key: cord-197818-asd39zbj authors: Wu, Kai; Saha, Renata; Su, Diqing; Krishna, Venkatramana D.; Liu, Jinming; Cheeran, Maxim C-J; Wang, Jian-Ping title: Magnetic Immunoassays: A Review of Virus and Pathogen Detection Before and Amidst the Coronavirus Disease-19 (COVID-19) date: 2020-07-09 journal: nan DOI: nan sha: doc_id: 197818 cord_uid: asd39zbj The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is a threat to the global healthcare system and economic security. As of July 2020, no specific drugs or vaccines are yet available for COVID-19, fast and accurate diagnosis for SARS-CoV-2 is essential in slowing down the spread of COVID-19 and for efficient implementation of control and containment strategies. Magnetic immunoassay is a novel and emerging topic representing the frontiers of current biosensing and magnetics areas. The past decade has seen rapid growth in applying magnetic tools for biological and biomedical applications. Recent advances in magnetic materials and nanotechnologies have transformed current diagnostic methods to nanoscale and pushed the detection limit to early stage disease diagnosis. Herein, this review covers the literatures of magnetic immunoassay platforms for virus and pathogen detections, before COVID-19. We reviewed the popular magnetic immunoassay platforms including magnetoresistance (MR) sensors, magnetic particle spectroscopy (MPS), and nuclear magnetic resonance (NMR). Magnetic Point-of-Care (POC) diagnostic kits are also reviewed aiming at developing plug-and-play diagnostics to manage the SARS-CoV-2 outbreak as well as preventing future epidemics. In addition, other platforms that use magnetic materials as auxiliary tools for enhanced pathogen and virus detections are also covered. The goal of this review is to inform the researchers of diagnostic and surveillance platforms for SARS-CoV-2 and their performances. In December 2019, a cluster of severe pneumonia cases of unknown cause was reported in Wuhan, Hubei province, China. [1] A novel strain of coronavirus belonging to the same family of viruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) was subsequently isolated from bronchoalveolar lavage fluid (BALF). [2, 3] The virus was initially named 2019 novel coronavirus (2019-nCoV) and later renamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [4, 5] The outbreak that began in China has rapidly expanded worldwide and on January 30, 2020 the World Health Organization (WHO) declared novel corona virus infection a Public Health Emergency of International Concern and the illness was named coronavirus disease 2019 . COVID-19 was declared as a pandemic by WHO on March 11, 2020 due to its rapid spread in various countries around the world. SARS-CoV-2 is an enveloped, positive-strand RNA virus with large RNA genome of ~30kb with genome characteristics similar to known coronaviruses. [6, 7] The coronavirus genomic RNA encodes replication and transcription complex from a single large open reading frame (ORF1ab) and structural proteins of the virus. [8] The major structural proteins of corona virus are spike (S), envelope (E), membrane (M), and nucleocapsid (N). There is currently no medication to treat COVID-19. Since clinical manifestation of COVID-19 ranges from mild flu-like symptoms to life threatening pneumonia and acute respiratory illness, it is essential to have proper diagnosis during early stage of infection for efficient implementation of control measures to slow down the spread of COVID-19. [9] [10] [11] Currently, real time reverse transcription polymerase chain reaction (RT-PCR) is the most widely used laboratory test for diagnosis of COVID-19. RT-PCR detects SARS-CoV-2 RNA and target different genomic regions of viral RNA. [12] [13] [14] Although RT-PCR is sensitive technique, they require expensive laboratory equipment, trained technicians to perform the test, and can take up to 48 hours to generate results. In addition, studies have found up to 30% false negative rate for RT-PCR early in the course of infection. [15] [16] [17] [18] Several laboratories around the world are working on improving RT-PCR methods and to develop alternative molecular diagnostic platforms. Isothermal nucleic acid amplification that allow rapid amplification of target sequences at a single constant temperature are employed in several tests including ID NOW COVID-19 test from Abbott diagnostics. ID NOW is a rapid, point-of-care test that allow direct detection of viral RNA from the clinical sample without the need for RNA extraction. However, recent studies have found false negative rates ranging from 12-48% mainly due to inappropriate condition of sample transportation and inappropriate sample. [19] [20] [21] Moreover, this can test only one sample per run. Serological methods like enzyme-linked immunosorbent assay (ELISA) and lateral flow immunochromatography test that detect antibodies can be used to monitor immunity to infection and disease progression. [22] Although negative SARS-CoV-2 antibody results does not rule out COVID-19, serological assays will help in assessing previous exposure to SARS-CoV-2 in a population and therefore have a potential use in understanding the epidemiology of COVID-19. Currently available serological assays can detect IgM, IgG, or IgA antibodies to spike (S) or nucleocapsid (N) protein. [23] [24] [25] However, potential cross reactivity of SARS-CoV-2 antibodies with antibodies generated against other coronaviruses is a challenge in developing accurate serological test for COVID-19. [26] Among other biosensing technologies, magnetic biosensors have attracted special attention in the past 20 years. Both surface-based and volume-based magnetic biosensors have been developed for the detection of viruses, pathogens, cancer biomarkers, metallic ions, etc. [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] In magnetic biosensors, the magnetic tags (usually magnetic nanoparticles (MNPs)) are functionalized with antibodies or DNA/RNA probes that can specifically bind to target analytes. The concentration of the target analytes is thus converted to the magnetic signals that are generated by these magnetic tags. Compared to optical, plasmonic, and electrochemical biosensors, magnetic biosensors exhibit low background noise since most of the biological environment is non-magnetic. The sensor signal is also less influenced by the types of the sample matrix, enabling accurate and reliable detection processes. [37] The number of published papers on magnetic biosensors is summarized in Figure 1 , which indicates an increasing scientific interest on this topic. Most magnetic biosensors fall into several categories, namely magnetoresistance (MR) sensors, magnetic particle spectroscopy (MPS) platforms, and nuclear magnetic resonance (NMR) platforms. MR sensors are surface-based technologies which are sensitive to the stray field from the MNPs bound to the proximity of the sensor surface. The MR-based magnetic immunoassays are reviewed in Section 2, this kind of assay scheme is achieved by converting the binding events of MNPs (due to the presence of target analytes) to readable electric signals. On the contrary, MPS platforms (reviewed in Section 3) directly detect the dynamic magnetic responses of MNPs and thus, MNPs are the only signal sources and indicators for probing target analytes from non-magnetic mediums. NMR platforms (reviewed in Section 4) are using MNPs as contrast enhancers to introduce local magnetic field inhomogeneity and to disturb the precession frequency variations in millions of surrounding water protons. Thus, the high sensitivity NMR-based immunoassays intrinsically benefit from the MNP contrast agents. In addition, other immunoassay platforms that use magnetic materials as auxiliary tools to enhance the detection performances are also reviewed in Section 5. In this review, magnetic biosensors' application in virus and pathogen detection will be summarized and discussed based on the different working principle of the technologies. Magnetoresistance (MR) was at first discovered by William Thompson who coined the term anisotropic magnetoresistance (AMR). [38] The physical observation of AMR shows that the resistivities of both Ni and Fe increase when the charge current is applied parallel to the magnetization and decrease when charge current is applied perpendicular to the magnetization. [39] This AMR effect originates from the spin orbit interactions and was experimentally and quantitatively demonstrated by Fert and Campbell. [40] However, the maximum resistance change recorded from AMR devices is only around 2 %, which renders it unsuitable for most applications. Regarding this, a detailed review of the AMR effect in thin films and bulk materials can be found in Ref. [39] . Herein, the AMR biosensors will not be discussed due to their limited applications in magnetic biosensing. Giant magnetoresistance (GMR) was at first observed from the Fe/Cr multilayers grown with molecular beam epitaxy (MBE) by Albert Fert and Peter Grunberg. [41, 42] These multilayers exhibit a resistance change significantly higher than the AMR devices. The GMR effect primarily exists in multilayer structures with alternating ferromagnetic and non-magnetic metallic layers. When the magnetizations of two adjacent ferromagnetic layers are parallel, the multilayers show low resistance and when magnetizations are anti-parallel, multilayers exhibit a high-resistance state. The industrial breakthrough for GMR discovery was made when Parkin et al. observed the GMR effect from DC sputtered multilayer structures. [43] Although the GMR effect was primarily observed in a thin film or layered system (see Figure 2 (A)), it is also observed in other systems such as Co-Au, Co-Ag and Fe-Ag granular films. [44] [45] [46] [47] [48] GMR effect in granular films (see Figure 2 (B)) is highly related to the spin dependent interfacial scattering, inter-particle coupling, and several are significant for biosensing purposes because of their capability to adapt to the shapes of different biomolecules. [49, 50] In comparison to other types of sensors, the ability of flexible GMR sensors to respond to external magnetic field makes them a perfect candidate for wearable real-time body activity monitoring and evaluating drug delivery effectiveness. As no experimental demonstration on flexible MR-based detection of viruses/pathogens has been reported, further discussion on flexible GMR-based bio-detection is restricted in the subsequent sections. Magnetic tunnel junctions (MTJs) have similar stack structure (see Figure 2 (C)) to that of the GMR spin valves except that the adjacent ferromagnetic layers are separated by an insulating layer which is usually an oxide. In the earlier days, AlOx was used [51, 52] . Later, this insulating layer was replaced by MgO material for smaller lattice mismatch and interface instability and thus, higher tunnel magnetoresistance (TMR) ratio [53, 54] . The most important characteristic of a MTJ structure is its transfer curve as shown in Figure 2 (D). In the transfer curve, two characteristics are of utmost importance: MR ratio and sensitivity. The physical characterization of the MR ratio is the rate of change in MR deice resistance along with varying magnetic field. Its sensitivity is measured by the slope of the transfer curve at an intensity of the magnetic field. In this regard, an interesting point to note is the tradeoff between the sensitivity and the linear magnetic field response range for MR sensors. A large linear response range in the transfer curve is attained with great ease in GMR sensors, although this comes with a compromise on the sensitivity. On the other hand, even though MTJ sensors possess high sensitivity, additional stack designs or supporting parts such as bias magnets are required to achieve high linearity. [55] [56] [57] Another factor which comes into play for all sensors in the nanoscale is the signal-to-noise ratio (SNR). Generally, MTJs show higher SNR than GMR sensors. However, the shot noise from the discontinuities in the conduction medium can cause the SNRs of MTJs to suffer. [58] With the advancing of thin film deposition and nanofabrication technologies, the TMR ratio has been increased dramatically during the past 20 years from ~20% to over 200%. [53, [59] [60] [61] Since Baselt et al. reported the first GMR-based biosensor using the Bead Array Counter (BARC) microarray, GMR-based biosensing has been attracting increasing attentions amongst the community. [62] This section reviews the GMR biosensors for detecting viruses and pathogens, and compares their limit of detections (LODs) and advantages over the existing biosensing tools. Take the sandwich immunoassay as an example (see Figure 3 (A)), where the capture antibodies specifically targeting on analytes (such as antigens from viruses/pathogens) are pre-functionalized on the GMR sensor surface. Then biofluid samples are added and specific antibody-antigen bindings take place on the sensor surface. Usually a wash step is added to remove the unbound analytes from sensing areas. Then the detection antibody functionalized MNPs are added to the GMR sensing areas, forming the MNPdetection antibodyantigencapture antibody complexes. Thus, the amount of MNPs captured to the proximity of sensor surface is directly proportional to the number of antigens in the testing sample. reported the detection of Mycobacterium tuberculosis specific antigen -ESAT-6 using the GMR scheme and reported a LOD of 1 pM. [69] The key take-away point here is that several experimental demonstrations of the magnetic assays for virus detection based on GMRs and the reported LOD indicate that GMR-based bioassay is one of the promising candidates for onsite, rapid, and sensitive detection of COVID-19. reprinted from [65] , Copyright (2016) Elsevier. The first ever proof-of-concept MTJ as biosensor was reported by Grancharov et al. in 2005. [70] They demonstrated a unique method for antigen and DNA detection at room temperature using monodispersed manganese ferrite nanoparticles as the magnetic tags. Since then, there have been several attempts to employ MTJs as biosensors. [61, [71] [72] [73] However, most of their attempts were limited to genotyping applications of TMR antigen p24 by MTJ sensors with an assay time of less than 10 mins and a LOD in the orders of 0.01 µg/mL. [75] With improved circuitry design and the ease of nanofabrication, there is a trend to use MTJ sensors for immunoassays. Gervasoni et al. used a 12-channel dual lock-in platform to improve the circuitry for the signal generation and acquisition in their MTJ sensing system (see Figure 4 (E)) [73] By customizing the differential amplifier, low-noise voltage references, and detailed analysis of temperature fluctuation within the system, they achieved a sub-ppm resolution of the lock-in amplifier and an order of magnitude better than commercial stateof-the-art instrument. However, there are several disadvantages of MTJs as biosensors compared to GMR sensors. The requirement for top electrodes increases the distance between the MNPs bound to the surface and the free layer of the MTJ sensor. As the stray fields of the MNPs decay rapidly with the increase of the distance, the sensitivity of the MTJ sensors is often sacrificed despite their high TMR ratio. Furthermore, the difficulty to achieve high linearity and low coercivity also remains a challenge for MTJs. More dedicate design of the stack structure and the fabrication process are needed to take full advantage of the high signal level induced by the large TMR ratio. Magnetic sinusoidal magnetic field with frequency f is applied and higher odd harmonics at 3f (the 3 rd harmonic), 5f (the 5 th harmonic), 7f (the 7 th harmonic), … are observed due to the nonlinear magnetic responses of MNPs. [86, 87, 91] On the other hand, in a dual-frequency MPS platform, two sinusoidal magnetic fields with frequencies fH and fL are applied. The low frequency field fL periodically magnetizes MNPs while the high frequency field fH modulates these higher odd harmonics to high frequency range. Thus, higher odd harmonics at fH ±2fL (the 3 rd harmonics), fH ±4fL (the 5 th harmonics), fH ±6fL (the 7 th harmonics), … are observed. [88, 90, [92] [93] [94] [95] Although different in excitation modes, the detection mechanisms of periodically magnetize the MNPs and the extraction of higher odd harmonics as a result of nonlinear magnetic responses are identical. Table 1 . Orlov The authors successfully combined MPS method with lateral flow method. By conjugating different capture antibodies onto different locations of a test strip, a multiplexed assay platform is achieved. By replacing the optical labels with MNPs, the measurements can analyze media regardless of the optical properties, offering sensitivity on the level of lab-based quantitative methods. Orlov et al. reported the application of MPS platform for detection of toxins produced by Staphylococcus aureus. [77] Due to the high stability and increasing resistance to antibacterial medications of these bacteria, the toxins are widely present in the environment and are frequently responsible for diverse fatal illnesses such as severe gastrointestinal diseases and toxic shock. In their work, they introduced a novel magnetic immunoassay on 3D fiber solid phase (see Figure 7 (D)) that fits into a standard automatic pipet tip, as shown in Figure 7 (A). The 3D porous filter surfaces are immobilized with capture antibodies specific to a definite toxin. These as- This point-of-care (POC) testing device allows for identifying people with immunity against SARS-CoV-2. Wu et al. reported the volume-based MPS immunoassay platform utilizing the polyclonal antibodies induced cross-linking of MNPs for one-step, wash-free detection of H1N1 nucleoprotein molecules. [78] In their work, the MNPs are anchored with polyclonal IgG antibodies specific to H1N1 nucleoprotein. The H1N1 nucleoprotein molecule hosts multiple epitopes that serve as binding sites for IgG polyclonal antibodies. Thus, each nucleoprotein can bind to more than one MNPs, consequently assembling into MNP clusters. As shown in Figure 8 This one-step, wash-free, volume-based MPS detection scheme allows for immunoassays on minimally processed biological samples and handled by non-technicians with minimum training requirements. Since the magnetic signals come for the whole volume of MNP suspension thus, removing the unbound MNPs from the sample could ensure higher detection sensitivity for this type of volume-based assay mode. Nuclear magnetic resonance (NMR) detects the MNP-labeled targets by measuring the precessional signal of 1 H proton from the whole sample volume. In this way, the NMR platform is categorized as one type of volume-based immunoassay methods. Note: NMR-based immunoassay platform is also called magnetic relaxation switching (MRS). As shown in Figure 9 (A), due to the high surface-to-volume ratio of MNPs, the local magnetic field inhomogeneity caused by MNP disturbs the precession frequency variations in millions of surrounding water protons, which accelerates the decay of the spin system's phase coherence. In addition, the NMR-based detection intrinsically benefits from signal amplification and is able to achieve high detection sensitivity. As the mono dispersed MNPs aggregates upon binding to targets, the self-assembled clusters become more efficient in dephasing the nuclear spins of surrounding water protons, resulting in decreased T2 relaxation time. The reverse is also true upon the cluster disassembly. Figure 9 (B) shows the steps of NMR-based immunoassay with MNPpathogen interaction, magnetic separation, and filtration. As is mentioned in Section 3.3, for volume-based biosensing platforms, the filtration step could effectively reduce the interference of unbound MNPs. The magnetic separation and filtration are not necessary but favored for high sensitivity immunoassays. Issadore et al. reported a miniaturized NMR platform for point-of-care (POC) diagnostics. [106] A photograph and the schematic of the portable NMR platform are shown in Figure 9 (C) & (D). The portable magnet, microcoil, and RF (radio frequency) matching circuit are packaged into a thermally insulating PMMA (polymethylmethacrylate) housing. The custom electronics provides the NMR pulse sequences, collects the NMR signal, and communicates with external terminals. Samples are loaded into thin-wall polyimide tubes and introduced into the coil bore for NMR measurements. The modular coils can be plugged into the system to optimally accommodate sample volumes from 1 mL to 100 mL. This portable NMR platform with automatic measurement setting tuning provides users with easy-to-use interface and offers sensitive on-site diagnosis. With these capabilities, it is expected that NMR handheld device can be an essential tool for personal care and accurate diagnostics for infectious diseases in resource-limited areas, mitigating the burden in public health. Recent advances in micro-and nanofabrication has accelerated the development of portable NMR devices. Luo et al. reported the detection of foodborne bacteria Escherichia coli O157:H7 from drinking water and milk samples using a portable NMR platform. [80] The NMR system is able to generate 0.47 T of magnetic field and a high-power pulsed RF transmitter with ultra-low noise sensing circuitry capable of detecting weak NMR signal at 0.1 μV. In their work, the bacteria are labeled with MNPs through the antibody-pathogen interactions. A 20 -30 min filtration step is carried out and followed by 1 min of NMR signal collection. Liong et al. reported the detection of nucleic acids based on a magnetic barcoding strategy. [81] Where the PCR-amplified mycobacterial genes are sequence-specifically captured on microspheres, labeled by MNPs, and detected by NMR. All the components and steps are integrated into a single, small fluidic cartridge for streamlined on-chip assays. As shown in Figure 10 In most magnetic immunoassay platforms, MNPs are used as labels (e.g., MR sensors and MPS platforms) or contrast enhancers (e.g., NMR platforms) due to the unique magnetic properties, large surface-to-volume ratio, good stability and biocompatibility, and the facile surface functionalization with a great variety of reagents. In addition to the above technologies, other platforms that utilize MNPs as auxiliary tools for virus and pathogen detections have also been extensively reported. In this section, we reviewed some representative works that use magnetic materials are auxiliary tools for high sensitivity virus and pathogen detections, as summarized in Table 3 . To sum it all up, in the midst of COVID-19 pandemic, the demands for high sensitivity, low cost, rapid, easy-touse, and reliable disease testing tools are increasing. Current diagnostic tests for COVID-19 are based on real time RT-PCR (rRT-PCR) assays. Although it is sensitive, PCR requires expensive equipment, trained technicians to perform the test and have long turnaround times. In addition, its availability is impeded by a shortage in supply during the current emergency. As of July 2020, there is no effective vaccine to prevent the spread of COVID-19. As the globe is searching for effective cures for COVID-19, actions are also being taken to search for better and faster diagnosis tools for timely diagnosis, management, and control the COVID-19. We reviewed the magnetic immunoassay literatures prior to COVID-19 and highlighted some promising tools for detecting pathogens as well as viruses with high specificity and sensitivity. All the detection platforms reviewed in this paper can be extended to other microbial or viral organisms with a change in the specificity of the reagents on MNPs. It is expected that the magnetic immunoassay platforms will transform today's expensive and labor-intensive diagnostic techniques into a user-friendly and cost-effective detection protocol with superior or comparable sensitivity. This paradigm shift could contribute to better surveillance and control of SARS-CoV-2 infection in populations. In addition, this review paper focuses on magnetic immunoassay platforms for pathogen and virus detections and different detection tools are reported and categorized by different technologies. However, detection platforms can also be categorized by the target biomarkers such as nucleic acid testing and protein testing (protein antigens and antibodies). Other non-magnetic diagnostic tools such as computed tomography (CT) scans and nucleic acid analysis are prevalently used for diagnosing and screening COVID-19. [120] [121] [122] [123] [124] In the end, however, a very basic question still lingers in our mind: where are these nanobiosensors when the world is fighting a global health pandemic? Why aren't they being put to commercialization? This can be answered from several point-of-views. From technical view, an ideal biosensor should meet most or all of the following requirements: high sensitivity, high selectivity, quick response time, multiplexing capabilities, multiple sensing modes, disposable, long shelf life and easy-to-use. Pros and cons for the magnetic biosensors given in Table 2 clearly indicate that all technologies lack something or the other from technical point of view. 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This study was financially supported by the Institute of Engineering in Medicine, the University of Minnesota Rapid Response Grant.