Magnetoresistive biosensors with on-chip pulsed excitation and magnetic correlated double sampling.

Giant magnetoresistive (GMR) sensors have been shown to be among the most sensitive biosensors reported. While high-density and scalable sensor arrays are desirable for achieving multiplex detection, scalability remains challenging because of long data acquisition time using conventional readout methods. In this paper, we present a scalable magnetoresistive biosensor array with an on-chip magnetic field generator and a high-speed data acquisition method. The on-chip field generators enable magnetic correlated double sampling (MCDS) and global chopper stabilization to suppress 1/f noise and offset. A measurement with the proposed system takes only 20 ms, approximately 50× faster than conventional frequency domain analysis. A corresponding time domain temperature correction technique is also presented and shown to be able to remove temperature dependence from the measured signal without extra measurements or reference sensors. Measurements demonstrate detection of magnetic nanoparticles (MNPs) at a signal level as low as 6.92 ppm. The small form factor enables the proposed platform to be portable as well as having high sensitivity and rapid readout, desirable features for next generation diagnostic systems, especially in point-of-care (POC) settings

Entwicklung eines magnetoresistiven Biosensors zur Detektion von Biomolekülen

Schotter J. Development of a magnetoresistive biosensor for the detection of biomolecules. Bielefeld (Germany): Bielefeld University; 2004.Diese Arbeit präsentiert eine neue Nachweismöglichkeit für Biomoleküle, in deren Rahmen Sub-Mikrometer große magnetische Marker and magnetoresistive Sensoren in einen magnetischen Biochip integriert werden. Die interessierenden Moleküle werden an Oberflächen-immobilisierte Proben hybridisiert und spezifisch mit magnetischen Partikeln markiert. Im Folgenden werden die Streufelder der magnetischen Marker als Widerstandsänderung in einem eingebetteten magnetoresistiven Sensor nachgewiesen. Jedes einzelne Sensorelement deckt die Fläche eines typischen Proben-DNA Spots ab, und über 200 Sensorelemente sind in einen magnetischen Sensor-Prototypen integriert, wodurch er kompatibel zu DNA-Microarray Applikationen ist. Die Eigenschaften verschiedener kommerziell erhältlicher magnetischer Partikel werden verglichen und hinsichtlich ihrer Eignung als Marker für magnetische Biosensoren untersucht. Sensoren, welche entweder auf dem Riesen-Magnetowiderstand oder dem Tunnel-Magnetowiderstand basieren, werden präsentiert, und ihre Reaktion auf lokale Streufelder, welche von magnetischen Markern auf ihrer Oberfläche induziert werden, wird untersucht. DNA-Hybridisierungsexperimente werden präsentiert, die zeigen, dass unser Prototyp eines magnetischen Biosensors komplexe DNA-Sequenzen mit einer Länge von tausend Basen bis herab zu einer Konzentration von etwa 20 pM nachweisen kann. Ein direkter Vergleich unserer magnetoresistiven und einer Fluoreszenz-basierten Detektionsmethode zeigt, dass unser magnetischer Biosensor bei dem Nachweis geringer DNA-Konzentrationen überlegen ist. Außerdem weist der magnetische Biosensor eine kompakte Größe auf und übersetzt die vorhandene Menge einer bestimmten Sorte Biomoleküle direkt in ein elektronisches Signal, wodurch dies eine sehr vielversprechende Wahl für die Detektionseinheit eines zukünftigen Lab-on-a-Chip Gerätes darstellt.In this thesis, a new sensing scheme for biomolecules is presented that combines sub-micron sized magnetic markers and magnetoresistive sensors into a magnetic biochip. The molecules of interest are hybridized to surface-immobilized probes and get specifically labeled by magnetic markers. Afterwards, the stray fields of the magnetic markers are detected as a resistance change by an embedded magnetoresistive sensor. Each sensor element covers the area of a typical probe DNA spot, and over 200 sensor elements are integrated into a magnetic biosensor prototype, thus making it compatible to standard DNA microarray applications. The properties of different commercially available magnetic particles are investigated and compared with respect to their suitability for magnetic biosensor applications. Sensors based both on giant and tunneling magnetoresistance are presented, and their response to local stray fields induced by magnetic markers on their surface is studied. DNA hybridization experiments are presented that prove that our prototype magnetic biosensor can detect complex DNA with a length of one thousand bases down to a concentration of about 20 pM. A direct comparison of the magnetoresistive and a fluorescent detection methods shows that our magnetic biosensor is superior to standard fluorescent detection at low DNA concentrations. Furthermore, the magnetic biosensor has compact size and directly translates the abundance of desired biomolecules into an electronic signal, thus making it a very promising choice for the detection unit of future lab-on-a-chip devices

Integration of GMR sensors with different technologies

Less than thirty years after the giant magnetoresistance (GMR) effect was described, GMR sensors are the preferred choice in many applications demanding the measurement of low magnetic fields in small volumes. This rapid deployment from theoretical basis to market and state-of-the-art applications can be explained by the combination of excellent inherent properties with the feasibility of fabrication, allowing the real integration with many other standard technologies. In this paper, we present a review focusing on how this capability of integration has allowed the improvement of the inherent capabilities and, therefore, the range of application of GMR sensors. After briefly describing the phenomenological basis, we deal on the benefits of low temperature deposition techniques regarding the integration of GMR sensors with flexible (plastic) substrates and pre-processed CMOS chips. In this way, the limit of detection can be improved by means of bettering the sensitivity or reducing the noise. We also report on novel fields of application of GMR sensors by the recapitulation of a number of cases of success of their integration with different heterogeneous complementary elements. We finally describe three fully functional systems, two of them in the bio-technology world, as the proof of how the integrability has been instrumental in the meteoric development of GMR sensors and their applications.Peer ReviewedPostprint (published version

A Frequency-Shift based CMOS Magnetic Biosensor with Spatially Uniform Sensor Transducer Gain

This paper presents a scalable and ultrasensitive magnetic biosensing scheme based on on-chip LC resonance frequency-shifting. The sensor transducer gain is demonstrated as being location-dependent on the sensing surface and proportional to the local polarization magnetic field strength |B|^2 generated by the sensing inductor. To improve the gain uniformity, a bowl-shape stacked coil together with floating shimming metal is proposed for the inductor design. As an implementation example, a 16-cell sensor array is designed in a 45nm CMOS process. The spatially uniform sensor gain of the array is verified by testing micron-size magnetic particles randomly placed on the sensing surface. The Correlated-Double-Counting (CDC) noise cancellation scheme is also implemented in the presented design, which achieves a noise suppression of 10.6dB with no power overhead. Overall, the presented sensor demonstrates a dynamic range of at least 85.4dB

An ultrasensitive CMOS magnetic biosensor array with correlated double counting noise suppression

This paper presents a scalable and ultrasensitive frequency-shift magnetic biosensing array scheme. The theoretical limit of the sensor noise floor is shown to be dominated by the phase noise of the sensing oscillators. To increase the sensitivity, a noise suppression technique, Correlated Double Counting (CDC), is proposed with no power overhead. As an implementation example, a 64-cell sensor array is designed in a standard 65nm CMOS process. The CDC scheme achieves an additional 6dB noise suppression. The magnetic sensing capability of the presented sensor is verified by detecting micron size magnetic particles with an SNR of 14.6dB for a single bead and an effective dynamic range of at least 74.5dB

A Low Noise CMOS Sensor Frontend for a TMR-based Biosensing Platform

In this paper, we propose a low noise CMOS frontend for a Point-of-Care (PoC) biosensing platform based on tunnel magnetoresistance (TMR) as sensors. The integration of a low noise and low power integrated circuit (IC) with the TMR sensors reduces power consumption compared to a realization with discrete electronics, and thereby paves the way towards a portable diagnostic system. The proposed chip uses a DC-coupled fully differential difference amplifier (FDDA) to amplify the minute signals generated by magnetic nanotags (MNTs) that will be used as biomarkers in the target biosensing application. The FDDA features a gain of around 60dB with a suitable offset calibration scheme to deal with the large DC offsets caused by TMR and/or magnetic field variations. The ability to deal with changing DC fields is crucial for a portable setup that is intended to be used in unshielded environments outside the lab. The offset cancellation is achieved by two on-chip current steering DACs that can accommodate TMR resistances between 535Ω and 4.7kΩ. The presented chip is manufactured in a 180nm SOI CMOS technology and features a thermal noise floor of 7nV/√Hz. It consumes a total of 7.7mA from a 1.8V supply

Magnetic DNA detection sensor for point-of-care diagnostics

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University LondonThis thesis focuses on inductive base sensor design at MHz range frequency. The background theory, design, experiments and results for a new magnetic particles sensor is presented. A new magnetic sensor based on a planar coil was investigated for DNA pathogen detection. Change in inductance of the planar coil due to the presence of magnetic particles with varying mass was measured. The experimental set-up consisted of different sized planar coil with associated electronics for inductance measurements. The best sensor performance was accomplished using two different inductors while oscillating at frequencies 2.4MHz using 9.5μH inductor and 7.2MHz with 85μH inductor. The sensor has very large signal to noise ratio (580×103), while the average amount of frequency drift was 0.58. This sensor was tested with various types of magnetic particles. In addition, iron-oxide nanoparticles were synthesized through water in oil microemulsion method and with an average size of 25nm. The best sensitivity achieved for detection of 50μg iron-oxide particles was with the bead size of 10nm. 81Hz frequency shift was attained in regard to that amount of particles. This research shows that increasing the resonance frequency to 7.2MHz can cause the larger output signal difference (frequency shift) in the presence of magnetic particles; however, the sensor stability is the most important factor for determining the detection resolution and sensitivity. The sensitivity is better if the sensor can detect smaller amount of magnetic sample. The results of this research demonstrate that while the sample consists of smaller size particles, the sensor can detect the lower amount of sample. This is due to the heating effect of nanoparticles. On the other hand the sample distance from the sensor has a major impact on the sensitivity too; the shorter the distance, the higher the sensitivity. This technique can potentially be extended to detect several different types of bacterial pathogens and can be modified for multiplex quantitative detection. This sensing technique will be incorporated into a handheld, disposable microfluidic chip for point-of-care diagnostics for sexually transmitted diseases. Key words: Point of care diagnostics, Magnetic particle Detection, Molecular detection, Inductive sensin