MODULAR POINT-OF-CARE DEVICES, SYSTEMS, AND USES THEREOF

• US 20090088336A1
• Filed: 10/02/2008
• Published: 04/02/2009
• Est. Priority Date: 10/02/2007
• Status: Active Grant

• Current Assignee: Labrador Diagnostics LLC (SoftBank Group Corp.)
• Original Assignee: Theranos Incorporated
• Inventors: Frenzel, Gary, Burd, Tammy, Nugent, Anthony Joseph, Gibbons, Ian, Holmes, Elizabeth A.
• Granted Patent: US 8,088,593 B2
• Time in Patent Office: Days
• US Class Current: 506/9
• CPC Class Codes: A61B 10/0038 Devices for taking faeces samples; Faecal examination devices anal receptacles A61F5/451
• CPC Class Codes: A61B 10/0045 Devices for taking samples of body liquids devices for taking blood samples A61B5/15
• CPC Class Codes: A61B 10/0051 for taking saliva or sputum samples devices for receiving spittle A61J9/00
• CPC Class Codes: A61B 10/0058 for taking sperm samples artificial insemination A61B17/43; for animals A61D19/021; genital receptacles for the male member A61F5/453; massage of the genitals A61H19/00
• CPC Class Codes: A61B 10/007 for taking urine samples measuring urological functions A61B5/20; genital receptacles A61F5/451; urinals for bed-ridden persons A61G9/006
• CPC Class Codes: A61B 10/02 Instruments for taking cell samples or for biopsy A61B10/0038 and A61B10/0045 take precedence; needle locating or guiding means A61B17/3403; samplers for enzymology or microbiology C12M1/26; sampling or preparing biological specimens G01N33/48
• CPC Class Codes: A61B 2010/0074 Vaginal or cervical secretions
• CPC Class Codes: A61B 2010/0077 Cerebrospinal fluid
• CPC Class Codes: A61B 5/15 Devices for taking samples of blood hypodermic syringes A61M5/178
• CPC Class Codes: A61B 5/150755 Blood sample preparation for further analysis, e.g. by separating blood components or by mixing
• CPC Class Codes: A61B 5/151 Devices specially adapted for taking samples of capillary blood, e.g. by lancets , needles or blades
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00292 in the shape of pipette tips
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00369 in multiple or parallel arrangements
• CPC Class Codes: B01J 2219/00371 comprising electrodes
• CPC Class Codes: B01J 2219/00385 Printing
• CPC Class Codes: B01J 2219/00466 in a slurry
• CPC Class Codes: B01J 2219/00495 Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/005 : Beads
• CPC Class Codes: B01J 2219/00693 : Means for quality control
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01L 2200/04 : Exchange or ejection of cartridges, containers or reservoirs
• CPC Class Codes: B01L 2200/0689 : Sealing
• CPC Class Codes: B01L 2200/141 : Preventing contamination, tampering
• CPC Class Codes: B01L 2200/148 : Specific details about calibrations
• CPC Class Codes: B01L 2300/0654 : Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0829 : Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 2300/1805 : Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
• CPC Class Codes: B01L 2400/043 : magnetic forces
• CPC Class Codes: B01L 3/021 : Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
• CPC Class Codes: B01L 3/0262 : using touch-off at substrate or container
• CPC Class Codes: B01L 3/5025 : for parallel transport of multiple samples
• CPC Class Codes: B01L 3/527 : for a plurality of reagents
• CPC Class Codes: B01L 7/52 : with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples amplification or hybridisation processes per se C12Q1/68; controlling sequential reactions for synthesis B01J19/0046
• CPC Class Codes: B01L 7/5255 : by moving sample containers
• CPC Class Codes: B01L 9/543 : for disposable pipette tips, e.g. racks or cassettes
• CPC Class Codes: G01N 1/38 : Diluting, dispersing or mixing samples
• CPC Class Codes: G01N 2035/00237 : Handling microquantities of analyte, e.g. microvalves, capillary networks
• CPC Class Codes: G01N 2035/00851 : process control parameters
• CPC Class Codes: G01N 2035/00881 : network configurations
• CPC Class Codes: G01N 2035/0097 : monitoring reactions as a function of time
• CPC Class Codes: G01N 2035/1032 : Dilution or aliquotting
• CPC Class Codes: G01N 2035/1034 : Transferring microquantities of liquid
• CPC Class Codes: G01N 2035/1048 : using the transfer device for another function
• CPC Class Codes: G01N 2333/4737 : C-reactive protein
• CPC Class Codes: G01N 2333/475 : Assays involving growth factors
• CPC Class Codes: G01N 2333/71 : for growth factors; for growth regulators
• CPC Class Codes: G01N 2333/912 : transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: G01N 2333/91205 : Phosphotransferases in general
• CPC Class Codes: G01N 2333/9129 : Transferases for other substituted phosphate groups (2.7.8)
• CPC Class Codes: G01N 2800/26 : Infectious diseases, e.g. generalised sepsis
• CPC Class Codes: G01N 2800/60 : Complex ways of combining multiple protein biomarkers for diagnosis
• CPC Class Codes: G01N 33/5302 : Apparatus specially adapted for immunological test procedures
• CPC Class Codes: G01N 33/5304 : Reaction vessels, e.g. agglutination plates for solid-phase systems G01N33/543
• CPC Class Codes: G01N 33/54326 : Magnetic particles
• CPC Class Codes: G01N 33/54366 : Apparatus specially adapted for solid-phase testing
• CPC Class Codes: G01N 33/54386 : Analytical elements
• CPC Class Codes: G01N 33/56966 : Animal cells
• CPC Class Codes: G01N 33/57484 : involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
• CPC Class Codes: G01N 33/6803 : General methods of protein analysis not limited to specific proteins or families of proteins
• CPC Class Codes: G01N 33/94 : involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
• CPC Class Codes: G01N 35/00732 : Identification of carriers, materials or components in automatic analysers
• CPC Class Codes: G01N 35/00871 : Communications between instruments or with remote terminals
• CPC Class Codes: G01N 35/028 : having reaction cells in the form of microtitration plates
• CPC Class Codes: G01N 35/10 : Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices G01N35/0099 takes precedence
• CPC Class Codes: G01N 35/1065 : Multiple transfer devices
• CPC Class Codes: G01N 35/1074 : arranged in a two-dimensional array
• CPC Class Codes: G16H 10/40 : for data related to laboratory analysis, e.g. patient specimen analysis
• CPC Class Codes: Y10T 29/49826 : Assembling or joining
• CPC Class Codes: Y10T 436/25375 : Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]

Abstract

The present invention provides devices and systems for use at the point of care. The methods devices of the invention are directed toward automatic detection of analytes in a bodily fluid. The components of the device are modular to allow for flexibility and robustness of use with the disclosed methods for a variety of medical applications.

Claims

1. A cartridge for automated detection of an analyte in a bodily fluid sample comprising:

an array of addressable assay units configured to run a chemical reaction that yields a detectable signal indicative of the presence or absence of the analyte; and

an array of addressable reagent units, wherein an individual addressable reagent unit of the array is addressed to correspond to an individual addressable assay unit of the array of assay units, and wherein the individual reagent unit is configured to be calibrated in reference to the corresponding individual assay unit before the arrays are assembled on the cartridge.

3. The device of claim 1 further comprising a sample collection unit configured to receive the bodily fluid sample.

4. The device of claim 1 or 2, wherein the individual reagent unit is configured to receive a movable assay unit.

5. The device of claim 1 or 2, wherein the individual assay unit comprises an assay tip.

6. The device of claim 1 or 2, wherein the individual assay unit is configured to run an immunoassay.

7. The device of claim 1 or 2, wherein the bodily fluid sample is a blood sample.

10. The device of claim 1 or 2 further comprising a pretreatment unit configured to retrieve a portion of the bodily fluid sample for running the chemical reaction to detect the analyte.

11. The device of claim 10, wherein the bodily fluid is a whole blood sample and the portion is plasma.

12. A system for automated detection of an analyte in a bodily fluid sample comprising:

a. a device of claim 1 or 2; and

b. a detection assembly for detecting the detectable signal indicative of the presence or absence of the analyte.

13. The system of claim 12 further comprising a programmable mechanical device configured to move the individual assay unit from a first location to a second location.

14. The system of claim 12 further comprising a fluid transfer device.

15. The system of claim 14, wherein the fluid transfer device is a pipette.

16. The system of claim 14, wherein the fluid transfer device is automated.

17. The system of claim 12 further comprising a communication assembly for transmitting a protocol based on the analyte to be detected.

18. The system of claim 12 further comprising a heating block configured to receive the individual assay unit.

19. The system of claim 12 further comprising a magnetic block.

38. A method of detecting an analyte in a bodily fluid sample comprising:

a. providing a blood sample to the device of claim 1 or 2;

b. allowing said sample to react within at least one assay unit; and

c. detecting said detectable signal generated from said analyte collected in said sample of bodily fluid.

39. The method of claim 38, wherein the bodily fluid sample is blood and the method further comprises retrieving plasma from the blood.

67. The method of claim 59, wherein the method is carried out in a system of claim 12 or 19.

75. The method of claim 68, wherein the method is carried out in a system of claim 12 or 19.

2. A cartridge for automated detection of an analyte in a bodily fluid sample comprising:

a sample collection unit configured to receive the bodily fluid sample;

an array of assay units configured to receive a portion of the sample from the sample collection unit and run a chemical reaction that yields a detectable signal indicative of the presence of the analyte in the sample; and

an array of reagent units containing reagents for running the chemical reaction;

wherein an individual assay unit of the array of assay units and an individual reagent unit of the array of reagent units are configured to be movable into fluid communication such that reagents for running the chemical reaction are brought to contact with the portion of the sample in the assay unit.

8. The device of claim 2 or 3, wherein the sample collection unit is configured to receive a volume of the bodily fluid sample about 20 microliters or less.

9. The device of claim 2 or 3, wherein the sample collection unit is configured to receive a volume of the bodily fluid sample that is a single drop of blood.

20. A system for automated detection of a plurality of analytes in a bodily fluid sample, comprising:

a fluidic device comprising;

a sample collection unit configured to contain the bodily fluid sample;

an array of assay units, wherein an individual assay unit of said array of assay units is configured to run a chemical reaction that yields a signal indicative of an individual analyte of said plurality of analytes being detected; and

an array of reagent units, wherein an individual reagent unit of said array of reagent units contains a reagent; and

a fluid transfer device comprising a plurality of heads, wherein an individual head of the plurality of heads is configured to engage the individual assay unit, and wherein said fluid transfer device comprises a programmable processor configured to direct fluid transfer of the bodily fluid sample from the sample collection unit and the reagent from the individual reagent unit into the individual assay unit.

21. The system of claim 20, wherein the configuration of the processor to direct fluid transfer effects a degree of dilution of the bodily fluid sample in the array of assay units to bring signals indicative of the plurality of analytes being detected within a detectable range, such that said plurality of analytes are detectable with said system.

22. The system of claim 21, wherein the bodily fluid sample comprises at least two analytes that are present at concentrations that differ by at least 2 orders of magnitude.

23. The system of claim 21, wherein the bodily fluid sample comprises at least two analytes that are present at concentrations that differ by at least 5 orders of magnitude.

24. The system of claim 22, wherein the degree of dilution of the bodily fluid sample brings the signals indicative of the at least two analytes within the detectable range.

25. The system of claim 21 further comprising a detector configured to detect signal intensities of the detectable range.

26. The system of claim 25, wherein the detector is a photomultiplier.

27. The system of claim 26, wherein the detectable range is about 1000 to about 1 million counts per second.

28. The system of claim 20, wherein the bodily fluid sample is less than about 20 ul.

29. The system of claim 20, wherein the bodily fluid sample is a single drop of blood.

30. The system of claim 20, wherein the individual head is configured to adhere to the individual assay unit.

31. The system of claim 20, wherein said individual assay unit provides an immunoassay reaction site.

32. The system of claim 20, wherein said individual assay unit is a pipette tip.

33. The system of claim 20, wherein the fluid transfer device is a pipette.

34. The system of claim 33, wherein the pipette is an air-displacement pipette.

35. The system of claim 20, wherein said fluid transfer device further comprises a motor in communication with the programmable processor.

36. The system of claim 35, wherein the motor moves said plurality of heads based on a protocol from said programmable processor, optionally wherein the programmable processor responds to a protocol transmitted from an external device.

37. A system for automated detection of an analyte in a plasma portion of a whole blood sample, comprising:

a. a device configured to automatically receive and process the whole blood sample to yield the plasma portion, from which a detectable signal indicative of the presence or absence of the analyte of interest is generated onboard the device; and

b. a detection assembly for detecting the detectable signal indicative of the presence or absence of the analyte.

40. A method of on-demand assembly of a cartridge for automated detection of an analyte in a bodily fluid sample, wherein the device comprises a housing, said housing comprising:

an array of addressable assay units, wherein an individual assay unit of the array is configured to run a chemical reaction that yields a detectable signal indicative of the presence or absence of the analyte; and

an array of addressable reagent units, wherein an individual reagent unit of the array is addressed to correspond to the individual assay unit, said method comprising;

(i) placing according to the analyte to be detected an array of addressable assay units, wherein an individual assay unit of the array is configured to run a chemical reaction that detects an analyte of interest ordered by said end user, into the housing;

(ii) placing according to the analyte to be detected an array of reagent units, wherein an individual reagent unit of the array corresponds to the individual assay unit, into the housing; and

(iii) securing the arrays of (i) and (ii) within the housing of the device.

41. The method of claim 40 further comprising selecting an analyte to be detected.

42. The method of claim 40 further comprising sealing the cartridge.

43. The method of claim 40 further comprising labeling the cartridge with a readable label indicating the analyte to be detected.

44. The method of claim 43, wherein the readable label is a bar code or RFID.

45. A method for automated detection of a plurality of analytes in a bodily fluid sample, comprising:

a. providing the bodily fluid sample to a fluidic device, wherein the fluidic device comprises;

a sample collection unit configured to contain the bodily fluid sample;

an array of assay units, wherein an individual assay unit of said array of assay units is configured to run a chemical reaction that yields a signal indicative of an individual analyte of said plurality of analytes being detected; and

an array of reagent units, wherein an individual reagent unit of said array of reagent units contains a reagent;

b. engaging the individual assay unit using a fluid transfer device;

c. transferring the bodily fluid sample from the sample collection unit to the individual assay unit using the fluid transfer device; and

d. transferring the reagent from the individual reagent unit to the individual assay unit, thereby reacting the reagent with the bodily fluid sample to yield the signal indicative of the individual analyte of the plurality of analytes being detected.

46. The method of claim 45, wherein the fluid transfer device comprises a plurality of heads, wherein an individual head of the plurality of heads is configured to engage the individual assay unit;

and wherein said fluid transfer device comprises a programmable processor configured to direct fluid transfer of the bodily fluid sample from the sample collection unit and the reagent from the individual reagent unit into the individual assay unit.

47. The method of claim 46 further comprising providing instructions to the programmable processor.

48. The method of claim 47, wherein the instructions direct the step of transferring the bodily fluid sample to the individual assay unit.

49. The method of claim 45, wherein the step of transferring the bodily fluid sample effects a degree of dilution of the bodily fluid sample in the individual assay unit to bring the signal indicative the individual analyte of the plurality of analytes being detected within a detectable range.

50. The method of claim 45, wherein the bodily fluid sample comprises at least two individual analytes that are present at concentrations that differ by at least 2 orders of magnitude.

51. The method of claim 45, wherein the bodily fluid sample comprises at least two individual analytes that are present at concentrations that differ by at least 5 orders of magnitude.

52. The method of claim 50, wherein the degree of dilution of the bodily fluid sample brings the signals indicative of the at least two individual analytes within the detectable range.

53. The method of claim 45, wherein the detectable range is detected with a photomultiplier and is about 1000 to about 1 million counts per second.

54. The method of claim 45, wherein the bodily fluid sample is less than about 20 ul.

55. The method of claim 45, wherein the bodily fluid sample is a single drop of blood.

56. The method of claim 45, wherein the reagent in the individual reagent unit is an enzyme substrate for an immunoassay.

57. The method of claim 56 further comprising repeating the step of transferring the reagent from the individual reagent unit after the reaction to yield the signal indicative of the individual analyte of the plurality of analytes being detected is complete, thereby creating a second reaction to yield a second signal indicative of the individual analyte.

58. The method of claim 57, wherein an intensity of the signal and a second intensity of the second signal indicative of the individual analyte are averaged to calculate the final intensity of the signal indicative of the individual analyte.

59. A method of measuring a volume of a sample of a biological fluid, comprising:

a. reacting a known quantity of a control analyte in said sample with a reagent to yield a detectable signal indicative of the quantity of the control analyte; and

b. comparing said detectable signal with an expected detectable signal, wherein the expected signal is indicative of an expected volume of the sample, and wherein said comparison provides a measurement of said volume of said sample being measured.

60. The method of claim 59, wherein the control analyte is normally not present in said sample in a detectable amount.

61. The method of claim 59 further comprising verifying the volume of said sample when the measurement of the volume of the sample is within about 50% of the expected volume of the sample.

62. The method of claim 59 further comprising:

a. reacting a bodily fluid sample containing a target analyte with a reagent to yield a detectable signal indicative of the target analyte; and

b. measuring the quantity of the target analyte in the bodily fluid sample based on of said detectable signal indicative of the target analyte and the measurement of said volume of said liquid sample.

63. The method of claim 59, wherein the liquid sample and the bodily fluid sample are the same sample.

64. The method of claim 59, wherein the control analyte does not react with the target analyte in the bodily fluid sample.

65. The method of claim 59, wherein the liquid sample and the bodily fluid sample are different liquid samples.

66. The method of claim 59, wherein the control analyte is selected from the group consisting of:

albumin, fluorescein, IgG, protein C, fluorescein-labeled albumin, fluorescein labeled IgG, anti-fluorescein, anti-digoxigenin, digoxigenin-labeled albumin, digoxigenin-labeled IgG, biotinylated proteins, and non-human IgG

68. A method of retrieving plasma from a blood sample comprising:

a. mixing a blood sample in the presence of magnetizable particles in a sample collection unit, wherein the magnetizable particles comprise an antibody capture surface for binding to non-plasma portions of the blood sample; and

b. applying a magnetic field above a plasma collection area to the mixed blood sample to effect suspension of the non-plasma portions of the blood sample on top of the plasma collection area.

69. The method of claim 68, wherein the sample collection unit is a capillary tube.

70. The method of claim 68, wherein the blood sample is less than about 20 microliters.

71. The method of claim 68, wherein the plasma retrieved is less than about 10 microliters.

72. The method of claim 68, wherein the blood sample is not diluted.

73. The method of claim 68, wherein the mixing occurs in the presence of antibodies unbound to a solid surface.

74. The method of claim 68, wherein the mixing comprises mixing by syringe action.

76. A method of using automated immunoassay for detecting an analyte present in plasma portion of a whole blood sample, comprising:

a. providing a whole blood sample to a device that is configured to automatically receive and process on board the whole blood sample to yield the plasma portion, from which a detectable signal indicative of the presence or absence of the analyte of interest is generated on board;

b. detecting said signal that is indicative of the presence or absence of the analyte in said bodily fluid sample; and

c. transmitting result of (b) to an end user.

77. The method of claim 76, wherein the immunoassay is ELISA.

78. The method of claim 76, wherein the result is transmitted wirelessly.