Ultrasensitive Electrical Detection of Follicle Stimulating Hormone

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Functional Inorganic Materials and Devices

Ultrasensitive Electrical Detection of Follicle Stimulating Hormone Using Functionalized Silicon Nanowire Transistor Chemosensor Mucian Lee, Sathyadevi Palanisamy, Bin-Hou Zhou, Li-Yu Wang, ChiaoYun Chen, Chen-Yi Lee, Shyng-Shiou F. Yuan, and Yun-Ming Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b11882 • Publication Date (Web): 26 Sep 2018 Downloaded from http://pubs.acs.org on October 6, 2018

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ACS Applied Materials & Interfaces

Ultrasensitive Electrical Detection of Follicle Stimulating Hormone Using Functionalized Silicon Nanowire Transistor Chemosensor Mucian Lee1,†, Sathyadevi Palanisamy1,†, Bin-Hou Zhou1, Li-Yu Wang1, Chiao-Yun Chen3,4, Chen-Yi Lee5, Shyng-Shiou F. Yuan6,7,8,* and Yun-Ming Wang1,2,* 1

Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan. 2

Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

3

Department of Radiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. 4

Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. 5

Department of Electronics Engineering, National Chiao Tung University, Hsinchu 300, Taiwan.

6

Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

7

Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

8

Faculty and College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

†

These two authors contributed equally

*Corresponding authors: Yun-Ming Wang: [email protected] Shyng-Shiou F. Yuan: [email protected]

Keywords: follicle stimulating hormone, chemosensor, field effect transistor, microfluidic chip, diagnosis

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Abstract Follicle stimulating hormone (FSH) is a hormone belongs to a member of the glycoprotein hormones. Determination of FSH can help in interpreting various factors that include physiology of the reproductive system, fertility maintenance, and identification or treatment of reproductive disorders. Sialic acids are derivatives of neuraminic acids with negative charges, present at the end of the sugar chains and further linked to the cell surfaces and glycoproteins. The direct measurement of FSH in a human body can be recorded by developing a sensor probe which response particularly to sialic acids over the other hormones. However, existing diagnostic methods still suffer from many difficulties in terms of complicated handling techniques, expensive instrumentation, etc. Development of accurate, rapid, and low-cost FSH detection chemosensors are important to meet out these demands. Herein, we utilized a novel sensing method for accurate and fast FSH detection using metal-oxide semiconductor (MOS) silicon nanowire field effect transistor (SiNW-FET) device. This is the first report to demonstrate boronic acid-functionalized SiNW-FET device in the FSH detection. The FSH detection has been successfully determined using an assay buffer solution with 0.72 fM detection limit as well as using a 20% serum condition with 1.1. fM detection limit. We also investigated the specificity with other gonadotropins/glycosylated serum proteins. The current measurements on FSH concentrations at different time intervals were also studied. Sensitive, cheap, and miniaturized SiNW-FET device can serve as an effective sensing approach for rapid screening of FSH and menopause diagnosis.


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1. Introduction Development in molecular biology provides much knowledge of effective biomarkers that can be used for disease diagnosis. The potential diagnostic method is required to identify various diseases and appropriate treatments. Healthcare diagnostics play pivotal functions in both the developing and developed countries. In addition, the increased chance of usage of point-of-care diagnostics is found to be higher.1 Nowadays, various diseases are recognized based on many symptoms that may lead to late detection or can mislead due to their subjective evaluation and undetermined connection to the existing disease level. Existing diagnostic techniques developed in a biomedical field such as enzyme-linked immunosorbent assay (ELISA) and nanomaterial-based chemosensors have many disadvantages including longer assay time, tedious assay steps, very expensive equipment, and quick screening applications.2-4 Therefore, there is an urge to develop highly sensitive methods for diagnosis during the early stages of the disease. It is demanding to develop a sensitive, rapid, miniaturized, cost-effective, disposable, and portable biosensing device for point-of-care testing. Novel chemosensor approaches would allow disease diagnosis to be accomplished more rapid, inexpensive, and in a reliable manner. Various electrical transducers are available in biomedical sensing applications such as field effect transistors (FETs), electrodes, and piezoelectrics. Among these existing transducer systems, FETs can provide more benefits such as rapid monitoring, real-time sensing of electrical detection, multiparameter readout, and signal amplifications.5-7 Advances in the field of nanotechnology raise up new circumstances for the electrical detection system of biomolecules. Increasing interest in semiconductor nanowires has been noted over past decade due to their unique optical, electrical, and mechanical characteristics,



particularly for biosensing.10-12 Among

the variety of nanowire biosensing devices

developed so far, silicon nanowires (SiNWs) received special attention because of their easy preparation using “top-down” and “bottom-up” strategies.13 The SiNW-FET sensors are representative FET devices that are comprised of three electrodes namely source, drain, and gate electrodes. This electrically based sensor merges the biomolecules with MOS compatible methods to record electrical signals when the analytes bind to the probe. The SiNWs are known as selective sensors for label-free and direct detection of metal ions, proteins, DNA-protein binding, nucleic acids, and protein-small molecule interactions14-18 due their high surface-to-volume ratio, one dimensional structure, biocompatibility, and tunable electrical characteristics. Ultrahigh sensitivity and high surface-to-volume ratio makes SiNW-FET as an excellent tool for detecting very low dosage of biomarkers.19 Nuzaihan et al. used top-down fabrication strategy to prepare silicon nanowires using silicon-on-insulator (SOI) wafers, followed by electron beam lithography, etching and reduction processes. This device displayed high performances in terms of sensitivity and selectivity with 10 fM detection limit, further permits potential accuracy of DNA detection.20 The FSH is a gonadotropin and belongs to a glycoprotein polypeptide hormone. The gonadotropic cells present in the anterior pituitary gland secretes FSH which helps to maintain the growth, development, puberty, and reproductive body functions.21 Sialic acid is a representative derivative of neuraminic acid family, known as the 9-carbon carboxylated monosaccharide.22-24 Sialic acids are widely located in animal tissues, a minimal extent in other organisms including plants, bacteria, and fungi but mostly present in gangliosides and glycoproteins. Sialic acids are negatively charged species occurring at the end of sugar


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chains which are further connected with cell surfaces and soluble proteins.24 The direct measurement of FSH on a human body would become possible by designing a sensor probe which particularly responds to sialic acids over the rest of the hormones. A traditional analytical technique ELISA is currently used for FSH analysis.25-27 This technique suffers from various factors such as long experimental time, performing many steps in the assay, and require expensive equipment that cannot meet out the requirements for POC diagnostics and fast sensing applications. Hence, it is necessary to create a potential method for easy and accurate detection of FSH. The FSH detection is essential to interpret various factors that include physiology of the reproductive system, fertility maintenance, and identification or treatment of reproductive disorders, and menopause. As far as we know, no reports are available in the literature for rapid detection of FSH using SiNW-FET. Hence, we deiced to develop a simple, fast, and high sensitivity sensor with a strong specific binding chemical site for further detection of FSH concentration in the human body. This is the first report to elucidate the FSH detection using SiNW-FET device. In this study, we developed highly sensitive chemosensor using SiNW-FET devices for simple, specific, and accurate human FSH detection without any nanomaterials conjugations and signal amplification. Improved accuracy and specificity were observed by modifying the surface of SiNW-FET with boronic acid for rapid detection of FSH. The device was fabricated using a top-down methodology followed by anisotropic wet etching. The rapid and sensitive electrical detection of FSH with high specificity was acquired using the SiNW-FET device. Rapid, low-price and miniaturized SiNW-FETs can serve as an useful sensing platform for the rapid screening of FSH and diagnosis of menopause. 2. Experimental section



2.1 Fabrication of SiNW-FET device In the fabrication of SiNW-FETs, top-down and bottom-up methodologies are the two major methods that are being used to develop a high sensitivity sensor. There are many factors caused the SiNW-FET device failure in the fabrication flow. For example, tiny critical dimension (CD), implant carry concentration, pattern alignment accuracy (AA) and electrical defect. Besides, the sensitivity of the nanowire device depends on the wire dimension and material quality due to the RC effect and surface plasma potential. The surface modification demonstrates the SiNW sensor selectivity.13 The nano designing tools such as e-beam lithography,28 lithographically designed nanowire electrodeposition,29 nanostencil and nanoimprint lithographies,30-31 are some of the top-down technologies used to produce nanowire structures. A top-down approach was used in combination with MOS compatible technology to fabricate a perfectly aligned SiNW array format.32 High-resolution FE-SEM was used to identify the structure of the SiNW-FET and further measure length/width of the fabricated SiNW-FET. In this study, metal-oxide-semiconductor (MOS) structure developed at National Device Laboratory (NDL) was used to fabricate SiNW-FET devices. The SiNW-FET sensor is nanowire-based transistors that consist of silicon on insulator (SOI) substrate and FET device. SOI (GlobalWafers Co., Ltd.) wafers refer to improve performance due to reduce parasitic capacitance, are a thickness of 675 ± 25 µm, 8 inch and buried oxide layer. The silicon–insulator–silicon layers with a 300 Å thickness were used on top of SOI wafer to form an oxidation layer. The hard mask of electrode pad made from NDL. The patterns of Si nanowire were fabricated by electron beam lithography (Elionix ELS-7500), landing energy 50 KeV and beam current 1.7 nA. The wet etching solution is the hydrofluoric acid and


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buffered oxide etch and primary use to remove the SiO2 and silicon. The surface The surface was washed with sulfuric acid (H2SO4) and hydrochloric acid (HCl). Ion implantation of boron (B) was performed to obtain a source and drain channel landing on the effective contact region. The isolation layers are made of 800 Å silicon dioxide (SiO2), and 500 Å silicon nitride (Si3N4) by the furnace and flowable CVD (FCVD). Leaf off technology, remove the photoresist after metal coated, were used on the 150 to 550 nm width silicon nanowire. The metal contact which designed a regular pad size 40X40 micrometer was coated 100 Å gold (Au) and ahead layer 50 Å Cr by thermal coater (ULVAC EBX-6D), coating rate 1 Å/second, 70°C chamber temperature. The silicon nanowire region which design for reactive binding and detection of target molecules are exposed due to the hard mask layout. 2.2 Modification of SiNW-FET with SB-OH The surface of the silicon nanowire was modified using the probe before using the sensor device to detect FSH so that the chemosensor device can identify a specific target molecule. At first, the SiNW chips were cleaned using a mixture of ethanol and deionized water (1:1). After thorough washing with ethanol, the chips were dipped in 10% SB-ester for half an hour to get a self-assembly on SiNW surface, washed with deionized water, and dried under the nitrogen atmosphere. Now, the boronic pinacol ester groups are the terminal moieties on the surface. Then, the device was immersed in 2.5% aqueous periodate (NaIO4) solution for another half an hour, washed with deionized water and dried under the nitrogen atmosphere. The boronic pinacol ester groups were deprotected using NaIO4 to the boronic acid groups and finally targeting sialic acid found on the surface of FSH in order to apply for sensing application. The direct detection of FSH in a human body would become possible by



developing a sensor probe that would particularly respond towards sialic acids over other biological compounds. 2.3 Functionalization of SiNW-FET device Silane coupling agent was used in this study to functionalize SiNW-FET. Silane coupling agent consists of three major groups that include an organofunctional group, linker, and hydrolyzable groups connected with the silicon atom. Initially, SB-ester was synthesized and then modified using nanowire followed by deprotection with NaIO4 to obtain boronic acid on SiNW surface. Finally, the modified SINW-FET targets sialic acid which is the parallel detection of FSH. X-ray Photoelectron Spectroscopy (XPS) was used to verify the modification of functional group on SiNW-FET surface. To check the modified SiNW surface, XPS was recorded to SiNWs before and after deprotection. 2.4 The reaction of SiNW-FET with FSH and current measurements PDMS kit was used to construct the microfluidic system. Materials A and B were taken in the ratio of 10:1 for 1 mL. After mixing, 0.9 ml was added to the microfluidic system. The vacuum in the system was sucked out to release the air bubbles for 30 min, heated for 3 h at 110 °C, and finally cooled down. All the electrical measurements were carried out using PBS buffer solution in a pH 7.4 at 25 oC. FSH (10 µL of 100 nM) in PBS buffer solution at pH 7.4 was added on nanowires, kept it for 5 mins, washed with deionized water and dried under the nitrogen atmosphere. The electrical signals were monitored after the addition of FSH with boronic acid modified SiNW. In this study, the surface of fabricated SiNW was scanned to measure the current by applying voltages in the range of 0.0V to 1.0V within 100 points step size with the source meter. The modified SiNW-FET was placed in the microfluidic system and an air stream


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pump was used to fix the chip on measuring platform of the source meter. Probes were attached to source and the drain electrode of the chip and varied the voltages from 0.00 V to 1.00 V with a step size of 0.01 V. The sample was injected at the rate of 0.01 µL/min by syringe pump into the microfluidic system with gate voltage 0.7 V. The FSH detection were also studied by monitoring changes in current with various FSH concentrations in different time intervals. 3. Results and Discussion 3.1 Fabrications, modification, and functionalization of SiNW-FET In this study, SiNW-FET was produced by a top-down fabrication process using 8-inch SOI wafers that are compatible with MOS methodology. The SiNW was designed by combinatorial methods involving e-beam lithography and anisotropic wet etching using hydrofluoric acid and thermal oxidation process. The pictorial representation of SiNW array chemosensors showing nanowires with the source (S) and drain (D) electrodes is depicted in Figure 1a. The cross sections of fabricated SiNW-FET are displayed in Figures 1b and 1c. The SEM image of SiNW with 505 nm width and 1µm length with a scale bar of (A) 5.00 µm (B) 1.00 µm is displayed in Figure 1d.



Figure 1. (a) Schematic design of SiNW-FET device showing nanowires with source and drain electrodes; (b,c) cross-section images of SiNW-FET; (d) SEM images of SiNW-FET with a scale bar of (A) 5.00 µm and (B) 1.00 µm. Initially, SB-ester was synthesized using triethoxy (3-isocyanatopropyl) silane and 4(4,4,5,5-tetramethyl-1,3,2 –dioxaborolan-2-yl) aniline as shown in Scheme S1. SiNW was chemically modified using SB-ester to produce SiNW-SB-ester in which the hydroxylterminated silicon dioxide binds with the ethoxy group of SB-ester. Modified SiNW-SBester underwent deprotection using NaIO4 to obtain SiNW-SB-OH by replacing the ethoxy group of SiNW-SB-ester with boronic acid. Finally, the boronic acid in SiNW-SB-OH specifically targets sialic acids, which paves the way for direct measurement of FSH as illustrated in Figure 2.


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Figure 2. Schematic view of the chemical process for surface functionalization of SiNWFET device showing a chemical modification of SiNW-SB-ester, deprotection, and FSH target. The current intensities between SiNW, SiNW-SB-ester, and SiNW-SB-OH were compared upon increasing the voltages and their corresponding results are displayed in Figure 3. These results indicated that the current of SiNW-SB-ester possessed lower intensity when compared to that of SiNW and SiNW-SB-OH intensities (Figure 3). The observation of lower current intensity (Figure 3a) of SiNW-SB-ester than SiNW is due to the weak conductivity of SiNW-SB-ester. On comparing the current intensities between



SiNW-SB-ester and SiNW-SB-OH, SiNW-SB-OH is found to have a higher intensity than that of SiNW-SB-ester, which is due to the fact that the hydroxyl group on SiNW was exposed after deprotection (Figure 3b). Bar diagram for the current response of SiNW, SiNW-SB-ester, and SiNW-SB-OH is shown in Figure 3c.

Figure 3. (a) The current response for SiNW and SiNW-SB-ester; (b) the current response for SiNW-SB-ester and SiNW-SB-OH; (c) bar diagram for the current response of SiNW, SiNW-SB-ester, and SiNW-SB-OH. 3.2 Surface analysis


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Many chemical methods were developed to improve the surface modification of SiNWFET chemosensor that promotes strong binding affinity between the analytes and the receptor.33-35 Therefore, improving sensitivity through a chemical method is an essential factor in the development of SiNW-FET chemosensor. It is reported that the modified SiNW can effectively target analytes and further convert it to an electrical signal.36 XPS spectrum showed the binding energy of the 1s orbital region of carbon, nitrogen, oxygen, and boron (Tables S1 and S2). It was observed that SiNW-SB-ester contains 61.13% of carbon, 2.96% of nitrogen, 21.81% oxygen, and 14.09% of boron before deprotection. After immobilization of boronic acid on the surface of SiNW-SB-ester, it was found that the percentage of carbon and nitrogen was increased to 67.98% and 5.81%, respectively. The percentage of oxygen was slightly reduced to 21.27% and the boron percentage was largely reduced to 4.95%. The comparison of the percentage of carbon, nitrogen, oxygen, and boron species before and after deprotection of SiNW-SB-ester indicated that the hydroxyl moieties located on the surface of nanowire were successfully modified with boronic acid. The successfully modified nanowire provides the platform for further conjugation of FSH. 3.3 Detection of FSH with SiNW-FET In the modified SiNW-FET device, the boronic acid groups were attached to FET surfaces were used to measure FSH concentrations. Figure 4 shows the assembly, construction, and measurement of SiNW-FET using the microfluidic system.



Figure 4. (a) The assembly, (b) construction of a microfluidic system, and (c) electrical measurements using the microfluidic system with SiNW-FET. SiNW-FET sensor for the detection of FSH was demonstrated by electrostatic interaction between the negative charge on the analytes and the positive charge on the chip.37 This results in charge carrier reduction in the current channels and further leads to increased current in the device. This extent of variation of current specifies the FSH concentration. The sensitivity of SiNW chemosensor was also checked by treating with various FSH concentration solutions (1, 10, 100, 500 fM, and 1 pM) and the current was monitored in different time intervals in both assay buffer and 20% serum conditions. The FSH solutions were injected at 0.0l µL/min flow rate using a syringe pump and the results of using the assay buffer solution are shown in Figure 5a. These results indicated that the change in current increased stepwise upon injection of different concentration of FSH ranging from 1 fM to 1pM. Increasing the concentration of FSH solutions say (1, 10, 100, 500 fM, and 1 pM) resulted in a current decrease. The changes in the current with FSH addition indicate the


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binding of the negative charge of analytes and the positive charge of the chip. In addition, the chemosensor showed a fast response of FSH less than one minute, demonstrating effective potential towards FSH detection and thus can diagnose menopause. The plot of current versus the logarithm of FSH is shown in Figure 5c which indicates that there exists a linear relationship between net change of current and the logarithm of FSH concentration. The limit of detection (LOD) was calculated using 3*σ/S, where S indicates the slope and σ is the blank standard deviation. The LOD was found to be 0.72 fM.

Figure 5. (a) Current measurement for SiNW-SB-OH with the addition of increasing concentration of FSH (1, 10, 100, 500, and 1 pM) in PBS solution; (b) current measurement for SiNW-SB-OH with addition of increasing concentration of FSH (1, 10, 100,500 fM, and



1 pM) in 20% serum condition; (c) plot of current versus the logarithm of FSH in PBS solution; (d) plot of current versus the logarithm of FSH in 20% serum condition. The physiological conditions were simulated by preparing a mixture of 20% of serum and 80% of PBS solution. The detection of FSH with SiNW-FET was also measured using different FSH concentrations (1, 10, 100, 500 fM, and 1 pM) in a 20% serum condition. The changes in current with different concentrations of FSH in physiological conditions were similar to 20% serum free condition as shown in Figure 5b. The changes of current intensities were linked to the various concentrations of target FSH in different time intervals. The plot of current versus the logarithm of FSH is shown in Figure 5d which indicates that there exists a linear relationship between net change of current and the logarithm of FSH concentration. The LOD was found to be 1.1 fM. Further testing will be carried out to minimize the error rate when performing under 20% serum conditions. 3.4 Selectivity Some of the control experiments were carried out to demonstrate the specificity and background environment of non-specific binding of hormones/glycosylated proteins using boronic acid functionalized SiNW chemosensors. Studies suggested that LH, HCG, and TSH are the main interferences that can disturb accuracy and concentration upon quantifying FSH.38 Hence, LH, HCG, and TSH was used to study the FSH specificity. In addition, boronic acid derivatives have the unique ability to bind with glucose and we examined whether the other glycosylated proteins present in the serum affect the SiNW-FET current measurements. To execute this experiment, glycosylated proteins present in the serum such as glycated hemoglobin (Hb1Ac), glycated albumin (GA), and fructosamine (FA) were selected. All the selected hormones (1 nM/1 pM) and glycosylated serum proteins (1 nM)


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were applied to SiNW-FET. The results are shown in Figure 6. These results showed an obvious increase in current when injected to the functionalized nanowire surface. These results indicated that boronic acid functionalized SiNW chemosensor showed non-specificity towards LH, HCG, TSH, HbA1c, GA, and FA and good specificity to FSH. Figure 6 showed the current changes after LH, HCG, TSH, HbA1c, GA, FA and FSH flow through the boronic acid modified nanowire chip (SiNW-FET). These results revealed that FSH (1 pM) showed a better selectivity over hormones (1 nM) and glycosylated serum proteins (1 nM). Selectivity results demonstrated that the functionalized chemosensor (SiNW-FET) could specifically capture FSH over the other hormonal proteins LH, HCG, TSH, and glycosylated serum proteins HbA1c, GA, and FA.

Figure 6. Bar diagram of current responses for SiNW-SB-OH with 1 pM FSH, 1 nM LH, 1 nM HCG, 1 nM TSH, 1 nM HbA1c,1 nM GA, and 1 nM FA. 4. Conclusions In this study, a MOS based SiNW-FET chemosensor was developed for the first time for accurate and fast FSH detection. The top-down methodology was used for the fabrication



followed by lithography and wet etching processes. Accurate, low-price and fast electrical detection of FSH with high performance were possible using the fabricated SiNW-FET device. The boronic acid-functionalized SiNW chips were used for FSH detection with a capability of detecting FSH as low as 0.72 fM and 1.1 fM using assay buffer and 20% serum conditions, respectively. Further testing will be carried out to minimize the error rate when performing under 20% serum conditions. Results of all the experimental data proved that the SiNW-FET can be used as a sensitive, rapid, low-cost, and portable device for FSH detection. This method using SiNW-FET device can act as a potential sensing platform for quick FSH screening and diagnosis of menopause. Supporting Information The details of materials and methods, animal care and handling, preparation of the stock solution, synthesis of SB-ester, data analysis are provided in supporting information. Synthesis of SB-ester (Scheme S1); 1H-NMR spectrum of SB-ester in CDCl3 (Figure S1); ESI-Mass spectrum of SB-ester (Figure S2); HR- ESI-Mass spectrum of SB-ester (Figure S3); SEM images of various sized SiNW ranging from 70 to 505 nm (Figure S4); XPS spectrum of SiNW-SB-ester (Table S1); XPS spectrum of SiNW-SB-OH (Table S2). Author Information Corresponding Author Yun-Ming Wang: [email protected] and Shyng-Shiou F. Yuan: [email protected] [email protected] and Shyng-Shiou F. Yuan: [email protected] Author contributions


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Yun-Ming Wang and Shyng-Shiou Yuan supervised the whole project. Mucian Lee, and Sathyadevi Palanisamy developed the idea and involved in carrying out the experiments, characterization and data analysis. Bin-Hou Zhou and Li-Yu Wang also participated in data analysis. Sathyadevi Palanisamy drafted the whole manuscript. All the authors were participated in the discussion of results and revised the manuscript. Notes The authors declare no competing financial interest. Acknowledgments All the authors are thankful to the Ministry of Science and Technology, Taiwan, R.O.C. for financial support under MOST 106-2113-M-009-023, 107-2218-E-009-010, and 106-3114-E009-005. This study was funded by “Center For Intelligent Drug Systems and Smart Biodevices (IDS2B)" from ‘The Featured Areas Research Center Program’ within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. The authors thank the core facility of EEE department in National Chiao Tung University, Hsinchu, Taiwan. References (1) Yager, P.; Domingo, G. J.; Gerdes, J. Point-Of-Care Diagnostics for Global Health. Annu. Rev. Biomed. Eng. 2008, 10, 107-44. (2) Moltzahn, F.; Olshen, A. B.; Baehner, L.; Peek, A.; Fong, L.; Stoppler, H.; Simko, J.; Hilton, J. F.; Carroll, P.; Blelloch, R. Microfluidic-Based Multiplex Qrt-PCR Identifies Diagnostic and Prognostic Microrna Signatures in the Sera of Prostate Cancer Patients. Cancer Res. 2011, 71, 550-560.



(3) Vashist, S. K.; Marion Schneider, E.; Lam, E.; Hrapovic, S.; Luong, J. H. One-Step Antibody Immobilization-Based Rapid and Highly-Sensitive Sandwich ELISA Procedure for Potential in Vitro Diagnostics. Sci. Rep. 2014, 4, 4407. (4) Xiang, Y.; Lu, Y. Using Personal Glucose Meters and Functional DNA Sensors to Quantify a Variety of Analytical Targets. Nature Chem. 2011, 3, 697-703. (5) Chen, K.-I.; Li, B.-R.; Chen, Y.-T. Silicon Nanowire Field-Effect Transistor-Based Biosensors for Biomedical Diagnosis and Cellular Recording Investigation. Nano Today 2011, 6, 131-154. (6) Matsumoto, A.; Miyahara, Y. Current and Emerging Challenges of Field Effect Transistor based Bio-Sensing. Nanoscale 2013, 5, 10702-10718. (7) Rim, T.; Baek, C. K.; Kim, K.; Jeong, Y. H.; Lee, J. S.; Meyyappan, M. Silicon Nanowire Biologically Sensitive Field Effect Transistors: Electrical Characteristics and Applications. J. Nanosci. Nanotechnol. 2014, 14, 273-287. (8) Patolsky, F.; Zheng, G. F.; Lieber, C. M. Nanowire-Based Biosensors. Anal. Chem. 2006, 78 (13), 4260-4269. (9) Rosi, N. L.; Mirkin, C. A. Nanostructures in Biodiagnostics. Chem. Rev. 2005, 105, 15471562. (10) Agarwal, R.; Lieber, C. M. Semiconductor Nanowires: Optics and Optoelectronics. Appl. Phys. A-Mater. 2006, 85, 209-215. (11) Li, Y.; Qian, F.; Xiang, J.; Lieber, C. M. Nanowire Electronic and Optoelectronic Devices. Mat. Today 2006, 9, 18-27.


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153x123mm (300 x 300 DPI)


Ultrasensitive Electrical Detection of Follicle Stimulating Hormone

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