In academic and industrial laboratories all over the world, rapidly expanding research and development (R&D) teams are working to ensure that trips to local healthcare centres for treatments involving painless, inconvenient and expensive injections could soon be a thing of the past. This is the exciting world of microneedle technology, where multidisciplinary fusions of biomedical engineering and pharmaceutical science are creating new devices that will revolutionise the fields of transdermal drug and vaccine delivery within the next decade. Although a limited number of transdermal (i.e. across-the-skin) patches, such as those sold for nicotine addiction and pain relief, are already commercially successful, the extraordinary barrier properties of human skin prevent the vast majority of drugs from being administered in this fashion. This is almost entirely due to the stratum corneum – the outermost, ultra-thin (20 micron-thick) skin layer that is comprised of dead cells that are in the process of being sloughed away from the body. This forms an almost impenetrable barrier to the passage of all but a very few substances. [login type="readmore"] The development of wearable devices that look, act and feel like conventional skin patches, but incorporate arrays of tiny pointed structures known as microneedles, could prove to be a game-changer in this field. This will enable the painless, discreet delivery of therapeutics ranging from flu vaccine to insulin. These microneedles are almost invisible to the naked eye and are generally just a fraction of a millimetre tall. Importantly, this is not long enough to stimulate underlying nerve endings in the skin, which means that microneedle use is completely painless – welcome news to the 10% of the population who suffer from the debilitating fear of needles known as trypanophobia. Other key advantages include the elimination of the need for trained healthcare personnel (meaning, for example, that mass vaccination programmes could utilise the postal system for home delivery of skin patches), dose sparing, waste reduction and high patient compliance. Microneedle development began in US biomedical engineering laboratories during the late 1990s and, fuelled by convergence of healthcare and information and communications technologies, is only in recent years emerging from science and engineering laboratories as a potentially disruptive technology as ‘big pharma’ has realised the impact of the technology. As a result, microneedle R&D has moved from a position as a niche engineering interest to take centre stage, and significant worldwide investment is accelerating development towards market deployment. TYPES OF MICRONEEDLES Microneedles are made using a range of microfabrication techniques such as etching, moulding and laser micromachining processes that will be more familiar to those in the semiconductor industry than to medical personnel. However, all aim at the same core target, i.e. painless perforation of the skin’s stratum corneum barrier and delivery of drugs and vaccines through and just beyond that outermost layer. Four main types of device are under development, namely solid, coated, dissolvable and hollow microneedles. Solid-needle devices: these are straightforward to manufacture and consist of arrays of sharp microspikes, which are applied to the skin in order to create tiny perforations in the aforementioned stratum corneum barrier. A second patch or dressing, which contains a drug or vaccine, is then applied to the same site, at which point the medicant can passively diffuse through the channels previously created by the microneedle array. Although the concept is straightforward, the two-part application process may prove impractical in real-life usage and is likely to be frowned upon by regulatory authorities, and so several other options are being explored. Coated microneedles: these involve the use of dipping, spraying or brushing techniques to deposit and dry a biodegradable polymer solution, into which the therapeutic agent of interest is mixed, onto the surface of the microneedle. After skin insertion, the polymer dissolves upon contact with the underlying, moist tissue and releases its cargo. This approach retains the sharpness and structural strength of the solid core material to result in a very strong design, but the nature of the thin coating means that adequate doses can be difficult to accomplish. Dissolvable microneedles: much attention is currently focused on the idea of dissolvable or biodegradable microneedles that are similar to coated versions, but in this case the entire structure is formed from a drug-loaded polymer material, which dissolves after skin insertion. These needles are formed using micromoulding techniques such as vacuum casting or centrifugation to drive liquid material into a needle-shaped mould, which is then dried, removed from the mould and assembled into a wearable dressing. This design allows much higher doses to be delivered and has several very attractive advantages (including no waste and low costs), but requires further development to ensure adequate structural strength and pharmaceutical stability during shipping, storage and use. Hollow needles: these mimic conventional syringe delivery – i.e. by delivering therapeutics through a needle bore or lumen, generally no more than 0.05-0.1mm in diameter. Although the microscopic nature of the device means that delivery rates are low, hollow microneedles are useful for long-term or timed treatments where small amounts of drug must be delivered in a controlled manner. When used in conjunction with micropumps and fluidic reservoirs, hollow microneedle technologies are expected to have significant impacts in fields such as insulin delivery. STRUCTURAL CHALLENGES Microneedle designers also face unique structural challenges. At this scale, conventional structural mechanics can break down as surface-to-volume ratios become very large, atomic-scale cracks and defects dominate failure mechanisms, and load measurements often lie in the micronewton range. The primary factors that concern designers are the force required to penetrate human skin, which is dependent on the tip sharpness of the needle and is generally in the 10-100mN range, as well as the failure forces and mechanisms of the needles. Structural failure of microneedles is usually due to buckling, which is particularly prevalent for columnar-type devices and occurs at around 1N, although shear failure may also occur if arrays are misapplied in a direction not normal to the skin surface. The ratio of failure to insertion forces is referred to as the safety margin, and must obviously be as high as possible to ensure safe and reliable skin penetration. Irish involvement in microneedle development is strong. At University College Cork, the Tyndall National Institute is a world leader in the development of microsystems hardware based on wet-etched, silicon microneedles. This particular design is made by etching of single-crystal silicon substrates, known as wafers, in hot potassium hydroxide solution. This results in the formation of smooth-walled microneedles that resemble an octagonal pyramid. These structures are a few hundred microns tall, and feature ultrasharp tips with radii below 100 nanometers. The combination of sharp tip and conical, buckling-resistant shape results in a very reliable device that has a very high safety margin, making them ideal for medical applications. TYNDALL NATIONAL INSTITUTE Tyndall microneedles are currently being evaluated for use by a global network of over twenty academic and industrial partners for applications including drug and vaccine delivery, cancer treatment, sensing and diagnostics, dentistry and x-ray generation. The research programme, primarily funded by Enterprise Ireland and Science Foundation Ireland, has made substantial progress in the field and has already resulted in significant inward investment in the form of R&D contracts by a number of EU and US multinationals. In collaboration with a team at the University College Cork School of Pharmacy, a primary target is development and commercial translation of the ImmuPatch, a band-aid sized, self-administered system for low-cost and painless vaccine delivery. Significant intellectual property and know-how has emerged from this project that is currently being translated to clinical and commercial settings. Global industrial interest in the field can be gauged by the level of investment made by companies such as US-based Zosano Pharma, who have staked over $120 million developing their titanium-based microneedle patch for osteoporosis treatment and who are currently preparing for a Phase III clinical trial. Others, such as 3M (USA), Nanopass (Israel) and Debiotech (Switzerland) are not far behind. Academic groups such as those at Queens University Belfast and Georgia Institute of Technology are also making exciting advances in fields such as flu vaccination and insulin delivery, and almost all major pharmaceutical companies are closely tracking these developments. Expect to see microneedle-based transdermal patches at your pharmacy within the next decade.

Dr Conor O’Mahony is the microneedle research manager at the Tyndall National Institute at University College Cork. For more information on microneedle technologies and opportunities, telephone: (021) 234 6200, email: conor.omahony@tyndall.ie or visit: www.tyndall.ie.