Tactile friction of topical creams and emulsions: Friction measurements on excised skin and VitroSkin® using ForceBoard™.

Tactile perception can be investigated through ex vivo friction measurements using a so-called ForceBoard™, providing objective assessments and savings in time and money, compared to a subjective human panel. In this work we aim to compare excised skin versus VitroSkin® as model substrates for tactile friction measurements. A further aim is to detect possible differences between traditional surfactant-based creams, and a particle-stabilized (Pickering) cream and investigate how the different substrates affect the results obtained. It was found that the difference in tactile friction between excised skin and VitroSkin® was small on untreated substrates. When topical creams were applied, the same trends were observed for both substrates, although the frictional variation over time relates to the difference in surface structure between the two substrates. The results also confirmed that there is a difference between starch-based Pickering formulations and surfactant-based creams after application, indicating that the latter is greasier than Pickering cream. It was also shown that the tactile friction of Pickering emulsions was consistently high even with high amounts of oil, indicating a non-greasy, and non-sticky formulation. The characteristics of starch-stabilized Pickering formulations make them promising candidates in the development of surfactant-free topical formulations with unique tactile properties.

Patch test-relevant concentrations of metal salts cause localized cytotoxicity, including apoptosis, in skin ex vivo.

BACKGROUND: Metal alloys containing contact sensitizers (nickel, palladium, titanium) are extensively used in medical devices, in particular dentistry and orthopaedic surgery. The skin patch test is used to test for metal allergy. OBJECTIVE: To determine whether metal salts, when applied to freshly excised skin at patch test-relevant concentrations and using a method which mimics skin patch testing, cause in changes in the epidermis and dermis. METHODS: Tissue histology, apoptosis, metabolic activity, and inflammatory cytokine release were determined for two nickel salts, two palladium salts, and four titanium salts. RESULTS: Patch test-relevant concentrations of all metal salts caused localized cytotoxicity. This was observed as epidermis separation at the basement membrane zone, formation of vacuoles, apoptotic nuclei, decreased metabolic activity, and (pro)inflammatory cytokine release. Nickel(II) sulfate hexahydrate, nickel(II) chloride hexahydrate, titanium(IV) bis(ammonium lactato)dihydroxide, and calcium titanate were highly cytotoxic. Palladium(II) chloride, sodium tetrachloropalladate(II), titanium(IV) isopropoxide, and titanium(IV) dioxide showed mild cytotoxicity. CONCLUSION: The patch test in itself may be damaging to the skin of the patient being tested. These results need further verification with biopsies obtained during clinical patch testing. The future challenge is to remain above the elicitation threshold at noncytotoxic metal concentrations.

What is the fate of multi-lamellar liposomes of controlled size, charge and elasticity in artificial and animal skin?

Multi-lamellar liposomes (MLLs), prepared by shearing a lamellar phase composed of lipids (phosphatidylcholine) and surfactant (Tween 80®), were designed to control their size, charge and elasticity, the key parameters known to influence liposomes penetration through skin. Their size was tuned by the water content of the sheared lamellar phase, and by the surfactant-to-lipid ratio as was their elasticity. Their charge was varied by the incorporation of DPPG and DOTAP to confer a high negative or positive zeta potential, respectively. Couples of MLLs differing solely in one physicochemical parameter, the others kept constant, were compared to discriminate the influence of the key parameters on their penetration through a synthetic membrane, Strat-M™. Using confocal Raman microscopy, the kinetics of MLLs penetration was established for 40 h using a Franz cell dispositive under non-occlusive conditions. From these comparisons, we showed that their transversal diffusion cannot be predicted by one sole parameter but depends on a combination of their physicochemical characteristics that were enlightened. Two types of liposomes designed for topic and systemic diffusion and tested on dog-excised skin exhibited the predicted behavior. Eventually, a mechanism supported by complementary TEM analysis is proposed to shed light on MLLs skin penetration.

Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels.

Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.

Drug delivery across intact and disrupted skin barrier: Identification of cell populations interacting with penetrated thermoresponsive nanogels.

Nanoscaled soft particles, such as nanogels, can be designed to incorporate different types of compounds and release them in a controlled and triggered manner. Thermoresponsive nanogels (tNG), releasing their cargo above a defined temperature, are promising carrier systems for inflammatory skin diseases, where the temperature of diseased skin differs from that of healthy skin areas. In this study a polyglycerol-based tNG with diameter of 156nm was investigated for penetration and release properties upon topical application on ex vivo human skin with intact or disrupted barrier. Furthermore, temperature-triggered effects and the internalization of tNG by skin cells upon translocation to the viable skin layers were analyzed. The investigated tNG were tagged with indodicarbocyanine and loaded with fluorescein, so that fluorescent microscopy and flow cytometry could be used to evaluate simultaneously particle penetration and release of the fluorochrome. Topically applied tNG penetrated into the SC of both intact and disrupted skin explants. Only in barrier-disrupted skin significant amounts of released fluorochrome and tNG penetrated in the epidermis and dermis 2h after topical application. When a thermal trigger was applied by infrared radiation (30s, 3.9mJ/cm2), a significantly higher penetration of tNG in the SC and release of the dye in the epidermis were detected with respect to non-triggered samples. Penetrated tNG particles were internalized by skin cells in both epidermis and dermis. Only few CD1a-positive Langerhans cells associated with tNG were found in the epidermis. However, in the dermis a significant percentage of cells associated with tNG were identified to be antigen presenting cells, i.e. HLA-DR+and CD206+cells. Thus, tNG represent promising carrier systems for the treatment of inflammatory skin diseases, not only because of their improved penetration and controlled release properties, but also because of their ability to effectively reach dermal dendritic cells in barrier-disrupted skin.