NMR device for detection of analytes

• US 8,334,693 B2
• Filed: 07/27/2010
• Issued: 12/18/2012
• Est. Priority Date: 08/31/2005
• Status: Active Grant

• Current Assignee: T2 Biosystems, Inc
• Original Assignee: T2 Biosystems, Inc
• Inventors: Lee, W. David
• Primary Examiner(s): SHRIVASTAV, BRIJ B
• Application Number:
  US12/844,672
• Publication Number:
  US 20110020787A1
• Time in Patent Office: 875 Days
• Field of Search: 324300-322, 600407-445, 436523-626, 435/6, 506/9
• US Class Current: 324/307
• CPC Class Codes: G01N 24/08 by using nuclear magnetic resonance G01N24/12 takes precedence
• CPC Class Codes: G01N 24/088 Assessment or manipulation of a chemical or biochemical reaction, e.g. verification whether a chemical reaction occurred or whether a ligand binds to a receptor in drug screening or assessing reaction kinetics
• CPC Class Codes: G01R 33/281 Means for the use of in vitro contrast agents G01R33/282 takes precedence; involving use of a contrast agent in MR imaging G01R33/5601; in vivo contrast agents A61K49/0002
• CPC Class Codes: G01R 33/285 Invasive instruments, e.g. catheters or biopsy needles, specially adapted for tracking, guiding or visualization by NMR
• CPC Class Codes: G01R 33/302 Miniaturized sample handling arrangements for sampling small quantities, e.g. flow-through microfluidic NMR chips
• CPC Class Codes: G01R 33/34007 Manufacture of RF coils, e.g. using printed circuit board technology; additional hardware for providing mechanical support to the RF coil assembly or to part thereof, e.g. a support for moving the coil assembly relative to the remainder of the MR system
• CPC Class Codes: G01R 33/34053 Solenoid coils; Toroidal coils
• CPC Class Codes: G01R 33/34061 Helmholtz coils
• CPC Class Codes: G01R 33/34069 Saddle coils
• CPC Class Codes: G01R 33/34084 implantable coils or coils being geometrically adaptable to the sample, e.g. flexible coils or coils comprising mutually movable parts
• CPC Class Codes: G01R 33/341 comprising surface coils
• CPC Class Codes: G01R 33/44 using nuclear magnetic resonance [NMR] G01R33/24, G01R33/62 take precedence
• CPC Class Codes: G01R 33/465 applied to biological material, e.g. in vitro testing
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Abstract

This invention relates generally to detection devices having one or more small wells each surrounded by, or in close proximity to, an NMR micro coil, each well containing a liquid sample with magnetic nanoparticles that self-assemble or disperse in the presence of a target analyte, thereby altering the measured NMR properties of the liquid sample. The device may be used, for example, as a portable unit for point of care diagnosis and/or field use, or the device may be implanted for continuous or intermittent monitoring of one or more biological species of interest in a patient.

Claims

1. A device for the magnetic resonance detection of one or more analytes in a liquid sample, the device comprising a support defining a well holding a liquid sample comprising magnetic particles and the one or more analytes and having an RF coil disposed about the well, the RF coil configured to detect an echo response produced by exposing the liquid sample to a bias magnetic field created using one or more magnets and an RF excitation, wherein the magnetic particles have binding moieties on their surfaces, the binding moieties operative to alter an aggregation of the magnetic particles in the presence of the one or more analytes, and wherein at least one of the binding moieties is operative to bind to at least one of the following:

(i) the one or more analytes;

(ii) another of the binding moieties; and

(iii) an aggregation-inducing molecule in the liquid sample, thereby producing an aggregate of multiply-linked magnetic particles as a function of the presence or concentration of the one or more analytes in the liquid sample.

2. The device of claim 1, wherein the well and the RF coil are configured to provide a filling factor of at least about 0.1.

3. The device of claim 1, wherein the well has a volume of less than about 300 μ

L.

4. The device of claim 1, wherein the well and the RF coil are configured such that the volume circumscribed by the RF coil is less than about 300 μ

L.

5. The device of claim 1, wherein the RF coil has a characteristic dimension from about 10 μ

m to about 1000 μ

m.

6. The device of claim 1, further comprising a tube for holding the liquid sample, the tube having a varying cross section.

7. The device of claim 1, wherein an aggregate of multiply-linked magnetic particles is disaggregated as a function of the presence or concentration of the one or more analytes in the liquid sample.

8. The device of claim 1, further comprising a plurality of compartments for holding one or more populations of magnetic particles, wherein magnetic particles having different binding moieties are disposed in different compartments for detection of the one or more analytes, the different binding moieties promoting aggregation or disaggregation of the magnetic particles in the presence of the one or more analytes.

9. The device of claim 8, wherein magnetic particles having different binding moieties are disposed in different compartments for detection of multiple analytes.

10. The device of claim 8, wherein magnetic particles having the same binding moieties are disposed in different compartments for replicate measurements.

11. The device of claim 8, wherein magnetic particles having the same binding moieties are disposed in different compartments for detection of varying analyte concentrations in the liquid sample.

12. The device of claim 1, wherein the bias magnetic field has a strength of from about 0.45 Tesla to about 7 Tesla.

13. The device of claim 1, wherein the device is implantable.

14. The device of claim 1, wherein the device comprises a reader configured to receive a signal from the liquid sample, the reader comprising (i) a single permanent magnet defining a magnetic field having a strength of from about 0.45 Tesla to about 7 Tesla;

(ii) an RF excitation coil for transmitting an RF excitation to the liquid sample;

(iii) an RF coil configured to detect an NMR relaxation response produced by exposing the liquid sample to the magnetic field and the RF excitation;

(iv) an electrical element in communication with the RF coil, the electrical element configured to amplify, rectify, transmit, and/or digitize the signal corresponding to the NMR relaxation response; and

(v) a display for indicating the presence or concentration of the one or more analytes.

15. The device of claim 1, wherein the liquid sample comprises blood.

16. The device of claim 1, wherein the liquid sample comprises urine.

17. The device of claim 1, wherein one of the one or more analytes is a biologically active substance.

18. The device of claim 17, wherein the biologically active substance is selected from a protein, a peptide, a polypeptide, an amino acid, a nucleic acid, an oligonucleotide, a therapeutic agent, a metabolite of a therapeutic agent, RNA, DNA, an antibody, a carbohydrate, a polysaccharide, glucose, a lipid, a gas, an electrolyte, a lipoprotien, cholesterol, a fatty acid, a glycoprotein, a proteoglycan, and a lipopolysaccharide.

19. The device of claim 18, wherein one of the one or more analytes is a protein.

20. The device of claim 19, wherein the protein is retinol binding protein.

21. The device of claim 19, wherein the peptide is an interleukin.

22. The device of claim 1, wherein one of the one or more analytes is a general chemistry analyte.

23. The device of claim 22, wherein the general chemistry analyte is creatinine.

24. The device of claim 1, wherein one of the one or more analytes is an immunosuppressive drug.

25. The device of claim 24, wherein the immunosuppressive drug is tacrolimus.

26. The device of claim 1, wherein one of the one or more analytes is an antifungal drug.

27. The device of claim 26, wherein the antifungal drug is fluconazole.

28. The device of claim 1, wherein one of the one or more analytes is an infectious disease pathogen.

29. The device of claim 28, wherein the infectious disease pathogen is a bacterial, viral, fungal, algal, protozoal, or helminthic pathogen.

30. A method for detecting one or more analytes in a liquid sample, the method comprising:

(a) placing the liquid sample in a device of claim 1, the device comprising a support defining a well holding a liquid sample comprising magnetic particles and the one or more analytes and having an RF coil disposed about the well, the RF coil configured to detect an echo response produced by exposing the liquid sample to a bias magnetic field created using one or more magnets and an RF excitation, wherein the magnetic particles have binding moieties on their surfaces, the binding moieties operative to alter an aggregation of the magnetic particles in the presence of the one or more analytes;

(b) contacting the liquid sample with the magnetic particles in the presence of the bias magnetic field;

(c) exposing the sample to an RF excitation;

(d) following step (c), detecting an echo response produced by the liquid sample; and

(e) on the basis of the result of step (d), detecting the one or more analytes.

31. The method of claim 30, further comprising using the result of step (e) to diagnose a medical condition.

32. The method of claim 31, wherein the medical condition is an adverse drug response.

33. The method of claim 31, wherein the medical condition is an infection.

34. The method of claim 31, wherein the medical condition is a renal disorder.

35. The method of claim 31, wherein the medical condition is selected from the group consisting of pain, fever, infection, a cardiac condition, stroke, thrombosis, heart attack, a gastrointestinal disorder, a urinary tract disorder, a skin disorder, a blood disorder, and a cancer.

36. The method of claim 30, wherein one of the one or more analytes is a marker for the detection of a chemical weapon.

37. The method of claim 30, wherein one of the one or more analytes is a marker for the detection of a biological weapon.

38. A method of monitoring one or more analytes in a liquid sample for the diagnosis, management, or treatment of a medical condition in a patient, the method comprising:

(a) placing the liquid sample in a device of claim 1, the device comprising a support defining a well holding a liquid sample comprising magnetic particles and the one or more analytes and having an RF coil disposed about the well, the RF coil configured to detect an echo response produced by exposing the liquid sample to a bias magnetic field created using one or more magnets and an RF excitation, wherein the magnetic particles have binding moieties on their surfaces, the binding moieties operative to alter an aggregation of the magnetic particles in the presence of the one or more analytes;

(b) contacting the liquid sample with the magnetic particles in the presence of the bias magnetic field;

(c) exposing the sample to an RF excitation;

(d) following step (c), detecting an echo response produced by the liquid sample;

(e) on the basis of the result of step (d), detecting the one or more analytes; and

(f) using the result of step (e) to diagnose, manage, or treat the medical condition.

39. The method of claim 38, wherein the monitoring is intermittent.

40. The method of claim 38, wherein the monitoring is continuous.

41. The method of claim 38, wherein the device is implantable.

42. A method of determining an appropriate dose of a therapeutic agent in a patient, the method comprising:

(a) administering the therapeutic agent to the patient;

(b) following step (a), obtaining a sample comprising the therapeutic agent or metabolite thereof from the patient;

(c) placing the liquid sample in a device of claim 1, the device comprising a support defining a well holding a liquid sample comprising magnetic particles and the one or more analytes and having an RF coil disposed about the well, the RF coil configured to detect an echo response produced by exposing the liquid sample to a bias magnetic field created using one or more magnets and an RF excitation, wherein the magnetic particles have binding moieties on their surfaces, the binding moieties operative to alter an aggregation of the magnetic particles in the presence of the one or more analytes;

(d) contacting the sample with the magnetic particles in the presence of the bias magnetic field;

(e) exposing the sample to an RF excitation;

(f) following step (e), detecting an echo response produced by the sample; and

(g) on the basis of the result of step (f), determining the concentration of the therapeutic agent or metabolite thereof, wherein, if the concentration of the therapeutic agent or metabolite thereof is above the appropriate therapeutic range, the dose of the therapeutic agent being administered to the patient is reduced, and if the concentration of the therapeutic agent or metabolite thereof is below the therapeutic range, the dose of the therapeutic agent being administered to the patient is increased.

43. The method of claim 42, wherein the determining is intermittent.

44. The method of claim 42, wherein the determining is continuous.

45. The method of claim 30, wherein the well and the RF coil are configured to provide a filling factor of at least about 0.1.

46. The method of claim 30, wherein the well has a volume of less than about 300 μ

L.

47. The method of claim 30, wherein the well and the RF coil are configured such that the volume circumscribed by the RF coil is less than about 300 μ

L.

48. The method of claim 30, wherein the RF coil has a characteristic dimension from about 10 μ

m to about 1000 μ

m.

49. The method of claim 30, further comprising a tube for holding the liquid sample, the tube having a varying cross section.

50. The method of claim 30, wherein the liquid sample comprises blood.

51. The method of claim 30, wherein the liquid sample comprises urine.

52. The method of claim 30, wherein one of the one or more analytes is a biologically active substance.

53. The method of claim 52, wherein the biologically active substance is selected from a protein, a peptide, a polypeptide, an amino acid, a nucleic acid, an oligonucleotide, a therapeutic agent, a metabolite of a therapeutic agent, RNA, DNA, an antibody, a carbohydrate, a polysaccharide, glucose, a lipid, a gas, an electrolyte, a lipoprotien, cholesterol, a fatty acid, a glycoprotein, a proteoglycan, and a lipopolysaccharide.

54. The method of claim 53, wherein one of the one or more analytes is a protein.

55. The method of claim 54, wherein the protein is retinol binding protein.

56. The method of claim 54, wherein the peptide is an interleukin.

57. The method of claim 30, wherein one of the one or more analytes is a general chemistry analyte.

58. The method of claim 57, wherein the general chemistry analyte is creatinine.

59. The method of claim 30, wherein one of the one or more analytes is an immunosuppressive drug.

60. The method of claim 59, wherein the immunosuppressive drug is tacrolimus.

61. The method of claim 30, wherein one of the one or more analytes is an antifungal drug.

62. The method of claim 61, wherein the antifungal drug is fluconazole.

63. The method of claim 30, wherein one of the one or more analytes is an infectious disease pathogen.

64. The method of claim 63, wherein the infectious disease pathogen is a bacterial, viral, fungal, algal, protozoal, or helminthic pathogen.