For something so fundamental, it’s taken us a long time to work out how our waterproofing works (Image: Robb Kendrick/Aurora/Getty Images)

Considering we know it like the back of our hands, we understand surprisingly little about how skin forms the watertight barrier that protects our body from the environment. Now, for the first time, the basic molecular structure of the skin layer that forms this barrier has been identified. The discovery could pave the way for new technology to deliver drugs directly through the skin in order to reduce side effects.

The structure and function of the skin barrier has long intrigued researchers. The barrier is known to lie in the outermost layer of skin – the stratum corneum – and more specifically in the fat that occupies the space between cells within this layer.

To get a clearer view of the fat, Lars Norlén at the Karolinska Institute in Stockholm, Sweden, and colleagues shaved a layer of skin from the forearm of five volunteers. They put the tissue in a high pressure freezer that immediately cooled it to below -140 °C. Using this technique, every atom is preserved in its native location, says Norlén.


They then sliced the tissue into layers just 25 to 50 nanometres thick using a cooled diamond knife and examined the layers using an electron microscope, itself cooled to -180 °C. Elements of the freezing, tissue positioning and slicing process are difficult to perfect and can take a lot of practice to get right. “It takes months to get a single slice that thin but it gives you unprecedented resolution,” Norlén says.

Hairpin turn

What the researchers saw surprised them. Lipids have a hydrophilic (water-attracting) head and two hydrophobic (water-repelling) tails. Normally, the two tails point in the same direction, giving the molecule a hairpin-like appearance.

A group of lipid molecules typically arrange themselves into a two-layered sheet – or bilayer – with all of the tails pointing inwards. However, the lipid molecules in between the cells of the stratum corneum are splayed outwards so that the two tails of each molecule point in opposite directions.

These lipid molecules are stacked on top of one another in an alternating fashion. “By stretching out like this they form a more condensed structure which is much more impermeable than a normal bilayer,” says Norlén.

Completely robust

This uniquely structured fatty layer prevents any water from getting past in either direction – except where the skin layer is modified to form pores. “There’s no water present within this extracellular space,” says Norlén. “It cannot perturb the barrier so it’s completely robust to hydration, which is necessary for the changing environment that we live in.”

The team now intend to construct a computer model of the skin to help them screen drugs that could potentially open this seemingly impermeable barrier. They hope this will enable widespread administration of drugs through the skin and directly into the blood supply, sidestepping side effects that are caused when orally administered drugs are metabolised in the liver and intestines.

Administering drugs through the skin would also allow doctors to target specific areas and over a more controlled time period. A further application would be the development of more realistic artificial skin.

“I think it’s an excellent paper. They have developed a new model for skin structure that should be very helpful in transdermal drug delivery,” says Robert Langer at the Massachusetts Institute of Technology, who has previously experimented using ultrasound to increase the skin’s permeability to drugs.

Journal reference: Journal of Investigative Dermatology, DOI: 10.1038/jid.2012.43