Model of drug delivery to populations composed of two cell types.

The rate of drug delivery to cells and the subsequent rate of drug metabolism are dependent on the cell membrane permeability to the drug. In some cases, tissue may be composed of different types of cells that exhibit order of magnitude differences in their membrane permeabilities. This paper presents a brief review of the components of the tissue scale three-compartment pharmacokinetic model of drug delivery to single-cell-type populations. The existing model is extended to consider tissue composed of two different cell types. A case study is presented of infusion mediated delivery of doxorubicin to a tumor that is composed of a drug reactive cell type and of a drug resistive cell type. The membrane permeabilities of the two cell types differ by an order of magnitude. A parametric investigation of the population composition is conducted and it is shown that the drug metabolism of the low permeability cells are negatively influenced by the fraction of the tissue composed of the permeable drug reactive cells. This is because when the population is composed mostly of drug permeable cells, the extracellular space is rapidly depleted of the drug. This has two compounding effects: (i) locally there is simply less drug available to the neighboring drug resistant cells, and (ii) the depletion of the drug from the extracellular space near the vessel-tissue interface leaves less drug to be transported to both cell types farther away from the vessel.

Theoretical model of the influence of irreversibly electroporated cells on post pulse drug delivery to reversibly electroporated cells.

This study numerically investigates the drug uptake by a population that includes both reversibly and irreversibly electroporated cells. A theoretical continuum model is developed and simulations are conducted in conditions representing low porosity (cells in tissues) and high porosity (cells in suspension). This model considers only passive diffusion following the electroporation pulse and estimates the permeability increases of reversibly electroporated cells using empirically based predictions that relate the long-lived electropore density to the electric field magnitude. A parametric study investigates whether the permeability and resealing rate of irreversibly electroporated cells influence the delivery to the surviving reversibly electroporated cells. The results show that this influence is negligible when the cell number density is low (cells in dilute suspensions). For conditions of cells in tissue when both the fraction of the total cells that are irreversibly electroporated and the permeability of the irreversibly electroporated cells are high enough, the irreversibly electroporated cells rapidly take up the drug and deplete the extracellular space of the available drug. This lowered extracellular concentration can result in less drug delivery to reversibly electroporated cells.

Communication Adjustment in Engineering Professional and Student Project Meetings.

BACKGROUND: communication is important for project teams. There is a need to better understand how members respond to communication at project meetings, and how this affects the team roles the participants adopt. METHODS: observational data were collected from (a) two engineering organisations and (b) five university engineering student teams. A mixed methods approach was used, comprising observations (recorded with the interaction diagram method), questionnaires and interviews. RESULTS: participants adjusted their communication style to the behaviour of other people and to different communication settings. This happened with three different dynamics: micro-level (grounding processes in conversation), mezzo-level (emotional and rational regulation) and macro-level (over a period of time). Originality: a new theory was presented for the process of team behaviour during project meetings; specifically, role adoption and communication behavioural changes. Participants change their team roles within three different dynamics: at the macro-, mezzo- and micro-levels, corresponding to the organisation, project and meeting, respectively. The changing of team roles in project meetings arises from rational and emotional regulation. The findings have the potential to assist managers and supervisors to better understand and manage the team dynamics on their projects.

Beamed UV sonoluminescence by aspherical air bubble collapse near liquid-metal microparticles.

Irradiation with UV-C band ultraviolet light is one of the most commonly used ways of disinfecting water contaminated by pathogens such as bacteria and viruses. Sonoluminescence, the emission of light from acoustically-induced collapse of air bubbles in water, is an efficient means of generating UV-C light. However, because a spherical bubble collapsing in the bulk of water creates isotropic radiation, the generated UV-C light fluence is insufficient for disinfection. Here we show, based on detailed theoretical modelling and rigorous simulations, that it should be possible to create a UV light beam from aspherical air bubble collapse near a gallium-based liquid-metal microparticle. The beam is perpendicular to the metal surface and is caused by the interaction of sonoluminescence light with UV plasmon modes of the metal. We estimate that such beams can generate fluences exceeding 10 mJ/cm2, which is sufficient to irreversibly inactivate most common pathogens in water with the turbidity of more than 5 Nephelometric Turbidity Units.

Circulation Cooling in Continuous Skin Sonoporation at Constant Coupling Fluid Temperatures.

Exposure of the skin to low-frequency ultrasound in the Franz diffusion cell has been found to increase the permeability of the skin to molecular transport. In many cases, significant heating of the coupling fluid requires the use of duty cycles that extend the total experimental time. This is a methodological study in which the coupling fluid is circulated between a modified Franz diffusion cell and a heat exchanger to allow for the continuous application of low-frequency ultrasound while the coupling fluid temperature is held constant. Dermatomed porcine skin was exposed to continuous ultrasound at 20 kHz for 10 min at an intensity of 55 W/cm2 while the coupling fluid was maintained at one of three target temperatures (13°C, 33°C or 46°C). Foil pitting and passive cavitation detection revealed that inertial cavitation activity decreased with increasing coupling fluid target temperature. Transport measurements revealed an increase in mean donor calcein concentration with increasing coupling fluid temperature, though these were not statistically significant. Taken together these findings suggest that the weakened stratum corneum lipid structure at higher temperatures is more susceptible to the introduction of defects from the jetting of cavitation.

A Thermoelectric Device for Coupling Fluid Temperature Regulation During Continuous Skin Sonoporation or Sonophoresis.

During skin sonoporation and sonophoresis, time-consuming duty cycles or fluid replacement is often required to mitigate coupling fluid temperature increases. This study demonstrates an alternative method for temperature regulation: a circulating, thermoelectric system. Porcine skin samples were sonoporated continuously for 10 min at one of three intensities (23.8, 34.2, 39.4 W/m2). A caffeine solution was then applied to the skin and left to diffuse for 20 h. During sonoporation, the system was able to maintain the temperature between 10 and 16°C regardless of the intensity. No increase in transdermal transport was achieved with an intensity of 23.8 W/m2. Intensities of 34.2 and 39.4 W/m2 resulted in 3.5-fold (p < 0.05) and 3.7-fold (p < 0.05) increases in mean transport, relative to a control case with no ultrasound. From these results, it is concluded that a significant transport increase can be achieved with a system that circulates and cools the coupling fluid during ultrasound application. Relative to the previous methods of temperature control (duty cycles and fluid replacement), use of this circulation system will lead to significant time savings in future experimental studies.

Influence of Acoustic Reflection on the Inertial Cavitation Dose in a Franz Diffusion Cell.

The exposure of the skin to low-frequency (20-100 kHz) ultrasound is a well-established method for increasing its permeability to drugs. The mechanism underlying this permeability increase has been found to be inertial cavitation within the coupling fluid. This study investigated the influence of acoustic reflections on the inertial cavitation dose during low-frequency (20 kHz) exposure in an in vitro skin sonoporation setup. This investigation was conducted using a passive cavitation detector that monitored the broadband noise emission within a modified Franz diffusion cell. Two versions of this diffusion cell were employed. One version had acoustic conditions that were similar to those of a standard Franz diffusion cell surrounded by air, whereas the second was designed to greatly reduce the acoustic reflection by submerging the diffusion cell in a water bath. The temperature of the coupling fluid in both setups was controlled using a novel thermoelectric cooling system. At an ultrasound intensity of 13.6 W/cm2, the median inertial cavitation dose when the acoustic reflections were suppressed, was found to be only about 15% lower than when reflections were not suppressed.

Macroscopic Modeling of In Vivo Drug Transport in Electroporated Tissue.

This study develops a macroscopic model of mass transport in electroporated biological tissue in order to predict the cellular drug uptake. The change in the macroscopic mass transport coefficient is related to the increase in electrical conductivity resulting from the applied electric field. Additionally, the model considers the influences of both irreversible electroporation (IRE) and the transient resealing of the cell membrane associated with reversible electroporation. Two case studies are conducted to illustrate the applicability of this model by comparing transport associated with two electrode arrangements: side-by-side arrangement and the clamp arrangement. The results show increased drug transmission to viable cells is possible using the clamp arrangement due to the more uniform electric field.

Experimental Factors to Be Considered in Electroporation-Mediated Transdermal Diffusion Experiments.

In this paper, we discuss some of the primary experimental factors that should be considered when interpreting and implementing the published results of skin electroporation studies concerning measurements of mass transport across the stratum corneum (SC) in the Franz cell. It is explained that the pulse magnitude should always be considered in the context of pulse shape and that transport measurements should always be presented in the context of the trans-SC potential difference (instead of the voltage between the electrodes). The condition of the SC prior to the application of the long-duration pulse strongly influences the evolution of the local transport region (LTR). This is quantified in a simple analytical investigation of the conditions that affect the thermodynamic response of the skin.

Transdermal transport pathway creation: Electroporation pulse order.

In this study we consider the physics underlying electroporation which is administered to skin in order to radically increase transdermal drug delivery. The method involves the application of intense electric fields to alter the structure of the impermeable outer layer, the stratum corneum. A generally held view in the field of skin electroporation is that the skin's drop in resistance (to transport) is proportional to the total power of the pulses (which may be inferred by the number of pulses administered). Contrary to this belief, experiments conducted in this study show that the application of high voltage pulses prior to the application of low voltage pulses result in lower transport than when low voltage pulses alone are applied (when less total pulse power is administered). In order to reconcile these unexpected experimental results, a computational model is used to conduct an analysis which shows that the high density distribution of very small aqueous pathways through the stratum corneum associated with high voltage pulses is detrimental to the evolution of larger pathways that are associated with low voltage pulses.

Skin electroporation for transdermal drug delivery: the influence of the order of different square wave electric pulses.

Electroporation can be used as an active enhancement method for intra- and transdermal drug delivery. Differences in response of skin to electric pulses depend on their amplitude, duration and number and have been a point of interest in the past. While protocols consisting of the same repetitive, mostly exponentially decaying pulses have been used before, this study is focused on comparing different combinations of square wave short high voltage (HV) and longer low voltage (LV) electroporation pulses. Our in vitro experimental results show that longer LV pulses significantly increase subsequent passive transport of calcein through dermatomed pig skin, while short HV pulses alone result in negligible calcein passive transdermal transport. Surprisingly, when the long LV pulses are preceded by short duration HV pulses, the total calcein transported is reduced significantly. This result is explained using a theoretical physics based model of individual local transport region (LTR) evolution during the applied LV pulse. The theoretical model shows that HV pulses alter the structure of the stratum corneum in such a way that when the LV pulses are applied, insufficient thermal energy is generated to initiate LTR expansion. Together, the experimental results and theoretical predictions show that the total pulse energy alone cannot account for total solute transport: that the order of the types of pulses administered must also be considered. Our findings open a direction for further improvement of the method using new protocols.