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Standard methods in dermal penetration research are tape stripping of the stratum corneum and static Franz-diffusion cells on excised skin. Both methods do not visualize penetration pathways and both techniques can over- and underestimate actual penetration.
It is unclear to what extent these techniques can be applied to the study of dermal penetration of nanoparticles, e.g. TiO2 with dimensions in the range of 20 nm, which is widely used in sunscreens with physical UV-filters. On the contrary, high-resolution transmission electron microscopy (HRTEM) on ultra thin skin crosssections visualizes individual nanoparticles but suffers from a very limited field of view.
There are several preparation steps involved in preparing ultra thin skin cross-sections with the possibility of preparation artefacts. Thus, there are controversial reports on HRTEM studies of dermal penetration of nanoparticles and novel microscopic techniques are required in order to clarify the situation. A relatively new and promising application is confocal laser scanning microscopy, which, however, requires a fluorescent label with the associated problem of the stability of the label.
The NANODERM used complementary techniques like HRTEM, ion beam analysis (PIXE, RBS, STIM), in order to visualize putative pathways of nanoparticles in skin cross-sections.
The advantage of these techniques is that very few sample preparation steps are required and thus the risk for preparation artefacts is reduced. A further advantage is that preparation artefacts, should they occur, can be easily identified, contrary to HRTEM. Moreover, larger samples can be analyzed in order to get an overview over large areas; subsequently one can zoom into a region of interest. A disadvantage is that individual nanoparticles cannot be visualized and the measurements are time consuming.
A third technique was applied which has not been used thus far for dermal penetration studies: autoradiography using skin cross-sections and nuclear microemulsions. For these studies we used TiO2 and the radiolabel 48-V. This method has extreme sensitivity.
Several formulations, skin types, pre-treatments of skin, and exposure times were applied.
Biopsies from porcine skin and healthy human skin from volunteers, as well as from human foreskin transplanted to SCID-mice were studied. In addition, healthy human skin explants from surgery was used for autoradiography. Biopsies from patients suffering from psoriasis were included in the study.
In all but a few cases Ti was detected on top of the stratum corneum and in the topmost layers of the stratum corneum disjunctum for healthy skin. Frequently the nanoparticles were aggregated. In most cases Ti-spots in vital tissue could be identified as preparation artefacts. In none of the roughly 500 images a coherent pathway of nanoparticles was observed, let alone a concentration profile characteristic of diffusive transport. Hence, we conclude that the TiO2 nanoparticles are penetrated into the topmost 3-5 corneocyte layers by mechanical action and no diffusive transport takes place. Thus, penetration studies with static Franz-diffusion cells do not seem adequate for nanoparticles. Clearance is expected to proceed via desquamation.
There is deep penetration into hair follicles, but not into vital tissue. Clearance is expected to proceed via sebum excretion.
No new species were detected by static Secondary Ion Mass Spectrometry (SSIMS) and Laser Modulated Mass Spectrometry (LMMS) due to the interaction of the formulations with coated TiO2 nanoparticles without and with UV-light. The interaction of cells with TiO2 nanoparticles both coated and uncoated was studied both in-vitro and in-vivo by immuno-histochemical methods and Atomic Force Microscopy.
The cellular response to TiO2 nanoparticles was found to depend on the cell type; various endpoints were examined. The elasticity of cells was affected by uncoated TiO2 nanoparticles and UV-light. Radical scavengers suppressed the change in elasticity.
The relevance of these observations on the cellular level is still an open question because the exposure is rather low, if it exists at all. Nevertheless, we conclude that for the sake of safety, direct contact of skin cells with TiO2 nanoparticles should better be avoided, e.g. application of sunscreens into open wounds is not recommended.
The situation with psoriatic skin is less clear. Instead of a stratum corneum of about 10 - 15 µm thickness, psoriatic skin has a stratum corneum of about 100 µm thickness with corneocytes and vital keratinocytes intermingled. Here, there is no real barrier and TiO2 nanoparticles can come into direct contact with vital cells. However, we have no evidence that the TiO2 nanoparticles become systemic.
Summing up, we do not expect any health effects for the topical application of sunscreens containing TiO2 nanoparticles (especially when coated) on healthy skin, which are related to the particulate state.
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