getting under the skin
TRANSCRIPT
OPINION
DECEMBER 2006 | VOLUME 9 | NUMBER 1272
The needle and syringe may be on their way out as materials scientists begin to find better ways of delivering drugs through the skin.
Mark Kendall | The University of Queensland, Australia | [email protected]
The mapping of the human genome1 in 2001
has provided us with a means of deciphering the
complex functions and interactions of our genes,
chemicals, proteins, and cells. This understanding
is being applied to develop advanced sensors
and drugs for monitoring and treating major
diseases. Consequently, an explosion of new drugs
is expected in the next ten years. How will they
be delivered effectively to the body? The most
obvious and convenient drug delivery routes are
via ingestion or inhalation. However, these are
frequently inappropriate because drugs must survive
the harsh environments of the gastrointestinal
tract, lung lining, and the first-pass metabolism of
the liver. As a result, the most common delivery
route is the needle and syringe, a method invented
in 1853.
Despite being around for more than 150 years, the
needle and syringe is far from perfect. Let’s start
with needle-phobia. Most of us do not like needles
and, with many, needle-phobia can be a major
impediment to the provision of important vaccines
and drugs. But of greater concern is the risk of
cross-contamination through needle-stick injuries in
health workers. It is estimated by the World Health
Organization (WHO) that one billion vaccination
injections are administered through national
immunization programs each year, and up to 30%
of these injections are thought to be unsafe2. The
primary risks are infection with hepatitis B and C and
HIV. Consequently, effective needle-free vaccination
strategies are a major priority of international groups
and organizations, such as the WHO and the Global
Alliance for Vaccines and Immunization (GAVI).
However, the biggest limitation of the needle and
syringe is that the delivery route simply does not
work in the prevention, treatment, and monitoring
of a range of currently untreatable diseases. This is
because the needle and syringe is literally too blunt
an instrument to deliver new-generation drugs and
vaccines (e.g. DNA vaccines) to richly abundant
key skin cells that reside within a tightly-defined
location about a hair-width (~40 µm) below the
skin surface3. Immunologists have shown that these
cells – called antigen-presenting cells – are very
important in inducing strong immune responses in
the body4. The challenge for engineers and materials
scientists is to produce effective technologies for
targeting these key cells just below the skin surface.
Initially, materials scientists were slow in responding
to this need. Up until about 15 years ago, the key
needle-free approach for drug delivery to skin was
the diffusive patch. Most of us are familiar with
the diffusive patch from well-marketed nicotine
products, but it has also had great success in
delivering many other drugs. As the name implies,
drug diffuses through the skin’s tough outer layer of
dead cells, called the stratum corneum. This works
well for small (< 500 Da) lipophilic molecules like
nicotine. But many of the newer drugs and vaccines
are much larger – sometimes in the megadaltons
range – and just simply do not diffuse into the skin.
Working collaboratively with biologists and
clinicians, engineers have applied aerospace
technologies to help solve this problem. In particular,
high-speed compressible flow and other rocket-
based technologies have been applied to deliver
drugs and vaccines ballistically into the skin. One
embodiment is the liquid-jet injector, which directs
a narrow (~100 µm) jet to the skin at ~100-200
m/s that breaches the outer skin layer ballistically.
This needle-free approach often delivers the jet
deeper into the skin layers, making contact with the
underlying nerve endings in the dermis – so it can
be quite painful. Liquid-jet injectors are currently
being commercialized by BioJect. A more precise
needle-free alternative directly descendant from
rockets is the gene gun (otherwise called biolistics).
In the gene gun, biological agents are reformulated
as dry microparticles (~2 µm in size) and
accelerated in a supersonic gas jet to give sufficient
momentum to penetrate the skin and achieve a
pharmacological effect5. Typically, the microparticles
impact ~1 cm2 of skin at a speed of ~600 m/s
– about the cruising speed of a Concorde aircraft.
The method has achieved strong immune responses
for DNA vaccines and is being commercialized by
PowderMed, which is conducting many clinical trials
(e.g. for influenza6).
Looking forward, the recent explosion of micro-
and nanotechnologies holds great promise in
further advanced needle-free drug and vaccine
delivery systems. For example, nanoparticles
have been shown to diffuse through the stratum
corneum, making them a potentially useful drug
carrier platform. Furthermore, developments in
microelectromechanical systems are opening up
new opportunities to make needle-free targeting
structures, such as micro/nanosized needle patches
that reach the key skin cells for improved vaccines.
Getting under the skin
REFERENCES
1. Lander, et al., Nature (2005) 409, 860
2. World Health Organization, In Safety of injections, Facts & Figures Fact Sheet No. 232,
(1999)
3. Kendall, M. A. F., Vaccine (2006) 24, 4651
4. Chen, D., et al., Expert Rev. Vaccines (2002) 1,
265
5. Kendall, M. A. F., Shock Waves J. (2002) 12, 23
6. Drape, R. J., et al., Vaccine (2006) 24, 4475