In Silico Study on the Contribution of the Follicular Route to Dermal Permeability of Small Molecules.

PURPOSE: This study investigates in silico the contribution of the hair follicle to the overall dermal permeability of small molecules, as published experimental work provides inconclusive information on whether the follicular route favours the permeation of hydrophobic or hydrophilic permeants. METHOD: A study is conducted varying physico-chemical parameters of permeants such as lipophilicity, molecular weight and protein binding. The simulated data is compared to published experimental data to discuss how those properties can modulate the contribution of the hair follicle to the overall dermal permeation. RESULTS: The results indicate that the contribution of the follicular route to dermal permeation can range from negligible to notable depending on the combination of lipophilic/hydrophilic properties of the substance filling the follicular route and the permeant. CONCLUSION: Characterisation of the substance filling the follicular route is required for analysing the experimental data of dermal permeation of small molecules, as changes between in vivo and in vitro due to handling of samples and cessation of vital functions can modify the contribution of the follicular route to overall dermal permeation, hence hindering data interpretation.

In-Silico Modelling of Transdermal Delivery of Macromolecule Drugs Assisted by a Skin Stretching Hypobaric Device.

OBJECTIVES: To develop a simulation model to explore the interplay between mechanical stretch and diffusion of large molecules into the skin under locally applied hypobaric pressure, a novel penetration enhancement method. METHODS: Finite element method was used to model the skin mechanical deformation and molecular diffusion processes, with validation against in-vitro transdermal permeation experiments. Simulations and experimental data were used together to investigate the transdermal permeation of large molecules under local hypobaric pressure. RESULTS: Mechanical simulations resulted in skin stretching and thinning (20%-26% hair follicle diameter increase, and 21%-27% skin thickness reduction). Concentration of dextrans in the stratum corneum was below detection limit with and without hypobaric pressure. Concentrations in viable epidermis and dermis were not affected by hypobaric pressure (approximately 2 µg [Formula: see text] cm-2). Permeation into the receptor fluid was substantially enhanced from below the detection limit at atmospheric pressure to up to 6 µg [Formula: see text] cm-2 under hypobaric pressure. The in-silico simulations compared satisfactorily with the experimental results at atmospheric conditions. Under hypobaric pressure, satisfactory comparison was attained when the diffusion coefficients of dextrans in the skin layers were increased from [Formula: see text] 10 µm2 [Formula: see text] s-1 to between 200-500 µm2 [Formula: see text] s-1. CONCLUSIONS: Application of hypobaric pressure induces skin mechanical stretching and enlarges the hair follicle. This enlargement alone cannot satisfactorily explain the increased transdermal permeation into the receptor fluid under hypobaric pressure. The results from the in-silico simulations suggest that the application of hypobaric pressure increases diffusion in the skin, which leads to improved overall transdermal permeation.

Needleless administration of advanced therapies into the skin via the appendages using a hypobaric patch.

Advanced therapies are commonly administered via injection even when they act within the skin tissue, and this increases the chances of off-target effects. Here we report the use of a skin patch containing a hypobaric chamber that induces skin dome formation to enable needleless delivery of advanced therapies directly into porcine, rat, and mouse skin. Finite element method modeling showed that the hypobaric chamber in the patch opened the skin appendages by 32%, thinned the skin, and compressed the appendage wall epithelia. These changes allowed direct delivery of an H1N1 vaccine antigen and a diclofenac nanotherapeutic into the skin. Fluorescence imaging and infrared mapping of the skin showed needleless delivery via the appendages. The in vivo utility of the patch was demonstrated by a superior immunoglobulin G response to the vaccine antigen in mice compared to intramuscular injection and a 70% reduction in rat paw swelling in vivo over 5 h with diclofenac without skin histology changes.

Biogas upgrading to biomethane as a local source of renewable energy to power light marine transport: Profitability analysis for the county of Cornwall.

In this work, the use of biomethane produced from local biogas plants is proposed as renewable fuel for light marine transport. A profitability analysis is performed for three real biogas production plants located in Cornwall (United Kingdom), considering a total of 66 different scenarios where critical parameters such as distance from production point to gas grid, subsidies, etcetera, were evaluated. Even though the idea is promising to decarbonize the marine transport sector, under the current conditions, the approach is not profitable. The results show that profitability depends on the size of the biogas plant. The largest biogas plant studied can be profitable if feed-in tariffs subsidies between 36.6 and 45.7 €/MWh are reached, while for the smallest plant, subsidies should range between 65 and 82.7 €/MWh. The tax to be paid per ton of CO2 emitted by the shipping owner, was also examined given its impact in this green route profitability. Values seven times greater than current taxes are needed to reach profitability, revealing the lack of competitiveness of renewable fuels vs traditional fuels in this application. Subsidies to make up a percentage of the investment are also proposed, revealing that even at 100% of investment subsidized, this green approach is still not profitable. The results highlight the need for further ambitious political actions in the pursuit of sustainable societies.

Numerical analysis of the strain distribution in skin domes formed upon the application of hypobaric pressure.

BACKGROUND: Suction cups are widely used in applications such as in measurement of mechanical properties of skin in vivo, in drug delivery devices or in acupuncture treatment. Understanding mechanical response of skin under hypobaric pressure is of great importance for users of suction cups. The aim of this work is to predict the hypobaric pressure induced 3D stretching of the skin. METHODS: Experimental skin tensile tests were carried out for mechanical property characterization. Both linear elasticity and hyperelasticity parameters were determined and implemented in Finite Element modelling. Skin suction tests were performed in both experiments and FEM simulations for model validation. 3D skin stretching is then visualized in detail in FEM simulations. RESULTS: The simulations showed that the skin was compressed consistently along the thickness direction, leading to reduced thickness. At the center of the dome, the radial and angular strain decreases from the top surface to the bottom surface, although always in tension. Hyperelasticity modelling showed superiority over linear elasticity modelling while predicting the strain distribution because the stretch ratio reaches values exceeding the initial linear elastic stage of the stress-strain curve for skin. CONCLUSION: Hyperelasticity modelling is an effective approach to predict the 3D strain distribution, which paves a way to accurately design safe commercial products that interface with the skin.