Bioelectronic silicon nanowire devices usingfunctional membrane proteinsNipun Misraa,b,1, Julio A. Martineza,c,1, Shih-Chieh J. Huanga,d, Yinmin Wanga, Pieter Stroevec, Costas P. Grigoropoulosb,and Aleksandr Noya,2

aPhysical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550; bDepartment of Mechanical Engineering, Universityof California, Berkeley, CA 94720; cDepartment of Chemical Engineering, University of California, Davis, CA 95616; and dDepartment of Civil Engineering,University of California, Los Angeles, CA 90095

Edited by Charles M. Lieber, Harvard University, Cambridge, MA, and approved June 23, 2009 (received for review May 1, 2009)

Modern means of communication rely on electric fields and cur-rents to carry the flow of information. In contrast, biologicalsystems follow a different paradigm that uses ion gradients andcurrents, flows of small molecules, and membrane electric poten-tials. Living organisms use a sophisticated arsenal of membranereceptors, channels, and pumps to control signal transduction to adegree that is unmatched by manmade devices. Electronic circuitsthat use such biological components could achieve drasticallyincreased functionality; however, this approach requires nearlyseamless integration of biological and manmade structures. Wepresent a versatile hybrid platform for such integration that usesshielded nanowires (NWs) that are coated with a continuous lipidbilayer. We show that when shielded silicon NW transistors incor-porate transmembrane peptide pores gramicidin A and alamethicinin the lipid bilayer they can achieve ionic to electronic signaltransduction by using voltage-gated or chemically gated ion trans-port through the membrane pores.

bionanoelectronics � ion channels � silicon nanowires � lipid bilayers �membrane transport

B iological systems use a combination of ion gradients, f lowsof small molecules, membrane electric potentials, and even

light to achieve an astonishingly effective control over signaltransduction that is still largely unmatched by manmade devices.To gain this level of sophistication nature has evolved a vastarsenal of highly specific receptors, active and passive ionchannels (1, 2), photo-activated proton pumps, and ion pumps(3). Utilization of these components in electronic circuits couldachieve seamless integration of biological and manmade struc-tures (4) that would enable superior biosensing and diagnosticstools (5), advanced neuroprosthetics (6), and more efficientcomputers (7). Previous attempts at integrating biological sys-tems with microelectronics range from the early works oncapacitive stimulation of cells (8) to monitoring neuronal activitywith field-effect transistors (FETs) (9) to a recent example ofusing nanowire (NW) transistor arrays to follow neuronal signalpropagation (6). Nanomaterials that have characteristic dimen-sions comparable to the size of biological molecules open up thepossibility of such integration at an even more localized level.Some early examples include using carbon nanotubes as carriersfor transporting intracellular proteins and DNA (10) and usingsilicon NWs (SiNWs) as gene delivery vehicles for mammaliancells (11). Other work has taken advantage of the superiorelectronic properties of NWs to create specific electronic de-tectors for a variety of biomolecules (5).

An important step toward building bionanoelectronic inter-faces would involve functional integration of nanomaterials withmembrane proteins. Lipid membranes occupy a special place inthe hierarchy of the cellular structures as they represent impor-tant structural and protective elements of the cell that form astable, self-healing, and virtually impenetrable barrier to the ionsand small molecules (12). However, a lipid membrane is also anearly universal matrix that can house a virtually unlimited

number of protein machines that perform a large number ofcritical recognition, transport, and signal transduction functionsin the cell (13). Despite some initial work (14–16), the possibil-ities of using lipid membranes in nanoelectronic devices remainvirtually untapped. We have incorporated lipid bilayer mem-branes into SiNW transistors by covering the NW with a con-tinuous lipid bilayer shell that forms a barrier between the NWsurface and solution species. We show that when this ‘‘shieldedwire’’ structure incorporates transmembrane peptide pores itenables ionic to electronic signal transduction by using voltage-gated and chemically gated ion transport through the membranepores.

Results and DiscussionWe have built our bionanoelectronic devices by using a micro-fabricated SiNW transistor platform. In these devices, a SiNW isconnected to a pair of metallic source and drain electrodes (Fig.1 A and B). We used semiconducting p-doped SiNWs with thediameters in the 20- to 40-nm range (Fig. 1C) synthesized bycatalytic chemical vapor deposition (CVD) procedures that havebeen well-described in the literature (17). High quality of thestarting NW material is important for achieving high perfor-mance of the transistor devices, and transmission electronmicroscopy (TEM) images (Fig. 1C) showed that the NWs werecrystalline with a thin layer of native oxide on the surface. Wethen fabricated NW transistors by depositing SiNWs on thesurface by using a flow-alignment procedure and then connect-ing them to the source and drain electrodes by using conven-tional photolithography. Good isolation of the electrodes iscritical for successful operation of these devices in liquid;therefore we passivated the source and drain electrodes bycoating them with a conformal 80-nm-thick layer of Si3N4 (seeMethods for details). The finished chips then were mounted in afluid cell that featured polydimethylsiloxane (PDMS) micro-channels for delivery of test solutions and a reference gateelectrode inserted in the solution channel. As-fabricated SiNWtransistors show Ohmic contacts, on–off ratios of �104, andtransconductances of 100–500 nS (Fig. 1D), comparable to theparameters reported for similar devices operating in liquids (18).

The key procedure for building our bionanoelectronic devicewas the formation of the lipid bilayer on the surface of the SiNW.The hydrophilic negatively charged native oxide present on theNW surface in solution makes NWs particularly attractive as atemplate for supporting lipid bilayer formation. We have re-

Author contributions: N.M., J.A.M., and A.N. designed research; N.M. and J.A.M. performedresearch; S.-C.J.H. and Y.W. contributed new reagents/analytic tools; N.M., J.A.M., P.S.,C.P.G., and A.N. analyzed data; and N.M., J.A.M., and A.N. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

1N.M. and J.A.M. contributed equally to this work.

2To whom the correspondence should be addressed. E-mail: noy1@llnl.gov.

This article contains supporting information online at www.pnas.org/cgi/content/full/0904850106/DCSupplemental.

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ported that unilamellar vesicles fuse onto a SiNW surfaceproducing a conformal lipid bilayer coating (19). Scanningconfocal f luorescence microscopy images (see SI Appendix)showed that 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)lipid bilayers form a continuous coatings on the NWs, which forthe surface-bound NWs is likely to be ‘‘omega’’-shaped (Fig.1A), and for the NWs suspended over a TEM grid hole it shouldresemble a core-shell NW-lipid structure. Significantly, in-planelipid molecule diffusion coefficients measured by fluorescencerecovery after photobleaching (FRAP), �8 �m2/s on suspendedwires and �5 �m2/s on substrate-bound NWs, were comparableto the values reported for the supported lipid bilayers on flatglass substrates (20). These results indicate that the lipid bilayerson SiNWs are highly fluid, which is a vital property that enablesincorporation of biologically active structures into the mem-brane. The second key property of the lipid bilayer is its abilityto shield the underlying NW surface from the solution species.Indeed, cyclic voltammetry measurements using K4Fe(CN)6 as aredox probe showed that formation of the lipid bilayer on theNW surface reduced the limiting current by 85–95% relative tothe uncovered NW device (Fig. 1E).

To show that our devices can detect selective and specifictransport of ions through the lipid membrane pore, we haveexploited the sensitivity of the NW electrical response to theproton concentration in the solution. As the solution pHchanges, charging of silanol groups at the silicon oxide layer onthe surface of p-type SiNWs leads to changes of the depletionregion in the SiNW channel that then affects the source-drain

current at a given gate voltage (21). Bare NW FETs showed apronounced increase in conductance when the pH of the fluidicenvironment around the NWs was changed from 6 to 9 (Fig. 1F),which corresponded to the average pH sensitivity of 50–100nS/pH in the pH range of 5 to 9. The observed response kineticsis not limited by the device speed; rather it reflects the kineticsof solution mixing in the fluid cell. Indeed, relative conductancetraces measured in a particular experiment typically collapse ona single curve shape when normalized to the same initial andfinal levels, which strongly argues that our kinetics are limited bythe reagent delivery.

Note that protons are much smaller and much more diffusiveionic species than most redox species, including Fe(CN)6

4�;hence they present a much more stringent test to the shieldingcapacity of the lipid bilayers. Still, lipid bilayer formation on theSiNW surface led to an �10 times decrease in the FET responseto the pH changes in the fluid cell. These data indicate that theDOPC bilayer membrane blocks proton transport between thefluid environment outside the lipid bilayer and the hydrationlayer situated between the inner leaflet of the bilayer and SiNWsurface.

The final element of our bioelectronic device platform is amembrane pore channel incorporated in the lipid bilayer. Thefirst device example that we report incorporates gramicidin Apores. Gramicidin A is a short helical polypeptide from Bacillusbrevis, which can dimerize in the lipid membrane to form atransmembrane channel (Fig. 2A) that allows passage of smallmonovalent cations, while being impermeable to anions (22).

Fig. 1. Bionanoelectronic devices incorporating lipid-coated SiNWs. (A) Device schematics showing a NW connected to microfabricated source (S) and drain (D)electrodes. (Insets) The configuration of the lipid bilayer and a pore channel placed in the bilayer membrane. (B) An SEM micrograph of the NW transistor showing aNW bridging the source and drain electrodes. (Inset) A photograph of the device chip covered with a PDMS flow channel. (C) TEM micrograph of the as-synthesizedSiNW. (D) A typical IV characteristic of the SiNW transistor in fluid. (E) Cyclic voltammetry curves measured for an uncoated SiNW device (black line) and a device coatedwith the lipidbilayer (red line). Fe(CN)6 solution (10mM)wasusedasa redoxagent. (F) Timetracesof thenormalizedconductanceofanuncoatedSiNWtransistor (blackline) and SiNW transistor coated with the lipid bilayer (red) as the pH of the solution in the fluid cell was changed from 6 to 9.

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The ionic conductance of the gramicidin channel can also beselectively blocked by divalent ions (22) such as Ca2� that canbind near the mouth of the pore (Fig. 2 A and B). Recentexperiments demonstrated that ionic conductance of gramicidinA channels could be used to gate macroscopic electrochemicaltransistors (23). Similarly, incorporation of gramicidin A channelinto the lipid bilayer NW FET device leads to a dramaticrecovery of the pH response of the NW FET device (Fig. 2C),indicating that functional ion channels were formed in the lipidbilayer coating the NW. These data also confirm the long-rangelateral f luidity of our lipid bilayer membranes, which is aprerequisite for the successful transleaflet dimerization of gram-icidin A. Moreover, addition of 1 mM Ca2� to the solutiondramatically alters the device behavior: the magnitude of theresponse to pH change drops by �60% (Fig. 2C). These resultsare consistent with reports that show a 20–50% decrease inconductance of gramicidin A channels in the presence of Ca2�

ions (24). Our measurements demonstrate that our bionano-electronic device platform can successfully convert chemicalsignals (pH change) into an electrical signal and that deviceefficiency can be regulated by using the same ligand-gatingmechanism used by the biological systems.

Another exciting possibility is to use the intrinsic electronicfunctionality of the device itself to control ion transport throughan ion channel in the lipid membrane surrounding the NW. Wedemonstrated this gating mechanism by using devices thatincorporated self-inserting voltage-gated alamethicin (ALM)pores. ALM is a peptide antibiotic from the fungus Trichodermaviride that is often used to mimic nerve cell action potentialacross artificial membranes. ALM forms ion channels in lipidbilayer membranes (Fig. 3A) by spontaneous insertion andaggregation of 4–6 individual ALM helices into a helix bundle

(22). Although some debate about the exact mechanism of thevoltage-gated transport in ALM pores remains (25–27), researchindicates that at positive applied transmembrane voltages on theinsertion side (cis-side) ALM forms barrel-staved functionalopen pores big enough for small monovalent cations to diffusethrough, whereas these pores do not form at zero bias or negativebias (25). Some evidence (28) indicates that at negative mem-brane potentials ALM helices do not span the entire transmem-brane thickness, yet at the positive membrane potentials thehelices tilt enough to penetrate the membrane completely andform a channel.

We exploited this behavior in our devices by using the electricfield applied by the device to open and close the ALM pores inthe lipid bilayer. Indeed, at zero applied gate bias, ALM poreswere ‘‘turned off’’ and the device response was nearly identicalto the response of the NW coated with a pure lipid bilayer (Fig.3B). However, when we applied a positive gate voltage of 150 mVto the device, we obtained a dramatically different response (Fig.3C): the device showed a strong response to the pH change ofup to 50% of the response observed for the bare NW, indicatingthat the ALM pores had been turned on. These results demon-strate that our device platform is not only capable of usingbiological components as functional parts of the device, but italso can control the functionality of the biological molecules,bringing the functional integration of the biological and nano-electronic components on a new level.

It is tempting to assign the observed levels of signal changeto the differences in shielding of the NW surface by the lipidbilayer with open ALM pores compared with the uncoatedNW. In reality, the situation is likely more complicated.Ionization of the silanol groups on the surface of the NWproduces immobile charges that interact with the mobilecharges present on both sides of the lipid membrane andestablish an electrical potential on the membrane in accor-dance with the Donnan membrane equilibrium (29). Thispotential also inf luences the ionization equilibrium of the NWsurface, causing the effective pH on the inner side of thebilayer to be lower than on the outer side. This situation isroutinely observed in biological systems where Donnan equi-librium causes the pH inside negatively charged lipid vesiclesto be lower than pH of the outside solution (30).

We can check the consistency of this interpretation by usingit to estimate the potential on the membrane and compare it withthe measured response of the NW transistor. The Donnanpotential on the membrane is given by the Nernst equation:

�� �RTF

ln�Cl� i

�Cl�o, [1]

where F is a Faraday constant, and [Cl]i(o) denotes the concen-tration of mobile chloride anions on the inner (outer) surface ofthe membrane respectively, and [Cl]i is given by:

�Cl�i ��M�

2� ��1 �

4C02

�M�2 � 1�, [2]

where [M] is the effective concentration of the immobile anionson the inner side of the membrane, and C0 is the concentrationof the background electrolyte on the outside of the membrane(see SI Appendix for the full derivation of Eq. 2).

We can estimate the concentration of immobile ions, [M], byusing the calibration data on the NW pH response (31).Conductance change values measured for proton transportthrough ALM pores (Fig. 3B) correspond to the NW surfacecharge density increase of 0.2 electron/nm2. If we assume thataverage thickness of the water layer between the NW surfaceand the lipid bilayer (32) is �1 nm, then this value corresponds toan effective concentration of immobile ions of 350 mM. For the

Fig. 2. Ligand-gated operation of devices incorporating gramicidin A pores.(A and B) Schematic showing proton transport in the bilayer incorporating agramicidin A pore in the absence (A) and presence (B) of Ca2� ions. (C) Timetraces of normalized conductance of the SiNW device recorded as the solutionwas changed from pH 5 to 7 for an uncoated NW device (red trace), a devicecoated with lipid bilayer incorporating gramicidin A pores (blue trace), and adevice coated with the lipid bilayer incorporating gramicidin A pores inpresence of Ca2� ions (black trace). Dashed vertical line indicates the timewhen the pH of the fluid cell input stream was switched from the lower to thehigher value.

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100-mM background electrolyte concentration used in our exper-iments, Eqs. 1 and 2 estimate the membrane potential as �34 mV.

If we use the IV characteristic of the NW transistor (Fig. 1D)to convert the measured conductance shifts into the effectivegate voltage shifts, then we can estimate that the presence of themembrane with ALM pores changes the effective gate voltageshift by �33 mV, the value that corresponds extremely well withour estimate of the Donnan membrane potential.

Device architecture that comprises a NW device coated witha lipid bilayer incorporating functional membrane proteinscould serve as a versatile platform for building bionanointerfaces that could enable direct conversion of biologicalsignals into electronic impulses. Although we have used SiNWdevices and proton transport as a proof-of-concept example ofsuch a platform, it is possible to use other nanomaterialsand transport of other species to create different ion-sensitivedesigns. The lipid bilayers provide a matrix for a virtually unlimitednumber of transmembrane proteins that can provide different

functionalities. This biomimetic device platform could thus enablenew applications in biosensing, bioelectronics, neuroscience, andmedicine.

MethodsNW Synthesis. Crystalline SiNWs were grown using the vapor liquid solidsynthesis with gold colloidal particles as catalysts. Gold nanoparticles (20–30-nm; Ted Pella, Inc.) were dispersed onto a silicon wafer with 250-nm-thickoxide layer. The oxide layer was incubated in 0.1% aqueous solution ofPoly-L-lysine (Ted Pella, Inc.) to promote adhesion of gold nanoparticles to thesurface. After deposition of the gold nanoparticles, the substrate was rinsedwith deionized (DI) water, dried with nitrogen, and cleaned in oxygen plasmato get clean catalyst surfaces. The NWs were grown at temperatures of420–460 °C at 100 Torr. Boron-doped SiNWs were grown by flowing 31standard cubic cm per min (sccm) of 10% silane in helium (Voltaix) and 3 sccmof 100 ppm diborane in helium (Voltaix) for 30 min.

Device Fabrication and Characterization. After NW synthesis, the grown NWswere dispersed in ethanol by sonication for 5 s. The wires were then depositedonto silicon wafers with a 250-nm-thick dry-oxide layer grown at 1,200 °C.Poly-L-lysine functionalization was used to promote adhesion of the NWs tothe substrate. The NW solution was flown onto the functionalized substratein PDMS microfluidic channels on the desired areas of the substrate. After anoxygen plasma cleaning step, the deposited wires were annealed at 200 °C for10 min to enhance adhesion. Metal contact regions were defined by photo-lithography, followed by e-beam deposition of Ti (10 nm)/Pt (70 nm) or Ni (80nm). The contact regions were cleaned with oxygen plasma (100 sccm, 30 W),and the native oxide was etched away in these regions with a 5:1 bufferedoxide etch for 10 s. An 80-nm conformal layer of stoichiometric silicon nitridewas deposited onto the metal contacts by plasma enhanced CVD at 100 °C.After liftoff, the devices were further annealed in forming gas at 450 °C for 3min to ensure good SiNW/metal contacts. The transistor performance insolution was tested in a DI water environment, with the solution gate voltageswept between �0.5 and 0.5 V by a leakage-free 3 M KCl Ag/AgCl referencemicroelectrode (Warner Instruments). All dc device measurements were donewith a Keithley 2602 digital sourcemeter, and ac measurements were per-formed with a Stanford Research SR8650 lock-in amplifier at frequencies of 19or 23 Hz.

Lipid Bilayer Formation and Characterization. Unilamellar vesicles of DOPC lipidwere prepared by sonication of a solution of 2 mg/mL DOPC (Avanti PolarLipids) in buffer. Vesicle fusion onto SiNWs was allowed for 24 h. The thicknessof resulting bilayers was measured to be 4.4 nm on flat oxide surfaces bysurface plasmon resonance (SPR). Home-built systems were used to charac-terize the lipid bilayers by fluorescence recovery after photobleaching, cyclicvoltammetry, and SPR.

Ion Channel Incorporation in Lipid Bilayers. Gramicidin A (2 mg/mL; Biochemika;�90% HPLC) in 200-proof ethanol was mixed with DOPC in chloroform followedby solvent evaporation with N2 and buffer hydration. Unilamellar vesicles ofDOPC/gramicidin mol ratio of 100:1 were formed by sonication. These vesicleswere then fused onto SiNW FET devices. ALM (Sigma; �90% HPLC) was incorpo-rated into bilayers by spontaneous insertion by exposing pristine NW-bilayerstructures to a solution of 5 mg/mL ALM for 30 min.

Electrical Measurements. Rapid exchange of fluids around the NW wasachieved by bonding PDMS microfluidic channels on top of the device chip andby using suction from suitable fluid reservoirs by a syringe pump. Different pHsolutions were prepared in 100 mM KCl and 5 mM PBS by the addition of NaOHor HCL to adjust the pH. All pH values were measured by a calibrated benchtoppH meter. All reagents were purchased from Sigma–Aldrich with the highestpurity available.

Other Information. For confocal fluorescence microscopy images and FRAPdata for suspended and surface bound SiNWs, SPR studies of lipid bilayerformation, and derivation of Eqs. 1 and 2 see SI Appendix.

ACKNOWLEDGMENTS: A.N. acknowledges support from Basic Energy ServicesBiomolecular Materials Program and University of California-Lawrence Liver-more National Laboratory Research Program, and use of the facilities at theMolecular Foundry at Lawrence Berkeley National Laboratory. J.A.M. andS.-C.J.H. acknowledge support from the Lawrence Livermore National Labo-ratory Lawrence Scholar Program. Parts of this work were performed underthe auspices of the U.S. Department of Energy by Lawrence Livermore Na-tional Laboratory under Contract DE-AC52-07NA27344.

Fig. 3. Voltage-gated operation of the devices incorporating ALM pores. (A)Schematics showing the mechanism of voltage-gated proton transport inself-assembled ALM pores in the lipid bilayer. (B) Time traces of normalizedconductance of the SiNW device held at gate bias of 0V recorded as thesolution was changed from pH 6 to 9 for the uncoated nanowire (blue trace),coated nanowire (black trace), and the coated NW device incorporating ALMpores. (C) Time traces of a similar experiment recorded at gate bias of 0.15 V.Vertical dashed lines indicate the time when the pH of the fluid cell inputstream was switched from the lower to the higher value.

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