Magnetic Nanoparticles: A Review on Synthesis, Characterization, Functionalization, and Biomedical Applications.

Nowadays, magnetic nanoparticles (MNPs) are applied in numerous fields, especially in biomedical applications. Since biofluidic samples and biological tissues are nonmagnetic, negligible background signals can interfere with the magnetic signals from MNPs in magnetic biosensing and imaging applications. In addition, the MNPs can be remotely controlled by magnetic fields, which make it possible for magnetic separation and targeted drug delivery. Furthermore, due to the unique dynamic magnetizations of MNPs when subjected to alternating magnetic fields, MNPs are also proposed as a key tool in cancer treatment, an example is magnetic hyperthermia therapy. Due to their distinct surface chemistry, good biocompatibility, and inducible magnetic moments, the material and morphological structure design of MNPs has attracted enormous interest from a variety of scientific domains. Herein, a thorough review of the chemical synthesis strategies of MNPs, the methodologies to modify the MNPs surface for better biocompatibility, the physicochemical characterization techniques for MNPs, as well as some representative applications of MNPs in disease diagnosis and treatment are provided. Further portions of the review go into the diagnostic and therapeutic uses of composite MNPs with core/shell structures as well as a deeper analysis of MNP properties to learn about potential biomedical applications.

Magnetic Particle Spectroscopy for Point-of-Care: A Review on Recent Advances.

Since its first report in 2006, magnetic particle spectroscopy (MPS)-based biosensors have flourished over the past decade. Currently, MPS are used for a wide range of applications, such as disease diagnosis, foodborne pathogen detection, etc. In this work, different MPS platforms, such as dual-frequency and mono-frequency driving field designs, were reviewed. MPS combined with multi-functional magnetic nanoparticles (MNPs) have been extensively reported as a versatile platform for the detection of a long list of biomarkers. The surface-functionalized MNPs serve as nanoprobes that specifically bind and label target analytes from liquid samples. Herein, an analysis of the theories and mechanisms that underlie different MPS platforms, which enable the implementation of bioassays based on either volume or surface, was carried out. Furthermore, this review draws attention to some significant MPS platform applications in the biomedical and biological fields. In recent years, different kinds of MPS point-of-care (POC) devices have been reported independently by several groups in the world. Due to the high detection sensitivity, simple assay procedures and low cost per run, the MPS POC devices are expected to become more widespread in the future. In addition, the growth of telemedicine and remote monitoring has created a greater demand for POC devices, as patients are able to receive health assessments and obtain results from the comfort of their own homes. At the end of this review, we comment on the opportunities and challenges for POC devices as well as MPS devices regarding the intensely growing demand for rapid, affordable, high-sensitivity and user-friendly devices.

Five-Minute Magnetic Nanoparticle Spectroscopy-Based Bioassay for Ultrafast Detection of SARS-CoV-2 Spike Protein.

In this work, we report a 5-min magnetic particle spectroscopy (MPS)-based bioassay strategy. In our approach, surface-functionalized magnetic nanoparticles are incubated with target analytes at 37 °C with agitation for 3 min, and the MPS reading is then taken at the fifth minute. We prove the feasibility of 5 min ultrafast detection of SARS-CoV-2 spike protein with a detection limit below 5 nM (0.2 pmol). Our proposed 5-min bioassay strategy may be applied to reduce the assay time for other liquid-phase, volumetric biosensors such as NMR, quantum dots, fluorescent biosensors, etc.

Magnetic nanoparticles and magnetic particle spectroscopy-based bioassays: a 15 year recap.

Magnetic nanoparticles (MNPs) have unique physical and chemical properties, such as high surface area to volume ratio and size-related magnetism, which are completely different from their bulk materials. Benefiting from the facile synthesis and chemical modification strategies, MNPs have been widely studied for applications in nanomedicine. Herein, we firstly summarized the designs of MNPs from the perspectives of materials and physicochemical properties tailored for biomedical applications. Magnetic particle spectroscopy (MPS), first reported in 2006, has flourished as an independent platform for many biological and biomedical applications. It has been extensively reported as a versatile platform for a variety of bioassays along with the artificially designed MNPs, where the MNPs serve as magnetic nanoprobes to specifically probe target analytes from fluid samples. In this review, the mechanisms and theories of different MPS platforms realizing volumetric- and surface-based bioassays are discussed. Some representative works of MPS platforms for applications such as disease diagnosis, food safety and plant pathology monitoring, drug screening, thrombus maturity assessments are reviewed. At the end of this review, we commented on the rapid growth and booming of MPS-based bioassays in its first 15 years. We also prospected opportunities and challenges that portable MPS devices face in the rapidly growing demand for fast, inexpensive, and easy-to-use biometric techniques.

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.

One-Step, Wash-free, Nanoparticle Clustering-Based Magnetic Particle Spectroscopy Bioassay Method for Detection of SARS-CoV-2 Spike and Nucleocapsid Proteins in the Liquid Phase.

With the ongoing global pandemic of coronavirus disease 2019 (COVID-19), there is an increasing quest for more accessible, easy-to-use, rapid, inexpensive, and high-accuracy diagnostic tools. Traditional disease diagnostic methods such as qRT-PCR (quantitative reverse transcription-PCR) and ELISA (enzyme-linked immunosorbent assay) require multiple steps, trained technicians, and long turnaround time that may worsen the disease surveillance and pandemic control. In sight of this situation, a rapid, one-step, easy-to-use, and high-accuracy diagnostic platform will be valuable for future epidemic control, especially for regions with scarce medical resources. Herein, we report a magnetic particle spectroscopy (MPS) platform for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biomarkers: spike and nucleocapsid proteins. This technique monitors the dynamic magnetic responses of magnetic nanoparticles (MNPs) and uses their higher harmonics as a measure of the nanoparticles' binding states. By anchoring polyclonal antibodies (pAbs) onto MNP surfaces, these nanoparticles function as nanoprobes to specifically bind to target analytes (SARS-CoV-2 spike and nucleocapsid proteins in this work) and form nanoparticle clusters. This binding event causes detectable changes in higher harmonics and allows for quantitative and qualitative detection of target analytes in the liquid phase. We have achieved detection limits of 1.56 nM (equivalent to 125 fmole) and 12.5 nM (equivalent to 1 pmole) for detecting SARS-CoV-2 spike and nucleocapsid proteins, respectively. This MPS platform combined with the one-step, wash-free, nanoparticle clustering-based assay method is intrinsically versatile and allows for the detection of a variety of other disease biomarkers by simply changing the surface functional groups on MNPs.

A Portable Magnetic Particle Spectrometer for Future Rapid and Wash-Free Bioassays.

Nowadays, there is an increasing demand for more accessible routine diagnostics for patients with respect to high accuracy, ease of use, and low cost. However, the quantitative and high accuracy bioassays in large hospitals and laboratories usually require trained technicians and equipment that is both bulky and expensive. In addition, the multistep bioassays and long turnaround time could severely affect the disease surveillance and control especially in pandemics such as influenza and COVID-19. In view of this, a portable, quantitative bioassay device will be valuable in regions with scarce medical resources and help relieve burden on local healthcare systems. Herein, we introduce the MagiCoil diagnostic device, an inexpensive, portable, quantitative, and rapid bioassay platform based on the magnetic particle spectrometer (MPS) technique. MPS detects the dynamic magnetic responses of magnetic nanoparticles (MNPs) and uses the harmonics from oscillating MNPs as metrics for sensitive and quantitative bioassays. This device does not require trained technicians to operate and employs a fully automatic, one-step, and wash-free assay with a user friendly smartphone interface. Using a streptavidin-biotin binding system as a model, we show that the detection limit of the current portable device for streptavidin is 64 nM (equal to 5.12 pmole). In addition, this MPS technique is very versatile and allows for the detection of different diseases just by changing the surface modifications on MNPs. Although MPS-based bioassays show high sensitivities as reported in many literatures, at the current stage, this portable device faces insufficient sensitivity and needs further improvements. It is foreseen that this kind of portable device can transform the multistep, laboratory-based bioassays to one-step field testing in nonclinical settings such as schools, homes, offices, etc.

Magnetic Particle Spectroscopy with One-Stage Lock-In Implementation for Magnetic Bioassays with Improved Sensitivities.

In recent years, magnetic particle spectroscopy (MPS) has become a highly sensitive and versatile sensing technique for quantitative bioassays. It relies on the dynamic magnetic responses of magnetic nanoparticles (MNPs) for the detection of target analytes in the liquid phase. There are many research studies reporting the application of MPS for detecting a variety of analytes including viruses, toxins, nucleic acids, and so forth. Herein, we report a modified version of the MPS platform with the addition of a one-stage lock-in design to remove the feedthrough signals induced by external driving magnetic fields, thus capturing only MNP responses for improved system sensitivity. This one-stage lock-in MPS system is able to detect as low as 781 ng multi-core Nanomag50 iron oxide MNPs (micromod Partikeltechnologie GmbH) and 78 ng single-core SHB30 iron oxide MNPs (Ocean NanoTech). We first demonstrated the performance of this MPS system for bioassay-related applications. Using the SARS-CoV-2 spike protein as a model, we have achieved a detection limit of 125 nM (equal to 5 pmole) for detecting spike protein molecules in the liquid phase. In addition, using a streptavidin-biotin binding system as a proof-of-concept, we show that these single-core SHB30 MNPs can be used for Brownian relaxation-based bioassays while the multi-core Nanomag50 cannot be used. The effects of MNP amount on the concentration-dependent response profiles for detecting streptavidin were also investigated. Results show that by using a lower concentration/ amount of MNPs, concentration-response curves shift to a lower concentration/amount of target analytes. This lower concentration-response indicates the possibility of improved bioassay sensitivities by using lower amounts of MNPs.

Analysis of a GMR-based plethysmograph transducer and its utility for real-time Blood Pressure measurement.

The paper presents study and analysis of a Giant Magneto Resistance (GMR)-based magneto plethysmograph and illustrates its efficacy as a tool for real-time cuff-less measurement of Blood Pressure (BP). The proposed scheme employs two GMR sensors and associated biasing and signal conditioning in its architecture. The delay between output of the GMR sensors is used to estimate the BP. The methodology, circuits and signal processing stages used are described in the paper. A prototype of the GMR-sensing solution is developed and tested. Initially, tests are carried out to determine the quality and characteristics of the plethysmographs produced by developed sensor unit, in different conditions such as various body positions, bias current etc. Good quality bio-signals were obtained during the above tests. Then, the experiments were conducted on 29 volunteers to find the feasibility of developed scheme as a BP monitor. The results obtained show that the performance of developed BP monitor is within acceptable limits.

Feasibility Study of a Giant Magneto-Resistance Based Respiration Rate Monitor.

This paper reports a simple and reliable electronic technique for the estimation of respiration rate (RR). Giant Magneto-Resistance (GMR) based sensors are employed to extract a plethysmograph signal from the subject. This signal is filtered and processed further through simple signal processing stages to obtain RR indication. The feasibility of the system has been studied on a prototype built and associated experimentation on 20 volunteers. The developed system provided clean plethysmographic signals, whose relevant features are shown to possess a relation with RR. Test results shows that the worst-case error in RR estimation of the system is merely 2 breaths per minute. Further, the capability of the system for detecting breathing cessations is studied and results reported. The system can be extended to function as a heart-rate (HR) monitor. Some basic results which proves the working and accuracy of system as a HR estimator is also given in the paper. The proposed system can be used for effective estimation of the above two vital signs in clinics, automotives, wearable devices, etc.

Non-invasive heart rate monitoring system using giant magneto resistance sensor.

A simple heart rate (HR) monitoring system designed and developed using the Giant Magneto-Resistance (GMR) sensor is presented in this paper. The GMR sensor is placed on the wrist of the human and it provides the magneto-plethysmographic signal. This signal is processed by the simple analog and digital instrumentation stages to render the heart rate indication. A prototype of the system has been built and test results on 26 volunteers have been reported. The error in HR estimation of the system is merely 1 beat per minute. The performance of the system when layer of cloth is present between the sensor and the human body is investigated. The capability of the system as a HR variability estimator has also been established through experimentation. The proposed technique can be used as an efficient alternative to conventional HR monitors and is well suited for remote and continuous monitoring of HR.