key: cord-0865117-hh7l6s4l
authors: Torrente-Rodríguez, Rebeca M.; Lukas, Heather; Tu, Jiaobing; Min, Jihong; Yang, Yiran; Xu, Changhao; Rossiter, Harry B.; Gao, Wei
title: SARS-CoV-2 RapidPlex: A Graphene-based Multiplexed Telemedicine Platform for Rapid and Low-Cost COVID-19 Diagnosis and Monitoring
date: 2020-10-05
journal: Matter
DOI: 10.1016/j.matt.2020.09.027
sha: 01b02af2aceb8106b43860ca603fa28887f90165
doc_id: 865117
cord_uid: hh7l6s4l

The COVID-19 pandemic is an ongoing global challenge for public health systems. Ultrasensitive and early identification of infection is critical to prevent widespread COVID-19 infection by presymptomatic and asymptomatic individuals, especially in the community and in-home settings. We demonstrate a multiplexed, portable, wireless electrochemical platform for ultra-rapid detection of COVID-19: the SARS-CoV-2 RapidPlex. It detects viral antigen nucleocapsid protein, IgM and IgG antibodies, as well as the inflammatory biomarker C-reactive protein, based on our mass-producible laser-engraved graphene electrodes. We demonstrate ultrasensitive, highly selective, and rapid electrochemical detection in the physiologically relevant ranges. We successfully evaluated the applicability of our SARS-CoV-2 RapidPlex platform with COVID-19 positive and negative blood and saliva samples. Based on this pilot study, our multiplexed immunosensor platform may allow for high frequency at-home testing for COVID-19 telemedicine diagnosis and monitoring.

protein and the outer spike protein. 9, 18 However, it is not possible to differentiate between asymptomatic carriers and immune persons using antibody detection. Therefore, to effectively mitigate the risks of COVID-19 community spread, systems are required that determine simultaneously both the viral and serologic status of an individual. Moreover, recent studies show correlation between circulating inflammatory biomarker concentration and COVID-19 severity. 19 Increased C-reactive protein (CRP) concentration is found in patients diagnosed with COVID-19 pneumonia and is associated with increasing severity, suggesting a role in diagnosis and prognosis of COVID-19 patients. 20, 21 There is a clear and urgent need for a highly sensitive, rapid, inexpensive, telemedicine COVID-19 test that can identify a patient's past and present infection status. 22 There has been progress towards POC COVID-19 testing, but all commercially available test kits provide only qualitative results. Quantitative analysis of COVID-19 biomarkers using a telemedicine device may provide predictive information of disease severity and provide seroconversion information regarding disease time course. Electrochemical biosensors, in this regard, are advantageous due to their rapid detection efficacy and ease of use for POC applications. [23] [24] [25] [26] [27] Simple, safe and effective COVID-19 sample collection has proved challenging given current assay requirements. Saliva-compatible POC assays would be advantageous since saliva contains rich information and can be easily and non-invasively collected by patients themselves for telemedicine testing. 28 Here, we present a novel multiplexed, portable, wireless electrochemical platform for ultrarapid detection of COVID-19: SARS-CoV-2 RapidPlex (Figure 1 ). This platform quantitatively detects biomarkers specific to COVID-19 in both blood and saliva including

As illustrated in Figure 1A , SARS-CoV-2 RapidPlex is composed of four graphene working electrodes (WEs), a Ag/AgCl reference electrode (RE), and a graphene counter electrode (CE), all of them patterned on a polyimide (PI) substrate via CO 2 laser engraving, a fast, high-throughput, and cost-effective production method (Figure 1B and 1C) . Our group has recently demonstrated the use of mesoporous graphene structure fabricated by laser engraving for high performance and low-cost biosensing. 29, 30 The materials cost for the unmodified RapidPlex platform is within $0.05; additional chemical and reagent costs for the multiplexed sensor preparation are at the level of dollars depending on the order sizes.

Detection of selected target proteins (NP and CRP) and specific immunoglobulins (S1-IgG and S1-IgM) is achieved through sandwich-and indirect-based immunosensing strategies onto the LEG electrodes, respectively. The superior properties of graphene, in terms of high charge mobility and surface area together with the high sensitivity and selectivity of sensing strategies involving both capture and detector receptors, make our device ( Figure 1D ) a highly convenient tool for the rapid, accurate, and stage-specific COVID-19 infection detection in blood as well as in non-invasive biofluid samples, such as saliva.

Functionalization and modification steps carried out on the LEG surfaces for the covalent attachment of each of the specific receptors required for the development of our SARS-CoV-2 RapidPlex platform is schematized in Figure 2A . 1-pyrenebutyric acid (PBA) is used as the linker to anchor the required receptors to the graphene layer. Although attachment of functional groups directly on the sp 2 carbon atom surface is one of the common ways to functionalize graphene, these methods are associated with the requirement of defects or edges in the sensor material, which could alter its specific physical properties. 32, 33 In contrast, introduction of functional groups on the sensing layer by means of pyrene derivatives is preferred here as it does not disrupt the conjugation of the graphene sheets and improves its stability. 34, 35 PBA consisting of a pyrene group that contains π-electrons and a carboxylic group is used to functionalize graphene layers via π-stacking and hydrophobic interactions.

The pyrene units of PBA strongly interact with graphene layers in the way that original structure and properties of the graphene are well maintained. The functional moieties contained in each PBA molecule allow the preparation of the affinity-based biosensing platform through the covalent coupling between the carboxylic groups on PBA units and the J o u r n a l P r e -p r o o f -NH 2 groups of the respective capture receptors (specific antibodies or capture proteins).

Blocking of unreacted sites with bovine serum albumin (BSA) impedes the non-specific adsorption of other molecules involved in each assay configuration or circulating in the sample of interest.

Differential pulse voltammetry (DPV) and open circuit potential-electrochemical impedance spectroscopy (OCP-EIS) techniques are employed to electrochemically characterize and prove the stepwise self-assembled processes in both assay configurations for the detection of selected target molecules. DPV readings reflect lower peak current intensity after each modification step related to S1-Ig assay due to the hindered diffusion of the redox label to the electrode surface derived from both the carboxyl groups and the attached proteins and biological macromolecules (Figure 2B ). At the same time, resistance in the Nyquist plots from OCP-EIS is increased after each functionalization step ( Figure 2C ). The successful anchorage of PBA was also verified with scanning electron microscopy (SEM) ( Figure S1 ).

Electrochemical characterization of the sandwich assay-based sensor modification using CRP protein as a model molecule and the aforementioned techniques are presented in Figure S2 .

To preserve the native structure and properties of the bound biomolecules, PBA was chosen as a heterobifunctional linker, effectively preventing the direct interaction between large biomolecules and the graphene surface. 33 In order to verify this selection, CRP and SARS-CoV-2 specific IgG assay configurations were constructed on graphene electrodes functionalized with PBA and another common linker, 1H-pyrrole-1-propionic acid (PPA). 30 Greater signal-to-blank (S/B) ratios were observed for both assays where PBA was used as a linker support (Figure 2D) , mainly due to a significant decrease in the signals obtained in the absence of the corresponding target molecule when PBA was used instead of PPA. Together with an optimal blocking strategy, PBA can be used for the immobilization of specific biomolecular probes (e.g. antibodies, proteins, etc.) while avoiding non-specific adsorptions in the context of immunoassays. 36 The orientation of modified antigenic proteins on solid surfaces is strongly associated with their activity and reactivity. Specific anti-His antibodies can be used to orient the immobilization of antigenic receptors containing histidine residues, but this implies an additional step compared with their direct attachment on the sensing layer, as it is schematized in Figure S3A . Our results show no significant differences in assay performance for IgG detection on PBA-graphene electrodes covalently functionalized with the specific J o u r n a l P r e -p r o o f coating protein (direct immobilization) and with anti-His antibodies for the previous capture of the polyhistidine-tag specific coating protein (oriented immobilization) (Figure S3B ), proving that random protein orientation does not interfere with the epitope accessibility for effective recognition by specific target antibodies. This is in agreement with other reports confirming that His-tagged fusion antigens can be directly immobilized on different surfaces with protein orientations completely compatible with antibody recognition. [37] [38] [39] [40] In order to simplify and reduce the cost and time of the assay, direct immobilization of S1 protein was carried out for specific Ig detection.

Considering that rapid target binding is essential to the successful implementation of our proposed platform as a POC system, we investigated how target (or sample) incubation time affects the response of each biosensor comprising our SARS-CoV-2 RapidPlex platform. Figure 2E summarizes the amperometric signals obtained for each of the four sensing units at different incubation times (1, 5 and 10 minutes) in the absence (blank, B) and in the presence (S) of 500 pg mL -1 , 250 ng mL -1 , and 50 ng mL -1 of NP, SARS-CoV-2 specific IgG and IgM isotypes, and CRP, respectively. It is important to note that although a 10-minute incubation time was selected for most of the studies here in order to ensure the highest sensitivity for the determination of ultra-low levels of each target molecule, a significant difference between the absence and the presence of each of the corresponding targets is obtained with just 1-minute incubation time. This provides one of the major advantages of our SARS-CoV-2 RapidPlex system as a rapid POC device for SARS-CoV-2 infection monitoring with the required sensitivity for both protein and Ig determination. ELISA, 17, [41] [42] [43] [44] nucleic acid amplification, 45-49 mass spectrometry, 50 or even combinations 51 have been increased concentrations of NP, S1-IgG, S1-IgM, and CRP (Figure 3) . The selected strategies for NP viral antigen and CRP proteins are based on double sandwich and sandwich configurations, respectively, as illustrated in Figure 3A . The sandwich-based immunoassays for antigen detection are, in general, highly sensitive due to the involvement of two different antibodies as capture and detector entities. According to the low levels that must be reached for NP and CRP in diluted serum and saliva (pg mL -1 to ng mL -1 ), we think these strategies are the most suitable to be implemented on our platform. Variation of cathodic currents with the concentration for NP and CRP in buffered solutions are presented in Figure 3B and 3C, respectively. S1-IgG and S1-IgM were detected based on indirect immunoassays (Figure 3D ), which are considered highly suitable for detection of circulating macromolecules in antisera and other biofluids. Figure 3E and 3F show the calibration curves for S1 specific Ig determination (S1-IgG and S1-IgM, respectively) in buffered solutions. Reproducibility was demonstrated through the relative standard deviation (RSD) values obtained with different biosensors prepared in the same manner on different days. RSD values of 6.3%, 8.4%, 6.0% and 7.6% for 20 ng mL -1 CRP, 250 ng mL -1 S1-IgG, 250 ng mL -1 S1-IgM and 500 pg mL -1 NP antigen (n=5) demonstrate good reproducibility in both device preparation and signal transduction. In addition, the sensors showed stable responses over a 5-day storage period at 4 °C ( Figure S5) . We did not observe significant slope variations between data obtained in properly diluted human serum and in buffered solutions for the determination of each target analyte (for instance, the slope sensitivity value (16.28 nA mL ng -1 ) obtained for CRP as model analyte in PBS buffered solutions is nearly the same as that in diluted serum samples from a healthy volunteer (16.64 nA mL ng -1 )); therefore, accurate quantification of the proposed target analytes can be carried out by conducting a simple interpolation of the cathodic readings obtained for each sample tested in the corresponding calibration curve constructed in buffered solution.

Since diagnostic sensitivity and specificity of seroprevalence studies can be improved by using a mixture of antigenic proteins instead of a single protein, 52,53 we modified graphene with a mixture of SARS-CoV-2 related antigens, NP and S1, to capture specific immunoglobulin isotypes against both antigens in the same WE. A calibration curve for (NP + S1)-IgG detection is shown in Figure S4 . Thus, this methodology can be tailored for detecting isotype-specific IgG (or IgM) or a combination of both Ig isotypes in the same sensing surface to better capture total Ig concentration and thus increase assay sensitivity across the patient population.

Human biofluids contain a complex and variable mixture of circulating molecules that could interfere with molecular sensing. In addition, negligible crosstalk between different working surfaces is an essential requirement to perform multiplexed detection readings accurately and meaningfully. Therefore, selectivity and crosstalk of the SARS-CoV-2 RapidPlex platform were evaluated. Amperometric readings obtained for each developed biosensor against nontarget molecules are presented in Figure 4A . We evaluated the specific binding for SARS-CoV-2 biomarkers in comparison to biomarkers of similar coronaviruses, including SARS-CoV and MERS-CoV. We observed no significant cross-reaction for NP, S1-IgG, S1-IgM and CRP assays in the presence of each tested interferent, including SARS-CoV-2 S1, SARS-CoV S1, and CRP (for NP assay), SARS-CoV-2 NP-IgG, SARS-CoV IgG, MERS-CoV IgG, S1-IgG, and negative controls containing mixtures of IgG and IgM against both MERS-CoV and SARS-CoV (for S1-IgG and S1-IgM assays), and BNP, NP, SARS-CoV NP and SARS-CoV S1 (for CRP assay), respectively. However, SARS-CoV NP viral antigen interferent provided a cathodic current corresponding to ~80% of the raw current obtained for the detection of the specific NP antigen. Spike, envelope, and membrane SARS-CoV-2 proteins share 76-95% sequence identity with those of SARS-CoV. This percentage homology is reduced to 30-40% for MERS-CoV. Similarly, since SARS-CoV-2 NP is 90% identical to SARS-CoV NP, 17,54-56 the interference observed from SARS-CoV NP antigen was expected.

However, the lack of selectivity in this particular case is not a major concern due to the absence of new SARS-CoV cases detected recently; therefore, it can be inferred that this interference will not produce a barrier for selective SARS-CoV-2 NP determination in real samples. We further evaluated the amperometric-derived concentrations with absorbancederived concentrations collected via ELISA. As it is presented in Figure 4B , the results from our functionalized electrochemical biosensor were linearly correlated (r = 0.955) with the results using the same reagents in a traditional ELISA protocol.

Once the performance and selectivity of each constructed biosensor was individually and exhaustively evaluated, we demonstrate the multiplexing capabilities of our four-workingelectrode (4WEs) graphene array device designed with a Ag/AgCl RE and a graphene CE.

The block diagram showing the functional units that comprise the integrated electronic system is illustrated in Figure 4C and 4D. Amperometric readings from the four channels are concurrently taken and data is wirelessly transmitted to a user device over Bluetooth Low J o u r n a l P r e -p r o o f Energy. The electronic system, including the printed circuit board (PCB) and a lithium-ion polymer battery, is 20 × 35 × 7.3 mm in dimension. The compact device can perform amperometric measurements continuously for over 5 hours in a single charge.

With the objective of demonstrating the utility of our SARS-CoV-2 RapidPlex array for multiplexed and simultaneous quantification of selected target molecules, we evaluated the potential cross-reaction resulting from the diffusion of signal substances between adjacent immunosurfaces. For this, each of the four conveniently functionalized working surfaces were incubated with buffered solutions containing significantly high concentration of each of the selected targets, followed by the corresponding detector receptors in each case. The absence of cross-talk between the adjacent working electrodes is verified from the experimental readings in buffered solutions containing 1.0 ng mL -1 NP antigen (I), 250 ng mL -1 S1 specific IgG (II) and -IgM (III), and 50 ng mL -1 CRP (IV) ( Figure 4E ). As envisaged, significantly higher signal was obtained when each target was specifically captured and further labeled by its tracer antibody in the corresponding functionalized immunosurface. These results, in conjunction with those from Figure 4A demonstrate the feasibility of the developed SARS-CoV-2 RapidPlex platform for fast, selective and reliable determination of NP, S1-IgG and S1-IgM isotypes, and CRP in one single experiment. It should be noted that since IgG and IgM have similar binding mechanisms to viral antigens and individual quantification of Igs require no mixing of the specific detector labels, individual droplets were used on IgG and IgM sensing electrodes during modification and labelling.

To prove the utility of our device in a more complex and real scenario, we evaluated the To further investigate NP, S1-IgG, S1-IgM, and CRP response to SARS-CoV-2 infection using our LEG-based biosensors, each target molecule was measured in serum and saliva samples from RT-PCR confirmed COVID-19 positive and negative subjects. Obtained results were plotted as the ratio between the amperometric readings for each sample tested (S) and the respective blank (B) in each case to compare target detection in different concentration ranges. Using the graphene sensors, a total of 17 COVID-19 RT-PCR tested serum samples (10 positive, 7 negative) were assayed, and a total of 8 COVID-19 RT-PCR tested saliva samples (5 positive, 3 negative) were analyzed (Table S1). Figure 5D and 5E corroborate that, as expected, compared to RT-PCR negative (Table 1) .

To address the increasing demands for effective diagnostic tools for simple COVID-19 detection with immediate sample-to-answer turnaround, we have developed and implemented the first multiplexed electrochemical graphene-based platform, SARS-CoV-2 RapidPlex, for sensitive, rapid and selective simultaneous interrogation of NP viral antigen, S1-IgG and - pandemic. [63] [64] [65] [66] [67] Our platform pioneers multiplexed detection of stage-specific SARS-CoV-2 related biomarkers to provide a detailed and personalized snapshot of the COVID-19 infection. We firmly believe that our developed platform will be a high utility testing method towards fighting this and future pandemics, helping to end one of the deepest global health, economic and humanitarian crises in modern history.

Further information and requests for materials should be directed to and will be fulfilled by the Lead Contact, Wei Gao, weigao@caltech.edu.

The materials generated in this study are available from the corresponding author upon request.

The data used to support the findings of this study are available from the corresponding author upon request. Polyimide film (PI, 125 µm thick) was purchased from DuPont. To characterize the morphology and material properties before and after surface modification with PBA, SEM images of graphene electrodes were obtained by focused ion beam SEM (FIB-SEM, FEI Nova 600 NanoLab).

Amperometry, open circuit potential-electrochemical impedance spectroscopy (OCP-EIS), cyclic voltammetry (CV), and differential pulse voltammetry (DPV) were carried out on a CHI820 electrochemical station. The electrochemical setup comprised laser-induced graphene electrodes (LGEs) as the working electrodes (WEs), a platinum wire as the counter electrode (CE), and a commercial Ag/AgCl electrode as the reference electrode (RE).

For each type of proposed assay, surface modification after each step was electrochemically characterized by DPV and OCP-EIS. Corresponding readings by means of each technique J o u r n a l P r e -p r o o f were carried out in 0.01 M PBS (pH 7.4) containing 2.0 mM of K 4 Fe(CN) 6 /K 3 Fe(CN) 6 (1:1) and under the following detailed conditions: potential range, -0.2 and 0.6 V; pulse width, 0.2 s; incremental potential, 4 mV; amplitude, 50 mV; frequency range, 0.1-106 Hz; amplitude, 5 mV. Graphene functionalization methods were evaluated for both CRP and SARS-CoV-2 specific IgG assays, by comparing current responses obtained after developing each assay on both PBA and PPA-graphene, in the absence and in the presence of each of the corresponding target biomolecules (tested levels were 50 ng mL -1 for CRP and 500 ng mL -1 for SARS-CoV-2 specific IgG). Selectivity study was carried out by incubating corresponding interferential non-target molecules on the previously functionalized PBA-graphene. Concentration levels assayed for each interferent were the same as (or even higher than) the concentration of the target molecule in each case. Amperometric signals obtained for each interferent tested were compared to the current signals obtained in the absence and in the presence of the corresponding target analyte for each type of assay.

The 4 channel chronoamperometric measurements were performed by a custom PCB-based wireless potentiostat. An Arm Cortex-M4 microcontroller (STM32L432KC; STMicroelectronics), and a Bluetooth module (SPBT3.0DP2; STMicroelectronics) were used for potentiostat control and wireless communication. A single operational amplifier (AD8605;

Analog Devices) was used as the control amplifier, and a quad operational amplifier (AD8608; Analog Devices) was used as a four transimpedance amplifier to construct the potentiostat loop. A series voltage reference (ISL60002; Renesas Electronics) and the MCU's built-in digital to analog converter (DAC) were used to generate the voltage bias across the reference and working electrodes. 4 MCU built-in analog-to-digital converter (ADC) channels were used to concurrently acquire the measurements.

In compliance with the protocols approved by the Institutional Review Board (no. 19-089417-292-A2) at the California Institute of Technology (Caltech), the performance of SARS-CoV-2 RapidPlex was evaluated in human serum and saliva samples from healthy and confirmed COVID-19 infected patients. Serum samples from 10 RT-PCR and IgG/IgM serology confirmed COVID-19 patients (age range 24-77 years) and 7 healthy subjects (age range 18-65 years) were purchased from BioIVT and Ray Biotech. The severity information of the BioIVT samples was provided by the phlebotomists during sample collection. Saliva J o u r n a l P r e -p r o o f samples from 5 RT-PCR and IgG/IgM serology test confirmed COVID-19 patients (age range 28-46 years) were purchased from BioIVT. 3 healthy saliva samples were used from preexisting stocks collected from volunteers prior to the pandemic (recommended tips before saliva collection include avoiding foods with high sugar and caffeine content, not eating a major meal within 60 minutes of sample collection, and rinsing the mouth with water prior sample collection). After receiving, serum and saliva samples were stored at -80 ºC until required for its analysis. To perform the analysis of NP, CRP, S1-IgG and S1-IgM, no sample treatment was required for both serum and saliva samples; a simple dilution with 0.01 M PBS containing 1.0% BSA was performed prior to analysis.

Samples NP antigen, CRP, and S1-IgG and S1-IgM isotypes were analyzed in commercial serum and saliva samples from RT-PCR COVID-19 confirmed positive patients (n serum =10; n saliva =5) and healthy subjects (n serum =7; n saliva =3). After 100-and 5X dilution of corresponding serum and saliva samples in PBS with 1.0% BSA, respectively, 10 µL-aliquot was incubated in each WE for 10 minutes at room temperature (25X dilution was used for 1-minute incubation study in serum for Figure 5C ). After washing step with PBS buffer, corresponding detector reagents were incubated in each WE for 5 minutes and subsequent detection was performed.

Comparison of sensor performance in buffer and diluted body fluids from healthy subjects spiked with increasing concentrations of target molecule was performed using CRP as a model molecule. 6 (1:1) after each modification step (S1-IgG assay as representative example): bare graphene (Bare), functionalization with PBA (PBA), immobilization of SARS-CoV-2 S1 protein (Protein), blocking with BSA (BSA), recognition of specific S1-IgG (Target), and incubation with enzyme-tagged anti-human IgG antibody (DAb). (D) Scheme of sensor preparation for detection of S1-IgG and S1-IgM isotypes based on direct assay configurations.

(E) and (F) Calibration curves constructed for S1-IgG (E) and S1-IgM (F) isotypes detection in phosphate-buffered saline (PBS, pH 7.4) supplemented with 1.0% BSA. Data are presented as mean ± SD (n = 3). (A) Selective response of NP, S1-IgG and S1-IgM isotypes and CRP sensors against different non-target circulating analytes. Interferential molecules were tested at 500 pg mL -1 (with an exception of 50 ng mL -1 for CRP), 250 ng mL -1 and 50 ng mL -1 for NP, S1-IgG and S1-IgM, and CRP assays, respectively. Data are presented as mean ± SD (n = 3). supplemented with 1.0% BSA containing 1.0 ng mL -1 NP (I), 250 ng mL -1 S1-IgG (II), 250 ng mL -1 S1-IgM (III) and 50 ng mL -1 CRP (IV).

J o u r n a l P r e -p r o o f (D) A box-and-whisker plot of measured signal-to-blank ratios (S/B) for NP, S1-IgG, S1-IgM, and CRP in RT-PCR confirmed COVID-19 positive (n=5) and negative (n=6) serum samples.

(E) A box-and-whisker plot of measured signal-to-blank ratios (S/B) for NP, S1-IgG, S1-IgM, and CRP in RT-PCR confirmed COVID-19 positive (n=5) and negative (n=3) saliva samples.

(F) CRP levels in diluted serum samples plotted against given COVID-19 symptom severity, with "Healthy" referring to COVID-19 negative patient samples (n=7). Positive COVID-19 patients classified according to disease severity as asymptomatic (n=2), mild (n=5) and moderate (n=2).

J o u r n a l P r e -p r o o f [NP] by ELISA (µg mL -1 )

[NP] by sensor (µg mL -1 )

[CRP] or [S1-IgG] by sensor (µg mL -1 )

[CRP] or [S1-IgG] by ELISA (µg mL -1 ) Blank 500 pg mL -1 SARS-CoV-2 NP Blank 250 ng mL -1 SARS-CoV-2 S1-IgG Blank 250 ng mL -1 SARS-CoV-2 S1-IgM 

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We successfully demonstrated the platform's applicability using COVID-19 positive and negative serum and saliva samples. The SARS-CoV-2 RapidPlex has the potential to quickly and effectively triage patients and track infection progression