Analysis of the airflow features and ventilation efficiency of an Ultra-Clean-Air operating theatre by qDNS simulations and experimental validation.

Ultra-Clean-Air (UCA) operating theatres aim to minimise surgical instrument contamination and wound infection through high flow rates of ultra-clean air, reducing the presence of Microbe Carrying Particles (MCPs). This study investigates the airflow patterns and ventilation characteristics of a UCA operating theatre (OT) under standard ventilation system operating conditions, considering both empty and partially occupied scenarios. Utilising a precise computational model, quasi-Direct Numerical Simulations (qDNS) were conducted to delineate flow velocity profiles, energy spectra, distributions of turbulent kinetic energy, energy dissipation rate, local Kolmogorov scales, and pressure-based coherent structures. These results were also complemented by a tracer gas decay analysis following ASHRAE standard guidelines. Simulations showed that contrary to the intended laminar regime, the OT's geometry inherently fosters a predominantly turbulent airflow, sustained until evacuation through the exhaust vents, and facilitating recirculation zones irrespective of occupancy level. Notably, the occupied scenario demonstrated superior ventilation efficiency, a phenomenon attributed to enhanced kinetic energy induced by the additional obstructions. The findings underscore the critical role of UCA-OT design in mitigating MCP dissemination, highlighting the potential to augment the design to optimise airflow across a broader theatre spectrum, thereby diminishing recirculation zones and consequently reducing the propensity for Surgical Site Infections (SSIs). The study advocates for design refinements to harness the turbulent dynamics beneficially, steering towards a safer surgical environment.

Spreading of aqueous surfactant solutions on oil substrates: Superspreaders vs non-superspreaders.

HYPOTHESIS: The question of why aqueous solutions of some surfactants demonstrate a rapid spreading (superspreading) over hydrophobic solid substrates, while solutions of other similar surfactants do not, has no definitive explanation despite numerous previous studies. The suggested hypothesis for this study assumes that once the spreading coefficient of surfactant is positive, there is a concentration range for solutions of any surfactant which demonstrates rapid spreading. As it is impossible to calculate spreading coefficients for solid substrates, we compare the spreading performance of known superspreaders and non-superspreaders on liquid (oil) substrate. EXPERIMENTS: The kinetics of spreading of aqueous solutions of a series of branched ionic surfactants and non-ionic trisiloxane surfactants on two liquid substrates was studied and compared with the spreading of a surfactant-free liquid, silicone oil. Both dynamic and equilibrium spreading coefficients were calculated using measured surface and interfacial tensions. FINDINGS: There is no difference in spreading rate on liquid substrate between solutions of surfactants proven as superspreaders (while spreading on solid substrate) or non-superspreaders. A rapid spreading (superspreading) with the characteristic rate of spreading O(102-103) mm2/s occurs if the dynamic spreading coefficients exceeds the positive threshold value. If the dynamic spreading coefficient is negative or slightly positive, complete wetting still occurs, but the spreading is slow with the spreading rate is O(1) mm2/s. Spreading exponents for surfactant solutions in the rapid spreading regime are considerably larger than for the surfactant-free liquid. A number of spreading and dewetting patterns were observed depending on the surfactant type, its concentration and substrate.

Use of In Vitro Dynamic Colon Model (DCM) to Inform a Physiologically Based Biopharmaceutic Model (PBBM) to Predict the In Vivo Performance of a Modified-Release Formulation of Theophylline.

A physiologically based biopharmaceutic model (PBBM) of a modified-release formulation of theophylline (Uniphyllin Continus® 200 mg tablet) was developed and implemented to predict the pharmacokinetic (PK) data of healthy male volunteers by integrating dissolution profiles measured in a biorelevant in vitro model: the Dynamic Colon Model (DCM). The superiority of the DCM over the United States Pharmacopeia (USP) Apparatus II (USP II) was demonstrated by the superior predictions for the 200 mg tablet (average absolute fold error (AAFE): 1.1-1.3 (DCM) vs. 1.3-1.5 (USP II). The best predictions were obtained using the three motility patterns (antegrade and retrograde propagating waves, baseline) in the DCM, which produced similar PK profiles. However, extensive erosion of the tablet occurred at all agitation speeds used in USP II (25, 50 and 100 rpm), resulting in an increased drug release rate in vitro and overpredicted PK data. The PK data of the Uniphyllin Continus® 400 mg tablet could not be predicted with the same accuracy using dissolution profiles from the DCM, which might be explained by differences in upper gastrointestinal (GI) tract residence times between the 200 and 400 mg tablets. Thus, it is recommended that the DCM be used for dosage forms in which the main release phenomena take place in the distal GI tract. However, the DCM again showed a better performance based on the overall AAFE compared to the USP II. Regional dissolution profiles within the DCM cannot currently be integrated into Simcyp®, which might limit the predictivity of the DCM. Thus, further compartmentalization of the colon within PBBM platforms is required to account for observed intra-regional differences in drug distribution.

Review of the role of surfactant dynamics in drop microfluidics.

Surfactants are employed in microfluidic systems not just for drop stabilisation, but also to study local phenomena in industrial processes. On the scale of a single drop, these include foaming, emulsification and stability of foams and emulsions using statistically significant ensembles of bubbles or drops respectively. In addition, surfactants are often a part of a formulation in microfluidic drop reactors. In all these applications, surfactant dynamics play a crucial role and need to be accounted for. In this review, the effect of surfactant dynamics is considered on the level of standard microfluidic operations: drop formation, movement in channels and coalescence, but also on a more general level, considering the mechanisms controlling surfactant adsorption on time- and length-scales characteristic of microfluidics. Some examples of relevant calculations are provided. The advantages and challenges of the use of microfluidics to measure dynamic interfacial tension at short time-scales are discussed.

The Effect of Biorelevant Hydrodynamic Conditions on Drug Dissolution from Extended-Release Tablets in the Dynamic Colon Model.

The in vitro release of theophylline from an extended-release dosage form was studied under different hydrodynamic conditions in a United States Pharmacopoeial (USP) dissolution system II and a bespoke in vitro tubular model of the human colon, the Dynamic Colon Model (DCM). Five biorelevant motility patterns extracted from in vivo data were applied to the DCM, mimicking the human proximal colon under baseline conditions and following stimulation using polyethylene glycol or maltose; these represent the lower and upper bounds of motility normally expected in vivo. In the USPII, tablet dissolution was affected by changing hydrodynamic conditions at different agitation speeds of 25, 50 and 100 rpm. Applying different motility patterns in the DCM affected the dissolution profiles produced, with theophylline release at 24 h ranging from 56.74 ± 2.00% (baseline) to 96.74 ± 9.63% (maltose-stimulated). The concentration profiles of theophylline were markedly localized when measured at different segments of the DCM tube, highlighting the importance of a segmented lumen in intestine models and in generating spatial information to support simple temporal dissolution profiles. The results suggested that the shear stresses invoked by the unstimulated, healthy adult human colon may be lower than those in the USPII at 25 rpm and thus insufficient to achieve total release of a therapeutic compound from a hydroxyethyl cellulose matrix. When operated under stimulated conditions, drug release in the DCM was between that achieved at 25 and 50 rpm in the USPII.

Surfactant-laden droplet size prediction in a flow-focusing microchannel: a data-driven approach.

The control of droplet formation and size using microfluidic devices is a critical operation for both laboratory and industrial applications, e.g. in micro-dosage. Surfactants can be added to improve the stability and control the size of the droplets by modifying their interfacial properties. In this study, a large-scale data set of droplet size was obtained from high-speed imaging experiments conducted on a flow-focusing microchannel where aqueous surfactant-laden droplets were generated in silicone oil. Three types of surfactants were used including anionic, cationic and non-ionic at concentrations below and above the critical micelle concentration (CMC). To predict the final droplet size as a function of flow rates, surfactant type and concentration of surfactant, two data-driven models were built. Using a Bayesian regularised artificial neural network and XGBoost, these models were initially based on four inputs (flow rates of the two phases, interfacial tension at equilibrium and the normalised surfactant concentration). The mean absolute percentage errors (MAPE) show that data-driven models are more accurate (MAPE = 3.9%) compared to semi-empirical models (MAPE = 11.4%). To overcome experimental difficulties in acquiring accurate interfacial tension values under some conditions, both models were also trained with reduced inputs by removing the interfacial tension. The results show again a very good prediction of the droplet diameter. Finally, over 10 000 synthetic data were generated, based on the initial data set, with a Variational Autoencoder (VAE). The high-fidelity of the extended synthetic data set highlights that this method can be a quick and low-cost alternative to study microdroplet formation in future lab on a chip applications, where experimental data may not be readily available.

Correction: Schütt et al. Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model. Pharmaceutics 2022, 14, 184.

In the original publication [...].

Mechanism of gelation in high nickel content cathode slurries for sodium-ion batteries.

Sodium-ion batteries are a prospective sustainable alternative to the ubiquitous lithium-ion batteries due to the abundancy of sodium, and their cobalt free cathodes. The high nickel O3-type oxides show promising energy densities, however, a time dependency in the rheological properties of the composite electrode slurries is observed, which leads to inhomogeneous coatings being produced. A combination of electron microscopy and infra-red spectroscopy were used to monitor the O3-oxide surface changes upon exposure to air, and the effect upon the rheology and stability of the inks was investigated. Upon exposure to air, NaOH rather than Na2CO3 was observed on the surfaces of the powder through FTIR and EDS. The subsequent gelation of the slurry was initiated by the NaOH and dehydrofluorination with crosslinking of PVDF was observed through the reaction product, NaF. Approximately 15% of the CF bonds in PVDF undergo this dehydrofluorination to form NaF. As observed in the relaxation time of fitted rheological data, the gelation undergoes a three-stage process: a dehydrofluorination stage, creating saturated structures, a crosslinking stage, resulting in the highest rate of gelation, and a final crosslinking stage. This work shows the mechanism for instability of high nickel containing powders and electrode slurries, and presents a new time dependent oscillatory rheology test that can be used to determine the process window for these unstable slurry systems.

Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model.

The performance of solid oral dosage forms targeting the colon is typically evaluated using standardised pharmacopeial dissolution apparatuses. However, these fail to replicate colonic hydrodynamics. This study develops a digital twin of the Dynamic Colon Model; a physiologically representative in vitro model of the human proximal colon. Magnetic resonance imaging of the Dynamic Colon Model verified that the digital twin robustly replicated flow patterns under different physiological conditions (media viscosity, volume, and peristaltic wave speed). During local contractile activity, antegrade flows of 0.06-0.78 cm s-1 and backflows of -2.16--0.21 cm s-1 were measured. Mean wall shear rates were strongly time and viscosity dependent although peaks were measured between 3.05-10.12 s-1 and 5.11-20.34 s-1 in the Dynamic Colon Model and its digital twin respectively, comparable to previous estimates of the USPII with paddle speeds of 25 and 50 rpm. It is recommended that viscosity and shear rates are considered when designing future dissolution test methodologies for colon-targeted formulations. In the USPII, paddle speeds >50 rpm may not recreate physiologically relevant shear rates. These findings demonstrate how the combination of biorelevant in vitro and in silico models can provide new insights for dissolution testing beyond established pharmacopeial methods.

Luminal Fluid Motion Inside an In Vitro Dissolution Model of the Human Ascending Colon Assessed Using Magnetic Resonance Imaging.

Knowledge of luminal flow inside the human colon remains elusive, despite its importance for the design of new colon-targeted drug delivery systems and physiologically relevant in silico models of dissolution mechanics within the colon. This study uses magnetic resonance imaging (MRI) techniques to visualise, measure and differentiate between different motility patterns within an anatomically representative in vitro dissolution model of the human ascending colon: the dynamic colon model (DCM). The segmented architecture and peristalsis-like contractile activity of the DCM generated flow profiles that were distinct from compendial dissolution apparatuses. MRI enabled different motility patterns to be classified by the degree of mixing-related motion using a new tagging method. Different media viscosities could also be differentiated, which is important for an understanding of colonic pathophysiology, the conditions that a colon-targeted dosage form may be subjected to and the effectiveness of treatments. The tagged MRI data showed that the DCM effectively mimicked wall motion, luminal flow patterns and the velocities of the contents of the human ascending colon. Accurate reproduction of in vivo hydrodynamics is an essential capability for a biorelevant mechanical model of the colon to make it suitable for in vitro data generation for in vitro in vivo evaluation (IVIVE) or in vitro in vivo correlation (IVIVC). This work illustrates how the DCM provides new insight into how motion of the colonic walls may control luminal hydrodynamics, driving erosion of a dosage form and subsequent drug release, compared to traditional pharmacopeial methods.

Modelling and Simulation of the Drug Release from a Solid Dosage Form in the Human Ascending Colon: The Influence of Different Motility Patterns and Fluid Viscosities.

For colonic drug delivery, the ascending part of the colon is the most favourable site as it offers the most suitable environmental conditions for drug dissolution. Commonly, the performance of a drug formulation is assessed using standardised dissolution apparatus, which does not replicate the hydrodynamics and shear stress evoked by wall motion in the colon. In this work, computer simulations are used to analyse and understand the influence of different biorelevant motility patterns on the disintegration/drug release of a solid dosage form (tablet) under different fluid conditions (viscosities) to mimic the ascending colonic environment. Furthermore, the ability of the motility pattern to distribute the drug in the ascending colon luminal environment is analysed to provide data for a spatiotemporal concentration profile. The motility patterns used are derived from in vivo data representing different motility patterns in the human ascending colon. The applied motility patterns show considerable differences in the drug release rate from the tablet, as well as in the ability to distribute the drug along the colon. The drug dissolution/disintegration process from a solid dosage form is primarily influenced by the hydrodynamic and shear stress it experiences, i.e., a combination of motility pattern and fluid viscosity. Reduced fluid motion leads to a more pronounced influence of diffusion in the tablet dissolution process. The motility pattern that provoked frequent single shear stress peaks seemed to be more effective in achieving a higher drug release rate. The ability to simulate drug release profiles under biorelevant colonic environmental conditions provides valuable feedback to better understand the drug formulation and how this can be optimised to ensure that the drug is present in the desired concentration within the ascending colon.

Dynamic Colon Model (DCM): A Cine-MRI Informed Biorelevant In Vitro Model of the Human Proximal Large Intestine Characterized by Positron Imaging Techniques.

This work used in vivo MRI images of human colon wall motion to inform a biorelevant Dynamic Colon Model (DCM) to understand the interplay of wall motion, volume, viscosity, fluid, and particle motion within the colon lumen. Hydrodynamics and particle motion within the DCM were characterized using Positron Emission Tomography (PET) and Positron Emission Particle Tracking (PEPT), respectively. In vitro PET images showed that fluid of higher viscosity follows the wall motion with poor mixing, whereas good mixing was observed for a low viscosity fluid. PEPT data showed particle displacements comparable to the in vivo data. Increasing fluid viscosity favors the net forward propulsion of the tracked particles. The use of a floating particle demonstrated shorter residence times and greater velocities on the liquid surface, suggesting a surface wave that was moving faster than the bulk liquid. The DCM can provide an understanding of flow motion and behavior of particles with different buoyancy, which in turn may improve the design of drug formulations, whereby fragments of the dosage form and/or drug particles are suspended in the proximal colon.

Non-pathogenic Escherichia coli biofilms: effects of growth conditions and surface properties on structure and curli gene expression.

Biofilm formation is a harmful phenomenon in many areas, such as in industry and clinically, but offers advantages in the field of biocatalysis for the generation of robust biocatalytic platforms. In this work, we optimised growth conditions for the production of Escherichia coli biofilms by three strains (PHL644, a K-12 derivative with enhanced expression of the adhesin curli; the commercially-used strain BL21; and the probiotic Nissle 1917) on a variety of surfaces (plastics, stainless steel and PTFE). E. coli PHL644 and PTFE were chosen as optimal strain and substratum, respectively, and conditions (including medium, temperature, and glucose concentration) for biofilm growth were determined. Finally, the impact of these growth conditions on expression of the curli genes was determined using flow cytometry for planktonic and sedimented cells. We reveal new insights into the formation of biofilms and expression of curli in E. coli K-12 in response to environmental conditions.

Mass Transfer Accompanying Coalescence of Surfactant-Laden and Surfactant-Free Drop in a Microfluidic Channel.

The coalescence of two different drops, one surfactant-laden and the other surfactant-free, was studied under the condition of confined flow in a microchannel. The coalescence was accompanied by penetration of the surfactant-free drop into the surfactant-laden drop because of the difference in the capillary pressure and Marangoni flows causing a film of surfactant-laden liquid to spread over the surfactant-free drop. The penetration rate was dependent on the drop order, with considerably better penetration observed for the case when the surfactant-laden drop goes first. The penetration rate was found to increase with an increase of interfacial tension difference between the two drops, an increase of flow rate and drop confinement in the channel (for the case of the surfactant-laden drop going first), an increase of viscosity of the continuous phase, and a decrease of viscosity of the dispersed phase. Analysis of flow patterns inside the coalescing drops has shown that, unlike coalescence of identical drops, only two vortices are formed by asymmetrical coalescence, centered inside the surfactant-free drop. The vortices were accelerated by the flow of the continuous phase if the surfactant-laden drop preceded the surfactant-free one, increasing the rate of penetration; the opposite was observed if the drop order was reversed. The mixing patterns on a longer time scale were also dependent on the drop order, with better mixing being observed for the case when the surfactant-laden drop goes first.

Effect of soluble surfactants on pinch-off of moderately viscous drops and satellite size.

HYPOTHESIS: Surfactant redistribution in a liquid bridge close to drop detachment depends on competition between the bridge deformation rate and surfactant equilibration rate. Surfactant effect can be different in situations when diffusion coefficient changes independently of thinning kinetics or in line with it. Using moderately viscous liquids should allow both situations to be explored experimentally. EXPERIMENTS: Formation of liquid drops at the tip of capillary is studied experimentally for silicone oils and for surfactant-laden and surfactant-free water/glycerol mixtures of moderate viscosity with particular attention to the kinetics of liquid bridge close to pinch-off and formation of satellite droplets. FINDINGS: Effect of surfactant depends on the dynamic regime of the bridge thinning. In the presence of surfactant, inertial kinetics slows down close to pinch-off demonstrating effective surface tension smaller than dynamic surface tension. An acceleration of thinning kinetics caused by depletion of surfactant from the liquid bridge was observed in viscous and visco-inertial regimes. The size of satellite droplets has a maximum versus viscosity; increasing with surfactant concentration at smaller viscosities and decreasing with an increase of surfactant concentration at largest studied viscosity, where inversion of the pinch-off point was observed for surfactant solutions.

Simulation of immiscible liquid-liquid flows in complex microchannel geometries using a front-tracking scheme.

The three-dimensional two-phase flow dynamics inside a microfluidic device of complex geometry is simulated using a parallel, hybrid front-tracking/level-set solver. The numerical framework employed circumvents numerous meshing issues normally associated with constructing complex geometries within typical computational fluid dynamics packages. The device considered in the present work is constructed via a module that defines solid objects by means of a static distance function. The construction combines primitive objects, such as a cylinder, a plane, and a torus, for instance, using simple geometrical operations. The numerical solutions predicted encompass dripping and jetting, and transitions in flow patterns are observed featuring the formation of drops, 'pancakes', plugs, and jets, over a wide range of flow rate ratios. We demonstrate the fact that vortex formation accompanies the development of certain flow patterns, and elucidate its role in their underlying mechanisms. Experimental visualisation with a high-speed imaging are also carried out. The numerical predictions are in excellent agreement with the experimental data.

Bulk advection and interfacial flows in the binary coalescence of surfactant-laden and surfactant-free drops.

This work focuses on the study of bulk flows accompanying the coalescence of two aqueous drops, one containing surfactant and the other surfactant-free, in silicone oils of various viscosities. It is observed that the surfactant-free drop intrudes into the surfactant-laden drop in the form of a penetrating jet whose speed increases and average radius decreases with increasing outer phase viscosity. Mixing patterns within the coalescing drops are due to the force imbalance caused by capillary pressure difference and surfactant-induced Marangoni stresses. The driving force for mixing associated with the difference in interfacial tension between the drops is considerably stronger than that related to the drop size. The long timescale mixing of the drops is driven by rapid interior convection, and the subsequent, slow, diffusive process. Three-dimensional numerical simulations show excellent qualitative and quantitative agreement with the experimental results. The implications of our results to formulation strategies of complex microstructures in practical applications are also discussed.

Rapid enzyme regeneration results in the striking catalytic longevity of an engineered, single species, biocatalytic biofilm.

BACKGROUND: Engineering of single-species biofilms for enzymatic generation of fine chemicals is attractive. We have recently demonstrated the utility of an engineered Escherichia coli biofilm as a platform for synthesis of 5-halotryptophan. E. coli PHL644, expressing a recombinant tryptophan synthase, was employed to generate a biofilm. Its rapid deposition, and instigation of biofilm formation, was enforced by employing a spin-down method. The biofilm presents a large three-dimensional surface area, excellent for biocatalysis. The catalytic longevity of the engineered biofilm is striking, and we had postulated that this was likely to largely result from protection conferred to recombinant enzymes by biofilm's extracellular matrix. SILAC (stable isotopic labelled amino acids in cell cultures), and in particular dynamic SILAC, in which pulses of different isotopically labelled amino acids are administered to cells over a time course, has been used to follow the fate of proteins. To explore within our spin coated biofilm, whether the recombinant enzyme's longevity might be in part due to its regeneration, we introduced pulses of isotopically labelled lysine and phenylalanine into medium overlaying the biofilm and followed their incorporation over the course of biofilm development. RESULTS: Through SILAC analysis, we reveal that constant and complete regeneration of recombinant enzymes occurs within spin coated biofilms. The striking catalytic longevity within the biofilm results from more than just simple protection of active enzyme by the biofilm and its associated extracellular matrix. The replenishment of recombinant enzyme is likely to contribute significantly to the catalytic longevity observed for the engineered biofilm system. CONCLUSIONS: Here we provide the first evidence of a recombinant enzyme's regeneration in an engineered biofilm. The recombinant enzyme was constantly replenished over time as evidenced by dynamic SILAC, which suggests that the engineered E. coli biofilms are highly metabolically active, having a not inconsiderable energetic demand. The constant renewal of recombinant enzyme highlights the attractive possibility of utilising this biofilm system as a dynamic platform into which enzymes of interest can be introduced in a "plug-and-play" fashion and potentially be controlled through promoter switching for production of a series of desired fine chemicals.

Dissolution profile of theophylline modified release tablets, using a biorelevant Dynamic Colon Model (DCM).

The human proximal colon has been considered a favourable site to deliver drugs for local and systemic treatments. However, modified dosage forms face a complex and dynamically changing colonic environment. Therefore, it has been realized that in addition to the use of biorelevant media, the hydrodynamics also need to be reproduced to create a powerful in vitro dissolution model to enable in vivo performance of the dosage forms to be predicted. A novel biorelevant Dynamic Colon Model (DCM) has been developed which provides a realistic environment in terms of the architecture of the smooth muscle, the physical pressures and the motility patterns occurring in the proximal human colon. Measurements of pressure inside the DCM tube confirmed a direct association between the magnitude of the pressure signal with the occlusion rate of the membrane and the viscosity of the fluid. The dissolution profile and the distribution of the highly soluble drug, theophylline, were assessed by collecting samples at different locations along the DCM tube. Differences in the release rates of the drug were observed which were affected by the sampling point location, the viscosity of the fluid and the mixing within the DCM tube. Images of the overall convective motion of the fluid inside the DCM tube obtained using Positron Emission Tomography enabled relation of the distribution of the tracer to likely areas of high and low concentrations of the theophylline drug. This information provides improved understanding of how extensive phenomena such as supersaturation and precipitation of the drug may be during the passage of the dosage form through the proximal colon.

Effect of Soluble Surfactants on the Kinetics of Thinning of Liquid Bridges during Drops Formation and on Size of Satellite Droplets.

The results of an experimental study on thinning and breakage of liquid bridges during detachment of a drop from the tip of a capillary are presented for a series of surfactant solutions (including cationic, anionic, and nonionic surfactants) over a broad range of molecular masses, values of critical micelle concentration, and concentrations. The used experimental protocol revealed that the kinetics of the bridge thinning depends much more on the dynamics of adsorption at the surface of the drop before it destabilizes, rather than on the depletion of surfactant from the surface of the thinning bridge due to its stretching as the instability develops. The kinetics of the bridge thinning and the size of satellite droplets formed after the bridge breakage depend considerably on the surfactant concentration and the value of critical micelle concentration. It is proposed that the dynamic surface tension on the time scale of the drop formation can be used as an effective surface tension for the description of the bridge kinetics over the broad range of experimental conditions used.