Dual-Mode Drug Delivery By Electroosmotic Flow with Bipolar Porous Microneedles
Authors: Ichinose Sae , Kato Kosuke , Moriyama Natsuho , Wang Gaobo , Tottori Soichiro , Nishizawa Matsuhiko 
Published: December 2024

Transdermal drug delivery has various advantages including being minimally invasive, avoiding the first-pass effect in the gastrointestinal tract, and allowing local administration. Among them, the microneedle is a drug administration method that overcomes the skin barrier function by penetrating the stratum corneum. A porous microneedle (PMN) is a type of microneedle that has an interconnected pores network throughout the needle structure and exhibits characteristic solution permeability.[1]Iontophoresis is a method of facilitating drug delivery by passing an electric current through negatively charged skin tissue and has been used for transdermal drug delivery where the drug delivery rate can be controlled by adjusting the applied current. Iontophoresis promotes the transport of molecules mainly by electrophoresis and electroosmotic flow (EOF). EOF can deliver a wide variety of drugs regardless of the charge and size of the drug molecules. Previously, we have successfully generated EOF inside PMNs filled with ionic hydrogel.[2] However, it causes unwanted suctioning of interstitial fluid on the cathode side. Furthermore, the anode and cathode must be placed at a considerable distance from each other, and electrical stimulation may increase the risk of side effects and tissue damage. In this study, we developed a portable device that achieves drug release from both poles of microneedle arrays as shown in Fig 1. PMNs are functionalized with negatively and positively charged polymers, poly-2-acrylamido-2-methylpropanesulfonic acid (PAMPS) and poly-(3-acrylamidopropyl) trimethylammonium chloride (PAPTAC), respectively. By using negatively and positively charged PMNs on the anode and cathode compartments, therefore, the direction of EOF in both anode and cathode compartments is aligned.

To evaluate transportation efficiency by EOF, a thin-film modified PGMA plate (substrate of PMN) was placed between a donor side containing the drug model FITC-ovalbumin (44 kDa) and a receiver side filled with PBS buffer. The transportation was achieved by applying a current density of ± 0.5 mA/cm2 (Fig
.
1
a). Fig
.
1
b shows the amount of FITC-OVA transported by PAMPS-modified PMN (blue) and PAPTAC-modified PMN (orange), in comparison with the negligible amount of transport (white) without applied current. Next, preliminary dual delivery of 10 kDa FITC-dextran was investigated using two circular PMNs for the transportation of the drug into hydrogel(Fig
.
1c (i)). As shown in Fig
.
1c (ii), high fluorescence intensity was observed from both the anode and cathode, indicating the possibility of dual delivery using surface-modified PMNs. Finally, we developed a stamp-like integrated probe device that facilitates practical handling and minimizes electrical stimulation by bringing the bipolar PMNs into proximity (Fig
.
1d (i)). The device was 3D-printed, with a PMN glued to the tip and connected to a power source. Drug delivery to hydrogel was performed using a device with each reservoir filled with methylene blue and rhodamine (Fig
.
1d (ii)). In the case of passive diffusion , no dye transport was observed, whereas dyes penetrated the hydrogel from both anode and cathode compartments when the current was applied, suggesting that bipolar emission is possible using the device developed in this study.

In this study, we reported an iontophoresis-assisted dual-mode drug delivery using the stamp-like integrated PMN probe device. Two PMNs placed at anode and cathode compartments are modified with anionic PAMPS and cationic PAPTAC, respectively. Consequently, the alignment of EOF towards the skin effectively mitigates the unwanted cathodal ISF suction by inducing a counterflow for reverse iontophoresis. It is crucial for the applications of cytotoxic therapies to solid tumors based on the proposed device with minimized electrical stimulation. The center-to-center distance between two semicircular porous microneedles is 6 mm since the far positioning of anode and cathode electrodes in those reported iontophoretic devices may increase the discomfort of patients due to the high level of electrical stimulation required to drive ions across the larger gap. For example, it can unintentionally induce galvanotaxis, a process implicated in tumor invasion and metastasis, wherein cancer cells migrate from the primary tumor to distant locations within the body.

Reference:

[1] L. Liu et al., RSC Advances, 6 (2016) 48630.

[2] S. Kusama et al., Nat.
Commun., 12 (2021) 658.

Fig. 1 Stamp-like integrated porous microneedle device for dual delivery. (a) Schematic illustration of the generation of aligned electroosmosis flow from anode and cathode. (b) FITC-ovalbumin transportation via surface-modified PGMA monolith. (c) Experimental setup for dual delivery of FITC-dextran (i) and the fluorescence images of delivered 10 kDa FITC-dextran using hydrogel. (ii). (d) A stamp-like device by integrating two semicircular porous microneedles (i) and dual delivery of methylene blue and rhodamine into hydrogel (ii).

Figure 1