Magnetic biosensors

Magnetic biosensors, which employ the magnetic phenomena of magnetic materials to achieve sensitive detections of the analytes, have received surging interests for POC detection applications in the past decades ^{[53], [123], [252]}. Compared with other biosensors, magnetic biosensors have a couple of advantages. Firstly, magnetic biosensors are of low cost and improved detection efficiency due to the elimination of expensive optics components and decreased sample preparation time by utilizing magnetic field ^{[253], [254], [255]}. Besides, magnetic biosensors exhibit high specificity, sensitivity and high signal-to-noise ratio due to the negligible magnetic background signal of biological samples ^{[256], [257], [258]}. After several decades of development, there have been several classes of magnetic biosensors developed, such as giant magnetoresistance (GMR) biosensors, magnetic tunnel junction biosensors, magnetic particle spectroscopy (MPS) biosensors, and the nuclear magnetic resonance biosensors and so on ^{[252], [259]}. Among them, GMR biosensors and MPS biosensors have been widely investigated for POC detection of infectious diseases in the past years.

GMR effect, which was discovered in 1980s, usually happens in a multi-layer structure in which ferromagnetic (FM) and non-magnetic (NM) thin films are deposited alternately ^{[260], [261], [262]}. However, subsequently studies demonstrated that GMR effect could also happen in inhomogeneous media, granular films for example, which expanded the biomedical applications of GMR biosensors ^{[263], [264]}. Moreover, GMR effect can sense very low magnetic fields, making it very attractive for developing magnetic biosensors for highly sensitive POC detection of infectious diseases. For example, Wang at al. established a portable handheld GMR biosensor named Z-Lab for the POC detection of influenza A virus (IAV) ( Fig. 7A) ^[265]. This GMR biosensor displayed high specificity and sensitivity towards IAV nucleoprotein and purified H3N2v with quantitative results in less than 10 min and low detection limits of 15 ng mL⁻¹ and 6.25 × 10⁻³ ng mL⁻¹ for IAV nucleoprotein and purified H3N2v, respectively. However, the detection processes of Z-Lab involved multiple washing and incubating steps, which were time-consuming and tedious, and thus the detection efficiency was limited. To solve this problem, Wang et al. further developed a wash-free magnetic bioassay to integrate with the Z-Lab platform for POC detection of both purified IAV nucleoprotein and IAV in nasal swab samples (Fig. 7B) ^[266]. The wash-free magnetic bioassay greatly simplified the testing process and significantly improved the detection efficiency, which was able to achieve high sensitive detection of purified IAV nucleoprotein and IAV with limits of detection of 0.017 ng mL⁻¹ for IAV nucleoprotein and 1.25 × 10⁻² ng mL⁻¹ for IAV-spiked nasal swab samples. Although GMR biosensors can achieve POC detection of infectious diseases, the fabrication of GMR biosensors is very complex and the test is expensive. The further development of GMR biosensors may focus on their simplification and cost reduction.

(A) Schematic of Z-Lab diagnosis platform and magnetic sandwich assay mechanism. (a) Real-time data can be collected and transmitted to a smartphone, a tablet, a laptop and a desktop computer. (b) The Z-Lab platform consists of a plastic cartridge, an electrical interface connecting the electrodes from GMR chip to the circuit board, and a handheld device. (c) Schematic of the GMR chip. (d) Schematic of the magnetic sandwich assay. (e) Real-time binding curves of targeted binding. Reproduced with permission from Ref. ^[265] Copyright 2017, American Chemical Society. (B) Schematic of a wash-free magnetic bioassay based handheld GMR biosensors for POC detection (a) One-step wash-free magnetic bioassay based on a sandwich assay structure. (b) Photograph of one Z-Lab diagnosis platform. (i) disposable plastic cartridge; (ii) cartridge shell; (iii) Helmholtz coil with ferrite core; (iv) card edge connector; (v) microcontroller; (vi) UART to Bluetooth and USB; (vii) power supply; (viii) current source Helmholtz coil driver. (c) The circuit schematic of Z-Lab. Reproduced with permission from Ref. ^[266] Copyright 2019, Frontiers. (C) Schematic of the MPS biosensor for POC diagnostics (a) Schematic view of MPS system setups. (b) and (c) are the third and the fifth harmonics along varying driving field frequencies (only samples I, VIII, and IX are plotted) collected by the MPS system. (d) Boxplots of the harmonic ratios (R35) collected from samples I, VIII, and IX. Reproduced with permission from Ref. ^[271] Copyright 2020, American Chemical Society.

MPS is a novel flourishingly researched detection method closely related to magnetic particle imaging, which can also be interpreted as a zero-dimensional magnetic particle imaging scanner that conducts spectroscopic studies on superparamagnetic iron oxide nanoparticles (SPIONs) ^{[267], [268]}. In MPS, SPIONs are periodically driven into magnetically saturated regions in a sinusoidal magnetic field with sufficiently large amplitude and produce dynamic magnetic responses, which contain unique higher odd harmonics. Those harmonics are then obtained and extracted by filtering and fast Fourier transform, which contain important information about the SPIONs solution for analysis ^{[269], [270]}. Over the past years, MPS has been extensively explored as a portable, low cost and highly sensitive detection method for various biomedical detection applications, including POC diagnostics of infectious diseases. As a paradigm, a MPS biosensor was investigated for the POC detection of IAV subtype H1N1 nucleoprotein ^[271]. In this biosensing system, the oscillating harmonics of MNPs were measured by MPS, which was a metric of the freedom of rotational process that indicated the bound states of MNPs, and could be readily collected from nanogram quantities of MNPs within 10 s (Fig. 7C). In the presence of H1N1 nucleoprotein, IgG polyclonal antibodies anchored MNPs would specifically bind with H1N1 nucleoprotein molecules and trigger cross-linking between MNPs and H1N1 nucleoprotein, forming MNP self-assemblies. The MPS biosensor was finally demonstrated to be able to achieve rapid, sensitive, and wash-free detection of H1N1 nucleoprotein and the detection limit was as low as 2.49 ng mL⁻¹, which could be further developed into a portable MPS-based device for the POC detection of H1N1 virus ^[271].

Despite the well performances of the above summarized biosensors, there are still many shortcomings of them. The detailed comparisons among them are illustrated in Table 1 . Among the above biosensors, electrochemical biosensors are among the most widely investigated methods and show the most potential for POC diagnostic adaptation due to their high sensitivity, fast response and low cost. However, an electrochemical biosensor always displays weak stability and is susceptible to interference from environment ^{[272], [273], [274]}. Fluorescence biosensors are widely applied for POC detection because of their merits of rapid response and high sensitivity, flexibility and experimental simplicity. However, they are limited by high fluorescence background and limited fluorescence lifetime ^{[275], [276], [277]}. SERS-based biosensors can achieve single molecule detection of targets with high sensitivity, well multiplexing capabilities, no photobleaching and low background, the SERS-based biosensors still displayed limited field of view ^{[177], [178], [278]}. Colorimetric biosensors show the advantages of simplicity and detection by naked eyes without expensive instruments, which is the pioneered and most successful method for POC diagnostic applications, while it is difficult to achieve quantitative detection and the sensitivity is limited ^{[279], [280], [281]}. For a chemiluminescent biosensor, it has advantages of high sensitivity, wide linear dynamic ranges, simple instrumentation and has been widely employed in clinical detection, but it is limited by tedious washing steps, time-consuming, and is enzyme-dependent ^{[87], [282], [283], [284]}. SPR-based biosensors exhibit extreme sensitivity, ability of detection in complex matrices, label-free and real-time detection, distinctive fingerprint capability and ability to achieve high-throughput analysis. However, the SPR equipment is too bulky and expensive ^{[285], [286]}. With the booming development of nanotechnology and microfluidics in recent years, SPR-based biosensors have been attempted to be integrated with various POC devices to provide accurate, rapid, low cost and highly sensitive POC detection. Finally, a magnetic biosensor is able to achieve low cost, high-efficient and high signal-to-noise ratio detection without expensive optics components, there is a shortage of miniaturized magnetic signal readout systems. Thus, fabrication of miniaturized magnetic signal readout systems would contribute greatly to the development of portable devices to integrate with magnetic biosensors for POC detection ^{[123], [258], [259]}. Notwithstanding the merits and shortcomings of those detection methods, how to simplify those methods and adapt them into POC diagnostics for infectious diseases with increased sensitivity, specificity, detection speed and easy-to-use remains a great challenge and the industry is still in its infancy. The fast development of nanotechnology, materials science, microelectronic techniques and microfluidic systems has made the integration of the above detection methods into portable POC devices to achieve specific and low cost POC detection with low sample volumes, increased speed and sensitivity, and ability of multiplex detection possible.

Comparisons of the biosensors for POC diagnostics of infectious diseases.