Devices, systems and methods for evaluation of hemostasis

• US 9,977,039 B2
• Filed: 07/07/2017
• Issued: 05/22/2018
• Est. Priority Date: 02/15/2011
• Status: Active Grant

• Current Assignee: Hemosonics LLC (Stago International SAS)
• Original Assignee: Hemosonics LLC (Stago International SAS)
• Inventors: Viola, Francesco, Walker, William F., Browne, Gregory V., Magyar, Robert S., Hansen, Bjarne, Denny, Christopher G.
• Primary Examiner(s): Warden, Jill A
• Assistant Examiner(s): Fisher, Brittany I
• Application Number:
  US15/644,124
• Publication Number:
  US 20170315143A1
• Time in Patent Office: 319 Days
• Field of Search: None
• CPC Class Codes: B01L 2200/04 Exchange or ejection of cartridges, containers or reservoirs
• CPC Class Codes: B01L 2200/0647 Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2300/02 Identification, exchange or storage of information
• CPC Class Codes: B01L 2300/024 Storing results with means integrated into the container
• CPC Class Codes: B01L 2300/027 Digital display, e.g. LCD, LED
• 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 2300/0681 Filter
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• 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 2300/123 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 2400/0436 acoustic forces, e.g. surface acoustic waves [SAW]
• CPC Class Codes: B01L 2400/0439 ultrasonic vibrations, vibrating piezo elements
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/049 : vacuum
• CPC Class Codes: B01L 2400/0666 : Solenoid 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 3/502761 : 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 3/527 : for a plurality of reagents
• CPC Class Codes: G01N 2800/224 : Haemostasis or coagulation
• CPC Class Codes: G01N 29/024 : by measuring propagation velocity or propagation time of acoustic waves
• CPC Class Codes: G01N 29/222 : Constructional or flow details for analysing fluids optoacoustic fluid cells G01N29/2425
• CPC Class Codes: G01N 33/86 : involving blood coagulating time or factors, or their receptors
• 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

Abstract

Provided are devices, systems and methods for evaluation of hemostasis. Also provided are sound focusing assemblies.

Claims

1. A device comprising:

a housing;

a plurality of test chambers, wherein the plurality of test chambers includes at least a first test chamber and a second test chamber that are each at least partially defined by the housing, wherein the first test chamber and the second test chamber are each designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a reagent or combination of reagents, wherein a first reagent or combination of reagents in the first test chamber is different than a second reagent or combination of reagents in the second test chamber; and

a fluid pathway comprising a plurality of channels, each defined at least in part by the housing, wherein the fluid pathway includes an inlet, defined at least in part by the housing, through which the test sample is introduced into the device, wherein at least one channel of the plurality of channels is in communication with the inlet and with the first test chamber and the second test chamber to deliver a portion of the test sample to each of the first test chamber and the second test chamber, and wherein the fluid pathway includes a first port, defined at least in part by the housing, in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the first port draws the test sample through the at least one channel of the fluid pathway and into at least one of the test chambers, wherein the at least one channel of the fluid pathway includes an inlet channel, a first channel, and a second channel, wherein the inlet channel is in communication with the inlet, wherein the first channel is in communication with the inlet channel and at least with the first test chamber, and wherein the second channel is in communication with the inlet channel and at least with the second test chamber,

wherein the housing includes a thermally conductive wall configured to allow the test sample to be heated, the thermally conductive wall having an outer surface area and an inner surface area;

wherein the fluid pathway includes a portion at least partially defined by the inner surface area of the thermally conductive wall and the outer surface area of the thermally conductive wall is shaped to be held in at least partially conforming contact with or in close proximity to a heater to allow adjustment of a temperature of the test sample flowing through the portion at least partially defined by the inner surface area of the thermally conductive wall; and

wherein the device can be used with an interrogation device to measure at least one viscoelastic property of the test sample.

2. The device of claim 1, wherein the portion at least partially defined by the outer surface area of the thermally conductive wall is designed to be held against a heater external to the device.

3. The device of claim 2, wherein the device is designed to allow the test sample to reach about 37°

C. in the first test chamber and the second test chamber.

4. The device of claim 3, wherein the portion at least partially defined by the inner surface area of the thermally conductive wall comprises a thermally conductive polymer that has a thermal conductivity that exceeds 0.123 W/m °

K.

5. The device of claim 1, further comprising a second port, defined at least in part by the housing, and from which a pressure gradient when applied from a source external to the second port causes the test sample to move from an external vessel through the inlet and the at least one channel of the fluid pathway and into the housing.

6. The device of claim 5, wherein the device is designed such that a vacuum can be applied at the second port to introduce the test sample into the inlet and propel the sample into the at least one channel of the fluid pathway.

7. The device of claim 6, wherein the inlet is designed such that the external vessel can establish fluid communication to allow the inlet to receive the test sample.

8. The device of claim 7, wherein the device is designed to prevent the test sample from leaving through the first port or the second port.

9. The device of claim 8, wherein the fluid pathway can be coupled with a sample container to allow a portion of the test sample to be collected in the sample container after it has moved through the housing.

10. The device of claim 1, wherein the first port is configured, when applied with the pressure gradient, to draw the test sample from an external vessel through the inlet and the at least one channel of the fluid pathway and into the housing.

11. The device of claim 1, wherein the device is designed to prevent the test sample from leaving through the first port.

12. The device of claim 1, wherein the housing is designed to allow a fluid level to be monitored optically.

13. The device of claim 1, further comprising a magnetic stirrer.

14. The device of claim 1, wherein at least one of the plurality of test chambers is designed for interrogation by acoustic pulses.

15. The device of claim 14, wherein at least one of the plurality of test chambers comprises a sound focusing assembly comprising a rigid substrate and an elastomeric couplant positioned relative to the rigid substrate, wherein the rigid substrate and the elastomeric couplant are permeable by sound.

16. The device of claim 14, wherein the first test chamber includes the first reagent or combination or reagents and the second test chamber includes the second reagent or combination or reagents prior to receiving the test sample of blood therein.

17. The device of claim 16, wherein one of more of the reagents are lyophilized as lyophilized beads.

18. The device of claim 1, wherein the housing is configured for single use as part of a disposable cartridge.

19. The device of claim 1, wherein one of more of the reagents are lyophilized as lyophilized beads.

20. The device of claim 1, further comprising a third test chamber designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a third reagent or combination of reagents, wherein the third reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof.

21. The device of claim 20, further comprising a fourth test chamber designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a fourth reagent or combination of reagents, wherein the fourth reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof.

22. The device of claim 1, wherein the device is designed to evaluate at least one component of hemostasis selected from the group consisting of initial and final fibrin formation, fibrin and platelet activity, rate of fibrin polymerization, and clot dissolving process.

23. The device of claim 1, wherein the device is designed to evaluate at least one parameter selected from the group consisting of an intrinsic pathway coagulation factors index, an extrinsic pathway coagulation factors index, a platelet index, a fibrinogen index, and a fibrinolysis index.

24. The device of claim 23, wherein the first test chamber and the second test chamber are designed to be interrogated to measure clot stiffness, and a platelet index can be determined from a differential between the clot stiffness measurement in the first test chamber and the clot stiffness measurement in the second test chamber.

25. The device of claim 23, wherein the device is designed to evaluate a fibrinolysis index.

26. A device comprising:

a housing;

a plurality of test chambers, wherein the plurality of test chambers includes at least a first test chamber and a second test chamber that are each at least partially defined by the housing, wherein the first test chamber and the second test chamber are each designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a reagent or combination of reagents, wherein a first reagent or combination of reagents in the first test chamber is different than a second reagent or combination of reagents in the second test chamber; and

a fluid pathway comprising a plurality of channels, each defined at least in part by the housing, wherein the fluid pathway includes an inlet, defined at least in part by the housing, through which the test sample is introduced into the device, wherein at least one channel of the plurality of channels is in communication with the inlet and with the first test chamber and the second test chamber to deliver a portion of the test sample to each of the first test chamber and the second test chamber, and wherein the fluid pathway includes a first port, defined at least in part by the housing, in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the first port draws the test sample through the fluid pathway and into at least one of the test chambers, wherein the at least one channel of the fluid pathway includes an inlet channel, a first channel, and a second channel, wherein the inlet channel is in communication with the inlet, wherein the first channel is in communication with the inlet channel and at least with the first test chamber, and wherein the second channel is in communication with the inlet channel and at least with the second test chamber,

wherein at least a portion of the housing is thermally conductive to allow the test sample to be heated,

wherein the first reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof,

wherein the second reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof,

wherein at least one of the first reagent or combination of reagents and the second reagent or combination of reagents activates the test sample via the extrinsic pathway of coagulation,

wherein the second reagent or combination of reagents further includes one or both of abciximab and cytochalasin D, and

wherein the device can be used with an interrogation device to measure at least one viscoelastic property of the test sample.

27. The device of claim 26, further comprising a third test chamber designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a third reagent or combination of reagents, wherein the third reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof.

28. The device of claim 27, further comprising a fourth test chamber designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a fourth reagent or combination of reagents, wherein the fourth reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof.

29. The device of claim 28, wherein the at least one channel includes the inlet channel, the first channel, the second channel, a third channel, and a fourth channel,

wherein the third channel is in communication with the inlet channel and at least with the third test chamber, and

wherein the fourth channel is in communication with the inlet channel and at least with the fourth test chamber.

30. The device of claim 26, wherein the device is designed to evaluate at least one component of hemostasis selected from the group consisting of initial and final fibrin formation, fibrin and platelet activity, rate of fibrin polymerization, and clot dissolving process.

31. The device of claim 26, wherein the device is designed to evaluate at least one parameter selected from the group consisting of an intrinsic pathway coagulation factors index, an extrinsic pathway coagulation factors index, a platelet index, a fibrinogen index, and a fibrinolysis index.

32. The device of claim 31, wherein the first test chamber and the second test chamber are designed to be interrogated to measure clot stiffness, and a platelet index can be determined from a differential between the clot stiffness measurement in the first test chamber and the clot stiffness measurement in the second test chamber.

33. The device of claim 31, wherein the device is designed to evaluate a fibrinolysis index.

34. The device of claim 26,

wherein the housing includes a thermally conductive wall configured to allow the test sample to be heated, the thermally conductive wall having an outer surface area and an inner surface area,

wherein the fluid pathway includes a portion at least partially defined by the inner surface area of the thermally conductive wall and the outer surface area of the thermally conductive wall is shaped to be held in at least partially conforming contact with or in close proximity to a heater to allow adjustment of a temperature of the test sample flowing through the portion at least partially defined by the inner surface area of the thermally conductive wall, and

wherein the portion at least partially defined by the outer surface area of the thermally conductive wall is designed to be held against a heater external to the device.

35. The device of claim 34, wherein the device is designed to allow the test sample to reach about 37°

C. in the first test chamber and the second test chamber.

36. The device of claim 35, wherein the portion at least partially defined by the inner surface area of the thermally conductive wall comprises a thermally conductive polymer that has a thermal conductivity that exceeds 0.123 W/m °

K.

37. The device of claim 26, further comprising a second port, defined at least in part by the housing, and from which a pressure gradient when applied from a source external to the second port causes the test sample to move from an external vessel through the inlet and the at least one channel of the fluid pathway and into the housing.

38. The device of claim 37, wherein the device is designed such that a vacuum can be applied at the second port to introduce the test sample into the inlet and propel the sample into the at least one channel of the fluid pathway.

39. The device of claim 38, wherein the inlet is designed such that the external vessel can establish fluid communication to allow the inlet to receive the test sample.

40. The device of claim 39, wherein the device is designed to prevent the test sample from leaving through the first port or the second port.

41. The device of claim 40, wherein the fluid pathway can be coupled with a sample container to allow a portion of the test sample to be collected in the sample container after it has moved through the housing.

42. The device of claim 26, wherein the first port is configured, when applied with the pressure gradient, to draw the test sample from an external vessel through the inlet and the at least one channel of the fluid pathway and into the housing.

43. The device of claim 26, wherein the device is designed to prevent the test sample from leaving through the first port.

44. The device of claim 26, wherein the housing is designed to allow a fluid level to be monitored optically.

45. The device of claim 26, further comprising a magnetic stirrer.

46. The device of claim 26, wherein at least one of the plurality of test chambers is designed for interrogation by acoustic pulses.

47. The device of claim 46, wherein at least one of the plurality of test chambers comprises a sound focusing assembly comprising a rigid substrate and an elastomeric couplant positioned relative to the rigid substrate, wherein the rigid substrate and the elastomeric couplant are permeable by sound.

48. The device of claim 26, wherein the first test chamber includes the first reagent or combination or reagents and the second test chamber includes the second reagent or combination or reagents prior to receiving the test sample of blood therein.

49. The device of claim 26, wherein one of more of the reagents are lyophilized as lyophilized beads.

50. The device of claim 26, wherein the housing is configured for single use as part of a disposable cartridge.

51. A device comprising:

a housing;

a plurality of test chambers, wherein the plurality of test chambers includes at least a first test chamber, a second test chamber, and a third test chamber that are each at least partially defined by the housing, wherein each of the first test chamber, the second test chamber, and the third test chamber are designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a reagent or combination of reagents, wherein a first reagent or combination of reagents, a second reagent or combination of reagents, and a third reagent or combination of reagents each activate the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof, and wherein the first reagent or combination of reagents is different than the second reagent or combination of reagents; and

a fluid pathway comprising a plurality of channels, each defined at least in part by the housing,

wherein the fluid pathway includes an inlet, defined at least in part by the housing, through which the test sample is introduced into the device, wherein at least one channel of the plurality of channels is in communication with the inlet and with the first test chamber, the second test chamber, and the third test chamber to deliver a portion of the test sample to each of the first test chamber, the second test chamber, and the third test chamber, wherein the fluid pathway includes a first port, defined at least in part by the housing, in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the first port draws the test sample through the fluid pathway and into at least one of the test chambers wherein the at least one channel of the fluid pathway includes an inlet channel, a first channel, and a second channel, wherein the inlet channel is in communication with the inlet, wherein the first channel is in communication with the inlet channel and at least with the first test chamber, and wherein the second channel is in communication with the inlet channel and at least with the second test chamber,

wherein the fluid pathway includes a second port, defined at least in part by the housing, in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the second port draws the test sample to move from an external vessel through the inlet and the at least one channel of the fluid pathway into the housing, and

wherein the fluid pathway includes a portion designed to be held against a heater to allow adjustment of a temperature of the test sample flowing through the portion,

wherein the first port and/or the second port prevents the test sample from leaving the device,

wherein at least a portion of the housing is designed to be thermally conductive to allow the test sample to reach about 37°

C. in the test chambers; and

wherein the device is configured for use with an interrogation device to measure at least one viscoelastic property of the test sample.

52. A system for evaluation of hemostasis, the system comprising:

a consumable cartridge configured to be positioned in an analysis system, the consumable cartridge comprising

a cartridge housing;

a plurality of test chambers, wherein the plurality of test chambers includes at least a first test chamber and a second test chamber that are each at least partially defined by the cartridge housing, wherein the first test chamber and the second test chamber are each designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a reagent or combination of reagents, wherein a first reagent or combination of reagents in the first test chamber is different than a second reagent or combination of reagents in the second test chamber; and

a fluid pathway comprising a plurality of channels, each defined at least in part by the cartridge housing, wherein the fluid pathway includes an inlet, defined at least in part by the cartridge housing, through which the test sample is introduced into the consumable cartridge, wherein at least one channel of the plurality of channels is in communication with the inlet and with the first test chamber and the second test chamber to deliver a portion of the test sample to each of the first test chamber and the second test chamber, and wherein the fluid pathway includes a first port, defined at least in part by the cartridge housing, in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the first port draws the test sample through the at least one channel of the fluid pathway and into at least one of the test chambers, and

a heat exchanger, and a temperature control coupled thereto, designed to allow the temperature of the test sample to be adjusted before analysis in the test chambers;

an interrogation device designed to measure at least one viscoelastic property of the test sample;

a pressure control designed to apply the pressure gradient that causes the test sample to flow through the fluid pathway and into the test chambers; and

an analysis system, the analysis system comprising;

an analysis system housing having a pocket designed to receive the consumable cartridge, the pocket comprising an actuator system that allows the heat exchanger, the interrogation device, and the pressure control to be positioned adjacent to the consumable cartridge.

53. The system of claim 52,

wherein the cartridge housing includes a thermally conductive wall configured to allow the test sample to be heated, the thermally conductive wall having an outer surface area and an inner surface area,

wherein the fluid pathway includes a portion at least partially defined by the inner surface area of the thermally conductive wall and the outer surface area of the thermally conductive wall is shaped to be held in at least partially conforming contact with or in close proximity to a heater to allow adjustment of a temperature of the test sample flowing through the portion at least partially defined by the inner surface area of the thermally conductive wall, and

wherein the portion at least partially defined by the outer surface area of the thermally conductive wall is designed to be held against a heater external to the device.

54. The system of claim 53, wherein the system is designed to allow the test sample to reach about 37°

C. in the first test chamber and the second test chamber.

55. The system of claim 54, wherein the portion at least partially defined by the inner surface area of the thermally conductive wall comprises a thermally conductive polymer that has a thermal conductivity that exceeds 0.123 W/m °

K.

56. The system of claim 52, further comprising a second port, defined at least in part by the housing, and from which a pressure gradient when applied from a source external to the second port causes the test sample to move from an external vessel through the inlet and the at least one channel of the fluid pathway and into the cartridge housing.

57. The system of claim 56, wherein the system is designed such that a vacuum can be applied at the second port to introduce the test sample into the inlet and propel the sample into the at least one channel of the fluid pathway.

58. The system of claim 57, wherein the inlet is designed such that the external vessel can establish fluid communication to allow the inlet to receive the test sample.

59. The system of claim 52, wherein the fluid pathway can be coupled with a sample container to allow a portion of the test sample to be collected in the sample container after it has moved through the cartridge housing.

60. The system of claim 52, wherein the first port is configured, when applied with the pressure gradient, to draw the test sample from an external vessel through the inlet and the at least one channel of the fluid pathway and into the cartridge housing.

61. The system of claim 52, wherein the device is designed to prevent the test sample from leaving through the first port.

62. The system of claim 52, wherein the cartridge housing is designed to allow a fluid level to be monitored optically.

63. The system of claim 52, further comprising a magnetic stirrer.

64. The system of claim 52, wherein the first test chamber includes the first reagent or combination or reagents and the second test chamber includes the second reagent or combination or reagents prior to receiving the test sample of blood therein.

65. The system of claim 52, further comprising a third test chamber designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a third reagent or combination of reagents, wherein the third reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof.

66. The system of claim 65, further comprising a fourth test chamber designed to be interrogated to determine a hemostatic parameter of a test sample of blood that is received therein and a fourth reagent or combination of reagents, wherein the fourth reagent or combination of reagents activates the test sample via an intrinsic pathway of coagulation, an extrinsic pathway of coagulation, or a combination thereof.

67. The system of claim 52, wherein the consumable cartridge is designed to evaluate at least one component of hemostasis selected from the group consisting of initial and final fibrin formation, fibrin and platelet activity, rate of fibrin polymerization, and clot dissolving process.

68. The system of claim 52, wherein the consumable cartridge is designed to evaluate at least one parameter selected from the group consisting of an intrinsic pathway coagulation factors index, an extrinsic pathway coagulation factors index, a platelet index, a fibrinogen index, and a fibrinolysis index.

69. The system of claim 68, wherein the first test chamber and the second test chamber are designed to be interrogated to measure clot stiffness, and a platelet index can be determined from a differential between the clot stiffness measurement in the first test chamber and the clot stiffness measurement in the second test chamber.

70. The system of claim 68, wherein the consumable cartridge is designed to evaluate a fibrinolysis index.

71. The system of claim 52, wherein at least one of the plurality of test chambers is designed for interrogation by acoustic pulses.

72. The system of claim 71, wherein at least one of the plurality of test chambers comprises a sound focusing assembly comprising a rigid substrate and an elastomeric couplant positioned relative to the rigid substrate, wherein the rigid substrate and the elastomeric couplant are permeable by sound.

73. The system of claim 52, wherein the first test chamber includes the first reagent or combination or reagents and the second test chamber includes the second reagent or combination or reagents prior to receiving the test sample of blood therein.

74. The device of claim 73, wherein one of more of the reagents are lyophilized as lyophilized beads.

75. The system of claim 52, wherein the cartridge housing is configured for single use as part of a disposable cartridge.

76. The device of claim 52, wherein the at least one channel of the fluid pathway includes an inlet channel, a first channel, and a second channel,

wherein the inlet channel is in communication with the inlet,

wherein the first channel is in communication with the inlet channel and at least with the first test chamber, and

wherein the second channel is in communication with the inlet channel and at least with the second test chamber.

77. The system of claim 76, wherein one of more of the reagents are lyophilized as lyophilized beads.