Smartphone-powered iontophoresis-microneedle array patch for controlled transdermal delivery

The incidence rate of diabetes has been increasing every year in nearly all nations and regions. The traditional control of diabetes using transdermal insulin delivery by metal needles is generally associated with pain and potential infections. While microneedle arrays (MAs) have emerged as painless delivery techniques, the integration of MA systems with electronic devices to precisely control drug delivery has rarely been realized. In this study, we developed an iontophoresis-microneedle array patch (IMAP) powered by a portable smartphone for the active and controllable transdermal delivery of insulin. The IMAP in situ integrates iontophoresis and charged nanovesicles into one patch, achieving a one-step drug administration strategy of “penetration, diffusion and iontophoresis”. The MA of the IMAP is first pressed on the skin to create microholes and then is retracted, followed by the iontophoresis delivery of insulin-loaded nanovesicles through these microholes in an electrically controlled manner. This method has synergistically and remarkably enhanced controlled insulin delivery. The amount of insulin can be effectively regulated by the IMAP by applying different current intensities. This in vivo study has demonstrated that the IMAP effectively delivers insulin and produces robust hypoglycemic effects in a type-1 diabetic rat model, with more advanced controllability and efficiency than delivery by a pristine microneedle or iontophoresis. The IMAP system shows high potential for diabetes therapy and the capacity to provide active as well as long-term glycemic regulation without medical staff care.


1.
Drug delivery mechanism of "Penetration, Diffusion and Iontophoresis" The transdermal drug administration strategy of IMAP is "Penetration, Diffusion and Iontophoresis", including drug diffusion across intact skin, drug diffusion across poked skin, drug diffusion and iontophoresis across intact skin, and drug diffusion and iontophoresis across poked skin.
Briefly, since the IMAP is pressed, MA soaked in the porous reservoir will penetrate through the sponge and disrupt the SC, creating transient aqueous micro-holes. As the compression on IMAP is released, the MA will retract the sponge again. MA-induced micro-holes are directly exposed to the drug solution stored in the sponge. According to Fick's law, the drug solution will diffuse into the skin through micro-holes. Then, a mild electric current is conducted between a pair of electrodes, to drive charged drug molecules through micro-holes into systemic circulation by the predominant driving forces of electromigration and electroosmosis. One of the key advantages of this design is that the users can repeat the touch-actuated 'press and release' processes to reopen the micro-holes for a new round drug administration, resulting in a long-lasting positive diffusion and active iontophoresis.
Figure S1 Schematic representation of the drug delivery mechanism of IMAP: "Penetration, Diffusion and Iontophoresis". Since the IMAP is pressed, the micro-holes were created in the skin. Once compression is removed, the MA will retract in reservoir again. The drug solution will passively diffuse into the skin through micro-holes. And active iontophoresis will drive charged therapeutic molecules into systemic circulation when electric current is conducted.   Figure S3a shows the miniature iontophoresis-driven device for transdermal drug delivery with a size of 40 mm × 20 mm × 15 mm. The PCB of iontophoresis-driven circuit ( Figure S3b) was encapsulated with a 3D printed shell. The iontophoresis-driven circuit mainly consists of two modules: input voltage stabilization and output constant current ( Figure S3c). The iontophoresis-driven circuit can be powered through the smartphone charging port or USB charger. The power is rectified and the input voltage is stabilized using a low dropout voltage regulator (AMS1117, Zhiquan Electronics Fittings Factory, China) and two capacitor filters. The obtained stable voltage V CC is transferred into an output constant current. The output constant current I C2 is achieved using circuit of Wilson current source, which mainly contains three identical PNP-triodes (2N 3906B331), as shown in Figure S3d. Triode T 0 and T 1 are connected in a mirror symmetry, thus I B0 =I B1 = I B and I C0 =I C1 = I C . The emitter of triode T 2 is connected with the base and collector of T1 in series. There is a large equivalent resistance R between the emitter and collector, so the output current can be well stabilized. The detailed The derivation process of output constant current I C2 is

The iontophoresis-driven circuit
The current equation at point Q is in which is the triode gain. The I E2 also is equal to According to Eq. (1) and Eq.
(2), we can get The current equation at point P is So, the output current 2 is approximately equal to , which is independent of the external resistance.
Furthermore, the output current can be adjusted by changing the internal load through a switch (SW-SPDT). Finally, the iontophoresis-driven circuit can output constant different currents of 1 mA, 2 mA and 3 mA by adjustment of the equivalent resistance R.

Mechanical loading setup
A custom-made mechanical loading setup was developed for the investigation of mechanical performance of IMAP, as shown in Figure S4.

In vitro transdermal drug delivery test
In vitro transdermal delivery of FITC-insulin loaded in IMAP through rabbit skin was investigated.
The setup consisted of IMAP, vertical Franz diffusion cells (TP-3A, Albert Tech., China), iontophoresis-driven circuit, and smartphone, as shown in Figure S5.

The specific parameters of IMAP components
IMAP is mainly composed of medical tape, anti-seepage gasket, medical sponge and solid MA.
The specific parameters of IMAP components are listed in Table S1. The components of IMAP are simple, easy-obtained and low cost. The total cost of IMAP is less than 0.16 dollar. < 0.08

The Mechanical performance
On "Press stage", once the increasing stress reaches the rupture limit of skin, the microneedle tips penetrate into skin, resulting in a sudden drop of force at point 'P', as shown in Figure S7a. The critical penetration force at point 'P' is 1.6 N. On "Release stage", once the microneedles are detached from the skin owing to the elastic rebound energy of IMAP, the friction force becomes zero, thereby resulting in an increase of the measured resistance force at point 'Q', as shown in Figure S7b. The resistance force at point 'Q' is approximately 1 N.

Ethics statement
All animal procedures conducted in this work were reviewed, approved, and supervised by the Institutional Animal Care and Use Committee (IACUC) at the Sun Yat-Sen University (Approval Number: IACUC-DD-16-0904).

In vivo transdermal insulin delivery in diabetic rats
The diabetic rats whose BGL is in the range of 100-200 mg/dL is regarded in the normoglycemic state. The effective period that the diabetic rats are in normoglycemic states is defined as the  Figure S11-S12.
Figure S11 BGLs of diabetic rats of each group administrated with injection group, vesicles/1mA group and vesicles/MA/1mA group. The results are expressed as the mean ± standard deviation. Figure S12 The real-time BGLs measured by blood glucose meter of diabetic rats of (a) injection group, (b) vesicles/1mA group and (c) vesicles/MA/1mA group. The unit of measurement by using blood glucose meter is 'mmol/L' which can be converted to '18 mg/dL' (i.e., 1 mmol/L = 18 mg/dL)

Supplementary Video
Video S1: The smartphone-based drug delivery system and the transdermal drug delivery mechanism of IMAP