Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation

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1 Nano Today (2011) 6, available at journal homepage: REVIEW Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation Kuan-I Chen a,b,1, Bor-Ran Li a,b,1, Yit-Tsong Chen a,b, a Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan b Institute of Atomic and Molecular Sciences, Academia Sinica, P.O. Box , Taipei 106, Taiwan Received 31 October 2010; received in revised form 18 December 2010; accepted 7 February 2011 Available online 8 March 2011 KEYWORDS Silicon nanowire; Field-effect transistor; Protein protein interaction; DNA hybridization; Peptide small molecule interaction; Biomarker detection; Three-dimensional localized bioprobe Summary Silicon nanowire field-effect transistors (SiNW-FETs) have recently drawn tremendous attention as a promising tool in biosensor design because of their ultrasensitivity, selectivity, and label-free and real-time detection capabilities. Here, we review the recently published literature that describes the device fabrication and biomedical applications of SiNW- FET sensors. For practical uses, SiNW-FETs can be delicately designed to be a reusable device via a reversible surface functionalization method. In the fields of biological research, SiNW-FETs are employed in the detections of proteins, DNA sequences, small molecules, cancer biomarkers, and viruses. The methods by which the SiNW-FET devices were integrated with these representative examples and advanced to virus infection diagnosis or early cancer detection will be discussed. In addition, the utilization of SiNW-FETs in recording the physiological responses from cells or tissues will also be reviewed. Finally, the novel design of a three dimensional (3D) nano-fet probe with kinked SiNWs for recording intracellular signals will be highlighted in this review Elsevier Ltd. All rights reserved. Abbreviations: AFM, atomic force microscopy; ATP, adenosine triphosphate; CA, carbohydrate antigen; CaM, calmodulin; CEA, carcinoembryonic antigen; CgA, chromogranin A; CNT, carbon nanotube; CVD, chemical vapor deposition; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic acid; FET, field-effect transistor; GSH, glutathione; GST, glutathione S-transferase; His-tag, histidine-tag; mirna, microrna; MPC, microfluidic purification chip; NTA, nitrilotriacetic acid; PBS, phosphate buffered saline; PDMS, polydimethylsiloxane; PNA, peptide nucleic acid; PS, phosphate solution; PSA, prostate specific antigen; RNA, ribonucleic acid; RT-PCR, reverse transcription-polymerase chain reaction; SiNW, silicon nanowire; TnI, troponin I; VGCC, voltage-gated Ca 2+ channel; VLS, vapor liquid solid. Corresponding author at: Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan. Tel.: ; fax: address: (Y.-T. Chen). 1 These authors contributed equally to this work /$ see front matter 2011 Elsevier Ltd. All rights reserved. doi: /j.nantod

2 132 K.-I. Chen et al. Introduction Quantification and analysis of biological processes are of utmost importance for biomedical applications and cellular programming investigation. However, it is challenging to convert the biological information into an electronic signal due to the difficulties of connecting an electronic device into a biological environment. In recent years, there has been dramatic development of electrochemical biosensors because of their applications in toxicity testing [1], chemical analysis [2], medical diagnosis [3], food industry [4], environmental monitoring, and many other areas. An electrochemical biosensor, as defined by IUPAC, is a self-contained integrated device that allows for specific analytical detection by using a biological recognition element (a biochemical receptor) in direct spatial contact with a transduction element (Fig. 1(a)) [5,6]. Different from a bioanalytical system (e.g., immunoprecipitation usually used for protein analysis) that requires a reagent addition to proceed the analysis, an electrochemical biosensor provides an attractive platform to analyze the contents of biological samples because of the direct conversion of biological events to electronic signals (that can be detected directly), thus allowing more rapid and convenient sensing detection. Investigations of the materials and methods to construct an electrochemical biosensor have been underway for decades. Over the past 20 years, nanomaterials, such as quantum dots, nanoparticles, nanowires, nanotubes, nanogaps, and nanoscale films [7 13], have received enormous attention due to their suitable properties for designing novel nanoscale biosensors. For example, the dimension of nanomaterials of nm provides a perfect feature to study most biological entities, such as nucleic acids, proteins, viruses, and cells (as illustrated in Fig. 1(b)) [14]. In addition, the high surface-to-volume ratios for nanomaterials allow a huge proportion of the constituent atoms in the material to be located at or close to the surface. This characteristic makes the surface atoms play Figure 1 (a) The construction of typical biosensors with elements and selected components. The procedures are described as follows: (i) receptors specifically bind the analyte; (ii) an interface architecture where a specific biological event takes place and gives rise to a signal recorded by (iii) the transducer element; (iv) computer software to convert the signal into a meaningful physical parameter; finally, the resulting quantity is displayed through (v) an interface to the human operator. (b) The sizes of nanomaterials (NW and NT) in comparison to some biological entities, such as bacteria, viruses, proteins, and DNA. Reprinted from [6,14].

3 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 133 an extremely important role in determining the physical, chemical, or even electronic properties of nanomaterials. Moreover, some particular nanomaterials with surfaces that are easily chemically modified have made them significant candidates for nanoscale sensing applications. To date, a variety of nanoscale sensing techniques have been used for biological research and applications. In particular, when monitoring living systems, requiring rapid and precise detection, the demands of sensor architectures become challenging. Several essential factors, such as ultrasensitivity, specificity, high-speed sample delivery, and low cost must be considered when designing and fabricating nanoscale biosensors. Some sensing devices selecting quantum dots as their sensing elements possess the merits of high sensitivity, selectivity, and short response time. However, this kind of sensing technique generally requires integration with optical instruments to translate the successful binding phenomena into a readable signal [7], making the sensing measurements costly. On the other hand, devices like field-effect transistors (FETs) can be suitable candidates for designated sensors, owing to their ability to directly translate the interaction with target molecules taking place on the FET surface into a readable signal [15]. In recent years, one-dimensional semiconducting nanomaterials, such as silicon nanowires and carbon nanotubes, configured with FETs (referred to as SiNW-FET [16,17] and CNT-FET [18 20], respectively) have attracted great attention because they are an ideal biosensor with high selectivity and sensitivity, real-time response, and label-free detection capabilities. In this review article, we will mainly focus on the device fabrication of SiNW-FETs and their applications in biomedical diagnosis and cellular research. Field-effect transistor-based biosensors From the electrochemical point of view, SiNW-FET-based biosensors are a three-electrode system, including source, drain, and gate electrodes. The function of the source and drain electrodes is to bridge the semiconductor channel made of SiNWs and the gate electrode is responsible for modulating the channel conductance. In a representative NW-FET example illustrated in Fig. 2(a), the biological receptors were anchored to the surface of the semiconductor channel by chemical modification to recognize the target analytes through their high specificity and strong binding affinity in the buffer environment. The target receptor Figure 2 (a) The illustration of a nanoscale FET biosensor with a cross-sectional view. The semiconductor channel (NW or NT) is placed between the source and drain electrodes with a gate electrode on the bottom to modulate the conductivity of the semiconductor channel. Target molecules can be recognized by the receptor modified on the channel surface through strong binding affinity. (b) When positively charged target molecules bind the receptor modified on a p-type NW, positive carriers (holes) are depleted in the NW, resulting in a decrease in conductance. On the contrary, negatively charged target molecules captured by the receptor would make an accumulation of hole carriers, causing an increase in conductance. (c) Schematic representation of a CNT-FET device including the surface modification and molecular recognition procedures: (1) modification of linkers onto the single-walled CNT through interaction; (2) immobilization of antibody; (3) detection of antigen by antibody. (d) CgA was released from neurons stimulated by glutamate and was detected by CgA-Ab/CNT-FET. A coverslip with grown neurons was positioned on the CgA-Ab/CNT-FET device with neurons facing the FET circuits. Immediately after the glutamate (50 M) stimulation, a dramatic increase in current was detected due to the binding of the released CgA to CgA-Ab/CNT- FET. Reprinted from [14,38].

4 134 K.-I. Chen et al. interaction then varied the surface potential of the semiconductor channel and modulated the channel conductance, and the signal was eventually collected by a detection system. A diversity of FET-based biosensors has been employed for biological applications. Here, we tried to classify these biosensors into enzyme-modified FETs, cell-based FETs, and immunologically functionalized FETs. Enzyme-modified FETs comprise a redox active enzyme integrated with an electronic circuitry to give a real-time quantitative analysis of the enzyme substrate [21], e.g., sensing glucose from a catalytic reaction in the presence of glucose oxidase. Cell-based FETs were exploited to detect the released biochemical agents or real-time cellular responses from living cells, such as action potentials from neuron cells [22] or electrical recordings from chicken hearts [23]. In general, immunologically functionalized FETs are the most frequently used biosensors. For example, an antibodymodified FET sensor can be used to detect the corresponding antigen. Depending on the charge carriers in the semiconductive channel (holes for a p-type channel and electrons for an n-type channel), the direction of the conductance change represents the sign of the charges carried by the target antigen, and the magnitude of the conductance change reflects the antigen antibody interaction. In an example of a p-type NW-FET illustrated in Fig. 2(b), when the positively charged analytes bind the receptor-anchored NW-FET, a depletion of charge carriers occurs in the conductance channel, causing a decrease in the device conductivity. On the contrary, an increase in the device conductivity would result from the accumulation of charge carriers in the conductance channel while negatively charged molecules, such as DNA or RNA, bind the p-type NW-FET. In recent years, many types of semiconducting materials, such as carbon materials (e.g., CNT and graphene) [24 26] and metal-oxide nanowires (e.g., In 2 O 3 -NW and ZnO-NW) [27,28], have been selected as promising candidates for the development of FET-biosensors. For instance, graphenebased FETs were constructed for electrically detecting ph values, bovine serum albumin adsorption [25], and cellular recording [26]. In 2 O 3 -NW [27] and ZnO-NW [28] configured with FET-biosensors were also used to monitor protein protein interactions. Among them, CNTs, singledwalled CNTs in particular, were at the forefront of these explorations. Several recent articles about CNT-FETs, as represented in Fig. 2(c), have reviewed their biological applications [29 31], such as antigen antibody interactions [27,32 34], DNA hybridization [35,36], and enzymatic glucose detection [37]. As depicted in Fig. 2(d), a CNT-FET was specifically applied to the real-time detection of a cancer marker for neuroendocrine tumors, namely chromogranin A (CgA), released from embryonic cortical neurons [38,39]. The CNT-FET device modified with the antibody of CgA (referred to as CgA-Ab/CNT-FET) was employed to monitor the in situ release of CgA from living neurons in response to glutamate stimulation. Despite these advances of CNT-FETs in biosensory applications, several shortcomings were encountered in the fabrication and applications of CNT-FETs. First, in the fabrication of CNT-FETs, the mixtures of semiconducting and metallic CNTs still hamper future developments in nanoelectronics. Secondly, the determining factors for the sensing mechanisms of a CNT-FET are somewhat complex and were reported to involve field-effects [18,40], electron transfer [18], Schottky barriers [41,42], etc. In contrast, the sensing mechanism of a SiNW-FET sensor is straightforward and simply dominated by the field-effect [16,43] due to the interaction between the target analyte and the receptor modified on the surface of the SiNW-FET. Silicon nanowire field-effect transistors Taking advantage of the well-developed silicon industry, SiNW-FETs can benefit from existing and mature silicon industry processing techniques and fabrications. In the synthetic reactions that prepare SiNWs, different sizes [44,45], shapes [46], and dopants [47] of SiNWs could be precisely tailored. Because SiNWs could be well-controlled during the wire growth, the performance exhibits high reproducibility. Therefore, the n-/p-type semiconducting property, doping density, and charge mobility in a SiNW-FET can be designed in advance. In the following sections, we selectively discuss the nanowire fabrication, assembly techniques, device array design, and electrical measurement setup used in the performance of SiNW-FETs. Fabrication of SiNW-FETs There are two major fabrication techniques in preparing SiNW-FETs: top-down and bottom-up. The topdown method is carried out through lithographic processes combined with an electron-beam technique that defines SiNW-FETs by physically etching a single-crystalline silicon wafer [48]. On the other hand, the bottom-up processes start with the growth of SiNWs, normally in a chemical vapor deposition (CVD) reaction, followed by SiNW assembly and electrode fabrication via the photolithographic or electronbeam lithographic procedures [43]. Top-down SiNW-FETs The top-down method for the SiNW-FET fabrication is based on lithographic processing on a silicon-on-insulator (SOI) wafer. As illustrated in Fig. 3(a, i), the structure of an SOI wafer contains three layers: substrate Si wafer, buried silicon dioxide (about nm thick), and top Si layer (about nm thick). Through the standard procedures of photolithography, reactive ion etching (RIE), ion implantation, electron-beam lithography, and thermal evaporation, SiNWs and the connecting electrodes can be defined to form SiNW-FET devices, in which the width of SiNWs could reach the scale of 100 nm. A typical top-down process to fabricate SiNW-FETs is illustrated schematically in Fig. 3(a) [49 56]. In Step 1, the Si layer is doped with low-density boron or phosphorous of /cm 3 (about cm). Therefore, the n-/ptype semiconducting property and doping ratio of SiNWs are determined (Fig. 3(a, i)). Step 2 is to define the source and drain leads with heavy doping (10 19 /cm 3 ), of which the patterns are drawn with a photomask design (Fig. 3(a, ii)). In Step 3, the micrometer-sized source and drain electrodes are finished by RIE etching (Fig. 3(a, iii)). The following

5 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 135 Figure 3 (a) Schematic illustration of a typical top-down process to fabricate SiNW-FETs. (i) In Step 1, the silicon layer is doped with low-density boron or phosphorous of /cm 3. (ii) In Step 2, specific regions defined with a photomask pattern receive heavy doping (10 19 /cm 3 ). (iii) In Step 3, the micrometer-sized source and drain electrodes are finished by RIE etching. (iii) The following Step 4 is to fabricate the nanometer-sized SiNWs with an electric-resist pattern and RIE etching. (b) An illustration of a bottomup method to fabricate SiNW-FETs. (i) The growth of SiNWs in CVD reaction via the VLS mechanism. (ii) Deposition/alignment of SiNWs on a silicon substrate. (iii) A photomask pattern to define source/drain electrodes. (iv) Thermal evaporation to deposit the source/drain contacts. (v) Lift-off the remaining photoresist with Remover PG. Step 4 is to fabricate the nanometer-sized SiNWs with an electric-resist pattern and RIE etching (or tetramethylammonium hydroxide etching [49])(Fig. 3(a, iv)). Subsequently, a thermal evaporation is used to make the contact leads and back-gate, and finally an insulator layer (e.g., Al 2 O 3 [49,53], SiO 2 [51], orsi 3 N 4 [56]) is coated on the SiNW-FET devices. Compared with the bottom-up method, the topdown approach is more complex because the process relies on high-resolution lithography. For this reason, electron-beam lithography is necessary. Although the topdown approach needs many luxurious instruments, it has advantages of using standard semiconductor techniques to precisely design a desired device-array pattern without problems of positioning SiNWs. Another challenge to the top-down method is that the minimum width of the produced SiNWs is around 100 nm. To overcome this barrier, single SiNWs of triangular section were fabricated to reach the transverse dimension of 20 nm with the length of several micrometers [55]. Bottom-up SiNW-FETs The bottom-up processes start with the growth of SiNWs, normally in a chemical vapor deposition (CVD) reaction, followed by SiNW assembly (assisted by various techniques that are discussed in the next section), and finally the device fabrication via the photolithographic or electronbeam lithographic procedures [43]. With the bottom-up method, SiNWs can be synthesized catalytically in a CVD reaction via the vapor liquid solid (VLS) growing mechanism (Fig. 3(b, i)) [57]. The synthesis is usually catalytically assisted with metal nanoparticles [58,59] that not only catalyze the SiNW formation, but also control the size of the as-synthesized SiNWs. Subsequently, the as-synthesized SiNWs are suspended in ethanol solution and dispersed onto a support silicon substrate (Fig. 3(b, ii)). In the following photolithographic steps, a two-layer photoresist consisting of LOR3A and S1805 was first deposited onto a silicon substrate by spin coating where the electrodes were defined with a photomask design (Fig. 3(b, iii)). The next step is

6 136 K.-I. Chen et al. to deposit metal for the source/drain contacts by thermal evaporation (Fig. 3(b, iv)). Finally, the remaining photoresist layer was lifted off by Remover PG (Fig. 3(b, v)) [43]. Compared with the top-down technique, the bottom-up method has the advantages of synthesizing SiNWs of high crystallinity, designated dopant density, thin silicon oxide sheaths, and easily controlled diameters in a cost-effective preparation. However, without a deliberate alignment for the randomly orientated SiNWs on the silicon substrate, the device fabrication would suffer from inefficient fabrication yields, which could also limit their development in the industrial applications. Therefore, the success of producing high-quality SiNW-FETs calls for developing a uniform assembly of the bottom-up synthesized SiNWs on the support substrates. Nanowire assembly techniques Significant efforts have been invested in developing generic methods to align NWs for the device assembly to fabricate NW-FETs. Several techniques for the assembly of NWs have been achieved, including flow-assisted alignment [60], Langmuir Blodgett technique [61 64], bubble-blown technique [65], electric-field-directed assembly [66 69], smearing-transfer method [70], roll-to-roll printing assembly [71], and polydimethylsiloxane (PDMS) transfer method [72,73]. Flow-assisted alignment. In the flow-assisted alignment method (Table 1(a)), the suspended SiNWs were passed through the microfluidic channel structures formed between a PDMS mold and a flat SiO 2 /Si substrate [60]. The SiO 2 /Si substrate was pre-modified with 3- aminopropyltriethoxysilane (APTES), of which one end is anchored to the SiO 2 surface and the other end forms an NH 2 -terminated surface. This NH 2 -terminated surface will help the alignment of SiNWs via electrostatic interactions. While the angular spread of the SiNWs in the flow direction is flow-rate dependent, the density of the SiNWs assembled on the SiO 2 /Si substrate is time dependent. Langmuir Blodgett technique. The Langmuir Blodgett technique can be applied for the alignment of NWs/NTs. As shown in Table 1(b), this solution-based method assembles SiNWs in a monolayer of surfactant at the air water interface and then compresses the SiNWs on a Langmuir Blodgett trough to a specified pitch. The aligned SiNWs are then transferred to the surface of a substrate to make a uniform parallel array. Crossed SiNW structures could further be formed by uniform transfer of a second layer of aligned parallel SiNWs perpendicular to the first layer [61 64]. Compared with other methods, the Langmuir Blodgett technique can prepare an ultrahigh-density SiNW alignment. Bubble-blown technique. The bubble-blown technique is another physical assembly method (Table 1(c)), in which the SiNWs were suspended in tetrahydrofuran solution and then blown into a single bubble using a nitrogen flow to form SiNW blown-bubble films [65]. The uniqueness of this method is that blown-bubble films can be transferred to both rigid and flexible substrates during the expansion process. It can also be scaled to large wafers and non-rigid substrates [65]. Electric-field-directed assembly. The electric-fielddirected assembly of SiNWs is an intriguing and desirable method. From the appropriate electrode design and adjustment of the applied gate voltage (V g ) vs. source-drain voltage (V sd ), Freer et al. reported that single SiNWs could be assembled over 98.5% of 16,000 pre-patterned electrode sites through controlling the balance of surface, hydrodynamic, and dielectrophoretic forces (Table 1(d)) [66]. Smearing-transfer method. The smearing-transfer (or contact-printing) method is one of a series of alignment methods developed by Ali Javey s group. This method is based on a direct contact printing process that enables the direct transfer and positioning of SiNWs from a donor substrate to a receiver chip. This simple method can efficiently transfer a variety of NWs (such as SiNWs and Ge-NWs) to a wide range of receiver substrates, including silicon and flexible plastics. The technique actually uses chemical lawn and lubricant to increase the density and alignment quality and can be regarded as a rapid, efficient, and economic method (Table 1(e)) [70]. Roll-printing assembly. On the basis of the contactprinting process, Ali Javey s group also developed an approach for a scalable and large-area printing. Roll-to-roll assembly has made it possible to produce highly ordered, dense, aligned, and regular arrays of NWs with high uniformity and reproducibility using differential roll printing. The schematic of the differential-roll-printing system setup and the results of the wire alignment are shown in Table 1(f). The optical and scanning electron microscopy (SEM) images of the roller printed Ge-NWs on a Si/SiO 2 substrate clearly indicate the well-aligned and dense (about 6 NWs/ m) NW parallel arrays. The differential-roll-printing process is compatible with the smearing-transfer method and can also be implemented in a wide range of rigid and flexible substrates [71]. PDMS-transfer method. Chang et al. developed a NW alignment method using a PDMS stamp (Table 1(g)) [72]. Inthe report, a high-speed roller (20 80 cm/min) was used to assist the transfer of ZnO-NWs from the growth substrate to a PDMS stamp; these NWs were then re-transferred from the PDMS stamp to another receiver substrate. With this method, NWs can be aligned with high density, providing a convenient and efficient approach for the fabrication of NW-FETs. Array design and electrical measurement setup The SiNW-FET devices could be fabricated following a standard photolithographic procedure with a mask design depicted in Fig. 4(a). The synthesized SiNWs were dispersed on a SiO 2 /Si substrate (typically 400 nm-thick SiO 2 ). The as-dispersed SiNWs in the central area (the reddish rectangles in Fig. 4(a) and (b)) were electrically connected by metal leads (represented in yellow in Fig. 4(a)). The surfaces of the metal electrodes were further coated with an insulating layer to prevent electric leakage during sensing experiments. The bottom inset graph enlarged from the red region in Fig. 4(b) displays the array design, in which the individual nanowire device was connected by metal electrodes with a separation of several micrometers. The individual SiNW situation can be seen with the image scanned by atomic force microscope (AFM), as shown in Fig. 4(c). The experimental setup involved in electrical measurements includes a silicon chip (1.5 mm 1.5 mm) containing

7 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 137 Table 1 Nanowire assembly techniques. (a) Schematic and results of a flow-assisted NW assembly method. The suspending NWs were passed through a fluidic channel resulting in the alignment of NWs on a flat substrate, but often with low NW density. (b) A flow-assisted NW Langmuir Blodgett assembly method. This method involves packing aligned NWs in a monolayer of surfactant at the air water interface, followed by transferring to the surface of a substrate. The scalability and uniformity of alignment for large-scale is still challenging; however, the assembled NWs are highly aligned and of high density. (c) A bubble-blown NW assembly method. The NWs were suspended in tetrahydrofuran solution and then blown into a single bubble using a nitrogen flow to form the SiNW blown-bubble films, followed by transferring to the surface of a substrate by direct contact. Although this approach cannot align NWs to be of high density, it has advantage of fitting the receiver substrate in different shapes. (d) An electric-field NW assembly method. The alignment is induced by polarizing NWs in an applied electric field. Under a delicate control, the ratio for a successful alignment could be over 90%. (e) A smearing-transfer NW assembly method. This method is based on a direct contact-printing process that enables direct transferring and positioning of NWs from a donor substrate to a receiver chip. This method can be employed for large scale NWs transfer with high alignment and density. (f) A roll-printing NW assembly method. This method applies a glass roller as the substrate for NWs growth, and then uses this roller as a NWs donor to transfer NWs to a receiver substrate through shear force. (g) A PDMS-transfer NW assembly method. This method is an amboceptor in the NWs transfer process, which adheres NWs by stamping the donor substrate and transferring NWs to another receiver substrate. Although the directions of aligned NWs were not perfect, it is a convenient method with a potential to be developed further in the future. (a) Flow-assisted [60] (b) Langmuir Blodgett [61] (c) Bubble-blown [66] (d) Electric-field [65] (e) Smearing-transfer [70] (f) Roll-printing [71]

8 138 K.-I. Chen et al. Table 1 (Continued ) (g) PDMS-transfer [72] Reprinted from [60,61,65,66,70 72]. SiNW-FET device arrays, a PDMS microfluidic channel (6.25 mm 0.5 mm 0.55 mm), and a detection system. First, the silicon chip containing SiNW-FET device arrays was mounted on a plastic circuit board and electrically connected with 30 m-diameter aluminum wires (Fig. 4(d)) before electrical measurement. The PDMS microfluidic channel was then placed in the middle of the chip to allow sample solution delivery onto the SiNW-FET arrays (Fig. 4(e)). The detection system including a lock-in amplifier and a current pre-amplifier was to record the electrical signals resulting from the binding events occurring on the SiNW-FET surface during sensing experiments (Fig. 4(f)). It is noted that the laminar flow in an ordinary microfluidic channel used in FET-based measurements may restrict the detection sensitivity due to the diffusion-limited sample delivery [74]. Comparatively, a specially designed microscale solution chamber with efficient sample mixing during the fluid exchange has been demonstrated to improve the detection sensitivity [49,75]. Reusable SiNW-FET system In the application of SiNW-FETs for the biomedical diagnosis of a particular target (e.g., an antigen), the corresponding receptor (e.g., the antibody) is usually modified on the SiNW-FET surface prior to the detection. By virtue of the strong and specific binding affinity between antigen and antibody under normal physiological conditions, the receptor-modified SiNW-FET can serve as an extremely sensitive sensor with high selectivity. By the same token, because of this strong binding between the antigen and antibody, it is difficult to remove the antigen antibody complex from the surface of SiNW-FET after detection, meaning that a SiNW-FET could be used only for a single measurement. With this limitation, consecutively quantitative analysis by a calibratable SiNW-FET is hard to achieve. To solve this problem, several reversible surface modification techniques have been developed recently, leading to reusable SiNW-FET devices. Two well-known protein trapping systems wildly used in protein purifications, the GSH/GST-tag [51,76] and Ni 2+ /His 6 -tag [77 79], were adapted to serve as a reversible surface modification method on SiNWs and will be discussed in the following section. In addition, the application of a cleavable disulfide bond that served as a linker between the receptor and a SiNW-FET has also been reported for use as a reusable SiNW-FET system [49]. GSH/GST-tag The reversible binding between glutathione S-transferase (GST) and glutathione (GSH) has long been applied in protein purification. Through molecular cloning techniques, the GST sequence can be incorporated into an expression vector alongside the gene sequence encoding the protein of interest. Thus, various GST-fusion proteins can be easily produced in a large scale via bacterial or mammalian expression systems. By using GSH-conjugated resins to trap GST recombinant protein from whole cell extract and then washing the resins with buffer to remove contaminating bacterial or mammalian proteins, the pure GST-fused protein can be eluted easily by a high concentration of GSH. Taking advantage of the reversible GSH GST association dissociation, Lin et al. adapted this method to make SiNW-FET a reusable biosensor [51]. As illustrated schematically in Fig. 5(a), a SiNW-FET was first modified with GSH (referred to as GSH/SiNW-FET) and then anchored with a particular GST-fused protein (referred to as protein-gst). This protein-modified SiNW-FET could then be employed to screen possible interacting proteins. After the sensing measurements of protein protein interactions, the used protein-gst on the GSH/SiNW-FET could be easily removed with a GSH ( 1 mm) washing solution. The reversible GSH GST association dissociation has made the SiNW-FET sensorial device reusable and calibratable, thus allowing for quantitative analysis in sensing measurements. This biologically modified SiNW-FET can be applied as an ultrasensitive biosensor for fast high-throughput screening of biomolecular associations, such as protein protein interactions, protein DNA interactions, and protein carbohydrate interactions. Very recently, Lin et al. also applied this technique of using a reusable SiNW-FET to detect the interactions of calmodulin with purified cardiac troponin I ( 7 nm) and crude N-type Ca 2+ channel extracts [76]. Ni 2+ /His 6 -tag The polyhistidine-tag is an amino acid motif that consists of multiple histidine (His) residues at the N- or C-terminus of the protein. The total number of His residues may vary, but there are normally six in the tag; therefore, it generally named a His 6 -tag. Similar to the GST-tag system, the His 6 -tag is a popular and efficient system for purifying proteins via the reversible association dissociation between the His 6 -tag and the affinity resins; the association is assisted with metal ions, either nickel or cobalt. The reversible immobilization of His 6 -tagged proteins to a sensor surface was recently applied to CNT-FET [77] and demon-

9 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 139 Figure 4 (a) Mask design for the photolithographic fabrication of SiNW-FET device arrays. (b) Device arrays on a magnified scale. Top: Optical image of the circuits in the area of the yellow square in (a); bottom: SEM image of a SiNW-FET array with a source-drain separation of 2 m. The scale bar is 50 m. (c) The topograph of a SiNW-FET scanned by AFM. A SiNW of 50 nm in diameter is connected by two Ni/Al (70 nm/100 nm in thickness) electrodes of 2 m in separation. (d) The SiNW-FET device arrays on a silicon chip (1.5 mm 1.5 mm) are connected to a plastic circuit board with aluminum wires ( 30 m in diameter). (e) A sample solution was delivered onto the SiNW-FET arrays through a PDMS microfluidic channel (6.25 mm 0.5 mm 0.05 mm), which was designed to couple with the SiNW-FET device arrays. (f) The variation of electrical signals was monitored by a detection system that combined a lock-in amplifier and a current preamplifier. Reprinted from [38]. strated on SiNW [78]. As demonstrated in Fig. 5(b), the hexavalent Ni 2+ ions held by the nitrilotriacetic acid (NTA) chelator groups were chemically modified to the FET surface and then bound to His 6 -tagged protein through the coordination between His residues and the remaining two sites of the hexavalent Ni 2+ ions. The addition of imidazole or ethylenediaminetetraacetic acid (EDTA) can compete with the His metal interaction to cause a reversed process of the protein immobilization, resulting in the retrieval of the FET surface. In comparison with the GSH/GST-tag system, the smaller Ni 2+ /His 6 -tag has its advantages in the FET-based sensing measurements. First, because of its smaller size, more Ni 2+ /His 6 -tags could be anchored on the FET surface, thus increasing the sensing sensitivity. Secondly, the binding sites located on the smaller-sized Ni 2+ /His 6 -tag are closer to the FET surface, resulting in a lesser screening effect

10 140 K.-I. Chen et al. Figure 5 A schematic illustration for the reversible SiNW-FET system. (a) A SiNW-FET is first modified with 3-aminopropyltrimethoxysilane (APTMS) and 3-maleimidobenzoic acid N-hydroxysuccinimide ester (MBS) linkers, then functionalized with GSH to form GSH/SiNW-FET. A particular GST-fusion protein (referred to as protein-gst) is anchored on the GSH/SiNW-FET via the GST GSH association. The protein-immobilized SiNW-FET is then employed for screening possible interacting proteins. At the end of each measurement, the used protein-gsts are removed with GSH ( 1 mm) washing solution, making the GSH/SiNW-FET a reusable biosensor. (b) The Ni 2+ /His 6 -tag functionalized sensor surface was formed by (3-glycidyloxypropyl) trimethoxysilane (GPTMS) and N-(5-amino-1-carboxypentyl) iminodiacetic acid (AB-NTA). His 6 -tagged proteins can then be trapped on the sensor surface. After the measurement, the His 6 -tagged proteins can be removed by imidazole to retrieve the sensor surface. Reprinted from [51,78,79]. on the FET detections, which also increases the sensing sensitivity. Sensing measurements Size effect on sensing sensitivity The wire size of a SiNW-FET can also affect the sensitivity of the FET device. As illustrated in Fig. 6, the surface-tovolume ratio of thick wires is relatively small (Fig. 6(a)) compared to that of thin wires (Fig. 6(b)). Therefore, when thick wires are approached by charged particles, the area affected by the electric field exerted from the charged particles is only located at or close to the wire surface. Namely, the interior areas of the wires could still be unaffected. In sharp contrast, as the wire diameter decreased, say to nanoscale, the surface-to-volume ratio increases drastically and the influence of the external electric field could reach the whole cross-section of the NW. As such, the induced conductance change inside the NW-FET could overwhelmingly prevail over microwire-fets [6,54]. Elfstrom et al. have demonstrated the size-dependent sensitivity of SiNW- FETs [54]. When SiNW-FETs of different wire widths are immersed in an acidic buffer solution, the FET devices configured by smaller diameter SiNWs exhibit large conductance

11 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 141 Figure 6 An illustration for the concept of a size effect on the conductance change in a wire. (a) For thick wires, the surfaceto-volume ratio is relatively small. When the wire surface is approached by charge particles (red ball), only the conductance near the wire surface is affected. There is still a large interior area of the wire that might not be influenced (gray circle). (b) As the wire diameter is reduced to nanoscale, the surface-tovolume ratio drastically increases. Therefore, the same external electrical field (pink area) caused by the charge particles (red ball) could influence most of the interior area of the NW, thus drastically changing its conductance. Reprinted from [6]. changes, whereas those of larger diameter SiNWs remain unaffected. Debye Hückel screening In the FET-based biosensing measurements, the solution environment plays an important role in determining the sensing performance. In order to create a surrounding similar to a normal physiological environment, like human serum or urine, phosphate buffered saline (1 PBS, 137 mm NaCl, 2.7 mm KCl, 10 mm Na 2 HPO 4, 2 mm KH 2 PO 4, ph 7.4 with NaOH) or phosphate solution (1 PS, 2.4 mm NaH 2 PO 4, 7.6 mm Na 2 HPO 4, ph 7.4 with NaOH) was generally selected as the matrix, in which analytes dissolved during the measurements. However, in solutions containing such high-salt concentrations, the interaction potential (V(r)) between the receptor and analytes that cause the conductance change in the FET sensor could be partially screened by the strong ionic strength of the electrolytic buffer solution, thus reducing the signals obtained from the electrical measurements. The screening of V(r) in the FET measurements is enhanced exponentially by the distance (r bs ) measured from the binding site of receptor analyte complex to the FET surface and can be represented as V(r)e r/ D at r = r bs (1) where D is the Debye Hückel length [80,81] and is given by ε0 ε r k B T D = (2) 2N A e 2 I Figure 7 (a) A schematic showing the height of D from the sensor surface for an electrolytic buffer solution. The horizontal dashed lines mark the heights of D = 0.7, 2.4, and 7.4 nm for 1 PBS (blue), 0.1 PBS (red), and 0.01 PBS (black), respectively. (b and c) Real-time electrical measurements of the association and dissociation of GST on a GSH/SiNW-FET in (b) 0.1 PBS (black curve, D = 2.4 nm) and 1 PS (red curve, D = 1.9 nm) and (c) 0.01 PBS (black curve, D = 7.4 nm) and 0.1 PS (red curve, D = 6.1 nm). Reprinted from [51]. where ε 0 represents the vacuum permittivity, ε r is the relative permittivity of the medium, k B is the Boltzmann constant, T represents the absolute temperature, N A is Avogadro s number, e stands for the elementary charge, and I represents the ionic strength of the electrolytic buffer solution. It is obvious that an electrolytic solution of higher ionic strength (I) has a shorter D, thus creating a more severe screening effect on the FET-based sensing measurements. Calculations from Eq. (2) give D = 0.74 nm for the 1 PBS solution and D = 1.94 nm for the 1 PS solution. As represented schematically in Fig. 7(a), depending on the r bs value in a FET measurement, the electrolytic buffer solution needs to be properly selected to be of an appropriate D without jeopardizing the signal collection. In Fig. 7(b) and (c), the screening effect due to the electrolytic buffer solution was experimentally demonstrated from the binding of GST to GSH/SiNW-FET [51], where the conductance

12 142 K.-I. Chen et al. Figure 8 (a) Real-time electrical measurements of the association of CaM-GST with a GSH/SiNW-FET in 0.1 PS solution supplemented with 0.5 mm EDTA (ph 7.4). The arrow indicates the arrival of the CaM-GST solution. (b) Real-time detection of the binding of K + (red), Al 3+ (green), and Ca 2+ (blue) to CaM/SiNW-FET. The arrow indicates the arrival of the appropriate ion solution. (c) Real-time detection of the binding of cardiac TnI to CaM/SiNW-FET in 0.1 PS solution supplemented with 100 M Ca 2+. (d) Specificity of CaM/SiNW-FET. The electrical conductance of CaM/SiNW-FET showed no response until binding of TnI. (e) Plot of G vs. log[tni]. The addition of various concentrations of TnI in 0.1 PS supplemented with Ca 2+ (square) or 0.5 mm EDTA (circle). The red line represents a linear fit to the five concentration data points (correlation coefficient = 0.987). (f) Real-time electrical

13 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 143 change ( G) of the GSH/SiNW-FET in measuring 15 nm GST (Fig. 7(c)) in 0.01 PBS (black curve, D = 7.4 nm) or 0.1 PS (red curve, D = 6.1 nm) is enhanced roughly fourfold compared to the measurements (Fig. 7(b)) in 0.1 PBS (black curve, D = 2.4 nm) or 1 PS (red curve, D = 1.9 nm). Gao et al. have recently reported that the optimal sensitivity of a SiNW-FET in biosensing measurement can be achieved by judiciously selecting the subthreshold regime, where the gating effect from target molecules is most effective due to the reduced screening of carriers inside the SiNW [82]. The effectiveness of gating effect induced by target molecules at the surface of a SiNW-FET sensor is determined by the relative magnitude between carrier screening length ( Si ) and SiNW radius (R). In the high carrier concentration regime ( Si R), SiNW-FET works in a linear regime and the conductance varies with gate voltage linearly. In the low carrier concentration regime ( Si R), the SiNW-FET works in the depletion (subthreshold) regime and the conductance varies with gate voltage exponentially. It is demonstrated that the most sensitive SiNW-FET biosensor should utilize the field gating effect of surface charges throughout the whole cross-section of SiNW, which requires Si > R. Inthe subthreshold regime of a SiNW-FET, carriers in the SiNW have long screening length ( Si > R) and the field effect of surface charges can gate the whole SiNW, fully utilizing the high surface-to-volume ratio of SiNW and effectively reaching the optimal detection sensitivity of the FET sensor. Applications of SiNW-FET sensors Protein protein interaction A huge number of approaches have been developed to understand molecular complex interactions, such as protein protein or protein small molecule interactions. For example, a fluorescence detection method combined with a fiber-optic biosensor has been established to study the binding kinetics of immunoglobulin G (IgG)/anti-mouse IgG and human heart-type fatty acid-binding protein (its antibody) [83]. However, this labeling detection method was limited by some drawbacks. For instance, the surface characteristics of small proteins might be changed after chemical labeling, thus varying the labeling efficiency for different proteins, which consequently makes accurate quantification detection difficult. Also, this labeling technique usually requires a huge amount of time for the labeling procedures. In recent years, some label-free detection techniques, such as surface plasmon resonance imaging (SPRI) [84], AFM [85], and SiNW-FET and CNT-FET [86,87] have been invented for sensing protein protein interactions. Among these sensing approaches, SiNW-FET has attracted more and more attention lately for studying protein interaction mechanisms, not only because of its real-time and label-free detection, but also due to its high sensitivity and selectivity. An early measurement made by Cui et al. demonstrated the real-time detection of streptavidin binding to biotin-modified SiNW- FET [88]. They also explored the ability of biotin-modified SiNW-FET to detect streptavidin at the concentration of 10 pm, which is much lower than the nanomolar-range detection level obtained from other techniques, such as the stochastic sensing of single molecules [89]. In addition to the biotin streptavidin investigation, the concept of detecting protein protein interactions with SiNW-FET could be extended to broad applications. A calmodulin (CaM)-modified SiNW-FET sensor has recently been used to detect calcium ions (Ca 2+ ) by Lin et al. [76]; their experiments also showed that Ca 2+ -bound CaM is able to activate various proteins involved in physiological activities, such as the binding between Ca 2+ -bound CaM and cardiac troponin I (TnI). CaM was anchored to a reusable SiNW-FET (referred to as CaM/SiNW-FET) via the aforementioned GSH GST association dissociation. As shown in Fig. 8(a), a dramatic increase in conductance verified the successful binding of negatively charged GST-fused CaM (referred to as CaM-GST, pi of CaM 4 and pi of GST 6.72) to the p-type GSH/SiNW-FET. In order to examine how the binding of various metal ions affects the conductance of CaM/SiNW-FET, three different metal ions (Ca 2+,Al 3+, and K + ) were selected to be examined in this system. As demonstrated in Fig. 8(b), CaM/SiNW-FET showed a preference for binding Ca 2+ (blue curve), but not K + (red curve) or Al 3+ (green curve), according to the conductance change ( G) after the arrival of each metal ion solution. These results reveal a high specificity of CaM/SiNW-FET for sensing Ca 2+. Shown in Fig. 8(c) is the binding of the positively charged protein troponin I (TnI, pi 9.3) onto CaM/SiNW-FET in 0.1 PS (ph 7.4) containing 100 M Ca 2+, which led to a sizable decrease in the conductance of the FET sensor. The control experiments carried out in Fig. 8(d) reflected that the association between CaM and TnI is specific and can only be triggered in the presence of Ca 2+. It has been proven in Fig. 8(e) that the G increased with a rising concentration of TnI (i.e., log [CaM]) in the presence of Ca 2+. It is also demonstrated in Fig. 8(f) that the concentration of Ca 2+ required to activate the interaction between CaM and TnI was at the micromolar level (i.e., 10 6 MCa 2+ ). In addition, CaM/SiNW-FET was applied to detect Ca 2+ channels in cell lysate. The N-type voltage-gated Ca 2+ channels (VGCCs) located at the plasma membrane mediate the entry of Ca 2+ into cells in response to membrane depolarization. As illustrated in Fig. 8(g), transfected 293 T cells containing N-type VGCCs resuspended in 1 PBS were sonicated and then centrifuged to isolate the memmeasurement for determining the [Ca 2+ ] required to activate the interaction between TnI and CaM, where the binding of TnI to CaM/SiNW-FET was detected at various [Ca 2+ ]. The result revealed that the minimal [Ca 2+ ] 1 M is needed to trigger the CaM activation. (g) Schematic illustration for the detection of membrane fractions containing N-type VGCCs utilizing CaM/SiNW-FET. Real-time electrical detections of the binding of N-type VGCCs to CaM/SiNW-FET in 0.1 PS supplemented with (h) 100 M Ca 2+ ; (i) 0.5 mm EDTA. (j) (Top graph) Electrical detection of the membrane fraction without the 1b subunit by CaM/SiNW-FET in 0.1 PS supplemented with 100 MCa 2+ and (bottom graph) electrical detection of N-type VGCCs by GST/SiNW-FET in 0.1 PS supplemented with 100 M Ca 2+. Reprinted from [76].

14 144 K.-I. Chen et al. Figure 9 (a) A structure of the associated PNA and DNA. (b) Schematic representation showing that the distance from the bound DNA to the SiNW surface could be varied by controlling the location of the DNA PNA hybridization. (c) Distinguishable resistance changes in the PNA-modified SiNW-FET resulting from the varied hybridization sites measured for two different concentrations of target DNAs. (d) Plot of the experimental ratio of resistance change vs. calculated distance (L) from DNA strands to the SiNW surface. Reprinted from [81]. brane fractions. The solution retreated in 0.1 PS was subsequently introduced into CaM/SiNW-FET; the decreased conductance shown in Fig. 8(h) indicates the binding of VGCCs to CaM/SiNW-FET. On the other hand, an appreciable decrease in conductance of CaM/SiNW-FET was also observed for the association of CaM with a peptide covering the IQ domain at the C-terminal of the N-type VGCC in the absence of Ca 2+ (Fig. 8(i)), which is consistent with a previous study [90]. Finally in Fig. 8(j), two control experiments were performed to ensure that CaM/SiNW-FET was Ca 2+ channel-specific and that CaM was essential for the detection of N-type VGCCs. Lately, Zheng et al. has also demonstrated a new methodology based on a frequency (f) domain electrical measurement utilizing a SiNW-FET for protein detection [91]. The power spectral density of voltage from a currentbiased SiNW-FET shows 1/f-dependence in frequency domain for the measurements of antibody-functionalized SiNW-FET devices in buffer solution or in the presence of protein not specific to the antibody receptor. In the presence of the protein (antigen) which can be recognized specifically by the antibody-functionalized SiNW-FET, the frequency spectrum exhibits a Lorentzian shape with a characteristic frequency of several khz. They observed the shape of the frequency spectrum to monitor the binding events, and further to determine the detection limit. With the help of this new method in the frequency-domain measurement, the detection sensitivity was claimed to increase by 10-fold. All of the results outlined above suggest that proteinmodified SiNW-FET sensors exhibit high sensitivity and excellent specificity and are able to detect target molecules rapidly and precisely. This novel technique provides a promising tool to study protein protein or protein small molecule interactions and can be further applied to biomedical diagnosis. DNA hybridization In addition to the protein protein interactions mentioned above, SiNW-FETs were adapted for the detection of DNA or RNA. Due to the large amount of negative charges in the phosphate backbones of DNA or RNA, SiNW-FETs offer a good candidate for monitoring DNA or RNA hybridizations, because the hybridizations cause the accumulation or depletion of charge carriers in the SiNW-FET, leading to a conductance change. Peptide nucleic acid (PNA), an artificially synthesized polymer similar to DNA, is commonly used in biological research, especially in DNA or RNA hybridizations. As shown in Fig. 9(a), PNA hybridizes with DNA by base pairing through hydrogen bonds. Because PNA has no phosphate groups in its backbone, the binding of PNA/DNA or PNA/RNA strands is stronger than that of DNA/DNA or DNA/RNA duplexes due to the lacking of electrostatic repulsion. Hahm et al. have reported the real-time and label-free detection of DNA with a PNA-modified SiNW-FET [92]. In

15 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 145 that study, PNA was anchored to the SiNW surface by the strong interaction between avidin and biotin. The successful PNA DNA duplex formation was demonstrated by the observation of a sizable increase in conductance in the p-type PNA-modified SiNW-FET, because of the negatively charged phosphate backbones of DNA. Even the surface of the PNAmodified SiNW-FET was covered with a layer of avidin; this ultrasensitive biosensor for sensing DNA is capable of detecting down to 10 fm. The strategy utilizing PNA as a capture receptor has also been applied to study the detection sensitivity of a SiNW-FET by examining the distance from a binding site of charged analytes to the SiNW surface [81]. The illustration in Fig. 9(b) shows that the distance from the bound DNA to the SiNW surface can vary by controlling the location of the hybridization site. The neutral character of PNA avoids background electric charges to interfere with the binding phenomenon and allows for the hybridization to be performed in a low ionic-strength environment with a high signal-to-noise ratio. The species of target DNAs with different nucleotides (nt) in the study were designed to be separated into a 22-nt fully complementary, a 19-nt complementary, a 16-nt complementary, a 13-nt complementary, a 10-nt complementary, and a 7-nt complementary DNA fragment. In addition, a non-complementary DNA was used as a control. The hybridization of PNA DNA was monitored by the resistance change that results from the accumulation of negative charges on the n-type PNA-modified SiNW-FET. The resistance changes due to the hybridizations of the PNA receptors with these seven different target DNAs at two different concentrations have been recorded in Fig. 9(c). It is noted that the resistance change of the 7-nt complementary DNA ( 11%) is much smaller than that of fully complementary DNA ( 50%). The result reveals that when the complementary segments become shorter, which means that the distance between the bound DNA and the SiNW surface becomes longer, the ability of SiNW-FET to detect DNA hybridization is reduced exponentially, as shown in Fig. 9(d). This observation suggests that the corresponding detection sensitivity is mostly dependent on the distance of the charge layer to the SiNW surface. Viral infection monitoring and early cancer detection Specific PNA-modified SiNW-FET sensors have recently been established to diagnose Dengus virus infection [93]. As represented schematically in Fig. 10(a), the synthetic PNA receptors were first anchored to the SiNW-FET surface. A specific fragment (69 bp) derived from Dengus serotype 2 (DEN-2) virus genome sequences was selected as the target DNA and amplified by the reverse transcriptionpolymerase chain reaction (RT-PCR). Distinctive resistance changes between the two different PNA receptors (i.e., complementary and non-complementary to the target DNAs) can be distinguished, as seen in Fig. 10(b). The detection limit of this biosensor based on SiNW-FET was claimed to be 10 fm (Fig. 10(c)). These investigations suggest that the PNA-modified SiNW-FET sensor incorporated with RT-PCR has been successfully developed for a rapid and ultrasensitive diagnostic method of detecting Dengus virus. In addition, this promising method allows the detection of micrornas (mirnas) for early cancer diagnosis [94]. MiRNAs have been characterized to play a significant role in the cell development and to be related to a number of cancers and neurological disorders. Therefore, the detection of mirnas becomes more and more important in the field of medical science. As illustrated in Fig. 10(d), a PNA-immobilized SiNW-FET was used to probe mirna by detecting PNA-miRNA hybridization via base pairing. As shown in Fig. 10(e), from the resultant resistance change in the PNA-immobilized SiNW-FET, this approach exhibits an excellent detecting specificity capable of discriminating a single base mismatch in mirna. Moreover, as depicted in Fig. 10(f), the application of a PNA-functionalized SiNW-FET to probe the hybridization with complementary mirnas is obviously preferential to a DNA-functionalized SiNW-FET, again indicating that neutral PNA prefers to hybridize mirnas. Also, the PNA-functionalized SiNW-FET sensor is capable of sensing a specific mirna in total RNA extracted from HeLa cells. This technique provides a promising tool for early cancer detection in which the species and the amount of mirnas in the cancer cells were suggested to be different from those of normal cells. The combination of PNA and SiNW-FET provides a powerful technique to detect target molecules rapidly and precisely. This PNA-functionalized SiNW-FET sensor could also be applied in medical diagnosis of cancer cell growth or other diseases by simply varying the sequences of the PNA capture receptors. Peptide small molecule interaction The SiNW-FET system has also been applied to study peptide small molecule interactions, including ammonia (NH 3 ) and acetic acid (AcOH) [95]. As shown in Fig. 11(a), the specific peptides were modified covalently to a SiNW- FET (referred to as peptide/sinw-fet). X-ray photoelectron spectroscopy and water contact angle were utilized to verify the successful attachment of peptides on the SiNW- FET surface (Fig. 11(b)). To test the selectivity of a peptide/sinw-fet to AcOH, several experiments have been conducted to detect the AcOH diluted in acetone, which is a similar molecule to AcOH. In Fig. 11(c), an obvious increase (black curve) is obtained by subtracting the response caused by the binding of AcOH to peptide/sinw- FET (referred to as AcOH-peptide/SiNW-FET, green curve) from that of the addition of AcOH to peptide-free/sinw- FET (blue curve), indicating that the peptide/sinw-fet has an excellent specificity to AcOH in compound chemical backgrounds. Moreover, the performances of both AcOH-peptide/SiNW-FET and NH 3 -peptide/sinw-fet were investigated in simulated breath backgrounds as a closer approximation toward medical applications. As demonstrated in Fig. 11(d), the electrical response from both FET sensors can be observed after introducing the target analyte (AcOH or NH 3 ) in a background of 6% CO 2. These results show that peptide/sinw-fet can be used to monitor the exhaled breath content at high sensitivities and is able to serve as an electronic nose for further medical diagnosis.

16 146 K.-I. Chen et al. Figure 10 (a) A schematic diagram of the RT-PCR product of DEN-2 hybridized to a PNA-functionalized SiNW-FET sensor. (b) Specificity of the PNA-functionalized SiNW-FET to the RT-PCR product of DEN-2. The purified RT-PCR product was applied to the complementary (black) and non-complementary (red) PNA-functionalized SiNW-FETs. (R R 0 )/R 0 (%) represents the resistance change in percentage calculated from [(resistance after hybridization resistance before hybridization)/resistance before hybridization] 100. (c) Resistance change vs. various concentrations of the RT-PCR product of DEN-2 from 100 fm (blue) to 1 fm (black). A negative RT-PCR product was used as a control (light blue). (d) Schematic illustration of the label-free direct hybridization assay established for the ultrasensitive detection of mirna. (e) Hybridization specificity demonstrated by the responses of the PNA-functionalized SiNW-FET to fully complementary (black), one-base mismatched (red), and non-complementary (green) mirna sequences. (f) Comparison of the responses of the PNA-functionalized SiNW-FET (black) and a DNA-functionalized SiNW-FET (red) to the complementary mirna. Reprinted from [93,94].

17 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 147 Figure 11 (a) A scheme of covalent attachment of peptides to a SiNW-FET. (b) Characterization of the bare SOI (red), amine-terminated (green), and peptide-coupled (blue) surfaces by X-ray photoelectron spectroscopy. (Inset) Water contact angle goniometric measurements of the surfaces. (c) Electrical response of an AcOH recognition peptide/sinw-fet (blue) and an amineterminated peptide-free/sinw-fet (green) to 1000 ppm acetone (introduced at time 5 min) and 100 ppm AcOH (introduced at time 20 min). The black curve is the differential response, obtained by subtracting the green curve from the blue curve. (d) Electrical responses of an AcOH recognition peptide/sinw-fet (blue) and an NH 3 recognition peptide/sinw-fet (red) to sequential influxes of 6% CO 2, 100 ppm AcOH, and 100 ppm NH 3, introduced at the times indicated. Reprinted from [95]. Biomarker detection A biomarker is generally defined as something that can be used as an indicator for a particular disease state or some other biological state of an organism. For that reason, the detection of specific biomarkers can be applied to disease screening. For example, prostate-specific antigen (PSA) has already been wildly applied to prostate cancer diagnosis [96]. However, these biomarkers usually exist in the blood in extremely low concentrations. Therefore, finding a method to rapidly and precisely detect these biomarkers is an important issue in clinical diagnoses. Recently, Zheng et al. utilized a SiNW-FET array for the detection of multiple cancer markers [97]. This SiNW-FET array, shown in Fig. 12(a), is composed of three independent SiNW-FET devices on which different antibodies were immobilized. The antibodies used here were against prostate specific antigen (PSA), carcinoembryonic antigen (CEA), and mucin-1, respectively, each of which is a clinically confirmed cancer marker [98,99]. Fig. 12(b) demonstrates the realtime detection of the bindings of the three cancer markers (PSA, CEA, and mucin-1) to the specific SiNW-FETs. The conductance vs. time measurements showed the simultaneous recording of the PSA, CEA, and mucin-1 solutions, which were delivered sequentially to the SiNW-FET arrays. As displayed in Fig. 12(b), these three cancer markers induced significant signals caused by their binding with the cognate antibodies. By virtue of the ultrasensitive SiNW-FET, the detection limit for these three cancer markers has advanced to the pg/ml scale. Although the measurement of the cancer markers using the SiNW-FET turned out to be very successful [97], challenges remain in using the SiNW-FET devices to detect these markers from a whole blood sample. The reasons stem not only from biofoulings and/or non-specific bindings that might occur in the electrical measurements, but also because the ionic strength of the whole blood could cause a very short D to severely limit the FET signals [80].

18 148 K.-I. Chen et al. Figure 12 (a and b) Illustration for the detection of multiple cancer markers (PSA, CEA, and mucin-1) with SiNW-FET arrays. (a) The illustration of the structure of the SiNW-FET array, which is composed of three independent devices. Devices 1 3 are differentiated with different antibodies (1, red; 2, green; 3, blue) that are specific to the three different cancer markers (PSA, CEA, and mucin-1). (b) Real-time detection of the bindings of three cancer markers (PSA, CEA, and mucin-1) to the specific SiNW-FET devices modified with antibodies for PSA (NW1), CEA (NW2), and mucin-1 (NW3), respectively. The solutions were delivered to the SiNW-FET arrays sequentially as follows: (1) 0.9 ng/ml PSA, (2) 1.4 pg/ml PSA, (3) 0.2 ng/ml CEA, (4) 2 pg/ml CEA, (5) 0.5 ng/ml mucin-1, (6) 5 pg/ml mucin-1. (The solutions were injected following the points indicated by black arrows.) The PSA, CEA, and mucin-1 cancer markers induced signals only to the specific SiNW-FET modified with the cognate antibodies. (c) Illustration for detecting biomarkers from whole blood with a MPC-FET system. The MPC-FET system is composed of a microfluidic purification chip (larger gray block), a valve (pink), and a FET sensing cell (smaller gray block). (i) Primary antibodies (anti-psa and anti-ca15.3) are immobilized on the MPC with a photocleavable cross-linker. The valve (pink) directs fluid flow to exit the MPC to either the waste or the SiNW-FET sensing cell (smaller gray block). (ii) Whole blood is injected into the MPC (with the valve set to the waste compartment; black arrow shows the direction of fluid flow); meanwhile, biomarkers could bind to their cognate antibodies. (iii) After washing, the MPC was exposed to UV irradiation (orange arrows). During the UV exposure, the photolabile cross-linker cleaves, allowing the release of the antibody antigen complexes into solution. (iv) The valve was now set to the SiNW-FET sensing cell (black arrow indicating the direction of fluid flow) and the antibody antigen complexes are transferred to the cell for label-free sensing by the SiNW-FET arrays. (d) Response of an anti-psa-functionalized SiNW-FET to an MPC-purified blood sample initially containing 2.5 ng/ml PSA. (e) Response of an anti-ca15.3-functionalized SiNW-FET to an MPC-purified blood sample initially containing 30 U/mL CA15.3. Reprinted from [97,100].

19 Silicon nanowire field-effect transistor-based biosensors for biomedical diagnosis and cellular recording investigation 149 Therefore, pre-purifying the physiological fluid sample and changing the buffer to low salt conditions before the sample flows into the SiNW-FET sensor could substantially improve the sensing measurements. Recently, Stern et al. developed a microfluidic purification chip (MPC) system to pre-isolate the target molecules, followed by using SiNW-FET arrays to analyze the pre-purified sample [100]. As a demonstrative example, prostate specific antigen (PSA) and carbohydrate antigen 15.3 (CA15.3) were chosen to be analyzed with the MPC-FET system; these samples are standard clinical markers of prostate [98,99] and breast cancer [101,102], respectively. Fig. 12(c) illustrates schematically the structure and operation of the MPC-FET system, which comprises a microfluidic purification chip, a SiNW-FET sensing chamber, and a valve that controls whether fluid exits from the MPC to the waste or to the SiNW-FET sensing cell [99]. As shown in Fig. 12(c), the operation procedures are as follows: (i) the MPC is immobilized with primary antibodies (anti-psa and anti-ca15.3 in this case) via a photocleavable crosslinker. (ii) The whole blood is injected into the chip with the valve set on the waste compartment. In this step, biomarkers could bind to their cognate antibodies in the MPC. (iii) The MPC is washed before being exposed under UV irradiation to cleave the photolabile cross-linker. (iv) The valve is now set to the FET sensing chamber; meanwhile, the antibody antigen complexes are transferred to the cell for label-free sensing by the SiNW-FET arrays. With the help of the MPC to pre-purify the sample, PSA of 2.5 ng/ml and CA15.3 of 30 U/mL were able to be detected by SiNW-FET from a whole blood sample as revealed in Fig. 12(d) and (e), respectively. Recording electrical and transmitter signals from cells Using nano- and neuro-technologies to couple electrical interfacing with neural systems has great potential to unveil many details of neuron studies [103]. In the past few years, SiNW-FETs and CNT-FETs have been applied for electrophysiological measurements by recording signals from neuron cells and tissues [22,23,38, ], e.g., recording the electrical signal from a single neuron [22] and cardiomyocyte cells [104] and detecting the released neurotransmitter of CgA from living neurons [38]. In this section, we will introduce some current studies that demonstrate how SiNW-FET has been used to record these cell signals. Patolsky et al. have reported that hybrid SiNW-FET arrays integrated with individual axons and/or dendrites are capable of recording electrical signals from a single neuron cell [22]. On the designed SiNW-FET array structures, they defined the adhesive zones where poly-lysine was patterned for neuron cell growth. The strategy of preparing these neuron-sinw-fet devices is illustrated in Fig. 13(a), where the square regions with m onthe edge allow cell body adhesion and 2 m-wide lines support dendrite growth. Several challenges were undertaken in the device-array fabrication to prevent the source and drain electrodes from corrosion under the harsh conditions of cell culture and the subsequent electrical measurements. A single-step lithography process combined with an undercut multilayer resist was well designed to deposit isotropic silicon nitride on the metal electrodes as a passivation layer. Devices prepared in this way were able to survive under continuous cell-culture conditions at 37 C for at least 10 days. With this strategy of using poly-lysine to guide neuron growth, the goal of one-neuron/one-sinw device from an array has been reached, as shown in Fig. 13(b). After the successful growth of a single neuron cell, a linear array with a multiple SiNW-FETs system (Fig. 13(c)) was exploited to simultaneously investigate the propagation and back-propagation of the action potential spikes in axons and dendrites separately. As shown in Fig. 13(d), signal propagation rates of 0.16 m/s for dendrite and 0.43 m/s for axon were determined from a single neuron measurement. In total, the signal propagation rates obtained from different neurons revealed Gaussian distributions of 0.15 ± 0.04 (±SD) and 0.46 ± 0.06 m/s for dendrites and axons, respectively (Fig. 13(e)). These results are comparable to the reported propagation rates measured by conventional electrophysiological and optical methods [108,109]. Furthermore, SiNW-axon junction arrays were integrated to examine the neuronal excitability at a level of 50 artificial synapses per neuron. The structure was selected to demonstrate the capability of nanoelectronic devices for single-cell hybrid structures at much higher densities. The optical image shown in Fig. 13(f) represents the well-aligned neuron growth across these 50 SiNW-FET devices. It is impressive to see in Fig. 13(g) that the action potentials stimulated intracellularly in the soma produced a mapping of the spike propagation detected by the 43 functional devices over the 500 m-long axon. The data obtained from these SiNW-FET devices showed little decay in peak amplitude from NW1 to NW49, which is consistent with the active propagation process. In addition to the direct monitoring of the electrical signals from cells, SiNW-FETs and CNT-FETs have also been used to detect the neuron transmitter [38] and adenosine triphosphate (ATP) [110] released from living cells. Timko et al. [23] lately used both planar and flexible polymeric substrate-based SiNW-FET arrays to simultaneously record the voltage-calibrated signals from the different parts of embryonic chicken heart. All of these performances have demonstrated that the nanoscale FET devices are promising for many more fields of basic and clinical studies of cardiology in the future. Three-dimensional localized bioprobes Although a multitude of SiNW-FETs and CNT-FETs have been exploited to record extracellular electrical signals [22,23,38, ], these devices are normally created on planar substrates, making it difficult for the devices to detect the signals from arbitrary localization in three dimensions (3D). Therefore, it is highly desirable to develop a movable 3D nano-fet, containing the necessary source (S) and drain (D) electrical connections, that can be moved to contact a cell and even into the cell. Very recently, Tian et al. made a movable 3D nano-fet through the synthetic integration of kinked SiNWs [46,111]. As shown in Fig. 14(a) and (b), these kinked SiNWs (either p-type or

20 150 K.-I. Chen et al. Figure 13 Using SiNW-FETs to record neuronal axon signals. (a) A general schematic of the aligned NW-neuron device array. The open blue rectangle highlights a single SiNW-neuron device. (b) Optical image of a single cortex neuron aligned across a single SiNW device and (red box) a magnified image of the area. (c) Optical image of a cortex neuron with the axon and dendrite aligned on a multi-sinw structures. (d) Plot showing latency time as a function of distance from NW1 and NW6 for the axon (blue) and dendrite (red), respectively, for a single neuron. (e) Histogram of propagation speed through axons (blue) and dendrites (red). (f) Optical image of an aligned axon crossing an array of 50 SiNW devices with a 10- m inter-device spacing. (g) Electrical data from the 50 device arrays. The yield of the functional devices is 86% (43 devices were capable of conducting measurements). The peak latency from NW1 (top arrow) to NW49 (bottom arrow) was estimated to be 1060 s. Reprinted from [22]. n-type) can be synthesized in a CVD reaction via the VLS mechanism by varying the reactant pressure and the component of reactant gases during the SiNW growth, the results of which showed that the lengths, doping components, and growth direction of the as-synthesized SiNWs can be well controlled. Fig. 14(c) displays the image of this 3D nano-fet probe, where the FET is located at the tip of an acute-angle kinked SiNW that connects with the nanostructure arms composed of multilayer photoresists.

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