Method and apparatus for making measurements of accumulations of magnetically susceptible particles combined with analytes

• US 6,437,563 B1
• Filed: 11/30/1999
• Issued: 08/20/2002
• Est. Priority Date: 11/21/1997
• Status: Expired due to Term

• Current Assignee: Quantum Design International, Inc.
• Original Assignee: Quantum Design, Inc.
• Inventors: Diederichs, Jost Hermann, Jensen, Kurt Gordon, Black, Randall Christopher, Simmonds, Michael Bancroft
• Primary Examiner(s): PATIDAR, JAY M
• Application Number:
  US09/451,660
• Time in Patent Office: 994 Days
• Field of Search: 324/201, 324/204, 324/225, 324/237, 324/226, 324/71.4, 324/232, 324/233, 324/234, 324/236, 324/243, 324/239, 422/68.1, 436/526
• US Class Current: 324/239
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: B82Y 25/00 Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
• 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 35/0098 involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation magnetic particles used in immunoassays G01N33/54326; magnetic separation in general B03C
• CPC Class Codes: G01R 33/12 Measuring magnetic properties of articles or specimens of solids or fluids involving magnetic resonance G01R33/20
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/838 Magnetic property of nanomaterial
• CPC Class Codes: Y10S 977/96 Of magnetic property

Abstract

An apparatus is provided for quantitatively measuring combinations of magnetic particles combined with analytes whose amount or other characteristic quality is to be determined. The magnetic particles are complexed with the analytes to be determined and are excited in a magnetic field. The magnetizations of the magnetic particles are thereby caused to oscillate at the excitation frequency in the manner of a dipole to create their own fields. These fields are inductively coupled to at least one sensor such as sensing coils fabricated in a gradiometer configuration. The output signals from the sensing coils are appropriately amplified and processed to provide useful output indications.

Claims

1. An apparatus capable of quantitative magnetic measurement of samples, the samples each including a plurality of combinations of analytes and magnetically susceptible particles, each sample arranged in a predefined pattern and disposed in a sample holder, comprising:

a magnetic field source to apply an alternating magnetic field to the sample, the magnetic field source defining a gap in which a sample holder is movably disposed;

a substantially flat magnetic field sensor to sense an induced magnetic moment from the sample and configured and arranged in a gradiometer configuration to substantially eliminate the contribution of the magnetic field source to the sensing, the magnetic field sensor having a sensing area substantially the same as the extent of each sample, the magnetic field sensor having an output to communicate output signals, the magnetic field sensor disposed substantially within the gap of the magnetic field source; and

an electronic signal processor to process the output signals from the magnetic field sensor to provide a signal indicative of the quantity of magnetic material in the sample.

2. The apparatus of claim 1, wherein the magnetic field sensor is one or more inductive sensing coils.

3. The apparatus of claim 2, further comprising a set of reference coils spaced from said inductive sensing coils.

4. The apparatus of claim 2, wherein the inductive sensing coils are in the shape of circular spirals.

5. The apparatus of claim 2, wherein the sensing coils are rectangular in shape.

6. The apparatus of claim 2, wherein the sensing coils number two and are mounted on a substrate.

7. The apparatus of claim 1, further comprising a drive system, mechanically coupled to at least one of a sample holder or the sensor, wherein the drive system provides relative motion between the sample holder and the sensor.

8. The apparatus of claim 7, wherein the sensor is stationary and the drive system is structured and arranged to move the sample holder relative to the sensor.

9. The apparatus of claim 7, wherein the sample holder is stationary and the drive system is structured and arranged to move the sensor relative to the sample holder.

10. The apparatus of claim 7, wherein the drive system includes a pinch roller mechanism.

11. The apparatus of claim 1, further comprising means for providing relative motion between a sample holder and the sensor.

12. The apparatus of claim 11, wherein said means is mechanically coupled to the sample holder or to the sensor.

13. The apparatus of claim 11, wherein the sample holder further comprises a reference device disposed thereon.

14. The apparatus of claim 13, wherein the reference device is a bar code.

15. The apparatus of claim 13, wherein the reference device is a magnetic strip.

16. The apparatus of claim 1, wherein the magnetic field source includes an electromagnet with a magnetically permeable core having an extended pole piece, and wherein the extended pole piece has the sensor mounted thereon.

17. The apparatus of claim 1, wherein the magnetic field source includes an electromagnet with a magnetically permeable core having a gap.

18. The apparatus of claim 17, wherein the sensor is a thin film sensor fabricated on the magnetically permeable core.

19. The apparatus of claim 17, wherein the magnetic field source comprises:

a toroid having a gap; and

a drive coil wound around the toroid.

20. The apparatus of claim 7, wherein the drive system includes:

a motor and screw arrangement for moving the sensor with respect to the sample holder; and

a motor arrangement for moving the sample holder relative to the magnetic field source.

21. The apparatus of claim 20, wherein:

the sample holder is a disc to hold a pattern of samples; and

the motor and screw arrangement includes a stepper motor adapted to rotate the disc in a predetermined fashion.

22. The apparatus of claim 17, wherein the sensor is patterned within the gap.

23. The apparatus of claim 21, wherein the sensor is mounted on a substrate, the substrate and sensor capable of extending into the toroid gap.

24. The apparatus of claim 23, wherein the signal processor comprises:

an amplifier coupled to the output of the sensor;

a phase sensitive detector connected to the amplifier to condition the output signals;

an analog to digital converter to convert the output signals to digital form; and

a computer to receive the digitized signals.

25. The apparatus of claim 24, wherein at least a portion of the amplifier includes a circuit with components disposed on the substrate.

26. The apparatus of claim 23, wherein the substrate is elongated and has bonding pads on its proximal end to which conductors are connected to input and output signals from the sensing coils which are mounted on the distal end of the substrate, further comprising a conductive shield on the substrate around the bonding pads and the proximal end of the substrate to reduce stray signal and interference pickup.

27. The apparatus of claim 17, wherein the magnetic field source comprises:

two E-core magnets wherein open ends of the E-core magnets are substantially facing each other and wherein at least one set of poles defines the gap there between.

28. The apparatus of claim 27, wherein the sensor is patterned on at least one of said at least one set of poles defining said gap.

29. The apparatus of claim 17, further comprising a feedback loop to measure the strength of a field produced by the electromagnet, the output of the feedback loop connected to the signal processor, whereby the signal processor is capable of self-correcting for external influences.

30. The apparatus of claim 1, wherein the signal processor comprises:

an amplifier coupled to the output of the sensor;

a computer in which is implemented within hardware or software;

a phase sensitive detector connected to the amplifier to condition the output signals;

an analog to digital converter to convert the output signals to digital form; and

a controller to receive the digitized signals.

31. The apparatus of claim 1, wherein the magnetic field source is configured and arranged to apply power as AC power.

32. The apparatus of claim 1, wherein the magnetic field source is configured and arranged to apply power in field pulses.

33. The apparatus of claim 1, wherein the magnetic field source is configured and arranged to apply power in square wave pulses.

34. The apparatus of claim 1, wherein the sensor includes at least one Hall sensor.

35. The apparatus of claim 1, wherein the sensor includes at least one magnetoresistance sensor.

36. The apparatus of claim 35, wherein the sensor includes at least one giant magnetoresistance sensor.

37. A method for quantitatively measuring analytes using magnetically susceptible particles, comprising:

applying at least one sample on a sample holder, the sample including a plurality of bound complex particles, each bound complex particle including an analyte combined with a magnetically susceptible particle;

creating a magnetic field;

inductively exciting the magnetic particles in the sample with the magnetic field to cause oscillations of the magnetizations therein;

sensing the fields generated by the oscillating magnetizations, wherein the sensing includes sensing the fields using a sensor connected in a gradiometer configuration, and wherein the sensor has a sensing area substantially the same as an extent of the sample; and

creating a signal representative of the sensed field.

38. The method as recited in claim 37, wherein the sample holder is a rotatable disc.

39. The method as recited in claim 38, wherein the magnetic field is created in a gap in a toroidal core having a drive coil wound therearound.

40. The method as recited in claim 39, further comprising:

applying groups of sample patterns spaced around at least a portion of the periphery of the disc;

moving the disc periphery into the gap in the toroidal core; and

rotating the disc.

41. The method as recited in claim 37, wherein the magnetic field is created on a toroidal core having a drive coil wound therearound and the signal creating step is performed by a signal processor, the method further comprising:

applying a drive signal to the drive coil to create the magnetic field;

feeding back a signal representative of the drive signal in the drive coil to the signal processor.

42. The method of claim 41, wherein the drive signal is an AC signal.

43. The method of claim 41, wherein the drive signal is a field pulse.

44. The method of claim 41, wherein the drive signal is a square wave.

45. The method of claim 40, wherein the signal creating includes displaying the representative signal versus the relative position of the sample pattern with respect to the location of the sensor.

46. The method of claim 40, further comprising sensing the magnetic field with a set of reference coils.

47. The method of claim 40, wherein the signal creating employs a phase-sensitive fitting technique.

48. The method of claim 37, further comprising:

applying at least one standard sample pattern on a sample holder;

creating a magnetic field;

exciting the magnetic particles in the standard sample pattern with the magnetic field to cause oscillations of the magnetizations therein;

sensing the fields generated by the oscillating magnetizations;

creating a signal representative of the sensed fields; and

calibrating the sensor based on the signal created.

49. An apparatus capable of quantitative magnetic measurement of samples, comprising:

a sample holder to contain a plurality of samples, each sample including combinations of analytes and magnetically susceptible particles;

a magnetic field source to apply an alternating magnetic field to the samples, the magnetic field source defining a gap in which the sample holder may be disposed;

a substantially flat magnetic field sensor to sense an induced magnetic moment from the samples and configured and arranged in a gradiometer configuration to substantially eliminate the contribution of the magnetic field source to the sensing, the magnetic field sensor having an output to communicate output signals, the magnetic field sensor disposed substantially within the gap of the magnetic field source, the magnetic field sensor having a sensing area substantially the same as the extent of a sample; and

an electronic signal processor to process the output signals from the magnetic field sensor to provide a signal indicative of the quantity of the samples in the pattern.

50. An apparatus capable of quantitative magnetic measurement of samples comprising:

a sample holder to contain an extent of a plurality of samples including combinations of analytes and magnetically susceptible particles;

a magnetic field source to apply an alternating magnetic field to the samples, the magnetic field source defining a gap in which a sample holder may be disposed, the gap having a width of less than about 5 mm;

a substantially flat magnetic field sensor to sense an induced magnetic moment from the samples and configured and arranged in a gradiometer configuration to substantially eliminate the contribution of the magnetic field source to the sensing, the magnetic field sensor having an output to communicate output signals, the magnetic field sensor disposed substantially within the gap of the magnetic field source and having a sensing area substantially the same as the extent of the plurality of samples and having a dimension of the sensing area greater than a spacing between the plurality of samples and the magnetic field sensor; and

an electronic signal processor to process the output signals from the magnetic field sensor to provide a signal indicative of the quantity of the samples in the pattern.

51. An apparatus capable of quantitative magnetic measurement of samples, the samples each including a plurality of combinations of analytes and magnetically susceptible particles, each sample arranged in a pre-defined pattern and disposed in a sample holder, comprising:

a magnetic field source to apply an alternating magnetic field to the sample, the magnetic field source defining a gap in which a sample holder is movably disposed, the magnetic field source including an electromagnet with a magnetically permeable core whereby electromagnetic flux is directed in a predetermined manner to the sample;

a substantially flat magnetic field sensor to sense an induced magnetic moment from the sample and configured and arranged in a gradiometer configuration to substantially eliminate the contribution of the magnetic field source to the sensing, the magnetic field sensor having an output to communicate output signals, the magnetic field sensor disposed substantially within the gap of the magnetic field source; and

an electronic signal processor to process the output signals from the magnetic field sensor to provide a signal indicative of the quantity of magnetic material in the sample.