An aptamer-based magnetic flow cytometer using matched filtering.

Facing unprecedented population-ageing, the management of noncommunicable diseases (NCDs) urgently needs a point-of-care (PoC) testing infrastructure. Magnetic flow cytometers are one such solution for rapid cancer cellular detection in a PoC setting. In this work, we report a giant magnetoresistive spin-valve (GMR SV) biosensor array with a multi-stripe sensor geometry and matched filtering to improve detection accuracy without compromising throughput. The carefully designed sensor geometry generates a characteristic signature when cells labeled with magnetic nanoparticles (MNPs) pass by thus enabling multi-parametric measurement like optical flow cytometers (FCMs). Enumeration and multi-parametric information were successfully measured across two decades of throughput (37 - 2730 cells/min). 10-µm polymer microspheres were used as a biomimetic model where MNPs and MNP-decorated polymer conjugates were flown over the GMR SV sensor array and detected with a signal-to-noise ratio (SNR) as low as 2.5 dB due to the processing gain afforded by the matched filtering. The performance was compared against optical observation, exhibiting a 92% detection efficiency. The system achieved a 95% counting accuracy for biomimetic models and 98% for aptamer-based pancreatic cancer cell detection. This system demonstrates the ability to perform reliable flow cytometry toward PoC diagnostics to benefit NCD control plans.

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.

A CMOS Magnetoresistive Sensor Front-End With Mismatch-Tolerance and Sub-ppm Sensitivity for Magnetic Immunoassays.

Magnetic biosensing is an emerging technique for ultra-sensitive point-of-care (PoC) biomolecular detection. However, the large baseline-to-signal ratio and sensor-to-sensor mismatch in magnetoresistive (MR) biosensors severely complicates the design of the analog front-end (AFE) due to the high dynamic range (DR) required. The proposed AFE addresses these issues through new architectural and circuit level techniques including fast settling duty-cycle resistors (DCRs) to reduce readout time and a high frequency interference rejection (HFIR) sampling technique embedded in the ADC to relax the DR requirement. The AFE achieves an input-referred noise of 46.4 nT/√Hz, an input-referred baseline of less than 0.235 mT, and a readout time of 11 ms while consuming just 1.39 mW. Implemented in a 0.18 µm CMOS process, this work has state-of-the-art performance with 22.7× faster readout time, >7.8× lower baseline, and 2.3× lower power than previously reported MR sensor AFEs.

Giant Magnetoresistive Biosensor Array for Detecting Magnetorelaxation.

In this paper, a time-domain magnetorelaxometry biosensing scheme is presented using giant magnetoresistive (GMR) sensors to measure the fast relaxation response of superparamagnetic magnetic nanoparticles (MNPs) in a pulsed magnetic field. The system consists of an 8 × 10 GMR sensor array, a Helmholtz coil, an electromagnet driver, and an integrator-based analog front-end needed to capture the fast relaxation dynamics of MNPs. A custom designed electromagnet driver and Helmholtz coil improve the switch-off speed to >5 Oe/µs, limiting the dead zone time to <10 µs, and thus enables the system to monitor fast relaxation processes of 30 nm MNPs. A magnetic correlated double sampling technique is proposed to reduce sensor-to-sensor variation by 99.98% while also reducing temperature drift, circuit offset, and nonlinearity below the noise level. An optimum integration time is calculated and experimentally verified to maximize the SNR. Experiments with dried MNPs have shown successful relaxation detection, and immunoassay experiments have demonstrated their binding kinetics.

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.