Systems and methods for multi-analysis

• US 10,534,009 B2
• Filed: 09/21/2015
• Issued: 01/14/2020
• Est. Priority Date: 09/25/2011
• Status: Active Grant

• Current Assignee: Labrador Diagnostics LLC (SoftBank Group Corp.)
• Original Assignee: Theranos IP Company, LLC
• Inventors: Holmes, Elizabeth A., Pangarkar, Chinmay, Anekal, Samartha
• Primary Examiner(s): Whatley, Benjamin R
• Application Number:
  US14/860,149
• Publication Number:
  US 20160025763A1
• Time in Patent Office: 1,576 Days
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2300/1855 using phase changes in a medium
• CPC Class Codes: B01L 3/021 Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
• CPC Class Codes: B01L 3/5027 by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B01L 3/5082 Test tubes per se
• CPC Class Codes: B01L 3/50855 using modular assemblies of strips or of individual wells
• 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 9/06 Test-tube stands; Test-tube holders
• CPC Class Codes: B01L 9/52 Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
• CPC Class Codes: B01L 9/543 for disposable pipette tips, e.g. racks or cassettes
• CPC Class Codes: C12Q 1/42 involving phosphatase
• CPC Class Codes: C12Q 1/52 involving transaminase
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 1/70 involving virus or bacteriophage immunoassay for viruses G01N33/56983
• CPC Class Codes: G01N 15/1433 using image recognition
• CPC Class Codes: G01N 2015/012 Red blood cells
• CPC Class Codes: G01N 2015/016 White blood cells
• CPC Class Codes: G01N 2015/1006 for cytology
• CPC Class Codes: G01N 2015/1486 Counting the particles
• CPC Class Codes: G01N 2035/00138 Slides
• CPC Class Codes: G01N 2035/00148 : Test cards, e.g. Biomerieux or McDonnel multiwell test cards
• CPC Class Codes: G01N 2035/00237 : Handling microquantities of analyte, e.g. microvalves, capillary networks
• CPC Class Codes: G01N 2035/00306 : Housings, cabinets, control panels (details)
• CPC Class Codes: G01N 2035/00326 : Analysers with modular structure
• CPC Class Codes: G01N 2035/00356 : Holding samples at elevated temperature (incubation)
• CPC Class Codes: G01N 2035/00366 : Several different temperatures used
• CPC Class Codes: G01N 2035/00425 : Heating or cooling means associated with pipettes or the like, e.g. for supplying sample/reagent at given temperature
• CPC Class Codes: G01N 2035/00435 : Refrigerated reagent storage
• CPC Class Codes: G01N 2035/00495 : Centrifuges
• CPC Class Codes: G01N 2035/00633 : logging process history of individual samples
• CPC Class Codes: G01N 2035/0449 : using centrifugal transport of liquid
• CPC Class Codes: G01N 2035/0474 : Details of actuating means for conveyors or pipettes
• CPC Class Codes: G01N 2035/0486 : Gearing, cams
• CPC Class Codes: G01N 2035/0491 : Position sensing, encoding; closed-loop control
• CPC Class Codes: G01N 2035/0493 : Locating samples; identifying different tube sizes
• CPC Class Codes: G01N 2035/0494 : Detecting or compensating piositioning errors
• CPC Class Codes: G01N 21/25 : Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
• CPC Class Codes: G01N 21/27 : using photo-electric detection G01N21/31 takes precedence; circuits for computing concentration logarithmic circuits G06G7/24; photometric circuits in general G01J
• CPC Class Codes: G01N 2201/024 : Modular construction
• CPC Class Codes: G01N 2201/04 : Batch operation; multisample devices
• CPC Class Codes: G01N 2201/12 : Circuits of general importance; Signal processing
• CPC Class Codes: G01N 33/5005 : involving human or animal cells immunoassay G01N33/56966; immunoassays of protozoa G01N33/56905; protozoa in screening assays C12Q1/025
• CPC Class Codes: G01N 33/54306 : Solid-phase reaction mechanisms
• CPC Class Codes: G01N 33/54313 : the carrier being characterised by its particulate form
• CPC Class Codes: G01N 33/54366 : Apparatus specially adapted for solid-phase testing
• CPC Class Codes: G01N 33/56972 : White blood cells
• CPC Class Codes: G01N 33/56983 : Viruses
• CPC Class Codes: G01N 33/62 : involving urea
• CPC Class Codes: G01N 33/6827 : Total protein determination, e.g. albumin in urine
• CPC Class Codes: G01N 33/80 : involving blood groups or blood types or red blood cells white blood cells G01N33/56972
• CPC Class Codes: G01N 33/92 : involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743
• CPC Class Codes: G01N 35/00 : Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
• CPC Class Codes: G01N 35/00029 : provided with flat sample substrates, e.g. slides G01N35/028 takes precedence
• CPC Class Codes: G01N 35/00069 : whereby the sample substrate is of the bio-disk type, i.e. having the format of an optical disk
• CPC Class Codes: G01N 35/00623 : of instruments
• CPC Class Codes: G01N 35/00871 : Communications between instruments or with remote terminals
• CPC Class Codes: G01N 35/0092 : Scheduling
• CPC Class Codes: G01N 35/026 : having blocks or racks of reaction cells or cuvettes
• CPC Class Codes: G01N 35/04 : Details of the conveyor system G01N35/021 - G01N35/028 take precedence
• 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 35/1009 : Characterised by arrangements for controlling the aspiration or dispense of liquids
• CPC Class Codes: G01N 35/1011 : Control of the position or alignment of the transfer device
• CPC Class Codes: G01N 35/1065 : Multiple transfer devices
• CPC Class Codes: G01N 35/1072 : with provision for selective pipetting of individual channels
• CPC Class Codes: Y10T 436/111666 : Utilizing a centrifuge or compartmented rotor
• CPC Class Codes: Y10T 436/113332 : with conveyance of sample along a test line in a container or rack

Abstract

Systems and methods are provided for sample processing. A device may be provided, capable of receiving the sample, and performing one or more of a sample preparation, sample assay, and detection step. The device may be capable of performing multiple assays. The device may comprise one or more modules that may be capable of performing one or more of a sample preparation, sample assay, and detection step. The device may be capable of performing the steps using a small volume of sample.

Claims

1. An automated method of performing three or more assays for detecting a plurality of analytes in a biological sample, comprising:

receiving a cartridge comprising a biological sample obtained from a subject in a single biological sample processing device, wherein the cartridge further comprises;

at least three assay vessels for performing the three or more assays to detect a plurality of analytes in the biological sample,

wherein (i) each of the at least three assay vessels performs a different one of the three or more assays, (ii) the three or more assays comprise a nucleic acid amplification and immunoassay, and (iii) the plurality of analytes comprise an antibody, antigen, and nucleic acid; and

reagents for performing the three or more assays,

at least a first inert liquid for use in the nucleic acid amplification and a second inert liquid for use in the immunoassay, wherein the first and second inert liquids are immiscible with and have lower densities than the sample, and wherein the first and second inert liquids are different;

and wherein the biological sample processing device comprises;

at least one automated sample handling device comprising a first pipette head and a second pipette head, wherein the first pipette head and the second pipette head are mounted on a common support structure and are independently movable and independently controllable in relation to the other;

a thermal control unit providing thermocycling for the nucleic acid amplification;

and at least one optical detector;

performing in the biological sample processing device the three or more assays by introducing the sample, at least one of the reagents, and at least the first inert liquid or the second inert liquid into the assay vessel to form a barrier layer therein, wherein the three or more assays are performed at least partially in parallel, and;

detecting the presence or absence of the plurality of analytes with the at least one optical detector in the biological sample processing device;

bringing an open end of a pipette tip on the sample handling device into contact with the barrier layer in the assay vessel to cover a portion of the pipette tip, sealing the pipette tip with a portion of the barrier layer remaining on the pipette tip after the pipette tip is removed from the assay vessel.

2. The method of claim 1, wherein the biological sample is a blood sample.

3. The method of claim 2, wherein the blood sample obtained from the subject is about 500 μ

l or less.

4. The method of claim 2, wherein the three or more assays are performed from a single blood sample obtained from the subject.

5. The method of claim 2, wherein the blood sample is a plasma sample.

6. The method of claim 1, wherein the cartridge comprises at least four assay vessels and the biological sample processing device performs four or more assays at least partially in parallel, wherein the four or more assays comprise a nucleic acid amplification, immunoassay, and cytometric assay, and wherein the plurality of analytes comprise an antibody, antigen, nucleic acid, and cell.

7. The method of claim 6, wherein the biological sample processing device further comprises a cytometer.

8. The method of claim 1, wherein the biological sample processing device further comprises a centrifuge.

9. The method of claim 1, wherein at least one of reagents comprises beads for capturing the antibody and/or antigen from the biological sample.

10. The method of claim 1, wherein the nucleic acid is a nucleic acid of a virus selected from measles, mumps, rubella, poliomyelitis, hepatitis A, hepatitis B, hepatitis C, hepatitis delta, hepatitis E, influenza, adenovirus, rabies, yellow fever, Epstein-Barr virus, papillomavirus, Ebola virus, Japanese encephalitis, dengue virus, hantavirus, Sendai virus, respiratory syncytial virus, orthomyxovirus, vesicular stomatitis virus, visna virus, cytomegalovirus, human immunodeficiency virus, and herpes simplex virus.

11. The method of claim 1, wherein the at least one automated sample handling device comprises at least two different mechanisms for dispensing and/or aspirating a fluid.

12. The method of claim 11, wherein the two different mechanisms for dispensing and/or aspirating a fluid is selected from the group positive displacement, air displacement, and suction.

13. The method of claim 1, wherein the first pipette head is a positive displacement pipette head and the second pipette head is an air displacement pipette head.

14. The method of claim 1, wherein the first pipette head and the second pipette head each have a coefficient of variation of about 2% or lower.

15. The method of claim 1, wherein the at least one automated sample handling device has a dimension of about 500 cm³ or less total volume.

16. A biological sample processing system comprising;

a cartridge, wherein the cartridge comprises;

at least three assay vessels for performing at least partially in parallel three or more assays to detect a plurality of analytes in a biological sample obtained from a subject,

wherein (i) each of the at least three assay vessels performs a different one of the three or more assays, (ii) the three or more assays comprise a nucleic acid amplification and immunoassay, and (iii) the plurality of analytes comprise an antibody, antigen, and nucleic acid; and

reagents for performing the three or more assays,

at least a first inert liquid for use in the nucleic acid amplification and a second inert liquid for use in the immunoassay, wherein the first and second inert liquids are immiscible with and have lower densities than the sample, and wherein the first and second inert liquids are different;

and a biological sample processing device comprising;

at least one automated sample handling device comprising a first pipette head and a second pipette head, wherein the first pipette head and the second pipette head are mounted on a common support structure and are independently movable and independently controllable in relation to the other;

a thermal control unit providing thermocycling for the nucleic acid amplification;

and at least one optical detector for detecting the presence or absence of the plurality of analytes;

wherein the sample handling device comprises a controller programmed to introduce the sample, at least one of the reagents, and at least the first inert liquid or the second inert liquid into the assay vessel to form a barrier layer therein and to bring a pipette tip into contact with the barrier layer on the assay vessel to cover a portion of the pipette tip, sealing the pipette tip with a portion of the barrier layer remaining on the pipette tip after the pipette tip is removed from the assay vessel.

17. The system of claim 16, comprising at least four assay vessels for performing at least partially in parallel four or more assays, wherein the four or more assays comprise a nucleic acid amplification, immunoassay, and cytometric assay, and wherein the plurality of analytes comprise an antibody, antigen, nucleic acid, and cell.

18. The system of claim 17, wherein the biological sample processing device further comprises a cytometer.

19. The system of claim 16, wherein the biological sample processing device further comprises a centrifuge.

20. The system of claim 16, wherein the at least three assay vessels are each fluidically isolated and movable.

21. The system of claim 16, wherein the biological sample is a blood sample and the system is configured to receive a blood sample of about 500 μ

l or less.

22. The system of claim 16, wherein at least one of the reagents comprises beads for capturing the antibody and/or antigen from the biological sample.

23. The system of claim 16, wherein the nucleic acid is a nucleic acid of a virus selected from measles, mumps, rubella, poliomyelitis, hepatitis A, hepatitis B, hepatitis C, hepatitis delta, hepatitis E, influenza, adenovirus, rabies, yellow fever, Epstein-Barr virus, papillomavirus, Ebola virus, Japanese encephalitis, dengue virus, hantavirus, Sendai virus, respiratory syncytial virus, orthomyxovirus, vesicular stomatitis virus, visna virus, cytomegalovirus, human immunodeficiency virus, and herpes simplex virus.

24. The system of claim 16, wherein the at least one automated sample handling device comprises at least two different mechanisms for dispensing and/or aspirating a fluid.

25. The system of claim 24, wherein the two different mechanisms for dispensing and/or aspirating a fluid is selected from the group positive displacement, air displacement, and suction.

26. The system of claim 16, wherein the first pipette head is a positive displacement pipette head and the second pipette head is an air displacement pipette head.

27. The system of claim 16, wherein the first pipette head and the second pipette head each have a coefficent of variation of about 2% or lower.

28. The system of claim 16, wherein the at least one automated sample handling device has a dimension of about 500 cm³ or less total volume.