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New approach to boost immune response using barely visible Micron Sized Needles

New approach to boost immune response using barely visible Micron Sized Needles

Immunization can be made more efficient and convenient through the use of specially designed needles with size ranging between tens and hundreds of microns in length. These needles are designed to pierce the skin without causing pain or bleeding in the patient unlike conventional hypodermic needles which pierce deeper into the skin (Henry et al, 1998). In so doing they reduce the risk of infection and require no medical expertise leading to reduced cost of vaccination. They can also result in decrease in the amount of vaccine required to achieve desired immune response through dose sparing. Results from various studies so far have shown them to be able to deliver vaccines efficiently and lead to immune responses that match or even surpass that achieved through the conventional methods such as intramuscular injection (Mikszta et al, 2002). The development of this technology is in accordance with the global effort to ensure improved availability of vaccines. An easy to apply convenient delivery method ensures vaccination faster than the disease can spread hence making it possible to eradicate or at least reduce the spread of diseases such as polio and influenza.

Conventional immunization methods are laborious and require medical expertise due to the complexity of the method used such as delivery via intramuscular, intracutaneous or intradermal injections. Furthermore such methods draw blood and are likely to lead to infection from accidental needle reuse during immunization programs where due to large number of people to be immunized, medical experts are likely to reuse needles due to limited resources. Infections may also occur as a result of entry of microbes through the relatively large and deep wounds created by the needles. In addition to this, some microneedle devices can be designed to be self-destroyed after use such that they may not be reused. Microneedles generally create much smaller holes in the upper layer of the skin, away from blood vessels. These holes have been shown to reseal within a few hours and are not liable to entry of microbes which may cause infection (Gupta et al, 2011). Vaccines are also rather expensive and in short supply - therefore the dose sparing capability of microneedles could be of great advantage. Large volume of vaccine tends to be wasted in the conventional methods while targeted delivery using microneedles ensures that the bulk of the vaccine administered is delivered into the desired site in the skin.

Structure of the skin, showing comparison between microneedles and conventional needleMechanisms of action
In order to explain the mechanism by which microneedles act it is essential to briefly outline the structure of the skin. The skin is made up of three distinct layers; the epidermis, the dermis and the subcutaneous layer. The epidermis is the dead layer of the skin containing no blood vessels or nerves. The dermis is the lower layer which consists of blood vessels and pain receptors; it supplies the epidermis with sufficient nutrients. The subcutaneous layer mostly consists of fatty tissues which act as cushioning. The epidermis is further divided into the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and the stratum basale. The uppermost layer, the stratum corneum is the first point of contact between the skin and the environment and it serves to protect the internal organs from entry of foreign substances. Microneedles pierce through the stratum corneum and penetrate partially into the lower layers of the epidermis but without touching the pain receptors or the blood vessels in the dermis. The lower layers of the epidermis allow drugs to penetrate much quicker than the stratum corneum layer. Therefore microneedles facilitate improved delivery of vaccines through the skin but without causing pain sensation.
Images showing various designs of microneedles (Gill et al, 2008)
Within the epidermis exist antigen presenting cells (APCs) and these cells act as the body’s defence against infection. The APCs act by binding to the recognized pathogens and presenting them to the antibodies thereby triggering an immune response in the body. Microneedles were shown to be especially promising for vaccination as they can be made to target these APCs hence boosting the body’s immune response against infections (Gill et al, 2010).

The process of administration involves placing a patch containing an array of between tens and hundreds of microneedles onto the surface of the skin, either manually by hand or with the use of an applicator device. The microneedles may be fabricated from materials such as stainless steel, polymers and silicon and various dimensions have been fabricated by various research groups (see figure on the left).

Research and Commercial Interests
The idea to use microneedles for delivery of therapeutics to the skin has been around for just over a decade to date. The technology has since then attracted various commercial and research interests with a potential market worth billions of dollars and predicted to take up a significant portion of the drug market in the future with researchers and manufacturers competing to release microneedle devices into the clinical market. Research groups such as Georgia institute of technology in the US, Queens University School of pharmacy In Ireland, and Loughborough University in the UK are actively involved in research into microneedle-based drug delivery. Companies such as Zosanopharma, 3M and BD have also invested in the technology and to date over 500 patents have been released on microneedle devices.

Further research efforts are also aimed at developing a means to use these devices to boost the immune response of the dendritic cells in the skin to help provide immunity against HIV virus since this virus have been shown to attack the dendritic cells first. Therefore, boosting the immune response of the dendritic cells in the specified skin layer could offer the possibility of a boosted immune response against HIV (Blanchet et al, 2010).

Other research areas include developing better fabrication techniques suitable for faster and less costly mass manufacturing of microneedles, developing applicator devices for reliable insertion of microneedles into the skin and exploring the range of vaccines which may be delivered using microneedles.

Dose Control
Due to their small sizes microneedles are often designed in arrays of up to hundreds of single microneedle projections thus allowing them to deliver the required volume of drugs (Olatunji et al, 2011; Al-Qallaf et al, 2009). Optimization frameworks have been developed to predetermine the design of microneedle array to obtain desired delivery rate (Olatunji and Das, 2011). This allows design of microneedle devices specific to patient requirements.

Microneedles offer a promising prospect for improved vaccination programs. This has been highlighted by the various research findings and huge commercial interests in the technology as highlighted within this review.

Al-Qallaf, B., Das, D.B., Davidson, A. (2009). Transdermal Drug Delivery by Coated Microneedles: Geometry Effects on Drug Concentration in Blood. Asia-Pacific Journal of Chemical Engineering, 4(6), 845 - 857.

Blanchet, F.P. A. Moris, D.S. Nikolic, M.Laehmann, S.Cardinaud, R. Stalder, E.Garcia, C.Dinkins, F. Leuba, L.Wu, O.Schwartz, V.Deretic, V.Piguet. (2010) Immunity. 32; 654-669 DOI 10.1016/j.immuni.2010.04.011
Gill, H.S. D.D. Denson, B.A. Burris, M.R. Prausnitz. (2008) Effect of microneedles on pain in human volunteers. Clin J Pain. 24(7); 585-594.

Gill, H.S. Soderholm, J. Prausnitz, M.R. Sallberg, M. (2010) Cutaneous vaccination using 690 microneedles coated with hepatitis C DNA vaccine, Gene Ther. 17 (6) ; 811–814

Gupta, J., Gill, H.S., Andrews S.N., Prausnitz, M.R. (2011) Kinetics of Skin resealing after insertion of microneedles in human subjects. J. Contrl. Rel. doi:10.1016/j.jconrel.2011.05.021.
Henry S, McAllister VD, Mark GA, and Prausnitz RM (1998) Microfabricated microneedles: A novel approach to transdermal drug delivery. Journal of Pharmaceutical Sciences 87: 922–925.

Mikszta J.A, Alarcon JB, Brittingham JM, (2002) Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nature Medicine 8: 415–419.

Olatunji,O. Das,D.B. (2011) Drug Delivery Using microneedles. Comprehensive Biotechnology (Second Edition), 5 (48): 625-642
Olatunji, O., Das, D.B., Nassehi, V. (2011).Modeling transdermal drug delivery using microneedles: Effect of geometry on drug transport behavior.Journal of Pharmaceutical Sciences, DOI: 10.1002/jps.22736

Article was contributed by Lola Olatunji, PhD, at Loughborough University, UK

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