Development of a miniaturised drug delivery systemwith wireless power transfer and communication

S. Smith, T.B. Tang, J.G. Terry, J.T.M. Stevenson, B.W. Flynn, H.M. Reekie, A.F. Murray, A.M. Gundlach,D. Renshaw, B. Dhillon, A. Ohtori, Y. Inoue and A.J. Walton

Abstract: The development of an implantable system designed to deliver drug doses in a controlledmanner over an extended time period is reported. Key performance parameters are the physicalsize, the power consumption and also the ability to perform wireless communications to enablethe system to be externally controlled and interrogated. The system has been designed to facilitatewireless power transfer, which is very important for miniaturisation as it removes the need for abattery.

1 Introduction

The ability to deliver metered doses of a drug to a localisedsite is increasingly the focus of much micro- and nano-systems research. By releasing drugs in a controlledmanner at a required site, microdrug delivery systems canreduce the negative side effects associated with systemicmedication. In addition, drug doses can be delivered to thedisease location in a highly concentrated form that wouldbe damaging to the body if delivered in a traditional manner.The specific objective of the work described was to investi-

gate the feasibility of implementing an implantable micro-electro-mechanical systems (MEMS) drug delivery systemsuitable for intraocular applications. The device would be per-manently implanted and capable of delivering daily doses of adrug for up to 1 year. Power and communication with thedevice would be provided by a wireless link that would onlybe activated when required by the system, thereby reducingpower and exposure to radio frequency (RF) radiation. Thesingle operation to implant the device would obviate theneed for regular, painful and invasive injections.

2 Background

Micromachined drug release systems come in two mainforms: passive devices where the point is to control therate of diffusion of the drug being delivered, and activedevices where a dose of the drug can be released at a con-trolled time, usually with an external trigger. Passive drugdelivery devices are either large structures implanted atthe required position or smaller objects that can be injectedand then travel to the correct position. Examples of devices

# The Institution of Engineering and Technology 2007

doi:10.1049/iet-nbt:20070022

Paper first received 10th April and in revised form 9th July 2007

S. Smith, T.B. Tang, J.G. Terry, J.T.M. Stevenson, B.W. Flynn, H.M. Reekie,A.F. Murray, A.M. Gundlach, D. Renshaw and A.J. Walton are with theInstitute of Integrated Micro and Nano Systems, School of Engineering andElectronics, Scottish Microelectronics Centre, The University of Edinburgh,Kings Buildings, Edinburgh EH9 3JF, UK

B. Dhillon is with the Princess Alexandria Eye Pavilion, Chalmers Street,Edinburgh EH3 9HA, UK

A. Ohtori and Y. Inoue are with Senju Pharmaceutical Co. Ltd, 1-5-4, Murotani,Nishiku, Kobe, Hyogo 651-2241, Japan

E-mail: stewart.smith@ed.ac.uk

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using silicon structures to provide delayed drug releaseinclude chips with nanoengineered channels that enableslow, zero-order diffusion [1] and porous silicon pelletscoated in a drug [2]. The porous silicon is extremely inter-esting because it is biodegradable, in addition to being bio-compatible, and this means that it is suitable for othermedical applications such as a scaffold for bone growth.Active drug release systems include micropumps and

valves using shape memory alloys [3], [4], silicon piezo-electric micropumps [5], transdermal microneedles [6] andmicroreservoir chips, where the drug is released bymelting a metal membrane [7].The drug delivery system used here is based on a device

reported in Nature [8], consisting of a microarray of sealedsilicon reservoirs containing the required drug(s), which canbe released electrochemically by the removal of a gold cap.Fig. 1 illustrates this concept. More recently, the companyformed to commercialise the MIT work, MicroCHIPS,have presented results of an in vivo trial using their implan-table drug release system [9]. Their device consists of a drugdelivery chip with 100 cavities packaged along with abattery, control electronics and wireless communications.This device uses a different release mechanism, by whicha thin metal membrane sealing the drug cavity is removedelectrothermally as described in [10]. In this example, thecomplete device is �5 cm long and 4 cm wide, whichmakes it unsuitable for implantation into the posteriorcavity of the eye.In a silicon drug delivery device as originally envisaged

in [8], the gold cap over the reservoir forms the anode ofan electrochemical cell. In the presence of a solution con-taining chloride ions, the gold anode reacts to formgold(III) chloride complexes that are soluble in anaqueous electrolyte [11]. There have been some concernsabout the toxicity of gold(III) complexes, but in vivostudies based on the use of gold implants have onlyshown significant immune reactions when the dosage was.250 mg [12]. The amount of gold converted whenopening one of these devices is significantly lower, of theorder of 10 ng.The initial study found that the gold dissolution reaction

occurred when a voltage of þ1.04 V against saturatedcalomel reference electrode (SCE) was applied to theanode when immersed in 0.1 M phosphate-buffered saline(PBS). When this voltage is applied for 10–30 s, the cap

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is removed and the drug in the reservoir diffuses out into theelectrolyte over the space of 1–2 h. In order to ensure thatgold is only removed from the desired areas, the surfaceis covered with a passivation layer of silicon dioxide, ornitride, and patterned to expose certain areas to theelectrolyte.

3 System description

Fig. 2 shows a block diagram of an implantable drug deliv-ery system that consists of three main parts: the drug deliv-ery chip, the control circuitry to facilitate the release ofdrugs from the cavities and the RF/communicationssystem to transfer power and data. Integration of celladdressing onto the drug delivery chip, reduction ofcontrol circuitry to a single IC and the use of wirelesspower transfer without a battery will all help to reduce thesize of the system; the ultimate aim is a complete implanta-ble device with dimensions of 5 � 5 � 5 mm or less. It isthis combination of miniaturisation and integration,coupled with the addition of wireless power transfer, thatdistinguishes the drug delivery system described in thisarticle from systems described in the literature.

3.1 Drug delivery chip

The drug delivery chip comprises an array of cavities (Fig.1shows a cross-section through a single cavity), each ofwhich can be individually activated [13]. When thenumber of reservoirs is small, it is feasible for each goldcap to be individually wired to the control system.However, as the number of cavities increases, a row andcolumn addressing system, using on-chip complementarymetal oxide semiconductor (CMOS) circuitry, becomesessential to reduce the number of connections.

3.2 Control circuitry

When the system is activated, the control chip needs todetermine which of the cavities will be opened next and

Fig. 2 Block diagram of implantable drug delivery system withwireless communications and power transfer

Fig. 1 Schematic cross section through an electrochemical drugrelease cell where the anode forms a membrane that is removedduring drug release

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then apply the correct voltage signal to the drug deliverychip in order to release the dose of drug. In the absence ofon-board memory, the control chip must test the status ofeach cell on the drug delivery chip and determine whichcavities have already been opened. There are manyaspects of the control circuitry that require careful attention,not least of which is a fail-safe system that ensures thatunder no circumstances can multiple cavities be openedsimultaneously.

3.3 RF power and communications

The RF power system receives power wirelessly from anexternal base station and converts this into the voltagesrequired by the control and drug delivery chips. Iftwo-way communication is required, this system alsoneeds to transmit information about the status of thesystem back to the base station. For example, this couldinclude information about which cavities on the drug deliv-ery chip have been opened and the readings of any on-boardsensor measuring drug concentration or other environ-mental parameters.

4 Design considerations

Consideration must be given to the method of fabricatingsilicon cavities as this impacts on both the number andthe volume of the reservoirs. The gold cap on the reservoirhas an important role as it seals one end of the cavity. It isalso the most fragile part of the structure. Therefore a robustmethod of protecting the caps during processing is essentialin order to achieve acceptable yields for these devices.Once the cavities have been fabricated, they must be

filled and sealed, and a wide range of different techniquesfor achieving this have been assessed. The filled devicesmust then be packaged, which requires electrical connec-tions that are waterproof, bearing in mind that the goldcaps over the reservoirs must be exposed to the electrolyte.Finally, the correct electrical excitation required to

quickly and reliably open the gold caps must be determined,as this places limits on the systems used to power andcontrol the device.

5 Fabrication technology

This section describes the methods used to fabricate theinitial prototype drug delivery devices. These are fullywired structures that do not require any on-chip electronics.The process flow is shown in Fig. 3.

5.1 Cavity construction

The bulk etching or micromachining of silicon is a standardtechnology in MEMS fabrication [14]. Isotropic etch pro-cesses remove exposed silicon equally quickly in all direc-tions giving a rounded hole. Anisotropic etches can be splitinto two groups depending on whether a wet or dry processis used. Wet anisotropic etches tend to preferentiallyremove silicon in certain crystal planes and will be dis-cussed in more detail later in this document. Dry anisotropicetch processes can produce a number of different etch pro-files but the most common is the Bosch process, which iscapable of producing high aspect ratio cavities withalmost vertical sidewalls [15].Anisotropic wet silicon etch processes remove (1 1 1)

oriented silicon planes significantly more slowly than theother crystal planes. As a result, cavities fabricated usingthese methods will have smooth, well-defined (1 1 1)

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Fig. 3 Simplified process flow for drug release chip where each step is illustrated both in plan view and in cross section

a Silicon wafer is polished on both sides and oxidised. The oxide layer is thicker on one sideb Silicon nitride is deposited by low pressure chemical vapour deposition (LPCVD)c Opening for TMAH etch opened in side with thick SiO2

d Opening for TMAH etch opened in side with thick SiO2

e Gold deposited and patterned by lift-off processf Thick Parylene layer deposited over gold electrodesg Reactive ion etch (RIE) of oxide/nitride membraneh Oxygen plasma RIE of Parylene passivationi Drug reservoir filled and sealed

sidewalls. In practice, what this means is that a squarecavity etched into silicon with a (1 0 0) surface will havesidewalls with an angle of �54.748 to the surface. This isillustrated in Fig. 3f.A number of different etchants produce this type of

silicon profile, and tetramethyl ammonium hydroxide[TMAH, (CH3)4NOH) [16, 17] has been selected forthis work, as it is compatible with CMOS technology[18]. It has the further advantages that it can be mixedwith other chemicals to prevent it etching aluminiuminterconnect [19] and that it is less toxic than most

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other anisotropic etch solutions, such as alkaline metalhydroxides.The etch solution used was 22% TMAH in water, heated

to 908C, providing a ,100. etch rate of �40 mm min21.The relatively high concentration and temperature give aneven etch, without hillocking [17], while still stopping onthe membrane of silicon dioxide and nitride upon whichthe gold electrode is fabricated.The dimensions of cavities produced by TMAH etching

of (1 0 0) silicon depend on the thickness of the waferand the desired size of the small hole on the front side.

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If a 50 mm square hole is desired on the front of a 385 mmthick silicon wafer, a �590 mm square is required on theback and the resulting cavity has a volume of �50 nl.Assuming a 10 mm space between the cavities, the pitchis 600 mm, which limits the packing density of cavities onthe chip. An alternative would be to use the Boschprocess to produce high aspect ratio cavities with verticalsidewalls. This provides a huge increase in the packingdensity of the reservoirs, enabling many hundreds ofdoses to be placed on a chip ,5 mm square. However, a50 mm square, vertical-walled cavity in a 385 mm thickwafer has a volume of just under 1 nl. The key to thisapproach is to find a drug that can be sufficiently concen-trated to be useful in such a tiny dosage.

5.2 Drug release membranes

There are two different approaches to fabricate the goldelectrodes that will ultimately become the seal over thedrug reservoir. In one process, the gold is deposited onthe wafer before TMAH etching and covered with a passi-vation layer to protect it during subsequent steps.Alternatively, the cavities can be etched first, before thegold is deposited and patterned on the dielectric membranecovering the cavity opening. Each architecture has advan-tages and potential issues, but it was decided that depositingthe gold before wet etching (as shown in Fig. 3) was prefer-able. This avoids the need for processing on the thin dielec-tric membrane and allows the gold to be protected by a thickParylene layer during the wet etch.In either case, the final stages of processing are to remove

the dielectric membrane separating the gold from the cavity(Fig. 3g) and to pattern the passivation over the gold(Fig. 3h). The dielectric membrane, which consists of athin, low stress, bilayer of thermal silicon dioxide and lowpressure stoichiometric silicon nitride, is removed fromthe cavity side by a reactive ion etch process. The passiva-tion layer is a vapour-deposited organic polymer, ParyleneC, (trade name for a group of para-xylene-based polymersdeposited under vacuum at room temperature [20]) whichforms a conformal coating over the gold and is biocompati-ble [21–23]. Parylene is extremely chemically resistance,but can be etched at up to 220 nm/min in an oxygenplasma [24]. Fig. 4 shows a gold cap after it has beenreleased from the top passivation and the dielectricmembrane.The nominal thickness of the gold cap is 300 nm, which

should be capable of withstanding a pressure of up to 60 psi[25].

Fig. 4 Photomicrograph of a pair of gold electrodes where thecentral anode covers a micromachined cavity

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5.3 Filling and sealing

A number of different methods have been considered for thefilling of micromachined cavities with a drug solution andthereafter sealing them. The original plan was to use aninkjet system, normally used to spot liquids onto micro-scope slides for DNA arrays, but it was felt that this wasunnecessary for these prototype samples that had only asmall number of cavities. A manual system using a drawnglass capillary tube allowed the filling of individual cavitieswithout spreading the liquid between the reservoirs.Unfortunately, this typically led to air being sealed intothe cavities, as the liquid evaporated quickly before theseal could be put in place.The seal itself is an additional challenge. A number of

different adhesives, including cyanoacrylates, UV curingepoxies and polydimethylsiloxane elastomer (PDMS),were used to bond glass cover slips over the cavities. Thiswas partially successful, but had problems in that theadhesives tended to be hydrophilic and attracted the liquidout of the cavities, leading to a poor seal.A practical filling technique using a low-tack, water-

proof, adhesive tape was finally established as the pre-ferred approach. The cavities are overfilled before thetape is applied. Force is then applied to squeeze out theexcess liquid and fix the tape to the silicon surface.Fig. 5 shows the result of sealing liquid into an array ofmicromachined cavities. It should be noted that the tapeonly serves to seal the cavities until the chips are pack-aged. During packaging, the chips are encapsulated witha solid epoxy that immobilises the device to the packagesurface and should prevent any leakage from the cavities.However, it is likely that a more permanent seal would berequired in a device intended for long-term or permanentimplantation.

6 Control system

Test structures consisting of arrays of gold electrodes werefabricated to characterise the voltage levels required to openthe drug reservoirs. This established that the voltagerequired for the reaction without a reference electrode wasgreater than the figure reported in [11]. A square wave,1 Hz, signal stepping between 0 and þ3 V was appliedbetween an anode and nearby cathode, and the resultingcurrent flow is presented in Fig. 6. This stripped theexposed area of the anode in ,30 s, which was confirmedboth by observation of the electrode and by the reductionin the current drawn between 25 and 30 s of operation.

Fig. 5 Array of micromachined silicon cavities filled with liquidand sealed with low-tack, waterproof adhesive tape

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7 Prototype chip

A prototype device was designed with 12, TMAH-etched,cavities that can be individually addressed and the layoutis shown in Fig. 7. It has 14 bond pads, one for eachanode cap, and two separate cathode connections.

7.1 In vitro packaging

This 3 � 3 mm chip was designed for in vivo testingwhere it could be packaged into a system no larger than5 � 5 � 5 mm. However, for initial in vitro testing, thechip was packaged into a standard dual-in-line (DIL)package, as illustrated in Fig. 8.Once the chip was glued in place and the electrical bonds

were made to the package with gold wire, a thick, UVcuring epoxy was applied. This protected the wires whileleaving the front of the chip exposed. The plastic ring wasglued in place to provide a reservoir for the saline electro-lyte used in testing.

7.2 In vivo packaging

There is no suitable standard IC package available and sothe packaging for in vivo devices used a custom, double-sided printed circuit board (PCB) (Fig. 9a), �5 mmsquare, onto which the prototype chip was attached. ThePCB has gold-coated tracks, suitable for wire bondingbetween it and the chip. Connections from the PCB to theoutside world were made using �100 mm diameter,Teflon-coated, platinum wires. An example of a packagedin vivo device is shown in Fig. 9b.

Fig. 6 Current as a function of time for a square wave voltagesignal applied to Au electrode in PBS

Fig. 7 Schematic layout of prototype drug release chip

Front side shows gold electrodes while back side shows cavityopenings.

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Fig. 9 Packaging of drug delivery chips for in vivo testing

a PCB for in vivo packagingb Prototype chip packaged on PCB

Fig. 10 Electrical switch box used to control drug release proto-type chips

Fig. 8 DIL package with prototype drug release chip

Fig. 11 Microscope images of fluorescein release from prototypechip

a Startb After 5 sc After 10 sd After 25 s

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Fig. 12 Block diagram of a wireless power transfer and communications system

As with the DIL package, the wire bonds and other elec-trical connections are covered with a UV-cured epoxy. It isalso possible to use this material to cover any cavitiesdamaged during processing (a repaired cavity is shown inFig. 9b).

8 Drug release testing

Prototype chips were filled with a 20% solution of fluor-escein sodium: a yellow/green fluorescent dye commonlyused as a diagnostic aid in ophthalmology [26]. The filledchips were packaged as described earlier and a portablecontrol system was used to activate and open individualcavities. This control box (Fig. 10) was custom built fortesting these devices, containing a 9 V battery and the elec-tronics required to generate the correct square wave voltagesignal. A switch on the side of the box allowed the user tochoose any one of the 12 cavities on the chip under test.

8.1 In vitro testing

8.1.1 Wired: In vitro testing was performed using a 10%solution of PBS as the electrolyte. The images in Fig. 11show that fluorescein release begins within 5 s of activationand continues for some time afterwards. If the voltage sup-plied to the cell is a 3 V square wave with a 66% duty cycle,and the current that flows while the voltage is high is no.30 mA, the energy required to open the reservoir in 5 sis �300 mJ, with a maximum power of 90 mW.

8.1.2 Wireless: Fig. 12 shows the architecture of a wire-less power transfer and communications system designedto be used with the prototype drug release chips. It operatesby near-field inductive coupling between two resonant LCtanks. The transmission side includes a keypad controllinga Dual-Tone MultiFrequency (DTMF) encoder similar tothat used in touch-tone telephones. The output of theDTMF encoder is used to modulate the RF power signal.On the receiver, side part of the circuit decodes the infor-mation, whereas the other part turns the RF power intothe correct square wave voltage signal required to open acavity. The decoded DTMF information controls a demulti-plexer that directs the square wave voltage to the correctanode electrode on the drug release chip. This means thatany one of the 12 cavities can be selected and opened bypressing the correct key on the transmitter side keypad.The system operates at a frequency of 7.1 MHz and iscapable of transmitting over 500 mW of power over a dis-tance of 30 mm using 0.1 M PBS as a transmissionmedium. The receiver system requires �370 mW of

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power to operate, including the 90 mW required to open acavity, and the transmitter is certainly capable of supplyingthis. Further details of the RF power and communicationsystem, including results of transmitting power to a receiverimplanted into an ex vivo animal eye model, are presented in[27, 28].

8.2 In vivo testing

A prototype device similar to that shown in Fig. 9 has beenimplanted temporarily into the eye of a rabbit. This was suc-cessfully activated and the release of fluorescein wasobserved externally through the cornea. The fluoresceinwas visible 5 min after activation and diffused through thewhole of the vitreous cavity of the rabbit eye within 1 h.

9 Discussion and conclusions

An active, low-power MEMS drug delivery system,intended for ophthalmic applications, has been described.It comprises an MEMS drug release device, control circui-try and a wireless power and communications system. Itoperates by using an electrochemical reaction to remove agold cap that seals a reservoir containing a dose of a drug.Although the release method is well understood and isbeing commercialised by the original researchers, thesystem described here, using direct wireless power transferand communications, has the potential to allow for a minia-turised implant. Without a battery and discrete electronics,which would require bulky encapsulation, the entiresystem can be contained in a package only a few millimetresacross. This enables it to be implanted into a wider range oflocations within the body, such as into the vitreous cavity ofthe eye where it could release drugs to control chronic dis-eases such as glaucoma. It should be noted that the PCBrequired for the interconnect and the epoxy resin coveringthe prototype dominates the device volume. Obviously,this volume will be considerably reduced in a fully engin-eered implantable package.The fabrication process used to create the reservoirs, cap

them with a gold electrode membrane and then fill and sealthem has been described. Prototype devices were fabricatedand tested using a fluorescent dye as the reservoir contents.The release of the dye has been demonstrated in vitro andthe maximum power required is shown to be ,100 mW.Wireless powered drug release and in vivo results havealso been described.Future work is required to upgrade the packaging tech-

nology used, as well as to increase the density of the drugreservoirs.

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