Getting under the skin

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