Insoluble nano- and submicron-scale metal dioxides are widely used in pharmaceutical and cosmetic formulations designed for being applied on the skin surface and acting mainly as thickeners, sunscreens and pigments. Since it’s primarily for the insoluble nanoparticles that health concerns related to possible skin uptake arise, the EU requires producers to submit a detailed safety report on the nanomaterials used as well as declaring their presence on the label. As noted in the 2007 FDA Nanotechnology Task Force report, there may be a higher degree of uncertainty associated with nanoscale materials compared to conventional chemicals, both with respect to knowledge about them and the way that testing is performed. Indeed, the issue of insoluble nanoparticle skin penetration, mainly focusing on nanosized TiO2 and ZnO, is still controversial, divided between a penetration limited to the hair follicles and the translocation across the lipid pathway within SC cells sometimes reaching living skin cells. Among the metal dioxide materials, colloidal silicon dioxide, a submicroscopic amorphous hydrophilic silica is one of the most used in terms of commercial production amounts together with TiO2, ZnO and silver nanoparticles. With regard to topical formulations, it is used to stabilize emulsions and as a thixotropic thickening or suspending agent in gels, microemulsions, and semisolid preparations. Although amorphous silica is generally regarded as an essentially nontoxic and non-irritant excipient  also proposed for implants, the nano-scale feature might alter the bioavailability of the cosmetic formulation . Actually, silica nanoparticles have been shown in vitro to modulate the diffusion through animal skin of hydrophilic and hydrophobic model drugs (caffeine, retinol, quercetin) from topical emulsions to affect skin properties and also to penetrate up to the viable epidermis and upper dermis of excised porcine skin [3, 4]. Previously, we demonstrated on human beings that colloidal silica is able to penetrate in the upper region of the human stratum corneum (SC) and different mechanisms of translocation were hypothesized . A similar finding arose from a research on ultra-fine TiO2 . Therefore, the goal of the present work was to investigate in vivo the mechanism of silica entry into SC by means of qualitative and quantitative assays performed on stripped tapes removed from volunteers treated with silica incorporated in a standard cream. With this objective, the study took into account the influence of human hair follicle density by means of sample application on both volar and dorsal forearm. Moreover, by considering that skin surface is hydrophobic and skin penetration requires particle wetting by the SC lipids, the effect of silica surface hydrophobization was also investigated. Twelve repetitive tape strips removed from each forearm of the volunteers following sample application were evaluated by EDX analysis by points. All the tapes removed from the skin that has received silica and H-silica application showed nanosized and nearly spherical structures generally located in rather broad intercellular spaces. Their EDX spectra exhibited the characteristic peaks owing to X-ray emission from Si atoms (Fig. n. 1). The relative weight percentages of the metal and the metal to oxygen weight ratio were found to be equivalent to those detected in the samples before their application. These findings could give evidence of a movement of both the nanoparticles across the outermost part of SC reaching the corneum compactum along broad channels between the corneocytes. Silicon quantitative analysis carried out on the removed tapes indicated silica accumulation in the outer part of SC corresponding to the corneum disjunctum and its significant decrease inside the deepest tapes, regardless of the sample and the hair follicle density. Nevertheless, the higher silica level detected in the corneum disjunctum was achieved following H-silica application suggesting the penetration enhancement role of silica surface hydrophobization
In vivo silica nanoparticle translocation across human stratum corneum: the effect of surface hydrophobization in relation to hair follicle density / Iannuccelli, Valentina; Bertelli, Davide; Romagnoli, Marcello; Maretti, Eleonora; Sacchetti, Francesca; Leo, Eliana Grazia. - STAMPA. - 1:(2013), pp. 134-135. (Intervento presentato al convegno NanotechItaly 2013 - Workshop on "Innovative Medicine: the contribution of the Italian Nanopharmaceutical Network" tenutosi a Venice nel 27 November 2014).