Journal of Investigative Dermatology - The Human Skin Barrier Is Organized as Stacked Bilayers of Fully Extended Ceramides with Cholesterol Molecules Associated with the Ceramide Sphingoid Moiety
The Human Skin Barrier Is Organized as Stacked Bilayers of Fully Extended
Ceramides with Cholesterol Molecules Associated with the Ceramide
Sphingoid Moiety
Ichiro Iwai ¡* Lars Norl¨¦n 2012 doi 10.1038/jid.2012.43
Journal of Investigative Dermatology
The skin barrier is fundamental to terrestrial life & its evolution.
It upholds homeostasis,- and protects against the environment.
Skin barrier capacity is controlled by lipids that fill the extracellular
space of the skin's surface layer-the stratum corneum.
Here, we report on the determination of the molecular organization of the
skin's lipid matrix in situ, in its near-native state, using a
methodological approach combining
- very high magnification cryo-electron microscopy (EM) of vitreous skin
section defocus series,
- molecular modeling &
- EM simulation.
The lipids are organized in an arrangement not previously described in a
biological system - stacked bi-layers of fully extended ceramides (CERs)
with cholesterol molecules associated with the CER sphingoid moiety.
This arrangement rationalizes the skin's low permeability toward water &
toward hydro- & lipo-philic substances, as well as the skin barrier's
robustness toward hydration & dehydration, environmental temperature &
pressure changes, stretching, compression, bending & shearing.
______
Strange fat explains skin's waterproof properties - health - 27 April 2012 - New Scientist
Strange fat explains skin's waterproof properties
Helen Thomson 27.4.12
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 & 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 Norl¨¦n cs shaved a layer of skin
from the forearm of 5 volunteers.
They put the tissue in a high pressure freezer that immediately cooled it
to below -140¡ãC.
Using this technique, every atom is preserved in its native location, says
Norl¨¦n.
They then sliced the tissue into layers just 25 to 50 nm thick, using a
cooled diamond knife, and examined the layers using an electron
microscope, itself cooled to -180¡ãC.
Elements of the freezing, tissue positioning & 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."
Hairpin turn
What the researchers saw surprised them.
Lipids have a hydrophilic (water-attracting) head & 2 hydrophobic
(water-repelling) tails.
Normally, the 2 tails point in the same direction, giving the molecule a
hairpin-like appearance.
A group of lipid molecules typically arrange themselves into a 2-layered
sheet (bi-layer)– 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 2 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."
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 extra-cellular space.
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 & directly into the blood supply, side-stepping side effects that are
caused when orally administered drugs are metabolised in the liver &
intestines.
Administering drugs through the skin would also allow doctors to target
specific areas & over a more controlled time period.
A further application would be the development of more realistic
artificial skin.
Robert Langer (MIT, previously experimented using US to increase the
skin's permeability to drugs):
"I think it's an excellent paper.
They have developed a new model for skin structure that should be very
helpful in trans-dermal drug delivery."
The Human Skin Barrier Is Organized as Stacked Bilayers of Fully Extended
Ceramides with Cholesterol Molecules Associated with the Ceramide
Sphingoid Moiety
Ichiro Iwai ¡* Lars Norl¨¦n 2012 doi 10.1038/jid.2012.43
Journal of Investigative Dermatology
The skin barrier is fundamental to terrestrial life & its evolution.
It upholds homeostasis,- and protects against the environment.
Skin barrier capacity is controlled by lipids that fill the extracellular
space of the skin's surface layer-the stratum corneum.
Here, we report on the determination of the molecular organization of the
skin's lipid matrix in situ, in its near-native state, using a
methodological approach combining
- very high magnification cryo-electron microscopy (EM) of vitreous skin
section defocus series,
- molecular modeling &
- EM simulation.
The lipids are organized in an arrangement not previously described in a
biological system - stacked bi-layers of fully extended ceramides (CERs)
with cholesterol molecules associated with the CER sphingoid moiety.
This arrangement rationalizes the skin's low permeability toward water &
toward hydro- & lipo-philic substances, as well as the skin barrier's
robustness toward hydration & dehydration, environmental temperature &
pressure changes, stretching, compression, bending & shearing.
______
Strange fat explains skin's waterproof properties - health - 27 April 2012 - New Scientist
Strange fat explains skin's waterproof properties
Helen Thomson 27.4.12
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 & 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 Norl¨¦n cs shaved a layer of skin
from the forearm of 5 volunteers.
They put the tissue in a high pressure freezer that immediately cooled it
to below -140¡ãC.
Using this technique, every atom is preserved in its native location, says
Norl¨¦n.
They then sliced the tissue into layers just 25 to 50 nm thick, using a
cooled diamond knife, and examined the layers using an electron
microscope, itself cooled to -180¡ãC.
Elements of the freezing, tissue positioning & 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."
Hairpin turn
What the researchers saw surprised them.
Lipids have a hydrophilic (water-attracting) head & 2 hydrophobic
(water-repelling) tails.
Normally, the 2 tails point in the same direction, giving the molecule a
hairpin-like appearance.
A group of lipid molecules typically arrange themselves into a 2-layered
sheet (bi-layer)– 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 2 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."
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 extra-cellular space.
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 & directly into the blood supply, side-stepping side effects that are
caused when orally administered drugs are metabolised in the liver &
intestines.
Administering drugs through the skin would also allow doctors to target
specific areas & over a more controlled time period.
A further application would be the development of more realistic
artificial skin.
Robert Langer (MIT, previously experimented using US to increase the
skin's permeability to drugs):
"I think it's an excellent paper.
They have developed a new model for skin structure that should be very
helpful in trans-dermal drug delivery."