System and method for processing and detecting nucleic acids

• US 9,441,219 B2
• Filed: 05/05/2015
• Issued: 09/13/2016
• Est. Priority Date: 02/13/2012
• Status: Active Grant

• Current Assignee: Neumodx Molecular, Inc. (Qiagen NV)
• Original Assignee: Neumodx Molecular, Inc. (Qiagen NV)
• Inventors: Williams, Jeffrey, Brahmasandra, Sundaresh, Kusner, Michael T.
• Primary Examiner(s): Bowers, Nathan
• Assistant Examiner(s): EDWARDS, LYDIA E
• Application Number:
  US14/704,215
• Publication Number:
  US 20150232832A1
• Time in Patent Office: 497 Days
• US Class Current: 1/1
• CPC Class Codes: B01L 2200/025 Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/027 for microfluidic devices
• CPC Class Codes: B01L 2200/0605 Metering of fluids
• CPC Class Codes: B01L 2200/0615 Loss of fluid by dripping
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2200/0684 Venting, avoiding backpressure, avoid gas bubbles
• CPC Class Codes: B01L 2200/0689 Sealing
• 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 2200/12 Specific details about manufacturing devices
• CPC Class Codes: B01L 2200/142 Preventing evaporation
• CPC Class Codes: B01L 2300/021 Identification, e.g. bar codes
• CPC Class Codes: B01L 2300/022 Transponder chips
• CPC Class Codes: B01L 2300/044 pierceable, e.g. films, membranes
• CPC Class Codes: B01L 2300/06 Auxiliary integrated devices, integrated components
• CPC Class Codes: B01L 2300/0609 Holders integrated in container to position an object
• CPC Class Codes: B01L 2300/0627 Sensor or part of a sensor is integrated
• CPC Class Codes: B01L 2300/0636 Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0672 Integrated piercing tool
• CPC Class Codes: B01L 2300/0681 Filter
• 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 2300/0861 : Configuration of multiple channels and/or chambers in a single devices
• 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 2300/0883 : Serpentine channels
• CPC Class Codes: B01L 2300/0887 : Laminated structure
• CPC Class Codes: B01L 2300/0893 : having a very large number of wells, microfabricated wells
• CPC Class Codes: B01L 2300/123 : Flexible; Elastomeric
• CPC Class Codes: B01L 2300/14 : Means for pressure control
• CPC Class Codes: B01L 2300/16 : Surface properties and coatings
• 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 2300/1822 : using Peltier elements
• CPC Class Codes: B01L 2300/1827 : using resistive heater
• CPC Class Codes: B01L 2400/0406 : capillary forces
• CPC Class Codes: B01L 2400/043 : magnetic forces
• CPC Class Codes: B01L 2400/0478 : pistons
• CPC Class Codes: B01L 2400/0481 : squeezing of channels or chambers
• CPC Class Codes: B01L 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0622 : distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
• CPC Class Codes: B01L 2400/065 : sliding valves
• CPC Class Codes: B01L 2400/0655 : pinch valves
• CPC Class Codes: B01L 2400/0694 : vents used to stop and induce flow, backpressure valves
• CPC Class Codes: B01L 2400/086 : using baffles or other fixed flow obstructions
• CPC Class Codes: B01L 3/502 : with fluid transport, e.g. in multi-compartment structures centrifugal-type cuvettes G01N21/07; analysis by separation into components G01N30/00; automatic analysers G01N35/00
• CPC Class Codes: B01L 3/5025 : for parallel transport of multiple samples
• 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 3/502707 : characterised by the manufacture of the container or its components by shaping or joining plastic parts B29C59/00, B29C65/00; by laminating B32B37/00; manufacture of microstructural devices in general B81C
• 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 3/502746 : characterised by the means for controlling flow resistance, e.g. flow controllers, baffles B01L3/502738 takes precedence
• 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 3/508 : rigid containers not provided for above
• CPC Class Codes: B01L 3/527 : for a plurality of reagents
• CPC Class Codes: B01L 3/567 : Valves, taps or stop-cocks in combination with burettes B01L3/0203; in general F16K
• 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 7/525 : with physical movement of samples between temperature zones
• CPC Class Codes: B29C 65/08 : using ultrasonic vibrations non-plastics element to plastics elements B29C65/645
• CPC Class Codes: B29C 65/484 : Moisture curing adhesives
• CPC Class Codes: B29C 65/606 : the rivets being integral with one of the parts to be joined, i.e. staking
• CPC Class Codes: B29C 66/71 : characterised by the composition of the plastics material of the parts to be joined welding bar compositions B29C65/125
• CPC Class Codes: B29C 66/81423 : being concave
• CPC Class Codes: B29C 66/8322 : Joining or pressing tools reciprocating along one axis
• CPC Class Codes: B29K 2021/00 : Use of unspecified rubbers as moulding material
• CPC Class Codes: B29L 2031/756 : Microarticles, nanoarticles
• CPC Class Codes: C12M 23/42 : Integrated assemblies, e.g. cassettes or cartridges
• CPC Class Codes: C12N 13/00 : Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
• CPC Class Codes: C12N 15/1013 : by using magnetic beads
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• 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 1/6813 : Hybridisation assays
• CPC Class Codes: C12Q 1/686 : Polymerase chain reaction [PCR]

Abstract

A system and method for processing and detecting nucleic acids from a set of biological samples, comprising: a capture plate and a capture plate module configured to facilitate binding of nucleic acids within the set of biological samples to magnetic beads; a molecular diagnostic module configured to receive nucleic acids bound to magnetic beads, isolate nucleic acids, and analyze nucleic acids, comprising a cartridge receiving module, a heating/cooling subsystem and a magnet configured to facilitate isolation of nucleic acids, a valve actuation subsystem configured to control fluid flow through a microfluidic cartridge for processing nucleic acids, and an optical subsystem for analysis of nucleic acids; a fluid handling system configured to deliver samples and reagents to components of the system to facilitate molecular diagnostic protocols; and an assay strip configured to combine nucleic acid samples with molecular diagnostic reagents for analysis of nucleic acids.

Claims

1. A molecular diagnostic module configured to process a biological sample and separate a nucleic acid volume from the biological sample, the molecular diagnostic module comprising:

a valve actuation subsystem comprising a set of pins;

an actuator configured to provide relative displacement between a cartridge, for receiving the biological sample, and the valve actuation subsystem, thereby providing an active configuration, wherein in the active configuration the cartridge is disposed proximal the set of pins, and wherein the cartridge comprises a pathway; and

a cam module configured to displace a subset of the set of pins in the active configuration to define a pathway, that facilitates separation of the nucleic acid volume from the biological sample, in the cartridge, wherein in the active configuration the subset of the set of pins cooperatively defines and occludes the pathway of the cartridge.

2. The molecular diagnostic module of claim 1, wherein the actuator of the molecular diagnostic module is a linear actuator, configured to vertically displace the cartridge toward the valve actuation subsystem in the active configuration.

3. The molecular diagnostic module of claim 2, comprising a cartridge platform situated between the valve actuation subsystem and the actuator, the cartridge platform coupled to a set of springs configured to counteract a force provided by the linear actuator.

4. The molecular diagnostic module of claim 3, further comprising a pin housing configured to house the set of pins and to guide the set of pins through a set of slots of the cartridge platform in the active configuration.

5. The molecular diagnostic module of claim 1, wherein the cam module includes a cam card coupled to a cam card actuator configured to linearly displace the cam card in interfacing with the set of pins.

6. The molecular diagnostic module of claim 5, wherein the cam card comprises a fixed set of hills and valleys, such that a pin of the set of pins is in a first position when a hill of the cam card interfaces with the pin, and the pin of the set of pins is in a second position when a valley of the cam card interfaces with the pin.

7. The molecular diagnostic module of claim 1, further comprising:

a capture plate comprising a well containing a set of magnetic beads, a lysing reagent, and a sample process control, configured to be combined with the biological sample, wherein the capture plate facilitates production of a magnetic bead-sample from the biological sample and the set of magnetic beads;

an assay strip comprising a reagent well containing a molecular diagnostic reagent volume configured to be combined with the nucleic acid volume processed from the magnetic-bead sample, thereby generating a nucleic acid-reagent mixture; and

a liquid handling system configured to transfer the magnetic bead-sample from the capture plate to the cartridge, transfer the nucleic acid volume from the cartridge to the assay strip, and transfer the nucleic acid-reagent mixture from the assay strip back to the cartridge.

8. A system configured to process a biological sample, the system comprising:

a valve actuation subsystem comprising a set of pins;

a cartridge receiving module configured to receive a cartridge for processing the biological sample, and configured to provide an active configuration, wherein in the active configuration the cartridge is dispose proximal the set of pins; and

a cam module configured to displace a subset of the set of pins in the active configuration to define a pathway, that facilitates processing of the biological sample, in the cartridge, wherein in the active configuration the subset of the set of pins cooperatively defines and occludes the pathway of the cartridge.

9. The system of claim 8, wherein the cam module includes a cam card coupled to a cam card actuator configured to linearly displace the cam card in interfacing with the set of pins.

10. The system of claim 9, wherein the cam card comprises a fixed set of hills and valleys, such that a pin of the set of pins is in a first position when a hill of the cam card interfaces with the pin, and the pin of the set of pins is in a second position when a valley of the cam card interfaces with the pin.

11. The system of claim 8, wherein the cartridge receiving module comprises a cartridge platform, situated between the valve actuation subsystem and an actuator configured to displace the cartridge platform to provide the active configuration, the cartridge platform comprising a magnet receiving slot;

and a magnet that passes through the magnet receiving slot, in the active configuration to facilitate processing of the biological sample.

12. The system of claim 11, wherein the actuator is coupled to an optical subsystem and configured to position the optical subsystem proximal a detection chamber of the cartridge in the active configuration.

13. The system of claim 11, wherein the actuator is coupled to a heater and configured to position the heater proximal a heating region of the cartridge in the active configuration.

14. The system of claim 8, further comprising

a capture plate comprising a well containing a set of magnetic beads, a lysing reagent, and a sample process control, configured to be combined with the biological sample, wherein the capture plate facilitates production of a magnetic bead-sample from the biological sample and the set of magnetic beads;

and

a liquid handling system configured to transfer the magnetic bead-sample from the capture plate to the cartridge, and configured to transfer a nucleic acid volume processed from the magnetic bead-sample from the cartridge.

15. The system of claim 14, wherein the cam module is configured to displace a first subset of the set of pins in the active configuration to define a first pathway of the cartridge to facilitate processing of the biological sample in a first processing phase, and wherein the cam module is configured to displace a second subset of the set of pins in the active configuration to define a second pathway of the cartridge to facilitate processing of the biological sample in a second processing phase.

16. A method for processing a biological sample and separating a nucleic acid volume from the biological sample comprising:

receiving a cartridge at a cartridge receiving module comprising a set of pins and a cam module interfacing with the set of pins;

transitioning the cartridge to an active configuration that disposes the cartridge proximal the set of pins;

displacing a subset of the set of pins in the active configuration of the cartridge, using the cam module, to occlude a pathway of the cartridge; and

separating the nucleic acid volume from the biological sample, within the pathway of the cartridge.

17. The method of claim 16, wherein transitioning the cartridge to the active configuration comprises displacing a cartridge platform, in contact with the cartridge, by way of an actuator, and allowing the set of pins to pass through a valve actuation accommodating slot in the cartridge platform to access the cartridge.

18. The method of claim 16, wherein displacing the subset of the set of pins comprises linearly displacing a cam card of the cam module, comprising a set of hills and valleys, relative to the set of pins, wherein displacing the cam card affects an interface between the set of pins and the set of hills and valleys to transition at least one pin of the set of pins between a first position and a second position.

19. The method of claim 16, wherein separating the nucleic acid volume from the biological sample comprises occluding the pathway of the cartridge at a first set of occlusion positions to define a first truncated pathway upon displacing a first subset of the set of pins, and processing the biological sample in a first processing phase within the first truncated pathway.

20. The method of claim 19, wherein separating the nucleic acid volume from the biological sample comprises occluding the pathway of the cartridge at a second set of occlusion positions to define a second truncated pathway upon displacing a second subset of the set of pins, and processing the biological sample in a second processing phase within the second truncated pathway.