Evaluation of Electroosmotic Flow Promoted By a Porous Microneedle Array
Authors: Sato Kaito , Kusama Shinya , Matsui Yuya , Kimura Natsumi , Yoshida Shotaro , Nishizawa Matsuhiko 
Published: December 2020

A transdermal drug delivery (TDD) system has been an attractive method to delivery needed drug into our bodies directly with few side effect, and electroosmotic flow (EOF) is known as the method to enhance TDD and even the extraction of interstitial fluid (ISF) which contains biomarkers such as glucose. The limitation of these transdermal penetration / extraction arises from stratum corneum (SC), an outermost layer of skin. SC is highly resistive and functions as a barrier for harmful molecules, which makes it difficult to apply direct currents to the skin by mild and safe voltage and to deliver larger molecular drugs (>600 Da) into the skin1. The microneedle array (MNA) is one of the promising approaches to break through SC without pain, and solve problems of the electrical and the drug pass. Recently, we have realized organic polymer-based porous microneedles (PMN) made of poly(glycidyl methacrylate) (PGMA) which were prepared by the combination of molding process and the porogen method 2. In this study, we developed a PMN inducing the EOF for efficient TDD and extraction of ISF (Figure 1a). Furthermore, in order to enhance efficiency in the induction of the EOF, negatively-charged hydrogel was embedded in the porous channels of the PMN.
The modified PMN was prepared by the following steps. Briefly, naked PMN was prepared by the step described in the report2. After that, the naked PMN chips were immersed in an aqueous solution containing 0.05 M of AMPS, 0.10 M of MBAAm, ammonium persulfate and tetramethylenediamine at 4 ℃ for more than 8 h, followed by thermal copolymerization at 70 ℃ for more than 8 h.
First, we evaluated the property of water transport by EOF. A chip of PAMPS-modified PGMA was bound with side-by-side Franz cells with a horizontal capillary, and constant DC currents were applied by a source meter. McIlvaine buffer (pH 7.0) was used as the electrolyte. Flow velocity was calculated from the moving of the water surface in the capillary. The flow velocity of the EOF increased by the modification with AMPS (Figure 1b). The reason was that the negative charge was increased by the AMPS modification and that promoted the EOF.
In order to evaluate the property of large molecule transport, the same system as water transport was employed as well. The Franz cells were poured with McIlvaine buffer (pH 6.0) and 0.75 mg/mL FITC-dextran (10,000 Da, pKa 6.4) was added to the donor chamber. We applied a constant DC current in direction from the donor side to the receptor side, and a 100 µL portion was collected from the receptor chamber every hour for analysis by a fluorescence spectrophotometer. From the result, we found that PAMPS significantly contributes to transport for the large molecule transport (Figure 1c). This might be due to dense polymer chains of PMAPS capturing large molecules such as dextran.
Finally, the transdermal injection was demonstrated by enzymatic fructose / O2 battery into pig’s skin (Figure 1d). The injection of FITC-dextran at an anode was evaluated the PMN modified with 0.05 M AMPS and the cotton with 0.3 mL McIlvaine buffer (pH 6.0) containing 0.2 M D-fructose and 0.75 mg/mL FITC-dextran. The cross-sectional fluorescence image of the skin was observed after the application of the current around 0.2 mA/cm2 for 1 hour. These results showed that this novel PMN with negatively charged hydrogel can be a desirable tool for enhancing the injection of large molecules such as drugs and nutrients.
Reference
[1] Brown, M. B, Martin, G. P., Jones, S. A. & Akomeah, F. K. Dermal and transdermal drug delivery system: Current and future prospects. Drug Deliv. J. Deliv. Target. Ther. Agents
13, 175-187 (2006).
[2] Liu, L., Kai, H., Nagamine, K., Ogawa, Y. & Nishizawa, M. Porous polymer microneedles with interconnecting microchannels for rapid fluid transport. RSC Adv.
6, 48630-48635 (2016).

Figure 1