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Nano Energy

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Self-powered, on-demand transdermal drug delivery system driven bytriboelectric nanogenerator

Qingling Ouyanga,f,1, Xueling Fengb,e,1, Shuangyang Kuangd,g, Nishtha Panwara, Peiyi Songg,Chengbin Yangh, Guang Yanga, Xinya Hemui, Gong Zhanga, Ho Sup Yooni, James P. Tami,Bo Liedbergb, Guang Zhud,j,∗, Ken-Tye Yonga,∗∗, Zhong Lin Wangc,d,∗∗∗

a School of Electrical and Electronic Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singaporeb Centre for Biomimetic Sensor Science, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Drive, 637553, Singaporec School of Material Science and Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USAd Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, 100083, PR Chinae Key Lab of Science and Technology of Eco-Textile, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai,201620, PR Chinaf CINTRA CNRS/NTU/THALES UMI 3288, Research Techno Plaza, 50 Nanyang Drive, Border X Block, 637553, SingaporegMOE Key Laboratory of Fundamental Physical Quantities Measurement & Hubei Key Laboratory of Gravitation and Quantum Physics, School of Physics, HuazhongUniversity of Science and Technology, Wuhan, 430074, PR ChinahGuangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University,Shenzhen, 518060, PR Chinai School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, SingaporejNew Materials Institute, Department of Mechanical, Materials and Manufacturing Engineering, University of Nottingham Ningbo China, Ningbo, 315100, PR China

A R T I C L E I N F O

Keywords:Self-poweredOn-demandTransdermal drug deliveryTunable drug release rateTriboelectric nanogenerator

A B S T R A C T

In this work, we present a self-powered and on-demand transdermal drug delivery system driven by triboelectricnanogenerator (TENG). A miniaturized TENG and a home-built power management circuit were designed totrigger the electric-responsive drug carrier for controlled drug release, as well as to activate the iontophoresistreatment for enhanced drug delivery efficiency. In the system, the TENG can harvest electricity from bio-mechanical energy, and the power management circuit is able to store, adjust, and stabilize the electricity for on-demand drug release actions. Our results demonstrate that the on-demand drug release can be simply realized byoperating the TENG. Manually rotating the TENG (30–40 rpm) for 1.5 min can release a drug dosage of 3 μg/cm2.Furthermore, the system has achieved tunable drug release rate for the transdermal drug delivery: the rate can betuned from 0.05 to 0.25 μg/cm2 per minute by changing the duration of TENG charging or the resistance of thepower management circuit. In addition, ex vivo experiments on porcine skin validate the performance of suchTENG-based drug delivery system with ∼50% enhancement over conventional transdermal patches. The pro-posed system is intended to provide patients with an easy approach to achieve customized rate and dosage ofdrug release.

1. Introduction

The concept of personalized healthcare is rapidly emerging as thenew trend of advanced healthcare, since it is expected to improve thetherapeutic efficacy, as well as to save medical resources and thus,reduce costs [1,2]. One of the most important targets of personalizedhealthcare is to provide individuals with tools to monitor their health

and self-treat on their own terms. Therefore, miniaturized and con-trollable drug delivery devices for at-home treatment are being activelypursued. On-demand drug release is typically a clinical application ofcontrollable drug delivery in a way that it assists patients with varyingsymptoms and allows them to determine individual location, dosage,duration, rate, and efficiency of drug release [3].

In order to achieve on-demand drug release, consistent efforts are in

https://doi.org/10.1016/j.nanoen.2019.05.056Received 26 March 2019; Received in revised form 1 May 2019; Accepted 19 May 2019

∗ Corresponding author. Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences, Beijing, 100083, PR China.∗∗ Corresponding author.∗∗∗ Corresponding author. School of Material Science and Engineering, Georgia Institute of Technology, Atlanta, GA, 30332-0245, USA.E-mail addresses: Guang.Zhu@nottingham.edu.cn (G. Zhu), ktyong@ntu.edu.sg (K.-T. Yong), zhong.wang@mse.gatech.edu (Z.L. Wang).

1 These authors contributed equally.

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progress to develop controlled drug release technologies by using sti-muli-responsive drug carriers. Among the various carriers, responsivepolymers (or “triggerable” polymers) are the most extensively appliedin controlled drug delivery systems, since they can respond to bothexogenous (e.g., electric field, light, and ultrasound) and endogenousstimuli (e.g., enzymes, glucose, and pH) for actuating drug release [4].Upon the presence of a stimulus, the stimuli-responsive polymers re-lease the loaded drug molecules or other therapeutic compounds to theenvironment due to chemical or physical reactions such as redox re-actions, degradation, or swelling [5,6]. Each type of stimuli-responsivepolymer has its advantages and disadvantages and can be tailored forthe intended on-demand drug release applications. Generally, the en-dogenous stimuli-response based drug carriers can be injected or im-planted in the body for targeted drug release, since the associated areas(e.g., tumors and infected/inflamed tissues) are generally accompaniedby changes in pH or/and enzymes [7,8]. However, such endogenousstimuli are strongly influenced by individual physiological body state.Therefore, it is difficult to give precise triggers to control the drug re-lease. From this point of view, the carriers based on exogenous stimulinormally have higher controllability of drug release, since the externalstimuli can be precisely controlled by operating the auxiliary equip-ment, such as tuning the wavelength of laser light, or the voltage/current of the power supply [4]. But the use of bulky auxiliary equip-ment (i.e., laser, potentiostat, and oscillators) engenders the problem oflarge footprint to the drug delivery system, which leads to significantlimitations such as, i) limited therapeutic environment and space; ii)limited sustainability; and iii) reduced patient's compliance. Therefore,to address the challenge of on-demand drug delivery in a miniaturizeddrug delivery system, it is critical to develop novel solutions and de-vices that can achieve high controllability on drug release as well asallow small footprint.

In this article, we present a portable triboelectric nanogenerator(TENG)-based transdermal drug delivery system for precise and on-demand drug dosing. Transdermal drug delivery (TDD) is usuallyachieved by a medicated transdermal patch that is placed on the skin todeliver the drug to the bloodstream through skin tissues. Therefore,under certain circumstances, TDD has unique advantages than con-ventional drug delivery routes (e.g., oral, injection), due to low side-effect and non-invasive administration of pharmacological agents [9].Invented in 2012, TENG is an emerging nanodevice that enables toharvest and convert mechanical energy to electric energy [10]. TENGmainly consists of two materials with different tribological properties.When the two materials rub against each other, an electric potentialdifference is established between them due to contact electrificationand electrostatic induction. TENGs have been extensively investigatedand applied in various electrification self-powered systems, due to theirunique advantages of simple structure and high output [11–14]. Here,we propose to use TENG to generate the electric-stimulus for the elec-tric-responsive drug carriers in the TDD system to achieve the on-de-mand drug release. There are four reasons for choosing TENG as thestimulus generator: i) Compared with other types of exogenous stimulisuch as optical and thermal energy, electric energy offers more freedomin design, control and storage, and it can be easily converted into op-tical or thermal energy if necessary. Also, the electricity from TENG canbe further utilized to enhance the drug delivery efficiency of TDDthrough, for example, iontophoresis treatment (a specific transdermaldrug administration technique using voltage gradient on skin [15]. ii)The simple structure and the broad material range of TENGs make themcost-efficient and easy to minimize. In addition, they can be madeflexible, foldable and even washable, which are desirable character-istics for wearable drug delivery devices [16]. iii) The operation ofTENG is completely immune to environmental and spatial disturbances.From this point of view, TENGs stand out from other self-chargingtechnologies including solar cells and thermoelectric generators. iv) It isconvenient and easy for patients to operate the TENG (e.g., rotate, tapor rub) to control the exogenous stimuli and thus, the drug delivery

profile [16].The proposed self-powered transdermal drug delivery system has

two significant improvements compared with existing transdermal drugdelivery devices. First, our device is based on TENG operation andexhibits tunable drug release rate with the help of an electric-stimulatedpolymer, polypyrrole (PPy), and a home-built power management cir-cuit. It is worth noting that the drug release of conventional TDDspatches is passively controlled and hence, cannot be tuned dependingon demand [17]. Second, our proposed system demonstrates a non-in-vasive method for drug delivery with enhanced efficiency in the dermis.Most of the current TDDs use microneedles for enhanced drug delivery[18–20]. However, these systems suffer from risks such as needlebreakages and skin invasion [21,22]. Moreover, the needles made ofpolymers bring the danger of leaving a broken needle in the skin uponlateral movement of the drug patch [19]; while the needles made fromhigh strength materials such as silicon, nickel, suffer from the problemsof low biocompatibility and increased invasion to skin [19,23]. Hence,instead of needles, our system utilizes a flat drug patch for iontophor-esis treatment with enhanced drug delivery.

In our study, we evaluate the working performance of the self-powered transdermal drug delivery system. Upon hand rotation ofTENG for 1.5min, we recorded 3 μg/cm2 of drug release from theelectric-stimulated drug carriers. Furthermore, we demonstrate twodifferent methods for controlling the drug release rate: i) by tuning theTENG operation duration and ii) by changing the resistance of themanagement circuit, tunning the rate between ∼0.05 μg/cm2 to∼0.25 μg/cm2 per minute. As a proof of concept, we demonstrate theentire drug delivery process on porcine skin ex vivo, where ∼30 ng/cm2 of drug penetration into the skin is detected after 10min of TENGoperation. More importantly, the drug delivery efficiency in dermis wasnoted to improve by ∼50% when compared with the absence of TENG-triggered reaction. The above results convincingly showcase the TENG-based system as an easy and battery-free method to achieve on-demandtransdermal drug delivery with a small footprint.

System Design: As illustrated in Fig. 1, the proposed drug deliverysystem consists of three components: transdermal patches (drug patch &iontophoresis patch) electrodes, TENG, and power management circuit.The TENG harvests and converts the energy of human motion into ACelectric energy, which is in turn, converted to a desired DC voltage (thatis compatible for the transdermal patches) by the power managementcircuit. Inside the drug patch, a screen printed electrode (SPE) coveredwith a thin film of the conductive nanocomposite, PPy, serves as thedrug reservoir. The round drug-loaded electrode A (covered with PPyfilm) and the annular counter electrode B are integrated on the SPE, asshown in Fig. 1b. The PPy is chosen as the drug carrier as it offers goodconductivity, stability, biocompatibility as well as ease of surfacemodification [24–26]. The drug molecules that are initially loaded intothe PPy film get released by the film in response to certain electricalstimulation. A phosphate-buffered saline (PBS) soaked sponge is placedbetween the SPE surface and the skin. It fulfills two functions: first, itserves as the conductor between electrodes A and B for the electric-stimulated drug release; second, it temporarily stores the drug mole-cules released from PPy before they permeate into the skin. To enhancethe drug delivery efficiency or drug penetration depth in the skin, activedrug transport is achieved by iontophoresis treatment, which is con-trolled by a bidirectional switch in the circuit.

Patch Electrodes: We used Dexamethasone Sodium Phosphate(DEX-P), a commonly-used anti-inflammatory drug, to demonstrate thecontrolled drug release performance. DEX-P is a phosphorylated pro-drug of Dexamethasone, which is generally used to treat various in-flammations, allergic reactions, and musculoskeletal injuries [27]. Weelectrodeposited the DEX-P-loaded PPy porous films onto the electrodeA using one-step electro-polymerization. During the polymerization ofpyrrole, the negatively-charged drug, DEX-P-, (DEX-P in the anionicstate) is loaded into the polymer matrix to balance positive chargesformed on the backbone of PPy (Fig. 2a). Prior to electrodeposition, the

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electrode surface was treated with polystyrene (PS) nano-beads to forma template and thus, to obtain the nanoporous PPy films. Comparedwith conventional bulk planar PPy films, the nanostructured porousPPy films (Fig. S1) possess enhanced surface area and offer higher drugloading capacity [28].

Working Principle of the Drug Delivery System: When the PPy filmsare applied with proper negative voltages (or are reduced electro-chemically) via electrodes A and B, the anionic DEX-P- previouslydoped within the oxidized PPy backbone are released to the local

environment as the charges on the backbone are neutralized, as shownin the lower part of Fig. 2a [29,30]. It is noted that the effective voltageapplied on the PPy film for electrochemical reduction is usually re-ported to be -0.8∼ -1.5 V [25,31]. The patch electrode C (shown inFig. 1a) is used for iontophoresis treatment. Iontophoresis is a processof transdermal drug delivery by use of certain voltages on the skin toenhance the drug delivery efficiency (the current should be below0.5 mA/cm2 for human safety [32]). When a voltage is applied on theskin through two patch electrodes A and C, the charged drug molecules

Fig. 1. Schematic illustration of the self-powered,on-demand transdermal drug delivery system. (a)The system consisted of transdermal patches (drugpatch and iontophoresis patch electrode), TENG andpower management circuit. (b) The right side of theSPE. The DEX-P- loaded PPy porous films electro-deposited on the drug-loaded electrode A of the SPE,serves as a drug reservoir. The drug DEX-P- can bereleased from the PPy film into the PBS soakedsponge when TENG is operated to power the SPE(electrodes A, B). After the electric-stimulated re-lease, the TENG is further utilized to active ionto-phoresis by powering electrode A and the ionto-phoresis patch electrode C to enhance the drugdelivery efficiency in the skin. (c) The radial-arrayedrotary TENG consists of two copper layers and onePTFE layer.

Fig. 2. (a) Chemical reaction mechanism for drug loading (PPy polymerization) and electric-stimulated drug release. As shown in the first formulation, the PPys areformed by electro-polymerization while loading the anionic drug Dexamethasone phosphate (DEX-P-) as a dopant. In the second formulation, when the negativevoltage applied on PPys, the drug is released during the reduction reaction. (b) TENG electricity generation process: the TENG can effectively harness slightmovement and convert it to alternating-current electricity due to the contact electrification and electrostatic induction. (c) Through a management circuit, the TENGcan provide a customized direct-current source (0.8 V–1.2 V) for PPy to release the drug. The circuit consists of a rectifier, a capacitor (470 μF, 50 V), a Zener diode(1.1 V), a resistor (1MΩ), and a bidirectional switch. Terminals a, b, c are connected with electrodes A, B, C (shown in Fig. 1) respectively: when the switch connectedwith terminal a, TENG start to power electrically-controlled drug release process; when the switch connected with terminal c, TENG start to power iontophoresistreatment. (d) The voltage characterization of radial-arrayed rotary TENG in open-circuit, which is driven by a motor at a speed of 25 rpm.

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get transported across the stratum corneum by electrophoresis andelectroosmosis effects. Besides, the electric field built in the skinthrough the two electrodes can increase the permeability of the skin.Therefore, the drug transport efficiency in the skin is enhanced by theTENG-induced external voltage.

TENG: A radial-arrayed rotary TENG, which mainly consists of arotator and a stator, is employed for powering the on-demand drugdelivery system. The rotator is a copper film etched with equal-degreeand radially-arrayed sector intervals (as shown in Fig. S2). The statorcontains a copper electrode layer and a polytetrafluoroethylene (PTFE)film. The electrode layer is etched with a radially-arrayed sector patternto form two disconnected electrodes 1 and 2 [12]. The PTFE film isimmobilized on the surface of the copper electrode, which is sand-wiched between the two copper films. We use the basic unit of TENG todemonstrate the electricity-generation process as shown in Fig. 2b. Asthe rotator spins from state 1 to state 2 by human motion, the electronstransfer from copper rotator to PTFE as a result of contact electrifica-tion. Thus, the rotator surface is positively-charged while the PTFEsurface is negatively-charged. The charge density of rotator is twice ofthat of the PTFE due to charge conservation. Under continuous rotation,an alternating potential difference is built between electrode 1 and 2due to electrostatic induction. Such a mechanism allows the radial-ar-rayed rotary TENG to have high output power, with a high area powerdensity of 19mW/cm2 and an efficiency of up to 24% [12]. We mea-sured the open-circuit voltage of the fabricated TENG when it wasdriven by a motor and hand respectively (see Fig. 2d and Fig. S3). Whenthe TENG was driven by a motor, the instantaneous voltages could be ashigh as 250 V. In a similar way, the voltages could also reach to 100 Vand above when the TENG was gently rotated by human hand. Theseresults clearly demonstrate the ability of the rotary TENG to harvesttiny energy from human muscle motions. In addition to high outputpower, the rotary TENG is favorable for driving the drug deliverysystem because: i) it can be easily miniaturized and manufactured into aportable device allowing patients to operate (manual rotation) it any-where and anytime; ii) it can also be driven by other muscular bodymotions, such as walking, waving, etc (Fig. S4). It has been widelyreported that mechanical structures such as gear and spring, can con-vert linear motions from limbs, feet, body, etc., into rotational motionsand further accelerate them [33,34]. Therefore, the rotary TENG is apromising example of a micromechanical structure which can harvestmuscular motions from the entire body and can thus, be integrated withvarious types of wearable drug delivery devices.

The power management circuit: Since the AC output of TENGcannot be directly utilized by transdermal patches, a power manage-ment circuit is designed to convert the original output to the desired DCvoltage (within 0.8– 1.5 V). The power management circuit, shown inFig. 2c, can accumulate discontinuous TENG output and convert it tosustainable DC voltage source for electric-controlled drug release andiontophoresis treatment. For example, if we manually operate TENG for3min and apply the adjusted DC voltage on the load (transdermalpatches), an output voltage in the range of 0.8– 1.1 V is maintained foraround 20min. Detailed analysis and design for the management circuitare discussed in Figs. S5–S8. The entire set-up of the drug deliverysystem including the TENG, drug patches, and the power managementcircuit is shown in Fig. S9.

2. Results and discussion

Device Operation: To evaluate the drug release performance of thedrug-load electrode, we first assessed the electro-stimulus drug releasewith traditional power supply, a potentiostat device, in continuousapplied voltage mode. We immersed the drug-load electrode A andcounter electrode B in 100 μL PBS solution, and applied a voltage of-0.8 V between them for 60min (Fig. 3a, the blue line). The PBS solu-tion was sampled and analyzed by UV absorbance spectroscopy; theamount of released DEX-P- was quantified with the characteristic

absorption at 242 nm as shown in Figs. S10–S11. The blue line inFig. 3b demonstrates that the amount of DEX-P- released from the PPyfilm is proportional to the duration of potential applied to the drug-loadelectrode. Afterward, we replaced the potentiostat by TENG to providesustainable voltage to the electrodes by turning the rotator manually.Following TENG operation for around 3min, we observed that thevoltage applied on the electrodes increased gradually until a peak of∼1.05 V and then exhibited a slow decrease (Fig. 3a, red line). Thevoltage increase is attributed to the TENG charging operation, while thevoltage decrease occurs due to electric-stimulated drug release process(electrochemical reduction) on the drug-loaded electrode. With theadjustment of the power management circuit, a voltage ranging be-tween 0.8 and 1.1 V was maintained (the effective voltage) for around20min. When the voltage decreases below 0.8 V, a quick charging(∼30 s) can increase the voltage back to the peak value again. Asshown in Fig. 3b, the TENG-triggered release profile approximatelymatches with the potentiostat-triggered release profile in the 60mindrug release process. The amount of released DEX-P- is also propor-tional to the duration of the effective voltage applied to drug-loadedelectrodes. The cumulative amount of drug released in 60min wasnoted to be 35 μg/cm2, which was higher than that of the potentiostatpowered profile (27 μg/cm2). This is because the average voltage ap-plied on the electrode by TENG operation is higher than that of thepotentiostat. By comparing these two drug release curves, we canconclude that: i) the drug release rate is positively related to the ef-fective voltage as well as the duration of the effective voltage appliedon the drug-electrodes, and ii) TENG can be employed as an effectivesubstitute of bulky power supplies for drug delivery devices.

On-demand drug release: Furthermore, we evaluated the perfor-mance of on-demand drug release of the proposed system. During the4h measurement duration, TENG was operated to power the systemthree times. Each time, the TENG was charged for 3min, and the ef-fective voltages (> -0.8 V) were applied on the SPE for 20min followedby a 60min duration without any applied voltage, as shown in Fig. 3c.The on-demand drug release results (Fig. 3d) show that the drug releaseaction is activated only when the effective voltages are applied on theSPE; once the voltages cease to power the drug-loaded electrode, therelease stops completely. In addition, the similar release profiles in allthe three rounds of the electric-stimulated release, namely, the releaserate and amount of released drug, demonstrate that the TENG-triggereddrug release performance is repeatable and stable. As a control, almostnegligible drug diffusion from the as-fabricated porous film was ob-served in the absence of electric-stimuli. These results indicate that thedrug-loaded electrodes display a good and stable on-demand releaseprofile. In order to further investigate the bioactivity of the drug afterrelease from PPy, we conducted experiments on RAW 264.7 cells invitro. The results demonstrate that the drug released from PPy filmretains its bioactivity during the entire electric-stimulated release pro-cess (see Figs. S12–S14 and Tables S1–S3).

Tunable release rate: Since we found that the drug release rate wasproportional to the duration of the effective voltage applied on thedrug-electrodes, we explored two different methods for tuning the re-lease rate. The first method involves changing the charging time of theTENG. With the same power management circuit, we compared theeffect of the TENG charging time on the rate of drug release. Fig. 4ashows the profiles of the voltages applied on the SPE with various TENGcharging durations, namely 1.5 min, 2.5min, and 5min. A longercharging time (or TENG operating time) results in a higher voltage andthus the longer duration of effective voltages. As in Fig. 4a, we alsoobserved that with the TENG charging duration increasing, the voltagesapplied on the SPE increased rapidly followed by a slow decrease. Thecorresponding release profiles are shown in Fig. 4b, where the releaserates of the three conditions under different TENG charging durationswere estimated to be 0.05, 0.15 and 0.25 μg/cm2 per minute, respec-tively. It is obvious that the drug release rate and the cumulative drugamount are proportional to the TENG charging time. Thus, one can

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easily achieve on-demand drug delivery by tuning the TENG chargingtime. The second way to control the drug release rate is to change theresistance of the power management circuit. An external resistor in thecircuit is used to divide the voltage from the load, and thus, if the re-sistance increases, the voltage applied on the load decreases. In thisway, we can tune the voltage applied to the SPE by changing the re-sistance of the external resistor in the circuit, when the TENG chargingtime is fixed. In Fig. 4c, as the resistance increases from 1MΩ to3.75MΩ, the voltage applied on the SPE decreases gradually, and as aresult, the duration of the effective voltage decreases as well. Therefore,the corresponding drug release rate decreased from ∼0.25 to∼0.07 μg/cm2 per minute (Fig. 4d). We noted that when the voltagedecreased below -0.8 V, the drug release did not stop immediately as itdid in Fig. 3. This is because the structure of PPy films used in Fig. 3 wasmuch looser than that used in Fig. 4. The PPy films with loose structurecan easily release doped drug molecules and thus, show a quick re-sponse to the electric-stimulation to achieve precise and sensitive on-demand drug release. However, this quick-release property of loose PPyfilms hinder the possibility of tunable release rate, therefore, we syn-thesized PPy films with compact structures, as used in Fig. 4. Thecompact structures slow down the transport speed of the drug mole-cules, and thus we observe a hysteresis effect for drug release when theelectric-stimulation is stopped. This property can be appropriately uti-lized to achieve varying drug release rate in personalized healthcare.The synthesis procedure of loose and compact PPy films are detailed inthe experimental section. Herein, we have demonstrated two easy ways,namely, changing the TENG charging time and the resistance in thepower management circuit, to tune the drug release rate. Both themethods can be easily engineered and integrated with the proposeddrug delivery system to realize effective and on-demand drug dosing,which could provide patients with convenient dosing regimens and also

address personalized and varying needs of clinical healthcare ther-apeutics.

Ex vivo drug release: We tested the performance of the as-designedTENG-based drug delivery system on porcine skin ex vivo. The ex-perimental setup is shown in Fig. S9. We assayed the amount of DEX-P-

penetrating the porcine skin by high-performance liquid chromato-graphy (HPLC) as shown in Fig. 5a. Here, we carried out the experi-ments with our proposed system and the traditional device (potentio-stat) respectively. In the first group, the drug-load electrode SPE waspowered by the traditional power supply (potentiostat) for 10min forthe electric-stimulated DEX-P- release. For the TENG based system, theTENG was also charged for 10min to power the drug release processand iontophoresis treatment. In the second experimental group, the SPEwas powered by the traditional power supply for 18min for the DEX-P-

drug release. For the proposed system, the TENG was charged foraround 18min (discontinuous charging) to power the release processand the iontophoresis treatment. As their respective blank control, nopower supply was given during the overall duration. The results illus-trate that 30.7 ng/cm2 of DEX-P- was detected in the porcine dermisafter 10min of TENG operation, while only 5.7 ng/cm2 of DEX-P- wasdetermined with traditional device, and no DEX-P- was found in theblank control. The detailed measurements are shown in Figs. S15–S16.These results demonstrate that the drug can be successfully releasedfrom the drug reservoir and delivered into the dermis by TENG op-eration. As the TENG charging time increased to 18min, we recorded anotable increment in DEX-P- penetration into the dermis up to 69.1 ng/cm2. The amount of DEX-P- under the traditional device increased aswell, reach to 14.9 ng/cm2. We also recorded negligible DEX-P pene-tration into the porcine dermis during the entire duration in the blankcontrol, which demonstrates that the on-demand drug release is ex-plicitly governed by TENG operation.

Fig. 3. (a) In the 60min measurement, the continuous voltage from both TENG and the traditional device (potentiostat) were respectively applied to charge the SPE.(b) The released drug (DEX-P) amount is recorded as per square centimeter of the PPy-coated electrode surface. (c) In the 4 h measurement, the SPE is intermittentlycharged by TENG for three times (each time followed with a pause). The applied voltage is greater than the negative 0.8 V during each period of stimulation. (d) Drugrelease is observed in the 20min electric-stimulated duration, while no drug release is recorded in the 60min pause period. (The hand shape in the graphs mean atthose certain moments, the TENG is started to being charged by hands).

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In Fig. 3a and b, we have compared the drug release performance ofthe drug-load electrode with the TENG and the traditional power supply(potentiostat device). The results demonstrate that the TENG-triggeredrelease profile matches with that of the potentiostat-triggered one. Inother words, TENG can be used as an effective substitute of the tradi-tional power supplies for drug delivery. Here, it is noted that theamount of drug penetrated into the porcine dermis with our proposedsystem is much higher than that of the traditional devices. This ismainly due to our system can enhance drug delivery efficiency in thedermis with the help of iontophoresis treatment. While for the drugdelivery with traditional devices, since they do not have the ionto-phoresis treatment, most of the released drug were accumulated on theepidermis instead of penetrating into the dermis. Therefore, eventhough giving same charging time, the drug determined in the dermiswith traditional devices is much less than that of proposed TENGsystem.

In order to visualize the drug release process, we loaded 6-carbox-yfluorescein (FLU) instead of DEX-P into the PPy film carrier to conducta similar drug delivery experiment on porcine skin. With the aid offluorescence, we were able to observe the drug penetration profile ofthe skin under the microscope. Similar to DEX-P, the negatively-charged FLU also served as the counter-ion within the PPy films.Following the reduction reaction of PPy, FLU gets released to the localenvironment. Fig. 5b–d shows fluorescent images of cross-sections ofthe porcine skin that were taken after being subjected to three differenttreatments. The detailed experimental process is shown in Figs.S17–S18. Generally, the thickness of stratum corneum and epidermis ofporcine skin is within 100– 150 μm [35]. Therefore, the dash line in thefigures is set at around 100 μm away from the skin surface. In thecontrol group A, the TENG was not operated during the entire process.

We did not detect any traces of fluorescein in stratum corneum, epi-dermis, or dermis layer, indicating that there was no passive penetra-tion of the drug in the absence of TENG operation. In group B, the TENGwas rotated for around 2min to power a 15min process of electric-stimulated release. We sampled the skin 20min after the electric-sti-mulated release. Clearly, we observed a high concentration of fluor-escein in the epidermis and slight penetration of the FLU to the dermispart of the porcine skin. In group C, we operated the TENG for 7.5 minto power a 15min duration of electric-stimulated release and a 20minduration of the iontophoresis treatment. Compared with group B, weobserved an obvious enhancement in the penetration depth of FLU inthe dermis. The FLU molecules were evenly distributed in the dermisrather than mainly accumulating in the epidermis. Specifically, thefluorescence intensity of group C at around 800 μm (from the epi-dermis) equaled to that of group B at around 400 μm, indicating∼ 50%improvement in the drug delivery efficiency by the TENG-triggerediontophoresis treatment. These results convincingly support the abilityof TENG-based transdermal drug delivery system to address the issuesof on-demand drug release and drug delivery efficacy enhancement.

3. Conclusions

In summary, we have presented a self-powered and on-demandtransdermal drug delivery system based on a minimized triboelectricnanogenerator. Two methods were developed for tuning the drug re-lease rate, namely changing the TENG charging time and changing thecircuit resistance. The ex vivo experiment on porcine skin demonstratedthat the system exhibited good controllability of drug dosage by oper-ating the TENG. The electricity generated from TENG has further uti-lized to power the iontophoresis treatment, leading to an enhancement

Fig. 4. The drug release speed is directly correlated with the duration of the effective voltage (> -0.8 V) applied on the SPE. (a) The monitoring of voltages applied onthe SPE for varying TENG charging time. The resistance of the external resistor is fixed at 1MΩ. (b) The corresponding drug release profiles for increased TENGcharging time. (c) The monitoring of voltages applied on the SPE for varying resistance of the external resistor in the management circuit. The TENG charged time isfixed at 5min. (d) The corresponding drug release profiles for increased resistance of the external resistor.

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in drug delivery efficiency compared with conventional transdermalpatches. These results confirm that the TENG-based drug deliverysystem is able to realize effective and highly controllable drug dosingwith a small footprint, providing patients a convenient solution to sa-tisfy customized needs of personalized therapeutic healthcare.Furthermore, owing to TENG's advantages of having simple fabrication,low-cost, and immunity to external environment, the entire TENG-based transdermal drug delivery system can be engineered as a wear-able drug delivery device. In addition, this novel technology connectingthe TENG with drug delivery devices is expected to be applied in otherroutes of drug delivery, which will significantly expand the possibilitiesof personalized healthcare.

4. Experimental section

Fabrication of TENG: The TENG was composed of three layers: alayer of metal Cu patterned with radial-arrayed strips, a layer of PTFEfilm, and another layer of metal Cu patterned with two sets of com-plementary radial-arrayed electrodes (Fig. 1). We fabricated the metalstructure by using a standard printed circuit board technology. TheTENG layers were packaged in plastic sheets (PMMA) for motor driving.Two wires were connected to each side of the electrodes for producingthe output current/voltage. The PTFE film was fattened and pasted onthe layer of the Cu electrode (Fig. S2).

Preparation of drug patch: The drug delivery system was composedof two parts: i) a drug-containing electrode serving as the drug re-servoir, and ii) the control circuit. The commercial planar printable Auelectrode was employed for further modification. We used an AutolabPotentiostat (PGSTAT302 N, Metrohm) to grow the PPy/DEX-P film onthe gold electrode potentionstatically. Prior to the electropolymeriza-tion, we cleaned the Au electrode with UV ozone for 30min. Then, wedropped 10 μL of Polystyrene colloid particles (50 nm) on the surface toform the template. The deposition solution (1mL) contained 0.1Mpyrrole (Sigma) and 0.1M Dexamethasone disodium phosphate(Sigma). A constant positive voltage (0.8 V) was applied for electro-polymerization. For the loose structure of PPy, the voltage appliedduration was 60s, while for the compact structure of PPy, the durationwas 160s. After that, we removed the PS nanospheres by immersing thesamples in toluene overnight.

DEX-P Measurement: The TENG was driven by hand motion. Wemeasured the output voltage and current of the TENG by low-noisevoltage preamplifiers (Keithley 6514). We observed the UV absorbance(242 nm) of the released DEX-P solution with Nanodrop (2000a). Weused SEM to detect the morphology of the PPy.

Measurement of the bioactivity of released drug: We cultured RAW264.7 cells in Dulbecco's modified Eagles medium (DMEM) supple-mented with 100 μg/mL penicillin, 100 μg/mL streptomycin, and 10%fetal bovine serum (FBS) at 37 °C with 5% CO2. We plated RAW264.7 cells at 5× 105 cells/ml and stimulated with LPS (1 μg/ml) in thepresence or absence of DEX-P (0.01 μM, 0.1 μM, and 1 μM) for 48 h in24-well culture plates. The IL-1β containing supernatants were har-vested. We used the standard ELISA kit to determine the concentrationof IL-1β protein (Catalog No. EM2IL1B, Thermo Fisher) according to themanuals.

Ex vivo drug delivery on porcine skin: The target porcine skin wascut into pieces of 0.5× 0.5 cm and then soaked in PBS for 12 h. Thesupernatant was collected and centrifuged with the centrifuge tubefilters (Costar, Spin-X®, CLS8161) at 6000 rpm for 10min. The high-performance liquid chromatography (Shimadzu, UFLC, 20A) was em-ployed to assay the concentrations of DEX that penetrated into theporcine skin under isocratic conditions. The mobile phase of 30%–60%acetonitrile (0.5 mL/min) was pumped through a 4.6×150mmcolumn packed with 3.6 μm C18 end-capped silica reversed-phaseparticles (Aeris PEPTIDE 00B-4507-AN). The column temperature wasmaintained at 40 °C. The injection volume was 100 μL. The UV absor-bance at 242 nm was used for detection.

Frozen section procedure of porcine skin: The target skin was cutinto pieces of 0.5× 0.5 cm and stored at -20 °C. The temperature of themain cryostat chamber and the quick freeze compartment was set at -20 °C and -18 °C respectively (LEICA, CM 1950). The angle of the bladewas adjusted to 15°. An embedding compound was put on the stage firstand the sample tissue was then placed on the stage. The sample wasfrozen with the cryospray. Next, the stage with the sample was placedon the stage clamp and the angle was adjusted until the cross-section ofthe sample was parallel to the blade. The sample was cut to a thicknessof 20 μm and stick on to the prepared slide immediately. The slidesshould be stored at -20 °C until use.

Fig. 5. (a) The determination of the amount of released DEX-P- penetration intothe porcine dermis. First group: The SPE was powered by the traditional powersupply (potentiostat) for 10min for the drug release. For the proposed system,TENG was charged manually for 10min to power the SPE (for around 15min)and iontophoresis treatment (for around 30min). Second group, The SPE waspowered by the potentiostat for 18min for the drug release. For the proposedsystem, the TENG was operated for 18min to power the SPE (for around15min) and the iontophoresis (for around 60min). In both the two groups, weset the control groups, where no power supply was given during the entiretreatment. The three fluorescent images show the drug delivery test on porcineskin ex vivo for the proposed system. FLU was doped into the PPy films tovisualize the drug delivery procedure. (b) TENG is not operated during thewhole process. (c) The TENGs were rotated for 2 min to power the releaseelectrode for 15min followed by no power in the next 20min (d) The TENG wasoperated for 7.5 min to power the SPE for 15min, followed by iontophoresistherapy for 20min.

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Conflicts of interest

The authors declare no competing interests.

Authors contributions

Q. O., X. F., K. Y. and Z. W. jointly conceived the idea and design ofexperiments; S. K., P. Y., and G. Zhu. designed and fabricated TENG; Q.O., X. F., performed the drug release experiments, acquired data, ana-lyzed data, and wrote the manuscript; Q. O., C. Y., G. Y. and X. H.,performed the ex vivo experiments, H. Y. and J. T helped in the ex vivoexperiments; Q. O. and G. Z designed the management circuit; Q. O., X.F. and G. Z generated figures; N. P. and P. Y. helped write the manu-script; G. Zhu., K. Y. and Z. W. supervised and coordinated the entireproject.

Acknowledgements

The authors would like to acknowledge the support of SingaporeNTU-A*STAR Silicon Technologies, Centre of Excellence (Grant No.11235100003), Academic Research Grant Tier 3 (MOE2016-T3-1-003)from Singapore Ministry of Education (MOE), National Key R&D Project(Grant No. 2016YFA0202701 and 2016YFA0202703) from the Ministryof Science and Technology of China, Zhejiang Provincial NaturalScience Foundation of China (Grant No. LR19F010001), NationalScience Foundation of China (Grant No. 51572030), Natural ScienceFoundation of Beijing Municipality (Grant No. 2162047). X. F. and B. L.acknowledge support from National Research Foundation of Singaporeunder Competitive Research Program (Project number: NRF2014NRF-CRP001-002). Q. O. would like to thank the School of Electrical andElectronic Engineering and CINTRA at Nanyang TechnologicalUniversity, and Dr. Yi-Hsin Chien, Dr. Lixing Kang and Dr. Mingjie Yinfor their assistance with this project.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.nanoen.2019.05.056.

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Qingling Ouyang is currently a Ph.D. candidate in theSchool of Electrical and Electronic Engineering and a pro-ject officer in CNRS-International-NTU-THALES ResearchAlliances (CINTRA), at Nanyang Technological University,Singapore. She received her B.S. (2014) in ShenzhenUniversity, China. Her research interest is the applicationsof nanomaterials for nanomedicine and biophotonics fields,including drug delivery, triboelectric devices and plasmonicsensors for biomedical applications.

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Dr. Xueling FENG received her Ph.D. degree fromUniversity of Twente, the Netherlands in 2015. After that,she worked at Center of Biomimetic Sensor Science (CBSS)in Nanyang Technological University, Singapore, as aResearch Fellow. She now is a professor in DonghuaUniversity, China. Her research interests are focused onstimuli-responsive polymer and sensing system.

Dr. Shuangyang Kuang is currently a research fellow inHuazhong University of Science and Technology (HUST),China. He received his B.S. in Shandong University, China,and Ph.D. (2018) in Beijing Institute of Nanoenergy andNanosystems, Chinese Academy of Sciences, China. His re-search interests include applications and fabrication of tri-boelectric nanogenerators.

Dr. Nishtha Panwar completed her PhD at the NanyangTechnological University (Singapore, 2018) in the area ofminiature flow cytometry for applications in cancer ther-anostics. She graduated in Electrical Engineering at JamiaMillia Islamia (New Delhi, India, 2010) and received herMaster's degree in Advanced Instrumentation at CSIR-Central Scientific Instruments Organisation (Chandigarh,India, 2012). She is currently pursuing post-doctoral re-search at NTU on the use of novel nanomaterials for RNAinterference in cancer therapy. She is also exploring organ-on-a-chip studies for evaluating pancreatic cancer ther-anostics approaches.

Dr. Peiyi Song is currently an associate professor inHuazhong University of Science and Technology (HUST),China. He received his B.S. (2011) in HUST, and Ph.D.(2016) in Nanyang Technological University (NTU),Singapore. His research interests include micro-fabrica-tions, microfluidics, advanced sensors & actuators andmicro-electric thruster for cubesats.

Dr. Chengbin Yang is an assistant professor of the schoolof biomedical engineering, health science center, atShenzhen University. He received his Ph.D. degree in bio-photonics from Nanyang Technological University in 2018.His research interests are cancer gene therapy based onbiodegradable polymer and multifunctional hybrid nano-particles.

Guang Yang is currently a Ph.D. candidate in the School ofElectrical and Electronic Engineering, NanyangTechnological University, Singapore. His research interestis the application of lab-on-a-chip and triboelectric devicesfor biomedical research.

Dr. Xinya Hemu received her Ph.D degree from NanyangTechnological University in 2014. After graduation, shecontinued research as a post-doctoral fellow in School ofBiological Sciences. Her current research mainly focuses onchemical and enzymatic engineering of peptides and pro-teins and synthetic biotechnology.

Dr. Gong Zhang is a research fellow in the School ofElectrical and Electronic Engineering at NanyangTechnological University (NTU), Singapore. He received hisPh.D. degree in silicon photonics from NTU in 2019, and hisB.Eng. in mechanical engineering from Xi'an JiaotongUniversity, China (XJTU) in 2014. He has received anumber of awards, including the Best Paper Award in AQE2018 conference, and the University Best Final Year Project(thesis) award in XJTU (2014). His research interests in-clude silicon photonic applications, e.g., gas sensing, bio-sensing and quantum information.

Prof. Ho Sup Yoon is Research Director (BiomedicalSciences) in the President's Office and Professor in theSchool of Biological Sciences at Nanyang TechnologicalUniversity (NTU), Singapore. He received his BSc fromSeoul National University and MSc from Korea AdvancedInstitute of Science and Technology (KAIST) and PhD(Biochemistry & Molecular Biology) from University ofChicago. Prior to joining NTU, he worked as a ResearchScientist and Sr. Research Scientist at Abbott Laboratories,USA. Prof Yoon's current research programs focus onstructural plasticity of the anti-cell death proteins, roles ofimmunophilins in human diseases, transcriptional activa-tion mechanism of orphan nuclear receptors and role ofintrinsically disordered proteins in conformational dis-

orders such as Parkinson's Disease.

Prof. James P Tam is currently Director of Synzymes andNatural Products Center and Lee Wee Nam Professor atNanyang Technological University, Singapore. His Researchinterest: Discovery, design and development of ther-apeutics, particularly orally active biologics, immunologicsand anti-infectives. The awards received by Professor Tamare the Vincent du Vigneaud Award, the Rao MakineniAward by American Peptide Society, the Ralph F.Hirschmann Award by the American Chemical Society, theMerrifield Award by American Peptide Society and theAkabori Memorial Award by Japanese Peptide Society. In2018, Professor Tam was awarded the Josef RudingerMemorial Award by The European Peptide Society and theScience China Chemistry Award by The China Peptide

Society. He was also elected as a Fellow by the Singapore National Academy of Science forhis outstanding contributions to peptide and protein sciences.

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Prof. Bo LIEDBERG received his Ph.D degree fromLinköping University in 1986. He is currently the Directorof the Centre for Biomimetic Sensor Science (CBSS) inNanyang Technological University (NTU), Singapore. Thefocus has been on optical sensors based on surface plasmon,ellipsometric and reflectometric transduction principles.His current activities are devoted to the development ofadvanced surface chemistries and nanomaterials for nextgeneration robust sensor technology. He has long experi-ence in surface vibrational spectroscopy. Liedberg alsoserves as Senior Executive Director of InterdisciplinaryGraduate Programmes in the Graduate College, NTU.

Prof. Guang Zhu is currently a professor in University ofNottingham Ningbo China. His research mainly focuses onthe fundamentals and applications of functional flexiblematerials their uses in flexible transducers. He has pub-lished 50 first-authored and correspondence-authored re-search papers on internationally prestigious journals suchas Nat. Commun., Adv. Mater., and Nano Lett. Total pub-lication citations by 11,000 times with average impactfactor of 12 and H-index of 51. He has granted with 6 USpatents and 25 Chinese patents. His research achievementshave been highlighted by the top journals including Scienceand Nature, and reported by public media such as CNN,Reuters, CCTV, and Chinese Science News.

Prof. Ken-Tye Yong is director of the Bio Devices andSignal Analysis (VALENS) and associate professor in theSchool of Electrical and Electronic Engineering at NanyangTechnological University. He obtained his PhD degree inChemical and Biological Engineering from SUNY at Buffaloin 2006. His research focus is in the area of biophotonics,nanomedicine, and BioMEMS. He has published more than200 research papers on internationally journals, includingprestigious journals such as Nat Nanotechnol., Adv. Mater.,and Nano Lett. He was awarded the Rosenhain Medal andPrize in 2018 and is a recipient for the Beilby Medal andPrize for 2017.

Prof. Zhong Lin Wang received his Ph.D. from ArizonaState University in physics. He now is the Hightower Chairin Materials Science and Engineering, Regents' Professor,Engineering Distinguished Professor and Director, Centerfor Nanostructure Characterization, at Georgia Tech. Prof.Wang has made original and innovative contributions to thesynthesis, discovery, characterization and understanding offundamental physical properties of oxide nanobelts andnanowires, as well as applications of nanowires in energysciences, electronics, optoelectronics and biological science.His discovery and breakthroughs in developing nanogen-erators established the principle and technological roadmap for harvesting mechanical energy from environment

and biological systems for powering personal electronics. His research on self-powerednanosystems has inspired the worldwide effort in academia and industry for studyingenergy for micro-nano-systems, which is now a distinct disciplinary in energy researchand future sensor networks. He coined and pioneered the field of piezotronics and pie-zophototronics by introducing piezoelectric potential gated charge transport process infabricating new electronic and optoelectronic devices. Details can be found at: http://www.nanoscience.gatech.edu.

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