Disposable system for hemostatic function analysis

Abstract

In some embodiments, the disposable system includes a multi-channel or multi-chamber test cartridge device configured to operate with a test system for assessing hemostasis in a subject by assessing a test sample from the subject in vitro. In some embodiments, the disposable system is configured to interrogate the test sample to assess clot stiffness, strength, or other mechanical properties of the test sample to assess the function of various physiological processes that occur during coagulation and / or lysis of the resulting clot.

Description

[0001] This case is a divisional application based on the Chinese patent application with patent application number 201880035690.0 and invention name “Disposable system for hemostasis function analysis” filed on April 20, 2018.

[0002] Related applications

[0003] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 488,045, filed April 20, 2017, entitled “Disposable System for Hemostasis Analysis,” which is incorporated herein by reference in its entirety. Technical Field

[0004] The present application relates to devices, systems, and methods for assessing hemostasis in a subject by preparing and analyzing a test sample from the subject. Background Art

[0005] Hemostasis (physiologic control of bleeding) is a complex process involving the vasculature, platelets, coagulation factors, fibrinolytic proteins, and various activators and inhibitors.

[0006] Disruption of hemostasis plays a central role in the pathogenesis of myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, and excessive bleeding. in vitro Diagnostics (IVD) to quantify hemostatic function / dysfunction and guide appropriate treatment.

[0007] Furthermore, the coagulation process is highly dependent on the temperature it occurs in. Normally, coagulation occurs at body temperature, which is optimal for the proper enzymatic action of the cascade of coagulation factors.

[0008] Preparation of the blood to be tested is very important because the way the blood sample is prepared before evaluation can affect the effects of, for example, vasculature components, platelets and other cellular components, coagulation factors, fibrinolytic components, and any inhibitors or activators of hemostasis. Summary of the Invention

[0009] The present invention provides devices, systems, and methods for evaluating hemostasis. For example, a disposable system for analyzing hemostatic function is provided. In some embodiments, the disposable system includes a multi-channel or multi-chamber test cartridge device configured to operate with the test system for evaluating hemostasis in a subject by in vitro evaluation of a test sample from the subject. In some embodiments, the disposable system is configured to interrogate the test sample to assess clot firmness, strength, or other mechanical properties of the test sample, thereby assessing the function of various physiological processes occurring during clotting and / or dissolution of the resulting clot. The sample may comprise, in whole or in part, whole blood, plasma, platelet-rich plasma, or platelet-depleted plasma. Additionally, the sample may include one or more reagents (such as anticoagulants or antiplatelet drugs that may be present in the blood at the time of collection), one or more pharmacological treatments (such as in the case of heparin or low molecular weight heparin), or other inert components (such as polystyrene beads) added to the test sample prior to use of the cartridge device. A disposable system facilitates point-of-care assessment of hemostasis in a test sample that is robust (e.g., can be performed in a non-laboratory setting), rapid (e.g., takes only minutes to complete), easy to use, provides clear results (e.g., directly targets functional components of hemostasis), and facilitates accurate identification of hemostasis defects. Exemplary devices automate one or more pre-measurement steps, minimizing sample manipulation steps required by the user, thereby improving test reproducibility and / or test quality. In some embodiments, the disposable system includes multiple test circuits, each having a path defined by channels and chambers configured to prepare a blood test sample for evaluation by a measurement device. Within each test circuit, a portion of the test sample is introduced into a reagent or reagent combination specific to that test circuit.

[0010] In some embodiments, the disposable system is configured to condition the corresponding test sample before, during, and / or after mixing with reagents to optimize the appropriate effects of the available blood components and chemicals being evaluated (e.g., vasculature components, platelets or other cellular components, coagulation factors, fibrinolytic components, and any other inhibitors or activators of hemostasis, etc.).

[0011] In one aspect, a device (e.g., a cartridge) for hemostasis assessment is disclosed. The device includes a housing; an input port integrally formed with the housing, the input port structurally configured to establish fluid communication and discharge the contents of a sample holding tube; and a first chamber in fluid communication with the input port. The first chamber is configured to receive a sample contained in the sample holding tube and condition the received sample to a desired temperature (e.g., a predetermined temperature range) before allowing the received sample to contact one or more reagents in one or more fluid circuits located downstream of the first chamber, wherein each of the one or more fluid circuits includes i) a second chamber in fluid communication with the first chamber that meters the sample in the first chamber into aliquots, wherein the metered sample is introduced into a reagent or reagent combination (e.g., in the form of lyophilized reagent beads) located in a corresponding fluid circuit (e.g., a reagent bag) to form a mixed sample, and ii) a testing chamber in fluid communication with the second chamber, the testing chamber structurally configured to be interrogated by a measurement system configured to determine a property (e.g., mechanical or viscoelastic) of the mixed sample.

[0012] In some embodiments, at least one of the one or more fluid circuits comprises one or more bags (eg, each bag configured to contain lyophilized reagent beads comprising a reagent or combination of reagents).

[0013] In some embodiments, at least one of the one or more fluid circuits includes one or more reservoir bags (eg, each bag configured to contain an analyte in liquid form, the analyte including a reagent or combination of reagents).

[0014] In some embodiments, at least one of the one or more fluid circuits includes one or more lyophilized reagents located on one or more surfaces thereof (eg, lyophilized on each surface; lyophilized as a thin film disposed on or adhered to one or more surfaces).

[0015] In some embodiments, at least one of the one or more fluid circuits includes one or more reagents that are processed on a surface thereof (eg, dried on the surface; sprayed on the surface; baked on the surface).

[0016] In some embodiments, the input port is communicatively coupled to the pressure port, wherein pressure applied to the pressure port causes the contents of the sample holding tube to be expelled through the input port into the first chamber.

[0017] In some embodiments, the input port comprises a needle assembly.

[0018] In some embodiments, the needle assembly includes an input port and a second port, wherein the second port is configured to discharge a liquid or gas into the sample holding tube to facilitate expulsion of contents therein. In some embodiments, the input port is located (e.g., concentrically located) within the second port, wherein the second port is configured to discharge a liquid or gas into the sample holding tube to expel the contents of the sample holding tube.

[0019] In some embodiments, the input port comprises a Luer lock configured to connect to a sample holding tube, wherein the sample holding tube is a syringe.

[0020] In some embodiments, the input port is communicatively coupled to a first pressure port, wherein pressure, when applied to the first pressure port, causes the contents of the sample holding tube to be expelled through the input port into the first chamber.

[0021] In some embodiments, the first chamber is configured to cooperate with a corresponding thermal conditioning system (eg, a heating / cooling system) of the measurement system to condition the received sample to or near a desired temperature.

[0022] In some embodiments, the shape and / or material of the first chamber is optimized to facilitate thermal conditioning (eg, heating and / or cooling) of the sample to or near a desired temperature.

[0023] In some embodiments, the first chamber is configured to cooperate with a corresponding thermal conditioning surface of a subsystem component of the measurement system to condition the received sample to or near a desired temperature. In some embodiments, the channel portion of one or more fluid circuits is configured to cooperate with a corresponding heating / cooling system of the measurement system to condition the received sample to or near a desired temperature.

[0024] In some embodiments, the channel portions of the one or more fluid circuits are configured to cooperate with a corresponding thermal regulation system of the measurement system to regulate the received sample to a desired temperature. In some embodiments, the first chamber and / or the channel portions of the one or more fluid circuits are in physical proximity (e.g., in physical contact or near contact) to a sensor configured to measure the temperature of the sample received in the first chamber.

[0025] In some embodiments, the sensor is selected from the group consisting of a thermistor, a thermocouple, and an optical sensor (eg, an infrared sensor).

[0026] In some embodiments, the device includes a first pressure port in fluid communication with the first chamber, the first pressure port being configured to receive a negative pressure or a differential pressure (e.g., for filling the first chamber); and a filter positioned within the first pressure port in at least one fluid circuit (e.g., such that when the first chamber is full, the filter is clogged by the sample received in the first chamber). In some embodiments, the filter is configured to allow air to move through the first pressure port but prevent fluid from moving therethrough.

[0027] In some embodiments, the device includes a first pressure port configured to receive a negative pressure or a differential pressure for filling the first chamber; and a first fluid path extending from the first pressure port to the first chamber, wherein the filter is located within the first pressure port.

[0028] In some embodiments, for each of the one or more fluid circuits, fluid communication between the first chamber and the second chamber is via a second fluid path originating from a side (e.g., a side wall, a bottom wall, etc.) of the first chamber (e.g., such that bubbles present in the received sample are trapped away from the second chamber).

[0029] In some embodiments, each of the one or more fluid circuits includes a third fluid path in fluid communication with the second chamber, wherein the third fluid path leads to a second pressure port configured to receive a negative or differential pressure to fill the second chamber.

[0030] In some embodiments, the second pressure port has a second filter therein, wherein the second filter is configured to plug when the second chamber is filled.

[0031] In some embodiments, the device includes one or more fluid paths in fluid communication with the second pressure port for all of the one or more fluid circuits, wherein the one or more fluid paths are configured to provide negative pressure to the second pressure port for all of the one or more fluid circuits.

[0032] In some embodiments, for each of the one or more fluid circuits, the second chamber is in fluid communication with an exhaust port, wherein the exhaust port is configured to close when the sample is metered into the aliquot in the second chamber and is further configured to open to atmospheric pressure after the sample is metered into the aliquot in the second chamber.

[0033] In some embodiments, each of the one or more fluid circuits includes a third set of fluid paths in fluid communication between the corresponding second chamber (eg, metering chamber) and the testing chamber, wherein a portion of the third set of fluid paths is arranged as a serpentine conduit or channel.

[0034] In some embodiments, each of the one or more fluid circuits further comprises a serpentine reservoir between the testing chamber and the second chamber.

[0035] In some embodiments, the metered sample is optionally directed through portions of one or more fluid circuits to facilitate mixing of the metered sample and the reagent or reagent combination.

[0036] In some embodiments, for each of one or more fluid circuits, the metered sample is alternately and multiplexedly directed between a first location in the fluid circuit (eg, the second chamber) and a second location in the fluid circuit (eg, a location in the serpentine reservoir).

[0037] In some embodiments, each of the one or more fluid circuits further comprises a third pressure port in fluid communication with the second chamber and the testing chamber, the third pressure port being configured to receive a negative or differential pressure (e.g., for drawing an aliquot from the second chamber to the testing chamber), wherein the third pressure port is further configured to alternately receive alternating pressures, e.g., for alternately drawing an aliquot from the second chamber along the serpentine reservoir and pushing the aliquot through the serpentine reservoir to the second chamber.

[0038] In some embodiments, the serpentine reservoir includes an optical detection zone to facilitate optical detection of the metered sample in the serpentine reservoir or the position of the sample in the serpentine reservoir.

[0039] In some embodiments, each of the one or more fluid circuits further includes a mixing path between the testing chamber and the second chamber, the mixing path including one or more ferromagnetic beads or rods therein.

[0040] In some embodiments, at least one of the one or more fluid circuits includes one or more quality testing inlets.

[0041] In some embodiments, one or more quality test inlets are configured to be optically sensed, wherein the quality test inlets are transparent.

[0042] In some embodiments, the one or more quality test inlets are configured to be electrically sensed, wherein the quality test inlet comprises one or more sensing electrodes.

[0043] In some embodiments, one or more quality test inlets are configured to be sampled for a characteristic of a metered sample (eg, pressure, presence of flow, flow rate, temperature).

[0044] In some embodiments, for each of the one or more fluid circuits, the test chamber includes a mechanism to couple energy into the test chamber to perform the measurement, such as where a lens is configured to direct ultrasonic pulses into the test chamber.

[0045] On the other hand, a device for assessing hemostasis is disclosed, comprising: a housing; an input port integrally formed with the housing, the input port being structurally capable of establishing fluid communication with a sample holding tube and discharging the contents of the sample holding tube; a first chamber in fluid communication with the input port, the input port receiving a sample contained in a vacuum tube and thereby adjusting the temperature of the sample to a desired temperature before the sample contacts one or more reagents; one or more second chambers in fluid communication with the first chamber, the one or more second chambers being configured to meter the sample in the first chamber into one or more aliquots; one or more reagent bags, each filled with one or more lyophilized reagent beads, the lyophilized reagent beads being in fluid communication with each aliquot chamber and allowing the sample present in each aliquot to mix with the one or more reagent beads; and one or more test chambers in fluid communication with the aliquot chamber and being structurally capable of being interrogated to determine the viscoelasticity of the sample after the sample is mixed with the one or more reagents.

[0046] In some embodiments, the agent or combination of agents located in one or more fluid circuits includes or has a combination of an intrinsic pathway activator (eg, kaolin, diatomaceous earth, glass, ellagic acid, micronized silica, Hegman's factor, etc.).

[0047] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or has a combination of an exogenous pathway activator (eg, tissue factor, recombinant tissue factor, thromboplastin, etc.).

[0048] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or has a combination of a coagulation activator (eg, thrombin, Factor Xa, Reptilase, ecarin, Russell's viper venom or other snake venom, etc.).

[0049] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes a platelet activator or platelet inhibitor (e.g., a GPIIb / IIIa inhibitor (e.g., abciximab, eptifibatide, tirofiban, roxifiban, orbofiban), cytochalasin D, blebbistatin, PAR1 inhibitor, PAR4 inhibitor, glycoprotein IB inhibitor, TRAP, ADP, arachidonic acid, ADP inhibitor, nonsteroidal anti-inflammatory drugs, platelet activating factor, ristocetin, epinephrine, etc.) or a combination thereof.

[0050] In some embodiments, the agent or combination of agents located in one or more fluid circuits includes a fibrinolytic activator or inhibitor (e.g., tPA, uKA, streptokinase, TAFIa, plasmin / plasminogen, aprotinin, ε-aminocaproic acid, tranexamic acid, plasminogen activator inhibitor 1 (PAI1), α2-antiplasmin (α2-AP) or plasmin-antiplasmin complex, carboxypeptidase inhibitors) or a combination thereof.

[0051] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or comprises a FXIIIa inhibitor.

[0052] In some embodiments, the agent or combination of agents located in one or more fluid circuits includes or comprises thrombomodulin.

[0053] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or comprises low molecular weight heparin.

[0054] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or comprises hexamethylenetetramine (polybrene).

[0055] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or comprises heparin.

[0056] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or has a combination of corn trypsin inhibitor.

[0057] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or has a combination thereof.

[0058] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or has a combination of GPRP (Glycine-Proline-Arginine-Proline).

[0059] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes calcium or a combination thereof.

[0060] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or has a combination of fibronectin.

[0061] In some embodiments, the agent or combination of agents located in one or more fluid circuits includes or has a combination thereof.

[0062] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or comprises an immunodetection reagent.

[0063] In some embodiments, the reagent or combination of reagents located in one or more fluid circuits includes or comprises heparinase I.

[0064] In some embodiments, the agent or combination of agents located in one or more fluid circuits includes endothelial cells or activated endothelial cells.

[0065] In some embodiments, the measurement system is selected from the group consisting of an acoustic rheology-based system, a thromboelastometry-based system, a thromboelastometry-based system, an optical-based system, a fluorescence-based system, a colorimetric-based system, an agglomeration-based system, a resonance-based system, and an electrical impedance-based system.

[0066] In another aspect, a method for mixing a sample with one or more reagents in a device (e.g., a cartridge) and testing the mixed sample to assess hemostasis is disclosed. The method includes: receiving a plurality of metered samples from a plurality of metering chambers that receive a test fluid from a sample holding tube (e.g., via a mechanical coupling connecting the device to the sample holding tube or via an opening in the sample holding tube into which the sample is placed); alternatingly and multiplicatively flowing each aliquot until the aliquot is mixed with the reagent or reagent combination to form a mixed aliquot, wherein at least one aliquot is alternately and cyclically flowed i) from the metering chamber in a first direction through one or more reagent bags containing one or more reagents (e.g., lyophilized reagent beads) and along a serpentine in communication with the metering chamber; The invention relates to a method for driving the mixed aliquot along a serpentine path until at least a portion of the aliquot reaches a detection zone located within or after the serpentine path, and ii) from the detection zone through at least a portion of the serpentine path toward a metering chamber in a second direction opposite to the first direction until a triggering event occurs; and driving the mixed aliquot in a test chamber in fluid communication with the metering chamber, wherein the test chamber is structurally configured to be interrogated by a measurement system configured to determine a property (e.g., mechanical or viscoelastic) of the mixed aliquot, and wherein the interrogation of the test chamber is performed with the mixed aliquot located therein.

[0067] In some embodiments, the method includes receiving a fluid in a first chamber configured to adjust the temperature of a test sample to substantially body temperature or other desired temperature, wherein the metered sample received in the metering chamber is received from the first chamber.

[0068] In some embodiments, the test fluid is moved into the first chamber in response to an applied pressure applied or generated by the measurement system.

[0069] In some embodiments, the method includes conditioning a test fluid in a first chamber to or substantially near a desired temperature, wherein the test fluid is mixed with one or more reagents after exiting the first chamber.

[0070] In some embodiments, the method includes isolating (eg, blocking via a valve) the test fluid in the metering chamber to prevent the test fluid from contacting the one or more reagents during filling of the metering chamber.

[0071] In some embodiments, a second applied positive or negative pressure is applied or generated by the measurement system at a second port in communication with the serpentine path (eg, applied at a second pressure port in communication with ) to move the at least one aliquot in a second direction.

[0072] In some embodiments, the first applied positive or negative pressure is reversely applied or generated by the measurement system to move at least one aliquot in a second direction.

[0073] In some embodiments, receiving the mixed aliquot in the testing chamber further comprises receiving negative pressure via a third pressure port, wherein the third pressure port is further in fluid communication with the testing chamber.

[0074] In some embodiments, the test chamber is downstream of the serpentine path, and the third pressure port is downstream of the test chamber.

[0075] These and other features and advantages of the present invention will become more readily apparent to those skilled in the art upon consideration of the following detailed description and accompanying drawings, which describe preferred and alternative embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments and, together with the description, serve to explain the principles of the methods and systems.

[0077] Figure 1 A perspective view of an example biological sample input for a cartridge of a disposable system is depicted in accordance with an illustrative embodiment.

[0078] Figure 2 Shown is a device having a housing according to an illustrative embodiment, Figure 1 A side cross-sectional view of an example biological sample input.

[0079] Figure 3 shows a sample holding tube attached thereto, according to an illustrative embodiment, Figure 2 A side cross-sectional view of an example biological sample input.

[0080] Figure 4 According to an illustrative embodiment, Figure 3Detailed view of the example biospecimen input.

[0081] Figure 5A and Figure 5B Each shows biological fluid paths of four test circuits (eg, hemostasis test circuits) located on a sample preparation plane, according to an illustrative embodiment. Figure 5B Further shown is a sample holding tube further coupled to the sample holding tube according to an illustrative embodiment. Figure 5A cartridge body.

[0082] Figure 6A and Figure 6B Shown Figure 5A 、 Figure 5B and Figure 8 Front and rear perspective views of the heating chamber, where the markings correspond to the heating chamber filling.

[0083] Figure 6C and Figure 6D Shown Figure 5A 、 Figure 5B and Figure 8 Front and back perspective views of the device, with markings corresponding to sample chamber filling.

[0084] Figure 6E and Figure 6F Shown Figure 5A 、 Figure 5B and Figure 8 Front and back perspective views of a device with markings corresponding to sample mixing and test chamber filling.

[0085] Figure 7 According to an illustrative embodiment, Figure 5A The device is provided on the back of the cartridge and includes an interconnecting plane that engages with the sample preparation plane, which together form a biological fluid path for the test circuit.

[0086] Figure 8 According to an illustrative embodiment, Figure 7 The interconnected planes are portions of a biological fluid path.

[0087] Figure 9 An example test chamber portion is shown for use with an example drug cartridge in accordance with an illustrative embodiment.

[0088] Figure 10 An illustration of a cross-sectional view of an example test chamber in an example test chamber section is shown in accordance with an illustrative embodiment.

[0089] Figure 11 According to an illustrative embodiment, Figure 10 Detailed cross-sectional view of an example test chamber.

[0090] Figure 12A cross-sectional view of a disposable system operably coupled to a measurement system is shown in accordance with an illustrative embodiment.

[0091] Figure 13 An example shear modulus versus time curve is shown in accordance with an illustrative embodiment.

[0092] Figure 14 Examples of shear modulus curves obtained with a coagulation activator and with and without a fibrinolysis inhibitor are shown. Comparison of the differences in these curves can provide information about the fibrinolytic activity of the sample.

[0093] Figure 15 Possible examples of difference metrics that can be measured from shear modulus curves obtained with a coagulation activator and with or without a fibrinolysis inhibitor are shown.

[0094] Figure 16 FIG. 1 shows a schematic diagram of a disposable system for use in accordance with an illustrative embodiment. Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5A 、 Figure 5B 、 Figure 7 、 Figure 8 and Figure 9 Photograph of an exemplary cartridge.

[0095] Figure 17 According to an illustrative embodiment, Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5A 、 Figure 5B 、 Figure 7 、 Figure 8 and Figure 9 Front view of an exemplary cartridge.

[0096] Figure 18 According to an illustrative embodiment, Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5A 、 Figure 5B 、 Figure 7 、 Figure 8 and Figure 9 Front view of an exemplary cartridge. DETAILED DESCRIPTION

[0097] The present invention will now be described more fully hereinafter with reference to specific embodiments thereof. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

[0098] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0099] As used herein, the term "include" and variations thereof are used synonymously with the term "comprising" and variations thereof and are open, non-limiting terms.

[0100] As used throughout, "subject" refers to an individual. A subject can be a vertebrate, more specifically a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent), fish, bird, or reptile or amphibian. The term does not denote a particular age or sex.

[0101] The devices described herein include a disposable cartridge device configured to facilitate in vitro assessment of one or more hemostatic functions. Hemostatic function refers to the functional effects of various blood components, such as coagulation factors, fibrinogen, platelets, fibrinolytic factors, and components of the vasculature. In some embodiments, the cartridge device and associated measurement system are configured to assess hemostatic function by measuring changes in at least one mechanical property of the sample when exposed to one or more reagents. In some embodiments, the cartridge device and its test chamber are configured to facilitate viscoelastic measurements, for example, based on interrogation using ultrasonic pulses or energy. However, other interrogation systems may be used with cartridge devices having the features described herein. Examples of other interrogation systems include, but are not limited to, systems employing cup / lancet technology (such as in the context of thromboelastometry and thromboelastometry), vibrating pistons to measure changes in mechanical impedance, optical sensing, fluorescence sensing, colorimetric sensing, aggregation measurement, resonance sensing, or electrical impedance sensing.

[0102] A variety of reagents can be used in the cartridge device, including intrinsic pathway activators (not limited to kaolin, Hegmann factor, diatomaceous earth, glass, ellagic acid, micronized silica, etc.), extrinsic pathway activators (not limited to tissue factor, recombinant tissue factor, thromboplastin, etc.), other coagulation activators (not limited to thrombin, factor Xa, Reptilase, ecarin, Russell's viper venom or other snake venom, etc.), platelet activators or platelet inhibitors (not limited to GPIIb / IIIa inhibitors (such as abciximab, eptifibatide, tirofiban, roxifiban, orbofiban), cytochalasin D, blebbistatin, PAR1 inhibitors, PAR4 inhibitors, glycoprotein IB inhibitors, TRAP, ADP, arachidonic acid, ADP inhibitors, non-steroidal anti-inflammatory drugs, etc.), fibrinolytic function activators. or fibrinolytic function inhibitors (not limited to tPA, uKA, streptokinase, TAFIa, plasmin / plasminogen, aprotinin, ε-aminocaproic acid, tranexamic acid, plasminogen activator inhibitor 1 (PAI1), α2-antiplasmin (α2-AP) or plasmin-antiplasmin complex, carboxypeptidase inhibitors, etc.), as well as others (FXIIIa inhibitors, hexamethylenetetramine (polybrene), heparinase (e.g., heparinase I), ristocetin, heparin, low molecular weight heparin, corn trypsin inhibitor, adenosine, GPRP, calcium, fibronectin, collagen, epinephrine, immunoassay reagents, direct thrombin inhibitors, factor Xa inhibitors, reagents designed to reverse or eliminate the effects of new oral anticoagulants (e.g., direct thrombin inhibitors and factor Xa inhibitors), thrombomodulin, etc.). Additional non-functional reagents may also be used to preserve the functionality of other reagents (buffers and stabilizers for lyophilization or drying, dyes, etc.).

[0103] In some embodiments, the reagents are placed and stored in chambers of the cartridge device (e.g., bags located in a fluid circuit), but in alternative embodiments, the reagents may be placed and stored in various chambers or fluid channels within the fluid circuit of the cartridge device. A fluid circuit generally refers to one or more fluid pathways established between sample preparation and one or more test chambers where the sample is ultimately measured.

[0104] In some embodiments, the reagents are placed and stored in a cartridge device in liquid form, or can be lyophilized in spheres (such as Lyopheres manufactured by BioLyph LLC). TM In the case of a drug substance that is not completely hemostatic, the drug substance can be freeze-dried in a film, freeze-dried on a plastic surface, dried on a plastic surface, or sprayed on to improve stability during the shelf life. It will be appreciated by those skilled in the art that these agents are not exhaustive and that other agents or combinations of agents that act as inhibitors or activators of one or more hemostatic functions can be used in the drug cartridge.

[0105] The cartridge device disclosed herein is a component of a measurement system (e.g., a hemostasis measurement system). The measurement system (also referred to as an instrument) includes at least one interface element coupled between the cartridge device and a measurement element configured to measure the viscoelasticity or mechanics of a sample being processed within the cartridge device. The measured viscoelasticity or mechanics is output as a result to a user interface. An example user interface is described in commonly assigned U.S. Publication No. 2011 / 0252352 to Viola et al., which is incorporated by reference herein in its entirety.

[0106] In some embodiments, the interface element includes one or more heating and / or cooling elements.

[0107] In some embodiments, the interface element includes a fluidic manifold that facilitates connection to one or more pump elements and one or more valves.

[0108] In some embodiments, the interface element includes one or more sensors configured to perform, for example, a hemostasis measurement. In some embodiments, the one or more sensors include an ultrasonic sensor. In other embodiments, the one or more sensors include other interrogation devices that are based on thromboelastography, thromboelastometry (e.g., a system based on thromboelastography or a system based on thromboelastometry), or that measure changes in mechanical impedance, changes in observed perturbations via an optical-based system (e.g., with optical sensors), fluorescence, a colorimetric-based system, a system based on aggregation measurements (e.g., with optical sensors, acoustic sensors, or electrodes that measure aggregation of a test sample), a system based on resonance (e.g., with optical, acoustic, or mechanical position sensors that measure a sample when it is at or near resonance), a system based on electrical impedance (e.g., with electrodes configured to measure electrical impedance), or combinations thereof.

[0109] In some embodiments, the interface element includes a mechanical clamp configured to position the cartridge device in a desired orientation relative to components of the measurement system (one or more sensors, fluidic manifolds, heating and / or cooling elements, etc.). When the interface element is engaged with the components of the measurement system, in some embodiments, the cartridge device is driven via a series of controlled actions coordinated by the measurement system to prepare a test sample for measurement. In some embodiments, the preparation operations include aspirating a sample from a sample container (also referred to as a sample holding tube), heating and / or cooling the sample, performing a sample quantification, mixing the sample with reagents, and measuring the sample. Each of these steps is described below with reference to various embodiments. Upon completion of the measurement, the results are output in the instrument user interface.

[0110] In some embodiments, the cartridge device and its internal components are the only components that come into direct contact with the sample to be analyzed.

[0111] In some embodiments, the cartridge includes computer-readable information (e.g., a radio frequency identification tag, a computer-readable medium such as a flash integrated circuit, a QR code, a barcode, etc.) and / or human-readable information (e.g., indicia) that can be interrogated optically or by communication.

[0112] The various embodiments described below do not utilize any active valve elements in the cartridge design, but instead rely on a fluid manifold and one or more valves placed within the instrument. Fluid moves through the various cartridge components via pressure differentials and / or gravity and / or material properties (such as hydrophobicity or hydrophilicity) and / or capillary forces.

[0113] In these embodiments, the cartridge is configured to couple to the instrument via one or more connection ports aligned via alignment slots. The connection ports include one or more pressure ports and one or more exhaust ports. However, in alternative embodiments, actuated valves (such as elastomeric valves) may be included in the cartridge design to control fluid flow. In some embodiments, these valves are driven by corresponding hardware and software components in the measurement system.

[0114] The surface properties and texture of the cartridge surfaces that come into direct contact with the sample can be optimized to promote sample adhesion and / or sample flow. In some embodiments, the interior surfaces of the test chamber and / or other interior surfaces of the fluid circuit within the cartridge device are plasma treated to optimize surface energy and texture for adhesion of specific plasma proteins. In other embodiments, the interior surfaces of the test chamber and / or other interior surfaces of the fluid circuit are treated with surface roughness texturing, material coating (such as in the case of gold plating), biomaterial coating (such as in the case of fibronectin or collagen coating), raw material selection (for example, using specific plastics or other materials for plates that do not require additional treatment), etc. Such treatments can be performed independently or in combination with plasma treatment. Similarly, the cartridge material can be selected or manipulated to achieve a desired hydrophobicity or hydrophilicity. These properties can be altered through plasma treatment or surface coating.

[0115] As described in more detail below, the cartridge and associated measurement system can utilize one or more sensors of one or more types (e.g., optical, pressure, ultrasonic, etc.) as part of the automated operation of the cartridge. Furthermore, the output of such one or more sensors can be further used to perform quality control checks. These checks can be performed before, during, or after cartridge testing to ensure the functionality of one or more subsystems (e.g., ultrasonic or other interrogation systems, fluidics, level, clamping, cartridge positioning / orientation systems, or temperature control), to ensure proper cartridge function, to ensure that the sample was properly prepared before taking or completing a measurement, and can also be used to accept or reject a test result, or even abort a test before a measurement has been initiated.

[0116] Note that in the following discussion, a fluidic circuit includes a channel with fluidic components connecting one or more chambers together. The fluidic circuit is also referred to as a test channel in a plurality of channels that can be individually and controllably processed in a single cartridge device.

[0117] Cartridge input part

[0118] Figure 1 、 Figure 2 、 Figure 3 and Figure 4 is a schematic diagram of an example biological sample input portion of a cartridge 100 for assessing hemostasis. Specifically, Figure 1 shows a perspective view of an example biological sample input of a cartridge for use in a disposable system, according to an illustrative embodiment. Figure 2 shows a side view of an example biological sample input of a cartridge having a housing, according to an illustrative embodiment. Figure 1 shows a side view of an example biological sample input of a cartridge having a housing, according to an illustrative embodiment. Figure 3 shows a side view of an example biological sample input of a cartridge having a housing, according to an illustrative embodiment. Figure 2 shows a side view of an example biological sample input of a cartridge having a housing, according to an illustrative embodiment. Figure 4 shows a detailed view of an example biological sample input of a cartridge, according to an illustrative embodiment. In alternative embodiments, the input portion of the cartridge includes a well into which a fluid sample can be placed, for example, by a pipette or test tube. Figure 3

[0119] In some embodiments, as shown in Figure 1 , the cartridge 100 has dual connection tabs 28a, 28b for coupling the cartridge 100 to a sample container guide 1, as shown in Figure 2 . As shown in Figure 2 , when mated with the cartridge 100, the sample container guide 1 aligns a sample container 2 to the sample input port 3 of the cartridge 100. The cartridge 100 also includes an alignment tab 29 configured to slide into an alignment groove 30 of the sample container guide 1 to further stabilize the coupling of the sample container guide 1 to the cartridge 100. The sample container guide 1 can also provide a hard stop 5, as shown in Figure 3 , to hold the sample container 2 at an appropriate height to establish fluid communication with the cartridge 100.

[0120] In various embodiments, the sample container 2 is a vacuum tube, such as a BD Vacutainer TM tube, and the sample input port 3 includes a sample transfer 3a and one or more needles required for venting 4 (see Figure 1 ). Although shown as concentric in the figures, the needles can be configured as concentric, side-by-side, or integrated. In some embodiments, as shown in Figure 1 ​As shown in FIG, the sample delivery needle 3a includes inlets (3b and 3d) and an outlet 3c, which terminates in a sample inlet chamber 26 of the cartridge 100. The sample inlet chamber 26 is in fluid communication with the inlet path 8 leading to the holding / heating chamber 6 (see FIG. Figure 5A In some embodiments, as Figure 1 As shown in FIG, the exhaust needle 4 includes an outlet 4a that is configured to terminate within the sample container 2 when attached and is spaced apart from the inlet 3d to minimize bubbles drawn into the inlets 3b and 3d. The exhaust needle 4 also has an inlet 4b that terminates in an exhaust inlet chamber 27 of the cartridge. The exhaust inlet chamber 27 is in fluid communication with the exhaust path 9, which in some embodiments terminates in a filter chamber 9a (e.g., a filter housing) that receives a filter. Figure 5A ). Alternative sample containers 2 may be used, such as syringes, which require a Luer lock connection on the cartridge 100. Also, as described above, in other embodiments, the input portion of the cartridge includes a well into which a fluid sample may be placed, for example, via a pipette or tube.

[0121] Exhaust path

[0122] Figure 5A 、 Figure 5B 、 Figure 7 and Figure 8 is a schematic diagram of a biological fluid path of an exemplary cartridge 100 according to an embodiment. Specifically, Figure 5A and Figure 5B Each shows four test loops (corresponding to Figure 5A The biological fluid path of the test chambers 16a, 16b, 16c and 16d shown is also referred to herein as a hemostasis test circuit. Although four test circuits are shown, more or fewer circuits may be included, including, for example, two, three, five, six, seven, eight, etc. Figure 5B Further shown according to the illustrative embodiment Figure 5A The cartridge body is further coupled to the sample holding tube 2. Figure 7 According to an illustrative embodiment, Figure 5A The device is provided on the back of the cartridge and includes an interconnecting plane that engages with the sample preparation plane, which together form a biological fluid path for the test circuit. Figure 8 According to an illustrative embodiment, Figure 7 The interconnected planes are portions of a biological fluid path.

[0123] As described above, biological fluid pathways are formed on and through multiple planes defined in the cartridge 100 . Figure 5A and 5B1. The first fluid path plane of the cartridge 100 is shown in FIG. Figure 7 and Figure 8 Each shows a second fluid path plane of the cartridge 100, wherein for ease of understanding, Figure 8 The fluid paths are shown in a second plane isolated from the rest of the structure of the cartridge 100. The second fluid path plane of the cartridge 100 may alternatively be referred to as the rear plane of the cartridge 100. The fluid paths between the first and second planes are connected by fluid passages through the different planes of the cartridge 100.

[0124] As above combined Figure 1 As mentioned, in some embodiments, the exhaust inlet chamber 27 is in fluid communication with the exhaust path 9. The exhaust path 9 may terminate at a filter chamber 9a (e.g., Figure 5A As shown in FIG, the filter chamber 9a can accommodate a filter. The filter chamber 9a in the first fluid path plane of the cartridge 100 is connected to the exhaust port 22i in the second fluid path plane of the cartridge 100 (as shown in FIG. Figure 8 As discussed in more detail below, the cartridge 100 is coupled to a measurement system (also referred to herein as an instrument) via the exhaust port 22i to provide atmospheric pressure to the exhaust path 9.

[0125] Heating chamber path

[0126] As above combined Figure 1 As discussed, in some embodiments, the sample delivery needle outlet 3c terminates in the sample inlet chamber 26 of the cartridge 100. The sample inlet chamber 26 is in fluid communication with the inlet path 8. The sample inlet path 8 provides a fluid communication path (e.g., a flow path) between the sample inlet chamber 26 and the holding / heating chamber 6 (also referred to herein as the heating chamber 6 or the "first chamber"). Figure 5A ). The labels "first," "second," and "third" as used herein are provided merely as labels and are not intended to imply a sequence. The heating chamber 6 is configured to cooperate with a corresponding thermal regulation (e.g., heating / cooling) system in the measurement system to heat or cool the sample to or near a predetermined temperature.

[0127] As provided herein, the heating chamber 6 helps to uniformly condition the test fluids prior to being metered or aliquoted into their respective tests, thereby reducing variability in the test samples that can affect subsequent measurements and analysis. The shape of the heating chamber 6 can be optimized for heating / cooling transfer, as is the case here with a thin cross-section having a thin wall. The material of the cartridge 100 can also be optimized to facilitate heating / cooling. In some embodiments, the sample heating / cooling conditioning phase can also be implemented in one or more chambers / channels of the cartridge design and is not limited to occurring only in the heating chamber 6. In some embodiments, a stirring, rotating, or oscillating element (not shown) can be placed in the heating chamber 6, which can be controlled by the measurement system to facilitate uniform temperature heating or cooling. In other embodiments, the test fluids in the heating chamber 6 can be vibrated by the measurement system vibrating the cartridge 100 to facilitate uniform temperature conditioning of the test fluids.

[0128] In some embodiments, temperature measurements are taken of the test samples in the cartridge 100. To measure the temperature, a sensor can be incorporated in the measurement system or the cartridge 100. In some embodiments, a thermistor or thermocouple can be placed in physical contact with the cartridge 100 or the biological sample, such as blood. In other embodiments, an infrared thermometer is pointed at the cartridge 100 or the biological sample. In either case, the cartridge 100 can include a small well for the blood to pass into, rather than being in direct contact with the blood. In some embodiments, the temperature of the test sample can be assessed at or near the heating chamber 6. In other embodiments, the temperature of the test sample can be assessed while the test sample is flowing through the channel as it is being directed toward the test chamber 16

[0129] Referring now to Figure 5A , Figure 5B and Figure 8 , the sample inlet path 8 terminates at a first corner 6a of the heating chamber 6, as shown in the upper left corner of the heating chamber 6 in Figure 5A and Figure 5B . In some embodiments, the chamber along the fluid path is typically filled from the top to prevent backflow of blood into the inlet. A fill outlet channel 10a extends from a second corner 6b of the heating chamber 6 opposite the first corner 6a.

[0130] The fill outlet channel 10a extends to a filter chamber 10 having a filter therein. The filter chamber 10 in the first fluid path plane of the cartridge 100 (e.g., as shown in Figure 5A and Figure 5B ) is in fluid communication with a heating chamber fill channel 10b shown in the second fluid path plane of the cartridge 100 (see Figure 8 ). The fill conduit 10b is in fluid communication with the pressure port 22a (see also Figure 8) is fluidically connected to the cartridge 100, with pressure port 22a facilitating filling of the heating chamber 6. Conduit 10b is part of a network of conduits that integrates the cartridge 100's pressure ports (e.g., 22a, discussed above, and 22b-22i, discussed later) into one or more areas where a measurement system can couple with its pressure control interface. This configuration reduces the complexity of the measurement system controlling the movement of fluid within the cartridge 100. Indeed, the conduits that handle the movement of the fluid sample in the first plane of the cartridge 100 are primarily located in the second plane of the cartridge 100. Figure 6A and Figure 6B Shown Figure 5A 、 Figure 5B and Figure 8 with additional labels corresponding to the description of the part.

[0131] Heating chamber filling

[0132] In operation, the instrument's fluid pump is connected via port 22 (see Figure 7 ) (also referred to herein as the pressure port) through input port 3 (see Figures 1 to 2 ) draws the sample into the heating chamber 6 of the cartridge 100 (see Figure 5A or Figure 5B For example, a fluid pump of the instrument can be connected to the pressure port 22a and apply a differential pressure (eg, positive or negative pressure) thereto (see Figure 8 This in turn creates a pressure that is applied along the fill conduit 10b, within the heating chamber 6, and along the inlet path 8 to draw the sample into the heating chamber 6. Simultaneously, the internal exhaust needle 4 is connected to the isolated path 9, which is then connected to the isolated path 9 via the exhaust port 22i (see Figure 8 ) receives atmospheric pressure from the instrument to counteract the pressure in the sample container 2 when the sample is drawn into the heating chamber 6 of the cartridge 100. During the filling process of the heating chamber 6, all other ports (e.g., 22b-22i) are closed, for example by the measurement system.

[0133] As the heating chamber 6 fills, the filter within the filtration chamber 10 becomes clogged and creates a pressure peak that is detected by the instrument, causing the instrument to shut down the jet pump. The instrument may also close the exhaust port 22i or stop supplying atmospheric pressure via the exhaust port 22i when the pressure peak is detected. Alternative fill detection techniques may also be used, i.e., optical sensors placed at the desired fill level, volumetric controls, fixed times for pressure changes (negative and / or positive), ultrasonic detectors placed at the desired fill level, etc. The sample remains in the heating chamber until a desired temperature is reached, which may be, for example, (or close to) the body temperature of a normal and typical subject (e.g., approximately 37°C for a healthy person). In other cases, other desired temperatures may be required. The shape of the heating chamber 6 and the passage to the sample metering chamber 11 (described below) are configured so that bubbles that may be present in the fluid sample are trapped away from the rest of the fluid circuit. The shape of the inlet path 8 includes an anti-siphon feature 8a (see Figure 5A and Figure 5B ), and is configured to reduce the occurrence of bubble formation in heating chamber 6 and prevent siphoning to and from sample container 2. To this end, after heating and / or cooling a first drawn test sample, for example, while a processed test sample is drawn into metering chamber 11 (also referred to herein as sample chamber 11 and “second” chamber), additional unprocessed test sample (e.g., unheated blood) is prevented from being siphoned into the heating chamber. Figure 6A and Figure 6B Markings corresponding to the description of this section are also shown.

[0134] Sample aliquot (metering) chamber path

[0135] Reference Figure 5A 、 Figure 5B and Figure 8 , the first side 6c of the heating chamber 6 (see Figure 5A ) extends between the first corner 6a and the second corner 6b.

[0136] One or more outlet ports 6e-6h (see Figure 5A ) are arranged along the length of the second side 6d of the heating chamber. Each of the one or more outlets 6e-6h can be arranged in a different recess along the second side 6d of the heating chamber, wherein the recess guides the sample into a conduit leading to each corresponding test channel. In some embodiments, a test channel refers to an associated fluid path structure and test chamber that are used together to measure a given aliquot. In some embodiments, as Figure 5B As shown in FIG, each of the one or more outlets 6e-6h in the first fluid path plane of the cartridge 100 is connected to a corresponding one or more channels 20a-20d in the second fluid path plane of the cartridge 100 (see FIG. Figure 8) are connected to the first end of the fluid, and these channels are collectively referred to as channels 20 (see Figure 5B ). One or more channels 20a-20d in the second fluid path plane of the cartridge 100 (see Figure 8 ) are also aligned with the corresponding one or more channels 11a-11d in the first fluid path plane of the cartridge 100 (see Figure 5B ) is fluidically connected to the first end of the one or more channels 11a-11d. The second end of each of the one or more channels 11a-11d terminates in the corresponding one or more sample chambers 11 ( Figure 5B The "o" symbol is repeated ("x4"). Figure 5A 、 Figure 5B 、 Figure 7 and Figure 8 In the example shown, there are four sample chambers 11. In some configurations, there may be more or fewer sample chambers 11 and corresponding fluid communication paths with the heating chamber 6 on the cartridge 100.

[0137] The sample chamber 11 is fed by one or more channels 20 originating from the bottom of the heating chamber 6. This geometry avoids that air bubbles are sucked into the sample chamber 11 when they rise to the upper part of the heating chamber 6.

[0138] Each sample chamber 11 has a corresponding filling channel 11e, which is connected to a corresponding filtration chamber 12 (in the Figure 5B The filter chamber 12 in the first fluid path plane of the cartridge 100 is in fluid communication with the channel 12a in the second fluid path plane of the cartridge 100 (see FIG. Figure 8 ) fluid communication. Channel 12a is in fluid communication with pressure port 22g (see Figure 8 ).

[0139] In some configurations, when more than one sample chamber 11 is implemented on the cartridge 100, the channel 12a (see Figure 8 ) through the corresponding filling channel 11e and the filtration chamber 12 and all the sample chambers 11 (see Figure 5B ) fluid communication. Thus, channel 12a acts as a manifold for applying negative pressure to all sample chambers 11 via a single pressure port 22g. Thus, advantageously, no separate pressure port is required to fill each sample chamber 11. Figure 6C and Figure 6D Shown Figure 5A 、 Figure 5B and Figure 8 with additional markings corresponding to the description of this section.

[0140] Heating chamber exhaust path

[0141] Reference Figure 5A 、 Figure 5B and Figure 8 The heating chamber 6 includes exhaust paths 31a, 31b, 31c along a first side 6c of the heating chamber for exhausting the heating chamber 6 when the sample chamber 11 is filled. The exhaust channel 31 (not shown) includes a fluid path through conduit elements 31a-31d. The channels 31a-31b terminate at one end of the heating chamber 6 along the first side 6c and terminate at the other end at a filter chamber 31c having a filter therein. Thus, the channels 31a-b provide a fluid path between the heating chamber 6 and the filter chamber 31c. The filter chamber 31c in the first fluid path plane of the cartridge 100 (see FIG. 1 ) is shown in FIG. Figure 5A ) and the channel 31d in the second fluid path plane of the cartridge 100 (see Figure 8 ) fluid communication, the channel 31d is connected to the exhaust port 22c (see Figure 8 As discussed in more detail below, the cartridge 100 is coupled to the instrument via the exhaust port 22c of the instrument to provide atmospheric pressure to vent the heating chamber 6. Figure 6C and Figure 6D Markings corresponding to the description of this section are also shown.

[0142] Sample chamber exhaust path

[0143] Reference Figure 5A 、 Figure 5B and Figure 8 Each sample chamber 11 includes an exhaust path 18 that terminates at a first end of the corresponding sample chamber 11. The second end of the exhaust path 18 in the first fluid path plane of the cartridge 100 is in fluid communication with the exhaust manifold 18 in the second fluid path plane of the cartridge 100. When there is more than one sample chamber 11, all exhaust paths 18 of the sample chambers (see Figure 5B ) and the exhaust manifold 18a (see Figure 8 ) fluid communication. The exhaust manifold 18a in the second fluid path plane of the cartridge 100 (see Figure 8 ) further connects to the channel 18b in the first fluid path plane (see Figure 5B ) is connected to the first end of the fluid. The second end of the channel 18b (see Figure 5B ) and the filter chamber 18c (see Figure 5B ) fluid communication. The filter chamber 18c in the first fluid path plane of the cartridge 100 (see Figure 5B ) and exhaust port 22e (see Figure 8 ) fluid communication. Figure 6C and Figure 6D Markings corresponding to the description of this section are also shown.

[0144] Filling of sample aliquot (metering) chamber

[0145] During operation, once the sample is at or near the desired temperature, the sample is aliquoted (or metered) into one or more individual sample chambers 11 (see Figure 5B ). Reference Figure 5B Unless otherwise stated, in various embodiments, the pressure is supplied to the pressure port 22g (see Figure 8 ) to fill the sample chamber and simultaneously pass the exhaust port 22c (see Figure 8 ) to vent the heating chamber 6. Each filter chamber 12 has a filter therein, and when the corresponding sample chamber 11 is filled, the filter will clog and trigger the instrument's pressure sensor to shut off the pump, similar to filling the heating chamber 6. As described above, alternative filling detection techniques can be used. In various embodiments, all sample chambers 11 are connected via pressure port 22g (see Figure 8 ) is controlled by a single valve and fluid path in the instrument. The cutoff pressure is not triggered until the filters of all sample chambers are blocked in the corresponding filter chamber 12. The sample chamber 11 is used to separate the sample into independent functional channels, aliquot known volumes of sample, and place the sample to mix with reagents. When the sample chamber 11 is filled, the pressure ports 22b, 22d, 22f, and 22h (see Figure 8 ) and exhaust port 22e (see Figure 8 ) is closed by the instrument to prevent fluid from leaking through the location 19 arranged below the sample chamber 11. Once the sample chamber 11 has been filled, the exhaust port 22e (see Figure 8 ) is opened to atmospheric pressure so that one or more sample chambers 11 can be fluidically isolated from each other and from the heating chamber 6. As described below, the exhaust port 22e (see Figure 8 ) remain open to the atmosphere during sample mixing. Figure 6C and Figure 6D Markings corresponding to the description of this section are also shown.

[0146] Hybrid and test paths

[0147] Reference Figure 5B Unless otherwise specified, each sample chamber 11 is associated with one or more reagent bags 14 (see Figure 5A ) is fluidically connected, the reagent bag 14 is configured to contain at least one lyophilized bead containing a reagent. Figure 5A and Figure 5B As shown, two reagent bags 14 are provided (in Figure 5A In other embodiments, each test channel uses a single reagent bag. In other embodiments, each test channel uses more than two reagent bags 14. The reagent bags 14 are in fluid communication with the serpentine channel 13 (see FIG. Figure 5A, and are shown with a repeating symbol ("x4"). Each serpentine channel 13 has a first end in fluid communication with a reagent bag and a second end terminating in an optical detection zone 15. As described below, an instrument (i.e., a measurement system) can optically interrogate the optical detection zone 15 of the cartridge 100 to facilitate controlling a pump that facilitates mixing each aliquot with the corresponding reagent. Each serpentine channel 13 (see Figure 5A ) and test chamber 16 (see Figure 5B , repeating symbol "x4"), the test chamber 16 is in fluid communication with the filtration chamber 17, which has a filter therein. The filtration chamber 17 in the first fluid path plane of the cartridge 100 is in fluid communication with a corresponding one of the fluid channels 17a-17d in the second fluid path plane of the cartridge 100 (see Figure 8 ) is fluidically connected to the first end of the fluid communication channel 17a-17d (see Figure 8 ) and the second end of each of the corresponding pressure ports 22b, 22d, 22f and 22h (see Figure 8 ) fluid communication. The cartridge 100 is connected to the pressure ports 22b, 22d, 22f and 22h (see Figure 8 ) is coupled to the instrument to provide positive and negative pressure to facilitate sample mixing and testing, as described below. Figure 6E and Figure 6F Also shown Figure 5A 、 Figure 5B and Figure 8 with additional markings corresponding to the description of this section.

[0148] Sample mixing

[0149] Reference Figure 5B Unless otherwise indicated, each individual aliquot in the sample chamber 11 is drawn into a separate reservoir or channel (in various embodiments, a serpentine channel path 13 (see Figure 5A )) and contacted with a channel specific reagent located in one (or both) of the two reagent bags 14 (see Figure 5A Specifically, the pump in the instrument sends pressure to ports 22b, 22d, 22f, and 22h (see Figure 8 ) applies negative pressure to pass through the reagent bag 14 (see Figure 5A ) and serpentine channel path 13 (see Figure 5A) to draw the sample. The reagent and sample are kept separate from each other during filling of the sample chambers 11 to prevent the reagent from floating on the blood and being trapped in the filter in the filter chamber 12, as well as to ensure that one or more sample chambers 11 are fluidically isolated from the heating chamber 6. To this end, the precise time when the test sample comes into contact with the reagent can be measured, thereby facilitating accurate and precise measurement of the clotting time (e.g., from the start of mixing). Furthermore, in some embodiments, the reagent and test sample are kept separate from each other until all channels are metered to prevent unwanted siphoning that siphons the test sample from unprocessed sample in other channels or fluid paths. The sample passes through the serpentine channel 13 (see Figure 5A ) is drawn in until it triggers the optical sensor in the instrument (detection area in the optical detection area 15 (see Figure 5A ) near the top of the serpentine channel, the optical sensor isolates the channel from the pump. Mixing in the serpentine channel or area, or region, can be controlled by one or more independent valves and paths that allow individual channel control. Alternative sensor technologies can be used: pressure, through optical sensors, ultrasonic detection, time, volume control, etc. Once the optical sensors of all channels are triggered, the pump reverses and applies positive pressure to pressure ports 22b, 22d, 22f and 22h (see Figure 8 Positive pressure propels a biological sample (e.g., blood) along a serpentine path13 (see Figure 5A ) is pushed down for a specified time, or until a second set of optical sensors in the instrument trips (in an alternative embodiment). The process is repeated, moving the sample along the serpentine path 13 (see Figure 5A ) is pulled upwards to the optical detection zone (where the sample is detected by the instrument's optical sensor and pushed back for a given time) until complete mixing of the sample is achieved. Figure 6E and Figure 6F Markings corresponding to the description of this section are also shown.

[0150] Other sensors (e.g., impedance sensors), pressure sensors, etc., can be used. Alternatively, additional sensors can be used to detect both ends of the optical detection zone. Alternative path geometries, obstacles to create turbulence, number of cycles, and cycle speeds are all design options that can be used to achieve optimal results for different test types. In alternative embodiments, mixing can be achieved using one or more ferromagnetic beads or rods placed within the cartridge and controlled by the instrument.

[0151] Test chamber filling

[0152] Reference Figure 5A 、 Figure 5B and Figure 8, after mixing is complete, one or more test chambers 16 are filled. Using one or more independent valves and paths, each test chamber 16 is filled with sample via a pressure disturbance (negative and / or positive pressure) applied at pressure ports 22b, 22d, 22f and 22h. Specifically, the instrument pump will apply negative pressure to pressure ports 22b, 22d, 22f and 22h until all filters are blocked in one or more filter chambers and a pressure peak is generated, causing the instrument to shut down the pump, similar to filling the heating chamber 6. As described above, alternative filling detection techniques can be used. The test chamber 16 has design features, such as ridges 24a, which prevent bubbles from forming in the test chamber 16 during filling. Once filled, the instrument begins viscoelastic testing of the sample. Figure 6E and Figure 6F Markings corresponding to the description of this section are also shown.

[0153] In some embodiments, the cartridge device includes at least four independent fluid circuits configured with different sets of reagents for performing measurements (and / or sample preparation) in parallel. Measurements are performed on each of the at least four channels of the cartridge. In some embodiments, the measured values ​​include viscoelastic properties, such as the shear modulus of the sample. In other embodiments, the measured values ​​include other properties, such as viscosity, elastic modulus, or any other mechanical property of the sample, or a combination thereof.

[0154] Table 1 provides an example set of reagents and measurement parameters used in an example reagent cartridge device (e.g., device 100, etc.). As shown in Table 1, channel #1 of the example cartridge device was interrogated in the presence of kaolin, an activator of the intrinsic clotting pathway, to measure the clotting time of the test sample. As shown in Table 1, channel #2 was interrogated in the presence of kaolin and further in the presence of heparinase I, a neutralizer of the anticoagulant heparin, to measure the clotting time of the test sample. As shown in Table 1, channel #3 was interrogated in the presence of i) thromboplastin, an activator of the extrinsic coagulation pathway, and ii) polybrene, a neutralizer of the anticoagulant heparin, to measure the overall clot firmness of the test sample. As shown in Table 1, the same reagents as channel #3 were used, but with the addition of the platelet aggregation / contraction inhibitor abciximab (e.g., Clotinab). ® and / or ReoPro ® ), interrogating channel #4 to measure clot firmness of the test sample. As shown in Table 1, calcium was added to all reagent formulations when the assay was configured to operate with citrated whole blood samples.

[0155] Table 1. Reagents used in preferred embodiments

[0156]

[0157] Table 2 provides another example set of reagents and measurements used in an example reagent cartridge device (e.g., device 100, etc.). As shown in Table 2, channel #2 includes an extrinsic pathway activator that inhibits fibrinolysis via tranexamic acid (TXA). In addition to the measurements previously presented in Table 1, channels #2, #3, and #4 are interrogated to measure changes in clot firmness, which may be associated with, for example, the fibrinolytic process. In some embodiments, other channels may include agents that inhibit fibrinolysis and may also be interrogated to measure changes in clot firmness. For example, channel #4 may also include TXA or other fibrinolysis inhibitors to measure clot firmness in the absence of fibrinolysis.

[0158] Table 2. Reagents used in preferred embodiments

[0159]

[0160] In some embodiments, clotting time and clot firmness are measured by analyzing the shear modulus (clot firmness) versus time curves generated within each measurement channel in the cartridge. Figure 13 An example shear modulus versus time curve according to an illustrative embodiment is shown. Clotting time can be determined by identifying when clot hardness reaches or exceeds a threshold, or when a first or higher-order derivative of a measured property reaches or exceeds a threshold, or at the point of maximum acceleration of the clot hardness ratio, or some combination of the above. Clot hardness can be estimated by clot hardness at a fixed time after clotting time, or by the maximum overall clot hardness measured within a certain time limit, or by the clot hardness at the point of maximum change in clot hardness, or some combination of the above. Similar methods can also be used to measure the effect of fibrinolysis (i.e., clot dissolution) and the corresponding decrease in clot hardness. In some embodiments, the change in clot hardness can be calculated as a percentage decrease in clot hardness across a fixed time window, a rate of change of clot hardness over time, an area below or above clot hardness within a predetermined time window versus time, the time required to achieve a predetermined decrease in clot hardness, or a combination thereof. Curves and measurements similar to those just described can be generated by plotting Young's modulus, viscosity, or other viscoelastic properties of the sample being tested.

[0161] Table 3. Parameters reported by measurements of the preferred embodiment discussed in conjunction with Table 1.

[0162]

[0163] Those skilled in the art will recognize that a variety of methods and criteria can be used to estimate clotting time and clot firmness. Clotting time and clot firmness values ​​obtained from at least four channels / measurements can be combined to provide at least six parameters describing the functional status of a patient's hemostatic system. These indices are summarized in Table 3. The relationship between the results from the different channels (clotting time, clot firmness, clot firmness change, etc.) can be verified to be within the expected range as an additional quality control check to verify instrument, cartridge, and sample functionality.

[0164] In other embodiments, other reagents may be used and other hemostasis indices or output parameters may be obtained, such as in the case of a fibrinolysis index, an index corresponding to antiplatelet therapeutic function, an index corresponding to anticoagulant therapeutic function, etc.

[0165] For example, one or more fibrinolysis indices can be formed using the changes in clot firmness measured in any of the channels shown in Table 2, but preferably channels #3 and #4. Alternatively, a fibrinolysis index can be formed by a differential combination of the changes in clot firmness measured in channels #2 and #3 shown in Table 2. This combination can be in the form of a ratio, a difference, or a combination thereof. One benefit of utilizing a combination of changes in clot firmness measured with and without an antifibrinolytic agent is the ability to mitigate the interfering effects of non-fibrinolytically caused reductions in clot firmness values. In some embodiments, TXA or other fibrinolysis inhibitor reagents can be included in channels #2 and #4 of the example cartridges of Table 2. By such modifications, the parameters clot firmness, platelet contribution, and fibrinogen contribution can be derived without the influence of fibrinolysis by combining the clot firmness measurements obtained in channels #2 and #4.

[0166] As noted above, example user interfaces are described in commonly assigned US Publication No. 2011 / 0252352 to Viola et al., which is incorporated herein by reference in its entirety. An example user interface may be used to display the measured hemostatic index as discussed in conjunction with Table 4, as well as other parameters.

[0167] Table 4. Parameters reported by measurements of the preferred embodiment discussed in conjunction with Table 2.

[0168]

[0169] As previously mentioned, in various embodiments, the test chamber 16 is shaped to facilitate ultrasonic testing of the viscoelastic properties of a sample, but alternative geometries may be implemented to facilitate other types of testing. Such ultrasonic testing systems are described in commonly assigned U.S. Patent No. 9,726,647 and U.S. Publication No. 2016 / 0139159, both of which are incorporated herein by reference in their entireties. The ultrasonic transducer in the measurement system is connected to the test chamber 16 of the cartridge 100 via a flexible and deformable elastomer 21, which is secured to a test block 21d on the cartridge 100.

[0170] Example elastomeric materials may alternatively include Dynaflex D3202, Versaflex OM 9-802CL, Maxelast 54740, RTP 6035, Versaflex CL2003X, and the like. Figure 9 Unless otherwise noted, the test block 21d is aligned with the test chamber 16 via the alignment slots 23 and 24 on the cartridge 100 (see Figure 5B ). Still refer to Figure 9 , the elastomer 21 can be secured to the test block 21 d via a flange 21 a on the elastomer 21. The flange 21 a can have a plurality of alignment holes 21 b that can receive corresponding alignment pins (not shown) from the test block 21 d. The soft elastomers 21 can also each include a lens 21 c that focuses ultrasonic energy into the sample at the test chamber 16.

[0171] Figure 16 A schematic diagram of a disposable system for use in accordance with an illustrative embodiment is shown. Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5A 、 Figure 5B 、 Figure 7 、 Figure 8 and Figure 9 Photograph of an exemplary cartridge. Figure 17 According to an illustrative embodiment, Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5A 、 Figure 5B 、 Figure 7 、 Figure 8 and Figure 9 Front view of an exemplary cartridge. Figure 18 According to an illustrative embodiment, Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 Figure 5 A Figure 5B 、 Figure 7 、 Figure 8 and Figure 9 front view of an exemplary cartridge.

[0172] As described in U.S. Patent No. 9,272,280, which is incorporated by reference in its entirety, in various embodiments, a cartridge for consumption contains a lens assembly that focuses ultrasonic energy within a sample that can be used to generate flow and mixing. As shown in Figure 10 , Figure 11 and Figure 12 , the lens assembly or sound focusing assembly is designed using a soft material such as a thermoplastic elastomer 134 (previously referred to as 21) in combination with a rigid substrate 132 such as polystyrene (e.g., formed by test block 21d). This combination provides dry ultrasonic coupling that does not require the use of any fluid or gel couplant. Note that the same lens and ultrasonic driver used for hemostasis measurements can be used for this to provide mixing. Increasing the acoustic energy for mixing can be delivered by, for example, increasing the pulse length, pulse amplitude, or pulse repetition frequency.

[0173] Referring now to Figure 10 , a top cross-sectional view of a test chamber 116 (previously referred to as test chamber 16) is shown. To seal each test chamber, such as test chamber 116, the lens assembly 131 includes a rigid substrate 132 and a couplant 134, which can be located at the back end of each test chamber.

[0174] Still referring to Figure 10 , each couplant 134 includes an elastomeric material. Optionally, the elastomeric material is a thermoplastic elastomer (TPE). Example elastomeric materials can include Dynaflex D3202, Versaflex OM 9-802CL, Maxelast 54740, RTP 6035, Versaflex CL2003X, etc. Optionally, the couplant is overmolded onto the rigid substrate. Optionally, the couplant is mechanically anchored to the rigid substrate.

[0175] Still referring to Figure 10 , there is a rigid substrate 132 between each couplant 134 and the open space of each test chamber. The rigid substrate and couplant form an interface that focuses the ultrasonic waves emitted by the ultrasonic transducer (e.g., lens assembly) into the open space of the chamber and onto any biological fluid and / or reagents in the chamber. The rigid substrate of the lens can include a material that allows sound to pass through and can focus the ultrasonic waves at a certain horizontal plane within the space. Optionally, the rigid substrate includes styrene.

[0176] Referring now to Figure 11 , the lens assembly can be glued or welded to the surface 101 of the test block 21d (in Figure 11A rigid substrate 132 (shown as element 132) is provided to secure the lens in place, in an orientation that allows for the desired focusing of sound. Alternatively, the lens assembly can be manufactured integrally with surface 101 of test block 21 d. In this regard, a rigid substrate 132 can be molded integrally with surface 101 of test block 21 d, and couplant 134 can be overmolded or mechanically anchored to the rigid substrate. A variety of materials can be used to construct the device. For example, plastic can be used for single-use, disposable cartridges.

[0177] Still refer to Figure 11 Each test chamber 116 can have a lens assembly positioned over the large opening of the open space of each chamber. In this way, each chamber can be individually interrogated by focused ultrasound.

[0178] Still refer to Figure 11 When placed in the instrument, the couplant 134 can be placed in acoustic communication with the transducer for providing ultrasonic waves through the lens assembly and into the test chamber 116. Optionally, an intermediate layer of acoustically transparent material is positioned between the ultrasonic transducer and the couplant. For example, an intermediate layer or block of Rexolite® or TPX® can be used. The intermediate layer can be pressed against the couplant and can be in acoustic contact with the transducer.

[0179] Still refer to Figure 11 The sound generated by the transducer passes through the intermediate layer, the coupling agent, the rigid substrate, and is focused into the biological sample (e.g., blood) and the reagent in the test chamber. Some of the sound introduced into the chamber contacts the distal inner surface 111 of the test chamber, which is defined by surface 126. Optionally, the surface is polystyrene. The distal inner surface has a known geometry and is located at a known distance from the ultrasound source. The distal inner surface 111 serves as a calibrated reflector that is used to estimate the speed of sound and the attenuation of sound in the test chamber at baseline and during clot formation and clot lysis. For example, these measurements can be used to estimate the subject's hematocrit and hemostasis index. The sound generated by the transducer can be focused into the biological sample in the test chamber using a parabolic mirror that is coupled to the biological sample using an elastomer.

[0180] Other example cartridge devices and measurement systems and methods thereof are described in U.S. Patent No. 9,031,701, U.S. Provisional Application No. 61 / 443,084, U.S. Patent No. 9,272,280, U.S. Patent No. 9,410,971, U.S. Provisional Application No. 61 / 443,088, U.S. Publication No. 2011 / 0252352, published PCT Publication No. WO2011 / 127436, U.S. Publication No. 2012 / 0294767, U.S. Patent No. 7,892,188, U.S. Patent No. 8,740,818, and U.S. Publication No. 2016 / 0274067, each of which is incorporated herein by reference in its entirety.

[0181] As described above, the cartridges and features described herein can be modified for use with other types of measurement systems, such as thromboelastometry-based systems, thromboelastometry-based systems, optical-based systems, fluorescence-based systems, colorimetric-based systems, agglomeration-based systems, resonance-based systems, and electrical impedance-based systems, among others.

[0182] Many modifications and other embodiments of the invention set forth herein will occur to those skilled in the art having benefited from the teachings given in the foregoing description. Therefore, it should be understood that the invention is not limited to the particular embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims.

[0183] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0184] As used in the claims, the terms "first," "second," and "third" are provided merely as labels and are not intended to imply an order.

Claims

1. A device comprising: case; an input port integrally formed with the housing, the input port being structurally configured to receive the contents of a sample holding tube; as well as a first chamber in fluid communication with the input port, the first chamber being a heating chamber having a defined volume and configured to receive a sample contained in the sample holding tube and to maintain and condition the received sample to or near a desired temperature before allowing the received sample to contact one or more reagents in two or more fluid circuits located downstream of the first chamber, the two or more fluid circuits comprising a first fluid circuit and a second fluid circuit, wherein each of the two or more fluid circuits comprises i) a second chamber in fluid communication with the first chamber, the second chamber metering the sample in the first chamber into aliquots, wherein the metered sample is introduced into a reagent or combination of reagents located in the respective fluid circuit to form a mixed sample, and ii) a testing chamber in fluid communication with the second chamber, the testing chamber being structurally configured to be interrogated by a measurement system, the measurement system being configured to determine at least one viscoelastic property of the mixed sample, wherein at least one of said two or more fluid circuits comprises one or more holding bags to contain said reagent or said combination of reagents, and The second chamber of the first fluid circuit and the second chamber of the second fluid circuit are configured to be filled in parallel by a controller.

2. The device of claim 1, wherein at least one of the one or more holding bags comprises lyophilized beads.

3. The device of claim 1, wherein at least one of the one or more holding bags comprises a fluid reservoir bag.

4. The device according to claim 1, wherein The input port is communicatively coupled to a first pressure port, wherein pressure, when applied to the first pressure port, causes the contents of the sample holding tube to be expelled through the input port into the first chamber.

5. The device according to claim 1, wherein The input port forms part of a needle assembly that is structurally configured to establish fluid communication and evacuate the contents of the sample holding tube.

6. The device of claim 5, wherein the needle assembly comprises the input port and a second port, wherein the second port is configured to discharge liquid or gas into the sample holding tube to facilitate expelling the contents therein.

7. The device according to claim 1, wherein The input port is structurally configured to couple to a Luer lock configured to connect to the sample holding tube.

8. The device according to claim 1, wherein The first chamber is configured to cooperate with a corresponding thermal conditioning surface of a subsystem component of the measurement system to condition the received sample to or near the desired temperature.

9. The device according to claim 1, wherein The first chamber comprises an optimized shape and / or material to facilitate heating and / or cooling the sample to or near the desired temperature.

10. The device according to claim 1, wherein The channel portions of the two or more fluid circuits are configured to cooperate with corresponding thermal regulation systems of the measurement system to regulate the received sample to the desired temperature.

11. The device according to claim 10, wherein The first chamber and / or the channel portions of the two or more fluid circuits are physically proximate to a sensor of the measurement system, the sensor being configured to measure a temperature of the sample received in the first chamber.

12. The apparatus of claim 4, comprising a filter positioned within the first pressure port, wherein the filter is configured to allow air to move through the first pressure port but prevent fluid from moving therethrough.

13. The apparatus of claim 1, wherein each of the two or more fluid circuits comprises a third set of fluid paths in fluid communication between the corresponding second chamber and the testing chamber, wherein a portion of the third set of fluid paths is arranged as a serpentine conduit.

14. The apparatus of claim 13, wherein each of the second chambers is connected to a second pressure port, wherein pressure when applied to the second pressure port causes filling of the second chamber.

15. The apparatus of claim 14, wherein each of the second chambers is connected to an exhaust port, wherein the exhaust port is configured to close when the sample is metered into the aliquot in the second chamber, and further configured to open to atmospheric pressure after the sample is metered into the aliquot in the second chamber.

16. The device of claim 13, wherein a metered sample is directed through a portion of the serpentine conduit to facilitate mixing of the metered sample and the reagent or combination of reagents.

17. The device according to claim 16, wherein For each of the two or more fluid circuits, the metered sample is alternatively and multiplicatively directed between a first location in the fluid circuit and a second location in the fluid circuit, wherein the length of the first location and the second location includes at least a portion of the serpentine conduit.

18. The apparatus of claim 17, wherein each of the test chambers is connected to a third pressure port, wherein when pressure is applied to the third pressure port, the test sample is caused to flow through the corresponding serpentine conduit toward the test chamber.

19. The apparatus of claim 18, wherein when pressure is applied to the third pressure port in an opposite direction, the test sample is caused to flow away from the test chamber through the corresponding serpentine conduit.

20. The device of claim 19, wherein the serpentine conduit comprises an optical detection zone.

21. The device of claim 1, wherein each of the two or more fluid circuits further comprises a mixing zone between the testing chamber and the second chamber, the mixing zone comprising one or more ferromagnetic beads or rods therein.

22. The apparatus of claim 1, wherein at least one of the two or more fluid circuits comprises one or more quality test inlets, wherein The one or more quality test inlets are configured to be sensed optically or electrically.

23. The device according to claim 22, wherein At least one of the one or more quality test entries is configured to be sampled for a characteristic of the metrology sample.

24. The apparatus of claim 1, wherein the test chamber comprises a lens configured to direct ultrasonic pulses generated by the measurement system into the test chamber.

25. The device of claim 2, wherein for each of the two or more fluid paths, the second chamber is in fluid communication with the first chamber, the one or more reagent bags, and the testing chamber.

26. The device of claim 1, wherein at least one of the reagent or the combination of reagents located in the two or more fluid circuits is selected from the group consisting of an intrinsic pathway activator, an extrinsic pathway activator, and a coagulation activator.

27. The device of claim 1, wherein at least one of the reagent or the combination of reagents located in the two or more fluid circuits is selected from the group consisting of a platelet activator, a platelet inhibitor, and a fibrinolytic function inhibitor.

28. The device of claim 1, wherein at least one of the reagents or the combination of reagents located in the two or more fluid circuits is selected from the group consisting of a FXIIIa inhibitor, thrombomodulin, polybrene, heparin, corn trypsin inhibitor, adenosine, GPRP (glycine-proline-arginine-proline), calcium, fibronectin, collagen, an immunodetection reagent, and heparinase I, or a combination thereof.

29. The device of claim 1 , wherein the measurement system is selected from the group consisting of an acousto-rheology-based system, a thromboelastometry-based system, a thromboelastometry-based system, an optical-based system, a fluorescence-based system, a colorimetric-based system, an agglomeration-based system, a resonance-based system, and an electrical impedance-based system.

30. The apparatus of claim 1, comprising: At least four test channels, wherein a first test channel comprises an intrinsic pathway activator, wherein a second test channel comprises the intrinsic pathway activator and a heparin neutralizer, wherein a third test channel comprises an extrinsic pathway activator, and wherein a fourth test channel comprises the extrinsic pathway activator and a platelet inhibitor.

31. The apparatus of claim 1 , comprising: At least four test channels, wherein the first test channel comprises an intrinsic pathway activator, wherein the second test channel comprises an extrinsic pathway activator and a fibrinolytic function inhibitor, wherein the third test channel comprises an extrinsic pathway activator, and wherein the fourth test channel comprises the extrinsic pathway activator and a platelet inhibitor.

32. The device according to claim 30 or 31, wherein The third channel and the fourth channel each include hexamethylenetetramine (polybrene).

33. The apparatus according to claim 1, comprising: At least four test channels, wherein the first test channel comprises a combination of Reptisadin and FXIIIa, wherein the second test channel comprises a combination of Reptisadin, FXIIIa, and ADP, wherein the third test channel comprises a combination of Reptisadin, FXIIIa, and arachidonic acid (AA), and wherein the fourth test channel comprises a combination of Reptisadin, FXIIIa, and a platelet activator.

34. The apparatus of claim 1, comprising: At least two test channels, wherein a first test channel comprises an intrinsic / extrinsic pathway activator, and wherein a second test channel comprises the intrinsic / extrinsic pathway activator and heparin.

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