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.

[1]  Gil U. Lee,et al.  A biosensor based on magnetoresistance technology. , 1998, Biosensors & bioelectronics.

[2]  E. Purcell,et al.  Relaxation Effects in Nuclear Magnetic Resonance Absorption , 1948 .

[3]  Mwj Menno Prins,et al.  Rapid DNA multi-analyte immunoassay on a magneto-resistance biosensor. , 2009, Biosensors & bioelectronics.

[4]  M. Denoual,et al.  Magnetorelaxometry using Improved Giant MagnetoResistance Magnetometer , 2010 .

[5]  Ralph Weissleder,et al.  Magnetic relaxation switches capable of sensing molecular interactions , 2002, Nature Biotechnology.

[6]  Guanxiong Li,et al.  Spin valve biosensors: Signal dependence on nanoparticle position , 2006 .

[7]  Nan Sun,et al.  CMOS RF Biosensor Utilizing Nuclear Magnetic Resonance , 2009, IEEE Journal of Solid-State Circuits.

[8]  A. Pühler,et al.  Comparison of a prototype magnetoresistive biosensor to standard fluorescent DNA detection. , 2004, Biosensors & bioelectronics.

[9]  Thomas B. Sheridan,et al.  The System Perspective , 1988 .

[10]  S.X. Wang,et al.  Model and experiment of detecting multiple magnetic nanoparticles as biomolecular labels by spin valve sensors , 2004, IEEE Transactions on Magnetics.

[11]  S.X. Wang,et al.  GMR biosensor arrays: a system perspective. , 2010, Biosensors & bioelectronics.

[12]  Simone Gambini,et al.  Magnetic Relaxation Detector for Microbead Labels , 2012, IEEE Journal of Solid-State Circuits.

[13]  H. Arami,et al.  Detection of Cancer-Specific Proteases Using Magnetic Relaxation of Peptide-Conjugated Nanoparticles in Biological Environment. , 2016, Nano letters.

[14]  Eileen M. Crimmins,et al.  Lifespan and Healthspan: Past, Present, and Promise. , 2015, The Gerontologist.

[15]  Gustaaf Borghs,et al.  Silane Ligand Exchange to Make Hydrophobic Superparamagnetic Nanoparticles Water-Dispersible , 2007 .

[16]  Hugo Ferreira,et al.  Single magnetic microsphere placement and detection on-chip using current line designs with integrated spin valve sensors: Biotechnological applications , 2002 .

[17]  J. Sedat,et al.  Fluorescence microscopy: reduced photobleaching of rhodamine and fluorescein protein conjugates by n-propyl gallate. , 1982, Science.

[18]  Hua Wang,et al.  A frequency-shift CMOS magnetic biosensor array with single-bead sensitivity and no external magnet , 2009, 2009 IEEE International Solid-State Circuits Conference - Digest of Technical Papers.

[19]  Yi Wang,et al.  Magnetoresistive performance and comparison of supermagnetic nanoparticles on giant magnetoresistive sensor-based detection system , 2014, Scientific Reports.

[20]  P P Freitas,et al.  Spintronic platforms for biomedical applications. , 2012, Lab on a chip.

[21]  Donhee Ham,et al.  Chip–NMR biosensor for detection and molecular analysis of cells , 2008, Nature Medicine.

[22]  Frank Ludwig,et al.  Magnetorelaxometry of magnetic nanoparticles in magnetically unshielded environment utilizing a differential fluxgate arrangement , 2005 .

[23]  R. Street,et al.  A Study of Magnetic Viscosity , 1949 .

[24]  Boris Murmann,et al.  Matrix-insensitive protein assays push the limits of biosensors in medicine , 2009, Nature Medicine.

[25]  Simone Gambini,et al.  A 10 kPixel CMOS Hall Sensor Array With Baseline Suppression and Parallel Readout for Immunoassays , 2013, IEEE Journal of Solid-State Circuits.

[26]  Nan Sun,et al.  Palm NMR and 1-Chip NMR , 2011, IEEE Journal of Solid-State Circuits.

[27]  Gang Xiao,et al.  Quantitative detection of DNA labeled with magnetic nanoparticles using arrays of MgO-based magnetic tunnel junction sensors , 2008 .

[28]  B. Boser,et al.  A CMOS Hall-Effect Sensor for the Characterization and Detection of Magnetic Nanoparticles for Biomedical Applications , 2011, IEEE Transactions on Magnetics.

[29]  G. A. Prinz,et al.  Detection of a micron-sized magnetic sphere using a ring-shaped anisotropic magnetoresistance-based sensor: A model for a magnetoresistance-based biosensor , 2002 .

[30]  B Murmann,et al.  GMR biosensor arrays: correction techniques for reproducibility and enhanced sensitivity. , 2010, Biosensors & bioelectronics.

[31]  G. Fonnum,et al.  Characterisation of Dynabeads® by magnetization measurements and Mössbauer spectroscopy , 2005 .

[32]  Chin Chun Ooi,et al.  High performance wash-free magnetic bioassays through microfluidically enhanced particle specificity , 2015, Scientific Reports.

[33]  Shan X. Wang,et al.  Experimental and theoretical investigation of the precise transduction mechanism in giant magnetoresistive biosensors , 2016, Scientific Reports.

[34]  Ali Hajimiri,et al.  Design and Implementation of an Integrated Magnetic Spectrometer for Multiplexed Biosensing , 2013, IEEE Transactions on Biomedical Circuits and Systems.

[35]  Gustaaf Borghs,et al.  Magnetic particles as labels in bioassays : Interactions between a biotinylated gold substrate and streptavidin magnetic particles , 2007 .

[36]  Robert L White,et al.  Multiplex protein assays based on real-time magnetic nanotag sensing , 2008, Proceedings of the National Academy of Sciences.

[37]  S. Ferrari,et al.  Author contributions , 2021 .

[38]  Oliver Hayden,et al.  Magnetic fingerprints of rolling cells for quantitative flow cytometry in whole blood , 2016, Scientific Reports.

[39]  L. Trahms,et al.  Time domain study of Brownian and Néel relaxation in ferrofluids , 1995 .

[40]  V. Pott,et al.  Detection of a single magnetic microbead using a miniaturized silicon Hall sensor , 2002 .

[41]  Yi Wang,et al.  Giant magnetoresistive-based biosensing probe station system for multiplex protein assays. , 2015, Biosensors & bioelectronics.

[42]  Andrea Prieto Astalan,et al.  Sensitive High Frequency AC Susceptometry in Magnetic Nanoparticle Applications , 2010 .

[43]  H. Bryant,et al.  Characterization of magnetite nanoparticles for SQUID-relaxometry and magnetic needle biopsy. , 2009, Journal of magnetism and magnetic materials.

[44]  J. Aubin.  Autofluorescence of viable cultured mammalian cells. , 1979, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[45]  L. Trahms,et al.  Investigation of Brownian and Néel relaxation in magnetic fluids , 1999 .

[46]  Gang Xiao,et al.  In situ detection of single micron-sized magnetic beads using magnetic tunnel junction sensors , 2005 .

[47]  S. Gambini,et al.  Design Considerations for CMOS-Integrated Hall-Effect Magnetic Bead Detectors for Biosensor Applications , 2013, Journal of Microelectromechanical Systems.

[48]  Irreversible relaxation behaviour of a general class of magnetic systems , 1996 .

[49]  H. Ohno,et al.  Magnetic Tunnel Junctions for Spintronic Memories and Beyond , 2007, IEEE Transactions on Electron Devices.

[50]  E. Wohlfarth.  The coefficient of magnetic viscosity , 1984 .

[51]  H. Bryant,et al.  Magnetic Properties of Nanoparticles Useful for SQUID Relaxometry in Biomedical Applications. , 2011, Journal of magnetism and magnetic materials.

[52]  Man-Kay Law,et al.  A Handheld High-Sensitivity Micro-NMR CMOS Platform With B-Field Stabilization for Multi-Type Biological/Chemical Assays , 2016, IEEE Journal of Solid-State Circuits.

[53]  P Ertl,et al.  Magnetoresistive-based real-time cell phagocytosis monitoring. , 2012, Biosensors & bioelectronics.

[54]  Martin Dufva,et al.  Magnetoresistive sensor for real-time single nucleotide polymorphism genotyping. , 2014, Biosensors & bioelectronics.

[55]  Edward R Flynn,et al.  Magnetic Relaxometry with an Atomic Magnetometer and SQUID Sensors on Targeted Cancer Cells. , 2012, Journal of magnetism and magnetic materials.

[56]  B. Tanner,et al.  Time-dependent magnetization in fine-particle ferromagnetic systems , 1983 .

[57]  V C Martins,et al.  A bacteriophage detection tool for viability assessment of Salmonella cells. , 2014, Biosensors & bioelectronics.