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The topmost layer of the skin, the stratum corneum[1], comprises rigid non-viable corneocyte cells embedded in relatively rigid lipid multilayers. It is believed to provide the main barrier against passive permeation. There are three different routes for molecules to cross the stratum corneum: intercellular (via lipid phase only), transcellular (via both lipids and corneocytes) and appendageal (via sweat glands or hair follicles)[2]. Further down into the skin are the tight junction proteins (discovered recently) that are thought to play an important role in preventing large molecules entering the bloodstream and hence limiting possibility of sensitisation. The continuous lipid phase is considered to be the most important one for the barrier properties and both intercellular and transcellular permeation routes involve passing through the lipid phase. Even though the sweat glands and hair follicles occupy only 0.1% of the total surface area of human skin[2], the appendageal route may be an important delivery pathway for slowly diffusing compounds and high molecular weight substances, such as nanoparticles encapsulating drug molecules.

A variety of approaches have been proposed to reversibly breach this barrier. The most significant one is the ‘passive’ approach involving the use of chemical penetration enhancers [2]. The active approaches include iontophoresis (use of an electrical potential to enhance penetration), electroporation (application of short, high voltage pulses to induce temporary micropores in the skin tissue), sonophoresis (use of low-level ultrasound), and the use of microneedles [2]. Many of these are effective for specific applications. Whilst there are plentiful empirical data and data-driven model e.g. (Potts and Guy model [3]), our molecular level understanding of the skin structure and the effects of the chemical, mechanical, and electrical perturbations is rudimentary.

Various computational approaches have been employed for modelling transdermal permeation. Early modelling studies reported on quantitative structure property relationships [3].Traditionally finite element models and compartment models [4] have been also used to model skin permeation with varying degree of success. Over the last decade atomistic molecular dynamics simulations have been used to probe at the phase behaviour [5], stability [5-8], mechanical [5] and permeation [6-10] properties of the Stratum Corneum lipids – mainly when the lipids are in a hydrated bilayer structure. Atomistic simulations also give insights into understanding of the role of different lipid components [5,10], lipid mobility [10,11] and the possible arrangements of the intercellular lipid matrix[10,12]. Recently, the structure and interactions between intermediate filaments of keratins, the major skin proteins, has also been addressed by use of SCF coarse-grained approach [13] and atomistic molecular dynamic simulations [14]. Although in-silico models are widely used but none of the available models are accepted from the regulatory point of view. A main challenge is that many models are limited to confined conditions and not fully predictive. Recently, multi-scale modelling has been developed, with which the transport modelling of chemicals in various phase of skin lipid, coenocytes, dermis, and systemic circulation as well as appendages is integrated with sub-cellular and molecular modelling [15].

There is considerable interest in the skin, in maintaining its wellbeing, provision of therapy when it is diseased, and as a route for the delivery of active molecules into the body. A fundamental issue is how do molecules permeate across the skin? A better understanding of this will have immense socio-economic impact in the personal care and cosmetics sector, diagnostics and health, and pharmaceuticals. It will lead to strategies for developing safe formulations that neither irritate nor sensitise, non-invasive technology for monitoring biological markers (e.g. plasma sugar levels as in diabetes), and optimum transdermal drug delivery.

A policy challenge for research in this area is need to develop advanced non-animal methods. An EU Cosmetics Directive has banned testing of cosmetic products on animals and there is a need to reduce, refine, and replace animal tests. Computational modelling at a molecular resolution (atomistic simulation) represents a powerful alternative, with potential to deliver molecular level insights and in instances predictive capability.

The workshop will be led by the molecular simulation community and will bring together an inter-disciplinary group of researchers including theoreticians, modellers and experimentalists from diverse backgrounds (soft matter theory and experiment, atomistic simulation, finite-element modelling, dermatologists and medical practitioners, and cosmetic and pharmaceutical industries). The workshop will take stock of our current understanding, and currently unresolved or controversial findings, and develop a longer-term strategic research plan to enhance our molecular level understanding of the structure of skin and how it may be modulated using an inter-disciplinary approach with molecular simulations at the heart of the endeavour.

We will strive for a healthy balance across established researchers/professionals and young researchers (PhD students and postdocs). A key goal of this event is to open interdisciplinary communication channels across three communities: computer modelling, experimental and professional/medical experts.

Specific topics to be discussed during the workshop:

1. What finite-element and compartmental modelling and molecular simulation community can learn from each other’s expertise?

2. Role of defects: 3-d arrangements of multilayers around corneocytes necessarily accommodate defect structures. Significance of defects in physiology and disease states? Why do skin lipids form rigid membranes which are prone to defects? Are the permeation and mechanical properties of skin lipids predominantly determined by these defects? How do we incorporate defects in modelling?

3. Role of sweat glands and hair follicles: these structures may allow access to the innermost depths of the Stratum Corneum. What role do they play in permeation? Are the structures of the lining of these glands known? What is the nature of molecular pathway that a permeating molecule faces in these structures? Can they be modelled?

4. What are the pertinent questions that simulations can address and are of interest to the industry?

5. What are the main disagreements among researchers? What are the key experiments/calculations/simulations necessary to resolve the issues?

6. How might an understanding of the mechanism of action of penetration enhancers help the future medical or personal care product development?

7. Is it possible to conduct multi-disciplinary, multi-scale research on skin permeation via the following route:
understanding of molecular interactions => tissue properties => experimental validation => clinical trials?

8. Can molecular simulations help in understanding the reasons for common skin disorders (like eczema)?

9. How to validate in-silico model at high spatial and temporal resolution, e.g. sub-cellular molecular imaging?