Silicon nanowire-transistor biosensor for study of molecule-molecule interactions

Fan Yang 1  and Guo-Jun Zhang 1
  • 1 School of Laboratory Medicine, Hubei University of Chinese Medicine, 1 Huangjia Lake West Road, Wuhan 430065, China
Fan Yang
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  • Fan Yang received his BS in clinical medicine from Hubei University of Chinese Medicine in 2005 and his PhD from Sun Yat-sen University in 2011. After his postdoctoral research at the Shanghai Institute of Applied Physics, Chinese Academy of Sciences, he currently works as a lecturer at Hubei University of Chinese Medicine. His research interests are focused on microfluidics and nanobiosensors.
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and Guo-Jun Zhang
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  • Guo-Jun Zhang received his PhD in medicine from Tongji Medical School, Huazhong University of Science and Technology, China, in 1999. From 1999 to 2004, he was a postdoctoral fellow at Wuhan University (Wuhan, Hubei, China), Institute for Physical High Technology (Jena, Germany), and Waseda University (Tokyo, Japan), respectively. Afterwards, he became a visiting lecturer in 2004, a visiting associate professor in 2005 at Waseda University, and a member of the technical staff at the Institute of Microelectronics (Singapore), respectively. He currently works as a professor at Hubei University of Chinese Medicine. His main research interests lie in the fabrication of nanomaterial-based FET biosensor and its application in disease diagnostics.
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Abstract

Monitoring the molecular recognition, binding, and disassociation between probe and target is important in medical diagnostics and drug screening, because such a wealth of information can be used to identify the pathogenic species and new therapeutic candidates. Nanoelectronic biosensors based on silicon nanowire field-effect transistors (SiNW-FETs) have recently attracted tremendous attention as a promising tool in the investigation of biomolecular interactions due to their capability of ultrasensitive, selective, real-time, and label-free detection. Herein, we summarize the recent advances in label-free analysis of molecule-molecule interactions using SiNW-FETs, with a discussion and emphasis on small molecule-biomolecule interaction, biomolecule-biomolecule interactions (including carbohydrate-protein interaction, protein-protein or antigen-antibody binding, and nucleic acid-nucleic acid hybridization), and protein-virus interaction. Such molecular recognitions offer a basis of biosensing and the dynamics assay of biomolecular association or dissociation. Compared to the conventional technologies, SiNW-FETs hold great promise to monitor molecule-molecule interactions with higher sensitivity and selectivity. Finally, several prospects concerning the future development of SiNW-FET biosensor are discussed.

Introduction

Recently, silicon nanowire field-effect transistors (SiNW-FETs) have proven to be a promising tool in the investigation of molecular interactions due to their capability of ultrasensitive probing, real-time recording, and label-free detection (Duan et al. 2012b). Molecular interactions, such as protein-protein binding and nucleic acid-nucleic acid hybridization, are essential in extracellular and intracellular signaling (Pawson and Nash 2000, Sancar et al. 2004). To investigate such a molecular pairing is critical to elucidate their roles in cellular function that renders a better understanding of diseases and can provide the basis of new therapeutic protocols (Reilly et al. 2009). Besides, molecule recognition is the core of clinical diagnostics (Drummond et al. 2003), genetic screening (Singh et al. 1988), and drug development (Proske et al. 2005), especially for those that occurred on heterogeneous interface by attaching functional probes on solid surface to capture the targets of interest in solution (Song et al. 2010, Xu et al. 2014). It has been assumed that most, if not all, biosensing measurements rely on the information of the final complex followed by host-guest molecules association. Nevertheless, several binding events cannot form a stable complex, and the binding process is dynamic, even reversible, with a weak binding strength, which poses a great challenge for routine detection tools, like microarray that involves tedious fluorescent labeling and is generally incapable of real-time monitoring (Liang et al. 2005, Li et al. 2010). Thus, a reliable, label-free, and real-time transduction strategy for molecular interactions is highly desirable.

At present, the most widely used approach that allows label-free and real-time signaling is surface plasmon resonance (SPR) biosensor (Homola 2008). However, the poor performance in measuring small molecules (low molecule weights) and the integration of complicated optical components limit the application of SPR in the fields of ultrasensitive and portable biomonitoring. Moreover, the low sensitivity and low throughput in SPR further suppress its superiority in real-time recording of molecular binding information. Beyond SPR, quartz crystalline microbalance (QCM) and microcantilever sensors can also offer real-time probing of molecular interactions in a label-free manner and with a higher sensitivity, whereas the high operation cost remains a hurdle for their broad implementation (Marx 2003, Shekhawat et al. 2006, Ndieyira et al. 2008).

In contrast, SiNW-FETs can be constructed from either bottom-up deposition or top-down etching (a CMOS-compatible technology), which provides not only a real-time transduction of detailed information on binding interactions but also a useful tool for disease diagnostics (Cui et al. 2001, Zheng et al. 2005, Stern et al. 2007a, 2010). In addition, SiNW-FETs can perform rapid, ultrasensitive, and multiplexed detection of the desired targets independent of any labels (Patolsky et al. 2006a, Gao et al. 2007). In the past decade, this nanobiosensor has been widely used to detect a variety of molecule binding events with sensitivities below picomolar concentrations (Gao et al. 2011, 2012, 2013). Because of the broad implementation of SiNW biosensor in molecule-molecule interactions and an extendable application in real-time in vivo monitoring (Tian et al. 2010, Chen et al. 2011, Duan et al. 2012a, Li et al. 2014, Qing et al. 2014), we summarize the recent advances in SiNW-FETs with emphasis on a variety of molecule interactions. We start with a brief description of the working principle and fundamentally key information of an SiNW biosensor followed by a discussion on the micro-nano integration with microfluidics and various typical interacting events based on nanoscale FETs. Finally, challenges that may be encountered in the future with SiNW-FET probing are discussed.

SiNW-FET nanobiosensor

A typical SiNW-FET sensor is composed of a semiconductor channel and three electrodes (i.e., source, drain, and gate electrode) (Figure 1A). The source and drain electrodes intercommunicate mutually via a semiconductor channel, while the gate electrode modulates the channel conductance through an applied electrical potential. The commonly used gate (reference) electrode, in the liquid gating SiNW-FET, usually has three types, including Ag wire, Ag/AgCl, and Pt wire. The SiNW sandwiching between the source and the drain electrodes serves as a sensing element of the device, and its sensitivity is ascribed to the susceptible response to the alteration of an external electric bias that imposes on the sensing interface (Tsai et al. 2011). In biomolecule sensing application, SiNW surface-attached recognition molecules (charged or neutral) can specifically capture targets of interest (negatively or positively charged) by exposing the sensor to a solution containing targets, leading to a conductance change of semiconductor channel (Figure 1B). For an n-type SiNW nanobiosensor, the negatively charged targets would render a depletion of charge carriers through the entire cross-section of the device, thus lowering the source-drain current (Isd), and this mechanism can be extended to the interrogation of p-type SiNWs and positively charged biomolecules (Patolsky et al. 2007).

Figure 1
Figure 1

(A) Working principle of a SiNW-FET biosensor. The SiNW-FET contains a semiconductor channel, a single SiNW that is electrically connected between the source and drain electrodes. An Ag/AgCl reference electrode serves as a solution gate electrode by directly inserting into the buffer solution. The antibody molecule is immobilized on the SiNW surface and can specifically capture the target antigen molecule. (B) When a negatively charged antigen molecule binds on an n-type SiNW-FET, a depletion of charge carriers inside the SiNW leads to a decrease in the electrical conductance.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

Prior to measurement, sensor surface modification is a key step to improve the sensitivity of the nanodevice. Normally, a thin layer of silicon oxide is covering on the SiNW surface and serves as an active interface. To realize the surface functionalization, two approaches – electrostatic adsorption and covalent binding – have been used to immobilize the receptor molecules (Bunimovich et al. 2006, Park et al. 2007). Note that a chemical linker [e.g., 3-aminopropyltrimethoxysilane (APTMS)]-based covalent modifying strategy has a unique implementation (Li et al. 2013a). The SiNW surface-bound APTMS can survive the harsh photolithographic processes involving photoresist coating, organic solution rinsing, and thermal annealing in the bottom-up fabrication of SiNW sensors (Li et al. 2013a). Generally, the surface modification of SiNW is nonselective because this process would conjugate APTMS covering the entire silica surface beyond nanowire, which is incompatible to the ultrasensitive detection of minimal targets of interest due to the random capture of a large proportion of targets on the surrounding substrate. Therefore, an SiNW-selective modification methodology is urgently desirable. Several approaches, such as photolithography (Stern et al. 2007b), electrostatic attraction (Naujoks and Stemmer 2003), microcontact printing (Renault et al. 2002), and incomplete chemical etching (Masood et al. 2010), have been employed to decorate nanowire surface by focusing on the sensing area.

In sensing measurement, the electrolyte buffer produces screening effect that significantly jeopardizes the device performance (Stern et al. 2007b, Vacic et al. 2011). This screening effect is defined by the Debye length (λD), a distance separated away from the SiNW surface, where significant charge separation can take place. To improve sensitivity, a long λD is desirable that offers a large space to maintain the integrity of target charges. The λD can be increased by using dilute buffer solution with low electrolyte concentrations. However, overdilution yields a low salt concentration that may degrade the biological activity of proteins. Theoretically, the Debye length can be calculated using the formula: λD=0.304(I)-0.5, where I is the ionic strength of the buffer solution (Findenegg 1986). Governed by this equation, a higher salt buffer has a shorter λD, thus generating a more severe screening effect on sensing interface. As demonstrated in an investigation of biotin-streptavidin binding by a p-type SiNW biosensor, the λD in 1×, 0.1×, and 0.01× phosphate-buffered saline (PBS) was 0.7, 2.3, and 7.3 nm, respectively (Stern et al. 2007b).

Although a rational ionic strength of buffer solution can improve device performance, it is inadequate to realize high-efficiency molecular recognition for a rapid assay. We have thus developed a rectangular macroscale chamber for rapid fluidic delivery to accelerate the binding between sensing surface-bound probe and target, and this open chamber structure can precisely cover the nanosensing channel simply by a double-sided adhesive (Chua et al. 2009). Apart from open chamber, a polydimethylsiloxane (PDMS) microfluidic channel has also been exploited to guide fluids flowing through the sensing surface with high controllability, precision, and multiplexing capability, particularly for manipulating samples of minimal volumes. Patolsky and Shen separately directed samples flowing through an SiNW surface for real-time monitoring of airborne influenza H3N2 viruses (Patolsky et al. 2004, 2006b,c, Patolsky and Lieber 2005, Shen et al. 2011). Additionally, we have created a novel SiNW-FET by coupling to a microfluidic polymerase chain reaction (PCR) system that was integrated with heaters and temperature sensors on a silicon chip to shorten the cycling time (Kao et al. 2011). We believe that microfluidic technology should be further integrated with FET biosensors in order to establish multiplexed and ultrasensitive bioassays.

Study of molecule-molecule interactions

Small molecule-biomolecule interactions

Generally, the target that can be detected with SiNW-FETs is characteristic of large sizes, high molecular weights, and dense charges, which can impose a strong electric field on the sensing device, facilitating FET-based measurements (Zayats et al. 2006, Chen et al. 2011). However, it is challenging to probe weakly charged, small molecules with FET biosensors. A representative small molecule, dopamine (DA), is an important neurotransmitter that plays many important roles in multiple physiological activities. Nevertheless, the amount of DA is extremely low in bodies; thus, it is difficult to detect using existing approaches, such as electrochemical biosensors that have detection limits typically around nanomolar levels (10-9m). Chen et al. developed a multiple, parallel-connected SiNW-FET with sensing surface-bound aptamer probes for ultrasensitive and selective DA detection (Figure 2A) (Li et al. 2013b). The approach improves the limit of DA detection below 10-11m and can specifically distinguish DA from other chemical analogues, such as ascorbic acid, catechol, phenethylamine, tyrosine, epinephrine, and norepinephrine. Furthermore, this nanodevice realizes a real-time monitoring of DA release under hypoxic stimulation from living PC12 cells. Additionally, Lieber’s group presented a highly sensitive and label-free measurement of ATP binding to Abl (a protein tyrosine kinase) by using an SiNW sensor (Wang et al. 2005). The concentration-dependent ATP binding and the inhibition of ATP binding by a competitive small-molecule antagonist STI-571 were monitored via nanowire conductance variation.

Figure 2
Figure 2

(A) Illustration of the experimental setup of a DNA-aptamer modified MPC SiNW-FET device for detecting exocytotic DA under hypoxic stimulation from living PC12 cells. (B) A scheme of covalent attachment of peptides to an SiNW-FET and electrical responses of an AcOH recognition peptide/SiNW-FET. Reprinted with permission from Li et al. (2013) and McAlpine et al. (2008), respectively. Copyright © American Chemical Society.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

The SiNW-FET nanosensor has also been used to investigate peptide-small molecule interactions, including ammonia (NH3) and acetic acid (AcOH) (McAlpine et al. 2008). As shown in Figure 2B, the specific peptides were covalently attached to an SiNW surface for subsequent capture of small molecules. To test the selectivity of this nanoFET to AcOH, acetone (a similar molecule to AcOH) was employed to dilute AcOH for measurement. The addition of AcOH to the peptide-functionalized SiNW-FET generates an obvious responsive signal increase, indicating that the peptide-conjugated nanosensor has an excellent specificity to AcOH in high interference backgrounds (Figure 2B). In addition, a simulated clinical breath sample (a background of 6% CO2) has been used to test the performances of both AcOH and NH3-peptide FET sensors, and the results demonstrate that such nanoFETs can sensitively detect the targets from exhaled breath components, exhibiting their great potential to serve as an electronic nose for further medical diagnosis.

Actually, a universal small molecule-biomolecule pair, biotin-avidin/streptavidin, has frequently been used to characterize the nanodevice performances or serves as an analytical model. For example, Cui et al. (2001) developed a boron-doped SiNW-FET sensor functionalized with small molecule-biotin, which is able to probe streptavidin down to a picomolar level. Another group also employed this molecule pair to measure protein-ligand binding affinities and kinetics via an SiNW biosensor and further determined the rate constant of the association and dissociation of the molecule pair (Duan et al. 2012b).

Biomolecule-biomolecule interactions

Compared to the binding between small molecules and biomolecules, the biomolecule-biomolecule interactions are able to intrigue more extensive interest, because such molecule bindings offer a wealth of significant information pertinent to diagnosis and treatment of diseases ranging from cancer to infectious disease. Several aspects of such basic information have been summarized in Table 1. Next, we will discuss these biomolecule-biomolecule interactions that were recorded by SiNW-FETs in detail.

Table 1

Characteristics and applications of diverse SiNW-FETs.

Nanowire typeFabricationReceptor typeImmobilization strategyTargetDetection limitReferences
p-typeBottom-upDNA aptamerCovalent binding (sulfhydryl-maleimide)DA10 fMLi et al. 2013a,b
p-typeBottom-upPeptideFmoc-peptide couplingNH3, AcOH100 ppmMcAlpine et al. 2008
p-typeBottom-upBiotinPhysical adsorption (biotin-labeled BSA)Streptavidin10 pMCui et al. 2001
n-typeTop-downGalactoseOxime bondingLectin EC100 fg/mlZhang et al. 2013
n-typeTop-downDNACovalent binding (EDC-NHS)ERα10 fMZhang et al. 2011
n-typeTop-downDNACovalent binding (amine-isothiocyanate)HMGB1Femtomolar rangeDuan et al. 2012a,b
n-typeTop-downAnti-mouse IgANHS/ethylene dicarbodiimide couplingMouse IgA100 fMStern et al. 2007a,b
n-typeBottom-upAnti-PSA, anti-CEA, anti-mucin-1Aldehyde coupling mAbPSA, CEA, mucin-12, 0.55, and 0.49 fMZheng et al. 2005
n-typeTop-downAnti-PSACovalent bindingPSA30 aMKim et al. 2007
n-typeTop-downAnti-PSA, anti-CA15.3Avidin-biotinPSA, CA15.32.5 ng/ml, 30 U/mlStern et al. 2010
n-typeTop-downAnti-cTnTGlutaraldehyde-aminecTnT1 fg/mlChua et al. 2009
n-typeTop-downAnti-cTnT, anti-CK-MM, anti-CK-MBGlutaraldehyde-aminecTnT, CK-MM, CK-MB1 fg/mlZhang et al. 2012
n-typeTop-downPNAGlutaraldehyde-amineDNA10 fMZhang et al. 2008, 2010
p-typeBottom-upPNAAvdin-biotinylated PNADNA10 fMHahm and Lieber 2004
n-typeTop-downPNAGlutaraldehyde-aminemiRNA1 fMZhang et al. 2009
n-typeTop-downDNACovalent binding (EDC-NHS)DNA1 fM, 0.1 fM, 50 aMGao et al. 2011, 2012, 2013
n-typeTop-downDNACovalent binding (EDC-NHS)miRNA1 zMLu et al. 2014
p-typeBottom-upAntibodyAldehyde-amineInfluenza A, adenovirusSingle virusPatolsky et al. 2004
p-typeBottom-upMonoclonal antibodyDisulfide linkerH5N20.01 aMChiang et al. 2012

Carbohydrate-protein interactions

Carbohydrates are indispensible constituents in the cell membrane and can be specifically recognized by corresponding proteins. Such carbohydrate-protein recognitions are critical in cell communication and immune responses (Varki 2007). A better understanding of carbohydrate-protein binding would help to elucidate intercellular signaling pathways, possibly leading to new tools for diagnosis and therapeutics (Seeberger and Werz 2005). To this end, we developed an SiNW biosensor capable of label-free and real-time recording of carbohydrate-protein interactions with high specificity and sensitivity by covalently immobilizing unmodified carbohydrates on the sensor surface (Figure 3A) (Zhang et al. 2013). The SiNW sensor chips were fabricated via photolithography technology involving the routine processes, such as etching and oxidation (Chua et al. 2009). A total of 255 individual nanowires were arrayed to four groups (i.e., A–D), and groups A to C have 12 clusters each (5 nanowires in one cluster) with a distance of 300 μm in between and group D has 15 nanowire clusters with the same pitch (Figure 3B). The real-time monitoring of carbohydrate-protein interactions was then carried out using a galactose-modified SiNW biosensor. As shown in Figure 3C, the real-time responses of conductance upon injection of different concentrations of lectin EC ranging from 1 ng/ml to 10 fg/ml were observed. We also found that the addition of blank buffer (0.01× PBS) without lectin EC did not generate a current change and the conductance decreased with reducing concentrations of lectin EC. This galactose-modified SiNW biosensor is able to probe 100 fg/ml lectin EC.

Figure 3
Figure 3

(A) Schematic diagram of the SiNW biosensor for label-free detection of carbohydrate-protein interactions. (B) Optical image of an SiNW sensor chip with four clusters. (C) Real-time detection of lectin EC with the galactose-modified SiNW biosensor. Reprinted with permission from Zhang et al. (2013). Copyright © American Chemical Society.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

Nucleic acid-protein interactions

The estrogen receptor α (ERα) protein is an important DNA binding transcription factor that can promote aberrant growth of breast cancer cells. To record ERα-DNA interactions in a real-time manner, we developed a self-assembled monolayer (SAM)-assisted SiNW biosensor for the specific and highly sensitive detection of the binding event, even in nuclear extracts prepared from breast cancer cells (Zhang et al. 2011). As illustrated in Figure 4A, the SiNW biosensor surface was coated with a vinyl-terminated SAM to link the aminated double-stranded DNA (dsDNA), including wild-type (WT), mutant (MU), and scrambled sequences of ER elements (EREs). Such functionalized nanosensors demonstrate favorable selectivity between ERα and WT EREs, and a limit of detection (LOD) as low as 10 fM has been realized, which is 3 orders of magnitude lower than that obtained by SPR-based biosensors (Su et al. 2006). Furthermore, we presented a direct probing of ER-DNA interactions in complex nuclear extracts using this nanosenor (Zhang et al. 2011). Two breast cancer cell lines, MCF-7 (ER+) and MDA MB231 (ER-), were employed to test the specificity of the detection. The results showed the response of the WT-ERE-functionalized SiNW biosensor to the nuclear extracts and an important conductance change was obtained in the presence of ERα. This demonstrated the capability of the SiNW biosensor for the direct detection of protein-DNA interactions in the complex environment of real samples. Next, Duan et al. (2012b) showed that SiNW FETs can be used to measure the affinities and kinetics of protein-DNA interactions with sensitivity down to femtomolar range. A representative protein-DNA binding pair, high mobility group box 1 (HMGB1) proteins and DNA that shows slow association/dissociation kinetics, was selected as an analytical model to investigate the binding affinities and kinetics based on an SiNW biosensing platform (Figure 4B). Importantly, a calibration method has been presented to reduce device-to-device variation in the sensor response. By combining FET with the analytical model, the protein-DNA binding event was successfully recorded and analyzed in both the association and dissociation phases.

Figure 4
Figure 4

(A) Schematic diagram of an SiNW biosensor for studying protein-DNA interactions. Specificity of the interaction, various concentrations response, and the response to the nuclear extracts from MCF-7 and MDA MB231 breast cancer cells. (B) Cross-section of the p-doped (Pt) SiNW biosensor setup showing the source (S) and drain (D). Typical schematic binding cycle for measurements obtained using the SiNW-FET biosensor. Reprinted with permission from Zhang et al. (2011) and Duan et al. (2012a,b), respectively. Copyright © Elsevier Science and Nature Publish Groups.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

Protein-protein interactions

In addition to nucleic acid-protein binding, the protein molecule specific recognition, such as ligand-receptor association on cell surface and antigen-antibody binding in physiological fluids, is central to cell signaling. The development of a reliable platform or tool for real-time recording of the protein interactions is significant to advance our understanding of the biological and pathogenic mechanisms behind multiple physiopathological activities. However, many routine approaches, such as microarray, rely mainly on complex and time-consuming labeling technologies (Wilson and Nock 2003). Therefore, there is an urgent need to develop a rapid and label-free detection strategy to probe protein-protein interactions. Note that the SiNW-based nanoelectronic device has attracted intense interest due to its unique properties, such as the easy-to-decorate sensing surface and the capability of real-time recording of binding events with high sensitivity and target specificity. For instance, Stern et al. (2007a) presented a CMOS-compatible FET for the specific label-free detection of low concentrations of antibodies (<100 fM) and real-time monitoring of the cellular immune response (Figure 5A). By using commercially available (100) silicon-on-insulator wafers, they engineered trapezoidal cross-section nanowires with dominant Si(111)-exposed plane that is amenable to selective surface functionalization, and this CMOS compatibility enables the simultaneous fabrication of sensor arrays and integrated signal processing electronics. Subsequently, the as-prepared SiNW FET has been employed to demonstrate the sensitivity of protein binding by using the classic biotin-streptavidin interaction, and the detectable concentration of streptavidin was 10 fM. The immunodetection was demonstrated using goat anti-mouse IgA-functionalized sensors, and a specific detection limit of antibody (mouse IgA) as low as 100 fM in concentration was obtained (Figure 5B).

Figure 5
Figure 5

(A) Schematic after anisotropic etch and schematic of fluid exchange system superimposed on chip optical micrograph. The source (S), drain (D), and underlying backgate (G) are labeled. (B) Demonstration of immunodetection. Reprinted with permission from Stern et al. (2007a,b). Copyright © Nature Publish Groups.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

Besides immunodetection, SiNW FET has a broad implementation in the monitoring of protein biomarkers, such as prostate-specific antigen (PSA; free PSA <4 ng/ml, normal level). Zheng et al. (2005) engineered an SiNW biosensor array that was used to detect multiple cancer biomarkers simultaneously in a single, versatile detection platform. To facilitate the multiplexed detection, individual nanowires in parallel were fabricated using photolithography and metal deposition (Figure 6A). Three independent SiNW biosensors with the corresponding fluid-based assembly were immobilized with different antibodies that were against PSA, carcinoembryonic antigen (CEA; <5.01 ng/ml, normal level), and mucin-1, respectively, and the real-time, simultaneous measurement of the three protein targets was achieved by using antibody-functionalized nanobiosensors (Figure 6A). Each protein marker induced an obvious electronic signal variation and the detection limit for these markers was down to the picogram per milliliter level. Moreover, the SiNW arrays were directly applied in blood serum to further demonstrate their capability of multiplexed readout and a concentration-dependent conductance increase for PSA was obtained. Kim et al. (2007) also developed an ultrasensitive and real-time method for the detection of PSA using an n-type SiNW-FET biosensor. It was found that the ultrasensitive immunodetection (<1 fg/ml) could be achieved by controlling the dimension of the SiNW and the doping concentration of the Si channel. To circumvent the influence of complex background in blood, Stern et al. (2010) integrated a microfluidic purification chip (MPC) system and an SiNW-FET array to analyze PSA and carbohydrate antigen 15.3 (CA15.3) (6.0–23.4 U/ml, normal level). The MPC can pre-purify the target proteins from whole blood via specific antibodies immobilized on the channel and subsequently release them by photochemistry (Figure 6B). The purified protein molecules were then transferred to the nanowire cell for real-time sensing. PSA at a concentration of 2.5 ng/ml and CA15.3 at 30 U/ml were detected from whole blood.

Figure 6
Figure 6

(A) Nanowire sensor arrays and multiplexed detection of cancer marker proteins. (B) Schematic of MPC operation and purification of PSA and CA15.3. Reprinted with permission from Zheng et al. (2005) and Stern et al. (2010), respectively. Copyright © Nature Publish Groups.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

Human cardiac troponin-T (cTnT) is a key protein biomarker in myocardial injury (<0.01 ng/ml, normal level). To realize a highly sensitive detection of cTnT, we developed an SiNW array chip capable of measuring ultralow concentration of cTnT in biological samples (Chua et al. 2009). SiNW sensors functionalized with anti-cTnT antibodies were individually exposed to various concentrations of cTnT (from 1 fg/ml to 1 ng/ml). The results showed a concentration-dependent change of the sensor conductance, and the nanosensor is able to detect as low as 1 fg/ml cTnT. We further demonstrated a label-free and real-time detection of cTnT in an undiluted serum environment down to 30 fg/ml using this nanodevice, which is 3 orders of magnitude lower than that achieved by enzyme-linked immunosorbent assay (ELISA) methods (Müller-Bardorff et al. 1997).

In addition to cTnT, creatine kinase-MM (CK-MM) and creatine kinase-MB (CK-MB) each predict different cardiac events (<7.0 ng/ml, normal level); thus, a simultaneous assessment of multiple biomarkers is more reliable to diagnose cardiac injury. Generally, the raw sample requires desalting to analyze targets in serum using FET biosensors, and this additional step made real-time detection difficult to carry out. To eliminate the desalting process, we developed a new steady-state detection method based on the SiNW array biosensor, independent of the ionic strength of the sample solution, allowing the SiNW sensor to directly analyze the cTnT, CK-MM, and CK-MB in blood serum (Zhang et al. 2012). The antibody-antigen reaction was conducted in high-ionic-strength serum, but the measurement was carried out in the presence of 0.01× PBS (low ionic strength buffer) before and after probe-target binding. The cardiac biomarkers are negatively charged in a neutral PBS buffer (pH 7.4) with pIs of approximately 5.0, 5.8, and 6.5 for cTnT, CK-MB, and CK-MM, respectively; their binding to the SiNW surface thus increased the resistance. These results demonstrate that the antibodies-functionalized SiNW sensor is capable of multiplexed detection of proteins in undiluted and untreated blood serum with high sensitivity and selectivity down to femtogram per milliliter concentrations.

Nucleic acid-nucleic acid interactions

Nucleic acids (DNA and RNA) contain negatively charged phosphate backbones that enable DNA/DNA, DNA/RNA, and RNA/RNA duplexes with double-negative charges to enhance electrical potential on FET sensing surface, thus demonstrating a clear conductance variation and sensitive assay. To further improve the sensing sensitivity of SiNW-FETs, an electrically neutral nucleic acid analogue, peptide nucleic acid (PNA), has been used preferentially as capture probe molecule. PNA has several unique properties: (1) electric neutrality that makes PNA-DNA duplex more stable over its homocounterparts due to enhanced Tm, and the diminished repulsion provides an improved accessibility for hybridization; (2) enhanced differentiation of base mismatch; and (3) capable of surviving nuclease and enzymes. Such properties render PNA a versatile tool to investigate PNA-DNA or PNA-RNA interactions.

PNA-DNA hybridizations

To investigate the field effect in SiNW sensor, we first designed an approach to vary the distance of the charge layer away from the sensing surface by tuning the binding sites of DNA-PNA hybridization while maintaining charges constant (Zhang et al. 2008). The recorded results showed that the detection sensitivity was distance dependent that agreed well with the theoretical analysis. Next, we developed a novel SiNW nanobiosensor based on PNA-DNA hybridization for highly sensitive and rapid detection of dengue virus (Zhang et al. 2010). Dengue virus contains a single-stranded RNA (ssRNA) that can be amplified and detected through reverse transcription-PCR (RT-PCR), which enables the identification of different serotypes by serotype-specific primers. The basic principle of this method is illustrated in Figure 7A. A fragment of DEN-2 was selected and amplified by RT-PCR using as targets. The denatured single-stranded DNA (ssDNA; with negative charge) can complementarily bind to SiNW surface-tethered PNA probe and thus causes a conductance alteration for electrical readout. Moreover, two different PNA sequences, one complementary and the other noncomplementary to the RT-PCR product of DEN-2, were linked on the SiNW surface for selectivity characterization (Figure 7A). An obvious increase in resistance was observed in the presence of 1 nm of the amplicons, whereas a negligible change was obtained for the noncomplementary PNA-functionalized SiNW. The results demonstrated a high selectivity for the RT-PCR product of DEN-2 with this PNA-functionalized nanosensor. Using this method, a detection limit of 10 fM for the amplicons in unpurified RT-PCR product can be realized by the SiNW sensor within 30 min. We further integrated this SiNW nanosensor with a functionalized microfluidic chip using a multiplexed PCR module to identify subtypes of the H1N1 2009 strain versus the seasonal influenza (FluA) strain (Kao et al. 2011). The amplified dsDNA was first denatured to ssDNA and then delivered to the nanosensor for hybridization and subsequent measurements. The real-time response of the PNA-functionalized SiNW biosensor to either H1N1 or FluA was recorded once after the sample was flowing through the microfluidic channel. It was found that the microsystem was able to achieve a sensitivity of 20–30 fg/μl for H1N1 and FluA in a 10 μl sample.

Figure 7
Figure 7

(A) Schematic diagram of the RT-PCR product of DEN-2 hybridized to the PNA-functionalized SiNW biosensor. Characterization of specificity and resistance change. (B) Schematic diagram of the PNA-functionalized SiNW biosensor for ultrasensitive detection of miRNA. Hybridization specificity and concentration-dependent response. Reprinted with permission from Zhang et al. (2010) and Zhang et al. (2009), respectively. Copyright © Elsevier Science.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

In the monitoring of PNA-DNA hybridization, Hahm and Lieber (2004) also designed a PNA-modified SiNW-FET for ultrasensitive and selective detection of DNA sequences of WT or the ΔF508 MU site in the cystic fibrosis transmembrane receptor (CFTR) gene. The specific conductance changes from PNA-DNA recognition were obtained from the real-time recording of time-dependent conductance following the introduction of WT and MU DNA samples with the same SiNW device. The results demonstrated that this p-type SiNW sensor was capable of measuring DNA at concentrations down to the tens of femtomolar range.

PNA-RNA hybridizations

We also developed an ultrasensitive, direct, and label-free method based on PNA-functionalized SiNW nanosensor for microRNA (miRNA) detection (Zhang et al. 2009). As a class of 18- to 24-nucleotide-long noncoding RNA molecules, miRNAs have an important role in genetic regulation and tumor diagnostics (Lagos-Quintana et al. 2001). Existing methods for detecting miRNA are dependent on hybridization with a labeled target miRNA molecule, such as microarray that is indirect, involving labeling of target molecules. Therefore, it is necessary to develop a robust method for the detection of miRNAs with high sensitivity, selectivity, and simplicity. As shown in Figure 7B, PNA was covalently bound on the electrically addressable SiNW surface via conventional silane chemistry. Such a PNA-functionalized SiNW biosensor was then used to detect three miRNA sequences, including let-7b (complementary), let-7c (one-base mismatched), and control (noncomplementary). It was found that the SiNW biosensor allowed for label-free discrimination between the fully matched and mismatched miRNAs (Figure 7B). Furthermore, a concentration-dependent detection of let-7b by the SiNW biosensor was investigated (Figure 7B); the more the target miRNA molecules are hybridized, the higher the resistance increased. The results indicate that the biosensor is capable of detecting target miRNA at concentrations as low as 1 fM, which is 1 order of magnitude higher than that reported for detection of DNA (Cattani-Scholz et al. 2008). The assay was further tested for the detection of miRNA in real samples by analyzing let-7b in total RNA extracted from HeLa cells. The concentration of let-7b detectable in the total RNA extracted from HeLa cells was 2.15±0.25×107 copies/μg, which is in good agreement with the previously published data of miRNA expression profiling (Nelson et al. 2004). This method shows potential applications in label-free, early detection of miRNA associated with cancer with high sensitivity and specificity.

DNA-DNA/RNA hybridizations

In contrast to PNA receptor, DNA probe is low cost and can be synthesized with a long sequence that enables DNA-functionalized SiNW-FET to be an important sensing platform for the analysis of nucleic acids. For instance, Gao et al. (2011) reported a highly responsive FET sensor array for the ultrasensitive and real-time detection of DNA. A CMOS-compatible top-down anisotropic self-stop etching technology was used to fabricate a narrow-size nanowire with high surface-to-volume ratios (Figure 8A). The DNA-modified nanosensor showed ultrahigh sensitivity for the rapid and reliable detection of 1 fM target DNA as well as high specificity of single nucleotide polymorphism (SNP) discrimination. This nanodevice is capable of simultaneous recording of two virus DNA sequences, H1N1 and H5N1. Subsequently, the same group presented an enhanced sensitivity of sensing target DNA by using a back-gated SiNW-FET that has a triangle cross-section of nanowire functionalized with DNA probes and realized a detection limit of 0.1 fM of DNA molecules and high specificity of SNP discrimination (Gao et al. 2012). In order to further improve the sensitivity of the nanoFET sensor, they employed rolling circle amplification (RCA) for electrical signal augmentation (Figure 8B) (Gao et al. 2013). The RCA-based reaction yields a long ssDNA product that extremely increases the charge density of target DNA and thus enhances the electronic response of SiNW significantly. An enhanced signal-to-noise ratio (SNR; SNR>20 for 1 fM DNA) was obtained, implying a detection floor of 50 aM. Next, they used this DNA-modified CMOS-compatible FET biosensor to measure miRNA molecules (Lu et al. 2014). The nanosensor showed a rapid response of miR-21 and miR-205, with a low limit of detection of 1 zmol, and an excellent discrimination of single-nucleotide mismatched sequences. Based on these results, they further investigated the practical application of the nanosensor in extracted miRNA samples from lung cancer cells and human serum.

Figure 8
Figure 8

(A) Schematic diagram of the SiNW-FET sensor, and the nanosensor for real-time detection of target DNA. (B) Schematic illustration of RCA-based SiNW detection of DNA, and the nanosensor for real-time detection of target DNA. Reprinted with permission from Gao et al. (2011) and Gao et al. (2013), respectively. Copyright © American Chemical Society.

Citation: Reviews in Analytical Chemistry 33, 2; 10.1515/revac-2014-0010

Protein-virus interactions

In addition to the monitoring of the binding events at the molecular level, virus particles’ association with partner antibodies can also be probed using an antibody-functionalized SiNW-FET. Virus is one of the most lethal killers for humans; thus, a rapid, sensitive detection of viruses is critical to implementing an effective response to viral infection with medication. Patolsky et al. (2004) demonstrated a direct and real-time detection of individual virus particles using antibody-functionalized SiNW biosensors. The p-type SiNW biosensing surface was immobilized with a specific antibody by exposing to highly diluted influenza A virus solutions of the order of 80 aM (50 viruses/ml), and measuring results showed discrete conductance change characteristic of binding and unbinding of influenza A. Moreover, a multiplexed detection of different viruses using corresponding antibodies-modified SiNW biosensor arrays was carried out, in which influenza A and adenovirus could be selectively detected in parallel. Such work revealed the potential for the simultaneous detection of multiple viruses at the single virus level. In addition, an ultrasensitive detection of H5N2 avian influenza virus (AIV) has been realized by using a strategy of reversible surface functionalization of SiNW-FET in a dilute solution (Chiang et al. 2012). A disulfide linker that reversibly controls the surface modification of SiNW renders the SiNW-FET a reusable device for the fast detection of H5N2 AIV. The binding specificity of the nanoFET functionalized by a monoclonal antibody against H5N2 virus has also been demonstrated and this nanosensor can obtain a highly sensitive detection of H5N2 AIV in an extremely dilute concentration at 10-17m level. Atomic force microscopy (AFM) scanning further verified that the sensitive SiNW-FET is capable of detecting very few H5N2 AIV particles.

Conclusion and future outlook

In the past few years, SiNW-FET has achieved great progress in the monitoring of interfacial molecule-molecule interactions, which is capable of probing multiple molecular interactions, ranging from small molecule-biomolecule binding, biomolecule-biomolecule interaction to biomolecule-virus interaction due to its ultrasensitive, highly selective, label-free, and real-time detection properties that also render SiNW-FET a promising tool for biological analysis and cellular investigation. Moreover, SiNW-FET fabrication based on the CMOS-compatible top-down etching allows highly multiplexed sensing and permits flexible integration with electrical readout circuits. Beyond these merits, many technical challenges still exist, which hinders the practical application of nanoFETs in real-time recording of molecular interactions, such as neutral molecules recognition. Generally, the FET biosensors are typically responsive of charged species, such as nucleic acids, proteins, and viruses that can impose an electrical bias on semiconductor channel by triggering a measurable conductance change. Nevertheless, the uncharged or poor charged molecules are inadequate to induce such an observable electronic signal, thus requiring special strategies to overcome this obstacle. For instance, a preassembled neutralizer complex, composed of a negatively charged DNA aptamer and a positively charged peptide-DNA conjugate, can release the neutralizer and generate a dramatic change in the surface charge upon the target-aptamer binding (Das et al. 2012). Actually, such a similar sensing strategy has been exploited to probe the binding of neutral steroids with its receptor that was engineered with a sequestrated moiety (charged) (Chang et al. 2009). This charged moiety can be released and exposed to the SiNW surface upon the steroids-receptor binding, inducing a detectable electronic signal. A frequency (f)-domain electrical measurement opens up another opportunity to probe the uncharged target binding with receptor (Zheng et al. 2010). Even if the detection of neutral targets is possible in the future, direct probing of molecular interactions in physiological fluids (high salt environment) remains a challenge using SiNW biosensors, because the Debye screening effect from physiological buffer can deteriorate the electrical signals. Although a pre-purification-based two-stage method by using SiNW-FET has been successfully used for the label-free detection of biomarkers in whole blood, it relies on a microfluidics-based target capture and subsequent photo-induced release of the target to associate with downstream receptor. We believe that a one-step and direct measurement in high salt physiological buffer can be created in the near future due to the rapid development of microfluidics (Chin et al. 2011).

Acknowledgments

The authors acknowledge the support of the National Natural Science Foundation of China (Nos. 21275040 and 21305034).

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    (A) Working principle of a SiNW-FET biosensor. The SiNW-FET contains a semiconductor channel, a single SiNW that is electrically connected between the source and drain electrodes. An Ag/AgCl reference electrode serves as a solution gate electrode by directly inserting into the buffer solution. The antibody molecule is immobilized on the SiNW surface and can specifically capture the target antigen molecule. (B) When a negatively charged antigen molecule binds on an n-type SiNW-FET, a depletion of charge carriers inside the SiNW leads to a decrease in the electrical conductance.

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    (A) Illustration of the experimental setup of a DNA-aptamer modified MPC SiNW-FET device for detecting exocytotic DA under hypoxic stimulation from living PC12 cells. (B) A scheme of covalent attachment of peptides to an SiNW-FET and electrical responses of an AcOH recognition peptide/SiNW-FET. Reprinted with permission from Li et al. (2013) and McAlpine et al. (2008), respectively. Copyright © American Chemical Society.

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    (A) Schematic diagram of the SiNW biosensor for label-free detection of carbohydrate-protein interactions. (B) Optical image of an SiNW sensor chip with four clusters. (C) Real-time detection of lectin EC with the galactose-modified SiNW biosensor. Reprinted with permission from Zhang et al. (2013). Copyright © American Chemical Society.

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    (A) Schematic diagram of an SiNW biosensor for studying protein-DNA interactions. Specificity of the interaction, various concentrations response, and the response to the nuclear extracts from MCF-7 and MDA MB231 breast cancer cells. (B) Cross-section of the p-doped (Pt) SiNW biosensor setup showing the source (S) and drain (D). Typical schematic binding cycle for measurements obtained using the SiNW-FET biosensor. Reprinted with permission from Zhang et al. (2011) and Duan et al. (2012a,b), respectively. Copyright © Elsevier Science and Nature Publish Groups.

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    (A) Schematic after anisotropic etch and schematic of fluid exchange system superimposed on chip optical micrograph. The source (S), drain (D), and underlying backgate (G) are labeled. (B) Demonstration of immunodetection. Reprinted with permission from Stern et al. (2007a,b). Copyright © Nature Publish Groups.

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    (A) Nanowire sensor arrays and multiplexed detection of cancer marker proteins. (B) Schematic of MPC operation and purification of PSA and CA15.3. Reprinted with permission from Zheng et al. (2005) and Stern et al. (2010), respectively. Copyright © Nature Publish Groups.

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    (A) Schematic diagram of the RT-PCR product of DEN-2 hybridized to the PNA-functionalized SiNW biosensor. Characterization of specificity and resistance change. (B) Schematic diagram of the PNA-functionalized SiNW biosensor for ultrasensitive detection of miRNA. Hybridization specificity and concentration-dependent response. Reprinted with permission from Zhang et al. (2010) and Zhang et al. (2009), respectively. Copyright © Elsevier Science.

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    (A) Schematic diagram of the SiNW-FET sensor, and the nanosensor for real-time detection of target DNA. (B) Schematic illustration of RCA-based SiNW detection of DNA, and the nanosensor for real-time detection of target DNA. Reprinted with permission from Gao et al. (2011) and Gao et al. (2013), respectively. Copyright © American Chemical Society.