Devices, systems and methods for evaluation of hemostasis

• US 10,481,168 B2
• Filed: 02/26/2018
• Issued: 11/19/2019
• 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:
  US15/904,984
• Publication Number:
  US 20180231575A1
• Time in Patent Office: 631 Days
• Field of Search: 422 73
• 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. In some embodiments, an apparatus is disclosed comprising a housing; a plurality of test chambers located in the housing, the plurality of test chambers including chambers configured for measurements via a system that interrogates one or more viscoelastic properties of test samples in the test chambers, wherein the one or more viscoelastic properties is used to characterize dynamics of coagulation and/or fibrinolysis.

Claims

1. An apparatus configured as a disposable cartridge, the apparatus comprising:

a housing;

a plurality of test chambers located in the housing, the plurality of test chambers including chambers configured for viscoelastic measurements via a system that interrogates one or more viscoelastic properties of test samples in the test chambers, wherein the one or more viscoelastic properties is used to characterize dynamics of coagulation and/or fibrinolysis including clot stiffness of a clot formed in the test samples, wherein the plurality of test chambers comprise a first test chamber and a second test chamber each defined by a space sufficient to allow induced displacement of the test sample in the test chamber from an application of a force applied to the test sample when the system interrogates the one or more viscoelastic properties of the test sample; 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 a blood sample is introduced into the apparatus, wherein at least one channel of the fluid pathway is in communication with the inlet and with the first test chamber and a second test chamber to deliver a portion of the blood sample to each of the first test chamber and the second test chamber, 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, and 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;

a first reagent or a first combination of reagents configured to activate coagulation, wherein the first reagent or the first combination of reagents is preloaded in a first space associated with the first test chamber for a single use in the disposable cartridge, and wherein the first reagent or the first combination of reagents interacts with a portion of the blood sample drawn through the first channel to form a first test sample, wherein the first test sample can be interrogated in the first test chamber to provide a first viscoelastic measurement that provides a determination of one or more clot stiffness values of a first clot formed in the first test sample in which the first clot is formed without platelet aggregation being inhibited, wherein the first reagent or the first combination of reagents comprises abciximab; and

a second combination of reagents comprising i) a reagent, or a combination of reagents, configured to activate coagulation and ii) a reagent, or a combination of reagents, to inhibit platelet aggregation, wherein the second combination of reagents is preloaded in a second space associated with the second test chamber for a single use in the disposable cartridge, and wherein the second combination of reagents interacts with a portion of the blood sample drawn through the second channel to form a second test sample, wherein the second test sample can be interrogated in the second test chamber to provide a second viscoelastic measurement that provides a determination of one or more clot stiffness values of a second clot formed in the second test sample in which the second clot is formed with platelet aggregation being inhibited.

2. A system comprising the apparatus of claim 1, wherein the system comprises:

one or more transducers;

at least one processor; and

a memory having instructions stored thereon, wherein the instructions when executed by the at least one processor of the system cause the at least one processor to direct the one or more transducers in the interrogation of the first and second test samples to determine at least one viscoelastic property of the first and second clots, including the one or more clot stiffness values.

3. The system of claim 2, wherein the instructions when executed by the at least one processor cause the at least one processor to direct the one or more transducers to deform the test sample in the interrogation of the one or more viscoelastic properties.

4. The system of claim 3, wherein the system further comprises:

a heater configured to heat the apparatus.

5. The system of claim 4, wherein the instructions when executed by the at least one processor further cause the at least one processor to determine platelet function based on a difference in response of the first viscoelastic measurement and the second viscoelastic measurement.

6. The system of claim 4, wherein the instructions when executed by the at least one processor further cause the at least one processor to determine a curve associated with the one or more determined clot stiffness values of the first test sample, the curve being generated from the interrogation as a function of time.

7. The system of claim 6, wherein the instructions when executed by the at least one processor further cause the at least one processor to determine a parameter corresponding to a reduction in viscoelastic properties indicative of fibrinolysis processes to characterize dynamics of fibrinolysis.

8. The system of claim 6, wherein the instructions when executed by the at least one processor of the system cause the at least one processor to quantify functions of platelets, fibrinogen, plasma factors, and fibrinolytic proteins based on the one or more viscoelastic properties of the test samples.

9. The system of claim 6, further comprising

a display, wherein the system is configured, via the display, to output measurement results associated with the one or more clot stiffness values.

10. The apparatus of claim 2, wherein the one or more transducers comprise at least one ultrasonic transducer configured to generate an acoustic radiation force to cause deformation of the test sample, and wherein the interrogation comprises use of the acoustic radiation force.

11. The system of claim 1, wherein the housing comprises an outer surface having a shape that allows the outer surface to be held in at least partial contact with or in close proximity to one or more transducers, wherein the outer surface of the housing defines a portion of an exterior surface of each of the plurality of test chambers, wherein the one or more transducers are configured to deform the test sample in the interrogation of the one or more viscoelastic properties, and wherein each of the plurality of test chambers has an inner surface that extends away from the respective exterior surface of the test chamber, to form the space for interrogation of the one or more viscoelastic properties.

12. The apparatus of claim 1, wherein the first test chamber includes the first reagent or the first combination or reagents prior to receiving the test sample of blood therein, and wherein the second test chamber includes the second combination of reagents prior to receiving the test sample of blood therein.

13. The apparatus of claim 1, wherein the first reagent or a reagent of the first combination of reagents and/or a reagent of the second combination of reagents, is configured to activate coagulation comprises an extrinsic pathway activator.

14. A device configured as a disposable cartridge, the device comprising:

a housing;

a plurality of test chambers, wherein the plurality of test chambers include 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 receive a test sample of blood 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 an element having a surface defined at least in part by the housing, wherein the element is in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the device 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, and wherein the first channel is in communication with the inlet channel and at least with the first test chamber, 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;

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 sample via the extrinsic pathway of coagulation;

wherein the second reagent or combination of reagents further includes an antagonist of fibrinolytic function;

wherein the first reagent or combination of reagents and the second reagent or combination of reagents are preloaded for a single use in the disposable cartridge;

wherein the first reagent or combination of reagents interacts with the test sample to be interrogated in the first test chamber to provide a viscoelastic measurement for a determination of one or more clot stiffness values of a clot formed in the first test chamber; and

wherein the second reagent or combination of reagents interacts with the test sample to be interrogated in the second test chamber to provide a viscoelastic measurement for a determination of one or more clot stiffness values of a clot formed in the second test chamber.

15. The device of claim 14, further comprising a third test chamber designed to receive and a third reagent or combination of reagents, wherein the third reagent or combination of reagents is different from the reagents in the first test chamber and the second test chamber, and 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.

16. The device of claim 14, wherein the device is designed, to operate with an analysis system, 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.

17. The device of claim 14, wherein tithe first reagent or combination of reagents or ii) the second reagent or combination of reagents further includes one or both of abciximab and cytochalasin D.

18. The device of claim 14, wherein at least one of the plurality of test chambers includes a reagent or combination of reagents that allows for measurement of a hemostatic parameter based on a change in a mechanical property of a blood sample.

19. A device configured as a disposable cartridge, the 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 receive a test sample of blood 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, wherein the fluid pathway includes an element having a surface defined at least in part by the housing, wherein the element is in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the device 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, and 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;

wherein the first reagent or combination of reagents includes reptilase;

wherein the second reagent or combination of reagents includes one or both of adenosine diphosphate and arachidonic acid;

wherein the first reagent or combination of reagents and the second reagent or combination of reagents are each preloaded for a single use in the disposable cartridge;

wherein the first reagent or combination of reagents interacts with the test sample to be interrogated in the first test chamber that provides a viscoelastic measurement for a determination of one or more clot stiffness values of a clot formed in the first test chamber; and

wherein the second reagent or combination of reagents interacts with the test sample to be interrogated in the second test chamber that provides a viscoelastic measurement for a determination of one or more clot stiffness values of a clot formed in the second test chamber.

20. The device of claim 19, further comprising a third test chamber designed to receive a test sample of blood 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.

21. The device of claim 20, wherein the third reagent or combination of reagents that activates the test sample via the intrinsic pathway comprises kaolin.

22. The device of claim 20, wherein the device is designed to evaluate a platelet function index.

23. The device of claim 19, wherein one or more of the first reagent or combination of reagents, the second reagent or combination of reagents, and the third reagent or combination of reagents are lyophilized.

24. A device configured as a disposable cartridge, the 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 receive a test sample of blood 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 wherein one of the reagent combinations includes an antagonist of fibrinolysis; 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, wherein the first port is in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the device 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, and 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, wherein the second port is in communication with a channel of the fluid pathway and from which a pressure gradient when applied from a source external to the device 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;

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

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;

wherein the first reagent or combination of reagents, the second reagent or combination of reagents, and the third reagent or combination of reagents are each preloaded for a single use in the disposable cartridge; and

wherein the one of the reagent combinations that includes the antagonist of fibrinolysis interacts with the test sample to be interrogated in one of the plurality of test chambers to provide a viscoelastic measurement for a determination of one or more clot stiffness values of a clot formed in the one of the plurality of test chambers associated with the one of the reagent combinations.

25. The device of claim 24, wherein the device is designed such that a vacuum can be applied at the second port to provide the pressure gradient to introduce the test sample into the inlet and direct the sample into the at least one channel of the fluid pathway.

26. The device of claim 24, further comprising a coupling element defining the inlet to couple to a vacutainer or an external vessel and through which the test sample is introduced into the device.

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

28. The device of claim 24, wherein the housing is designed to allow a fluid level to be monitored optically.

29. The device of claim 24, wherein one of more of the first reagent or combination of reagents, the second reagent or combination of reagents, and third reagent or combination of reagents are lyophilized as lyophilized beads.