Conor O'Mahony

Processing difficulties and instability of carbohydrate microneedle arrays

Background: A number of reports have suggested that many of the problems currently associated with the use of microneedle (MN) arrays for transdermal drug delivery could be addressed by using drug-loaded MN arrays prepared by moulding hot melts of carbohydrate materials. Methods: In this study, we explored the processing, handling, and storage of MN arrays prepared from galactose with a view to clinical application. Results: Galactose required a high processing temperature (160°C), and molten galactose was difficult to work with. Substantial losses of the model drugs 5-aminolevulinic acid (ALA) and bovine serum albumin were incurred during processing. While relatively small forces caused significant reductions in MN height when applied to an aluminium block, this was not observed during their relatively facile insertion into heat-stripped epidermis. Drug release experiments using ALA-loaded MN arrays revealed that less than 0.05% of the total drug loading was released across a model silicone membrane. Similarly, only low amounts of ALA (approximately 0.13%) and undetectable amounts of bovine serum albumin were delivered when galactose arrays were combined with aqueous vehicles. Microscopic inspection of the membrane following release studies revealed that no holes could be observed in the membrane, indicating that the partially dissolved galactose sealed the MN-induced holes, thus limiting drug delivery. Indeed, depth penetration studies into excised porcine skin revealed that there was no significant increase in ALA delivery using galactose MN arrays, compared to control (P value < 0.05). Galactose MNs were unstable at ambient relative humidities and became adhesive. Conclusion: The processing difficulties and instability encountered in this study are likely to preclude successful clinical application of carbohydrate MNs. The findings of this study are of particular importance to those in the pharmaceutical industry involved in the design and formulation of transdermal drug delivery systems based on dissolving MN arrays. It is hoped that we have illustrated conclusively the difficulties inherent in the processing and storage of carbohydrate-based dissolving MNs and that those in the industry will now follow alternative approaches.

Coated Microneedle Arrays for Transcutaneous Delivery of Live Virus Vaccines

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8(+) T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices.

In-vivo dynamic characterization of microneedle skin penetration using optical coherence tomography.

The use of microneedles as a method of circumventing the barrier properties of the stratum corneum is receiving much attention. Although skin disruption technologies and subsequent transdermal diffusion rates are being extensively studied, no accurate data on depth and closure kinetics of microneedle-induced skin pores are available, primarily due to the cumbersome techniques currently required for skin analysis. We report on the first use of optical coherence tomography technology to image microneedle penetration in real time and in vivo. We show that optical coherence tomography (OCT) can be used to painlessly measure stratum corneum and epidermis thickness, as well as microneedle penetration depth after microneedle insertion. Since OCT is a real-time, in-vivo, nondestructive technique, we also analyze skin healing characteristics and present quantitative data on micropore closure rate. Two locations (the volar forearm and dorsal aspect of the fingertip) have been assessed as suitable candidates for microneedle administration. The results illustrate the applicability of OCT analysis as a tool for microneedle-related skin characterization.

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

Background Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8+ T cell responses to a malaria antigen induced by a live vaccine. Methodology and Findings Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. Conclusions/Significance This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes.

Analysis of electromechanical boundary effects on the pull-in of micromachined fixed-fixed beams

Using a commercial finite-element simulation tool, this work considers some of the electromechanical effects commonly neglected during the analysis of electrostatically actuated fixed–fixed beams. These structures are used in many applications of micromechanical systems, from relay switches and RF resonators to thin film characterization tests, but much of the analytical modelling of the device behaviour disregards the effects of electrostatic field fringing, plane-strain conditions and anchor compliance. It is shown that the cumulative total of these errors can be substantial, and may lead to large discrepancies in the expected operational characteristics of the device. We quantify the influence of these effects on the electrostatic pull-in of fixed–fixed beams, and illustrate some of the limitations of ideal pull-in theory. In order to more accurately predict the pull-in voltage for a real structure, a model is developed that combines ideal case theory with anchor compliance correction factors extracted using finite-element analysis. Three common anchor types (ideal, step-up and cup-style) are characterized. The final model takes account of the compliance of the beam anchors, electrostatic field fringing and plane-strain effects, and agrees well with simulated results.

Hydrogel-forming and dissolving microneedles for enhanced delivery of photosensitizers and precursors.

We present “one‐step application” dissolving and hydrogel‐forming microneedle arrays (MN) for enhanced delivery of photosensitizers/precursors. MN (280 μm) prepared from 20% w/w poly(methylvinylether/maelic acid) and cross‐linked with glycerol by esterification to form hydrogels upon skin insertion, or allowed to dissolve rapidly in skin, were combined with patches containing 19 mg cm−2 of 5‐aminolevulinic acid (ALA) or meso‐tetra (N‐methyl‐4‐pyridyl) porphine tetra tosylate (TMP) for drug delivery. Both MN types were mechanically robust, with compression forces of 20.0 N only causing height reductions of 14%. Application forces as low as 8.0 N per array allowed >95% of the MN in each array type to penetrate excised porcine skin, with the MN penetrating to approximately 220 μm. MN significantly enhanced transdermal delivery of ALA and TMP in vitro, with the hydrogel‐forming system comparable with the dissolving system for ALA delivery (approximately 3000 nmol cm−2 over 6 h), but superior for delivery of the much larger TMP molecule (approximately 14 nmol cm−2 over 24 h, compared to 0.15 nmol cm−2). As this technology clearly has potential in enhanced photodynamic therapy of neoplastic skin lesions, we are currently planning animal studies, to be followed by preliminary human evaluations. GMP manufacturing scale‐up is ongoing.

Titanium as a micromechanical material

The suitability of titanium for use in microelectromechanical applications is investigated. A range of titanium microdevices, including free-standing fixed–fixed beams and cantilevers, has been successfully fabricated using a fully CMOS compatible, dry-release surface micromachining process. Finite-element simulations have been used to extract a semi-analytical model which describes the pull-in behaviour of fixed–fixed beams, while taking into account the effects of the non-ideal beam anchors. This method has been used to obtain an estimate of the Youngs modulus and residual stress in the metal. Capacitance monitoring has shown that the beams remain flat after sacrificial layer release, and interferometry imaging has been used to investigate the stability of beam anchors during device actuation. Furthermore, titanium beams have remained stable under repeated actuation in initial cycle testing and may be suitable for use as a major component of microswitches. One such possible design is outlined.

A MEMS-based wireless multisensor module for environmental monitoring

Abstract In order to enable further developments in low cost wireless sensor networks (WSNs) for unobtrusive environmental monitoring, increased miniaturisation and integration of hardware is essential. This paper outlines the design concept and preliminary results for a multifunctional micromachined sensor unit, comprising CMOS-compatible temperature, humidity and gas sensors on a single silicon substrate. The sensor is being developed for integration with the highly modular and programmable Tyndall25 mote, where the “plug and play” stackable layers incorporate communications, power supply and on-board data processing capabilities. This will enable the assembly of a miniature sensor network node complete with wireless transmission capability as well as intelligent data mining and storage.

Modelling electrostatic behaviour of microcantilevers incorporating residual stress gradient and non-ideal anchors

The electrostatic behaviour of micromachined cantilevers incorporating residual stress gradient and non-ideal anchors is studied in this work. Using finite-element simulation data, behavioural models that predict the electrostatic deflection and pull-in voltage of such structures have been established. The models account for the effects of residual stress gradient and real supports on the mechanical behaviour of the microcantilevers, and have been validated via comparison with experimental data. For the deflection models, the level of correlation achieved was within 7%, and in the case of pull-in voltage analysis, the calculated and measured values agree to within 4%. The completed models offer an efficient means of design, analysis and optimization of cantilever-based electrostatically actuated MEMS devices. They can also be utilized for material property measurement and analysis.

Evaluation of Packaging Effect on MEMS Performance: Simulation and Experimental Study

The thermal cure required for die attach during microelectro-mechanical systems (MEMS) packaging causes thermal mismatch that induces undesirable stresses and strains in surface micromachined structures, which may adversely affect the performance and reliability of the packaged component. Understanding the influence of the packaging process is, therefore, critical for successful device design. This paper analyzes the influence of the die attach process on the electromechanical behavior of doubly-anchored surface micromachined beams. A number of different adhesive materials were considered, and the results of parametric studies on the effects of die attach on the pull-in behavior of beams of various lengths, widths, and anchor types are presented. An upward shift in pull-in voltage of the studied devices was observed in both simulation and experiment; modelled and measured data were found to correlate closely.