Developing an in silico, spectroscopic imaging toolkit for assessing skin penetration

Why did we fund this project?

This award aims to replace rodents in skin penetration studies with an in silico model to be developed using data from in vitro stimulated Raman scattering spectroscopy.

Chemicals are assessed in regulatory studies to determine if there is potential for the chemical to be absorbed into the circulation through the skin. Topical drugs will also be assessed in similar studies to ensure successful delivery. In vivo skin penetration studies of topically applied compounds are typically performed in mice and rats. Skin to be tested is shaved and the compound applied for the relevant time period. The animals are then culled, and the skin excised for analysis. Current in vitro methods using excised human skin have a limited capability in predicting clinical pharmacokinetic results such as absorption rate and distribution. This creates a reliance on in vivo models for these types of studies. In silico models could bridge this gap and enable better extrapolation from in vitro to clinical data without the need for animal studies.

The student will work with Dr Tao Chen using stimulated Raman scattering spectroscopy to analyse treated ex vivo human skin samples. They will generate quantitative images, with submicron resolution, to measure compound distribution and the role of penetration pathways (intercellular, transcellular and follicular pathways) on compound absorption. The student will also develop skills in mathematical modelling, confocal microscopy and statistical experimental design.

This award was made jointly with Unilever.

Skin penetration underpins the design, efficacy and risk assessment of many high-value products including topical and transdermal drugs, functional personal care products, amongst others. Given the ethical concerns with animal tests, this area is moving towards ex vivo / in vitro studies using excised human skin samples. Nevertheless, current in vitro tests have limited capability in predicting in vivo results. To this end, in silico modelling has been recognised as a promising approach for in vitro – in vivo extrapolation. However, existing models have limited accuracy due to paucity of reliable and quantitative information concerning penetration pathways and penetrant distribution at the site of action in the skin. In addition, in vivo animal studies are still widespread in the pre-clinical stage of drug development. In silico models, if sufficiently accurate, have great promise to help optimise such experiments with potentially substantial reduction of animal use.

To address this challenge, we propose to apply advanced spectroscopic imaging, stimulated Raman scattering (SRS) microscopy, to in vitro assessment of skin penetration. SRS microscopy provides quantitative images with submicron spatial resolution. For the first time, direct measurement of penetration pathways and microscopic distribution of the chemical in the skin will be obtained, which we will use to improve existing in silico models. The integrated modelling-imaging toolkit will significantly improve the in vitro – in vivo extrapolation capability, delivering a more systematic approach for skin penetration assessment. Importantly, the toolkit will help better design and reduce in vivo animal experiments that cannot be completely replaced at present.