Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor
- Giwan SeoGiwan SeoResearch Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of KoreaCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Giwan Seo,
- Geonhee LeeGeonhee LeeAdvanced Materials Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Geonhee Lee,
- Mi Jeong KimMi Jeong KimResearch Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of KoreaCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Mi Jeong Kim,
- Seung-Hwa BaekSeung-Hwa BaekCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaDepartment of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of KoreaMore by Seung-Hwa Baek,
- Minsuk ChoiMinsuk ChoiCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Minsuk Choi,
- Keun Bon KuKeun Bon KuCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Keun Bon Ku,
- Chang-Seop LeeChang-Seop LeeDepartment of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54986, Republic of KoreaBiomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of KoreaMore by Chang-Seop Lee,
- Sangmi JunSangmi JunCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaCenter for Research Equipment, Korea Basic Science Institute, Cheongju 28119, Republic of KoreaMore by Sangmi Jun,
- Daeui ParkDaeui ParkCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaDepartment of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of KoreaMore by Daeui Park,
- Hong Gi KimHong Gi KimCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Hong Gi Kim,
- Seong-Jun KimSeong-Jun KimCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Seong-Jun Kim,
- Jeong-O LeeJeong-O LeeAdvanced Materials Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Jeong-O Lee,
- Bum Tae KimBum Tae KimCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaMore by Bum Tae Kim,
- Edmond Changkyun Park*Edmond Changkyun Park*Email: [email protected]Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of KoreaCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaDepartment of Bio-Analysis Science, University of Science & Technology (UST), Daejeon 34113, Republic of KoreaMore by Edmond Changkyun Park, and
- Seung Il Kim*Seung Il Kim*Email: [email protected]Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of KoreaCenter for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of KoreaDepartment of Bio-Analysis Science, University of Science & Technology (UST), Daejeon 34113, Republic of KoreaMore by Seung Il Kim
Abstract
Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). Based on the rapid increase in the rate of human infection, the World Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. Because no specific drugs or vaccines for COVID-19 are yet available, early diagnosis and management are crucial for containing the outbreak. Here, we report a field-effect transistor (FET)-based biosensing device for detecting SARS-CoV-2 in clinical samples. The sensor was produced by coating graphene sheets of the FET with a specific antibody against SARS-CoV-2 spike protein. The performance of the sensor was determined using antigen protein, cultured virus, and nasopharyngeal swab specimens from COVID-19 patients. Our FET device could detect the SARS-CoV-2 spike protein at concentrations of 1 fg/mL in phosphate-buffered saline and 100 fg/mL clinical transport medium. In addition, the FET sensor successfully detected SARS-CoV-2 in culture medium (limit of detection [LOD]: 1.6 × 101 pfu/mL) and clinical samples (LOD: 2.42 × 102 copies/mL). Thus, we have successfully fabricated a promising FET biosensor for SARS-CoV-2; our device is a highly sensitive immunological diagnostic method for COVID-19 that requires no sample pretreatment or labeling.
KEYWORDS:
Note
This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease associated with severe respiratory distress. In December 2019, a series of cases of pneumonia of unknown cause were reported in Wuhan in the Hubei province of China. (1) Later, the 2019 novel coronavirus (2019-nCov) was identified from the bronchoalveolar lavage fluid of a patient; (2) it was subsequently renamed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. (3) As human-to-human transmission rapidly increased, the World Health Organization (WHO) classified the COVID-19 outbreak as a pandemic on March 12, 2020. (4) As of March 29, 2020, more than 634,000 cases of COVID-19 have been confirmed around the world, resulting in 29,891 deaths. (5) The estimated basic reproduction number (R0) of COVID-19 is approximately 2.2, meaning that, on average, each patient spreads infection to 2.2 people. (6) Because no specific drugs or vaccines are yet available for COVID-19, early diagnosis and management are crucial for containing the outbreak.
Coronaviruses (CoVs) cause mild to moderate upper respiratory tract illnesses in both humans and animals. (7) SARS-CoV-2, a betacoronavirus, has a single-positive strand RNA genome. CoV genomes encode four structural proteins: spike (S), envelope (E), matrix (M), and nucleocapsid (N). Two betacoronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), caused serious epidemics over the past two decades. (8) Phylogenetic analysis revealed that SARS-CoV-2 is more similar to SARS-CoV than MERS-CoV. (9) Although the viral pathogenesis of SARS-CoV-2 is unknown, recent studies reported that SARS-CoV-2 uses angiotensin-converting enzyme II (ACE2) as a cellular entry receptor; ACE2 is also a well-known host cell receptor for SARS-CoV. (10) SARS-CoV-2 colocalizes with ACE2 in animal cells, (11) and its spike (S) protein binds ACE2 with high affinity. (12,13)
For emerging pathogens, real-time reverse transcription–polymerase chain reaction (RT-PCR) is the primary means of diagnosis. Currently, real-time RT-PCR is used for the detection of SARS-CoV-2 based on previously published laboratory protocols. (14) SARS-CoV-2 is highly contagious and is currently spreading rapidly around the world; the rate of COVID-19 transmission is much faster than those of SARS and MERS. Moreover, cases of asymptomatic COVID-19 transmission have been reported. (15,16) Molecular diagnosis using real-time RT-PCR takes at least 3 h, including preparation of viral RNA. In addition, the RNA preparation step can affect diagnostic accuracy. Hence, highly sensitive immunological diagnostic methods that directly detect viral antigens in clinical samples without sample preparation steps are necessary for rapid and accurate diagnosis of COVID-19.
Among the many diagnostic methods currently available, field-effect transistor (FET)-based biosensing devices have several advantages, including the ability to make highly sensitive and instantaneous measurements using small amounts of analytes. (17,18) FET-based biosensors are considered to be potentially useful in clinical diagnosis, point-of-care testing, and on-site detection. Graphene is a two-dimensional sheet of hexagonally arranged carbon atoms, all of which are exposed on its surface. (19) It has proven to be a useful material for various sensing platforms due to its extraordinary properties, including high electronic conductivity, high carrier mobility, and large specific area. (20) Graphene-based FET biosensors can detect surrounding changes on their surface and provide an optimal sensing environment for ultrasensitive and low-noise detection. From this standpoint, graphene-based FET technology is very attractive for applications related to sensitive immunological diagnosis. (21,22)
In this study, we developed a graphene-based biosensing device functionalized with SARS-CoV-2 spike antibody (COVID-19 FET sensor) for use as a SARS-CoV-2 virus detection platform. SARS-CoV-2 spike antibody was immobilized onto the fabricated device through 1-pyrenebutyric acid N-hydroxysuccinimide ester (PBASE), an efficient interface coupling agent used as a probe linker (Figure 1). Our COVID-19 FET sensor detects target SARS-CoV-2 antigen protein with a limit of detection (LOD) of 1 fg/mL. Most critical of all, we confirmed the potential for clinical application by detecting SARS-CoV-2 antigen protein in transport medium used for nasopharyngeal swabs and cultured SARS-CoV-2 virus, as well as SARS-CoV-2 virus from clinical samples. Furthermore, our sensor could distinguish the SARS-CoV-2 antigen protein from those of MERS-CoV. These results demonstrate the successful fabrication of a COVID-19 FET sensor based on integration of SARS-CoV-2 spike antibody with graphene, enabling highly sensitive detection of the SARS-CoV-2 virus in clinical samples.
Figure 1
Figure 1. Schematic diagram of COVID-19 FET sensor operation procedure. Graphene as a sensing material is selected, and SARS-CoV-2 spike antibody is conjugated onto the graphene sheet via 1-pyrenebutyric acid N-hydroxysuccinimide ester, which is an interfacing molecule as a probe linker.
Results and Discussion
ARTICLE SECTIONS
Fabrication and Characterization of Biosensing Device
Figure 2A depicts the optical image of the COVID-19 FET sensor. The dimensions of the sensing area were 100 × 100 μm2 (L × W). To reduce interference during electrical measurements, the device was passivated with SU8-2010. Details of the fabrication of the COVID-19 FET sensor is provided in Materials and Methods. To confirm that the graphene surface was chemically functionalized using PBASE, we obtained Raman spectra and X-ray photoelectron spectroscopy (XPS) data (Figure 2B–H). Figure 2B shows the Raman spectra of the pristine and PBASE-modified graphene surfaces. In the spectrum for the surface of pristine graphene, two major peaks (the G and 2D peaks) were observed. The G peak corresponds to the lattice vibration mode, and the 2D peak stems from second-order Raman scattering. However, the D and D′ peaks obviously appeared due to the relative resonance of sp3 bonding, orbital hybridization, and a pyrene group in the binding of PABSE to the graphene surface. To provide a visual comparison of the qualities of graphene after modification with PBASE, we converted the measured data to histograms and mapping images (Figure 2C–E). After PBASE was applied to the graphene surface, the statistical data of the 2D peak position were shifted to a higher frequency (∼3.27 cm–1), indicating p-doping by the π–π interaction between PBASE and graphene (Figure 2C). (23,24) The mapping images also show that the average I2D/IG ratio of PBASE-treated graphene (I2D/IG = ∼1.87) is significantly lower than that of pristine graphene (I2D/IG = ∼3.61) due to existence of some disorder on the graphene (Figure 2D,E).
Figure 2
Figure 2. Surface analysis of pristine and PBASE-modified graphene using Raman spectroscopy, X-ray spectroscopy, and atomic force microscopy. (A) Optical image of the COVID-19 FET sensor. The dimensions were 100 × 100 μm2 (L × W). Scale bar in the image denotes 200 μm. (B) Representative Raman spectra of pristine and PBASE-modified graphene. (C) Comparison of statistical data of the 2D peak position between pristine and PBASE-modified graphene. Mapping images of average I2D/IG ratio (D) before and (E) after PBASE modification. (F) XPS survey data of pristine and PBASE-modified graphene. (G) N 1s peak of pristine and PBASE-treated graphene (shadow region in F). (H) Deconvoluted C 1s peak of PBASE-modified graphene. Atomic force microscopy (AFM) images of (I) pristine graphene (RMS = 0.961) and (J) PBASE-modified graphene (RMS = 1.530). Bottom graphs indicate the height profiles in the corresponding two AFM images. Scale bar in the image denotes 3 μm.
The XPS survey data show the principal C 1s, O 1s, and N 1s core levels (Figure 2F). Before functionalization, the graphene exhibited no meaningful N peak (black line), whereas the N 1s peak was observed in the PBASE-treated sample (red line). Figure 2G indicates the comparison of the N 1s peak intensity before and after PBASE functionalization. The increase in intensity of the N 1s peak suggests successful surface modification. The C 1s peak was composed of five components, 284.5, 285.5, 286.4, 287.7, and 288.6 eV, corresponding to C═C, C═N, C–N, C–OH, and C–C═O/C═O, respectively, originating from the substitutional doping of N atoms (Figure 2H). (25) These results suggest that the surface of PBASE-modified graphene can be successfully used as a substrate support for stable sensing.
Next, we characterized the morphology and quality of the graphene sheets using atomic force microscopy (AFM) and high-resolution transmission electron microscopy (HR-TEM). The surface roughness of graphene (RMS) increased slightly from ∼0.961 nm to ∼1.530 nm after PBASE modification (Figure 2I,J). The general profile of the graphene sheet and its electron diffraction pattern of the sheets reveal the fine crystallinity of the graphene on the EM grid (Figure S1).
Selection of the Antigen and Validation of the Antibody
SARS-CoV-2 encodes four structural proteins: spike, envelope, matrix, and nucleocapsid. (9) Among them, the spike protein is best suited for use as a diagnostic antigen because it is a major transmembrane protein of the virus and is highly immunogenic. In addition, the spike protein exhibits amino acid sequence diversity among coronaviruses, (9) enabling the specific detection of SARS-CoV-2. Therefore, we used SARS-CoV-2 spike antibody as a receptor to detect this virus.
Before immobilizing SARS-CoV-2 spike antibody onto the FET, we verified the performance of the antibody by enzyme-linked immunosorbent assay (ELISA). The results revealed that the antibody bound to the SARS-CoV-2 spike protein but not to the MERS-CoV spike protein or bovine serum albumin (BSA) (Figure S2). These observations confirm that the antibody is specific for the SARS-CoV-2 spike protein and is therefore suitable for detecting SARS-CoV-2. The detection limit of the antibody in the ELISA platform was 4 ng/mL.
Preparation of the COVID-19 FET Sensor
To evaluate the presence of the SARS-CoV-2 spike antibody on the graphene surface, we carried out electrical measurements. Figure 3C shows the current–voltage (I–V) curves of the graphene device over a range from −0.1 to +0.1 V before and after attachment of the antibody. After PBASE functionalization and immobilization of the antibody onto the graphene channel, the slopes (dI/dV) decreased. This difference in slope indicates the successful introduction of the SARS-CoV-2 spike antibody.
Figure 3
Figure 3. Electrical characterization of pristine, PBASE-modified, and SARS-CoV-2 spike antibody-immobilized graphene. (A) Schematic diagram of the aqueous-solution-gated FET (COVID-19 FET sensor) configuration using the antibody-conjugated graphene. (B) IDS–VDS output curves of the antibody-conjugated FET with various gating voltages from 0 to −1.5 V in steps of −0.3 V. IDS negatively increased as VGS negatively increased. (C) Current–voltage (I–V) characteristics of the graphene-based device of each functionalization process for the antibody modification. (D) Measurement of transfer curves of the COVID-19 FET sensor in steps of the antibody conjugation (VDS = 0.01 V).
To investigate the possibility of transducing an electrical signal with the COVID-19 FET sensor, we prepared an aqueous solution-gated FET. The geometry of the COVID-19 FET sensor was designed using a graphene channel conjugated to the SARS-CoV-2 spike antibody, and the FET was covered with phosphate-buffered saline (PBS; pH 7.4) buffer as the electrolyte to maintain an efficient gating effect. As shown in Figure 3A, the aqueous solution-gated FET system could detect SARS-CoV-2 based on changes in channel surface potential and the corresponding effects on the electrical response.
We measured the transfer curves of the graphene-based FET after each modification process (Figure 3D). After PBASE functionalization, an obvious positive shift was observed due to the p-doping effect of the pyrene group. However, the transfer curve was shifted negatively, suggesting that the positive charge of the antibody exerted an n-doping effect on graphene after the antibody was immobilized. Figure 3B shows the output curves of the COVID-19 FET sensor as a function of gate voltage (VG) over a range from 0 to −1.5 V in steps of −0.3 V. IDS negatively increased as VG negatively increased, corresponding to the predicted behavior of a p-type semiconductor. (26,27) Moreover, the linear I–V curves exhibited highly stable ohmic contact, indicating that the COVID-19 FET sensor provided a reliable electrical signal for detection of the target analytes (SARS-CoV-2 antigen protein, cultured SARS-CoV-2 virus, or SARS-CoV-2 virus from clinical samples).
Real-Time Detection of SARS-CoV-2 Antigen Protein
To investigate the performance of the COVID-19 FET sensor, we evaluated the dynamic response of the sensor to spike protein (Figure 4A). First, we measured the sensor’s LOD for spike protein. The sensor responded to 1 fg/mL of SARS-CoV-2 spike protein in PBS (Figure 4B); that is, the LOD of the FET sensor was substantially lower than that of the ELISA platform (Figure S2). However, the pristine graphene-based device without SARS-CoV-2 spike protein conjugation did not show any remarkable signal change after the introduction of various sample concentrations (gray line in Figure 4D). The control experiment indicates that the SARS-CoV-2 spike protein is essential for specific binding with the SARS-CoV-2 antigen. In addition, the COVID-19 FET sensor exhibited no response to MERS-CoV spike proteins (Figure 4D), indicating that the COVID-19 FET sensor was both highly sensitive and specific for the SARS-CoV-2 spike antigen protein.
Figure 4
Figure 4. Detection of SARS-CoV-2 antigen protein. (A) Schematic diagram for the COVID-19 FET sensor for detection of SARS-CoV-2 spike protein. (B) Real-time response of COVID-19 FET toward SARS-CoV-2 antigen protein in PBS and (C) related dose-dependent response curve (VDS = 0.01 V). Graphene-based FET without SARS-CoV-2 antibody is presented as negative control. (D) Selective response of COVID-19 FET sensor toward target SARS-CoV-2 antigen protein and MERS-CoV protein. (E) Real-time response of COVID-19 FET toward SARS-CoV-2 antigen protein in UTM and (F) related dose-dependent response curve.
In the clinic, diagnosis of COVID-19 is performed using nasopharyngeal swabs suspended in universal transport medium (UTM). The UTM contains various reagents that may affect performance of the FET sensor, such as Hank’s balanced salts and BSA. Therefore, we assessed the response of the FET sensor to antigens in UTM. To determine whether the FET sensor could be used in the field, we measured the response of the FET sensor to SARS-CoV-2 spike proteins in 0.01× UTM. The results revealed that the FET sensor could successfully detect SARS-CoV-2 spike antigen proteins starting from a concentration of 100 fg/mL (Figure 4E). This indicates that the COVID-19 FET sensor can detect antigens in clinical samples without any preparation or preprocessing. To further investigate the normalized sensitivity of the COVID-19 FET sensor, the changes in sensitivity as a function of SARS-CoV-2 antigen protein concentration were characterized by fitting each data point, as shown in Figure 4C,F.
Real-Time Detection of Cultured SARS-CoV-2 Virus
Next, we investigated whether the COVID-19 FET sensor could detect SARS-CoV-2 virus (Figure 5A). To this end, we propagated SARS-CoV-2 in cultured cells and inactivated viral infectivity by heating. Upon application of cultured SARS-CoV-2, the COVID-19 FET sensor responded to concentrations as low as 1.6 × 101 pfu/mL (Figure 5B), and the normalized response curve was linear from 1.6 × 101 to 1.6 × 104 pfu/mL (Figure 5C). This result suggests that the COVID-19 FET sensor has the potential to be used for COVID-19 diagnosis.
Figure 5
Figure 5. Detection of cultured SARS-CoV-2 virus. (A) Schematic diagram for the COVID-19 FET sensor for detection of SARS-CoV-2 cultured virus. (B) Real-time response of COVID-19 FET toward SARS-CoV-2 cultured virus and (C) related dose-dependent response curve.
Detection of SARS-CoV-2 Virus from Clinical Samples
Finally, we tested the detection performance of the COVID-19 FET sensor using clinical samples (Figure 6A). To this end, we collected nasopharyngeal swab specimens from COVID-19 patients and normal subjects and stored them in UTM. Prior to addition of patient samples to the device, we evaluated nasopharyngeal swab samples from normal subjects to determine the basal signal. The COVID-19 FET sensor clearly discriminated between patient and normal samples (Figure 6B,C). In addition, the FET sensor responded to patient samples diluted as much as 1:1 × 105 (242 copies/mL) (Figure 6D), and the normalized response curve of the FET sensor was linear (Figure 6E). Given that UTM includes various reagents and generates noise signals, we consider the LOD of the COVID-19 FET sensor to be low enough for practical use Table S2. Nevertheless, development of novel materials of the FET sensor for UTM should be necessary for more accurate detection by reducing the noise signals. For reference, the detection limit of current molecular diagnostic tests of COVID-19 is ∼50–100 copies. (28) Taken together, our findings show that our COVID-19 FET sensor successfully detected SARS-CoV-2 virus from clinical samples without any preprocessing and with a large dynamic range.
Figure 6
Figure 6. Detection of SARS-CoV-2 virus from clinical samples. (A) Schematic diagram for the COVID-19 FET sensor for detection of SARS-CoV-2 virus from COVID-19 patients. (B,C) Comparison of response signal between normal samples and patient ones. (D) Real-time response of COVID-19 FET toward SARS-CoV-2 clinical sample and (C) related dose-dependent response curve.
Conclusion
ARTICLE SECTIONS
During the COVID-19 pandemic, the development of highly sensitive and rapid biosensing devices has become increasingly important. We developed a COVID-19 FET sensor in which the SARS-CoV-2 spike antibody is conjugated to a graphene sheet, which is used as the sensing area. The sensor was able to detect SARS-CoV-2 virus in clinical samples, the SARS-CoV-2 antigen in practical use (Table S2). standard buffer, transport medium,, and cultured SARS-CoV-2 virus. Furthermore, the device exhibited no measurable cross-reactivity with MERS-CoV antigen. Therefore, our functionalized graphene-based sensor platform provides simple, rapid, and highly responsive detection of the SARS-CoV-2 virus in clinical samples. Moreover, this technology could be adapted for diagnosis of other emerging viral diseases.
Materials and Methods
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Fabrication of Graphene-Based Sensing Devices
Graphene was transferred to a SiO2/Si substrate using conventional wet-transfer methods. Poly(methyl methacrylate) (PMMA) C4 (MicroChem, Newton, MA) was spin-coated at 500 rpm for 10 s and at 3000 rpm for 30 s onto graphene on Cu foil (Grolltex, San Diego, CA). PMMA/graphene on Cu foil was etched in CE-100 copper etchant (Transene, Oakland, CA). After the Cu foil was etched, the PMMA/graphene layers were moved using clean glass slides into a deionized (DI) water bath, and the copper etchant was washed away. Subsequently, the PMMA/graphene layer was transferred to a SiO2/Si substrate and dried under ambient conditions overnight. The PMMA layer was removed in an acetone bath for 2 h. Finally, the graphene was transferred onto the substrate, followed by isopropyl alcohol washing and drying under a stream of N2 gas.
To fabricate practical graphene-based devices, the transferred graphene was patterned into linear shapes by photolithography and etched by a reactive ion-etching method. To generate a Au/Cr electrode layer on the etched graphene layer, metallization was performed using a thermal evaporation method and a lift-off technique. The device dimensions were 100 × 100 μm2 (L × W). To reduce interference during electrical measurements, the device was passivated with SU8-2010 (MicroChem).
Immobilization of SARS-CoV-2 Antibody on the Graphene Surface
The fabricated graphene-based device was soaked in 2 mM PBASE (Thermo Fisher Scientific, Waltham, MA) in methanol for 1 h at room temperature and then rinsed several times with PBS and DI water. Finally, the functionalized device was exposed to 250 μg/mL SARS-CoV-2 spike antibody for 4 h.
Instruments
Pristine graphene and graphene with PBASE modification were characterized by Raman spectroscopy, XPS, AFM, and HR-TEM.
Raman spectrum and mapping analysis was acquired with an inVia Raman system (Renishaw, UK). Mapping images were obtained from 196 spectra (30 × 30 μm area on graphene). The intervals between adjacent spectrum points were 2.5 μm (horizontal and vertical). Analysis of the chemical binding component was determined by XPS on a K-Alpha instrument (Thermo Fisher Scientific), with the incident beam produced by an Al X-ray source (hν = 1486.6 eV) and a pass energy of 50 eV. Surface roughness analysis was conducted by AFM on a Dimension 3000 instrument (Digital Instruments/Veeco Science). HR-TEM imaging was performed on a ZEISS Libra ultracorrected energy filtering transmission electron microscope (ZEISS, Germany) with a 200 kV acceleration voltage.
Sensing Measurement
Electrical performance was evaluated on a 2634B semiconductor analyzer (Keithley Instruments, Cleveland, OH) and probe station. A drain–source bias voltage of ∼10 mV was maintained during measurement. The detected electrical response signal was normalized as [ΔI/I0] = (I – I0)/I0, where I is the detected real-time current and I0 is the initial current.
Enzyme-Linked Immunosorbent Assay
A 96-well plate was coated with SARS-CoV-2 spike antigen protein (40591-V08H; Sino Biological, Inc., China) or MERS-CoV spike antigen protein (40069-V08H, Sino Biological) for 1 h at 37 °C and then blocked with 5% BSA. A proper dilution of SARS-CoV-2 spike antibody (40150-R007, Sino Biological) was added to the blocked well, and the sample was incubated for 1 h at room temperature. After being washed with TBST (Tris-buffered saline, 0.1% Tween 20), horseradish peroxidase-conjugated anti-rabbit IgG antibody (#7074, Cell Signaling Technology, Danvers, MA) was added, and the sample was incubated for 1 h at room temperature. After extensive washing with TBST, the ELISA substrate (1-Step Ultra TMB-ELISA, Thermo Fisher Scientific) was applied, and signals were obtained on a Synergy HTX plate reader (BioTek Instruments, Winooski, VT).
Virus Culture
Virus infection experiments were performed in a biosafety level 3 laboratory. African green monkey kidney Vero E6 cells were infected with a clinical isolate of SARS-CoV-2 (BetaCoV/Korea/KCDC03/2020, provided by Korea CDC). After 48 h, the culture medium containing mature infectious virions (virus medium) was collected, and viral titer was determined by plaque assay. Live virus was inactivated by heating at 100 °C for 15 min and was stored at −80 °C for further use.
Clinical Sample Preparation
The clinical samples used in this study (Figure S3 and Table S1) were collected from subjects as part of registered protocols approved by Institutional Review Board (IRB) of Jeonbuk National University Hospital, and all patients provided written informed consent (IRB registration number: CUH 2020-02-050-008). Nasopharyngeal swabs from COVID-19 patients and healthy subjects were stored in UTM (Noble Biosciences, South Korea). Viral copy number was determined by real-time RT-PCR. Clinical samples were inactivated by heating at 100 °C for 10 min and were stored at −80 °C for further use.
Supporting Information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c02823.
Figures of TEM observation of the graphene sheet, ELISA details, clinical sample information on COVID-19 patients, and performance comparison on SARS-CoV-2 detection technologies (PDF)
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Author Information
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- Edmond Changkyun Park - Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea; Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Bio-Analysis Science, University of Science & Technology (UST), Daejeon 34113, Republic of Korea;
http://orcid.org/0000-0001-6699-4886;
- Seung Il Kim - Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea; Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Bio-Analysis Science, University of Science & Technology (UST), Daejeon 34113, Republic of Korea;http://orcid.org/0000-0001-6681-4486;
- Giwan Seo - Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea; Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;http://orcid.org/0000-0002-8734-6199
- Daeui Park - Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea;http://orcid.org/0000-0002-9452-5849
- Jeong-O Lee - Advanced Materials Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;http://orcid.org/0000-0002-7343-4892
Acknowledgments
ARTICLE SECTIONS
This work was supported by National Research Council of Science and Technology (NST) funded by the Ministry of Science and ICT, Republic of Korea (Grant No. CRC-16-01-KRICT), and Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Nos. HI20C0033 and HI20C0363).
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- 2Wu, F.; Zhao, S.; Yu, B.; Chen, Y. M.; Wang, W.; Song, Z. G.; Hu, Y.; Tao, Z. W.; Tian, J. H.; Pei, Y. Y.; Yuan, M. L.; Zhang, Y. L.; Dai, F. H.; Liu, Y.; Wang, Q. M.; Zheng, J. J.; Xu, L.; Holmes, E. C.; Zhang, Y. Z. A New Coronavirus Associated with Human Respiratory Disease in China. Nature 2020, 579, 265– 269, DOI: 10.1038/s41586-020-2008-3[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXksFKlsLc%253D&md5=0163a684829e880a0c3347e19f0ce52aA new coronavirus associated with human respiratory disease in ChinaWu, Fan; Zhao, Su; Yu, Bin; Chen, Yan-Mei; Wang, Wen; Song, Zhi-Gang; Hu, Yi; Tao, Zhao-Wu; Tian, Jun-Hua; Pei, Yuan-Yuan; Yuan, Ming-Li; Zhang, Yu-Ling; Dai, Fa-Hui; Liu, Yi; Wang, Qi-Min; Zheng, Jiao-Jiao; Xu, Lin; Holmes, Edward C.; Zhang, Yong-ZhenNature (London, United Kingdom) (2020), 579 (7798), 265-269CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 Jan. 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 Dec. 2019. Epidemiol. investigations have suggested that the outbreak was assocd. with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 Dec. 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic anal. of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
- 3Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-nCoV and Naming It SARS-CoV-2. Nat. Microbiol. 2020, 5, 536– 544, DOI: 10.1038/s41564-020-0695-z[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXktFemu7Y%253D&md5=3e43e7781469c6d748726b24b3a60361The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2Coronaviridae Study Group of the International Committee on Taxonomy of VirusesNature Microbiology (2020), 5 (4), 536-544CODEN: NMAICH; ISSN:2058-5276. (Nature Research)A review. The present outbreak of a coronavirus-assocd. acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clin. manifestations assocd. with SARS-CoV-2 infections in humans remains to be detd., the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus-host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.
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- 6Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; Ren, R.; Leung, K. S. M.; Lau, E. H. Y.; Wong, J. Y.; Xing, X.; Xiang, N.; Wu, Y.; Li, C.; Chen, Q.; Li, D.; Liu, T.; Zhao, J.; Liu, M.; Tu, W. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020, 382, 1199– 1207, DOI: 10.1056/NEJMoa2001316[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmt1Whtrw%253D&md5=d82c8e8a173f6ab879d332f0abb7228eEarly transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumoniaLi, Qun; Guan, Xuhua; Wu, Peng; Wang, Xiaoye; Zhou, Lei; Tong, Yeqing; Ren, Ruiqi; Leung, Kathy S. M.; Lau, Eric H. Y.; Wong, Jessica Y.; Xing, Xuesen; Xiang, Nijuan; Wu, Yang; Li, Chao; Chen, Qi; Li, Dan; Liu, Tian; Zhao, Jing; Liu, Man; Tu, Wenxiao; Chen, Chuding; Jin, Lianmei; Yang, Rui; Wang, Qi; Zhou, Suhua; Wang, Rui; Liu, Hui; Luo, Yinbo; Liu, Yuan; Shao, Ge; Li, Huan; Tao, Zhongfa; Yang, Yang; Deng, Zhiqiang; Liu, Boxi; Ma, Zhitao; Zhang, Yanping; Shi, Guoqing; Lam, Tommy T. Y.; Wu, Joseph T.; Gao, George F.; Cowling, Benjamin J.; Yang, Bo; Leung, Gabriel M.; Feng, ZijianNew England Journal of Medicine (2020), 382 (13), 1199-1207CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in Dec. 2019 and Jan. 2020. We analyzed data on the 1st 425 confirmed cases in Wuhan to det. the epidemiol. characteristics of NCIP. We collected information on demog. characteristics, exposure history, and illness timelines of lab.-confirmed cases of NCIP that had been reported by Jan. 22, 2020. We described characteristics of the cases and estd. the key epidemiol. time-delay distributions. In the early period of exponential growth, we estd. the epidemic doubling time and the basic reproductive no. Among the 1st 425 patients with confirmed NCIP, the median age was 59 yr and 56% were male. The majority of cases (55%) with onset before Jan. 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days, with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days, the basic reproductive no. was estd. to be 2.2. On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of Dec. 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk.
- 7Li, G.; Fan, Y.; Lai, Y.; Han, T.; Li, Z.; Zhou, P.; Pan, P.; Wang, W.; Hu, D.; Liu, X.; Zhang, Q.; Wu, J. Coronavirus Infections and Immune Responses. J. Med. Virol. 2020, 92, 424– 432, DOI: 10.1002/jmv.25685[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXntVKntr4%253D&md5=f2de904af37ab888695f51c9b9222ac0Coronavirus infections and immune responsesLi, Geng; Fan, Yaohua; Lai, Yanni; Han, Tiantian; Li, Zonghui; Zhou, Peiwen; Pan, Pan; Wang, Wenbiao; Hu, Dingwen; Liu, Xiaohong; Zhang, Qiwei; Wu, JianguoJournal of Medical Virology (2020), 92 (4), 424-432CODEN: JMVIDB; ISSN:0146-6615. (Wiley-Blackwell)A review. Coronaviruses (CoVs) are by far the largest group of known pos.-sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathol. and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV-induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clin. treatment.
- 8de Wit, E.; van Doremalen, N.; Falzarano, D.; Munster, V. J. SARS and MERS: Recent Insights into Emerging Coronaviruses. Nat. Rev. Microbiol. 2016, 14, 523– 534, DOI: 10.1038/nrmicro.2016.81[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGiur7L&md5=518b1155a64d3e9d9a1878fec7db3a2fSARS and MERS: recent insights into emerging coronavirusesde Wit, Emmie; van Doremalen, Neeltje; Falzarano, Darryl; Munster, Vincent J.Nature Reviews Microbiology (2016), 14 (8), 523-534CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)A review. The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiol. and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses.
- 9Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; Bi, Y.; Ma, X.; Zhan, F.; Wang, L.; Hu, T.; Zhou, H.; Hu, Z.; Zhou, W.; Zhao, L.; Chen, J. Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding. Lancet 2020, 395, 565– 574, DOI: 10.1016/S0140-6736(20)30251-8[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFOmsLY%253D&md5=3a644f602ea1c68114e23b5f12625265Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor bindingLu, Roujian; Zhao, Xiang; Li, Juan; Niu, Peihua; Yang, Bo; Wu, Honglong; Wang, Wenling; Song, Hao; Huang, Baoying; Zhu, Na; Bi, Yuhai; Ma, Xuejun; Zhan, Faxian; Wang, Liang; Hu, Tao; Zhou, Hong; Hu, Zhenhong; Zhou, Weimin; Zhao, Li; Chen, Jing; Meng, Yao; Wang, Ji; Lin, Yang; Yuan, Jianying; Xie, Zhihao; Ma, Jinmin; Liu, William J.; Wang, Dayan; Xu, Wenbo; Holmes, Edward C.; Gao, George F.; Wu, Guizhen; Chen, Weijun; Shi, Weifeng; Tan, WenjieLancet (2020), 395 (10224), 565-574CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)In late Dec., 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions detd. by rapid amplification of cDNA ends. Phylogenetic anal. of these 2019-nCoV genomes and those of other coronaviruses was used to det. the evolutionary history of the virus and help infer its likely origin. Homol. modeling was done to explore the likely receptor-binding properties of the virus. The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic anal. revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homol. modeling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic anal. suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural anal. suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University. These data have been deposited in the ChinaNational Microbiol. Data Center (accession no. NMDC10013002 and genome accession nos. NMDC60013002-01 to NMDC60013002-10) and the datafrom BGI have been deposited in the China National GeneBank (accession nos. CNA000733235).
- 10Li, W.; Moore, M. J.; Vasilieva, N.; Sui, J.; Wong, S. K.; Berne, M. A.; Somasundaran, M.; Sullivan, J. L.; Luzuriaga, K.; Greenough, T. C.; Choe, H.; Farzan, M. Angiotensin-Converting Enzyme 2 Is a Functional Receptor for the SARS Coronavirus. Nature 2003, 426, 450– 454, DOI: 10.1038/nature02145[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1GlsLs%253D&md5=884851c53d0f77cbdd6520aaa79efbedAngiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirusLi, Wenhui; Moore, Michael J.; Vasilieva, Natalya; Sui, Jianhua; Wong, Swee Kee; Berne, Michael A.; Somasundaran, Mohan; Sullivan, John L.; Luzuriaga, Katherine; Greenough, Thomas C.; Choe, Hyeryun; Farzan, MichaelNature (London, United Kingdom) (2003), 426 (6965), 450-454CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), assoc. with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a sol. form of ACE2, but not of the related enzyme ACE1, blocked assocn. of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.
- 11Zhou, P.; Yang, X. L.; Wang, X. G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H. R.; Zhu, Y.; Li, B.; Huang, C. L.; Chen, H. D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R. D.; Liu, M. Q.; Chen, Y.; Shen, X. R.; Wang, X.; Zheng, X. S. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579, 270– 273, DOI: 10.1038/s41586-020-2012-7[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXksFKlsLg%253D&md5=236f17d4d3c7978d72513e5e0258f1b3A pneumonia outbreak associated with a new coronavirus of probable bat originZhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-LiNature (London, United Kingdom) (2020), 579 (7798), 270-273CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Abstr.: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large no. of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 Dec. 2019, had caused 2,794 lab.-confirmed infections including 80 deaths by 26 Jan. 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence anal. of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addn., 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.
- 12Tian, X.; Li, C.; Huang, A.; Xia, S.; Lu, S.; Shi, Z.; Lu, L.; Jiang, S.; Yang, Z.; Wu, Y.; Ying, T. Potent Binding of 2019 Novel Coronavirus Spike Protein by a SARS Coronavirus-Specific Human Monoclonal Antibody. Emerging Microbes Infect. 2020, 9, 382– 385, DOI: 10.1080/22221751.2020.1729069[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsVGks78%253D&md5=6d73882867e561b2056895c525136512Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibodyTian, Xiaolong; Li, Cheng; Huang, Ailing; Xia, Shuai; Lu, Sicong; Shi, Zhengli; Lu, Lu; Jiang, Shibo; Yang, Zhenlin; Wu, Yanling; Ying, TianleiEmerging Microbes & Infections (2020), 9 (1), 382-385CODEN: EMIMC4; ISSN:2222-1751. (Taylor & Francis Ltd.)The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 lab.-confirmed human infections, including 259 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. These results suggest that CR3022 may have the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, implying that the difference in the RBD of SARS-CoV and 2019-nCoV has a crit. impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.
- 13Wrapp, D.; Wang, N.; Corbett, K. S.; Goldsmith, J. A.; Hsieh, C. L.; Abiona, O.; Graham, B. S.; McLellan, J. S. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. Science 2020, 367, 1260– 1263, DOI: 10.1126/science.abb2507[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvFemt70%253D&md5=27d08cbb9a43d1da051a8a92a9f68aa5Cryo-EM structure of the 2019-nCoV spike in the prefusion conformationWrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola; Graham, Barney S.; McLellan, Jason S.Science (Washington, DC, United States) (2020), 367 (6483), 1260-1263CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we detd. a 3.5-angstrom-resoln. cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophys. and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Addnl., we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
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- 17Janissen, R.; Sahoo, P. K.; Santos, C. A.; da Silva, A. M.; von Zuben, A. A. G.; Souto, D. E. P.; Costa, A. D. T.; Celedon, P.; Zanchin, N. I. T.; Almeida, D. B.; Oliveira, D. S.; Kubota, L. T.; Cesar, C. L.; Souza, A. P.; Cotta, M. A. InP Nanowire Biosensor with Tailored Biofunctionalization: Ultrasensitive and Highly Selective Disease Biomarker Detection. Nano Lett. 2017, 17, 5938– 5949, DOI: 10.1021/acs.nanolett.7b01803[ACS Full Text
], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVKqsLzP&md5=66f17e677fb3cc81638e97109d3a46feInP Nanowire Biosensor with Tailored Biofunctionalization: Ultrasensitive and Highly Selective Disease Biomarker DetectionJanissen, Richard; Sahoo, Prasana K.; Santos, Clelton A.; da Silva, Aldeliane M.; von Zuben, Antonio A. G.; Souto, Denio E. P.; Costa, Alexandre D. T.; Celedon, Paola; Zanchin, Nilson I. T.; Almeida, Diogo B.; Oliveira, Douglas S.; Kubota, Lauro T.; Cesar, Carlos L.; Souza, Anete P. de; Cotta, Monica A.Nano Letters (2017), 17 (10), 5938-5949CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Elec. active field-effect transistors (FET) based biosensors are of paramount importance in life science applications, as they offer direct, fast, and highly sensitive label-free detection capabilities of several biomols. of specific interest. The authors report a detailed study on surface functionalization and covalent immobilization of biomarkers using biocompatible ethanolamine and poly(ethylene glycol) derivate coatings, as compared to the conventional approaches using silica monoliths, to substantially increase both the sensitivity and mol. selectivity of nanowire-based FET biosensor platforms. Quant. fluorescence, at. and Kelvin probe force microscopy allowed detailed study of the homogeneity and d. of immobilized biomarkers on different biofunctionalized surfaces. Significantly enhanced binding specificity, biomarker d., and target biomol. capture efficiency were thus achieved for DNA as well as for proteins from pathogens. This optimized functionalization methodol. was applied to InP nanowires that due to their low surface recombination rates were used as new active transducers for biosensors. The developed devices provide ultrahigh label-free detection sensitivities ∼1 fM for specific DNA sequences, measured via the net change in device elec. resistance. Similar levels of ultrasensitive detection of ∼6 fM were achieved for a Chagas Disease protein marker (IBMP8-1). The developed InP nanowire biosensor provides thus a qualified tool for detection of the chronic infection stage of this disease, leading to improved diagnosis and control of spread. These methodol. developments are expected to substantially enhance the chem. robustness, diagnostic reliability, detection sensitivity, and biomarker selectivity for current and future biosensing devices. - 18Liu, J.; Chen, X.; Wang, Q.; Xiao, M.; Zhong, D.; Sun, W.; Zhang, G.; Zhang, Z. Ultrasensitive Monolayer MoS2 Field-Effect Transistor Based DNA Sensors for Screening of Down Syndrome. Nano Lett. 2019, 19, 1437– 1444, DOI: 10.1021/acs.nanolett.8b03818[ACS Full Text], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVSgtrw%253D&md5=14863eb703d060fa57bf44fd44db9cc2Ultrasensitive Monolayer MoS2 Field-Effect Transistor Based DNA Sensors for Screening of Down SyndromeLiu, Jingxia; Chen, Xihua; Wang, Qinqin; Xiao, Mengmeng; Zhong, Donglai; Sun, Wei; Zhang, Guangyu; Zhang, ZhiyongNano Letters (2019), 19 (3), 1437-1444CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Field-effect transistor (FET) biosensors based on low-dimensional materials present the advantages of low cost, high speed, small size, and excellent compatibility with integrated circuits (ICs). In this work, the authors fabricated highly sensitive FET-based DNA biosensors based on chem. vapor deposition (CVD)-grown monolayer MoS2 films in batches and explored their application in noninvasive prenatal testing (NIPT) for trisomy 21 syndrome. Specifically, MoS2 was functionalized with gold nanoparticles (Au NPs) of an optimized size and at an ideal d., and then, probe DNAs for the specific capture of target DNAs were immobilized on the nanoparticles. The fabricated FET biosensors are able to reliably detect target DNA fragments (chromosome 21 or 13) with a detection limit below 100 aM, a high response up to 240%, and a high specificity, which satisfy the requirement for the screening of Down syndrome. In addn., a real-time test was conducted to show that the biosensor clearly responds to the target DNA at concns. as low as 1 fM. The approach shows the potential for detecting the over-expression of chromosome 21 in the peripheral blood of pregnant women and achieving Down syndrome screening.
- 19Cooper, D. R.; D’Anjou, B.; Ghattamaneni, N.; Harack, B.; Hilke, M.; Horth, A.; Majlis, N.; Massicotte, M.; Vandsburger, L.; Whiteway, E.; Yu, V. Experimental Review of Graphene. ISRN Condens. Matter Phys. 2012, 2012, 501686, DOI: 10.5402/2012/501686
- 20Geim, A. K.; Novoselov, K. S. The Rise of Graphene. Nat. Mater. 2007, 6, 183– 191, DOI: 10.1038/nmat1849[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXit1Khtrg%253D&md5=c2c02ce70a1725e6c559c173156568c5The rise of grapheneGeim, A. K.; Novoselov, K. S.Nature Materials (2007), 6 (3), 183-191CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)A review. Graphene is a rapidly rising star on the horizon of materials science and condensed-matter physics. This strictly two-dimensional material exhibits exceptionally high crystal and electronic quality, and, despite its short history, has already revealed a cornucopia of new physics and potential applications, which are briefly discussed here. Whereas one can be certain of the realness of applications only when com. products appear, graphene no longer requires any further proof of its importance in terms of fundamental physics. Owing to its unusual electronic spectrum, graphene has led to the emergence of a new paradigm of 'relativistic' condensed-matter physics, where quantum relativistic phenomena, some of which are unobservable in high-energy physics, can now be mimicked and tested in table-top expts. More generally, graphene represents a conceptually new class of materials that are only one atom thick, and, on this basis, offers new inroads into low-dimensional physics that has never ceased to surprise and continues to provide a fertile ground for applications.
- 21Lei, Y. M.; Xiao, M. M.; Li, Y. T.; Xu, L.; Zhang, H.; Zhang, Z. Y.; Zhang, G. J. Detection of Heart Failure-Related Biomarker in Whole Blood with Graphene Field Effect Transistor Biosensor. Biosens. Bioelectron. 2017, 91, 1– 7, DOI: 10.1016/j.bios.2016.12.018[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVyitr7K&md5=3681cfe6fa2d5c69780b4a07445dd824Detection of heart failure-related biomarker in whole blood with graphene field effect transistor biosensorLei, Yong-Min; Xiao, Meng-Meng; Li, Yu-Tao; Xu, Li; Zhang, Hong; Zhang, Zhi-Yong; Zhang, Guo-JunBiosensors & Bioelectronics (2017), 91 (), 1-7CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)Since brain natriuretic peptide (BNP) has become internationally recognized biomarkers in the diagnosis and prognosis of heart failure (HF), it is highly desirable to search for a novel sensing tool for detecting the patient's BNP level at the early stage. Here we report a platinum nanoparticles (PtNPs)-decorated reduced graphene oxide (rGO) field effect transistor (FET) biosensor coupled with a microfilter system for label-free and highly sensitive detection of BNP in whole blood. The PtNPs-decorated rGO FET sensor was obtained by drop-casting rGO onto the pre-fabricated FET chip and subsequently assembling PtNPs on the graphene surface. After anti-BNP was bound to the PtNPs surface, BNP was successfully detected by the anti-BNP immobilized FET biosensor. It was found that the developed FET biosensor was able to achieve a low detection limitation of 100 fM. Moreover, BNP was successfully detected in human whole blood sample treated by a custom-made microfilter, suggesting the sensor's capability of working in a complex sample matrix. The developed FET biosensor provides a new sensing platform for protein detection, showing its potential applications in clinic sample.
- 22Zhou, L.; Mao, H.; Wu, C.; Tang, L.; Wu, Z.; Sun, H.; Zhang, H.; Zhou, H.; Jia, C.; Jin, Q.; Chen, X.; Zhao, J. Label-Free Graphene Biosensor Targeting Cancer Molecules Based on Non-Covalent Modification. Biosens. Bioelectron. 2017, 87, 701– 707, DOI: 10.1016/j.bios.2016.09.025[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWiur7I&md5=b4f8d6f7edb119b54d20af2be7f880ecLabel-free graphene biosensor targeting cancer molecules based on non-covalent modificationZhou, Lin; Mao, Hongju; Wu, Chunyan; Tang, Lin; Wu, Zhenhua; Sun, Hao; Zhang, Honglian; Zhou, Hongbo; Jia, Chunping; Jin, Qinghui; Chen, Xianfeng; Zhao, JianlongBiosensors & Bioelectronics (2017), 87 (), 701-707CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)A label-free immunosensor based on antibody-modified graphene field effect transistor (GFET) was presented. Antibodies targeting carcinoembryonic antigen (Anti-CEA) were immobilized to the graphene surface via non-covalent modification. The bifunctional mol., 1-pyrenebutanoic acid succinimidyl ester, which is composed of a pyrene and a reactive succinimide ester group, interacts with graphene non-covalently via p-stacking. The succinimide ester group reacts with the amine group to initiate antibody surface immobilization, which was confirmed by XPS, Atomic Force Microscopy and Electrochem. Impedance Spectroscopy. The resulting anti-CEA modified GFET sufficiently monitored the reaction between CEA protein and anti-CEA in real-time with high specificity, which revealed selective elec. detection of CEA with a limit of detection (LOD) of less than 100 pg/mL. The dissocn. const. between CEA protein and anti-CEA was estd. to be 6.35×10-11 M, indicating the high affinity and sensitivity of anti-CEA-GFET. Taken together, the graphene biosensors provide an effective tool for clin. application and point-of-care medical diagnostics.
- 23Wu, G.; Tang, X.; Meyyappan, M.; Lai, K. W. C. Doping Effects of Surface Functionalization on Graphene with Aromatic Molecule and Organic Solvents. Appl. Surf. Sci. 2017, 425, 713– 721, DOI: 10.1016/j.apsusc.2017.07.048[Crossref], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtF2htrvO&md5=e8135c536719358e2bc5ac3d1a1f0113Doping effects of surface functionalization on graphene with aromatic molecule and organic solventsWu, Guangfu; Tang, Xin; Meyyappan, M.; Lai, King Wai ChiuApplied Surface Science (2017), 425 (), 713-721CODEN: ASUSEE; ISSN:0169-4332. (Elsevier B.V.)Arom. mol. functionalization plays a key role in the development of graphene field-effect transistors (G-FETs) for bio-detection. The authors have investigated the doping effects of surface functionalization and its influence on the carrier mobility of graphene. The arom. mol. (1-pyrenebutanoic acid succinimidyl ester, PBASE), which is widely used as a linker to anchor bio-probes, was employed here to functionalize graphene. DMF and methanol (CH3OH) were used as two solvents to dissolve PBASE. Raman spectra showed that both PBASE and these two solvents imposed doping effects on graphene. The PBASE was stably immobilized on the graphene surface, which was confirmed by the new peak at around 1623.5 cm-1 and the disordered D peak at 1350 cm-1. Elec. measurements and Fermi level shift anal. further revealed that PBASE imposes a p-doping effect while DMF and CH3OH impose an n-doping effect. More importantly, CH3OH causes a smaller redn. in the carrier mobility of G-FETs (from 1095.6 cm2/V s to 802.4 cm2/V s) than DMF (from 1640.4 cm2/V s to 5.0 cm2/V s). Therefore, CH3OH can be regarded as a better solvent for the PBASE functionalization. This careful study on the influence of org. solvents on graphene during PBASE functionalization process provides an effective approach to monitor the surface functionalization of graphene.
- 24Liu, Y.; Yuan, L.; Yang, M.; Zheng, Y.; Li, L.; Gao, L.; Nerngchamnong, N.; Nai, C. T.; Sangeeth, C. S.; Feng, Y. P.; Nijhuis, C. A.; Loh, K. P. Giant Enhancement in Vertical Conductivity of Stacked CVD Graphene Sheets by Self-Assembled Molecular Layers. Nat. Commun. 2014, 5, 5461, DOI: 10.1038/ncomms6461[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVentLc%253D&md5=ae92259a956ee855158d0339ff81430eGiant enhancement in vertical conductivity of stacked CVD graphene sheets by self-assembled molecular layersLiu, Yanpeng; Yuan, Li; Yang, Ming; Zheng, Yi; Li, Linjun; Gao, Libo; Nerngchamnong, Nisachol; Nai, Chang Tai; Sangeeth, C. S. Suchand; Feng, Yuan Ping; Nijhuis, Christian A.; Loh, Kian PingNature Communications (2014), 5 (), 5461CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Layer-by-layer-stacked chem. vapor deposition (CVD) graphene films find applications as transparent and conductive electrodes in solar cells, org. light-emitting diodes and touch panels. Common to lamellar-type systems with anisotropic electron delocalization, the plane-to-plane (vertical) cond. in such systems is several orders lower than its in-plane cond. The poor electronic coupling between the planes is due to the presence of transfer process org. residues and trapped air pocket in wrinkles. Here we show the plane-to-plane tunnelling cond. of stacked CVD graphene layers can be improved significantly by inserting 1-pyrenebutyric acid N-hydroxysuccinimide ester between the graphene layers. The six orders of magnitude increase in plane-to-plane cond. is due to hole doping, orbital hybridization, planarization and the exclusion of polymer residues. Our results highlight the importance of interfacial modification for enhancing the performance of LBL-stacked CVD graphene films, which should be applicable to other types of stacked two-dimensional films.
- 25Liu, J.-Y.; Chang, H.-Y.; Truong, Q. D.; Ling, Y.-C. Synthesis of nitrogen-doped graphene by pyrolysis of ionic-liquid-functionalized graphene. J. Mater. Chem. C 2013, 1, 1713– 1716, DOI: 10.1039/c3tc00191a[Crossref], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitFantLg%253D&md5=7dfbef71f93a607892256d34badc6d4fSynthesis of nitrogen-doped graphene by pyrolysis of ionic-liquid-functionalized grapheneLiu, Jen-Yu; Chang, Hsin-Yun; Truong, Quang Duc; Ling, Yong-ChienJournal of Materials Chemistry C: Materials for Optical and Electronic Devices (2013), 1 (9), 1713-1716CODEN: JMCCCX; ISSN:2050-7534. (Royal Society of Chemistry)Nitrogen-doped graphene with up to 22.1% N/C atom and 7.15 × 104 Sm-1 elec. cond. was synthesized by ionic-liq.-assisted electrolysis with subsequent thermal annealing of the resultant ionic-liq.-functionalized graphene sheet.
- 26Choi, Y.; Kang, J.; Jariwala, D.; Kang, M. S.; Marks, T. J.; Hersam, M. C.; Cho, J. H. Low-Voltage Complementary Electronics from Ion-Gel-Gated Vertical van der Waals Heterostructures. Adv. Mater. 2016, 28, 3742– 3748, DOI: 10.1002/adma.201506450[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1Cju74%253D&md5=da6429347773e8ff06cabb36ec939babLow-Voltage Complementary Electronics from Ion-Gel-Gated Vertical Van der Waals HeterostructuresChoi, Yongsuk; Kang, Junmo; Jariwala, Deep; Kang, Moon Sung; Marks, Tobin J.; Hersam, Mark C.; Cho, Jeong HoAdvanced Materials (Weinheim, Germany) (2016), 28 (19), 3742-3748CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)The ion-gel-gated van der Waals heterojunction VFETs have been demonstrated for both n-type MoS2 and p-type WSe2. By replacing conventional oxides or nitrides with ion-gel gate dielecs., multiple advantages over pre-existing VFET designs have been achieved including: (i) significant redn. in operating voltage without compromising the applied elec. field; (ii) soln. processability at room temp.; (iii) an unconventional coplanar gate geometry with substantial flexibility in device architecture design. The high specific capacitance of the ion-gel dielec. also allows new regimes of charge transport to be accessed such as p-channel phenomena in graphene - MoS2 vertical heterostructures. The net effect is that both n-type and p-type ion-gel-gated VFETs possess desirable device performance including high c.d. (>3000 A cm-2) and on/off ratio (>104) in a narrow voltage window below 3 V. The low operating voltage of these complementary VFETs allows fabrication of an inverter with low power consumption and full rail-to-rail voltage swing. Overall, the scalable and low-temp. deposition of ion-gel gate dielecs. combined with 2D heterostructures holds significant promise for transparent, flexible, and low-voltage nanoelectronics.
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Abstract
Figure 1
Figure 1. Schematic diagram of COVID-19 FET sensor operation procedure. Graphene as a sensing material is selected, and SARS-CoV-2 spike antibody is conjugated onto the graphene sheet via 1-pyrenebutyric acid N-hydroxysuccinimide ester, which is an interfacing molecule as a probe linker.
Figure 2
Figure 2. Surface analysis of pristine and PBASE-modified graphene using Raman spectroscopy, X-ray spectroscopy, and atomic force microscopy. (A) Optical image of the COVID-19 FET sensor. The dimensions were 100 × 100 μm2 (L × W). Scale bar in the image denotes 200 μm. (B) Representative Raman spectra of pristine and PBASE-modified graphene. (C) Comparison of statistical data of the 2D peak position between pristine and PBASE-modified graphene. Mapping images of average I2D/IG ratio (D) before and (E) after PBASE modification. (F) XPS survey data of pristine and PBASE-modified graphene. (G) N 1s peak of pristine and PBASE-treated graphene (shadow region in F). (H) Deconvoluted C 1s peak of PBASE-modified graphene. Atomic force microscopy (AFM) images of (I) pristine graphene (RMS = 0.961) and (J) PBASE-modified graphene (RMS = 1.530). Bottom graphs indicate the height profiles in the corresponding two AFM images. Scale bar in the image denotes 3 μm.
Figure 3
Figure 3. Electrical characterization of pristine, PBASE-modified, and SARS-CoV-2 spike antibody-immobilized graphene. (A) Schematic diagram of the aqueous-solution-gated FET (COVID-19 FET sensor) configuration using the antibody-conjugated graphene. (B) IDS–VDS output curves of the antibody-conjugated FET with various gating voltages from 0 to −1.5 V in steps of −0.3 V. IDS negatively increased as VGS negatively increased. (C) Current–voltage (I–V) characteristics of the graphene-based device of each functionalization process for the antibody modification. (D) Measurement of transfer curves of the COVID-19 FET sensor in steps of the antibody conjugation (VDS = 0.01 V).
Figure 4
Figure 4. Detection of SARS-CoV-2 antigen protein. (A) Schematic diagram for the COVID-19 FET sensor for detection of SARS-CoV-2 spike protein. (B) Real-time response of COVID-19 FET toward SARS-CoV-2 antigen protein in PBS and (C) related dose-dependent response curve (VDS = 0.01 V). Graphene-based FET without SARS-CoV-2 antibody is presented as negative control. (D) Selective response of COVID-19 FET sensor toward target SARS-CoV-2 antigen protein and MERS-CoV protein. (E) Real-time response of COVID-19 FET toward SARS-CoV-2 antigen protein in UTM and (F) related dose-dependent response curve.
Figure 5
Figure 5. Detection of cultured SARS-CoV-2 virus. (A) Schematic diagram for the COVID-19 FET sensor for detection of SARS-CoV-2 cultured virus. (B) Real-time response of COVID-19 FET toward SARS-CoV-2 cultured virus and (C) related dose-dependent response curve.
Figure 6
Figure 6. Detection of SARS-CoV-2 virus from clinical samples. (A) Schematic diagram for the COVID-19 FET sensor for detection of SARS-CoV-2 virus from COVID-19 patients. (B,C) Comparison of response signal between normal samples and patient ones. (D) Real-time response of COVID-19 FET toward SARS-CoV-2 clinical sample and (C) related dose-dependent response curve.
References
ARTICLE SECTIONSThis article references 28 other publications.
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- 10Li, W.; Moore, M. J.; Vasilieva, N.; Sui, J.; Wong, S. K.; Berne, M. A.; Somasundaran, M.; Sullivan, J. L.; Luzuriaga, K.; Greenough, T. C.; Choe, H.; Farzan, M. Angiotensin-Converting Enzyme 2 Is a Functional Receptor for the SARS Coronavirus. Nature 2003, 426, 450– 454, DOI: 10.1038/nature02145[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1GlsLs%253D&md5=884851c53d0f77cbdd6520aaa79efbedAngiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirusLi, Wenhui; Moore, Michael J.; Vasilieva, Natalya; Sui, Jianhua; Wong, Swee Kee; Berne, Michael A.; Somasundaran, Mohan; Sullivan, John L.; Luzuriaga, Katherine; Greenough, Thomas C.; Choe, Hyeryun; Farzan, MichaelNature (London, United Kingdom) (2003), 426 (6965), 450-454CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), assoc. with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a sol. form of ACE2, but not of the related enzyme ACE1, blocked assocn. of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.
- 11Zhou, P.; Yang, X. L.; Wang, X. G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H. R.; Zhu, Y.; Li, B.; Huang, C. L.; Chen, H. D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R. D.; Liu, M. Q.; Chen, Y.; Shen, X. R.; Wang, X.; Zheng, X. S. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579, 270– 273, DOI: 10.1038/s41586-020-2012-7[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXksFKlsLg%253D&md5=236f17d4d3c7978d72513e5e0258f1b3A pneumonia outbreak associated with a new coronavirus of probable bat originZhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-LiNature (London, United Kingdom) (2020), 579 (7798), 270-273CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Abstr.: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large no. of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 Dec. 2019, had caused 2,794 lab.-confirmed infections including 80 deaths by 26 Jan. 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence anal. of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addn., 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.
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- 13Wrapp, D.; Wang, N.; Corbett, K. S.; Goldsmith, J. A.; Hsieh, C. L.; Abiona, O.; Graham, B. S.; McLellan, J. S. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. Science 2020, 367, 1260– 1263, DOI: 10.1126/science.abb2507[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvFemt70%253D&md5=27d08cbb9a43d1da051a8a92a9f68aa5Cryo-EM structure of the 2019-nCoV spike in the prefusion conformationWrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola; Graham, Barney S.; McLellan, Jason S.Science (Washington, DC, United States) (2020), 367 (6483), 1260-1263CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we detd. a 3.5-angstrom-resoln. cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophys. and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Addnl., we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
- 14WHO. Coronavirus Disease (COVID-19) Technical Guidance: Laboratory Testing for 2019-nCoV in Humans. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/laboratory-guidance (accessed 2020-04-15).Google ScholarThere is no corresponding record for this reference.
- 15Bai, Y.; Yao, L.; Wei, T.; Tian, F.; Jin, D. Y.; Chen, L.; Wang, M. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA 2020, 323, 1406– 1407, DOI: 10.1001/jama.2020.2565[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnvVOjtLk%253D&md5=6fa919d2a905953ba2be7b7f539694a1Presumed asymptomatic carrier transmission of COVID-19Bai, Yan; Yao, Lingsheng; Wei, Tao; Tian, Fei; Jin, Dong-Yan; Chen, Lijuan; Wang, MeiyunJAMA, the Journal of the American Medical Association (2020), 323 (14), 1406-1407CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)The authors report the potential person-to-person transmission of SARSCoV-2 from an asymptomatic carrier with normal chest computed tomog. (CT) findings.
- 16Zou, L.; Ruan, F.; Huang, M.; Liang, L.; Huang, H.; Hong, Z.; Yu, J.; Kang, M.; Song, Y.; Xia, J.; Guo, Q.; Song, T.; He, J.; Yen, H. L.; Peiris, M.; Wu, J. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N. Engl. J. Med. 2020, 382, 1177– 1179, DOI: 10.1056/NEJMc2001737[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB387jslCntw%253D%253D&md5=3305835609ec483d1969119366736843SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected PatientsZou Lirong; Liang Lijun; Yu Jianxiang; Kang Min; Song Yingchao; Guo Qianfang; Song Tie; He Jianfeng; Wu Jie; Ruan Feng; Huang Huitao; Huang Mingxing; Hong Zhongsi; Xia Jinyu; Yen Hui-Ling; Peiris MalikThe New England journal of medicine (2020), 382 (12), 1177-1179 ISSN:.There is no expanded citation for this reference.
- 17Janissen, R.; Sahoo, P. K.; Santos, C. A.; da Silva, A. M.; von Zuben, A. A. G.; Souto, D. E. P.; Costa, A. D. T.; Celedon, P.; Zanchin, N. I. T.; Almeida, D. B.; Oliveira, D. S.; Kubota, L. T.; Cesar, C. L.; Souza, A. P.; Cotta, M. A. InP Nanowire Biosensor with Tailored Biofunctionalization: Ultrasensitive and Highly Selective Disease Biomarker Detection. Nano Lett. 2017, 17, 5938– 5949, DOI: 10.1021/acs.nanolett.7b01803[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVKqsLzP&md5=66f17e677fb3cc81638e97109d3a46feInP Nanowire Biosensor with Tailored Biofunctionalization: Ultrasensitive and Highly Selective Disease Biomarker DetectionJanissen, Richard; Sahoo, Prasana K.; Santos, Clelton A.; da Silva, Aldeliane M.; von Zuben, Antonio A. G.; Souto, Denio E. P.; Costa, Alexandre D. T.; Celedon, Paola; Zanchin, Nilson I. T.; Almeida, Diogo B.; Oliveira, Douglas S.; Kubota, Lauro T.; Cesar, Carlos L.; Souza, Anete P. de; Cotta, Monica A.Nano Letters (2017), 17 (10), 5938-5949CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Elec. active field-effect transistors (FET) based biosensors are of paramount importance in life science applications, as they offer direct, fast, and highly sensitive label-free detection capabilities of several biomols. of specific interest. The authors report a detailed study on surface functionalization and covalent immobilization of biomarkers using biocompatible ethanolamine and poly(ethylene glycol) derivate coatings, as compared to the conventional approaches using silica monoliths, to substantially increase both the sensitivity and mol. selectivity of nanowire-based FET biosensor platforms. Quant. fluorescence, at. and Kelvin probe force microscopy allowed detailed study of the homogeneity and d. of immobilized biomarkers on different biofunctionalized surfaces. Significantly enhanced binding specificity, biomarker d., and target biomol. capture efficiency were thus achieved for DNA as well as for proteins from pathogens. This optimized functionalization methodol. was applied to InP nanowires that due to their low surface recombination rates were used as new active transducers for biosensors. The developed devices provide ultrahigh label-free detection sensitivities ∼1 fM for specific DNA sequences, measured via the net change in device elec. resistance. Similar levels of ultrasensitive detection of ∼6 fM were achieved for a Chagas Disease protein marker (IBMP8-1). The developed InP nanowire biosensor provides thus a qualified tool for detection of the chronic infection stage of this disease, leading to improved diagnosis and control of spread. These methodol. developments are expected to substantially enhance the chem. robustness, diagnostic reliability, detection sensitivity, and biomarker selectivity for current and future biosensing devices.
- 18Liu, J.; Chen, X.; Wang, Q.; Xiao, M.; Zhong, D.; Sun, W.; Zhang, G.; Zhang, Z. Ultrasensitive Monolayer MoS2 Field-Effect Transistor Based DNA Sensors for Screening of Down Syndrome. Nano Lett. 2019, 19, 1437– 1444, DOI: 10.1021/acs.nanolett.8b03818[ACS Full Text], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVSgtrw%253D&md5=14863eb703d060fa57bf44fd44db9cc2Ultrasensitive Monolayer MoS2 Field-Effect Transistor Based DNA Sensors for Screening of Down SyndromeLiu, Jingxia; Chen, Xihua; Wang, Qinqin; Xiao, Mengmeng; Zhong, Donglai; Sun, Wei; Zhang, Guangyu; Zhang, ZhiyongNano Letters (2019), 19 (3), 1437-1444CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Field-effect transistor (FET) biosensors based on low-dimensional materials present the advantages of low cost, high speed, small size, and excellent compatibility with integrated circuits (ICs). In this work, the authors fabricated highly sensitive FET-based DNA biosensors based on chem. vapor deposition (CVD)-grown monolayer MoS2 films in batches and explored their application in noninvasive prenatal testing (NIPT) for trisomy 21 syndrome. Specifically, MoS2 was functionalized with gold nanoparticles (Au NPs) of an optimized size and at an ideal d., and then, probe DNAs for the specific capture of target DNAs were immobilized on the nanoparticles. The fabricated FET biosensors are able to reliably detect target DNA fragments (chromosome 21 or 13) with a detection limit below 100 aM, a high response up to 240%, and a high specificity, which satisfy the requirement for the screening of Down syndrome. In addn., a real-time test was conducted to show that the biosensor clearly responds to the target DNA at concns. as low as 1 fM. The approach shows the potential for detecting the over-expression of chromosome 21 in the peripheral blood of pregnant women and achieving Down syndrome screening.
- 19Cooper, D. R.; D’Anjou, B.; Ghattamaneni, N.; Harack, B.; Hilke, M.; Horth, A.; Majlis, N.; Massicotte, M.; Vandsburger, L.; Whiteway, E.; Yu, V. Experimental Review of Graphene. ISRN Condens. Matter Phys. 2012, 2012, 501686, DOI: 10.5402/2012/501686
- 20Geim, A. K.; Novoselov, K. S. The Rise of Graphene. Nat. Mater. 2007, 6, 183– 191, DOI: 10.1038/nmat1849[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXit1Khtrg%253D&md5=c2c02ce70a1725e6c559c173156568c5The rise of grapheneGeim, A. K.; Novoselov, K. S.Nature Materials (2007), 6 (3), 183-191CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)A review. Graphene is a rapidly rising star on the horizon of materials science and condensed-matter physics. This strictly two-dimensional material exhibits exceptionally high crystal and electronic quality, and, despite its short history, has already revealed a cornucopia of new physics and potential applications, which are briefly discussed here. Whereas one can be certain of the realness of applications only when com. products appear, graphene no longer requires any further proof of its importance in terms of fundamental physics. Owing to its unusual electronic spectrum, graphene has led to the emergence of a new paradigm of 'relativistic' condensed-matter physics, where quantum relativistic phenomena, some of which are unobservable in high-energy physics, can now be mimicked and tested in table-top expts. More generally, graphene represents a conceptually new class of materials that are only one atom thick, and, on this basis, offers new inroads into low-dimensional physics that has never ceased to surprise and continues to provide a fertile ground for applications.
- 21Lei, Y. M.; Xiao, M. M.; Li, Y. T.; Xu, L.; Zhang, H.; Zhang, Z. Y.; Zhang, G. J. Detection of Heart Failure-Related Biomarker in Whole Blood with Graphene Field Effect Transistor Biosensor. Biosens. Bioelectron. 2017, 91, 1– 7, DOI: 10.1016/j.bios.2016.12.018[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVyitr7K&md5=3681cfe6fa2d5c69780b4a07445dd824Detection of heart failure-related biomarker in whole blood with graphene field effect transistor biosensorLei, Yong-Min; Xiao, Meng-Meng; Li, Yu-Tao; Xu, Li; Zhang, Hong; Zhang, Zhi-Yong; Zhang, Guo-JunBiosensors & Bioelectronics (2017), 91 (), 1-7CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)Since brain natriuretic peptide (BNP) has become internationally recognized biomarkers in the diagnosis and prognosis of heart failure (HF), it is highly desirable to search for a novel sensing tool for detecting the patient's BNP level at the early stage. Here we report a platinum nanoparticles (PtNPs)-decorated reduced graphene oxide (rGO) field effect transistor (FET) biosensor coupled with a microfilter system for label-free and highly sensitive detection of BNP in whole blood. The PtNPs-decorated rGO FET sensor was obtained by drop-casting rGO onto the pre-fabricated FET chip and subsequently assembling PtNPs on the graphene surface. After anti-BNP was bound to the PtNPs surface, BNP was successfully detected by the anti-BNP immobilized FET biosensor. It was found that the developed FET biosensor was able to achieve a low detection limitation of 100 fM. Moreover, BNP was successfully detected in human whole blood sample treated by a custom-made microfilter, suggesting the sensor's capability of working in a complex sample matrix. The developed FET biosensor provides a new sensing platform for protein detection, showing its potential applications in clinic sample.
- 22Zhou, L.; Mao, H.; Wu, C.; Tang, L.; Wu, Z.; Sun, H.; Zhang, H.; Zhou, H.; Jia, C.; Jin, Q.; Chen, X.; Zhao, J. Label-Free Graphene Biosensor Targeting Cancer Molecules Based on Non-Covalent Modification. Biosens. Bioelectron. 2017, 87, 701– 707, DOI: 10.1016/j.bios.2016.09.025[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWiur7I&md5=b4f8d6f7edb119b54d20af2be7f880ecLabel-free graphene biosensor targeting cancer molecules based on non-covalent modificationZhou, Lin; Mao, Hongju; Wu, Chunyan; Tang, Lin; Wu, Zhenhua; Sun, Hao; Zhang, Honglian; Zhou, Hongbo; Jia, Chunping; Jin, Qinghui; Chen, Xianfeng; Zhao, JianlongBiosensors & Bioelectronics (2017), 87 (), 701-707CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)A label-free immunosensor based on antibody-modified graphene field effect transistor (GFET) was presented. Antibodies targeting carcinoembryonic antigen (Anti-CEA) were immobilized to the graphene surface via non-covalent modification. The bifunctional mol., 1-pyrenebutanoic acid succinimidyl ester, which is composed of a pyrene and a reactive succinimide ester group, interacts with graphene non-covalently via p-stacking. The succinimide ester group reacts with the amine group to initiate antibody surface immobilization, which was confirmed by XPS, Atomic Force Microscopy and Electrochem. Impedance Spectroscopy. The resulting anti-CEA modified GFET sufficiently monitored the reaction between CEA protein and anti-CEA in real-time with high specificity, which revealed selective elec. detection of CEA with a limit of detection (LOD) of less than 100 pg/mL. The dissocn. const. between CEA protein and anti-CEA was estd. to be 6.35×10-11 M, indicating the high affinity and sensitivity of anti-CEA-GFET. Taken together, the graphene biosensors provide an effective tool for clin. application and point-of-care medical diagnostics.
- 23Wu, G.; Tang, X.; Meyyappan, M.; Lai, K. W. C. Doping Effects of Surface Functionalization on Graphene with Aromatic Molecule and Organic Solvents. Appl. Surf. Sci. 2017, 425, 713– 721, DOI: 10.1016/j.apsusc.2017.07.048[Crossref], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtF2htrvO&md5=e8135c536719358e2bc5ac3d1a1f0113Doping effects of surface functionalization on graphene with aromatic molecule and organic solventsWu, Guangfu; Tang, Xin; Meyyappan, M.; Lai, King Wai ChiuApplied Surface Science (2017), 425 (), 713-721CODEN: ASUSEE; ISSN:0169-4332. (Elsevier B.V.)Arom. mol. functionalization plays a key role in the development of graphene field-effect transistors (G-FETs) for bio-detection. The authors have investigated the doping effects of surface functionalization and its influence on the carrier mobility of graphene. The arom. mol. (1-pyrenebutanoic acid succinimidyl ester, PBASE), which is widely used as a linker to anchor bio-probes, was employed here to functionalize graphene. DMF and methanol (CH3OH) were used as two solvents to dissolve PBASE. Raman spectra showed that both PBASE and these two solvents imposed doping effects on graphene. The PBASE was stably immobilized on the graphene surface, which was confirmed by the new peak at around 1623.5 cm-1 and the disordered D peak at 1350 cm-1. Elec. measurements and Fermi level shift anal. further revealed that PBASE imposes a p-doping effect while DMF and CH3OH impose an n-doping effect. More importantly, CH3OH causes a smaller redn. in the carrier mobility of G-FETs (from 1095.6 cm2/V s to 802.4 cm2/V s) than DMF (from 1640.4 cm2/V s to 5.0 cm2/V s). Therefore, CH3OH can be regarded as a better solvent for the PBASE functionalization. This careful study on the influence of org. solvents on graphene during PBASE functionalization process provides an effective approach to monitor the surface functionalization of graphene.
- 24Liu, Y.; Yuan, L.; Yang, M.; Zheng, Y.; Li, L.; Gao, L.; Nerngchamnong, N.; Nai, C. T.; Sangeeth, C. S.; Feng, Y. P.; Nijhuis, C. A.; Loh, K. P. Giant Enhancement in Vertical Conductivity of Stacked CVD Graphene Sheets by Self-Assembled Molecular Layers. Nat. Commun. 2014, 5, 5461, DOI: 10.1038/ncomms6461[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXksVentLc%253D&md5=ae92259a956ee855158d0339ff81430eGiant enhancement in vertical conductivity of stacked CVD graphene sheets by self-assembled molecular layersLiu, Yanpeng; Yuan, Li; Yang, Ming; Zheng, Yi; Li, Linjun; Gao, Libo; Nerngchamnong, Nisachol; Nai, Chang Tai; Sangeeth, C. S. Suchand; Feng, Yuan Ping; Nijhuis, Christian A.; Loh, Kian PingNature Communications (2014), 5 (), 5461CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)Layer-by-layer-stacked chem. vapor deposition (CVD) graphene films find applications as transparent and conductive electrodes in solar cells, org. light-emitting diodes and touch panels. Common to lamellar-type systems with anisotropic electron delocalization, the plane-to-plane (vertical) cond. in such systems is several orders lower than its in-plane cond. The poor electronic coupling between the planes is due to the presence of transfer process org. residues and trapped air pocket in wrinkles. Here we show the plane-to-plane tunnelling cond. of stacked CVD graphene layers can be improved significantly by inserting 1-pyrenebutyric acid N-hydroxysuccinimide ester between the graphene layers. The six orders of magnitude increase in plane-to-plane cond. is due to hole doping, orbital hybridization, planarization and the exclusion of polymer residues. Our results highlight the importance of interfacial modification for enhancing the performance of LBL-stacked CVD graphene films, which should be applicable to other types of stacked two-dimensional films.
- 25Liu, J.-Y.; Chang, H.-Y.; Truong, Q. D.; Ling, Y.-C. Synthesis of nitrogen-doped graphene by pyrolysis of ionic-liquid-functionalized graphene. J. Mater. Chem. C 2013, 1, 1713– 1716, DOI: 10.1039/c3tc00191a[Crossref], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitFantLg%253D&md5=7dfbef71f93a607892256d34badc6d4fSynthesis of nitrogen-doped graphene by pyrolysis of ionic-liquid-functionalized grapheneLiu, Jen-Yu; Chang, Hsin-Yun; Truong, Quang Duc; Ling, Yong-ChienJournal of Materials Chemistry C: Materials for Optical and Electronic Devices (2013), 1 (9), 1713-1716CODEN: JMCCCX; ISSN:2050-7534. (Royal Society of Chemistry)Nitrogen-doped graphene with up to 22.1% N/C atom and 7.15 × 104 Sm-1 elec. cond. was synthesized by ionic-liq.-assisted electrolysis with subsequent thermal annealing of the resultant ionic-liq.-functionalized graphene sheet.
- 26Choi, Y.; Kang, J.; Jariwala, D.; Kang, M. S.; Marks, T. J.; Hersam, M. C.; Cho, J. H. Low-Voltage Complementary Electronics from Ion-Gel-Gated Vertical van der Waals Heterostructures. Adv. Mater. 2016, 28, 3742– 3748, DOI: 10.1002/adma.201506450[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1Cju74%253D&md5=da6429347773e8ff06cabb36ec939babLow-Voltage Complementary Electronics from Ion-Gel-Gated Vertical Van der Waals HeterostructuresChoi, Yongsuk; Kang, Junmo; Jariwala, Deep; Kang, Moon Sung; Marks, Tobin J.; Hersam, Mark C.; Cho, Jeong HoAdvanced Materials (Weinheim, Germany) (2016), 28 (19), 3742-3748CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)The ion-gel-gated van der Waals heterojunction VFETs have been demonstrated for both n-type MoS2 and p-type WSe2. By replacing conventional oxides or nitrides with ion-gel gate dielecs., multiple advantages over pre-existing VFET designs have been achieved including: (i) significant redn. in operating voltage without compromising the applied elec. field; (ii) soln. processability at room temp.; (iii) an unconventional coplanar gate geometry with substantial flexibility in device architecture design. The high specific capacitance of the ion-gel dielec. also allows new regimes of charge transport to be accessed such as p-channel phenomena in graphene - MoS2 vertical heterostructures. The net effect is that both n-type and p-type ion-gel-gated VFETs possess desirable device performance including high c.d. (>3000 A cm-2) and on/off ratio (>104) in a narrow voltage window below 3 V. The low operating voltage of these complementary VFETs allows fabrication of an inverter with low power consumption and full rail-to-rail voltage swing. Overall, the scalable and low-temp. deposition of ion-gel gate dielecs. combined with 2D heterostructures holds significant promise for transparent, flexible, and low-voltage nanoelectronics.
- 27Teng, F.; Hu, K.; Ouyang, W.; Fang, X. Photoelectric Detectors Based on Inorganic p-Type Semiconductor Materials. Adv. Mater. 2018, 30, 1706262, DOI: 10.1002/adma.201706262
- 28Jung, Y. J.; Park, G.-S.; Moon, J. H.; Ku, K.; Beak, S.-H.; Kim, S.; Park, E. C.; Park, D.; Lee, J.-H.; Byeon, C. W.; Lee, J. J.; Maeng, J.-S.; Kim, S. J.; Kim, S. I.; Kim, B.-T.; Lee, M. J.; Kim, H. G. Comparative Analysis of Primer-Probe Sets for the Laboratory Confirmation of SARS-CoV-2. BioRixv https://doi.org/10.1101/2020.02.25.964775 (accessed 2020-04-15).
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ARTICLE SECTIONSThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.0c02823.
Figures of TEM observation of the graphene sheet, ELISA details, clinical sample information on COVID-19 patients, and performance comparison on SARS-CoV-2 detection technologies (PDF)
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