Using
ultrasound waves, MIT engineers have found a way to enhance the
permeability of skin to drugs, making transdermal drug delivery more
efficient. This technology could pave the way for noninvasive drug
delivery or needle-free vaccinations, according to the researchers.
“This
could be used for topical drugs such as steroids—cortisol, for
example—systemic drugs and proteins such as insulin, as well as antigens
for vaccination, among many other things,” says Carl Schoellhammer, an
MIT graduate student in chemical engineering and one of the lead authors
of a recent paper on the new system.
Ultrasound—sound
waves with frequencies greater than the upper limit of human
hearing—can increase skin permeability by lightly wearing away the top
layer of the skin, an effect that is transient and pain-free.
In a paper appearing in the Journal of Controlled Release,
the research team found that applying two separate beams of ultrasound
waves—one of low frequency and one of high frequency—can uniformly boost
permeability across a region of skin more rapidly than using a single
beam of ultrasound waves.
Senior
authors of the paper are Daniel Blankschtein, the Herman P. Meissner
’29 Professor of Chemical Engineering at MIT, and Robert Langer, the
David H. Koch Institute Professor at MIT. Other authors include Baris
Polat, one of the lead authors and a former doctoral student in the
Blankschtein and Langer groups, and Douglas Hart, a professor of
mechanical engineering at MIT.
Two frequencies are better than one
When
ultrasound waves travel through a fluid, they create tiny bubbles that
move chaotically. Once the bubbles reach a certain size, they become
unstable and implode. Surrounding fluid rushes into the empty space,
generating high-speed “microjets” of fluid that create microscopic
abrasions on the skin. In this case, the fluid could be water or a
liquid containing the drug to be delivered.
In
recent years, researchers working to enhance transdermal drug delivery
have focused on low-frequency ultrasound, because the high-frequency
waves don’t have enough energy to make the bubbles pop. However, those
systems usually produce abrasions in scattered, random spots across the
treated area.
In
the new study, the MIT team found that combining high and low
frequencies offers better results. The high-frequency ultrasound waves
generate additional bubbles, which are popped by the low-frequency
waves. The high-frequency ultrasound waves also limit the lateral
movement of the bubbles, keeping them contained in the desired treatment
area and creating more uniform abrasion, Schoellhammer says.
“It’s
a very innovative way to improve the technology, increasing the amount
of drug that can be delivered through the skin and expanding the types
of drugs that could be delivered this way,” says Samir Mitragotri, a
professor of chemical engineering at the University of California at
Santa Barbara, who was not part of the research team.
The
researchers tested their new approach using pig skin and found that it
boosted permeability much more than a single-frequency system. First,
they delivered the ultrasound waves, then applied either glucose or
inulin (a carbohydrate) to the treated skin. Glucose was absorbed 10
times better, and inulin four times better. “We think we can increase
the enhancement of delivery even more by tweaking a few other things,”
Schoellhammer says.
Noninvasive drug delivery
Such
a system could be used to deliver any type of drug that is currently
given by capsule, potentially increasing the dosage that can be
administered. It could also be used to deliver drugs for skin conditions
such as acne or psoriasis, or to enhance the activity of transdermal
patches already in use, such as nicotine patches.
Ultrasound
transdermal drug delivery could also offer a noninvasive way for
diabetics to control their blood sugar levels, through short- or
long-term delivery of insulin, the researchers say. Following ultrasound
treatment, improved permeability can last up to 24 hours, allowing for
delivery of insulin or other drugs over an extended period of time.
Such
devices also hold potential for administering vaccines, according to
the researchers. It has already been shown that injections into the skin
can induce the type of immune response necessary for immunization, so
vaccination by skin patch could be a needle-free, pain-free way to
deliver vaccines. This would be especially beneficial in developing
countries, since the training required to administer such patches would
be less intensive than that needed to give injections. The Blankschtein
and Langer groups are now pursuing this line of research.
They
are also working on a prototype for a handheld ultrasound device, and
on ways to boost skin permeability even more. Safety tests in animals
would be needed before human tests can begin. The U.S. Food and Drug
Administration has previously approved single-frequency ultrasound
transdermal systems based on Langer and Blankschtein’s work, so the
researchers are hopeful that the improved system will also pass the
safety tests.
The research was funded by the National Institutes of Health.
