Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport out of pharmaceutical pellets. Water-soluble HPC leaches out and forms a porous structure that controls the drug transport. Industrially, the pellets are coated using a fluidized bed spraying device, and a layered film exhibiting varying porosity and structure after leaching is obtained. A detailed understanding of the formation of the multilayered, phase-separated structure during production is lacking. Here, we have investigated multilayered EC/HPC films produced by sequential spin-coating, which was used to mimic the industrial process. The effects of EC/HPC ratio and spin speed on the multilayer film formation and structure were investigated using advanced microscopy techniques and image analysis. Cahn-Hilliard simulations were performed to analyze the mixing behavior. A gradient with larger structures close to the substrate surface and smaller structures close to the air surface was formed due to coarsening of the layers already coated during successive deposition cycles. The porosity of the multilayer film was found to vary with both EC/HPC ratio and spin speed. Simulation of the mixing behavior and in situ characterization of the structure evolution showed that the origin of the discontinuities and multilayer structure can be explained by the non-mixing of the layers.

A new concept has been developed for characterizing the real-time evolution of the three-dimensional pore and lamella microstructure of bread during baking using synchrotron X-ray microtomography (SRµCT). A commercial, combined microwave-convective oven was modified and installed at the TOMCAT synchrotron tomography beamline at the Swiss Light Source (SLS), to capture the 3D dough-to-bread structural development in-situ at the micrometer scale with an acquisition time of 400 ms. This allowed characterization and quantitative comparison of three baking technologies: (1) convective heating, (2) microwave heating, and (3) a combination of convective and microwave heating. A workflow for automatic batchwise image processing and analysis of 3D bread structures (1530 analyzed volumes in total) was established for porosity, individual pore volume, elongation, coordination number and local wall thickness, which allowed for evaluation of the impact of baking technology on the bread structure evolution. The results showed that the porosity, mean pore volume and mean coordination number increase with time and that the mean local cell wall thickness decreases with time. Small and more isolated pores are connecting with larger and already more connected pores as function of time. Clear dependencies are established during the whole baking process between the mean pore volume and porosity, and between the mean local wall thickness and the mean coordination number. This technique opens new opportunities for understanding the mechanisms governing the structural changes during baking and discern the parameters controlling the final bread quality. © 2023 The Author(s)

Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport out of pharmaceutical pellets. The films are applied on the pellets using fluidized bed spraying. The drug transport rate is determined by the structure of the porous films that are formed as the water-soluble HPC leaches out. However, a detailed understanding of the evolution of the phase-separated structure during production is lacking. Here, we have investigated EC/HPC films produced by spin-coating, which mimics the industrial manufacturing process. This work aimed to understand the structure formation and film shrinkage during solvent evaporation. The cross-sectional structure evolution was characterized using confocal laser scanning microscopy (CLSM), profilometry and image analysis. The effect of the EC/HPC ratio on the cross-sectional structure evolution was investigated. During shrinkage of the film, the phase-separated structure undergoes a transition from 3D to nearly 2D structure evolution along the surface. This transition appears when the typical length scale of the phase-separated structure is on the order of the thickness of the film. This was particularly pronounced for the bicontinuous systems. The shrinkage rate was found to be independent of the EC/HPC ratio, while the initial and final film thickness increased with increasing HPC fraction. A new method to estimate part of the binodal curve in the ternary phase diagram for EC/HPC in ethanol has been developed. The findings of this work provide a good understanding of the mechanisms responsible for the morphology development and allow tailoring of thin EC/HPC films structure for controlled drug release. 

The three-dimensional microstructure of functional materials determines its effective properties, like the mass transport properties of a porous material. Hence, it is desirable to be able to tune the properties by tuning the microstructure accordingly. In this work, we study a class of spinodoid i.e. spinodal decomposition-like structures with tunable anisotropy, based on Gaussian random fields. These are realistic yet computationally efficient models for bicontinuous porous materials. We use a convolutional neural network for predicting effective diffusivity in all three directions. We demonstrate that by incorporating the predictions of the neural network in an approximate Bayesian computation framework for inverse problems, we can in a computationally efficient manner design microstructures with prescribed diffusivity in all three directions. © 2022, The Author(s).

Small-angle X-ray scattering (SAXS) is a useful technique for nanoscale structural characterization of materials. In SAXS, structural and spatial information is indirectly obtained from the scattering intensity in the spectral domain, known as the reciprocal space. Therefore, characterizing the structure requires solving the inverse problem of finding a plausible structure model that corresponds to the measured scattering intensity. Both the choice of structure model and the computational workload of parameter estimation are bottlenecks in this process. In this work, we develop a framework for analysis of SAXS data from disordered materials. The materials are modeled using Gaussian Random Fields (GRFs). We study the case of two phases, pore and solid, and three phases, where a third phase is added at the interface between the two other phases. Further, we develop very fast GPU-accelerated, Fourier transform-based numerical methods for both structure generation and SAXS simulation. We demonstrate that length scales and volume fractions can be predicted with good accuracy using our machine learning-based framework. The parameter prediction executes virtually instantaneously and hence the computational burden of conventional model fitting can be avoided. Copyright © 2022 Röding, Tomaszewski, Yu, Borg and Rönnols.

Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport from pharmaceutical pellets. The drug transport rate is determined by the structure of the porous films that are formed as water-soluble HPC leaches out. However, a detailed understanding of the evolution of the phase-separated structure in the films is lacking. In this work, we have investigated EC/HPC films produced by spin-coating, mimicking the industrial fluidized bed spraying. The aim was to investigate film structure evolution and coarsening kinetics during solvent evaporation. The structure evolution was characterized using confocal laser scanning microscopy and image analysis. The effect of the EC:HPC ratio (15 to 85 wt% HPC) on the structure evolution was determined. Bicontinuous structures were found for 30 to 40 wt% HPC. The growth of the characteristic length scale followed a power law, L(t) ∼ t(n), with n ∼ 1 for bicontinuous structures, and n ∼ 0.45-0.75 for discontinuous structures. The characteristic length scale after kinetic trapping ranged between 3.0 and 6.0 μm for bicontinuous and between 0.6 and 1.6 μm for discontinuous structures. Two main coarsening mechanisms could be identified: interfacial tension-driven hydrodynamic growth for bicontinuous structures and diffusion-driven coalescence for discontinuous structures. The 2D in-plane interface curvature analysis showed that the mean curvature decreased as a function of time for bicontinuous structures, confirming that interfacial tension is driving the growth. The findings of this work provide a good understanding of the mechanisms responsible for morphology development and open for further tailoring of thin EC/HPC film structures for controlled drug release. © 2022 The Royal Society of Chemistry

Liposomes can efficiently deliver messenger RNA (mRNA) into cells. When mRNA cocktails encoding different proteins are needed, a considerable challenge is to efficiently deliver all mRNAs into the cytosol of each individual cell. In this work, two methods are explored to co-deliver varying ratiometric doses of mRNA encoding red (R) or green (G) fluorescent proteins and it is found that packaging mRNAs into the same lipoplexes (mingle-lipoplexes) is crucial to efficiently deliver multiple mRNA types into the cytosol of individual cells according to the pre-defined ratio. A mixture of lipoplexes containing only one mRNA type (single-lipoplexes), however, seem to follow the “first come – first serve” principle, resulting in a large variation of R/G uptake and expression levels for individual cells leading to ratiometric dosing only on the population level, but rarely on the single-cell level. These experimental observations are quantitatively explained by a theoretical framework based on the stochasticity of mRNA uptake in cells and endosomal escape of mingle- and single-lipoplexes, respectively. Furthermore, the findings are confirmed in 3D retinal organoids and zebrafish embryos, where mingle-lipoplexes outperformed single-lipoplexes to reliably bring both mRNA types into single cells. This benefits applications that require a strict control of protein expression in individual cells. © 2021 The Authors. 

While molecular doping is ubiquitous in all branches of organic electronics, little is known about the spatial distribution of dopants, especially at molecular length scales. Moreover, a homogeneous distribution is often assumed when simulating transport properties of these materials, even though the distribution is expected to be inhomogeneous. In this study, electron tomography is used to determine the position of individual molybdenum dithiolene complexes and their three-dimensional distribution in a semiconducting polymer at the sub-nanometre scale. A heterogeneous distribution is observed, the characteristics of which depend on the dopant concentration. At 5 mol% of the molybdenum dithiolene complex, the majority of the dopant species are present as isolated molecules or small clusters up to five molecules. At 20 mol% dopant concentration and higher, the dopant species form larger nanoclusters with elongated shapes. Even in case of these larger clusters, each individual dopant species is still in contact with the surrounding polymer. The electrical conductivity first strongly increases with dopant concentration and then slightly decreases for the most highly doped samples, even though no large aggregates can be observed. The decreased conductivity is instead attributed to the increased energetic disorder and lower probability of electron transfer that originates from the increased size and size variation in dopant clusters. This study highlights the importance of detailed information concerning the dopant spatial distribution at the sub-nanometre scale in three dimensions within the organic semiconductor host. The information acquired using electron tomography may facilitate more accurate simulations of charge transport in doped organic semiconductors. 

Phase-separated polymer films are commonly used as coatings around pharmaceutical oral dosage forms (tablets or pellets) to facilitate controlled drug release. A typical choice is to use ethyl cellulose and hydroxypropyl cellulose (EC/HPC) polymer blends. When an EC/HPC film is in contact with water, the leaching out of the water-soluble HPC phase produces an EC film with a porous network through which the drug is transported. The drug release can be tailored by controlling the structure of this porous network. Imaging and characterization of such EC porous films facilitates understanding of how to control and tailor film formation and ultimately drug release. Combined focused ion beam and scanning electron microscope (FIB-SEM) tomography is a well-established technique for high-resolution imaging, and suitable for this application. However, for segmenting image data, in this case to correctly identify the porous network, FIB-SEM is a challenging technique to work with. In this work, we implement convolutional neural networks for segmentation of FIB-SEM image data. The data are acquired from three EC porous films where the HPC phases have been leached out. The three data sets have varying porosities in a range of interest for controlled drug release applications. We demonstrate very good agreement with manual segmentations. In particular, we demonstrate an improvement in comparison to previous work on the same data sets that utilized a random forest classifier trained on Gaussian scale-space features. Finally, we facilitate further development of FIB-SEM segmentation methods by making the data and software used open access. © 2021 The Authors.