This invention relates generally to magnetic sensors and in particular to an excitation and measurement method for a magnetic biosensor.
A magnetic biosensor system comprises an array of magnetic sensor elements coated with a biochemical layer capable of bonding with molecules of a predetermined species of molecules. Magnetic beads are activated with a biochemical coating that selectively bonds with molecules of the predetermined species. The biochemically activated beads are placed into a given solution where the biochemical coating of the beads bonds with molecules of the predetermined species, if present. After this process, molecules of the predetermined species are tagged by a magnetic bead. Once the solution is brought into contact with the biochemical layer of the magnetic sensor elements, tagged molecules of the predetermined species, diffuse to the biochemical layer and the molecules bond therewith. Presence or non-presence of the magnetic beads is measured at each magnetic sensor element based upon the magnetic properties of the beads.
The magnetic beads are either ferromagnetic—larger—or superparamagnetic—smaller—with the terms larger/smaller referring to the product magnetization volume of the bead. Magnetic beads that are superparamagnetic need to be magnetized first and after magnetization their stray field is measured using a magnetic sensor. An external magnetic field pulse is used for magnetizing superparamagnetic beads. Ideally, the external magnetic field pulse does not influence the sensor function.
Currently, magnetic biosensor systems are based on analog magnetic sensors for measuring Anisotropic or Giant MagnetoResistance (AMR or GMR). In parallel, non-volatile Magnetoresistive Random Access Memories (MRAM) have been developed based on bistable magnetic memory elements. Memory elements are employable as digital magnetic sensors when an extra magnetic field is used for influencing the switching of such a memory element.
Typically, MRAM devices rely on Tunnel MagnetoResistance (TMR) rather than AMR or GMR. However, bistable magnetic memory operation is not limited to TMR devices only, as is the digital magnetic sensor concept. Using a MRAM array enables use of a common platform with numerous different applications in biosensor systems, substantially reducing development and manufacturing cost.
However, in order to efficiently employ MRAM technology in biosensor systems there is a need for a simple, efficient and accurate excitation and measurement method employing MRAM technology.
It is, therefore, an object of the invention to provide an excitation and measurement method for a magnetic biosensor employing MRAM technology.
It is further an object of the invention to provide an excitation and measurement method for a magnetic biosensor employing MRAM technology that is simple, efficient and accurate.
In accordance with the present invention there is provided a method for sensing a presence of a magnetic bead comprising: providing at least a digital magnetic sensor element, the digital magnetic sensor element comprising a magnetic element, a bit line, and a word line, the word line oriented orthogonal to the bit line; measuring an initial state of the magnetic element of the at least a digital magnetic sensor element; providing a predetermined current pulse to each of the bit line and the word line of the at least a digital magnetic sensor element, the current pulses being capable of switching the state of the magnetic element of the at least a digital magnetic sensor element; measuring a first state of the magnetic element of the at least a digital magnetic sensor element after provision of the current pulses; and, comparing the measured first state of the magnetic element of the at least a digital magnetic sensor element with the initial state and providing a comparison result in dependence thereupon.
In accordance with the present invention there is further provided a storage medium having data stored therein, the data for when executed resulting in a method for sensing a presence of a magnetic bead using at least a digital magnetic sensor element comprising a magnetic element, a bit line, and a word line, the word line oriented orthogonal to the bit line, the method comprising: measuring an initial state of the magnetic element of the at least a digital magnetic sensor element; providing a predetermined current pulse to each of the bit line and the word line of the at least a digital magnetic sensor element, the current pulses being capable of switching the state of the magnetic element of the at least a digital magnetic sensor element; measuring a first state of the magnetic element of the at least a digital magnetic sensor element after provision of the current pulses; and, comparing the measured first state of the magnetic element of the at least a digital magnetic sensor element with the initial state and providing a comparison result in dependence thereupon.
In accordance with the present invention there is yet further provided a digital magnetic sensor system for sensing a presence of a magnetic bead comprising: at least a digital magnetic sensor element, the at least a digital magnetic sensor element comprising a magnetic element, a bit line, and a word line, the word line oriented orthogonal to the bit line, the at least a digital magnetic sensor element for sensing the presence of a magnetic bead in close proximity to its top surface; a processor in communication with the at least a digital magnetic sensor element, the processor for executing program data, the program data when executed resulting in a method for sensing the presence of a magnetic bead, the processor when executing the program data performing: measuring an initial state of the magnetic element of the at least a digital magnetic sensor element; controlling provision of a predetermined current pulse to each of the bit line and the word line of the at least a digital magnetic sensor element, respectively, the current pulses being capable of switching the state of the magnetic element of the at least a digital magnetic sensor element; measuring a first state of the magnetic element of the at least a digital magnetic sensor element after provision of the current pulses; and, comparing the measured first state of the magnetic element of the at least a digital magnetic sensor element with the initial state and providing a comparison result in dependence thereupon.
Exemplary embodiments of the invention will now be described in conjunction with the following drawings, in which:
a to 1d are simplified block diagrams schematically illustrating a digital magnetic sensor element in various modes of operation of an excitation and sensing method according to the invention;
a and 3b are simplified timing diagrams schematically illustrating operation of two embodiments of the excitation and sensing method according to the invention;
Referring to
The magnetic beads 110 are magnetized in a magnetic field with a time constant given by a relaxation process. When the magnetic field is switched off, the magnetization of the magnetic beads 110 decays with a time constant according to the same relaxation. The equilibrium magnetic moment of a nano-bead in an applied magnetic field H and at a given temperature T is given by
where L is the Langevin function, m0 he saturation magnetic moment for T=0 K, and μ0 the magnetic constant, i.e. the product of saturation magnetization and magnetic volume. The Langevin function compares the magnetic energy delivered to the magnetic bead 110 with the thermal energy. The net magnetization is zero in absence of a magnetic field. After a magnetic field is applied at t=0, the magnetic moment per nano-bead increases according to
m(t,H,T)=m(H,T)(1−exp(−t/τ)) (2)
To magnetize nano-beads, a magnetic field pulse exceeding τ is needed to yield ≈70% of the equilibrium magnetic moment. After the magnetic field is switched off, the decay of the magnetization takes place within the same time frame. In the case that τ reflects Neel relaxation N, then
Moreover, it is possible to take Brownian motion into account with a relaxation time B
τB=3Vη/kT (4)
in which V denominates the magnetic volume of the nano-bead, and η the viscosity of a liquid disposed between the nano-bead 110 and the top surface 101 of the digital magnetic sensor element 100 (e.g. for water 10−3 Pa.s).
Given the fact that the time delay between the first and the second action is limited, it is likely not possible to measure the state of the magnetic element 108 between the two actions. Therefore, it is desired that the first action does not disturb the state of the magnetic element 108. In conventional MRAMs a single magnetic field component is normally not sufficient for switching the magnetic element 108, i.e. only a combination of two orthogonal magnetic field components is able to switch the magnetic element 108. In advanced MRAMs an even better selectivity is realized by ensuring that a single pulse is never able to switch the magnetic element 108, i.e. there is no restriction in the pulse height. A further description of conventional and advanced MRAM can be found in a variety of publications. For conventional MRAM one is referred to Tehrani et al, Proceedings of the IEEE, Vol. 91, No. 5, May 2003, Page 703-714. A publication introducing the advanced (or toggling) MRAM is by Durlam et al, IEDM Technical Digest 2003, Session 34, Paper #6.
Referring now to
The digital magnetic sensor element 100 senses a change-of-state in the magnetic element 108 upon electromagnetic excitation. In a preferred embodiment the excitation pulse is chosen to be identical to the switching pulses applied to a standard MRAM element. This is possible when the stray field caused by a magnetized bead 110 is large enough to prevent the magnetic element 108 from switching.
Tondra et al., J. Vac Sci. Technol. A 18.4, pp. 1125, 2000, published a calculation performed on a system comprising a single superparamagnetic bead and a GMR sensor. The measurement was performed using an externally applied field. The result of their calculation shows that the magnetic stray field Hbead created by the superparamagnetic bead is approximately 5-10% of the applied magnetic field Happ. Since Hbead has the opposite sign to Happ, the average total magnetic field during measurement is reduced to approximately 95%. Therefore, the sensor element measures a difference in switching threshold between the 100% field created during the single pulse of the first action and an approximately 95% field during the second action. In summary, Tondra et al. conclude that a GMR sensor is capable of detecting a single superparamagnetic bead of any size as long as the following conditions are met: (1) the sensor is approximately the same size as the bead, (2) the bead surface is approximately 0.2 bead radii away from the surface of the sensor, (3) the bead has a dimensionless magnetic susceptibility λm of 0.05, and (4) the GMR sensor response is adequate. Using a TMR based sensor all conditions are met, except condition (2). Since a contact must be provided on top of the TMR device, the distance between the bead surface and the sensor cannot follow the above scaling law. The digital magnetic sensor concept is generally applicable for AMR and GMR devices as well.
Referring to
Above, operation of a single digital magnetic sensor element has been described. It is to be noted that the implementation of a single digital magnetic sensor element 100 may comprise multiple magnetoresistive devices that are combined in a parallel and/or series connection into a single digital magnetic sensor. Alternatively, using MRAMs the digital magnetic sensor element 100 is one of a plurality of sensor elements arranged in a matrix-like array. Based on the array structure of the MRAM employed different techniques are applied to speed up the excitation and measurement process. For example, the single pulse event in a particular sensor element is performed simultaneously by sending a double pulse to one of the neighboring sensor elements, for example, by sharing one of the lines—bit line or word line—with the neighboring sensor element. However, according to an embodiment relying on this accelerated measurement technique either the state of the magnetic elements is measured between the first and the second action, or a set of measurements of the initial state of each digital magnetic sensor element is taken before sending pulses and is stored, for example, in a compatible memory such as a MRAM and the second measurement of the state of the magnetic elements is postponed until the complete array of digital magnetic sensor elements has been excited.
In an alternative embodiment a plurality of sensor elements 100 are disposed in parallel sharing a common bit line and word line, as shown in
In a further embodiment repetitive measurements on a single sensor are taken to increase accuracy, either with a similar current pulse level—averaging, or with a varying current pulse level—discrete field sweep.
The excitation and measurement method according to the present invention is highly advantageous enabling use of MRAM memory technology for biosensor systems. A matrix of a plurality of sensor elements of a single MRAM chip is utilized for measuring magnetically tagged biological species. The method enables use of MRAM technology for producing a single bead event sensor allowing more detailed determination of concentration, or alternatively position mapping.
Referring now to
Numerous other embodiments of the invention will be apparent to persons skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/IB2005/053871 | 11/22/2005 | WO | 00 | 3/31/2009 |
Number | Date | Country | |
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60522989 | Nov 2004 | US |