System and method for processing biological samples

• US 9,637,775 B2
• Filed: 03/28/2014
• Issued: 05/02/2017
• Est. Priority Date: 02/13/2012
• Status: Active Grant

• Current Assignee: Neumodx Molecular, Inc. (Qiagen NV)
• Original Assignee: Neumodx Molecular, Inc. (Qiagen NV)
• Inventors: Kusner, Michael T., Williams, Jeffrey
• Primary Examiner(s): Bowers, Nathan
• Assistant Examiner(s): EDWARDS, LYDIA E
• Application Number:
  US14/229,396
• Publication Number:
  US 20140227146A1
• Time in Patent Office: 1,131 Days
• 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 2200/0631 Purification arrangements, e.g. solid phase extraction [SPE]
• 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 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0681 Filter
• CPC Class Codes: B01L 2300/087 Multiple sequential chambers
• CPC Class Codes: B01L 2300/123 Flexible; Elastomeric
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2300/1844 using fans
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0655 pinch valves
• 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 3/502738 characterised by integrated valves microvalves F16K99/0001
• 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: C12Q 1/6806 : Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay C12Q1/6804 takes precedence
• CPC Class Codes: F16K 2099/0084 : Chemistry or biology, e.g. "lab-on-a-chip" technology
• CPC Class Codes: F16K 99/0005 : Lift valves

Abstract

A system and method for processing and detecting nucleic acids from a set of biological samples, comprising: 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 including an actuation substrate, and a set of pins interacting with the actuation substrate, and a spring plate configured to bias at least one pin in a configurations, the 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; and a fluid handling system configured to deliver samples and reagents to components of the system to facilitate molecular diagnostic protocols.

Claims

1. A system configured to receive a cartridge including a set of fluidic pathways for processing and detecting nucleic acids, each fluidic pathway in the set of fluidic pathways including a set of occlusion positions, wherein the system comprises:

a cartridge platform for receiving and aligning the cartridge, including an access region that provides access to the set of occlusion positions;

a valve actuation subsystem situated inferior to the cartridge platform including;

an actuation substrate including an array of active regions and an array of inactive regions, wherein each of the array of active regions is configured to provide a force in a displacement direction normal to a surface of the actuation substrate,

a set of pins, each pin in the set of pins including a distal end and a displacement region_and operable between a retracted configuration and an extended configuration, wherein in the retracted configuration an active region of the actuation substrate is aligned with the displacement region of the pin and the distal end of the pin is displaced in the displacement direction, and wherein in the extended configuration an inactive region of the actuation substrate is aligned with the displacement region of the pin and the distal end of the pin is displaced in a direction opposing the displacement direction and occludes the fluidic pathway at the occlusion position,

a spring plate including a set of springs, each of the set of springs coupled to a corresponding pin in the set of pins, and wherein in the retracted configuration the spring corresponding to each pin is compressed by the force provided by the active region, and

an actuator coupled to at least one of the actuation substrate, the pin housing, and the spring plate, and configured to provide relative displacement in a direction tangential to the displacement direction between the array of active regions and the set of pins; and

a linear actuator configured to provide relative displacement between the cartridge platform and the valve actuation subsystem, to facilitate cartridge placement.

2. The system of claim 1, further including a pin housing including a set of cavities that surround and guide displacement of each pin in the set of pins between the retracted configuration and the extended configuration, wherein a cavity in the set of cavities includes a stop region configured to define a range of motion for a pin within the cavity.

3. The system of claim 1, further comprising a magnet situated inferior to the access region of the cartridge platform, wherein the magnet is configured to provide a magnetic field spanning at least three fluidic pathways of the set of fluidic pathways, thereby facilitating isolation and extraction of three purified nucleic acid volumes at the cartridge.

4. The system of claim 1, further comprising an optical subsystem comprising a set of units, wherein each unit includes an excitation filter, an emission filter, a photodetector aligned with the emission filter, and a dichroic mirror configured to reflect light from the excitation filter toward a sample at the cartridge, and to transmit light from the sample, through the emission filter, and toward the photodetector.

5. The system of claim 1, further comprising the cartridge, wherein the cartridge includes a set of sample port-reagent port pairs, a fluid port, a set of detection chambers, a waste chamber, an elastomeric layer, and a set of fluidic pathways, wherein each fluidic pathway of the set of fluidic pathways is coupled to a sample port-reagent port pair of the set of sample port-reagent port pairs, the fluid port, and a detection chamber of the set of detection chambers, and is configured to transfer a waste fluid to the waste chamber and to be occluded upon deformation of the elastomeric layer.

8. The system of claim 1, wherein each pin in the set of pins is substantially concentric with a cavity of the set of cavities, and wherein the set of cavities is substantially aligned with the set of springs of the spring plate.

9. The system of claim 1, wherein each cavity in the set of cavities includes a stop region, thereby defining a set of stop regions configured to define ranges of motion for the set of pins surrounded by the pin housing.

10. The system of claim 1, wherein the base end of each pin in the set of pins abuts one spring of the set of springs of the spring plate.

11. The system of claim 1, wherein for each pin, the protrusion comprises a semi-cylindrical protrusion defined at an inferior portion of the slot.

6. A valve actuation system for processing nucleic acids, comprising:

an actuation substrate including an array of peaks and an array of valleys, wherein each peak extends away from a plane defined by the actuation substrate in a displacement direction;

a set of pins, each pin in the set of pins including a base end, a distal end, and a slot including a protrusion defined within the slot, and operable in;

a retracted configuration, wherein a peak of the array of peaks is aligned with the protrusion and the pin is displaced in the displacement direction, and

an extended configuration, wherein a valley of the array of valleys is aligned with the protrusion and the pin is displaced in a direction opposing the displacement direction and the distal end occludes a valve contacting the distal end;

a pin housing including a set of cavities that surround and guide displacement of each pin in the set of pins between the retracted configuration and the extended configuration;

a spring plate including a set of springs that bias each pin in the set of pins toward the extended configuration, and wherein transitioning from the extended configuration to the retracted configuration compresses a spring of the set of springs; and

an actuator coupled to the actuation substrate and configured to displace the array of peaks and the array of valleys through the slots and into contact with the protrusions of the set of pins.

7. The system of claim 6, wherein the actuation substrate includes a set of arms, each arm including a subset of the array of peaks and the array of valleys, wherein the slot of each pin in the set of pins is configured to receive an arm in the set of arms to transition each pin into at least one of the retracted configuration and the extended configuration.

12. A valve actuation system for processing nucleic acids, comprising:

an actuation substrate including an array of active regions and an array of inactive regions, wherein each active region is configured to provide a force in a displacement direction normal to a surface of the actuation substrate;

a set of pins, each pin in the set of pins including a base end, a distal end, and a displacement region and operable in;

a retracted configuration, wherein an active region of the array of active regions is aligned with the displacement region and the pin is displaced in the displacement direction, and

an extended configuration, wherein an inactive region of the array of inactive regions is aligned with the displacement region and the pin is displaced in a direction opposing the displacement direction and the distal end occludes a valve contacting the distal end;

a pin housing including a set of cavities that surround and guide displacement of each pin in the set of pins between the retracted configuration and the extended configuration;

a spring plate including a set of springs that bias each pin in the set of pins toward the extended configuration, and wherein transitioning from the extended configuration to the retracted configuration compresses a spring of the set of springs; and

an actuator coupled to at least one of the actuation substrate, the pin housing, and the spring plate, and configured to provide relative displacement in a direction tangential to the displacement direction between the array of active regions and the set of pins.

13. The system of claim 12, wherein the array of active regions includes an array of peaks and an array of valleys defined at an inferior surface of the actuation substrate.

14. The system of claim 13, wherein the displacement region of a first pin in the set of pins comprises a protrusion directed in a superior direction, and wherein alignment of a peak of the array of peaks with the protrusion transitions the first pin toward the retracted configuration.

15. The system of claim 14, wherein the protrusion is a semi-cylindrical protrusion defined within the inferior portion of the slot.

16. The system of claim 13, wherein the actuation substrate includes a set of arms, each arm including a subset of the array of peaks and the array of valleys, wherein each pin in the set of pins includes a slot configured to receive an arm in the set of arms to transition each pin into at least one of the retracted configuration and the extended configuration.

17. The system of claim 12, wherein the base end of each pin in the set of pins abuts one spring of the set of springs of the spring plate.

18. The system of claim 12, wherein each cavity in the set of cavities includes a stop region, thereby defining a set of stop regions configured to define ranges of motion for the set of pins surrounded by the pin housing.

19. The system of claim 12, wherein the actuator is coupled to the actuation substrate and configured to laterally displace the actuation substrate relative to the displacement region of each pin in the set of pins, and wherein displacement of the actuation substrate in a first direction produces displacement of at least one pin in the set of pins in a second direction, perpendicular to the first direction, by way of the array of active regions.

20. The system of claim 12, wherein the spring plate is situated inferior to the pin housing, and the actuation substrate is substantially aligned with the set of pins, between the base end and the distal end of each pin in the set of pins.