Instrument for processing cartridge for performing assays in a closed sample preparation and reaction system

• US 9,498,778 B2
• Filed: 11/11/2014
• Issued: 11/22/2016
• Est. Priority Date: 11/11/2014
• Status: Active Grant

• Current Assignee: Roche Molecular Systems (Roche Holding AG)
• Original Assignee: Genmark Diagnostics Incorporated (Roche Holding AG)
• Inventors: Murphy, Brian, Schneider, Eric, Fish, Andrew, Srinivasan, Jay, Maltezos, George, Corey, Scott, Wright, David Walter, Aiello, Dominic
• Primary Examiner(s): Gordon, Brian R
• Application Number:
  US14/538,565
• Publication Number:
  US 20160129445A1
• Time in Patent Office: 742 Days
• US Class Current: 1/1
• CPC Class Codes: B01L 2200/027 for microfluidic devices
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2200/0684 Venting, avoiding backpressure, avoid gas bubbles
• 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 2200/14 Process control and prevention of errors
• CPC Class Codes: B01L 2300/021 Identification, e.g. bar codes
• CPC Class Codes: B01L 2300/022 Transponder chips
• CPC Class Codes: B01L 2300/0609 Holders integrated in container to position an object
• CPC Class Codes: B01L 2300/0636 Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0645 Electrodes
• CPC Class Codes: B01L 2300/0663 Whole sensors
• CPC Class Codes: B01L 2300/0681 Filter
• CPC Class Codes: B01L 2300/0809 rectangular shaped
• CPC Class Codes: B01L 2300/0858 Side walls
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/087 Multiple sequential chambers
• CPC Class Codes: B01L 2300/123 Flexible; Elastomeric
• CPC Class Codes: B01L 2300/18 Means for temperature control
• 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 2300/1827 : using resistive heater
• CPC Class Codes: B01L 2400/0427 : Electrowetting
• CPC Class Codes: B01L 2400/043 : magnetic forces
• CPC Class Codes: B01L 2400/0481 : squeezing of channels or chambers
• CPC Class Codes: B01L 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/06 : Valves, specific forms thereof
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502723 : characterised by venting arrangements
• CPC Class Codes: B01L 3/50273 : characterised by the means or forces applied to move the fluids micropumps F04B19/006, of the membrane type F04B43/043
• CPC Class Codes: B01L 3/502738 : characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B01L 3/502792 : for moving individual droplets on a plate, e.g. by locally altering surface tension
• CPC Class Codes: B01L 3/505 : flexible containers not provided for above
• 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: C12Q 1/6806 : Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay C12Q1/6804 takes precedence
• CPC Class Codes: C12Q 1/6846 : Common amplification features
• CPC Class Codes: C12Q 2563/113 : the label being electroactive, e.g. redox labels
• CPC Class Codes: C12Q 2563/143 : Magnetism, e.g. magnetic label
• CPC Class Codes: C12Q 2563/159 : Microreactors, e.g. emulsion PCR or sequencing, droplet PCR, microcapsules, i.e. non-liquid containers with a range of different permeability's for different reaction components
• CPC Class Codes: C12Q 2565/629 : being a microfluidic device

Abstract

In one embodiment, a multiplex fluid processing cartridge includes a sample well, a deformable fluid chamber, a mixing well with a mixer disposed therein, a lysis chamber including a lysis mixer, an electrowetting grid for microdroplet manipulation, and electrosensor arrays configured to detect analytes of interest. An instrument for processing the cartridge is configured to receive the cartridge and to selectively apply thermal energy, magnetic force, and electrical connections to one or more discrete locations on the cartridge and is further configured to compress the deformable chamber(s) in a specified sequence.

Claims

1. An instrument configured to process a fluid sample processing cartridge including a deformable fluid chamber supported on a planar substrate and configured to hold a fluid therein when in an undeformed state and to collapse upon application of an external compression force to expel at least a portion of the fluid from the fluid chamber, said instrument comprising:

a cartridge carriage assembly configured to receive and hold a fluid sample processing cartridge inserted into the instrument;

a heating and control assembly adjacent the cartridge carriage assembly and configured for movement with respect to the cartridge carriage assembly between a first position not in operative contact with the cartridge carried within the cartridge carriage assembly and a second position in operative contact with the cartridge carried within the cartridge carriage assembly;

one or more movable magnet assemblies, each mounted for movement with respect to the cartridge carriage assembly independently of the heating and control assembly between a first position applying substantially no magnetic force to the cartridge and a second position applying magnetic force to corresponding discrete portions of the cartridge;

a cam block assembly configured for powered movement and operatively coupled to the heating and control assembly for converting powered movement of the cam block assembly into movement of the heating and control assembly with respect to the cartridge carriage assembly between the first position of the heating and control assembly and the second position of the heating and control assembly and operatively coupled to the one or more moveable magnet assemblies for converting powered movement of the cam block assembly into movement of each magnet assembly with respect to cartridge carriage assembly between the first position of the magnet assembly and the second position of the magnet assembly; and

a deformable chamber compression assembly configured to selectively apply an external compression force to the deformable fluid chamber to collapse the deformable chamber and expel at least a portion of the fluid from the fluid chamber.

2. The instrument of claim 1, wherein said heating and control assembly comprises:

one or more heater assemblies configured to apply a thermal gradient to corresponding discrete portions of the cartridge when the heating and control assembly is in the second position; and

a connector board including one or more electrical connector elements configured to effect an electrical connection between the instrument and the cartridge when the heating and control assembly is in the second position.

3. The instrument of claim 1, wherein said deformable chamber compression assembly comprises:

a cam follower plate configured for powered movement in a first direction that is generally parallel to the plane of the substrate; and

a compression mechanism associated with the deformable chamber of the cartridge and configured to apply a force compressing the chamber against the substrate by movement in a second direction having a component that is generally normal to the plane of the substrate,

wherein the cam follower plate is operatively coupled to the compression mechanism to convert movement of the cam follower plate in the first direction into movement of the compression mechanism in the second direction to thereby apply an external compression force to the chamber.

4. The instrument of claim 1, further comprising a pneumatic pump and a pneumatic port connected to the pneumatic pump, wherein the pneumatic port is configured to couple the pneumatic pump to a pressure port of the fluid sample processing cartridge when the cartridge is inserted into the instrument.

5. The instrument of claim 1, further comprising an optical detector configured to detect fluid flow through a part of the fluid sample processing cartridge.

6. The instrument of claim 1, wherein the fluid sample processing cartridge includes a driven mixing apparatus including a drive gear, and wherein the instrument further comprises a mixing motor assembly including a powered driving gear and moveable between a first position in which the driving gear is not engaged with the drive gear of the driven mixing apparatus and a second position in which the driving gear is operatively engaged with the drive gear to actuate the driven mixing apparatus, and wherein the cam block assembly is operatively coupled to the mixing motor assembly for converting powered movement of the cam block assembly into movement of the mixing motor assembly between the first position of the mixing motor assembly and the second position of the mixing motor assembly.

7. The instrument of claim 2, further comprising a heater cooling assembly comprising:

a fan; and

a cooling duct configured to direct air flow from the fan to a portion of one of said heater assemblies.

8. The instrument of claim 1, wherein said cartridge carriage assembly comprises:

a cartridge holder configured to hold a cartridge inserted therein;

a cartridge latch biased into a cartridge-latching position and configured to latch onto a cartridge inserted into the cartridge holder to retain the cartridge within the cartridge holder; and

a cartridge eject mechanism configured to automatically push a cartridge at least partially out of the cartridge holder when the cartridge latch is released from a cartridge-latching position.

9. The instrument of claim 2, wherein said heating and control assembly comprises a support plate on which said one or more heater assemblies and said connector board are supported, said support plate being mounted in a constrained configuration preventing horizontal movement of the support plate but permitting vertical movement of the support plate to enable movement of the heating and control assembly between its first and second positions.

10. The instrument of claim 2, wherein one of said heater assemblies of the heating and control assembly comprises a resistive heating element attached to the connector board and a heat spreader comprising a thermally-conductive material thermally coupled to the resistive heating element.

11. The instrument of claim 2, wherein one of said heater assemblies of the heating and control assembly comprises:

a thermoelectric element;

a heat spreader comprising a thermally-conductive material thermally coupled to the thermoelectric element; and

a heat sink including a panel that is in thermal contact with the thermoelectric element and a plurality of heat-dissipating rods.

12. The instrument of claim 2, wherein the electrical connector elements of the connector board of the heating and control assembly comprise a plurality of connector pin arrays, each connector pin array comprising a plurality of pogo pins.

13. The instrument of claim 1, wherein one of the movable magnet assemblies comprises:

a magnet holder mounted on a spindle so as to be rotatable about the spindle between the first position and the second position of the magnet assembly;

a magnet supported on the magnet holder;

an actuator bracket extending from the magnet holder; and

a torsion spring configured to bias the magnet holder to a rotational position corresponding to the first position of the magnet assembly.

14. The instrument of claim 1, wherein one of the movable magnet assemblies comprises:

a magnet holder frame mounted on a spindle so as to be rotatable about the spindle between the first position and the second position of the magnet assembly;

a magnet array disposed within the magnet holder frame;

a focusing magnet disposed within an opening formed in the magnet holder frame and configured to focus magnetic forces of the magnet array;

an actuator bracket extending from the magnet holder frame; and

a torsion spring configured to bias the magnet holder frame to a rotational position corresponding to the first position of the magnet assembly.

15. The instrument of claim 13, wherein the cam block assembly is operatively coupled to each movable magnet assembly by a magnet actuator coupled at one portion thereof to the cam block assembly so as to be moveable by powered movement of the cam block assembly and including a tab configured to be engageable with the actuator bracket of each magnet assembly as the magnet actuator is moved with the cam block assembly to cause corresponding rotation of the magnet assembly from the first position to the second position.

16. The instrument of claim 1, wherein the cam block assembly comprises:

a cam frame;

a cam block motor coupled to the cam frame and configured to effect powered movement of the cam frame; and

first and second cam rails attached to the cam frame, each of the cam rails having two cam slots, wherein the cam block assembly is operatively coupled to the heating and control assembly by cam followers extending from the heating and control assembly into the cam slots such that movement of the cam frame and the cam rails with respect to the heating and control assembly causes corresponding relative movement between the cam followers and the cam slots to move the cam followers between respective first segments of the cam slots corresponding to the first position of the heating and control assembly and respective second segments of the cam slots corresponding to the second position of the heating and control assembly.

17. The instrument of claim 16, wherein the cam frame comprises:

a first longitudinal spar extending along one side of the heating and control assembly;

a second longitudinal spar extending along an opposite side of the heating and control assembly; and

a cross spar extending between the first and second longitudinal spars, and wherein each cam rail is attached to one of the first and second longitudinal spars.

18. The instrument of claim 3, wherein the compression mechanism of the deformable chamber compression assembly comprises:

a cam arm having a cam surface and mounted so as to be pivotable about one end of the cam arm; and

a compression pad disposed at an opposite end of the cam arm, wherein the cam arm is pivotable between a first position in which the compression pad does not contact the associated deformable chamber and a second position in which the compression pad applies a compressive force to the associated deformable chamber to at least partially collapse the chamber.

19. The instrument of claim 18, wherein the deformable chamber compression assembly further comprises a cam arm plate, and the cam arm of the compression mechanism is pivotably mounted within a slot formed in the cam arm plate for pivotable movement of the cam arm with respect to the cam arm plate, and wherein the cam surface of the cam arm projects out of the slot above a surface of the cam arm plate, and wherein the cam follower plate is operatively coupled to the compression mechanism by a cam follower element of the cam follower plate that is engaged with the cam surface of the compression mechanism during movement of the cam follower plate with respect to the cam arm plate to cause the cam arm to pivot from its first position to its second position.

20. The instrument of claim 19, wherein the cam follower plate comprises a cam groove that receives the cam surface of the cam arm projecting above the surface of the cam arm plate, and the cam follower element comprises a follower ridge disposed within the cam groove that contacts the cam surface as the cam follower plate moves with respect to the cam arm plate to cause the cam arm to pivot from its first position to its second position.

21. The instrument of claim 20, comprising a plurality of compression mechanisms each comprising a cam arm pivotably mounted within a slot formed in the cam arm plate and a cam arm surface, and the cam follower plate comprises a plurality of cam grooves, each cam groove being associated with at least one of the compression mechanisms and wherein each cam groove includes a follower ridge disposed within the cam groove that contacts the cam surface of the associated compression mechanism as the cam follower plate moves with respect to the cam arm plate to cause the cam arm of the associated compression mechanism to pivot from its first position to its second position.

22. The instrument of claim 3, wherein the sample processing cartridge includes a plurality of deformable fluid chambers and wherein the deformable chamber compression assembly comprises a plurality of compression mechanisms, each compression mechanism being associated with one of the deformable fluid chambers, and wherein the cam follower plate is operatively coupled to the compression mechanisms to convert movement of the cam follower plate in the first direction into movement of each of the compression mechanisms in the second direction to thereby apply an external compression force to each of the associated chambers in a specified sequence.

23. The instrument of claim 3, wherein the fluid sample processing cartridge includes an externally-actuatable control valve configured to selectively control fluid flow by permitting fluid flow through the valve when not externally actuated and preventing fluid flow through the valve when externally actuated, and wherein the instrument further comprises a valve actuator compression mechanism associated with the externally-actuatable control valve of the sample processing cartridge and configured to actuate the associated externally-actuatable control valve by movement in a second direction having a component that is generally normal to the plane of the substrate, and wherein the cam follower plate is operatively coupled to the valve actuator compression mechanism to convert movement of the cam follower plate in the first direction into movement of the valve actuator compression mechanism in the second direction to thereby actuate the associated externally-actuatable control valve.