MONOLITHIC DEVICE COMBINING CMOS WITH MAGNETORESISTIVE SENSORS

• US 20140323337A1
• Filed: 07/03/2014
• Published: 10/30/2014
• Est. Priority Date: 01/04/2012
• Status: Active Grant

• Current Assignee: Magnomics S.A.
• Original Assignee: Magnomics, Lda.
• Inventors: Cardoso, Filipe Arroyo, da Costa, Tiago Miguel Lopes Marta, Germano, Jos Antnio Henriques, Piedade, Moiss Simes
• Granted Patent: US 9,567,626 B2
• Time in Patent Office: Days
• US Class Current: 506/9
• CPC Class Codes: C12Q 1/6825 Nucleic acid detection involving sensors
• CPC Class Codes: G01N 2035/00158 Elements containing microarrays, i.e. "biochip"
• CPC Class Codes: G01N 27/745 for detecting magnetic beads used in biochemical assays concerning the assays G01N33/54326; sensors therefor G01R33/1269; automatic analysers therefor G01N35/0098
• CPC Class Codes: G01N 33/54326 Magnetic particles
• CPC Class Codes: G01N 33/54333 Modification of conditions of immunological binding reaction, e.g. use of more than one type of particle, use of chemical agents to improve binding, choice of incubation time or application of magnetic field during binding reaction
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01R 33/091 Constructional adaptation of the sensor to specific applications

Abstract

A monolithic device comprises a substrate. An array of sensing elements is coupled to the substrate, and each sensing element includes a magnetoresistive sensor. An analog electric drive generator is coupled to the substrate, and the electric drive generator produces a sensor-biasing signal that biases the magnetoresistive sensors of the array. An analog multiplexer is coupled to the substrate, and outputs of the array are coupled to inputs of the multiplexer. An analog signal conditioning circuit is coupled to the substrate, wherein at least one output of the multiplexer is coupled to at least one input of the signal conditioning circuit. The monolithic device is fabricated using both complementary metal-oxide semiconductor (i.e., CMOS) technology and thin film technology. For example, the electric drive generator, the multiplexer, and the signal conditioning circuit may be fabricated with CMOS technology, while the magnetoresistive sensors of the array are fabricated with thin film technology.

Claims

1. A monolithic device comprising:

a substrate;

an array of sensing elements coupled to the substrate, wherein each sensing element includes a linear magnetoresistive sensor and a switching device;

a metallic structure coupled to the substrate, wherein the metallic structure is driven by a driving signal to generate a magnetic field about the array of sensing elements;

an analog electric drive generator coupled to the substrate, wherein the electric drive generator produces a sensor-biasing signal that biases the magnetoresistive sensors of the array;

an analog multiplexer coupled to the substrate, wherein outputs of the array are coupled to inputs of the multiplexer through the corresponding switching device; and

an analog signal conditioning circuit coupled to the substrate, wherein an output of the multiplexer is coupled to an input of the signal conditioning circuit;

wherein the metallic structure includes two opposite magnetic field generator lines and a third magnetic field generator line arranged such that a magnetoresistive sensor of the array of sensing elements is between the opposite magnetic field generator lines and above the third magnetic field generator line; and

the array, the electric drive generator, the multiplexer and signal conditioning circuit form a monolithic integrated circuit on the substrate.

2. The monolithic device of claim 1, wherein:

the array of sensing elements is arranged into columns and rows of sensing elements;

the magnetoresistive sensor of each sensing element is formed using thin film technology;

each switching device is implemented as a complementary metal-oxide semiconductor switching device that couples the corresponding linear magnetoresistive sensor to an associated column;

the magnetoresistive sensors formed using thin film technology are placed over the switching devices formed using complementary metal-oxide semiconductor technology;

the switching device couples the corresponding magnetoresistive sensor to an associated one of the columns;

the sensor-biasing signal drives a select one of the rows; and

the columns of sensing elements along the selected one of the rows feed the outputs of the array of sensing elements.

3. The monolithic device of claim 1, wherein:

the opposite magnetic field generator lines define at least one gradient magnetic field generator that generates a magnetic field gradient that attracts label particles with labeling molecules of a target species, and unbound label particles to binding molecules, on the monolithic device; and

the third magnetic field generator line comprises at least one homogeneous magnetic field generator that generates a homogeneous magnetic field that magnetizes magnetizable label particles bound to the labeling molecules of the target species attached to the binding molecules.

4. The monolithic device of claim 1, wherein:

the metallic structure heats the monolithic device; and

each switching device of the array, magnetoresistive sensor or metallic structure senses the temperature such that the sensed temperature is related to the corresponding switching device signal.

5. The monolithic device of claim 1, wherein at least one electric drive generator produces a driving signal that drives the metallic structure to produce a magnetic field.

6. The monolithic device of claim 1, wherein the electric drive generator is configurable to produce a desired signal.

7. The monolithic device of claim 1, wherein the multiplexer implements Time Division Multiple Access to choose a select input of the multiplexer to transfer to the output of the multiplexer.

8. The monolithic device of claim 1, wherein the signal conditioning circuit includes a linear low noise amplifier with a programmable gain and capable of decoupling the input signals.

9. The monolithic device of claim 1, wherein the signal conditioning circuit includes a low pass filter.

10. The monolithic device of claim 1 further comprising a microfluidic channel to pass a washing solution.

11. The monolithic device of claim 1, wherein the monolithic device is incorporated into a system, further comprising:

a processing device coupled to the monolithic device, wherein the processing device is programmed to;

receive the output of the signal conditioning circuit; and

calculate a presence and concentration of a target species based at least in part on the output of the signal conditioning circuit.

12. A monolithic device comprising:

a substrate;

an array of sensing elements coupled to the substrate, wherein each sensing element includes a magnetoresistive sensor;

a metallic structure coupled to the substrate, wherein the metallic structure is driven by a driving signal to generate a magnetic field about the array of sensing elements;

a drive generator coupled to the substrate, wherein the drive generator produces a sensor-biasing signal that biases the magnetoresistive sensors of the array; and

an analog multiplexer coupled to the substrate, wherein outputs of the array are coupled to inputs of the multiplexer;

wherein;

the metallic structure includes two opposite magnetic field generator lines and a third magnetic field generator line arranged such that a magnetoresistive sensor of the array of sensing elements is between the opposite magnetic field generator lines and above the third magnetic field generator line; and

the array, the electric drive generator, and the multiplexer form a monolithic integrated circuit on the substrate.

13. The monolithic device of claim 12, wherein:

the opposite magnetic field generator lines define at least one gradient magnetic field generator that generates a magnetic field gradient that attracts label particles with labeling molecules of a target species, and unbound label particles to binding molecules, on the monolithic device; and

the third magnetic field generator line comprises at least one homogeneous magnetic field generator that generates a homogeneous magnetic field that magnetizes magnetizable label particles bound to the labeling molecules of the target species attached to the binding molecules.

14. A method comprising:

providing a monolithic device comprising;

a substrate;

an array of sensing elements coupled to the substrate, wherein each sensing element includes a linear magnetoresistive sensor and a switching device;

a metallic structure coupled to the substrate, wherein the metallic structure is driven by a driving signal to generate a magnetic field about the array of sensing elements;

an analog electric drive generator coupled to the substrate, wherein the electric drive generator produces a sensor-biasing signal that biases the magnetoresistive sensors of the array;

an analog multiplexer coupled to the substrate, wherein outputs of the array are coupled to inputs of the multiplexer; and

an analog signal conditioning circuit coupled to the substrate, wherein an output of the multiplexer is coupled to an input of the signal conditioning circuit and the signal conditioning circuit produces an output based at least in part on the input of the signal conditioning circuit;

wherein;

the metallic structure includes two opposite gradient magnetic field generator lines and a homogeneous magnetic field generator line arranged such that a magnetoresistive sensor of the array of sensing elements is between the opposite gradient magnetic field generator lines and above the homogeneous magnetic field generator line; and

the array, the electric drive generator, the multiplexer and signal conditioning circuit form a monolithic integrated circuit on the substrate;

15. The method of claim 14, further comprising:

utilizing binding molecules that selectively bind to molecules of a target species;

labeling molecules of the target species in the sample with magnetizable label particles;

generating a magnetic field by driving the metallic structure;

attracting the molecules of the target species to the binding molecules of the monolithic device using the magnetic field;

attaching the molecules of the target species to the binding molecules of the monolithic device;

removing unbound label particles;

magnetizing the magnetizable label particles attached to the binding molecules, wherein the magnetizable label particles are attached to the binding molecules via the molecules of the target species;

sensing the magnetized label particles with the array of sensing elements; and

calculating a presence of the target species in the sample based at least in part on the sensed magnetized label particles.

16. The method of claim 15, wherein generating a magnetic field includes generating the magnetic field at least from a metallic structure integrated in the monolithic device, wherein the metallic structure is driven by at least one electric drive generator.

17. The method of claim 15, further comprising:

heating the monolithic device; and

sensing a temperature of the device;

wherein calculating a presence of the target species further comprises calculating a presence of the target species in the sample based at least in part on the sensed temperature.

18. The method of claim 15, wherein sensing the magnetized label particles with the array of sensing elements comprises:

selecting an output of the array with the multiplexer to generate an output signal; and

conditioning the output signal from the multiplexer with the signal conditioning circuit.

19. The method of claim 15, wherein removing unbound label particles comprises passing a washing solution in a microfluidic channel of the monolithic device such that the unbound label particles are removed.

20. The method of claim 15, wherein removing unbound label particles comprises using the magnetic field to propel the unbound label particles away from the monolithic device.