Giant Magnetoresistive Biosensors Research Articles

Giant Magnetoresistance Based Biosensors for Cancer Screening and Detection.

Early-stage screening of cancer is critical in preventing its development and therefore can improve the prognosis of the disease. One accurate and effective method of cancer screening is using high sensitivity biosensors to detect optically, chemically, or magnetically labeled cancer biomarkers. Among a wide range of biosensors, giant magnetoresistance (GMR) based devices offer high sensitivity, low background noise, robustness, and low cost. With state-of-the-art micro- and nanofabrication techniques, tens to hundreds of independently working GMR biosensors can be integrated into fingernail-sized chips for the simultaneous detection of multiple cancer biomarkers (i.e., multiplexed assay). Meanwhile, the miniaturization of GMR chips makes them able to be integrated into point-of-care (POC) devices. In this review, we first introduce three types of GMR biosensors in terms of their structures and physics, followed by a discussion on fabrication techniques for those sensors. In order to achieve target cancer biomarker detection, the GMR biosensor surface needs to be subjected to biological decoration. Thus, commonly used methods for surface functionalization are also reviewed. The robustness of GMR-based biosensors in cancer detection has been demonstrated by multiple research groups worldwide and we review some representative examples. At the end of this review, the challenges and future development prospects of GMR biosensor platforms are commented on. With all their benefits and opportunities, it can be foreseen that GMR biosensor platforms will transition from a promising candidate to a robust product for cancer screening in the near future.

Rapid, Point-of-Care Host-Based Gene Expression Diagnostics Using Giant Magnetoresistive Biosensors.

Host-based gene expression analysis is a promising tool for a broad range of clinical applications, including rapid infectious disease diagnostics and real-time disease monitoring. However, the complex instrumentation requirements and slow turnaround-times associated with traditional gene expression analysis methods have hampered their widespread adoption at the point-of-care (POC). To overcome these challenges, we have developed an automated and portable platform that utilizes polymerase chain reaction (PCR) and giant magnetoresistive (GMR) biosensors to perform rapid multiplexed, targeted gene expression analysis at the POC. As proof-of-concept, we utilized our platform to amplify and measure the expression of four genes (HERC5, HERC6, IFI27, and IFIH1) that were previously shown to be upregulated in hosts infected with influenza viruses. The compact instrument conducted highly automated PCR amplification and GMR detection to measure the expression of the four genes in multiplex, then utilized Bluetooth communication to relay results to users on a smartphone application. To validate the platform, we tested 20 cDNA samples from symptomatic patients that had been previously diagnosed as either influenza-positive or influenza-negative using a RT-PCR virology panel. A non-parametric Mann-Whitney test revealed that day 0 (day of symptom onset) gene expression was significantly different between the two groups (p < 0.0001, n = 20). Hence, we preliminarily demonstrated that our platform could accurately discriminate between symptomatic influenza and non-influenza populations based on host gene expression in ∼30 min. This study not only establishes the potential clinical utility of our proposed assay and device for influenza diagnostics but it also paves the way for broadscale and decentralized implementation of host-based gene expression diagnostics at the POC.

Real-time temperature correction for magnetoresistive biosensors integrated with temperature modulator

Magnetoresistance-based biosensors utilize changes in electrical resistance upon varying magnetic fields to measure biological molecules or events involved with magnetic tags. However, electrical resistance fluctuates with temperature. To decouple unwanted temperature-dependent signals from the signal of interest, various methods have been proposed to correct signals from magnetoresistance-based biosensors. Yet, there is still a need for a temperature correction method capable of instantaneously correcting signals from all sensors in an array, as multiple biomarkers need to be detected simultaneously with a group of sensors in a central laboratory or point-of-care setting. Here we report a giant magnetoresistive biosensor system that enables real-time temperature correction for individual sensors using temperature correction coefficients obtained through a temperature sweep generated by an integrated temperature modulator. The algorithm with individual temperature correction coefficients obviously outperformed that using the average temperature correction coefficient. Further, temperature regulation did not eliminate temperature-dependent signals completely. To demonstrate that the method can be used in biomedical applications where large temperature variations are involved, binding kinetics experiments and melting curve analysis were conducted with the temperature correction method. The method successfully removed all temperature-dependent artifacts and thus produced more precise kinetic parameters and melting temperatures of DNA hybrids.

Point-of-Care Testing of Enzyme Polymorphisms for Predicting Hypnotizability and Postoperative Pain

Hypnotizability is a stable trait that moderates the benefit of hypnosis for treating pain, but limited availability of hypnotizability testing deters widespread use of hypnosis. Inexpensive genotyping of four single-nucleotide polymorphisms in the catechol-o-methyltransferase (COMT) gene was performed using giant magnetoresistive biosensors to determine if hypnotizable individuals can be identified for targeted hypnosis referrals. For individuals with the proposed optimal COMT diplotypes, 89.5% score highly on the Hypnotic Induction Profile (odds ratio,6.12; 95% CI,1.26-28.75), which identified 40.5% of the treatable population. Mean hypnotizability scores of the optimal group were significantly higher than the total population (P=0.015; effect size=0.60), an effect that was present in women (P=0.0015; effect size=0.83), but not in men (P=0.28). In an exploratory cohort, optimal individuals also reported significantly higher postoperative pain scores (P=0.00030; effect size=1.93), indicating a greater need for treatment.

Giant Magnetoresistance Biosensors for Food Safety Applications.

Nowadays, the increasing number of foodborne disease outbreaks around the globe has aroused the wide attention of the food industry and regulators. During food production, processing, storage, and transportation, microorganisms may grow and secrete toxins as well as other harmful substances. These kinds of food contamination from microbiological and chemical sources can seriously endanger human health. The traditional detection methods such as cell culture and colony counting cannot meet the requirements of rapid detection due to some intrinsic shortcomings, such as being time-consuming, laborious, and requiring expensive instrumentation or a central laboratory. In the past decade, efforts have been made to develop rapid, sensitive, and easy-to-use detection platforms for on-site food safety regulation. Herein, we review one type of promising biosensing platform that may revolutionize the current food surveillance approaches, the giant magnetoresistance (GMR) biosensors. Benefiting from the advances of nanotechnology, hundreds to thousands of GMR biosensors can be integrated into a fingernail-sized area, allowing the higher throughput screening of food samples at a lower cost. In addition, combined with on-chip microfluidic channels and filtration function, this type of GMR biosensing system can be fully automatic, and less operator training is required. Furthermore, the compact-sized GMR biosensor platforms could be further extended to related food contamination and the field screening of other pathogen targets.

Magnetic supercluster particles for highly sensitive magnetic biosensing of proteins.

A strategy is reported to improve the detection limits of current giant magnetoresistance (GMR) biosensors by augmenting the effective magnetic moment that the magnetic tags on the biosensors can exert. Magnetic supercluster particles (MSPs), each of which consists of ~ 1000 superparamagnetic cores, are prepared by a wet-chemical technique and are utilized to improve the limit of detection of GMR biosensors down to 17.6 zmol for biotin as a target molecule. This value is more than four orders of magnitude lower than that of the conventional colorimetric assay performed using the same set of reagents except for the signal transducer. The applicability of MSPs in immunoassay is further demonstrated by simultaneously detecting vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) in a duplex assay format. MSPs outperform commercially available magnetic nanoparticles in terms of signal intensity and detection limit.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00604-022-05354-x.

Giant Magnetoresistance Biosensors in Biomedical Applications.

The giant magnetoresistance (GMR) effect has seen flourishing development from theory to application in the last three decades since its discovery in 1988. Nowadays, commercial devices based on the GMR effect, such as hard-disk drives, biosensors, magnetic field sensors, microelectromechanical systems (MEMS), etc., are available in the market, by virtue of the advances in state-of-the-art thin-film deposition and micro- and nanofabrication techniques. Different types of GMR biosensor arrays with superior sensitivity and robustness are available at a lower cost for a wide variety of biomedical applications. In this paper, we review the recent advances in GMR-based biomedical applications including disease diagnosis, genotyping, food and drug regulation, brain and cardiac mapping, etc. The GMR magnetic multilayer structure, spin valve, and magnetic granular structure, as well as fundamental theories of the GMR effect, are introduced at first. The emerging topic of flexible GMR for wearable biosensing is also included. Different GMR pattern designs, sensor surface functionalization, bioassay strategies, and on-chip accessories for improved GMR performances are reviewed. It is foreseen that combined with the state-of-the-art complementary metal-oxide-semiconductor (CMOS) electronics, GMR biosensors hold great promise in biomedicine, particularly for point-of-care (POC) disease diagnosis and wearable devices for real-time health monitoring.

An automated and mobile magnetoresistive biosensor system for early hepatocellular carcinoma diagnosis

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most patients, however, are not diagnosed until advanced stage because early HCC lesions generally cause no overt symptoms, and the presence of cirrhosis adds another layer of complexity. While early diagnosis enables more therapeutic options and greatly improves survival rates, it is difficult to achieve. In order to detect early stage HCC, high-risk patients need to frequently measure serum biomarkers such as alpha-fetoprotein (AFP), and gold standards for detection involve less accessible and costly tests. In this work, we present an automated and mobile magnetoresistive biosensor system that allows quick, easy, and accurate detection of a panel of HCC related biomarkers. We first discuss the underlying principles of the giant magnetoresistive (GMR) biosensor system and its unique advantages in early detection of HCC. We also describe the development of hardware, software, and the bioassay, and demonstrate that it can perform an automated assay in 28 min, providing both qualitative and quantitative results. The user only needs to manually add sample into a disposable cartridge and press a button on the smartphone app, without the need for direct interaction with reagent liquids, or lab skills such as pipetting. With its portability, high sensitivity, and ease-of-use, the presented biosensor system has the potential to empower both medical practitioners and patients to achieve early HCC diagnosis. Furthermore, the GMR biosensor platform can be adapted to detect other protein or DNA biomarkers beyond HCC, bringing the goals of accessible mobile health even closer to reality.

Prospect of core-shell Fe3O4@Ag label integrated with spin-valve giant magnetoresistance for future point-of-care biosensor

Magnetic-based biosensors are the analytical instruments that convert the biological recognition into the electrical signal through the generating of the stray-field of the magnetic nanoparticles (MNPs) attached to the biomolecule target. The magnetic biosensor feature relies on the transducer and the MNPs label selection. Recently, the biosensor with a point-of-care feature is the most expected device in the nowadays medical diagnostic field. So that, a review of the recent research related to the novel integration of magnetoresistance-based transducers with MNPs for biosensor application is vital for the point-of-care diagnostic development. Hence, the basic principle of biosensors and the giant magnetoresistance (GMR) with exchange bias phenomena are introduced. Furthermore, we provide a review of the cutting edge method in GMR biosensor with spin-valve structure (SV-GMR) which is integrated to MNPs for biomolecule labelling. As review results, among the nano-sized magnetoresistance transducer, the SV-GMR has some predominance, i.e. electrical robustness and moderate magnetoresistance ratio. Meanwhile, as compared to the other proposed MNPs such as pure Fe3O4, Fe2O3, and hybrid Fe3O4-graphene, the core-shell Fe3O4@Ag is potent to be used, which offers not only moderate saturation magnetisation but also good protein affinity, antimicrobial activity, and minimal cytotoxicity. According to the sensor performance comparison, the usage of Fe3O4@Ag for biomolecule labelling in synergy with SV-GMR transducer is prospective to be developed. The Ag shell espouses the protein immobilisation to the surface of the MNPs label that improves the sensor sensitivity. Furthermore, the SV-GMR possessed two modes of the Fe3O4@Ag rapid detection, which are through the moderate voltage change and the switching field shifting. Meanwhile, the concentration increase of Fe3O4@Ag can be well quantified. Moreover, the Fe3O4@Ag/SV-GMR system had a low operating magnetic field with rapid data collection. In conclusion, the Fe3O4@Ag/SV-GMR biosensor system is believed to be applied as a real-time, portable, and cost-effective biosensor.

Dynamic Range Expansion of the C-Reactive Protein Quantification with a Tandem Giant Magnetoresistance Biosensor.

In this study, we report a convenient analytical method for a full-range quantification of the C-reactive protein (CRP), a blood biomarker of infection and cardiovascular events. We determine CRP over the entire diagnostically relevant concentration range in undiluted human blood serum in a single test, using a tandem giant magnetoresistance (GMR) sensor. The tandem principle combines a sandwich assay and a competitive assay, which allows for the discrimination of the concentration values resulting from the multivalued dose–response curve (“Hook” effect), which characterizes the one-step sandwich assay at high CRP concentrations. The sensor covers a linear detection range for CRP concentration from 3 ng/mL to 350 μg/mL, the detection limit (s/n = 3) is 1 ng/mL. The prominent features of the chip-based method are its expanded dynamic range and low sample volume (50 μL), and the need for a short measurement time of 15 min. These figures of merit, in addition to the low detection limit equal to the established assay instrumentation, make it a viable candidate for use in point-of-care diagnostics.

Point-of-care detection of tuberculosis using magnetoresistive biosensing chip

In this paper, a highly sensitive and specific technique based on the principle of giant magnetoresistance (GMR) has been proposed for the early stage Tuberculosis (TB) diagnostics. This GMR biosensing assay employs monoclonal antibodies against M. tuberculosis specific ESAT-6 antigen with the use of magnetic nanoparticles (MNPs) as labels. MNPs bind to the GMR sensor in presence of ESAT-6 and the binding is proportional to the ESAT-6 protein concentration leading to the change in overall resistance of GMR sensor. GMR biosensor simulation showed that ESAT-6 concentration can be detected in the range of pg/mL in comparison to the other transduction techniques available for ESAT-6 detection and further, the signal strength increased with the increase in the concentration. This work has shown that the GMR biosensing strategy is pertinent for the TB detection at the primitive phases when compared with other magnetic techniques used for TB diagnostics.

Early Multiplexed Detection of Cirrhosis using Giant Magnetoresistive Biosensors with Protein Biomarkers

Liver cirrhosis is one of the leading causes of death in adults worldwide. It is highly prevalent in developing countries and is growing in prevalence in developed countries mostly because of chronic liver diseases, such as chronic hepatitis B and C and alcoholic and nonalcoholic fatty liver disease. However, the prevalence of cirrhosis may be highly underestimated because early stages are asymptomatic and current early detection methods are inadequate. Here, we evaluate the potential of a set of novel cirrhotic protein biomarkers, including soluble intercellular adhesion molecule-1 and mac-2 binding protein glycosylation isomer, for early detection of cirrhosis in a multiplexed assay using our giant magnetoresistive (GMR) sensor arrays. We evaluated the diagnostic performance of the biomarkers, individually and in combination, using multivariate logistic regression and random forest in a blinded proof-of-concept retrospective case-controlled study. The biomarkers in combination exhibited high diagnostic performance in both logistic regression and random forest models, with an area under the curve of 0.98 (0.94-1.00). In addition, the combination of biomarkers resulted in a high sensitivity of 0.97 (0.95-1.00) and a high specificity of 1.00. We showed that the diagnostic performance of our novel set of cirrhotic protein biomarkers on our multiplexed GMR sensor arrays is higher than the performance of currently used clinical biomarkers and factors (i.e., age, sex, alanine aminotransferase, aspartate aminotransferase, etc.). With this combination of novel biomarkers and GMR technology, we could potentially boost the diagnostic power of early cirrhosis detection.

Giant magnetoresistive biosensors for real-time quantitative detection of protease activity

Proteases are enzymes that cleave proteins and are crucial to physiological processes such as digestion, blood clotting, and wound healing. Unregulated protease activity is a biomarker of several human diseases. Synthetic peptides that are selectively hydrolyzed by a protease of interest can be used as reporter substrates of unregulated protease activity. We developed an activity-based protease sensor by immobilizing magnetic nanoparticles (MNPs) to the surface of a giant magnetoresistive spin-valve (GMR SV) sensor using peptides. Cleavage of these peptides by a protease releases the magnetic nanoparticles resulting in a time-dependent change in the local magnetic field. Using this approach, we detected a significant release of MNPs after 3.5 minutes incubation using just 4 nM of the cysteine protease, papain. In addition, we show that proteases in healthy human urine do not release the MNPs, however addition of 20 nM of papain to the urine samples resulted in a time-dependent change in magnetoresistance. This study lays the foundation for using GMR SV sensors as a platform for real-time, quantitative detection of protease activity in biological fluids.

Spindle-like Fe3O4 nanoparticles for improving sensitivity and repeatability of giant magnetoresistance biosensors

Magnetic labels are one of the most important components in giant magnetoresistance (GMR) biodetection systems and affect detection signals directly. Many researchers have improved the detection performance of GMR biosensors by optimizing the properties of their magnetic labels, including size, shape, coercivity, and magnetization. In most studies, magnetic labels are usually spherical, and there is little research involving alternative shapes. In this work, we prepared spindlelike Fe3O4 nanoparticles (NPs) by hydrothermal and heating reduction. The as-prepared magnetic NPs were incorporated in the GMR biodetection system. An ultralow limitation of detection concentration of 0.05 ng/ml was achieved, which can be attributed to the shape anisotropy of the spindlelike magnetic particles. A wide linear work range, 0.05–1000 ng/ml, can be achieved by the use of the spindlelike Fe3O4 NPs in GMR biodetection. Moreover, the NPs exhibit good repeatability after multiple measurements, which can be attributed to the NPs’ stable and effective magnetic diffusion field. The use of spindlelike Fe3O4 NPs as magnetic labels in this work provides a new method for improving the sensitivity and repeatability of GMR biodetection.

DARPin based GMR Biosensor for the detection of ESAT-6 Tuberculosis Protein

Tuberculosis (TB), a life threatening communicable disease, is mainly caused by the bacterium named Mycobacterium tuberculosis (MTB). This high burden infectious threat is the ninth leading killer disease worldwide and also the foremost cause of death from a single infectious agent, even ranking above HIV/AIDS. In this work, a novel magnetic biosensing technique based on giant magneto-resistance (GMR) has been proposed for the on-field detection of Tuberculosis (TB) through assessment of MTB specific protein- ESAT-6. This portable highly sensitive diagnostic tool provides the results with a low turnaround time and the achieved limit of detection in the range of pg/ml can be a breakthrough in TB diagnostics. In addition, the use of DARPins (designed ankyrin repeat proteins) leads to high specificity and help in early detection, thus enabling early onset of treatment and thereby reduced mortality. This study compares the results of conventional and GNP-ELISA and it has been shown that the proposed GMR technique is more sensitive. Further, the effect of different sized magnetic nanoparticles on the performance of GMR biosensor is also presented.

Quantification of cDNA on GMR biosensor array towards point-of-care gene expression analysis

Gene expression analysis at the point-of-care is important for rapid disease diagnosis, but traditional techniques are limited by multiplexing capabilities, bulky equipment, and cost. We present a gene expression analysis platform using a giant magnetoresistive (GMR) biosensor array, which allows multiplexed transcript detection and quantification through cost-effective magnetic detection. In this work, we have characterized the sensitivity, dynamic range, and quantification accuracy of Polymerase chain reaction (PCR)-amplified complementary DNA (cDNA) on the GMR for the reference gene GAPDH. A synthetic GAPDH single-stranded DNA (ssDNA) standard was used to calibrate the detection, and ssDNA dilutions were qPCR-amplified to obtain a standard curve. We demonstrate that the GMR platform provides a dynamic range of 4 orders of magnitude and a limit of detection of 1 pM and 0.1 pM respectively for 15 and 18-cycle amplified synthetic GAPDH PCR products. The quantitative results of GMR analysis of cell-line RNA were confirmed by qPCR.

Recent Advances Incorporating Superparamagnetic Nanoparticles into Immunoassays.

Superparamagnetic nanoparticles (SPMNPs) have attracted interest for various biomedical applications due to their unique magnetic behavior, excellent biocompatibility, easy surface modification, and low cost. Their unique magnetic properties, superparamagnetism, and magnetophoretic mobility have led to their inclusion in immunoassays to enhance biosensor sensitivity and allow for rapid detection of various analytes. In this review, we describe SPMNP characteristics valuable for incorporation into biosensors, including the use of SPMNPs to increase detection capabilities of surface plasmon resonance and giant magneto-resistive biosensors. The current status of SPMNP-based immunoassays to improve the sensitivity of rapid diagnostic tests is reviewed, and suggested strategies for the successful adoption of SPMNPs for immunoassays are presented.

Localized detection of reversal nucleation generated by high moment magnetic nanoparticles using a large-area magnetic sensor

This report introduces a local-magnetic-reversal-nucleation based giant magnetoresistance (GMR) sensor with a large sensing area and further discusses its novel sensing scheme of high magnetic moment nanoparticles (MNPs). We demonstrated experimentally that this large-area GMR sensor could successfully detect high moment MNPs. The detection scheme of localized reversal nucleation of GMR sensor induced by MNPs was analyzed and further confirmed by the micromagnetic simulations. This work may provide one pathway in designing next generation GMR biosensors with large area and high sensitivity. This sensing scheme could be applicable to other magnetic biosensors such as magnetic tunnel junction sensors and planar Hall sensors.

Simultaneous Profiling of DNA Mutation and Methylation by Melting Analysis Using Magnetoresistive Biosensor Array.

Epigenetic modifications, in particular DNA methylation, are gaining increasing interest as complementary information to DNA mutations for cancer diagnostics and prognostics. We introduce a method to simultaneously profile DNA mutation and methylation events for an array of sites with single site specificity. Genomic (mutation) or bisulphite-treated (methylation) DNA is amplified using nondiscriminatory primers, and the amplicons are then hybridized to a giant magnetoresistive (GMR) biosensor array followed by melting curve measurements. The GMR biosensor platform offers scalable multiplexed detection of DNA hybridization, which is insensitive to temperature variation. The melting curve approach further enhances the assay specificity and tolerance to variations in probe length. We demonstrate the utility of this method by simultaneously profiling five mutation and four methylation sites in human melanoma cell lines. The method correctly identified all mutation and methylation events and further provided quantitative assessment of methylation density validated by bisulphite pyrosequencing.

Giant Magnetoresistive Biosensors for Time-Domain Magnetorelaxometry: A Theoretical Investigation and Progress Toward an Immunoassay

Magnetorelaxometry (MRX) is a promising new biosensing technique for point-of-care diagnostics. Historically, magnetic sensors have been primarily used to monitor the stray field of magnetic nanoparticles bound to analytes of interest for immunoassays and flow cytometers. In MRX, the magnetic nanoparticles (MNPs) are first magnetized and then the temporal response is monitored after removing the magnetic field. This new sensing modality is insensitive to the magnetic field homogeneity making it more amenable to low-power portable applications. In this work, we systematically investigated time-domain MRX by measuring the signal dependence on the applied field, magnetization time, and magnetic core size. The extracted characteristic times varied for different magnetic MNPs, exhibiting unique magnetic signatures. We also measured the signal contribution based on the MNP location and correlated the coverage with measured signal amplitude. Lastly, we demonstrated, for the first time, a GMR-based time-domain MRX bioassay. This approach validates the feasibility of immunoassays using GMR-based MRX and provides an alternative platform for point-of-care diagnostics.