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

Magnetoresistive Biosensor Circuits and Systems for Ultrasensitive Point-of-Care Diagnostics

Over the past several decades, early diagnoses and disease monitoring that rely upon biomolecular testing are the primary factors that have led to the substantial increase in average life expectancy. Molecular tests, which analyze patient samples for disease-specific biomarkers, are becoming the basis of the majority of diagnoses and therapy monitoring. Point-of-care (PoC) diagnostics uses a portable analytical device for accurate and fast tests to avoid frequent clinic visits and long turn-around time. Among biosensing techniques, magnetic sensors take advantage of the intrinsic lack of magnetic background in biological samples to achieve high sensitivity and are compatible with semiconductor-based fabrication processes to enable low-cost and small-size devices for PoC applications. In this dissertation, magnetic sensor analog front-ends (AFEs) are designed to measure the signal from magnetoresistive (MR) sensors and overcome challenges such as small signal to baseline ratio, 1/f noise, and temperature drift. Two sensing techniques, magnetometry and magneto-relaxometry (MRX), are discussed and compared. Printed circuit boards (PCBs) and CMOS chips are designed to implement both techniques.First, a CMOS chip based on magnetometry is presented, which reduces the baseline using a double modulation scheme and a reference sensor. The residual baseline from the sensor mismatch is further reduced using a high frequency interference rejection (HFIR) sampling technique embedded in the ADC. A fast settling duty-cycled resistor (DCR) is used to reduce the AFE settling time, thus enabling a readout time that is 22.7× faster than the state-of-the-art. This work results in sub-ppm sensitivity and a sensor mismatch tolerance of up to 10%.While promising, the sensor mismatch still limits the baseline cancellation. MRX measures the relaxation signal after removing the excitation magnetic field, thus enabling baseline-free detection. PCBs, including an AFE and an electromagnet driver that can collapse the magnetic field within 10 μs, were designed to validate the time-domain MRX. The signal dependency on the sensor coverage, applied field strength, and magnetization time was investigated.Lastly, a CMOS chip based on MRX was designed that uses magnetic or magnetoresistive correlated double sampling to reject the systematic 1/f noise. Moreover, a fast settling Miller compensation (FSMC) technique was presented to save the power, while maintaining the amplifier’s linearity and stability. As a result, this work achieves the best-reported magnetic sensor figure-of-merit (FoM).These works enable ultrasensitive, broad dynamic range, and fast response magnetic sensing systems towards PoC diagnostics

Magnetoresistive Biosensor Circuits and Systems for Ultrasensitive Point-of-Care Diagnostics

Over the past several decades, early diagnoses and disease monitoring that rely upon biomolecular testing are the primary factors that have led to the substantial increase in average life expectancy. Molecular tests, which analyze patient samples for disease-specific biomarkers, are becoming the basis of the majority of diagnoses and therapy monitoring. Point-of-care (PoC) diagnostics uses a portable analytical device for accurate and fast tests to avoid frequent clinic visits and long turn-around time. Among biosensing techniques, magnetic sensors take advantage of the intrinsic lack of magnetic background in biological samples to achieve high sensitivity and are compatible with semiconductor-based fabrication processes to enable low-cost and small-size devices for PoC applications. In this dissertation, magnetic sensor analog front-ends (AFEs) are designed to measure the signal from magnetoresistive (MR) sensors and overcome challenges such as small signal to baseline ratio, 1/f noise, and temperature drift. Two sensing techniques, magnetometry and magneto-relaxometry (MRX), are discussed and compared. Printed circuit boards (PCBs) and CMOS chips are designed to implement both techniques.First, a CMOS chip based on magnetometry is presented, which reduces the baseline using a double modulation scheme and a reference sensor. The residual baseline from the sensor mismatch is further reduced using a high frequency interference rejection (HFIR) sampling technique embedded in the ADC. A fast settling duty-cycled resistor (DCR) is used to reduce the AFE settling time, thus enabling a readout time that is 22.7× faster than the state-of-the-art. This work results in sub-ppm sensitivity and a sensor mismatch tolerance of up to 10%.While promising, the sensor mismatch still limits the baseline cancellation. MRX measures the relaxation signal after removing the excitation magnetic field, thus enabling baseline-free detection. PCBs, including an AFE and an electromagnet driver that can collapse the magnetic field within 10 μs, were designed to validate the time-domain MRX. The signal dependency on the sensor coverage, applied field strength, and magnetization time was investigated.Lastly, a CMOS chip based on MRX was designed that uses magnetic or magnetoresistive correlated double sampling to reject the systematic 1/f noise. Moreover, a fast settling Miller compensation (FSMC) technique was presented to save the power, while maintaining the amplifier’s linearity and stability. As a result, this work achieves the best-reported magnetic sensor figure-of-merit (FoM).These works enable ultrasensitive, broad dynamic range, and fast response magnetic sensing systems towards PoC diagnostics

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

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

Atom Probe Tomography Unveils Formation Mechanisms of Wear-Protective Tribofilms by ZDDP, Ionic Liquid, and Their Combination

The development of advanced lubricant additives has been a critical component in paving the way for increasing energy efficiency and durability for numerous industry applications. However, the formation mechanisms of additive-induced protective tribofilms are not yet fully understood because of the complex chemomechanical interactions at the contact interface and the limited spatial resolution of many characterizing techniques currently used. Here, the tribofilms on a gray cast iron surface formed by three antiwear additives are systematically studied; a phosphonium-phosphate ionic liquid (IL), a zinc dialkyldithiophosphate (ZDDP), and an IL+ZDDP combination. All three additives provide excellent wear protection, with the IL+ZDDP combination exhibiting a synergetic effect, resulting in further reduced friction and wear. Atom probe tomography (APT) and scanning transmission electron microscopy (STEM) imaging and electron energy loss spectroscopy (EELS) were used to interrogate the subnm chemistry and bonding states for each of the tribofilms of interest. The IL tribofilm appeared amorphous and was Fe, P, and O rich. Wear debris particles having an Fe-rich core and an oxide shell were present in this tribofilm and a transitional oxide (Fe₂O₃)-containing layer was identified at the interface between the tribofilm and the cast iron substrate. The ZDDP+IL tribofilm shared some of the characteristics found in the IL and ZDDP tribofilms. Tribofilm formation mechanisms are proposed on the basis of the observations made at the atomic level