Novel Hollow Microneedle Technology for Depth-Controlled Microinjection-Mediated Dermal Vaccination: A Study with Polio Vaccine in Rats

Pharmaceutical Research (Impact Factor: 3.42). 01/2014; 31(7). DOI: 10.1007/s11095-013-1288-9
Source: PubMed


The aim of the study was to develop a cheap and fast method to produce hollow microneedles and an applicator for injecting vaccines into the skin at a pre-defined depth and test the applicability of the system for dermal polio vaccination.
Hollow microneedles were produced by hydrofluoric acid etching of fused silica capillaries. An electromagnetic applicator was developed to control the insertion speed (1-3 m/s), depth (0-1,000 μm), and angle (10°-90°). Hollow microneedles with an inner diameter of 20 μm were evaluated in ex vivo human skin and subsequently used to immunize rats with inactivated poliovirus vaccine (IPV) by an intradermal microinjection of 9 μL at a depth of 300 μm and an insertion speed of 1 m/s. Rat sera were tested for IPV-specific IgG and virus-neutralizing antibodies.
Microneedles produced from fused silica capillaries were successfully inserted into the skin to a chosen depth, without clogging or breakage of the needles. Intradermal microinjection of IPV induced immune responses comparable to those elicited by conventional intramuscular immunization.
We successfully developed a hollow microneedle technology for dermal vaccination that enables fundamental research on factors, such as insertion depth and volume, and insertion angle, on the immune response.

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    • "Various hollow MNA designs and their fabrication technologies have been developed. The fabrication of such hollow MNAs can be performed by using combinations of several advanced microelectronics processing techniques or more classical routes of precision engineering and assembly (Gardeniers et al., 2003; van der Maaden et al., 2014; Indermun et al., 2014). "
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    ABSTRACT: Current vaccination technology can advance from the use of novel ceramic nanoporous microneedle arrays (npMNA), where the material serves as a storage reservoir for vaccines. Moreover, npMNA will enhance vaccine efficacy by more precisely reaching skin dendritic cells, the kickstarters of T and B cell immunity. In the present study we assessed the efficacy of vaccination using npMNAs by in vivo application of OVA257-264 peptides mixed with agonistic anti-CD40 antibodies as adjuvant. The induction of OVA-specific CD8(+) T cells via npMNA was comparable with the frequency induced via intradermal injection using needle-syringe. However, only when expanding the vaccination area by using two npMNAs the frequencies of induced IFN-γ-specific effector CD8(+) T cells were comparable with those induced via needle-syringe injection. Analysis of vaccine release from npMNA in a human ex vivo skin explant model revealed that OVA257-264 peptides were indeed delivered intradermal, and release also increased by prolonging the npMNA application time on the human skin. Together, our studies demonstrate the potential of npMNA for vaccine delivery in human skin and in vivo induction of CD8(+) effector T cell responses. Copyright © 2015. Published by Elsevier B.V.
    International Journal of Pharmaceutics 06/2015; 491(1-2). DOI:10.1016/j.ijpharm.2015.06.025 · 3.65 Impact Factor
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    • "There has been a lot of research conducted on MNs for the delivery and monitoring of various drugs such as glucose control for diabetics (Ito et al., 2006; Nordquist et al., 2007; Ainslie & Desai, 2008; El-Laboudi et al., 2013; Taylor & Sahota, 2013; Ita, 2014), Alzheimer's disease (Wei-Ze et al., 2010), anticancer (Fang et al., 2008) and other conditions (Ezan, 2013). Vaccines have also been a prominent research field with numerous studies developed to allow dose sparing effects (Edens et al., 2013; Norman et al., 2014; van der Maaden et al., 2014). There have been multiple studies conducted to optimize the delivery of drugs using MNs with numerous methods to fabricate them. "
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    ABSTRACT: Abstract In recent years, there has been a surge in the research and development of microneedles (MNs), a transdermal delivery system that combines the technology of transdermal patches and hypodermic needles. The needles are in the hundreds of micron length range and therefore allow relatively little or no pain. For example, biodegradable MNs have been researched in the literature and have several advantages compared with solid or hollow MNs, as they produce non-sharp waste and can be designed to allow rapid or slow release of drugs. However, they also pose a disadvantage as successful insertion into the stratum corneum layer of the skin relies on sufficient mechanical strength of the biodegradable material. This review looks at the various technologies developed in MN research and shows the rapidly growing numbers of research papers and patent publications since the first invention of MNs (using time series statistical analysis). This provides the research and industry communities a valuable synopsis of the trends and progress being made in this field.
    Drug Delivery 12/2014; DOI:10.3109/10717544.2014.986309 · 2.56 Impact Factor
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    ABSTRACT: Microneedles represent promising tools for delivery of drugs to the skin. However, before these microneedles can be used in clinical practice, it is essential to understand the process of skin penetration by these microneedles. The present study was designed to monitor both penetration depth and force of single solid microneedles with various tip diameters ranging from 5 to 37 µm to provide insight into the penetration process into the skin of these sharp microneedles. To determine the microneedle penetration depth, single microneedles were inserted in human ex vivo skin while monitoring the surface of the skin. Simultaneously, the force on the microneedles was measured. The average penetration depth at 1.5 mm displacement was similar for all tip diameters. However, the process of penetration depth was significantly different for the various microneedles. Microneedles with a tip diameter of 5 µm were smoothly inserted into the skin, while the penetration depth of microneedles with a larger tip diameter suddenly increased after initial superficial penetration. In addition, the force at insertion (defined as the force at a sudden decrease in measured force) linearly increased with tip diameter ranging from 20 to 167 mN. The force drop at insertion was associated with a measured penetration depth of approximately 160 μm for all tip diameters, suggesting that the drop in force was due to the penetration of a deeper skin layer. This study showed that sharp microneedles are essential to insert microneedles in a well-controlled way to a desired depth.
    Journal of the Mechanical Behavior of Biomedical Materials 10/2014; 40:397–405. DOI:10.1016/j.jmbbm.2014.09.015 · 3.42 Impact Factor
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