Devices and methods for molecular diagnostic testing

• US 10,052,629 B2
• Filed: 05/04/2017
• Issued: 08/21/2018
• Est. Priority Date: 12/31/2014
• Status: Active Grant

• Current Assignee: Visby Medical, Inc.
• Original Assignee: Click Diagnostics, Inc.
• Inventors: Andreyev, Boris, Moravick, Keith E., Ciopyk, Brian, Briones, Victor, Loney, Gregory, de la Zerda, Adam, Ching, Jesus, Chu, Steven, Swenson, David, Huang, Helen
• Primary Examiner(s): Hurst, Jonathan M
• Application Number:
  US15/586,780
• Publication Number:
  US 20170259263A1
• Time in Patent Office: 474 Days
• CPC Class Codes: B01L 2200/025 Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/028 Modular arrangements
• CPC Class Codes: B01L 2200/0647 Handling flowable solids, e.g. microscopic beads, cells, particles
• 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 2300/0627 Sensor or part of a sensor is integrated
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0672 Integrated piercing tool
• CPC Class Codes: B01L 2300/0681 Filter
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/0883 Serpentine channels
• CPC Class Codes: B01L 2300/18 Means for temperature control
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2300/1844 using fans
• CPC Class Codes: B01L 2400/0457 passive flow or gravitation
• CPC Class Codes: B01L 2400/0478 pistons
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0605 check valves
• CPC Class Codes: B01L 2400/0611 duck bill valves
• CPC Class Codes: B01L 2400/0644 : rotary valves
• 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 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/5029 : using swabs
• 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 7/525 : with physical movement of samples between temperature zones

Abstract

A hand-held molecular diagnostic test device includes a housing, an amplification (or PCR) module, and a detection module. The amplification module is configured to receive an input sample, and defines a reaction volume. The amplification module includes a heater such that the amplification module can perform a polymerase chain reaction (PCR) on the input sample. The detection module is configured to receive an output from the amplification module and a reagent formulated to produce a signal that indicates a presence of a target amplicon within the input sample. The amplification module and the detection module are integrated within the housing.

Claims

1. An apparatus, comprising:

a housing;

an amplification module irreversibly coupled within the housing, the amplification module including a flow member and a heater, the flow member defining a reaction volume configured to receive an input sample, the heater coupled to the flow member and configured to convey thermal energy into the reaction volume to amplify a nucleic acid within the input sample to produce an amplified output containing a target amplicon;

a reagent module disposed within the housing, the reagent module containing a reagent;

a detection module defining a detection channel in fluid communication with the reaction volume of the amplification module and the reagent module, the detection module including a detection surface within the detection channel, the detection surface configured to retain the target amplicon when the amplified output flows across the detection surface at a first time, the reagent formulated to cause the production of a signal associated with the target amplicon after the reagent flows across the detection surface at a second time;

a fluid pump disposed within the housing, the fluid pump including a movable member configured to move in a first direction and a second direction different than the first direction, movement of the movable member in the first direction producing a flow of the amplified output within the detection channel, movement of the movable member in the second direction producing a flow of the reagent within the detection channel; and

a control module within the housing, the control module including a processor configured to control movement of the movable member.

2. The apparatus of claim 1, wherein:

the heater is coupled to the flow member such that a first heating portion of the heater can produce a first temperature zone within a first portion of the reaction volume and a second heating portion of the heater can produce a second temperature zone within a second portion of the reaction volume, the first temperature zone and the second temperature zone maintained such that the input sample within the reaction volume can be thermally cycled.

3. The apparatus of claim 2, wherein:

the reaction volume is a serpentine flow path; and

the first heating portion is separated from the second heating portion by an opening.

4. The apparatus of claim 1, further comprising:

the heater is coupled to the flow member such that a first heating portion of the heater intersects the reaction volume at a first plurality of locations within a first temperature zone and a second heating portion of the heater intersects the reaction volume a second plurality of locations within a second temperature zone, the first temperature zone configured to be maintained at a first temperature, the second temperature zone configured to be maintained at a second temperature different than the first temperature such that the amplification module performs a polymerase chain reaction (PCR) on the input sample when a flow of the input sample is produced within the reaction volume.

5. The apparatus of claim 4, wherein the flow member is constructed from at least one of a cyclic olefin copolymer or a graphite-based material and has a thickness of less than about 0.5 mm.

6. The apparatus of claim 2, wherein:

the reaction volume is a serpentine flow path;

the movable member is a plunger; and

the fluid pump includes a barrel, the plunger having a portion movably disposed within the barrel, the barrel in fluid communication with the serpentine flow path such that movement of the plunger within the barrel in the first direction produces a flow of the input sample within the serpentine flow path.

7. The apparatus of claim 2, wherein:

the reaction volume is a serpentine flow path;

the movable member is a plunger; and

the fluid pump includes a first barrel and a second barrel, the plunger having a first portion movably disposed within the first barrel and a second portion movably disposed within the second barrel, the fluid pump configured to produce the flow of the amplified output when the first portion of the plunger moves in a first direction, the fluid pump configured to produce the flow of the reagent within the detection channel when the second portion of plunger moves in a second direction.

8. The apparatus of claim 1, wherein the reagent is one of a detection reagent formulated to produce the signal or a substrate reagent formulated to catalyze the production of the signal.

9. The apparatus of claim 1, wherein the heater is irreversibly coupled to the flow member via an adhesive bond.

10. The apparatus of claim 1, wherein the movable member is a rigid plunger.

11. The apparatus of claim 1, wherein the fluid pump defines a first chamber and a second chamber isolated from the first chamber, the first chamber configured to be placed in fluid communication with the reaction volume to produce the flow of the amplified output, the second chamber configured to be placed in fluid communication with the detection channel to produce the flow of the reagent.

12. An apparatus, comprising:

a housing;

an amplification module fixedly coupled within the housing, the amplification module including a flow member and a heater, the flow member defining a flow path configured to receive an input flow of a sample, the heater coupled to the flow member such that a first heating portion of the heater can produce a first temperature zone within a first portion of the flow path and a second heating portion of the heater can produce a second temperature zone within a second portion of the flow path, the first temperature zone and the second temperature zone spaced apart such that the input flow of the sample within the flow path can be thermally cycled to amplify a nucleic acid within the sample to produce an output flow containing a target amplicon;

a detection module defining a detection channel in fluid communication with the flow path of the amplification module, the detection channel in fluid communication with a reagent module containing a reagent formulated to produce a signal indicating a presence of the target amplicon, the detection module including a detection surface within the detection channel, the detection surface configured to retain the target amplicon within the output flow produced by the amplification module;

a fluid pump including an electric motor disposed within the housing, the electric motor configured to generate a first force that causes the input flow of the sample within the flow path and a second force that causes a flow of the reagent within the detection channel, the second force in a different direction than the first force; and

a control module within the housing, the control module including a processor configured to regulate a power input to the electric motor of the fluid pump to control a rate of the input flow of the sample within the flow channel.

13. The apparatus of claim 12 wherein the first temperature zone and the second temperature zone are configured to be maintained such that the amplification module performs a polymerase chain reaction (PCR) on the input flow of the sample within the flow path.

14. The apparatus of claim 12, wherein:

the first heating portion and the second heating portion are coupled to a first side of the flow member, the first heating portion being separated from the second heating portion by an opening; and

the amplification module includes a heat sink coupled to a second side of the flow member, the second side opposite the first side.

15. The apparatus of claim 12, wherein:

the flow path is a serpentine flow path including a plurality of amplification flow channels;

the flow member defines a hot start flow path; and

the first heating portion of the heater is aligned with a central portion of the plurality of amplification flow channels, the second heating portion of the heater is aligned with a switch back portion of the plurality of amplification flow channels, and a third heating portion of the heater is aligned with the hot start flow path.

16. The apparatus of claim 12, wherein the flow member is constructed from at least one of a cyclic olefin copolymer or a graphite-based material and has a thickness of less than about 0.5 mm.

17. The apparatus of claim 12, wherein the fluid pump includes a barrel and a plunger having a portion movably disposed within the barrel, the barrel in fluid communication with the flow path such that a movement of the portion of the plunger within the barrel produces the input flow within the flow path and the output flow within the detection channel.

18. The apparatus of claim 12, wherein the control module is configured to regulate the power input based on at least one of an encoder signal or a current measurement associated with the electric motor.

19. The apparatus of claim 12, wherein the control module and the fluid pump are collectively configured to produce the rate of the input flow between 0.3 μ

L/sec and 0.5 μ

L/sec.

20. An apparatus, comprising:

a housing;

an amplification module fixedly coupled within the housing, the amplification module including a flow member and a heater, the flow member defining a flow path configured to receive an input flow of a sample, the heater coupled to the flow member and configured to convey thermal energy into the flow path to amplify a nucleic acid within the sample to produce an output flow containing a target amplicon;

a detection module defining a detection channel in fluid communication with the flow path of the amplification module, the detection channel in fluid communication with a reagent module containing a reagent formulated to produce a signal indicating a presence of the target amplicon, the detection module including a detection surface within the detection channel, the detection surface configured to retain the target amplicon within the output flow produced by the amplification module;

a fluid pump disposed within the housing, the fluid pump including an actuator and a movable member, the actuator configured to generate, within the housing, a first force and a second force, the second force in a different direction than the first force, the first force configured to move the movable member to produce the input flow of the sample within the flow path and the output flow within the detection channel; and

a control module within the housing, the control module including a processor configured to regulate a power input to the actuator of the fluid pump to control a rate of the input flow of the sample within the flow channel.

21. The apparatus of claim 20, wherein the fluid pump includes a barrel and a plunger having a portion movably disposed within the barrel, the barrel in fluid communication with the flow path such that a movement of the portion of the plunger within the barrel produces the input flow within the flow path and the output flow within the detection channel.

22. The apparatus of claim 21, wherein:

the movement of the portion of the plunger is a first movement; and

the barrel is configured to be placed in fluid communication with a sample mixing module such that a second movement of the portion of the plunger within the barrel produces a mixing flow of the sample within the mixing module.

23. The apparatus of claim 22, wherein:

the first movement is caused by the first force in a first direction; and

the second movement is caused by the second force in a second direction, the second direction opposite the first direction.

24. The apparatus of claim 20, wherein the fluid pump is configured to produce the output flow within the detection channel when the movable member moves in response to the first force in a first direction, the fluid pump configured to produce a flow of the reagent within the detection channel when the movable member moves in response to the second force in a second direction.

25. The apparatus of claim 20, wherein:

the heater is coupled to the flow member such that a first heating portion of the heater can produce a first temperature zone within a first portion of the flow path and a second heating portion of the heater can produce a second temperature zone within a second portion of the flow path, the first temperature zone and the second temperature zone maintained such that the input flow of the sample within the flow path can be thermally cycled to amplify the nucleic acid within the sample.

26. The apparatus of claim 25, wherein the first temperature zone and the second temperature zone are configured to be maintained such that the amplification module performs a polymerase chain reaction (PCR) on the input flow of the sample within the flow path.

27. The apparatus of claim 20, wherein the actuator is an electric motor.