186 … · 186 IEEETRANSACTIONSONNANOBIOSCIENCE,VOL.15,NO.3,APRIL2016...

186 IEEE TRANSACTIONS ON NANOBIOSCIENCE, VOL. 15, NO. 3, APRIL 2016

Nanowire-Based Sensors for Biological andMedical Applications

Zongjie Wang, Student Member, IEEE, Suwon Lee, Kyo-in Koo , Member, IEEE, andKeekyoung Kim*, Member, IEEE

Abstract—Nanomaterials such as nanowires, carbon nanotubes,and nanoparticles have already led to breakthroughs in the fieldof biological and medical sensors. The quantum size effects of thenanomaterials and their similarity in size to natural and syntheticnanomaterials are anticipated to improve sensor sensitivity dra-matically. Nanowires are considered as key nanomaterials becauseof their electrical controllability for accurate measurement, andchemical-friendly surface for various sensing applications. Thisreview covers the working principles and fabrication of siliconnanowire sensors. Furthermore, we review their applications forthe detection of viruses, biomarkers, and DNA, as well as fordrug discovery. Advances in the performance and functionality ofnanowire sensors are also surveyed to highlight recent progress inthis area. These advances include the improvements in reusability,sensitivity in high ionic strength solvent, long-term stability, andself-powering. Overall, with the advantages of ultra-sensitivityand the ease of fabrication, it is expected that nanowires will con-tribute significantly to the development of biological and medicalsensors in the immediate future.

Index Terms—Biological applications, medical applications,nanomaterial, nanowire, sensor.

I. INTRODUCTION

I N BIOLOGICAL and medical fields, sensors with suffi-cient sensitivity can detect diseases in their early state, in-

creasing rates of potentially life-saving detection and interven-tion. For example, if breast cancer can be detected at an earlystage (local disease) and treated with existing therapies, the fiveyear survival rate is greater than 90%, while the survival ratedrops to around 20% if the breast cancer develops into late stage(distant disease) [1]. The need for highly sensitive biosensorsfor the early detection of cancer remains unaddressed [2], [3].Many approaches to increasing biomedical sensor sensitivity

Manuscript received July 11, 2015; revised September 22, 2015, November17, 2015, and January 12, 2016; accepted February 07, 2016. Date of publi-cation March 10, 2016; date of current version June 09, 2016. This work wassupported by 2013 Research Funds provided by Hyundai Heavy Industries forthe University of Ulsan. Asterisk indicates corresponding author.Z. Wang is with the School of Engineering, University of British Columbia,

Kelowna, BC V1V 1V7, Canada (e-mail: [email protected]).S. Lee is with the Department of Biomedical Engineering, University of

Ulsan, Ulsan, South Korea, 680-749 (e-mail: [email protected]).*K. Koo is with the Department of Biomedical Engineering, University of

Ulsan, Ulsan, South Korea, 680-749 (e-mail: [email protected]).*K. Kim is with the School of Engineering, University of British Columbia,

Kelowna, BC V1V 1V7, Canada, (e-mail: [email protected]).Color versions of one or more of the figures in this paper are available online

at http://ieeexplore.ieee.org.Digital Object Identifier 10.1109/TNB.2016.2528258

have already been applied, but recent dramatic developments innanotechnology are expected to lead to great breakthroughs inbiomedical sensors. Nanotechnology is a broad field that com-bines science and engineering to investigate the synthesis, prop-erties and applications of materials and structures with at leastone critical dimension that is less than approximately 100 nm[4]. As material size decreases to the nanometer order, its phys-ical and chemical properties are dominated by high surface tovolume ratios and quantum size effects, which can result inthe material having completely different properties than at themacroscale [5].On the one hand, the surface area to volume ratio increases

rapidly as scale decreases. As shown in Fig. 1(a), the highsurface to volume ratio means that most of the regions of thesensing structure will be affected by the target. In other words,a nanostructure is ultra sensitive to the changes on its surface,which leads to the heightened sensitivity of the device usingsuch structures. In addition, the movement of electrons in thenanostructure is confined by the appearance of quantizationeffects. This results in the discrete energy levels of the devicedepending on the size of the structure, which is known asquantum size effects. Both the energy of the lowest excitedstate of the semiconductor and volume-normalized oscillatorstrength are increased by decreasing the scale [6]. Thus, thenanostructure has a high energy conversion efficiency andrelatively a low thermal noise [7], which facilitate to sensing,transducing and recording minute changes in the nanostructure.Similarity in size between biomolecules ( 10 – 100 nm)and synthetic nanostructures offers an intrinsic advantage inhandling these biomolecules (Fig. 1(b)), another dominant mo-tivating factor for applying developments in nanotechnology toprobes, transducers, and other tools for biomedical sensors.Detecting and characterizing chemical and biological species,

ranging from disease diagnosis to drug discovery, are the pri-mary tasks of biomedical applications. Nanomaterials such asnanowires, carbon nanotubes and nanoparticles provide novelfunctions for primary biomedical tasks [8]. These nanomaterialsdemonstrate distinct optical, magnetic, and electrical propertiesfor imaging and sensing. For instance, semiconductor nanocrys-tals and colloidal gold have been examined and considered foruse as detection labels for disease markers and other biologicalspecies [9], [10] and serve as contrast agents for use in opticalimaging and magnetic resonance [11], [12]. Fig. 1(c) providesan overview of the schematics and the functions of nanostruc-tures used in biological and medical applications.Among nanomaterials, semiconducting nanowire is one of

the most powerful tools for biomedical applications. Specifi-

1536-1241 © 2016 IEEE. Personal use is permitted, but republication/redistribution requires IEEE permission.See http://www.ieee.org/publications_standards/publications/rights/index.html for more information.

WANG et al.: NANOWIRE-BASED SENSORS FOR BIOLOGICAL AND MEDICAL APPLICATIONS 187

Fig. 1. Advantages of the nanostructures for sensing biomolecules. (A) Schematic to illustrate the benefits of high surface to volume ratios. For sensing a givenkind of target particles, in the cross sectional view, a greater percentage of the region in the structure with a high surface to volume ratio is affected. That means mostregions can be considered as sensing areas. However, for the situation with low surface to volume ratios, only limited region near the surface can respond to thetarget particles. (B) The size of nanostructures is comparable with several biomolecules, which makes nanostructures a prefect tool for handling biomolecules. (C)An overview of nanostructures used in biological and medical applications. Nanostructures with blue backgrounds are used as supports to immobilize receptors orlabels, those with yellow backgrounds function as labels, and those with green backgrounds function as both labels and supports. The insets in the white backgroundshow the major bioconjugation protocol used to immobilize receptors on the corresponding nanomaterial. The green antibody in the insets represents a genericbiomolecule (Adopted from Kurkina et al. [8]).

cally, semiconducting nanowires make it possible to directly de-tect various species electrically without labels [13]. Nanowirescan be constructed from semiconducting materials, and theirdopant type can be controlled with ease [14]. The surface ofnanowires can be modified to be sensitive to chemical and bio-logical species [15], [16].Similar to nanowires, carbon nanotubes can also be employed

in biomedical sensors. Nanotubes, however, are synthesizedfrom mixtures of semiconducting and metallic materials [17],[18], necessitating further purification. Even though this onlyrequires one additional step, it is almost impossible to harvestnanotubes composed purely of the semiconducting material.Moreover, the interface protocol for the binding of a broadrange of analytes has not been well established for nanotubes[14], [19], which has made the precise fabrication of carbonnanotubes difficult. Overall, nanowires are one of the bestnanostructures for biomedical sensors as their ultrasensitivityand ease of fabrication ensures the uniformity, reproducibility,scalability, and manufacturability of nanowire sensors [20].This paper reviews the working principles and diverse appli-

cations of nanowire sensors for biological and medical applica-tions, including the detection of DNA, RNA, viruses, proteins,and biomarkers. Recent advances, including improvements inreusability, sensitivity in high ionic strength solvent, long-termstability, and self-powering are also discussed briefly in view oftheir significant impact on solving the critical shortcomings ofnanowire biosensors.

II. NANOWIRE FIELD-EFFECT SENSORS

A. Working PrinciplesOne type of nanowire sensor is the nanowire field-effect tran-

sistor (FET). Nanowire FETs originate from the standard planarFETs which consist of a gate, source, drain, and body (Fig. 2(a)(1)). On the body, the source and drain are fabricated in micro-

or nanoscale with a metallic material. A gate with a criticallythin isolation layer (usually ) is constructed between thesource and drain. This isolation layer causes changes in the elec-tric potential on the gate to adjust the conductivity between thesource and drain to capacity [21]. In addition to conventionalchanges in potential in the gate in response to external voltageapplication, chemically or biologically charged species can alterthe potential (and further the conductivity) in the gate by bindingthe charged species. This type of electrical detection via an accu-mulation of charged species was proposed several decades ago[22]. The need for massive samples for detection (i.e., low sen-sitivity) prevents large impacts on the planar gate FET sensor.Compared to the planar FET sensor, the nanowire FET re-

places the doped channel with nanowire and employs the recep-tors as a “gate” (Fig. 2(a) (2)). Although the structure of the FETchanges, the core concept remains the same external changesby charged species can affect the conductivity of nanowire. Thesemiconducting nanowire can be made by silicon or other ma-terials [23]–[25]. Silicon and silica nanowire are used widelyin view of their high compatibility with standard CMOS (com-plementary metal-oxide-semiconductor) technology, the naturalgrowth of the silicon oxidation (the isolation layer) on the sil-icon surface, and the ease with which the surface of siliconand silica can be modified. The original silicon and silica sur-face is not responsive to the changes of biomolecules. Eventhough the biomolecules contain the charges, their accumula-tion near the isolation layer could not alter the conductivityof nanowires [14]. In other words, the physical appearance ofcharged biomolecules near the isolation layer could not affectthe sensing capability of nanowires. Tomake the surface respon-sive, it needs to be functionalized and bound with receptors forcapturing the specific charged species, such as DNA, RNA, avirus, and so on. The functionalization process builds a chem-ical connection between the top surface of isolation layer (as


well as the nanowires) and biomolecules (Fig. 2(b)). The recep-tors can control the “gate” of the nanowire-based FET. Throughthe changes in the number of collected species, the receptors in-duce an electric field to the nanowire through the thin isolationoxidation, determining the conductivity of the nanowire. There-fore, if we consider the species to be the input signal, the func-tion of the receptors is very similar to the gate since they con-vert the input signal to changes in the conductivity of the device.The most widely used method for receptor attachment is cova-lent binding since the oxide layer can form easily on the siliconsurface. After exposure to air or plasma, the silicon nanowirewill form silicon oxide to passivate the silicon surface. Covalentbinding aims to modify the silicon surface with a silane deriva-tive monolayer. For example, 3-amino propoyltriethoxysilane(APTES) is a receptor for DNA, peptide nucleic acid (PNA),and antibodies [14]. Fig. 2(b) shows the typical binding flowwhen using APTES (refined based on [26]). APTES convertssilicon-oxygen bonds to a silane chemistry layer (Si-O-Si-X),where X can be further modified or linked with specific re-ceptors. Fig. 2(c) shows the working principle of the nanowiresensor. When negatively charged species in an aqueous solutionbind to the receptor, the negative charges in species induce pos-itive charges in the Si nanowire FET surface via the receptor.The generation of positive charges can be considered as the dis-appearance of electrons (negatively charged carrier) or the ap-pearance of holes (positively charged carrier). Thus, the conduc-tivity (or current) between the source and the drain is changed.If the Si nanowire is n-type, the conductivity will decrease asthe charge carriers for the n-type nanowire are the electrons. Onthe contrary, for p-type Si nanowire, the current will increase asthe charge carriers in the p-type nanowire are the holes. The Sinanowire FET can be electrically connected to a semiconductorparameter analyzer or other measuring and logging equipmentfor the real-time monitoring of conductivity [27], [28]. The con-ductivity modulation of nanowires in various conditions is sum-marized in Table I. Unlike the FET used in electronic circuits,the nanowire FET is usually at the ON state (DC currents alwayspass through) in view of the nature of sensing. Also, multiple oran array of nanowires are usually used in a single sensing devicesince multiple nanowires are more sensitive to the accumulationof species and experience a lower noise as a result of averaging[29].

B. Fabrication Methods

Both bottom-up (Fig. 2(d)) and top-down (Fig. 2(e)) ap-proaches are suitable for the fabrication of nanowire sensors.Bottom-up techniques have been widely applied to the growthof high-quality nanowires (20 nm or less) in different sub-strates, commonly Si wafers [30]. Although most of thenanowires are cylindricalin shape, existing bottom-up tech-niques are capable of varying the cross-sectional shape of thenanowire, producing round, square, and triangular versions[31]. The “bottom-up” fabrication process starts with growingSi nanowires using a chemical vapor deposition (CVD) [32].Through the vapor-liquid-solid (VLS) mechanism [33], Sinanowires can be grown catalytically in the CVD reactionas shown in Fig. 2(d) (1). Subsequently, the suspended Si

nanowires in ethanol solution are deposited onto a siliconsubstrate as shown in Fig. 2(d) (2). Then, a photoresist isspin-coated on the silicon substrate with dispersed Si nanowiresand metal electrodes are patterned by the lift-off method asshown in Fig. 2(d) (3). The bottom-up fabrication ends withthe passivation and the surface modification (receptor binding)[32]. The cross-sectional view of the fabricated sensor is givenin Fig. 2(d) (4). Note that the isolation layer on the surface ofthe nanowire is easily formed by exposing the device to an air oroxygen environment. The limitation of the bottom-up approachis that the orientation of the nanowires is random. Randomlydistributed wires result in poor uniformity and low yield rate ofnanowire sensors. An additional alignment step during fabrica-tion can be added to improve the orientation of the nanowires.These alignment methods include Langmuir-Blodgett [34],blown-bubble [35], microfluidic flow [36], contact printing[37], and electric-field [38], [39]. However, these methodsare not compatible with the standard CMOS fabrication flow,impeding the mass manufacturing of aligned nanowire sensors.Conversely, the top-down method offers a way to preciselycontrol the nanowire orientation that is compatible with thestandard CMOS technology. The “top-down” method is basedon the microfabrication process on a silicon-on-insulator (SOI)wafer. First, low-density boron or phosphorous is doped to thetop Si layer of a SOI wafer to determine the property of n- orp-type semiconductor and doping ratio of Si nanowire as shownFig. 2(e) (1). Photolithographic patterning and heavy densitydoping are conducted to define the source and drain leads asshown in Fig. 2(e) (2). Reactive ion etching (RIE) is used topattern the micrometer-sized source and drain electrodes asshown Fig. 2(e) (3). Then, the nanometer-sized Si nanowireis fabricated by the electron-beam (E-beam) lithography andthe metal contact leads is formed by a thermal evaporationas shown in Fig. 2(e) (4). Finally, similar to the bottom-upmethod, the fabrication flow ends with the passivation and thesurface modification [40], [41]. A cross-sectional view of thedevice fabricated by top-down method is presented in Fig. 2(e)(5). In comparison with the device fabricated by bottom-upmethod (Fig. 2(d) (4)), the drain and source were formedthrough the heavily doped silicon (Fig. 2(e) (5)). The advantageof the top-down method is its high compatibility with CMOSprocesses as well as the capacity to control the orientation.However, the diameter of the nanowires is bigger than thatproduced by the bottom-up method. Recent developments ofnanoimprint lithography have enabled the rapid fabricationof large scale nanowires compatible with standard CMOSprocesses [40], [41]. This method has become very popularsince it results in excellent nanowire alignment and a high yieldrate. Fig. 2(f) and 2(g) show the SEM (scanning electron mi-croscope) pictures of nanowire devices fabricated by top-down[42] and bottom-up methods [43], respectively. These figuresshow that the nanowire fabricated by the top-down methodis well aligned with a larger diameter. The diameter of thenanowire fabricated by the bottom-up method is small, butits orientation is relatively random. Despite the difference innanowire orientation and materials for drain and source, suchdevices share the same architecture (drain-nanowire-source) asschematically illustrated in Fig. 2(d) (4) and 2(e) (5).


Fig. 2. Conceptual schematic of field effect transistors: (A) (1) standard field effect transistors and (2) nanowire field effect transistor. (B) APTES based func-tionalization process of the nanowire. With the help of APTES, the silicon-oxygen bonds was converted to a silane chemistry layer and can be bound with variousreceptors (Refined based on [32]). (C) Working principle of nanowire sensors. When the receptor captured charged molecules, the charges from the moleculesinduced changes in the conductivity of the nanowire, resulting in increased or decreased current passing through the nanowire.(D) Bottom-up fabrication processof the Si nanowire sensor: (1) The Si nanowire was grown from a gold nanocrystal. (2) The nanowire was deposited on the with random orientation. (3) Thedrain and source were developed to connect nanowires through photolithography. (4) Cross-section al view of the device fabricated through bottom-up method.(E) Top-down fabrication process of the Si nanowire sensor: (1) The Si layer of SOI wafer was slightly doped to control the doping ratio of the nanowire. (2) The Silayer was further doped to define the source and the drain. (3) Drain and source were formed by RIE etching. (4) Nanowire was formed by high resolution E-beamlithography. (5) Cross-sectional view of the device fabricated using the top-down method. (F) Oriented but relatively large Si nanowire fabricated by top-downmethod(Adopted from Park et al. [42]). Scale bar: 4 . (G) Tiny but randomly oriented nanowire fabricated by bottom-up method (Adopted fromWu et al. [43]).Scale bar: 5 . (H) Effects of different Debye lengths (Gray color means the undetectable area and peachy color means the detectable area): (1) With Debyelength shorter than the height of receptor, it is unable to detect any charges from the molecule. (2) With Debye length in-between the height of receptor and theheight of molecules, only parts of the charges are detectable. (3) With long enough Debye length, all the charges from the molecule can be detected.

C. Fluid Exchange SystemsFluid exchange system is a very important component of the

nanowire sensor. The fluid exchange system should deliver theanalytes or fluids to the surface, or at least near the surface ofthe nanowire sensor. In view of its ease of fabrication, poly-dimethylsiloxane (PDMS) based channel is widely used forfeeding analytes to nanowire sensors. For the application of thebiosensor, PDMS also has advantages in its high biocompati-bility [44], [45]. However, a PDMS microfluidic fluid exchangehas intrinsic limitations. One is that the flow in the channelis laminar, which makes the particle inside the flow difficultto approach the surface of the nanowire sensors. Another isthat the sensitivity of the sensor may be reduced as PDMS canabsorb biomolecules [44]. The use of an acrylic chamber asthe fluid exchange system can overcome these limitations ofPDMS microfluidic channels [46]. Another problem broughtabout by the PDMS microfluidic channel is the difficultly ofremoving attached particles from receptors, which makes thenanowire biosensors disposable. This limitation becomes moreserious in the biosensing, as the antigen-antibody binding isstronger [20]. Recent advances in interfacial chemistry designhave made it possible to achieve reusable nanowire biosensors[47]. The details are discussed in Section IV.

D. Surface Charge and Ion Condensation EffectsAs described in Section II-A, the specific binding between re-

ceptors and target charged molecules alters the conductivity of

nanowires. Therefore, the nanowires can be utilized as sensingelements for biomedical applications. However, in practicalapplications, many other effects occur near an isolation layer(i.e., modified ) and further influence the conductivity ofnanowires through various mechanisms. Among them, twomajor mechanisms, including surface charge and ion conden-sation effects, are discussed in this section.In addition to the specific binding between receptors and

target specimens, surface charge variation in the isolation layeralso contributes to conductivity modulation. According toCui et al. [14], pH of solvents linearly alters the conductivityof nanowires by regulating the surface charge of nanowires.The modulation mechanisms start from the covalent bindingof APTES in nanowires, resulting in surface terminating in

and –SiOH groups (Fig. 2(b)). Then groupconsumes positively charged holes from the nanowire surfaceand becomes at low pH. At high pH, –SiOH consumeselectrons (negative charge) from the nanowire surface and be-comes –SiO . The conductivity modulation of nanowires dueto pH is combined effects of these two mechanisms [14]. Con-sidering that the accuracy of nanowire sensors mainly dependson conductivity changes, it is required to pay extra attentionto pH variation since measurement results from solutions withdifferent pH are not comparable.The effect of counterion condensation also affects the con-

ductivity of nanowires. For example, if the bound molecules arenegatively charged in the solvent, because of electrostatic inter-


TABLE ICONDUCTIVITY MODULATION OF NANOWIRES IN VARIOUS CONDITIONS

TABLE IIPARAMETERS TO MODULATE THE CONDUCTIVITY OF FUNCTIONALIZED P-TYPE NANOWIRES. (NOTE THAT N-TYPE NANOWIRES WORK IN THE OPPOSITE WAY)

actions, it will be surrounded by positively charged counterions.Table II summarizes parameters that can affect the conductivityof functionalized p-type nanowires. On a certain length scale,the number of positive charges from counterions approachesthe number of negative charges from the target biomolecules,which results in the elimination of the charges from the targetbiomolecules [48]. This length scale is termed the Debye length

, the critical length that sensors are able to distinguish thesignal from target molecules in the electrostatic system. Debyelength is the measure of a charge carrier's net electrostatic effectin solution, that is, how far those electrostatic effects are main-tained. The negatively charged molecules outside the Debyelength can be considered as electrical neutrality for the sen-sors, since the effect of their negative charges was offset bythe positive charges generated by the electrostatic interactionof the analyte. Therefore, the parts of the molecules outside theDebye length will not contribute to any conductivity change ofthe nanowire. In other word, only the target molecules withinthe Debye length result in the conductivity change. Thus, thereceptors capture same number of molecules with the differentDebye length. However, the detect ability of negatively chargedmolecules decreased with the shorter Debye length [48]. Fig.

2(h) shows an illustration of different Debye lengths to the de-tection of charges from the molecules. The charges on the mole-cule can be fully detected only with long enough Debye lengths,which result in the highest sensitivity and the most significantchanges in conductivity. The suitable Debye length is still themajor concern in the design of nanowire sensors. A long Debyelength ensures that the effect from counterions is small [49]. Fora nanowire sensor, the Debye length can be approximately cal-culated as follows [50], [51]:

where is the ionic strength of the solvent solution utilized forthe measurement.In general, the Debye length increases as the ionic strength

decreases. Thus, by using a less conductive solvent, the sensi-tivity of nanowire sensor is more increased. Stern et al. foundsignificant increment in Debye length by diluting phosphatebuffered saline (PBS) with deionized water [52]. However,in order to maintain a suitable osmolarity for cells and otherbiomolecules, researchers must compromise between sensorperformance and solution osmolarity. Very recently, a new


Fig. 3. Nanowire biosensor for virus detection: (A) Experimental procedure of virus detection in EBC samples using Si nanowire sensing device. (B) Experimentalresults for the detection of the H3N2 virus without the nanoparticle treatment. (C) Experimental results for the detection of the H3N2 virus with the nanoparticletreatment. (Adopted from Shen et al. [55]).

method of overcoming the limitations of the Debye length hasbeen reported. This result is introduced in Section IV.

III. BIOMEDICAL APPLICATIONS OF NANOWIRE SENSORS

A. Virus DetectionViruses are the most common cause of human disease [53],

and there is increasing concern about their capacity to be utilizedas a biological weapon [54]. The ability to detect viruses moreeffectively will lead to improved health and increased security.To date, Si nanowire sensors have successfully detected manydangerous viruses, including Dengue [26], Influenza A H3N2[55], H1N1 [56], and HIV [57]. It is also possible to detect twodistinct viruses at the single virus level [27]. Antibodies spe-cific to the target virus are selected and attached to the nanowiresensor surface, followed by the fabrication of the nanowire de-vice. During the detection, target viruses captured by the anti-bodies affect the conductivity of the nanowire. Shen et al. devel-oped a Si nanowire-based biosensor for the rapid diagnosis offlu [55]. This biosensor can detect as few as 29 fromexhaled breath condensate (EBC) samples. Although this device

required nano particles to achieve high sensitivity, it provided arapid, low-cost, and reliable diagnosis method that replaces theexpensive standard qPCR method.The viral detection flow is given in Fig. 3(a). EBC samples

were collected from patients with and without flu symptoms anddiluted 100 times. The samples were then fed into the nanowirebiosensor via microfluidic channels (Fig. 3(a) Case 1). Thesensors were then functionalized with H3N2 and 8 iso PGF2a antibodies. The sensor was able to detect viruses in the flusample diluted one hundred fold (285 ) (Fig. 3(b))but unable to detect samples that were diluted 1000 times (28.5

). To improve the sensitivity, magnetic silica beadswere used (Fig. 3(a) Case 2). After bead size and concentrationwere optimized, the viruses were detected in the samples thatwere diluted 1000 times (Fig. 3(c)). When compared to theqPCR results of a previous study [58], the sensitivity of thenanowire biosensor was at least 50 times higher.

B. Biomarker DetectionRecent proteomics and genomics research has revealed many

new biomarkers that have great potential for use in disease di-


Fig. 4. Breathe volatolome-based nanowire sensor: (A) Detection process flow of the breath volatolome-based nanowire sensor. Step 1: Fabrication of the standardnanowire sensor.(White rectangular boxes indicate the position of the nanowires). Step 2: Modification of the nanowire surface with molecular layers. Step 3:Exposure of the biosensor to VOCs linked with gastric cancer conditions. Step 4: Exposure of nanowire sensor to real breath samples. (B) Typical source-draincurrent vs. back-gate voltage curves of the sensor under vacuum upon exposure to N2 and upon exposure to increasing concentrations of VOC2 and(C) VOC5. (Adopted from Shehada et al. [62]).

agnosis [1]. The heterogeneity of complicated diseases, such ascancer, prohibits the single marker test from providing adequatediagnosis results and requires the increased needs for multiplebiomarkers [3]. The detection of multiple biomarkers relatedto disease stage is particularly important in cancer treatment[4]. The p-type silicon nanowire sensor was first applied to theelectric detection of proteins in solution [14]. After that, manysensing platforms based on nanowires and nanowire arrays werebuilt to detect multiple disease marker proteins simultaneously[23], [28].In recent years, many studies have focused on building

comprehensive platforms for the real-time detection [59] ordirect detection of diseases from whole blood [60]. The type ofdetected molecules has also extended to include a wide varietyof biomarkers such as cardiac biomarkers [46]. Nanostructureshave been widely applied as label free electrical detectionmethods for various proteins, including but not limited to thoseindicating cancer, Parkinson's disease, pregnancy, diabetes,autoinflammatory diseases, and atherothrombosis [61]. Ifreceptors can be properly immobilized, nanowire biosensorswill be able to detect many biomolecules and function ashigh-throughput, ultra-sensitive, low-cost, low-consumptionclinical diagnosis systems.Shehada et al. recently developed a nanowire-based cancer

diagnosis system using breath volatolome as the input [62].This sensor functions by using a nanowire with a modifiedsurface that can selectively detect volatile organic compounds(VOCs), which can be further linked with gastric cancer con-ditions. By using VOCs as an “agent,” this sensor is able toachieve 85% accuracy and has the potential to become a simple,portable, painless, and rapid method for the early detection

of disease. The detection flow is given in Fig. 4(a), and thetypical I-V vs. curves of the sensor are presented inFig. 4(b) and 4(c). As shown in the figure, the sensor can detectextremely low concentrations (minimum 5 ppb) of VOC2,which is a biomarker of gastric cancer in exhaled breath. Bycontrast, there was no difference between a vacuum and var-ious concentrations of VOC5; thus, the sensor is not sensitiveto VOC5, a confounding environmental VOC not related togastric cancer. These findings indicate that the sensor onlyresponds to gastric cancer related biomarkers and can discrimi-nate against the effects of unrelated biomarkers. With such highselectivity, this nanowire sensor can accomplish more practicalmeasurements while ignoring unrelated factors such as tobaccoconsumption and gender in the case of gastric cancer. The com-prehensive biomarker detection system also has the potentialto be further developed as a nanowire-on-a-chip system. In thison-chip system, the separation, filtering, preconcentration, anddetection are all done by nanowire, providing an express andpractical solution for clinical applications [63].

C. DNA and RNA DetectionNanowire sensors are capable of detecting specific sequences

of DNA [64]. Complementary single-stranded sequences ofPNAs are employed as receptors for DNA on silicon nanowiresurfaces [65]. The Si nanowire sensor was shown to have theability to detect DNA at the 10 femtomolar level [66], which isbetter than quartz-crystal microbalance [67], surface plasmonresonance (SPR) [68] and nanoparticle-enhanced SPR [69] forDNA detection.In addition to the detection of individual strands of DNA,

nanowires can also be utilized to detect the bonding between


Fig. 5. Nanowire biosensors to investigate the interactions between protein and DNA: (A) Schematic of working principle. (B) Specificity of the interaction ofwith three different EREs including wild-type, mutant and scrambled ERE. (C) Response of the wt-ERE-functionalized biosensor to various concentrations

of specific . (D) Response of the wt-ERE-functionalized biosensor to the nuclear extracts from MCF-7 and MDA MB231 breast cancer cells. (Adopted fromZhang et al. [70]).

protein and DNA [51], [70], [71]. Zhang et al. developed aself-assembled monolayer Si nanowire biosensor to detect theinteraction of estrogen receptor (ER ) and DNA [70], inwhich ER is an important protein for breast cancer prolifera-tion and invasion [72]. A schematic of this process is shown inFig. 5(a). After the fabrication of the nanowire sensors, three dif-ferent estrogen receptor elements (EREs), wild-type (wt), mu-tant, and scrambled DNA sequences, were immobilized on theSiNW surface via a carboxyl-terminated self-assembly method.The binding specificity of to the EREs was then investi-gated. The most obvious conductance changes were found whenthe wt was used (Fig. 5(b)), and the magnitude of response de-creased as the concentration of decreased (Fig. 5(c)). Sub-sequently, a rapid detection method to investigate the interac-tions of was developed. As is shown by Fig. 5(d), signif-icant conductance changes occurred when in the nucleiof MCF-7 breast cancer cells bound to the wt-functionalizednanowire. Since the control cells, MDA MB231, did not ex-press , there were no obvious changes when the biosensorwas tested with MDA MB231. This experiment demonstratesthe method using Si nanowire biosensors to investigate the in-teractions between protein and DNA, as well as the feasibilityof applying this technique to early breast cancer detection.Similarly, nanowire devices can become RNA sensors by ap-

plying PNA-functionalization [73], [74]. Dorvel et al. reportedan ultra sensitive Si nanowire biosensor with high-k oxide di-electrics for the detection of micro RNA [74]. Specifically, theyemployed a top-down method to fabricate standard nanowire

sensors functionalized by DNA probes to detect miRNA-10band miRNA-21.By detecting the DNA or RNA expressed by the cells as

biomarkers, it is also feasible to apply nanowire devices to theearly detection of cancer, such as the device developedby Zhang et al. [70]. Furthermore, nanowire sensors are ableto monitor many DNA level cancer biomarkers, such as telom-erase, opening a door for using nanowire-based DNA sensor forcancer diagnosis and treatment [28].

D. Drug Discovery and Electrophysiological ApplicationIn addition to the detection of various biomolecules,

nanowire-based biosensors have the potential to benefit drugdiscovery and fundamental life science studies. Specific typesof drugs can be immobilized to nanowires as drug nanocarriersto treat multiple drug-resistant cancer cells. The nanowire-de-livered Doxorubicin (DOX), a widely used chemotherapyagents for cancer treatment, is an example [75]. As shown inFig. 6(a), without the nanowires, DOX molecules can onlydiffuse in intact cell membranes, which results in their rapidremoval from drug-resistant cancer cells and a difficulty inaccumulating DOX molecules in the cell nuclei. With the lim-ited number of DOX molecules in cell nuclei, the therapeuticefficiency is decreased. However, if a nanowire-DOX complexintroduce to the cytoplasm via endocytosis, the nanowire-DOXcomplex loaded inside can be released more efficiently toimprove the therapeutic performance significantly (Fig. 6(b)).This concept has been confirmed experimentally (Fig. 6(c) and


Fig. 6. Mechanisms utilized to overcome the MDR effect of free DOX (A) and Si nanowire-DOX complexes (B). Cell viability of (C) MCF-7 cells and (D)MCF-7/ADR during treatment with different concentrations of DOX and nanowire-DOX. (Adopted from Peng et al. [75]).

Fig. 7. Strategies to overcome the Debye length limitation using polymer coating. (A) Schematic illustration of a silicon nanowire with and without a porous bio-compatible and permeable polymer. (Polymer in green color and regular receptor bound by APTES in pink color). (B) Real-time measured signals from nanowirewithout the help of PEG at solvents with different ionic strength. (C) Real-time measured signals from nanowire with the help of PEG at 150 mM.(Adopted fromGao et al. [103]).

6(d)). At all concentrations tested, the cell viability of MCF-7(regular cells) in the environment with the nanowire-DOXcomplex was significantly higher than that of cells culturedin free DOX. In contrast, the cell viability of MCF-7/ADR(resistant cells) was lower in the presence of nanowire-DOX.These findings demonstrate that nanowire-DOX is an effectivetool for the removal of cancer resistant cells from normal cancercells. Such devices will help researchers manipulate groups ofcells more precisely and will benefit drug delivery processes.

This strategy can also be employed to effectively release drugsfor therapy. Electromagnetic field responsive nanowire devicesare also effective tools for the controlled release of drugs[76]–[78].Nanowire biosensors have also been used in electrophysio-

logical signal generation and measurement. These applicationsinclude the measurements of intracellular action potentials gen-erated by beating cardiomyocytes [79]–[81] and extracellularaction potentials from brain tissues and cells [82], [83], the de-


velopment of 3D macroporous tissues [84], and the study of themetabolism of cells [85]. Nanowires are considered as local bio-probes in those applications. The most widely used structure forbioprobes is the kink structure. Accurately controlled flexibility[79] and bending [80] of the kinked nanowire were used to mea-sure both extra cellular [79] and intracellular action potentials[80], [81]. Nanowires can also be integrated into a porous hy-drogel network to offer long-term and real-time monitoring ofthe local electrical activity and distinct pH changes inside andoutside of tissue constructs [84]. The integration of hydrogelnetwork with nanowires provides a new direction for nanoelec-tronics-based tissue engineering. For example, the nanowire-embedded scaffold could be used as nanoscale stimulators toprovide electrical and mechanical stimulation to promote cellgrowth [84]. Nanowire-based platforms also demonstrated ca-pable of aligning, proliferating, and differentiating cells, as wellas serving as a therapeutic application [86].

IV. RECENT ADVANCES IN NANOWIRE BIOSENSORThis section provide a brief introduction to the important

technologies emerged in recent years to solve the intrinsicproblems of traditional nanowire-based biosensors, includingreusability, long-term stability, sensitivity in solvent with highionic strength, and energy harvesting. With the help of thesetechnologies, nanowire-based biosensors have become morepractical and suitable for various biomedical applications.

A. ReusabilityThe binding between antigen and antibodies is almost

irreversible [87], which results in difficulties for the reuseof nanowire based biosensors. In order to make the sensorreusable, a new binding chemistry needs to be developed, suchas adding reversible binding groups or competitive groups.Currently there are two feasible methods for generating re-versible bindings. One is the reversible association-dissociationinteraction of affinity-based recognition motifs [88], [89]. Theother one are cleavable chemical linkers [60], [90].Affinity-based recognition motifs can reduce the probability

of denaturizing the selective agent upon surface immobiliza-tion, which contributes to the promotion of the interactionbetween target analytes and receptors. There are many bindingsolutions reported for affinity-based interactions, includingglutathione: glutathione S-transferase [91], glutathione S-trans-ferase: calmodulin [92], and histidine : nitrilotriaceticacid [93]. However their applications are limited to screeningthe interaction between proteins [91]–[93]. Cleavable linkersare the more versatile compared to affinity based reversiblebinding. A disulfide linker [90], [94], [95], which can bereverted by dithiothreitol [94] and tris(2-carbox-yethyl) [90]phosphine, can be employed to detect the avian influenzavirus [94]. In addition, the andadamantine groups, whichcan be destabilized by -cyclodextrin, were reported to be auseful cleavable linker groups [96]–[98] and can be used forsingle-stranded DNA [99].

B. Overcoming Debye Length LimitationAs discussed in Section II-D, the sensitivity of the nanowire

sensor is affected by the Debye length, which correlates to the

ionic strength of the solvent. To achieve high sensitivity, thenanowire sensor has to be utilized with low ion strength solvent.How to overcome the Debye length limitation in highly salinesolvent is a key challenge.Indirect methods, such as “desalting” the solvent to lower

the ionic strength, worked to increase the Debye length insome degree [28], [60]. However, these cannot be applied inmost cases. Recently, several researches have focused on usingsmaller receptors to reduce the distance between the surface ofnanowire and the analytes [100], [101]. Kulkarni et al. reportedthat by replacing the traditional DC measurement circuit (suchas the semiconductor analyzer) with a nonlinear high frequencymixing circuit, the Debye length limitation could be mitigated[102]. However, this strategy required more complex devicegeometry as well as the high frequency measuring circuit,limiting its applicability. Recently, Gao et al. reported a generaldetection method in high ionic strength solutions using a porouspolymer coating [103]. In this work, they coated a polyeth-ylene glycol (PEG), a porous biocompatible and biomoleculepermeable polymer layer, on to the surface of the nanowire(Fig. 8(a)) during the APTES binding process. As shown inFig. 8(b) and 8(c), while the traditional sensor lost most of itssensitivity at a 5 mM concentration of the phosphate buffer(PB), the PEG coated nanowire sensor can keep its functionwith PB as high as 150 mM. Since PEG is a FDA approvedbiocompatible material [104], the PEG coating is safer andhas strong potential as a general solution for the detectionof analytes in high saline solvent. Also, this research opensthe door to using the combination of nanowire and polymersto study the behavior of a single cell since the mechanicaland chemical properties of PEG is highly controllable, and itcan be mixed with other cell attachable polymers to build 3Dmicro- and nanoscaffolds [105]. However, the mechanism howpolymer coating eliminates the effects of high ionic strength isunknown and need to be investigated.

C. Long-Term StabilityThe long-term stability of nanoscale structures in air is ex-

cellent since silicon is passivated by its natural oxidation in air[106]. However, for biomedical applications, this silicon oxida-tion layer can be dissolved by hydrolysis in aqueous solutions,especially in high ionic strength environments [107]. Previousresearches have reported the limited stability of nanowires usedwith cells [84], [108]. Zhou et al. recently introduced a simplemethod for improving the long-term stability of the nanowire[109]. This method is based on a core/shell architecture (Fig.10(a)). With the protection of the 10 nm thick shell, itwas observed that the diameter of the nanowire remained almostthe same for at least 100 days in PBS and neurobasal solvent,respectively, while the nanowire without the shell was disap-peared (Fig. 10(b)). A limitation of the core/shell method is thatwith the increase of shell thickness, the sensitivity of nanowireis decreased [110]. Therefore, there is a trade-off between per-formance and long-term stability. Regardless, this strategy cansignificantly improve the long-term stability of the nanowires incomplex environments, opening up the further investigation ofusing nanowire as the platform for the in vivo injectable elec-tronics [111], and in vitro maturation of cardiomyocytes [112].


Fig. 8. Strategies to improve the long-term stability using a shell-core structure. (A) Schematic illustration of the long-term changes of nanowire diameter in 1XPBS. (B) Dark-field microscope images showing the evolution of Si nanowire with different thickness of shell in 1X PBS at 37 . (Adopted from Zhouet al. [109]).

It is interesting to examine the feasibility of integrating the core/shell method with the porous biocompatible polymer to achievea super-sensitive in vivo nanowire sensor with long-term sta-bility.

D. Self-Powering and Energy Harvesting

Although nanowire-based biosensors are ultra-sensitive andsuitable for in vivo investigation, for more practical applica-tions, a challenge is how to operate the nanowire sensor withoutan external power supply. Researchers demonstrated the directpower generation using ultrasonic waves [111] and the piezo-electric effects of Zinc oxide (ZnO) nanowires [112]. Throughapplying mechanical force to a well-aligned, serially connectedZnO nanowire array, they achieved a maximum 1.26 volt outputvoltage, which is enough to power the nanowire based pH sensor[113] and thewireless data transmission system [114]. However,mechanical energy generated by significant physical motion isstill limited inside human body. If the device can derive en-ergy from the bodily fluids in it will more suitable for operatinginside human body. [115]–[117] and glucose/air[118] can be used as a compartment less biofuel with activeenzyme as catalysts. In addition, Hansen et al. demonstratedthe potential use of piezoelectric effects and biofuels togetherto build a self-powered system in vivo [119]. On the one hand,they employed a biocompatible nanofiber, poly(vinylidene fluo-ride), to harvest mechanical energy generated by the organ, forexample, the breathing motion of the lung or the beating mo-tion of the heart. On the other hand, a flexible enzymatic biofuelcell was utilized to collect biochemical energy from biofluids.By combing those two strategies, they achieved a higher output

power and potentially a longer operating time, providing an ad-vanced solution for in vivo biomedical sensing applications. Re-cently, an organic film-based nanogenerator was developed tocollect acoustic energy from a daily life environment [120]. Thistechnology may also be applied to power nanowire biosensorsfor in vitro and in vivo applications.

V. SUMMARY AND CONCLUSIONNanowire sensors with specific receptors have been proven

effective and show great promise to become feasible andpowerful detection platforms for biological and medical appli-cations. These devices have many positive attributes, includingbeing label-free and capable of real-time electrical signal trans-duction with ultra-high sensitivity. These features result in theirsuitability for application to disease diagnosis, drug discovery,and biological weapon detection. It is expected that these toolswill be widespread and commonly used in the near future.Nanowire biosensors, however, still require improvement forthe commercialization. In order to achieve higher yield rates atlower costs, the current top-down fabrication method needs tobe modified to become more compatible with standard CMOStechnologies. Moreover, although the sensitivity of currentnanowire-based devices is relatively high, its analytical signalintensity is still low and easily contaminated by a high mag-nitude background noise, especially for in vivo environments.Modification of the surface chemistry and read-out circuitswill improve both the sensitivity and robustness of nanowirebiosensors. In order to achieve more comprehensive and spe-cific sensing systems, receptor binding methods are needed toreduce complexity and time to immobilize receptors. In sum-mary, nanowire biosensors have a promising solution for many


biomedical areas, not only because of their high sensitivity, butalso because of their low-cost, rapid detection, and simplicity.

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