Analysis of flow field and turbulence predictions in a lung model applying RANS and implications for particle deposition.

Airflow and aerosol deposition in the human airways are important aspects for applications such as pulmonary drug delivery and human exposure to aerosol pollutants. Numerical simulations are widely used nowadays to shed light in airflow features and particle deposition patterns inside the airways. For that purpose, the Euler/Lagrange approach is adopted for predicting flow field and particle deposition through point-particle tracking. Steady-state RANS (Reynolds-averaged Navier-Stokes) computations of flow evolution in an extended lung model applying different turbulence models were conducted and compared to measurements as well as high resolution LES (large-eddy simulations) for several flow rates. In addition, various inlet boundary conditions were considered and their influence on the predicted flow field was analysed. The results showed that the mean velocity field was simulated reasonably well, however, turbulence intensity was completely under-predicted by two-equation turbulence models. Only a Reynolds-stress model (RSM) was able predicting a turbulence level comparable to the measurements and the high resolution LES. Remarkable reductions in wall deposition were observed when wall effects were accounted for in the drag and lift force expressions. Naturally, turbulence is an essential contribution to particle deposition and it is well known that two-equation turbulence models considerably over-predict deposition due to the spurious drift effect. A full correction of this error is only possible in connection with a Reynolds-stress turbulence model whereby the predicted deposition in dependence of particle diameter yielded better agreement to the LES predictions. Specifically, with the RSM larger deposition is predicted for smaller particles and lower deposition fraction for larger particles compared to LES. The local deposition fraction along the lung model was numerically predicted with the same trend as found from the measurements, however the values in the middle region of the lung model were found to be somewhat larger.

Potential and constraints for the application of CFD combined with Lagrangian particle tracking to dry powder inhalers.

For about 15 years the performance of dry powder inhalers (DPIs) has been numerically analysed through CFD (computational fluid dynamics) approaches with the objective of understanding the evolving flow structures and the resulting transport of drug particles. Naturally the main interest is the numerical prediction of the emitted fine particle fraction (FPF) which is able to penetrate the lung airways. Due to the mostly used drug formulations (i.e. carrier-based or agglomerated drug powder) and the complex elementary processes occurring during the transport of such particles through inhalers this is not an easy task. Essential for a good and efficient performance of DPI is the drug particle detachment from a carrier or the aerosolisation of agglomerated drug powder. Mostly the motion of particulate matter through an inhaler is described in a Lagrangian way using either a discrete particle method (DPM) or a discrete element method (DEM). This paper reviews the major published contributions related to the numerical calculations of dry powder inhalers by considering particles which may be coarse carrier or fine drug particles or even clusters including agglomerated fine particles or carriers covered with many drug particles. This review also considers simulations on the behaviour of single clusters interacting with flows or colliding with rigid walls. Following that, the potentials and constraints of the DPM and DEM are critically assessed with regard to inhaler applications. As a result, the DPM is most suitable since the clusters (i.e. carrier with drug or agglomerated drugs) are considered and tracked as single entities. On the other hand, in DEM all individual primary particles within clusters are tracked accounting for the acting fluid forces and multiple contact interactions between particles. In most applications published so far, the fluid dynamic interactions between these primary particles are not adequately accounted for. Hence, both approaches need further modelling activities for realistically capturing all relevant elementary processes, such as, flow induced drug detachment from clusters, cluster-wall collisions and recollection of drug particles on clusters. Moreover, recent calculations on the motion of carrier particles through an inhaler for statistically analysing the experienced flow stresses are presented. Also, carrier-wall collisions were evaluated with regard to number and intensity. The flow simulations were conducted for steady-state conditions based on RANS (Reynolds-averaged Navier-Stokes) in connection with the k-ω-SST (shear-stress transport) turbulence model. Carrier particle tracking was done considering all relevant forces, especially transverse lift forces. Based on this information, fully resolved simulations of the flow over particle clusters (i.e. carrier particle coated with thousands of drug particles) using the Lattice-Boltzmann method (LBM) are introduced. Therefrom, the detachment probabilities by lift-off, as well as sliding and rolling stripping of fine drug particles are evaluated. For that purpose, laminar and turbulent plug flows, as well as shear flows, were assumed to interact with the fixed cluster in a cubic domain. Even at the highest relative velocities typically found in an inhaler, lift-off in a laminar flow was not possible when considering experimentally determined adhesion forces. However, turbulence is very effective in drug powder detachment from a carrier. Finally results are presented using a novel carrier-wall collision model for describing drug detachment in Euler/Lagrange simulations. The results for two inhalers (i.e. Cyclohaler and Unihaler, a modular inhaler developed at the University of Kiel) revealed that carrier-wall collisions are very effective for inertia-induced drug detachment. Hence, the predicted fine particle fraction was found to be close to 100% for both inhalers. As a conclusion of this study, it has become clear that the wall deposition of fine drug particles is an important mechanism during carrier or agglomerate wall collisions, which are responsible for the low emitted fine particle fraction (FPF) observed experimentally. It is hoped that this article provides requirements and guidelines for the further development of Euler/Lagrange simulations applied to dry powder inhaler devices.

Regional aerosol deposition in the human airways: The SimInhale benchmark case and a critical assessment of in silico methods.

Regional deposition effects are important in the pulmonary delivery of drugs intended for the topical treatment of respiratory ailments. They also play a critical role in the systemic delivery of drugs with limited lung bioavailability. In recent years, significant improvements in the quality of pulmonary imaging have taken place, however the resolution of current imaging modalities remains inadequate for quantifying regional deposition. Computational Fluid-Particle Dynamics (CFPD) can fill this gap by providing detailed information about regional deposition in the extrathoracic and conducting airways. It is therefore not surprising that the last 15years have seen an exponential growth in the application of CFPD methods in this area. Survey of the recent literature however, reveals a wide variability in the range of modelling approaches used and in the assumptions made about important physical processes taking place during aerosol inhalation. The purpose of this work is to provide a concise critical review of the computational approaches used to date, and to present a benchmark case for validation of future studies in the upper airways. In the spirit of providing the wider community with a reference for quality assurance of CFPD studies, in vitro deposition measurements have been conducted in a human-based model of the upper airways, and several groups within MP1404 SimInhale have computed the same case using a variety of simulation and discretization approaches. Here, we report the results of this collaborative effort and provide a critical discussion of the performance of the various simulation methods. The benchmark case, in vitro deposition data and in silico results will be published online and made available to the wider community. Particle image velocimetry measurements of the flow, as well as additional numerical results from the community, will be appended to the online database as they become available in the future.

Towards the optimisation and adaptation of dry powder inhalers.

Pulmonary drug delivery by dry powder inhalers is becoming more and more popular. Such an inhalation device must insure that during the inhalation process the drug powder is detached from the carrier due to fluid flow stresses. The goal of the project is the development of a drug powder detachment model to be used in numerical computations (CFD, computational fluid dynamics) of fluid flow and carrier particle motion through the inhaler and the resulting efficiency of drug delivery. This programme will be the basis for the optimisation of inhaler geometry and dry powder inhaler formulation. For this purpose a multi-scale approach is adopted. First the flow field through the inhaler is numerically calculated with OpenFOAM(®) and the flow stresses experienced by the carrier particles are recorded. This information is used for micro-scale simulations using the Lattice-Boltzmann method where only one carrier particle covered with drug powder is placed in cubic flow domain and exposed to the relevant flow situations, e.g. plug and shear flow with different Reynolds numbers. Therefrom the fluid forces on the drug particles are obtained. In order to allow the determination of the drug particle detachment possibility by lift-off, sliding or rolling, also measurements by AFM (atomic force microscope) were conducted for different carrier particle surface structures. The contact properties, such as van der Waals force, friction coefficient and adhesion surface energy were used to determine, from a force or moment balance (fluid forces versus contact forces), the detachment probability by the three mechanisms as a function of carrier particle Reynolds number. These results will be used for deriving the drug powder detachment model.

Repair of inguinal hernias using the mesh technique during extraperitoneal pelvic lymph node dissection.

PURPOSE: This article describes our experience of using a totally extraperitoneal approach for endoscopic pelvic lymphadenectomy and inguinal hernia repair with the mesh technique in one procedure. MATERIALS AND METHODS: A total of 52 patients underwent modified pelvic lymph node dissection for the staging of prostate cancer. Eight of them had hernia defects; 1 was recurrent. Five patients with direct and 3 patients with indirect inguinal hernias were treated by totally extraperitoneal hernia repair with the placement of a mesh measuring at least 10 x 15 cm (prolene mesh with incision and flap). RESULTS: The mean duration of the lymphadenectomy itself was decreased from 150 min (first 20 patients) to 70 min (n = 21-52). The mean additional procedure time for hernioplasty was 15 min. The overall lymph node-positive rate was 9.6%. The complication rate was 7.7%. Four patients developed symptomatic lymphoceles, 1 of whom developed deep venous thrombosis. No complications occurred which were attributed to hernia repair. Morbidity did not rise, and hospitalization time did not increase for the patients who underwent hernioplasty. There were no recurrences or neuralgias on follow-up up to 2 years. CONCLUSIONS: By avoiding entry into the peritoneal cavity, the extraperitoneal approach obviates intra-abdominal complications (ileus, bowel injury, peritonitis) in both techniques. The extraperitoneal approach for pelvic lymph node dissection allows concomitant inguinal hernia to be repaired with low morbidity and within an acceptable operating time.

Down-regulation of the neurotrophin receptor TrkB following ligand binding. Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB.

This study examines the mechanisms by which the tyrosine kinase receptor TrkB is down-regulated following binding of brain-derived neurotrophic factor (BDNF). In primary cultures of cerebellar granule neurons, BDNF-induced reduction of TrkB receptors was largely prevented by the addition of specific proteasome inhibitors. HN10 cells, a neuronal cell line that can be readily transfected, also showed a marked down-regulation of cell surface TrkB following BDNF exposure. In addition, we observed that prolonged exposure to nerve growth factor of TrkA-transfected cells did not lead to the down-regulation seen with BDNF and TrkB. TrkA and TrkB chimeric molecules were therefore expressed in HN10 cells and tested for ligand-induced regulation. These experiments led to the conclusion that the motives responsible for down-regulation are contained in the cytoplasmic domain of TrkB, and a short sequence in the juxtamembrane domain of TrkB was identified that confers nerve growth factor-induced down-regulation when inserted into TrkA.

Liquid-gas partitioning of the gasoline oxygenate methyl tert-butyl ether (MTBE) under laboratory conditions and its effect on growth of selected algae.

The partitioning of the widely used gasoline additive methyl tert-butyl ether (MTBE) between liquid growth media and gaseous phase was measured daily under laboratory conditions to determine how closely dissolved MTBE concentrations matched nominal concentrations. Total (gaseous and dissolved) MTBE averaged across 6 days for 29.6, 503.2, and 1005.7 mg L-1 MTBE treatments were 89.9, 90.3, and 73.0% of nominal, respectively, and mean dissolved MTBE in these same treatments were 74.6, 73.8, and 69.6% of total MTBE, respectively. This suggests that dissolved MTBE concentrations can vary substantially from nominal. The effect of MTBE on the growth of selected algae was also evaluated under laboratory conditions. Three unicellular algae, Selenastrum capricornutum (Chlorophyta), Navicula pelliculosa (Bacillariophyta), and Synechococcus leopoliensis (= Anacystic nidulans, Cyanophyta = Cyanobacteria), representative of three taxonomic groups, were used as test organisms. Toxicity tests were acute and increase in cell number was used as an indicator of growth. Algal species were exposed by injection of MTBE into sealed vessels containing defined liquid growth media. The growth of N. pelliculosa and S. leopoliensis was negatively affected at nominal 2400 mg L-1 MTBE, whereas the growth of S. capricornutum was negatively affected at nominal 4800 mg L-1 MTBE and positively affected at nominal 600 mg L-1 MTBE. The differential sensitivity of the growth of these representative species suggests that MTBE may alter algal community composition in the natural environment.

Trans unsaturated fatty acids in natural products and processed foods.

Various representatives of trans unsaturated fatty acids have been detected in plants. The main trans monoenoic acids in ruminants, elaidic acid and vaccenic acid are not found in plants. Most oil seeds used for production of edible fats do not contain any trans fatty acids. Trans fatty acids in non-ruminant animals are derived from food. In adult ruminants, however, trans fatty acids are produced by microbial hydrogenation of linoleic acid and linolenic acid in the rumen; in consequence, a variety of positional and stereoisomers of both cis and trans fatty acids appear in both meat and milk. The total trans content of 5-10% in beef fat is largely trans monoene, mainly 9-trans (elaidic acid), 10-trans and 11-trans (vaccenic acid). The trans fatty acid content of human fat is dependent on the uptake of trans fatty acid from food. The usual content is about 2%, though up to 15% has been recorded. The isomer distribution is similar to that of the trans isomers of butter and margarine. The trans fatty acid content in ruminant products such as milk, butter, cheese, curds and tallow is 5-10%. These products contain nearly all possible stereo- and positional isomers of oleic and linoleic acid. The trans fatty acid content of margarines fluctuates widely according to raw material and process conditions. According to one investigation, an average of 16% of all unsaturated fatty acids in margarines consists of geometrical and positional isomers of the "natural" acids, a similar percentage to that in butter. Diet and health margarines have much lower contents of trans fatty acids. The total trans content of margarines is largely due to trans-18:1 monoenes. The positional isomers of the trans-monoenes are more evenly distributed in margarine than in butter. Hardened oils do not contain trans fatty acid isomers other than those produced by the microflora of ruminants. Therefore, claims that trans fatty acid isomers are "synthetic", "nonphysiological" or "unnatural" are unjustified if these words are used to imply "not produced by the living organism".

Influence of stabilizer concentration on effectiveness of chlorine as an algicide.

Cyanuric acid, used as chlorine stabilizer in swimming pool waters, has a relatively minor effect on the algicidal efficiency of free chlorine. The toxicity of free chlorine to three swimming pool algae was reduced slightly by 25 mg of cyanuric acid per liter if inhibiting, but less than algicidal, concentrations of chlorine were employed. Higher stabilizer concentrations (50, 100, and 200 mg/liter) generally resulted in no further reduction in the algicidal efficiency of free chlorine beyond that observed at 25 mg/liter.

Cellulose in the cell walls of the bangiophyceae (rhodophyta).

Mechanically isolated cell walls of the conchocelis phase of Bangia fuscopurpurea yield cellulose II (regenerated cellulose) upon treatment with Schweitzer's reagent. X-ray powder analysis and thin-layer chromatography of partial hydrolyzates confirm the presence of cellulose in this extract. Gas-liquid chromatographic analysis of wall hydrolyzates indicates that xylose, mannose, galactose, and glucose are major wall constituents. The presence of cellulose in the conchocelis provides evidence that this bangiophycean life cycle phase represents a transitional form or link between the two classes of red algae, Bangiophyceae and Florideophyceae. This suggests a close affinity of the two classes of the Rhodophyta and supports the hypothesis that bangiophycean algae were precursors of the Florideophyceae.

Laboratory comparison of the effectiveness of several algicides on isolated swimming pool algae.

The most frequently encountered species of algae found in swimming pools in the Phoenix metropolitan area were used to evaluate the laboratory effectiveness of five commercially available pool chemicals used for algal control. The pool algae used were the xanthophyte Pleurochloris pyrenoidosa, the chlorophyte Oocystis sp., and the cyanophytes Phormidium minnesotense and Plectonema sp. Pad Algae Kill (a chlorine derivative) was effective in the control of all test organisms. Algaedyn, a silver-containing algicide, was effective on P. minnesotense and Plectonema sp., but caused only a slight inhibition in the growth of P. pyrenoidosa and Oocystis sp. Quarternary ammonium (Padicide) was more effective in controlling the growth of Phormidium and Plectonema than Pleurochloris and Oocystis. Algimycin (herbicide) only reduced the growth of Oocystis and was ineffective on the other species. Bio-Gard (copper) reduced the growth of Pleurochloris, but had no effect on the other test organisms. The technique used to quantify the influence of algicides on isolated pool algae appears to be adaptable to those algae that form distinct colonies on an agar substratum.

PYROLYSIS-GAS-LIQUID CHROMATOGRAPHIC ANALYSIS OF CHLOROPHYCEAN AND RHODOPHYCEAN ALGAE(1).

Eight chlorococcalean algae and 5 rhodophycean algae have been grown in axenic cultures. These organisms have been "fingerprinted" using a pyrolysis-gas-liquid chromatographic analysis. Each alga has a distinctive pyrogram which characterizes it both quantitatively and qualitatively. The pyrograms are given and the significance for possible future uses of this technique in developmental, evolutionary, and systematic studies with algae is discussed.