Three-dimensional Cellular Model Research Articles

(006) ADVANCING PD.SPHERE: ENHANCED PROTOCOLS FOR A MORPHOLOGICALLY AND PATHOLOGICALLY ACCURATE 3D CELLULAR MODEL IN PEYRONIE’S DISEASE RESEARCH

Abstract Introduction Peyronie's disease (PD) affects about 10% of men and is often studied using traditional monolayer fibroblast monolayer cultures and limited animal models, which do not adequately replicate the complex cellular interactions of PD. We have developed an advanced three-dimensional (3D) cellular model named PD.SPHERE using a novel 'micro-gravity' cell culture technique from human PD tissues. Significant advancements in the culturing protocol have improved the morphology and physiopathology of these models, providing an essential platform for in vitro treatment screening. Objective The aim is to refine the culturing protocol for generating PD.SPHEREs that more accurately mimics the morphological and physiological features of PD plaques and to assess the efficacy of these refined models as tools for treatment screening. Methods Fibroblasts from human PD tissues were isolated and cultured using the 'micro-gravity' technique with modifications. The PD fibroblast cells were cultured and propagated in a non-adhesive 96-well plate, with and without 10 ng/ml transforming growth factor-beta (TGF-β) supplementation, under micro-gravity conditions. The plates were then placed on an orbital shaker inside the incubator and incubated at 37°C with 5% CO2 and 95% relative humidity. We confirmed the appropriate morphology and cellular compositions, including α-smooth muscle actin (α-SMA) and cellular collagen, using microscopic assays. The refined 3D model was subsequently used to evaluate the effects of collagenase from Clostridium histolyticum (CCH) and actinidin, a collagenase-like enzyme derived from kiwi fruits. Results Our findings from the refined 3D model revealed significant changes in cellular morphology. Specifically, PD.SPHEREs developed from cells that were not initially supplemented with TGF-β, but were later cultured in micro-gravity with TGF-β supplementation, and PD.SPHEREs from cells both propagated and cultured with TGF-β were approximately 2.3 and 3.5 times larger, respectively, than those PD.SPHEREs propagated and cultured entirely without TGF-β (P < 0.0001). The collagen content was significantly highest (P < 0.01) in PD.SPHEREs that were both propagated and cultured with TGF-β, compared to all other groups. The refined model was susceptible to both CCH and actinidin. The size and collagen content of the refined PD.SPHEREs significantly decreased (P < 0.05) following treatment with CCH and actinidin. Conclusions The advancements made in the culturing protocol of PD.SPHEREs represent a significant improvement in the modeling of PD for in vitro studies. Our results demonstrate the critical role of TGF-β in the growth and morphology of PD.SPHEREs. The increase in sized collagen content of the spheroids when cultured in the presence of TGF-β suggests that this factor plays a substantial role in cellular proliferation and cellular matrix accumulation, which are key aspects of PD pathogenesis. Furthermore, the increased collagen content in PD.SPHEREs cultured with TGF-β aligns with the known pathophysiology of PD, where collagen accumulation contributes to plaque formation and disease progression. This finding underscores the utility of our model in replicating key pathological features of PD and supports the potential of PD.SPHERE as an effective tool for screening and evaluating the efficacy of treatments aimed at modulating these pathological processes. Disclosure No.

(113) A Novel 3D Cellular Model for Peyronie's Disease Treatment Screening: PD.SPHERE

Abstract Introduction Peyronie's disease (PD) is a common issue that affects approximately 10% of males. Currently, researchers primarily study the pathogenesis and potential treatments for PD using monolayer fibroblast cells and a limited number of animal models. However, these models do not accurately represent the complex cellular structure and interactions involved in PD pathogenesis. We have successfully developed a three-dimensional (3D) cellular model, called PD.SPHERE, using a ground-breaking 'micro-gravity' cell culture method. This model is cultivated from extracted human PD tissues and serves as a valuable tool for in vitro treatment screening for PD. However, we have yet to use this model to evaluate the effectiveness of available and potential treatments. Objective Our objective is to determine the efficacy of the novel 3D cellular PD model, PD.SPHERE, as a treatment screening tool. Methods To achieve this, we cultured fibroblasts isolated from human PD tissues using the 'micro-gravity' approach. In this method, cells were seeded in a non-adhesive 96-well plate, placed on an orbital shaker, and incubated at 37°C with 5% CO2 and 95% relative humidity. We confirmed the proper morphology and cellular composition through microscopic assays. This 3D model was then used to assess the effects of collagenase clostridium histolyticum (CCH) and the actinidin enzyme, obtained from kiwi fruits. The PD.SPHERE was treated with actinidin at 10 mg/ml for 48 hours. We subsequently quantified collagen content using a soluble collagen quantification kit and observed viability, morphology, and changes in cellular compositions of the spheroids through immunofluorescent techniques and confocal microscopy. Results Preliminary results from our model have indicated significant changes in cellular morphology. Treatment with actinidin led to a significant decrease in spheroid size and density compared to the control group (P<0.01). The ratio of vimentin and actin filaments to nuclei staining was slightly but significantly reduced (P<0.05) in the spheroids treated with actinidin at 10 mg/ml. The cellular viability of the treated group showed a slight decrease, as revealed by Sytox Green staining. The assessment of collagen contents in the treated spheroids is ongoing. Conclusions Preliminary results suggest that our PD.SPHERE model can be effectively used to assess morphological and cellular component changes in PD tissues after treatment. Actinidin appears to compromise the plasma membrane of fibroblasts in PD.SPHERE. Our model holds promise for personalized treatment planning and potential for developing high-throughput treatment screening platforms. It also demonstrates consistency and reproducibility while closely mimicking the morphology of a PD plaque. Further research is required to collect signature gene expression data, physiological and immunological information, such as collagen production, extracellular matrix organization, and cellular expression of tight junctions, chemokines, and cytokines. These additional measures will help verify our model's pathophysiological, immunological, and treatment response aspects. Disclosure No.

Spatial lipidomics and metabolomics of multicellular tumor spheroids using MALDI-2 and trapped ion mobility imaging

Lipids and metabolites are small biological molecules that act major roles in cellular functions. Multicellular tumor spheroids (MCTS) are a highly beneficial three-dimensional cellular model for cancer research due to their ability to imitate numerous characteristics of tumor tissues. Increasing studies have performed spatial lipidomics and metabolomics in MCTS using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). However, these approaches often lack the sensitivity and specificity to offer a comprehensive characterization of lipids and metabolites within MCTS. In this study, we addressed this challenge by utilizing MALDI combined with laser-induced postionization (MALDI-2) and trapped ion mobility spectrometry (TIMS) imaging in H295R adrenocortical MCTS. Our results showed that MALDI-2 could detect more lipids and metabolites in MCTS than the traditional MALDI. TIMS data revealed a successful separation of many isomeric and isobaric ions of lipids and metabolites with different locations (e.g., proliferative region and necrotic region) within MCTS, suggesting an enhanced peak capacity for spatial lipidomics and metabolomics. To further identify these isomeric and isobaric ions, we performed MS/MS imaging experiments to compare the differences in signal intensities and spatial distributions of product ions. Our data highlight the strong potential of MALDI-2 and TIMS imaging for analyzing lipids and metabolites in MCTS, which may serve as valuable tools for numerous fields of biological and medical research.

An approach for simulating and evaluating the effect of sulfate attack on the durability of concrete bridges based on a three-dimensional cellular automata model

An accurate evaluation of sulfate attack (SA) diffusion and damage processes is critical for durability design in sulfate-contaminated environments. This study presents a three-dimensional cellular automata model algorithm (3D-CAm) that effectively simulates sulfate diffusion processes in concrete. The model's efficacy was verified through comparison with analytical solutions of Fick's second law (FSL), experimental data, and numerical methods reported in the literature. The outcomes demonstrate that the model has a high degree of accuracy in simulating the diffusion processes of SA in concrete. Moreover, based on the diffusion characteristics of sulfate, damage evolution, and deterioration of concrete mechanical properties, the 3D-CAm is developed and applied for modeling and evaluating the long-term effects of SA on the durability of a concrete bridge. The time and space-dependent multifactorial diffusivity stochastic effects were considered. The model algorithms are developed in Python to achieve this purpose. The simulation results revealed that the randomness of the multifactorial had a negative effect on the increasing sulfate diffusion and accelerating the degradation of the mechanical properties of concrete. Moreover, the relationship between sulfate concentration, damage degree, and corrosion time is presented. The results indicate that the damage degree plays a critical role in the deterioration of the mechanical properties of concrete, where with the increase in service time, the mechanical properties show a noteworthy decrease due to the increase in corrosion depth and deterioration of the cross-section area. To conclude, the 3D-CAm model provides a suitable and effective method for evaluating the diffusion and damage processes of SA in concrete bridges. It offers a valuable way to evaluate damage risk and design durable projects in corrosive environments.

Quantification of Irinotecan in Single Spheroids Using Internal Standards by MALDI Mass Spectrometry Imaging.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been used to visualize molecular distributions in various biological samples. While it has succeeded in localizing molecules ranging from metabolites to peptides, quantitative MSI (qMSI) has remained challenging, especially in small biological samples like spheroids. Spheroids are a three-dimensional cellular model system that replicate the chemical microenvironments of tumors. This cellular model has played an important role in evaluating the penetration of drugs to better understand the efficacy of clinical chemotherapy. Therefore, we aim to optimize a method to quantify the distribution of therapeutics in a single spheroid using MALDI-MSI. Studies were performed with the therapeutic irinotecan (IR). The calibration curve showed a linear relationship with a limit of detection (LOD) of 0.058 ng/mm2 and R2 value at 0.9643. Spheroids treated with IR for different lengths of time were imaged using the optimized method to quantify the drug concentration during the penetration process. With a dosing concentration of 20.6 μM, the concentration of IR at 48 h of treatment was 16.90 μM within a single spheroid. Furthermore, spheroids were divided into different layers by spatial segmentation to be quantified separately. This MALDI-qMSI method is amenable to a wide range of drugs as well as their metabolites. The quantification results show great potential to extend this method to other small biological samples such as organoids for patient derived therapies.

(149) PD.SPHERE, a Novel Three-dimension Cellular Model for Peyronie’s Disease via ‘Microgravity’ Condition: The New Era of in vitro Cell Culture-based Model for PD

Abstract Introduction Peyronie's disease (PD) is a common problem that affects 4-13% of the male population and results in a significant decline in patient and partner quality of life. Currently, in vitro monolayer fibroblast culture and animal models are actively used to study pathogenesis and treatments. However, both models are not a great pathophysiological representative for human PD due to the lack of cellular architecture and limited insight into the PD mechanism. Objective We aimed to develop a three-dimensional (3D) cellular model to reveal the PD pathogenesis mechanism and perhaps use this model as a treatment screening tool. Methods Human PD fibroblasts isolated from PD patients during surgery were cultured in various non-adhesive culture plates under the 'microgravity' condition. Complete media (DMEM+10% FBS+2mM L-glutamine) with and without TGF-β supplement was used to optimize the conditions for the PD.SPHERE, a 3D cell culture model of PD fibroblasts. Molecular probes against nucleus, actin, vimentin (VIM) and smooth muscle actin (SMA) were used to study the morphology and expression of molecular markers. Confocal-microscopic analyses were performed to obtain the morphological snapshots of and molecular data of the PD.SPHERE. Results We successfully developed a 3D cell culture (spheroid) model from human PD fibroblasts with our defined conditions. The PD spheroids were formed individually in each vessel of a 96-well plate coated with a non-adhesive substance. A PD.SPHERE was made in each well in a 96-well plate from three different individuals. Moreover, the size and circularity of spheroids were consistent across the plate. Although TGF-β supplemented condition significantly increased the cell division capability of the PD fibroblasts in the monolayer model, this supplementation was not necessary for our 3D model since TGF-β did not significantly increase the size and circularity of the 3D model. Despite the spheroids' increases in cell density over the culturing period, TGF-β did not affect the cell density in the 3D-cellular structure. Throughout the PD.SPHERE architecture, it also expressed SMA and VIM, the intracellular skeletal markers. Conclusions In conclusion, our model is consistent, reproducible and morphologically relevant to a PD plaque. Our model also demonstrates that we have the potential to produce high throughput treatment screening platforms for PD. Additionally, the PD.SPHERE platform is personalized and customizable to the specific individual; thus, our model indicated the potential to develop this platform for personalized treatment planning. However, signature gene expression and physiological and immunological information (i.e., collagen production, extracellular matrix organization, cellular expression of tight junctions, chemokines, and cytokines) should be further collected to verify the pathophysiological, immunological and treatment response for this model. Disclosure No

A Matrigel-based 3D construct of SH-SY5Y cells models the α-synuclein pathologies of Parkinson's disease.

ABSTRACTParkinson's disease (PD) is associated with α-synuclein-based Lewy body pathology, which has been difficult to observe in conventional two-dimensional (2D) cell culture and even in animal models. We herein aimed to develop a three-dimensional (3D) cellular model of PD to recapitulate the α-synuclein pathologies. All-trans-retinoic acid-differentiated human SH-SY5Y cells and Matrigel were optimized for 3D construction. The 3D cultured cells displayed higher tyrosine hydroxylase expression than 2D cells and improved dopaminergic-like phenotypes, as suggested by RNA-sequencing analyses. Multiple forms of α-synuclein, including monomer, and low- and high-molecular mass oligomers, were differentially present in the 2D and 3D cells, but mostly remained unchanged upon N-methyl-4-phenyl pyridine or rotenone treatment. Phosphorylated α-synuclein was accumulated, and detergent-insoluble α-synuclein fraction was observed, in the neurotoxin-treated 3D cells. Importantly, Lewy body-like inclusions were captured in the 3D system, including proteinase K-resistant α-synuclein aggregates, ubiquitin aggregation, and β-amyloid and β-sheet protein deposition. The study provides a unique and convenient 3D model of PD that recapitulates critical α-synuclein pathologies and should be useful in multiple PD-associated applications.

Simulation of pit interactions of multi-pit corrosion under an anticorrosive coating with a three-dimensional cellular automata model

To study the corrosion process and the pit interactions of multi-pit corrosion covered by an anticorrosive coating, we present a three-dimensional cellular automata model that is efficient of modeling multi-pit corrosion the spatial separation of anodic and cathodic semireactions results in the interaction of pits. Through the corrosion simulation of different number of pits, when there are more than one pits, some pits grow much faster than single-pit case, while some other pits filled with basic ions may stop growing for a long time. Therefore, the heterogeneous distribution of pH in multi-pit corrosion can be observed in the simulation results, and they are shown to be consistent with experimental studies. Specially, the concentration of basic ions in some areas can be seen both from the modal and the experimental results. The permeability of breakdown anticorrosive coating is considered in the model, and the results show that it plays an important role in the corrosion process.

Potential-based three-dimensional route choice model for pedestrian evacuation on terraced stands

This study proposes a potential-based three-dimensional cellular automata model to describe the route choice behavior of pedestrians while evacuating terraced stands. The model takes into account the pedestrians’ states of sitting, standing, and moving, and the possible transitions on terraced stands. The proposed potential field algorithm reflects the influence on route choice behavior of heterogeneous heights, route distance, pedestrian congestion, and route capacity. Three parameters related to the pedestrians’ behaviors in the spaces with heterogeneous heights are then analyzed to demonstrate the ability of the model to reproduce pedestrian route choice behaviors on terraced stands. Finally, empirical data observed in a terraced stand of a stadium are applied for further validation. The results show that the proposed model performs consistently well with the observed data.

Negative compressibility property in hinging open-cell Kelvin structure* *Project supported by the National Natural Science Foundation of China (Grant Nos. U1601203 and U19A20104), the Jilin Provincial Science and Technology Development Program, China (Grant Nos. 20180101321JC and 20190302099GX), the Jilin Provincial Industrial Technology of Research and Development, China (Grant No. 2019C037-3), the Science and Technology Project of Jilin Provincial Department of

A new three-dimensional (3D) cellular model based on hinging open-cell Kelvin structure is proposed for its negative compressibility property. It is shown that this model has adjustable compressibility and does exhibit negative compressibility for some certain conformations. And further study shows that the images of compressibility are symmetrical about the certain lines, which indicates that the mechanical properties of the model in the three axial directions are interchangeable and the model itself has a certain geometric symmetry. A comparison of the Kelvin model with its anisotropic form with the dodecahedron model shows that the Kelvin model has stronger negative compressibility property in all three directions. Therefore, a new and potential method to improve negative compressibility property can be derived by selecting the system type with lower symmetry and increasing the number of geometric parameters.

Computational modeling of degradation process on the mechanical performance of Poly-lactic acid /Magnesium composite

In this study, the corrosion behavior of biodegradable composites is modeled. These composites are made of Poly-Lactic acid and Magnesium with different volume fractions. The scanning electron microscopy images of these composites were taken, and statistical reconstruction of the composite based on scanning electron microscopy images was done by the phase recovery algorithm, the three-dimensional structure of this composite was extracted with this reconstruction, then a three-dimensional cellular automata model was developed to predict the corrosion of this composite. Results of experiments for the composite with 10% of Magnesium volume fraction were used to calibrate the parameters of the cellular automata model, and with these parameters, the results for the composite with 5% of Magnesium volume fraction was obtained, and with comparing these data with the results of the experiment, our model was validated. In the end, we estimated the mechanical properties of these composites and analyzed the results.

Практическое применение биотехнологий трехмерного клеточного культивирования в онкологии и персонализированной терапии

The creation of in vitro three-dimensional cellular model systems (in vitro 3D cultures) is a fast-growing leading-edge segment of the biotechnological industry. We have examined in this work the key 80 articles published after 2008, and focused on applications of in vitro 3D culture in translational oncology. We described a broad range of 3D culture systems, including models with and without extracellular matrix (ECM). 3D culture models based on decellularized ECM were discussed in more detail. The role of ECM in pathogeneis of malignant neoplasms, in particular, in the phenomenon of the tumor resistance to chemotherapy, was evaluated. 2D and 3D culture systems were compared, and natural and synthetic ECM were described, as well as the model creation based on 3D bioprinting. Particular attention was paid to in vitro models of various cancers, including those at the metastatic stage, based on 3D cell cultures, which maximally mimic the in vivo tumor behavior. The prospects of the practical application of 3D cell culture models in preclinical drag screening and in personalized therapy were discussed. We also presented our data on in vitro 2D and 3D culturing of human cells on various substrates. 3D cellular models, 3D bioprinting, biotechnology, extracellular matrix, cancer, translational medicine, personalized medicine, drag development, in vitro, ex vivo, oncology The authors are grateful to Dr. E. Shabalina for providing part of the experimental data and to OKA-Biotech Company for the samples of recombinant Funding-The work was supported by a Grant from the Russian Science Foundation (no. 18-15-00391). doi: 10.21519/0234-2758-2020-36-3-3-15

Application of human organotypic skin raft cultures for analysis of retinoid metabolism, retinoic acid signaling, and screening of bioactive rexinoids.

Several human enzymes of the short-chain dehydrogenase/reductase (SDR) superfamily of proteins exhibit catalytic oxidoreductive activity toward retinoid substrates in vitro. For some retinoid-active enzymes, their physiological significance for retinoid metabolism is supported by phenotypes linked to naturally occurring mutations in human genes or by targeted gene knockout studies of their murine homologs. However, for those enzymes that are not well conserved or display properties different from their murine counterparts, evaluation of their physiological roles can be challenging. Here, we describe the adaptation of stratified organotypic culture of human epidermis for evaluating the contribution of human putative SDR retinol dehydrogenases to biosynthesis of all-trans-retinoic acid in a three-dimensional cellular model highly sensitive to the levels of all-trans-retinol and all-trans-retinoic acid. In addition to providing a valuable readout of metabolic changes occurring in the presence or absence of the enzyme of interest, this model allows for evaluation of the effects of various retinoid and rexinoid therapeutic compounds on retinoic acid signaling, cell growth and differentiation.

Remote Actuation of Apoptosis in Liver Cancer Cells via Magneto-Mechanical Modulation of Iron Oxide Nanoparticles.

Lysosome-activated apoptosis represents an alternative method of overcoming tumor resistance compared to traditional forms of treatment. Pulsed magnetic fields open a new avenue for controlled and targeted initiation of lysosomal permeabilization in cancer cells via mechanical actuation of magnetic nanomaterials. In this study we used a noninvasive tool; namely, a benchtop pulsed magnetic system, which enabled remote activation of apoptosis in liver cancer cells. The magnetic system we designed represents a platform that can be used in a wide range of biomedical applications. We show that liver cancer cells can be loaded with superparamagnetic iron oxide nanoparticles (SPIONs). SPIONs retained in lysosomal compartments can be effectively actuated with a high intensity (up to 8 T), short pulse width (~15 µs), pulsed magnetic field (PMF), resulting in lysosomal membrane permeabilization (LMP) in cancer cells. We revealed that SPION-loaded lysosomes undergo LMP by assessing an increase in the cytosolic activity of the lysosomal cathepsin B. The extent of cell death induced by LMP correlated with the accumulation of reactive oxygen species in cells. LMP was achieved for estimated forces of 700 pN and higher. Furthermore, we validated our approach on a three-dimensional cellular culture model to be able to mimic in vivo conditions. Overall, our results show that PMF treatment of SPION-loaded lysosomes can be utilized as a noninvasive tool to remotely induce apoptosis.

Multi-scale modeling of solidification and microstructure development in laser keyhole welding process for austenitic stainless steel

A multi-scale model is developed in this paper to investigate the growth of grains and sub-grain dendrites during the molten pool solidification of austenitic stainless steel AISI304 in laser keyhole welding processes. A macro-scale dynamic model is used to predict the fluid flow and heat transfer in the keyhole as well as the molten pool. The generated thermal history is fed to a three-dimensional Cellular Automata model to predict the meso-scale grain growth and to a two-dimensional Cellular Automata–Phase Field model to predict the micro-scale dendrite morphology. The multi-scale model is applied to simulate multiple cases of different welding parameters. The model predictions are validated against experiments and studied further for detailed information. The effects of the welding parameters are discussed based on the numerical and experimental results.

The pedestrian evacuation model with collision probability in three-dimensional space

In order to effectively depict the evacuation process in a three-dimensional space, a novel three-dimensional cellular automata model was proposed with the stair factors. Based on the position attractiveness, collision probability, and vacancy degree, the calculation formula for transition probability was provided by the model, and the evacuation strategy was explained through defining the cellular evolutionary process. Meanwhile, the experiments were conducted on the simulation platform to study the relationships of evacuation time, exit width, pedestrian density, as well as average system velocity. The results showed that evacuation time had a positive correlation with pedestrian density, and a negative correlation with exit width; in addition, concerning the optimum evacuation time, there exists a desirable threshold value for vacancy parameter and collision parameter.

Surface roughening and rippling during plasma etching of silicon: Numerical investigations and a comparison with experiments

Atomic- or nanometer-scale surface roughening and rippling during Si etching in high-density Cl2 and Cl2/O2 plasmas have been investigated by developing a three-dimensional atomic-scale cellular model (ASCeM-3D), which is a 3D Monte Carlo-based simulation model for plasma–surface interactions and the feature profile evolution during plasma etching. The model took into account the behavior of Cl+ ions, Cl and O neutrals, and etch products and byproducts of SiClx and SiClxOy in microstructures and on feature surfaces therein. The surface chemistry and kinetics included surface chlorination, chemical etching, ion-enhanced etching, sputtering, surface oxidation, redeposition of etch products desorbed from feature surfaces being etched, and deposition of etch byproducts coming from the plasma. The model also took into account the ion reflection or scattering from feature surfaces on incidence and/or the ion penetration into substrates, along with geometrical shadowing of the feature and surface reemission of neutrals. The simulation domain was taken to consist of small cubic cells of atomic size, and the evolving interfaces were represented by removing Si atoms from and/or allocating them to the cells concerned. Calculations were performed for square substrates 50 nm on a side by varying the ion incidence angle onto substrate surfaces, typically with an incoming ion energy, ion flux, and neutral reactant-to-ion flux ratio of Ei = 100 eV, Γi0 = 1.0 × 1016 cm−2s−1, and Γn0/Γi0 = 100. Numerical results showed that nanoscale roughened surface features evolve with time during etching, depending markedly on ion incidence angle; in effect, at θi = 0° or normal incidence, concavo-convex features are formed randomly on surfaces. On the other hand, at increased θi = 45° or oblique incidence, ripple structures with a wavelength of the order of 15 nm are formed on surfaces perpendicularly to the direction of ion incidence; in contrast, at further increased θi ≥ 75° or grazing incidence, small ripples or slitlike grooves with a wavelength of <5 nm are formed on surfaces parallel to the direction of ion incidence. Such surface roughening and rippling in response to ion incidence angle were also found to depend significantly on ion energy and incoming fluxes of neutral reactants, oxygen, and etch byproducts. Two-dimensional power spectral density analysis of the roughened feature surfaces simulated was employed in some cases to further characterize the lateral as well as vertical extent of the roughness. The authors discuss possible mechanisms responsible for the formation and evolution of the surface roughness and ripples during plasma etching, including stochastic roughening, local micromasking, and effects of ion reflection, surface temperature, and ion angular distribution. Moreover, plasma etching experiments of blank Si substrates in Cl2 were conducted by varying the rf bias power or ion incident energy to verify the validity of our ASCeM-3D model. A comparison of the etch rate and root-mean-square (rms) surface roughness between experiments and simulations indicated that the ASCeM-3D with θi = 0° reproduces well the experiments at Ei < 250 eV, while does not reproduce the rms roughness at higher Ei > 250 eV, where the roughness decreases with increasing Ei in experiments, while continues to increase with Ei in simulations. Possible mechanisms for this disagreement at increased Ei are discussed with the help of several plasma and surface diagnostics and classical molecular dynamics simulations for Si/Cl and Si/SiCl systems.

The effects of group and position vacancy on pedestrian evacuation flow model

Abstract In order to reduce the simulation error of pedestrian evacuation model, a novel three-dimensional cellular automata model was proposed with ladder factor. The calculation formula for transition probability was given in the model based on floor field, position vacancy degree and group attraction, and the evacuation strategy was presented. Meanwhile, the experiment studied the relationships of evacuation time, mean system velocity as well as pedestrian density. The result showed that the evacuation time could be reduced effectively when the mean system velocity and position vacancy had proper degree, and the bigger group had negative effect with the evacuation time, so the bigger group should be avoided in actual evacuation process.

Floating gastroretentive drug delivery systems: Comparison of experimental and simulated dissolution profiles and floatation behavior

IntroductionGastroretentive drug delivery systems (GRDDS) play an important role in the delivery of drug substances to the upper part of the gastrointestinal tract; they offer a possibility to overcome the limited gastric residence time of conventional dosage forms. AimsThe aim of the study was to understand drug-release and floatation mechanisms of a floating GRDDS based on functionalized calcium carbonate (FCC). The inherently low apparent density of the excipient (approx. 0.6g/cm3) enabled a mechanism of floatation. The higher specific surface of FCC (approx. 70m2) allowed sufficient hardness of resulting compacts. The floating mechanism of GRDDS was simulated in silico under simulated acidic and neutral conditions, and the results were compared to those obtained in vitro. MethodsUnited States Pharmacopeia (USP) dissolution methods are of limited usefulness for evaluating floating behavior and drug release of floating dosage forms. Therefore, we developed a custom-built stomach model to simultaneously analyze floating characteristics and drug release. In silico dissolution and floatation profiles of the FCC-based tablet were simulated using a three-dimensional cellular automata-based model. ResultsIn simulated gastric fluid, the FCC-based tablets showed instant floatation. The compacts stayed afloat during the measurement in 0.1N HCl and eroded completely while releasing the model drug substance. When water was used as dissolution medium, the tablets had no floating lag time and sank down during the measurement, resulting in a change of release kinetics. ConclusionsFloating dosage forms based on FCC appear promising. It was possible to manufacture floating tablets featuring a density of less than unity and sufficient hardness for further processing. In silico dissolution simulation offered a possibility to understand floating behavior and drug-release mechanism.

A cellular automata model of pedestrian evacuation in three-dimensional space

In order to effectively depict the evacuation process in three-dimensional space, combining with the ladder factors, a novel three-dimensional cellular automata model is proposed. Based on the position attraction and collision possibility, the model presents a formula for calculating the transition probability, and expounds the evacuation strategy through defining the cellular evolutionary process. Meanwhile, experiments are conducted using the simulation platform to study the relationships between evacuation time, exit flow rate, exit width, original pedestrian density and system average velocity. The results show that evacuation time and exit flow rate have a positive correlation with original pedestrian density, and a negative correlation with exit width; in addition, concerning the optimum evacuation time, there exists a desirable threshold value for system average velocity and exit width.