high sensitivity toward anatomical information. However, the vision of making clinical theranostics a routine clinical procedure is encumbered by limited stability of complex nanoparticles in biological milieu and lack of standardization of therapy response. Despite the widely acclaimed advantages of integrating diagnostic imaging, drug delivery, and therapeutic monitoring in a single nanotheranostic probe, the clinical utilization of engineered nanoprobes demands concerted efforts in the domains of nanoparticle and surface chemistry/charge, new chelator ligands, pharmaceutical technology, radioactive labeling of nanovectors, biokinetics, and pharmacodynamics of nanoprobes, and biological tests (cell tests and animal models).
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| 9. |
- Röding, Magnus, 1984, et al.
(författare)
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Three-dimensional reconstruction of porous polymer films from FIB-SEM nanotomography data using random forests
- 2021
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Ingår i: Journal of Microscopy. - : Wiley. - 1365-2818 .- 0022-2720. ; 281:1, s. 76-86
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Tidskriftsartikel (refereegranskat)abstract
- Combined focused ion beam and scanning electron microscope (FIB-SEM) tomography is a well-established technique for high resolution imaging and reconstruction of the microstructure of a wide range of materials. Segmentation of FIB-SEM data is complicated due to a number of factors; the most prominent is that for porous materials, the scanning electron microscope image slices contain information not only from the planar cross-section of the material but also from underlying, exposed subsurface pores. In this work, we develop a segmentation method for FIB-SEM data from ethyl cellulose porous films made from ethyl cellulose and hydroxypropyl cellulose (EC/HPC) polymer blends. These materials are used for coating pharmaceutical oral dosage forms (tablets or pellets) to control drug release. We study three samples of ethyl cellulose and hydroxypropyl cellulose with different volume fractions where the hydroxypropyl cellulose phase has been leached out, resulting in a porous material. The data are segmented using scale-space features and a random forest classifier. We demonstrate good agreement with manual segmentations. The method enables quantitative characterization and subsequent optimization of material structure for controlled release applications. Although the methodology is demonstrated on porous polymer films, it is applicable to other soft porous materials imaged by FIB-SEM. We make the data and software used publicly available to facilitate further development of FIB-SEM segmentation methods. Lay Description For imaging of very fine structures in materials, the resolution limits of, e.g. X-ray computed tomography quickly become a bottleneck. Scanning electron microscopy (SEM) provides a way out, but it is essentially a two-dimensional imaging technique. One manner in which to extend it to three dimensions is to use a focused ion beam (FIB) combined with a scanning electron microscopy and acquire tomography data. In FIB-SEM tomography, ions are used to perform serial sectioning and the electron beam is used to image the cross section surface. This is a well-established method for a wide range of materials. However, image analysis of FIB-SEM data is complicated for a variety of reasons, in particular for porous media. In this work, we analyse FIB-SEM data from ethyl cellulose porous films made from ethyl cellulose and hydroxypropyl cellulose (EC/HPC) polymer blends. These films are used as coatings for controlled drug release. The aim is to perform image segmentation, i.e. to identify which parts of the image data constitute the pores and the solid, respectively. Manual segmentation, i.e. when a trained operator manually identifies areas constituting pores and solid, is too time-consuming to do in full for our very large data sets. However, by performing manual segmentation on a set of small, random regions of the data, we can train a machine learning algorithm to perform automatic segmentation on the entire data sets. The method yields good agreement with the manual segmentations and yields porosities of the entire data sets in very good agreement with expected values. The method facilitates understanding and quantitative characterization of the geometrical structure of the materials, and ultimately understanding of how to tailor the drug release.
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