Devices, systems and methods for evaluation of hemostasis

• US 10,031,144 B2
• Filed: 07/05/2016
• Issued: 07/24/2018
• 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 Alice
• Assistant Examiner(s): Fisher, Brittany I
• Application Number:
  US15/202,059
• Publication Number:
  US 20160313357A1
• Time in Patent Office: 749 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. An apparatus for evaluation of hemostasis, comprising:

a housing that is configured to couple to a system, wherein the system comprises one or more transducers for each of a plurality of test chambers, wherein the system comprises at least one processor and memory having instructions stored thereon, wherein the instructions when executed by the at least one processor cause the at least one processor to direct the one or more transducers associated with each of the plurality of test chambers in the interrogation of the test sample to determine at least one viscoelastic property of the test sample;

the plurality of test chambers, including a first test chamber, a second test chamber, and a third test chamber, that are each at least partially defined by the housing; and

a fluid pathway having an inlet, defined by the housing, and from which an external vessel establishes fluid communication, to receive a test sample, wherein the fluid pathway is in fluid communication with the first test chamber, the second test chamber, and the third test chamber to deliver the test sample, or a portion thereof, to the first test chamber, the second test chamber, and the third test chamber,

wherein each of the plurality of test chambers comprises a reagent or combination of reagents, and wherein each of the plurality of test chambers, including the first, second, and third test chambers, is configured to receive, via the fluid pathway, blood of a test sample to be interrogated to determine a plurality of hemostatic parameters;

wherein the first test chamber comprises a first reagent or a first combination of reagents that interact with the blood received therein, wherein the first reagent, or a reagent included in the first combination of reagents, is configured to activate coagulation via extrinsic or intrinsic pathway;

wherein the second test chamber comprises a second combination of reagents that interact with blood of the test sample received therein, wherein the second combination of reagents includes i) a reagent, or a combination of reagents, configured to activate coagulation via the extrinsic or intrinsic pathway and ii) a reagent, or a combination of reagents, configured to inhibit platelet contraction; and

wherein the third test chambers comprises a third reagent or a third combination of reagents that interact with the blood received therein, wherein the third reagent, or a reagent included in the third combination of reagents, is configured to activate coagulation via the extrinsic or intrinsic pathway.

2. The apparatus of claim 1, wherein the interrogation to determine the hemostatic parameter of the blood is based on a change in clot mechanical properties.

3. The apparatus of claim 1, wherein at least one of the first reagent, the second combination of reagents, and the third reagent is provided as lyophilized beads prior to interacting with the test samples.

4. The apparatus of claim 1, wherein the housing forms a cartridge comprising the plurality of test chambers and the fluid pathway.

5. The apparatus of claim 4, wherein the cartridge defines at least a portion of the fluid pathway, and wherein at least a portion of the cartridge is thermally conductive.

6. The apparatus of claim 5, wherein the thermally conductive portion of the cartridge defines at least a portion of the fluid pathway.

7. The apparatus of claim 5, wherein the thermally conductive portion comprises a thermally conductive polymer.

8. The apparatus of claim 4, wherein the fluid pathway further comprises a channel in fluid communication with at least one test chamber, and wherein sample delivered from the channel into the test chamber results in mixing of at least a portion of the sample and the reagent within the test chamber.

9. The apparatus of claim 4, wherein the cartridge is disposable.

10. The apparatus of claim 4, wherein the cartridge comprises a material containing polystyrene.

11. The apparatus of claim 1, wherein the first reagent or the first combination of reagents includes one or more of reagents selected from the group consisting of kaolin, celite, glass, thrombin, ellagic acid, and tissue factor, and wherein the second combination of reagents include two or more reagents selected from the group consisting of kaolin, celite, glass, thrombin, ellagic acid, tissue factor, abciximab, and cytochalasin D.

12. The apparatus of claim 11, wherein the second combination of reagents includes a first group selected from a group consisting of kaolin, celite, glass, thrombin, ellagic acid, tissue factor, and a combination thereof, and a second group selected from the group consisting of abciximab, cytochalasin D, and a combination thereof.

13. The apparatus of claim 1, wherein the evaluation of hemostasis comprises an assessment of components of hemostasis that include combined effects of coagulation, platelets, and fibrinolysis.

14. The apparatus of claim 1, wherein the evaluation of hemostasis comprises an assessment of components of hemostasis that include plasma coagulation factors, platelets, fibrinogen, and fibrinolytic factors of the plasma.

15. The apparatus of claim 1, wherein the one or more transducers comprise one or more ultrasonic transducer elements.

16. The apparatus of claim 1, wherein a first transducer of the one or more transducers comprises a light emitting diode (LED) emitter and a second transducer of the one or more transducers comprises a detector.

17. The apparatus of claim 1, wherein at least three measurements are performed in parallel within the plurality of test chambers using a combination of agonists and antagonists of hemostasis in at least one of the three test chambers.

18. The apparatus of claim 1, wherein the first reagent or the first combination of reagents are mixed with the test sample in a portion of the fluid pathway prior to being delivered to the first test chamber.

19. The apparatus of claim 1, wherein the one or more transducers can interrogate viscoelastic properties of the test samples within the plurality of test chambers based on induced displacement of the test sample produced by the one or more transducers.

20. A system for evaluation of hemostasis comprising:

a plurality of test chambers, including a first test chamber and a second test chamber, wherein each of the plurality of test chambers comprises a reagent or combination of reagents, and wherein each of the plurality of test chambers is configured to receive blood of a test sample and to be interrogated to determine a hemostatic parameter of the blood received therein;

one or more transducers for transmitting energy into one or more test chamber and for receiving reflected energy from the chamber and the sample therein;

at least one processor in communication with the one or more transducers, wherein the processor is configured to determine the hemostatic parameters from signals transmitted to the processor from the one or more transducers; and

a memory having instructions stored thereon, wherein the instructions when executed by the at least one processor, cause the at least one processor to perform at least three measurements in parallel;

wherein the first test chamber comprises a first reagent or a first combination of reagents that interact with the blood of the test sample received therein, wherein the first reagent, or at least one reagent included in the first combination of reagents, is an activator of coagulation; and

wherein the second test chamber comprises a second combination of reagents that interact with blood of the test sample received therein, the second combination of reagents including an activator of coagulation and a reagent, or a combination of reagents, configured to cause a reduction in measurable changes in clot mechanical properties of the test sample when the test sample is interrogated by the one or more transducers.

21. The system of claim 20, wherein the clot mechanical properties comprises one or more viscoelastic properties of the test sample.

22. The system of claim 20 wherein the memory further comprises additional instructions stored thereon, wherein the additional instructions when executed by the at least one processor, cause the at least one processor to:

determine a curve associated with a viscoelastic property of the blood of each test sample, the curve being generated from the interrogation as a function of time.

23. The system of claim 20, wherein the hemostasis parameters are selected from the group consisting of TC1, TC2, clot stiffness, clot formation rate (CFR), TL1, TL2, baseline viscosity, and post lysis viscosity.

24. The system of claim 20, wherein the memory further comprises additional instructions stored thereon, wherein the additional instructions when executed by the at least one processor, cause the at least one processor to determine at least one parameter selected from the group consisting of an intrinsic pathway coagulation factors index, an extrinsic pathway coagulation factors index, a platelets index, a fibrinogen index, and a fibrinolysis index.

25. The system of claim 20, wherein at least one of the first reagent or the first combination of reagents and the second combination of reagents is provided as lyophilized beads prior to interacting with the test samples.

26. The system of claim 20, wherein the plurality of test chambers and a fluid pathway having an inlet for receiving a test sample form a part of a cartridge, wherein the fluid pathway is in fluid communication with at least one test chamber to deliver the test sample, or a portion thereof, to one or more of the test chambers.

27. The system of claim 26, wherein at least a portion of the cartridge comprises a thermally conductive material.

28. The system of claim 27, wherein the portion of the cartridge defines at least a portion of the fluid pathway.

29. The system of claim 28, wherein the thermally conductive material comprises a thermally conductive polymer that has a thermal conductivity higher than Styron 666.

30. The system of claim 20, wherein the first reagent or the first combination of reagents are mixed with the test chamber in a part of a fluid pathway prior to being delivered to the first test chamber.

31. The system of claim 20, wherein the plurality of test chambers form a part of a single use disposable cartridge.

32. The system of claim 31, further comprising a pocket to which the single use disposable cartridge is securely received and held in position.

33. The system of claim 20, comprising a pocket to receive the plurality of test chambers and to securely position the plurality the test chambers in a predefined orientation.

34. The system of claim 20, wherein the plurality of test chambers comprises a material containing polystyrene.

35. The system of claim 20,

wherein the first reagent or the first combination of reagents is selected from the group consisting of kaolin, celite, glass, thrombin, ellagic acid, tissue factor, and a combination thereof,

wherein the second combination of reagents includes two or more reagents selected from the group consisting of kaolin, celite, glass, thrombin, ellagic acid, abciximab, cytochalasin D, and tissue factor.

36. The system of claim 35, wherein the second combination of reagents includes a first group selected from a group consisting of kaolin, celite, glass, thrombin, ellagic acid, tissue factor, and a combination thereof, and a second group selected from the group consisting of abciximab, cytochalasin D, and a combination thereof.

37. The system of claim 20, wherein the system is capable of assessing components of hemostasis that include plasma coagulation factors, platelets, fibrinogen, and fibrinolytic factors of the plasma.

38. The system of claim 20, wherein the one or more transducers comprise one or more ultrasonic transducer elements.

39. The system of claim 20, wherein a first transducer of the one or more transducers comprises a light emitting diode LED emitter and a second transducer of the one or more transducers comprises a detector.

40. The system of claim 20, wherein the system is capable of assessing components of hemostasis that include combined effects of coagulation, platelets, and fibrinolysis.

41. The system of claim 20, wherein the memory further comprises additional instructions stored thereon, wherein the additional instructions when executed by the at least one processor, cause the at least one processor to determine the hemostatic parameters based on signals transmitted to the processor, wherein the signals are generated from induced displacement of the test sample produced by the one or more transducers.

42. A system for evaluation of hemostasis comprising:

a plurality of test chambers, including a first test chamber and a second test chamber, wherein each of the plurality of test chambers comprises a reagent or a combination of reagents, and wherein each of the plurality of test chambers is configured to receive blood of a test sample and to be interrogated to determine a hemostatic parameter of the blood received therein;

one or more transducers for transmitting energy into one or more test chamber and for receiving reflected energy from the chamber and the sample therein;

at least one processor in communication with the one or more transducers, the processor being configured to determine the hemostatic parameters from signals transmitted to the processor from the one or more transducers; and

a memory having instructions stored thereon, wherein execution of the instructions by the at least one processor cause the at least one processor to determine the hemostatic parameters in parallel;

wherein the first chamber comprises a first reagent or a first combination of reagents that interact with the blood received therein, wherein the first reagent, or a reagent included in the first combination of reagents, is an activator of coagulation; and

wherein the second chamber comprises a second combination of reagents that interact with blood of the test sample received therein, the second combination of reagents including an activator of coagulation and a reagent, or a combination of reagents, configured to inhibit platelet functions.

43. The system of claim 42, wherein the memory further comprises additional instructions stored thereon, wherein execution of the additional instructions by the at least one processor, cause the at least one processor to determine a coagulation factors index.

44. The system of claim 42, wherein the memory further comprises additional instructions stored thereon, wherein execution of the additional instructions by the at least one processor, cause the at least one processor to determine at least one parameter selected from the group consisting of an intrinsic pathway coagulation factors index, an extrinsic pathway coagulation factors index, a platelets index, a fibrinogen index, and a fibrinolysis index.

45. The system of claim 42, wherein at least one of the first reagent or the first combination of reagents and the second combination of reagents is provided as lyophilized beads prior to interacting with the test sample.

46. The system of claim 42, comprising a fluid pathway having an inlet for receiving the test sample, wherein the fluid pathway is in fluid communication with at least one test chamber to deliver the test sample, or a portion thereof, to one or more of the test chambers.

47. The system of claim 46, wherein at least a portion of the fluid pathway comprises a thermally conductive material.

48. The system of claim 46, wherein the fluid pathway and the plurality of test chambers form a portion of a cartridge, wherein a portion of the cartridge is thermally conductive.

49. The system of claim 48, wherein the thermally conductive portion comprises a thermally conductive polymer having a thermal conductivity higher than Styron 666.

50. The system of claim 46, wherein the test sample is mixed with the reagent or the combination of regents prior to being delivered into the test chamber.

51. The system of claim 42, wherein the plurality of test chambers form a part of a cartridge.

52. The system of claim 42, further comprising a pocket to securely receive and hold in position a housing that defines the plurality of test chambers.

53. The system of claim 42, further comprising a pocket to receive a housing that defines the plurality of test chambers and to securely position the housing in a predefined orientation.

54. The system of claim 42,

wherein the first reagent or the first combination of reagents is selected from the group consisting of kaolin, celite, glass, thrombin, ellagic acid, tissue factor, and a combination thereof, and

wherein the second combination of reagents is two or more reagents selected from the group consisting of kaolin, celite, glass, thrombin, abciximab, cytochalasin D, ADP, arachidonic acid, reptilase, ellagic acid, tissue factor, and a combination thereof.

55. The system of claim 54, wherein the second combination of reagents include a first group selected from a group consisting of kaolin, celite, glass, thrombin, ellagic acid, tissue factor, and a combination thereof, and a second group selected from the group consisting of abciximab, cytochalasin D, and a combination thereof.

56. The system of claim 42, wherein the system is capable of assessing components of hemostasis that include plasma coagulation factors, platelets, fibrinogen, and fibrinolytic factors of the plasma.

57. The system of claim 42, wherein the one or more transducers comprise one or more ultrasonic transducer elements.

58. The system of claim 42, wherein a first transducer of the one or more transducers comprises one or more light emitting diode LED emitter and a second transducer of the one or more transducers comprises a detector.

59. The system of claim 42, wherein the system is capable of assessing components of hemostasis that include combined effects of coagulation, platelets, and fibrinolysis.

60. The system of claim 42, wherein the memory further comprises additional instructions stored thereon, wherein execution of the additional instructions by the at least one processor cause the at least one processor to determine the hemostatic parameters based on signals transmitted to the processor, wherein the signals are generated from induced displacement of the test sample produced by the one or more transducers.

61. A system for evaluation of hemostasis comprising:

a plurality of test chambers, including a first test chamber and a second test chamber, wherein each of the plurality of test chambers comprises a reagent or combination of reagents, and wherein each of the plurality of test chambers is configured to receive blood of a test sample and to be interrogated to determine a hemostatic parameter of the blood received therein;

one or more transducers for transmitting energy into one or more test chamber and for receiving reflected energy from the chamber and the sample therein;

at least one processor in communication with the one or more transducers, wherein the processor is configured to determine the hemostatic parameters from signals transmitted to the processor from the one or more transducers; and

a memory having instructions stored thereon, wherein the instructions when executed by the at least one processor, cause the at least one processor to determine a curve associated with a viscoelastic property of the blood of each test sample, the curve being generated from the interrogation as a function of time;

wherein the first test chamber comprises a first reagent or a first combination of reagents that interact with the blood of the test sample received therein, wherein the first reagent, or at least one reagent included in the first combination of reagents, is an activator of coagulation; and

wherein the second test chamber comprises a second combination of reagents that interact with blood of the test sample received therein, the second combination of reagents including an activator of coagulation and a reagent, or a combination of reagents, configured to cause a reduction in measurable changes in clot mechanical properties of the test sample when the test sample is interrogated by the one or more transducers.

62. The system of claim 61, wherein the one or more transducers comprise one or more ultrasonic transducer elements.

63. The system of claim 61, wherein a first transducer of the one or more transducers comprises a light emitting diode LED emitter and a second transducer of the one or more transducers comprises a detector.