Point of care sensor systems

• US 9,458,488 B2
• Filed: 03/15/2013
• Issued: 10/04/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Nanomix Incorporated (CJY Holdings Ltd.)
• Original Assignee: Nanomix Incorporated (CJY Holdings Ltd.)
• Inventors: Johnson, Bradley N., Yang, Jui-Ming, Joshi, Kanchan A., Radtkey, Ray R., Gruener, Garrett, Skarupo, Sergei
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US13/844,334
• Publication Number:
  US 20140273187A1
• Time in Patent Office: 1,299 Days
• US Class Current: 1/1
• CPC Class Codes: B01L 2200/04 Exchange or ejection of cartridges, containers or reservoirs
• CPC Class Codes: B01L 2200/10 Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
• CPC Class Codes: B01L 2300/0645 Electrodes
• CPC Class Codes: B01L 2300/0809 rectangular shaped
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0883 Serpentine channels
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0633 with moving parts
• CPC Class Codes: B01L 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502738 characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: C12Q 1/001 Enzyme electrodes
• CPC Class Codes: G01N 2035/1018 Detecting inhomogeneities, e.g. foam, bubbles, clots
• CPC Class Codes: G01N 2035/1034 Transferring microquantities of liquid
• CPC Class Codes: G01N 27/27 Association of two or more measuring systems or cells, each measuring a different parameter, where the measurement results may be either used independently, the systems or cells being physically associated, or combined to produce a value for a further parameter
• CPC Class Codes: G01N 27/3272 Test elements therefor, i.e. disposable laminated substrates with electrodes, reagent and channels optical biosensors G01N33/52
• CPC Class Codes: G01N 27/3274 Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration coding of calibration information G01N33/48771
• CPC Class Codes: G01N 27/4163 checking the operation of, or calibrating, the measuring apparatus G01N27/3274, G01N27/4175 and G01N33/0006 take precedence
• CPC Class Codes: G01N 33/492 Determining multiple analytes
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: G01N 35/1079 with means for piercing stoppers or septums

Abstract

Provided are point of care sensor systems that include portable readers and disposable cartridges for receiving and analyzing samples. A cartridge may be equipped with one or more sensor channels, each containing one or more sensors. After providing a sample to a cartridge, the cartridge can be inserted into a reader, which can interact with the cartridge to perform on-cartridge sensing and receive signals indicating the presence and/or quantity of one or more targets in the sample. Examples of cartridges can include cardiac panels, sepsis panels and the like. In some embodiments, the same sensor hardware may be configured for multiple measurements of different targets conducted at different time frames. Also provided herein are novel on-cartridge solid and liquid reagent storage and delivery mechanisms.

Claims

1. A cartridge for sensing one or more analytes in a sample, the cartridge comprising:

a sample inlet chamber for receiving a sample;

a reagent chamber configured to store a solid phase reagent;

a mixing circuit connected to the sample inlet chamber and comprising a mixing chamber and the reagent chamber;

one or more sensors; and

a detection channel providing a flow path over the one or more sensors, wherein the cartridge includes at least two sensors and is configured to perform non-capture electrochemical enzymatic sensing and electrochemical enzyme-linked immunosorbent assay (ELISA) sensing on a single sample.

2. The cartridge of claim 1, further comprising a de-bubbling channel disposed between the reagent chamber and the detection channel and configured to vent out bubbles in the sample.

3. The cartridge of claim 2, wherein the mixing circuit comprises the de-bubbling channel.

4. The cartridge of claim 2, wherein the de-bubbling channel is external to the mixing circuit.

5. The cartridge of claim 4, further comprising a buffer zone between the reagent chamber and the de-bubbling channel.

6. The cartridge of claim 2, wherein the de-bubbling channel is covered by a hydrophobic membrane.

7. The cartridge of claim 1, further comprising one or more puncture-able compartments containing liquid reagents.

8. The cartridge of claim 7, further comprising puncture mechanisms configured to puncture the puncture-able compartments.

9. The cartridge of claim 8, wherein the puncture mechanisms are configured to be pneumatically actuated.

10. The cartridge of claim 1, further comprising a screen-printed heater configured to heat the detection channel.

11. The cartridge of claim 1, further comprising a screen-printed thermocouple.

12. The cartridge of claim 1, wherein the cartridge is configured to receive only pneumatic and electric inputs from a reader.

13. The cartridge of claim 1, further comprising a microfluidic layer, the microfluidic layer comprising the reagent chamber, mixing chamber, and the detection channel.

14. The cartridge of claim 1, further comprising a sensing assembly including screen-printed electrodes, the one or more sensors including the screen-printed electrodes.

15. The cartridge of claim 1, further comprising a plasma filtration membrane.

16. The cartridge of claim 15, further comprising a vacuum line connected to the plasma filtration membrane.

17. The cartridge of claim 1, wherein all liquid movement within the cartridge is pneumatically actuated.

18. The cartridge of claim 1, further comprising a plurality of fluid stops connected to a hydrophobic membrane.

19. The cartridge of claim 1, wherein each of the two sensors is configured to sense a different cardiac-related biomarker.

20. The cartridge of claim 1, wherein each of the two sensors is configured to sense a different biomarker for traumatic brain injury.

63. The cartridge of claim 1, wherein each of the two sensors is configured to sense a different biomarker for sepsis.

64. The cartridge of claim 63, wherein the biomarkers for sepsis are selected from the group consisting of CRP, PCT, IL-6, lactate, endotoxin, and 1-3 beta glucan.

65. The cartridge of claim 9, wherein the cardiac-related biomarkers are selected from the group consisting of a cardiac troponin, myoglobin, fatty acid binding protein, D-dimer, brain natriuretic peptide, creatine kinase-MB, and creatinine.

21. A cartridge for sensing first and second target analytes in a biological sample, comprising:

a first working electrode coated with one or more enzymes configured to react with a first target analyte to directly or indirectly produce a first electrochemical signal; and

a second working electrode having capture species attached thereto, the capture species configured to capture the second target analyte to directly or indirectly produce a second electrochemical signal,

wherein the cartridge is a single sample, single use, disposable cartridge.

22. The cartridge of claim 21, wherein the first working electrode and the second working electrode are carbon-based electrodes.

23. The cartridge of claim 21, wherein the first target analyte is lactate and the second target analyte is procalcitonin (PCT) or C-reactive protein (CRP).

24. The cartridge of claim 21, wherein at least one of the first target analyte and the second target analyte is a biomarker for sepsis selected from the group consisting of:

CRP, PCT, IL-6, lactate, endotoxin, and 1-3 beta glucan.

25. The cartridge of claim 21, wherein the first and second target analytes include two or more biomarkers for sepsis selected from the group consisting of:

CRP, PCT, IL-6, lactate, endotoxin, and 1-3 beta glucan.

26. The cartridge of claim 21, wherein the first target analyte is creatinine and the second target analyte is a cardiac troponin.

27. The cartridge of claim 26, wherein the cardiac troponin is cardiac troponin I.

28. The cartridge of claim 21, wherein the first and second target analytes include two or more cardiac related biomarkers selected from the group consisting of a cardiac troponin, myoglobin, fatty acid binding protein, D-dimer, brain natriuretic peptide, creatine kinase-MB, and creatinine.

29. The cartridge of claim 28, wherein the cardiac troponin is cardiac troponin I.

30. The cartridge of claim 21, wherein at least one of the first and second target analytes is a traumatic brain injury biomarker.

31. The cartridge of claim 21, wherein the first target analyte is selected from the group consisting of for glucose, galactose, lactose, glutamic acid, cholesterol, xanthine, hypoxanthine, uric acid, choline, creatinine, acetylcholine, tyrosine, and hydrogen peroxide.

32. The cartridge of claim 21, wherein the one or more enzymes comprise one or more of an oxidase, an esterase, uricase, and a kinase.

33. The cartridge of claim 21, wherein the first working electrode coated with one or more enzymes is further coated with a water-soluble polymer.

34. The cartridge of claim 21, wherein the first working electrode is further coated with one or more mediators.

35. The cartridge of claim 21, wherein the first working electrode and the second working electrode are in a detection channel on the cartridge, the detection channel having a sample inlet and wherein the second working electrode is closer to the sample inlet than the first working electrode is to the sample inlet.

36. The cartridge of claim 21, further comprising an additional working electrode configured to produce a control electrochemical signal.

37. The cartridge of claim 21, further comprising an additional working electrode configured to react with or capture the third target analyte to directly or indirectly produce a third electrochemical signal.

38. A reader configured to detect bubbles on a sensor of a cartridge comprising:

an interface for receiving the cartridge; and

computer readable media including instructions to;

measure the impedance of a sensor well on the cartridge;

determine the series resistance Rs and the series capacitance Cs of an equivalent circuit;

determine if a relationship between series resistance Rs and the series capacitance Cs meets a specified criteria; and

based on the determination of the relationship, determine whether a bubble is detected.

39. The reader of claim 38, wherein the specific criteria is based on parameters k0, k1, ε

, and ε

max, wherein ε

is an error, ε

max is a maximum acceptable error, and k0 and k1are experimentally established parameters following the linear relationship Cs =k0+k1*Rs+ε and

|Cs−

k0−

k1*Rs |≦

ε

max.

40. A cartridge for sensing one or more analytes in a sample, the cartridge comprising:

a sample inlet chamber for receiving a sample;

a reagent chamber configured to store a solid phase reagent;

a mixing circuit connected to the sample inlet chamber and comprising a mixing chamber and the reagent chamber;

one or more sensors; and

a detection channel providing a flow path over the one or more sensors, wherein the cartridge is configured to receive only pneumatic and electric inputs from a reader.

41. The cartridge of claim 40, further comprising a de-bubbling channel disposed between the reagent chamber and the detection channel and configured to vent out bubbles in the sample.

42. The cartridge of claim 40, further comprising one or more puncture-able compartments containing liquid reagents, and one or more pneumatically-actuatable puncture mechanisms.

43. The cartridge of claim 40, further comprising a screen-printed heater configured to heat the detection channel.

44. The cartridge of claim 40, further comprising a screen-printed thermocouple.

45. The cartridge of claim 40, further comprising a microfluidic layer, the microfluidic layer comprising the reagent chamber, mixing chamber, and the detection channel.

46. The cartridge of claim 40, further comprising a sensing assembly including screen-printed electrodes, the one or more sensors including the screen-printed electrodes.

47. The cartridge of claim 40, further comprising a plasma filtration membrane.

48. A cartridge for sensing one or more analytes in a sample, the cartridge comprising:

a sample inlet chamber for receiving a sample;

a reagent chamber configured to store a solid phase reagent;

one or more sensors;

a detection channel providing a flow path over the one or more sensors;

a de-bubbling channel disposed between the reagent chamber and the detection channel and configured to vent out bubbles in the sample; and

a mixing circuit connected to the sample inlet chamber and comprising a mixing chamber, the de-bubbling channel, and the reagent chamber.

49. A cartridge for sensing one or more analytes in a sample, the cartridge comprising:

a sample inlet chamber for receiving a sample;

a plasma filtration membrane;

a vacuum line connected to the plasma filtration membrane;

a reagent chamber configured to store a solid phase reagent;

a mixing circuit connected to the sample inlet chamber and comprising a mixing chamber and the reagent chamber;

one or more sensors; and

a detection channel providing a flow path over the one or more sensors.

50. The cartridge of claim 49, further comprising a de-bubbling channel disposed between the reagent chamber and the detection channel and configured to vent out bubbles in the sample.

51. The cartridge of claim 49, further comprising one or more puncture-able compartments containing liquid reagents, and one or more pneumatically-actuatable puncture mechanisms.

52. The cartridge of claim 49, further comprising a screen-printed heater configured to heat the detection channel.

53. The cartridge of claim 49, further comprising a screen-printed thermocouple.

54. The cartridge of claim 49, wherein the cartridge is configured to receive only pneumatic and electric inputs from a reader.

55. The cartridge of claim 49, further comprising a de-bubbling channel disposed between the reagent chamber and the detection channel and configured to vent out bubbles in the sample.

56. The cartridge of claim 55, wherein the mixing circuit comprises the de-bubbling channel.

57. The cartridge of claim 55, wherein the de-bubbling channel is external to the mixing circuit.

58. The cartridge of claim 49, further comprising a microfluidic layer, the microfluidic layer comprising the reagent chamber, mixing chamber, and the detection channel.

59. The cartridge of claim 49, further comprising a sensing assembly including screen-printed electrodes, the one or more sensors including the screen-printed electrodes.

60. A cartridge for sensing one or more analytes in a sample, the cartridge comprising:

a sample inlet chamber for receiving a sample;

a reagent chamber configured to store a solid phase reagent;

a mixing circuit connected to the sample inlet chamber and comprising a mixing chamber and the reagent chamber;

one or more sensors;

a detection channel providing a flow path over the one or more sensors; and

a de-bubbling channel disposed between the reagent chamber and the detection channel and configured to vent out bubbles in the sample, wherein the de-bubbling channel is covered by a hydrophobic membrane.

61. The cartridge of claim 60, wherein the de-bubbling channel is external to the mixing circuit.

62. A cartridge for sensing one or more analytes in a sample, the cartridge comprising:

a sample inlet chamber for receiving a sample;

a reagent chamber configured to store a solid phase reagent;

a mixing circuit connected to the sample inlet chamber and comprising a mixing chamber and the reagent chamber;

one or more sensors;

a detection channel providing a flow path over the one or more sensors; and

a plurality of fluid stops connected to a hydrophobic membrane.