Devices and method for hemostasis assessment

专利摘要:
DEVICES, SYSTEMS AND METHODS FOR ASSESSING HEMOSTASIS. The present invention relates to devices, systems and methods for the assessment of hemostasis. Sound focusing kits are also provided.
公开号:BR112013020675B1
申请号:R112013020675-6
申请日:2012-02-15
公开日:2022-01-25
发明作者:Christopher G. Denny；Francesco Viola；William H. Walker；Gregory V. Browne；Robert S. Magyar；Bjarne Hansen
申请人:Hemosonics, Llc；
IPC主号:

专利说明:

Cross-reference to Related Orders
[001] The present application claims the benefit of provisional application US 61/443,088, filed February 15, 2011, which is incorporated by reference herein in its entirety. Technical Field
[002] The present application pertains to devices, systems, and methods for assessing hemostasis in a subject by analyzing a test sample from the subject to determine one or more indices of hemostasis. background
[003] Hemostasis, the physiological control of hemorrhage, is a complex process that incorporates vasculature, platelets, clotting factors (FI-FXIII), fibrinolytic proteins, and clotting inhibitors. Interruption of hemostasis plays a central role in the onset of myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, and excessive bleeding. Consequently, in vitro diagnostics (IVD) are critically needed to quantify hemostatic dysfunction and direct appropriate treatment. This need is particularly acute during cardiac surgeries that require cardiopulmonary bypass (CPB), where post-surgical hemorrhage is a common complication requiring transfusion of blood products.
[004] Existing IVDs include biochemical endpoint assays, platelet aggregation assays, and viscoelastic clot measurement systems. End-point biochemical assays such as prothrombin time (PT) and partial thromboplastin time (PTT) are widely used to assess clotting. However, these tests measure only a part of the hemostatic process and operate under non-physiological conditions incorporating only the plasma function. As a result of these limitations, complications such as postoperative hemorrhage often occur despite normal perioperative PT and PTT measurements.
[005] Activated clotting time (ACT) is an endpoint assay that is most often applied in support of CPB. This assay applies strong initiation of the surface (intrinsic) activation pathway to quantify heparinization. Limitations of ACT include its disregard for platelet function, lysis, and clotting kinetics along with the use of large aliquots of whole blood (WB) (generally 2 mL) and moving mechanical parts. For these reasons, ACT is used for rapid assessment of heparinization and associated protamine inversion with limited utility for additional applications.
[006] Platelets play a crucial role in advancing coagulation and suppressing arterial bleeding. Furthermore, the modern cell-based theory of hemostasis recognizes that platelets play a modulating role in clotting. Platelet function is clinically monitored through both central laboratory assays and point-of-treatment (POC) tests, which utilize anticoagulated WB. Both approaches are limited in that they use platelet aggregation as a proxy for overall platelet function. In addition to disabling clotting, these methods neglect the interaction between platelets and the clotting cascade.
[007] Techniques that monitor the viscoelastic properties of WB, such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), avoid many of the limitations of biochemical endpoint assays and platelet aggregation assays by measuring the combined effects of all the components of hemostasis. TEG has been shown to diagnose hyperfibrinolysis in patients with hemorrhage, indicate better transfusion requirements than standard biochemical assays, and reduce transfusion requirements during CPB when used with transfusion algorithms. While these tests provide valuable clinical information, the devices are typically complex to operate and difficult to interpret. Furthermore, TEG applies relatively large shear strains, which transgress the non-linear viscoelastic regime, thereby stopping clot formation. For these reasons, TEG sees very limited utility as a POC test. summary
[008] Devices, systems and methods for the assessment of hemostasis are provided. For example, sonorheometric devices are provided for assessing hemostasis in a subject by in vitro evaluation of a test sample from the subject. An exemplary device comprises a cartridge having a plurality of test chambers each configured to receive a test sample of blood from the subject. Each test chamber comprises a reagent or combination of reagents.
[009] A first chamber of the plurality comprises a first reagent or a combination of reagents that interact with the blood test sample received therein. A second chamber of the plurality comprises a second reagent or combination of reagents that interact with the blood test sample received therein. The first and second chambers are configured to be interrogated with sound to determine a hemostatic parameter of the test samples.
[0010] The example device may further comprise a third chamber having a third reagent or combination of reagents that interact with the blood test sample received therein and a fourth chamber having a fourth reagent or combination of reagents that interact with the blood test sample received therein. The third and fourth chambers are also configured to be interrogated with sound to determine a hemostatic parameter of the test samples. The example reagents are selected from the group consisting of kaolin, celite, glass, abciximab, cytochalasin D, thrombin, recombinant tissue factor, reptilase, arachidonic acid (AA), adenosine diphosphate (ADP), and combinations of the same. Optionally, reagents are lyophilized before interacting with test samples.
[0011] The example devices can be used in a system comprising a transducer for transmitting ultrasound into one or more chambers and for receiving reflected sound from the chamber and the test sample therein. The system may further comprise at least one processor configured to determine a hemostasis parameter from the received sound. The parameters are optionally selected from the group consisting of TC1, TC2, clot stiffness, clot formation rate (CFR), TL1 and TL2. The processor is optionally further configured to determine an intrinsic pathway clotting factor index, an extrinsic pathway clotting factor index, a platelet index, a fibrinogen index, and a fibrinolysis index value. Intrinsic and extrinsic clotting factors are optionally combined to form a clotting factor index.
[0012] Also provided are sonorheometric methods for assessing hemostasis in a subject, comprising a cartridge with at least two test chambers. Each test chamber comprises a reagent or combination thereof. The subject's blood is introduced into the test chambers to mix with the reagents and ultrasound is transmitted into each test chamber. Sound reflected from the blood reagent mixture in the test chamber is received and processed to generate a hemostasis parameter. The parameters are optionally selected from the group consisting of TC1, TC2, clot stiffness, clot formation rate (CFR), TL1 and TL2. The disclosed methods may further include determining an intrinsic pathway clotting factor index, an extrinsic pathway clotting factor index, a platelet index, a fibrinogen index and a fibrinolysis index value. Intrinsic and extrinsic clotting factors are optionally combined to form a clotting factor index. Reagents or combinations thereof are optionally lyophilized prior to mixing with blood.
[0013] Sound focusing kits are additionally provided. An example sound focusing assembly includes a rigid sound permeable substrate and a sound permeable elastomeric bonding means. The elastomeric bonding means is positioned relative to the rigid substrate to create an interface between the elastomeric bonding means and the rigid substrate, wherein the interface focuses sound transmitted through the assembly.
[0014] 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 both preferred and alternative embodiments of the present invention. Brief Description of Drawings
[0015] Figures 1A-G are schematic illustrations of an example cartridge to assess hemostasis.
[0016] Figure 2 is a schematic illustration of biological fluid pathways of the example cartridge of Figures 1A-G.
[0017] Figure 3 is a schematic illustration of an example processing system for use with the example cartridge of Figures 1A-G.
[0018] Figure 4 is a schematic illustration of a portion of a system for assessing hemostasis.
[0019] Figure 5 is a schematic illustration of a portion of a system for assessing hemostasis.
[0020] Figure 6A is a schematic illustration showing that N acoustic pulses are sent into a blood sample to generate a force. The resulting strain can be estimated from the relative time delays between the N return echoes.
[0021] Figure 6B is a graph showing example displacement curves generated in a blood sample. As the blood clots, reduced displacement is observed.
[0022] Figure 6C is a graph that shows displacements combined to form graphs of relative stiffness, which characterize the hemostatic process. The parameters described in the panel are estimated from parameters found by fitting a sigmoidal curve.
[0023] Figure 7 is a flowchart illustrating an example method for estimating hemostasis parameters.
[0024] Figures 8A-D are schematic illustrations of an example cartridge for assessing hemostasis.
[0025] Figures 9A-C are schematic illustrations of portions of a system to assess hemostasis including pressure control mechanisms.
[0026] Figures 10A and 10B are schematic illustrations of an example sample flow pattern for use with the described devices and systems and an example cartridge for assessing hemostasis.
[0027] Figure 11 is a graph showing blood heating data on an example cartridge to assess hemostasis.
[0028] Figures 12A-C are schematic illustrations of example sound focusing mechanisms. Detailed Description
[0029] The present invention will now be described more fully below with reference to specific embodiments of the invention. Indeed, the invention may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; rather, these modalities are provided so that such disclosure satisfies applicable legal requirements.
[0030] As used in the specification, and the appended claims, the singular forms "a", "an", "the, a" include plural referents unless the context clearly dictates otherwise.
[0031] The term "comprising" and variations thereof as used herein are used synonymously with the term "including" and variations thereof and are open, non-limiting terms.
[0032] As used throughout, by a "subject" is meant an individual. The subject may 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), a fish, a bird or a reptile or an amphibian. The term does not indicate specific age or dryness.
[0033] Figures 1A-G illustrate an example cartridge 100 for use in assessing hemostasis in a subject. The cartridge 100 includes a front surface 101 and a rear surface 126. Figure 1A shows a front view of the cartridge 100 and the corresponding front surface 101. The cartridge includes an inlet 102, also referred to herein as an inlet or inlet port. , as a nozzle, through which a biological sample from the subject can be introduced into the cartridge. Optionally, a sample of blood from the subject is introduced into the cartridge at inlet 102. Another biological sample that can be introduced for analysis is plasma. The inlet 102 is in fluid communication with a channel 202, which is shown in Figure 2, and which directs the biological sample to other portions of the cartridge as described herein.
[0034] The cartridge further includes a hole 106 for applying a vacuum to the cartridge. When a vacuum is applied to orifice 106, biological fluid introduced at inlet 102 into channel 202 the fluid is propelled along channel 202 towards orifice 106.
[0035] As shown in Figure 2, when moving between the inlet 102 and the orifice 106, the biological fluid or a portion thereof, moves along the channel 202, into the channel 204, the channel 206, and along the channels 208, 210, 212 and 214. Each of the channels 208, 210, 212 and 214 is in fluid communication with a test chamber, also referred to herein, for example, as a test chamber, cavity or cavity or the like. For example, as illustrated in Figure 2, channel 208 is in fluid communication with a test chamber 116, channel 210 is in fluid communication with a test chamber 114, channel 212 is in fluid communication with a chamber 112, and channel 214 is in fluid communication with a test chamber 110.
[0036] Referring again to Figure 1, each test chamber comprises an open space 124 defined by a portion of the rear surface 126. Figure 1B shows a cross-sectional illustration through the test chamber 116 taken across line BB of the Figure 1A. Figure 1C shows a cross-sectional illustration taken across the C-C line of Figure 1A. Figure 1F shows an exploded view of the encircled portion of Figure 1B. In addition, Figure 1D shows a cross-sectional illustration through the D-D line of Figure 1A, which illustrates the open space of each of the four test chambers.
[0037] Each test chamber is configured to accept an amount of biological fluid into the open space. Referring to test chamber 116, illustrated in detail in Figure 1F, a portion of biological fluid introduced into inlet 102 moves through channels 202, 204 and 214 and into open space 124 of test chamber 116.
[0038] Biological fluid may also exit each respective test chamber and continue along an outlet channel 130 towards orifice 106. Thereby, fluid introduced into inlet 102 flows under vacuum through the device channels and into inside the test chambers. From each test chamber (110, 112, 114, 116), biological fluid continues to flow along outlet channels towards the vacuum.
[0039] Near orifice 106 each outlet channel can direct the flowing biological fluid into a hydrophobic filter at location 222, 220, 218 and 216, respectively. The filters or filter prevents movement of biological fluid out of the cartridge 100 into orifice 106. As the volume of the channels and test chamber is fixed, the vacuum can pull the biological fluid into the cartridge until the channels and each test chamber are filled with biological fluid.
[0040] Pressure can be controlled in cartridge 100 to, for example, control flow rate in consumable article 100 and lessen reliability issues related to possible misuse by the user. To measure the properties of a target biological sample, such as a blood sample, a user of the hemostasis system optionally attaches a syringe filled with blood to the cartridge unit 100. There is a possibility that the user of the hemostasis system 300 (see Figure 3) may attempt to inject the contents of the syringe applied to the cartridge 100 manually, rather than allowing the device to automatically aspirate the sample. This action may lead to system or measurement error. A pressure control device in the consumable flow path is used to prevent this user action.
[0041] Improper mixing of the biological sample with the reagents described here may result in variation in hemostasis measurements. Rapidly aspirating the blood sample is optionally used to provide increased mixing of the reagents with the biological sample, such as a blood sample. This is optionally achieved by creating a pressure differential between the cartridge and the suction mechanism of the hemostasis system.
[0042] In this regard, Figures 9A-C illustrate three example configurations that can be used to control the pressure differential between the cartridge and the suction mechanism and can therefore be used to obtain desired mixing levels and reduce user errors.
[0043] Figure 9A schematically illustrates an example system 900 for controlling pressure in a cartridge 100. The cartridge includes four test chambers (110, 112, 114 and 116). Each test chamber optionally includes a reagent and system operation causes a biological sample to enter one or more test chambers. The example system 900 includes a two-way pump 908 that operates to aspirate a biological sample, such as a blood sample. For example, a blood sample can be aspirated into the cartridge from a sample container 902. Pump 908 is in fluid communication with cartridge 100 and therefore pump activation can be used to move the biological sample through cartridge 100. A pressure transducer 904 is in communication with the pump which measures the gauge pressure drawn by the pump 908. A solenoid actuated valve 906 operates to block flow downstream of the pump allowing gauge pressure to build up. The solenoid can be selectively triggered to quickly expose the pressure gradient to the cartridge. The sample is allowed to progress through the cartridge and is optionally collected in a 910 sample container.
[0044] Figure 9B schematically illustrates another example system 920 for controlling pressure in a cartridge 100. The cartridge includes four test chambers (110, 112, 114 and 116). Each test chamber optionally includes a reagent and system operation causes a biological sample to enter one or more test chambers. The example system 920 includes a two-way pump 908 that operates to aspirate a biological sample, such as a blood sample. For example, a blood sample can be aspirated into the cartridge from a sample container 902. Pump 908 is in fluid communication with cartridge 100 and therefore pump activation can be used to move the biological sample through cartridge 100. A pressure activated membrane 912 is positioned upstream or downstream of cartridge 100 from pump 908. Membrane 912 is configured to rupture at a predetermined cartridge gauge pressure, thereby controlling the pressure at which the sample is drawn through the cartridge. The sample is allowed to progress through the cartridge and is optionally collected in a 910 sample container.
[0045] Figure 9C schematically illustrates another example system 930 for controlling pressure in a cartridge 100. The cartridge includes four test chambers (110, 112, 114 and 116). Each test chamber optionally includes a reagent and system operation causes a biological sample to enter one or more test chambers. The example system 930 includes a two-way pump 908 that operates to aspirate a biological sample, such as a blood sample. For example, a blood sample can be aspirated into the cartridge from a sample container 902. Pump 908 is in fluid communication with cartridge 100 and therefore pump activation can be used to move the biological sample through cartridge 100. A closed loop actuated valve 916 contains an internal pressure control mechanism and is used to block downstream flow from the pump allowing gauge pressure to build up to a valve pressure set point. After the gauge pressure setpoint is reached, valve 916 unfolds thereby exposing the cartridge to a desired pressure gradient. The sample is allowed to progress through the cartridge and is optionally collected in a 910 sample container.
[0046] The sample level in each chamber can also be monitored. For example, as shown in Figures 8A-8D, the fluid level in each chamber can be monitored optically. Figure 8A is a schematic illustration of an example consumable cartridge placed in an example hemostasis assessment system. Figure 8B is a schematic illustration of a cross section taken through line B-B of Figure 8A. Figure 8C is an expanded schematic illustration of the encircled portion of Figure 8B. Figure 8D is a schematic illustration of an example consumable cartridge.
[0047] The fact that a desired level has been reached in a given chamber can be indicated by an LED or other visual indicator. Employing a single beam of light from an LED emitter 802 reflecting out of the chamber onto a target blood detection reservoir 224, which is then detected by a detector 800 can optionally be used to optically monitor the fluid level of chamber.
[0048] For example, blood entering a test chamber reduces light reflection originating from an emitter 802 located along the detector 800, and aimed at the test chamber. A dual beam approach can be used whereby two sources of different wavelengths were reflected out of the test chamber. Blood has a deep red color that can be distinguished by comparing the red wavelength reflection to that of another color.
[0049] The difference in intensity of individually reflected red light is sufficient to determine when blood has entered a chamber. The intensity of the red light reflected from the test chamber containing blood was approximately half that of the cavity containing air, and approximately two-thirds that of the cavity containing water.
[0050] To control the temperature of the biological sample entering the test chambers, cartridge 100 may comprise a heat exchanger in communication with channel 204. The heat exchanger may be used to maintain, raise or lower the temperature of biological fluid prior to analysis in each test chamber. Optionally, the temperature of the biological fluid for analysis in each test chamber is equal such that the common portion of the channel system, as shown in Figure 2, is subjected to temperature manipulation by the heat exchanger. Optionally, in embodiments not shown, the temperature of the biological fluid entering each test chamber can be separately controlled.
[0051] For example, to heat the biological fluid, it can be passed through channel 204 through a polystyrene labyrinth held against a copper block. The copper block can be thin (eg below 2 mm) and sized just larger than the labyrinth to minimize thermal mass. A thermistor can be incorporated into the block so that a control circuit can maintain a constant set temperature in the block. A heater is used which optionally comprises two Watlow® (St. Louis, MO) coil sheet heating elements bonded to a flexible kapton plastic substrate, and the interface between the block and the heater may be a thin layer of silicone heat sink.
[0052] Various flow rates, eg up to and including 5.99 ml/min. or 6.0 ml/min. can be used, and power input to the heater can optionally vary between 8 and 16 Watts. Blood or other biological fluid can be heated in the cartridge from room temperature (approximately 20°C) to 37°C at a nominal flow rate of 6 ml/min., which is fast enough to fill the cartridge in 20 seconds . The surface area of the maze used was less than 8 cm2.
[0053] Physiologically, the clotting process is highly dependent on the temperature at which it occurs. Under normal conditions, clotting occurs at body temperature (37°C) which is optimal for proper enzymatic action of the clotting factors in the cascade.
[0054] Blood can be heated from its inlet temperature, ranging between 18°C and 37°C, to an arbitrary or desired temperature, such as body temperature, of 37°C, by passing through a serpentine channel in close proximity. narrow with a heater block. To perform heating in a short time over a short distance the block can be heated to almost 60°C when the blood entering is at the lower end of its temperature range. Blood temperature can also be measured and the heater block optionally set to a temperature ranging from 40°C to 58°C.
[0055] To measure the temperature a sensor can be incorporated in the 300 system (Figure 5) or in the cartridge. Optionally, a thermistor or thermocouple is placed in physical contact with the cartridge or blood and an IR thermometer is pointed at the cartridge or blood. In either case the cartridge may incorporate a small cavity through which the incoming blood passes, rather than having direct contact with the blood. When the cartridge material (polystyrene) is thin and the blood is kept moving through the cavity, then the increased heat capacity of the blood ensures that the cavity wall temperature is close to that of the blood. Optionally, a window allowing IR to pass through is used. The window may comprise a thin layer (e.g. 20 µm or less) of polyethylene or polystyrene.
[0056] Changes in temperature can occur in the body due to fever or in hospital settings like the emergency room (ER) or operating room (OR). Trauma patients arriving at the ER are treated with large volumes of saline intravenously, which lowers their body temperature to as much as 17°C. In OR, patients undergoing cardiac bypass surgery (CPB) have their whole blood volume passed through a heart-lung machine, which also lowers blood temperature can adversely affect clotting. Also, if there is a time delay between the time of blood draw and measurement, time is given for the temperature of the blood to change.
[0057] Polystyrene Styron® 666 (Styron Inc. Berwyn, PA) and microfluidic heat exchanger channel 204 allow a blood sample to be heated by a copper block outside the cartridge that is maintained at a constant temperature of 37° Ç. When a sample enters the cartridge at temperatures substantially lower than 37°C, it is optionally desirable to use a modified cartridge to allow faster heating of the biological sample. For example, in a model that simulates temperature changes over time of blood entering the polystyrene cartridge at 17°C, Styron® 666 was found to reduce the ability to heat blood and blood leaving the heat exchanger is not reached 37°C. These disadvantages of Styron® 666 are due to its relatively low thermal conductivity. The faster or more efficient heating of the biological sample is desired than is possible through Styron® 666, the cartridge can include materials with higher thermal conductivity than Styron® 666. For example, a thermally conductive polymer (E1201®) from Cool Polymers Inc. (North Kingstown, RI) with improved thermal conductivity properties can be used. This polymer can form a portion of the cartridge between the heating block and channel 204. By using this polymer in a portion of the cartridge between the heating block and the sample, the sample can be heated more efficiently. For example, Figure 11 shows that in a cartridge comprising this material blood entering the heat exchanger at 17°C reaches 37°C in 15 seconds.
[0058] Cartridges optionally include both materials, E1201® and Styron® 666, to improve heat transfer to the sample with E1201® on the heated side while maintaining flow visibility on the other side of the consumable with Styron® 666. Other alternative is to use E1201® as an insert that fits over the bend heater and in a chassis made of Styron® 666. This is optionally accomplished by overmolding the separate parts into a single piece or affixing the E1201® to the Styron® 666 chassis by medium such as laser, ultrasonic or RF welding. Changing the geometry of the E1201® insert to fit the larger chassis like a puzzle piece can further improve the assembly of the separate parts and help seal the microfluidic flow chambers.
[0059] It may also be desirable to cool the biological fluid in the cartridge. In these examples, and similar to when heating is desirable, the cartridge may include materials with higher thermal conductivity than Styron® 666. For example, the thermally conductive polymer (E1201®), described above, with improved thermal conductivity properties. can be used. This polymer can form a portion of the cartridge between a cooling device, such as a peliter cooling device, and channel 204. By using this polymer in a portion of the cartridge between the cooling device and the sample, the sample can be efficiently cooled.
[0060] Each test chamber may comprise one or more reagents useful in analyzing one or more indices of hemostasis. Optionally, the reagents are lyophilized. Optionally, one or more lyophilized bead type reagent is used. For example, the lyophilized bead can be a LyoSphere® produced by BioLyph (Minnetonka, MN). A standalone lyophilized bead is a format that allows for clinical chemistry and immunochemistry reagents that require two or three components that are incompatible as liquids due to their pH level or reaction with each other to compatibly coexist. As such lyophilized beads are stable and non-reactive, chemicals can be packaged together in the same test chamber.
[0061] To produce lyophilized reagents, a lyophilization device can be used. For example, the reagent for a given test chamber can be frozen to solidify all of its water molecules. Once frozen, the product is placed in a vacuum and gradually heated without melting the product. This process, called sublimation, transforms ice directly into water vapor, without first passing through the liquid state. The water vapor given off by the product in the sublimation phase condenses as ice in a collection trap, known as a condenser, in the vacuum chamber of a freeze dryer. Optionally, the freeze-dried product contains 3% or less of its original moisture content. The lyophilized product, which may be a pellet, can then be positioned in each test chamber. Once placed in a test chamber, the test chamber can be sealed to prevent unwanted product rehydration.
[0062] To locate the lyophilized reagents in the test chambers, the components can first be lyophilized and then the resulting lyophilized product can be placed in the test chambers. Using UV-curing epoxy glue or a welding process (such as ultrasound or RF welding), the lens assembly is sealed over each of the test chambers. The assembled cartridge can be sealed in a vapor-proof barrier (eg a bag) and the vapor barrier can be sealed to preserve the dehydrated nature of the product in the test chambers. When ready for use, the cartridge can be removed from the bag or vapor barrier and placed in a 300 analysis system, which is described in further detail below.
[0063] Antistatic treatment of plastic cartridges is optionally used with lyophilized reagents. Lyophilized reagents are inherently water-free, giving them significant electrical isolation.
[0064] Materials that are electrical insulators more easily accumulate static charge than materials that act as electrical conductors. This can create problems with process control when mounting cartridges and loading reagents. Since the cartridges are optionally made of an electrically insulating material (polystyrene, for example) it is not likely to dissipate a buildup of static charge in the lyophilized reagents. As a result, lyophilized reagents can statically adhere to the interior walls of the consumable. To prevent this from happening, three techniques are optionally implemented to remove static buildup.
[0065] Air ionization is a method of passing ionized, directed air over a target material to neutralize residual static charge on the material surface. Guiding ionized air into one or more cartridge test chambers and/or the reagents during the assembly process improves manufacturability by reducing reagent bead sticking to cartridge test chambers.
[0066] A second method implements cartridge construction using a plastic material that exhibits significantly more conductivity than standard injection molding materials. PermaStat® RTP Plastics (Winona, MA) are an example of such materials. The use of this material for the cartridge reduces the adhesion of lyophilized reagents to the cartridge test chamber walls.
[0067] Third sprays of anti-static liquid are used to temporarily create a dust-free coating on optical lenses and equipment. These sprays reduce static charge on the target surface and are useful for static reduction during the cartridge assembly process.
[0068] When lyophilized reagents are exposed to the fluid sample, they can generate foam that floats on the surface of the sample in the test chambers. As illustrated in Figures 10A and B, the consumable cartridge 1002 optionally comprises a fluidic circuit 202 that dispenses the sample from an external container, such as a syringe or vacutainer, into one or more test chambers (110, 112, 114, 116). ) where measurements are performed.
[0069] Figure 10A shows an example fluidic circuit that can be implemented in a consumable cartridge 1002. This circuit includes an inlet port 102, a channel 202, at least one test chamber (110, 112, 114, 116) , a filter 1004 and an outlet port 1006. The biological sample can be supplied into the chamber by applying a vacuum to the outlet port, with the filter allowing air to escape but stopping the fluid. A variety of different reagents can be placed in the test chamber, for example, as described from beginning to end. To generate accurate measurements, reagents are mixed into the sample before testing begins. For example, ultrasound emitted into the test chambers can be used to mix the reagents with the sample as described below.
[0070] As shown in Figures 10A and 10B, to optimize foam mixing, a sample of biological fluid may flow through channel 202, which enters the test chamber on the side at a tangent to the chamber. In addition, changing channel diameter from large to small increases flow velocity (flow rate conservation) at the inlet to the test chamber. This high flow velocity, in collaboration with gravity, helps generate a recirculating rotational flow pattern that improves mixing and dispersion of reagent with the sample. As the flow enters from the side, it causes any foam formed to be pulled into the flow stream and pushed below the surface.
[0071] Figure 10B shows a flow pattern implemented in a consumable cartridge designed for injection molding. The fluidic circuit was repeated four times to distribute the sample and mix reagents in four different test chambers. The circuit shown in Figure 10B also includes a coil heat exchanger to adjust the temperature of the incoming sample to a desired level.
[0072] Reagents are mixed with the sample before starting the test. The mixing of reagents can be performed using passive and/or active mechanisms. Passive methods include, for example, the use of serpentine channels and built-in barriers to create flow turbulence. Active methods include, for example, magnetic beads, pressure disturbance, and artificial cilia. The consumable cartridge contains a lens that focuses ultrasound energy on the sample that can be used to generate flow formation and mixing. The lens, also referred to herein as a lens assembly, or sound focusing assembly, is designed using a soft material such as a thermoplastic elastomer 134 in combination with a rigid substrate 132 such as polystyrene. This combination provides a dry ultrasound coupling that does not require the use of any fluid or gel binding media. Note that the same lens and ultrasound driver used for hemostasis measurement can be used in this matter to provide mixing. The increase in acoustic energy for mixing can be provided, for example, by increasing the pulse length, pulse amplitude or pulse repetition frequency.
[0073] The mixture can also be supplied by a varying magnetic field applied by a series of coils placed outside a test chamber or each test chamber. A small magnetic bead or magnetic stirrer can be placed in a test chamber and when the fluid sample enters the chamber, the current through the turns can be modulated to generate a changing magnetic field. This generates movement of the magnetic bead or magnetic stirrer which, in turn, generates mixing of the sample with the reagent.
[0074] Exposure of blood to surface proteins such as collagen or von Willebrand factor (vWF) on damaged blood vessel walls is an essential part of the clotting process. These proteins not only contribute to the coagulation cascade but also modulate several steps that lead to clot formation and hemostasis.
[0075] While exposure to these proteins is essential for the clotting cascade, standard point-of-treatment (POC) clotting assays and devices fail to account for this interaction. Optionally, the test well(s) and/or channel(s) of a consumable cartridge, such as those described herein, are coated with such surface proteins for the measurement of clotting in a POC medical device.
[0076] The use of surface protein coatings includes collagen, vWF, fibronectin and any other molecule that modulates clotting such as fibrinogen and thrombin. A protein layer on a substrate (glass, polystyrene, polypropylene) creates binding sites that allow measurement of ligand-receptor interactions between the substrate and other biological materials such as blood in a way that improves clotting assessment or provides new information. of test.
[0077] The interior surfaces of a consumable cartridge can be coated using, for example: (1) a layer of such proteins by covalent bonding using linker molecules, (2) covalent bonding using photochemicals, or (3) single protein adsorption. Binding molecules such as streptavidin or avidin and biotin can be used for this purpose. With linker molecules, the surface of any interior portion of the cartridge that will be exposed to the biological sample is biotinylated (coated with a layer of biotin) using commercially available biotin that is conjugated to a reactive group that non-specifically and covalently binds to the substrate. A solution with a high concentration of streptavidin or avidin, which have high affinity for biotin, is added to create a layer of biotin-bound streptavidin/avidin. The addition of bitynylated protein (collagen, vWF, fibronectin, thrombin, fibrinogen) then creates a layer of protein bound to the test cavity surface that specifically affects coagulation through interactions with plasma and platelet proteins.
[0078] Protein adsorption can be accomplished by filling the cavities with a highly concentrated protein solution. Adsorption to the plastic surface occurs almost immediately depending on temperature, pH, surface charges, surface morphology and chemical composition. The solution can then be removed and the surface air dried. Brushing a highly concentrated protein solution onto the surface of the cavities or soaking the cavities in such a solution will accomplish the same purpose.
[0079] The concentration of molecules in the solutions used for coating, either using binding proteins or adsorption, can be altered to modulate the amount of protein that binds the substrate and thereby modulate the effects on the coagulation cascade in a way that is relevant to physiology and hemostasis.
[0080] Referring again to Figure 1F, to seal each test chamber, for example the test chamber 116, a lens assembly 131 includes a rigid substrate 132 and a connecting means 134 which can be positioned at the rear end of each test chamber. Each connecting means 134 comprises an elastomeric material. Optionally, the elastomeric material is a thermoplastic elastomer (TPE). Exemplary elastomeric materials optionally include Dynaflex D3202, Versaflex OM 9-802CL, Maxelast S4740, RTP 6035. Optionally, the bonding means is overmolded onto the rigid substrate.
[0081] Between each connecting means 134 and the open space of each test chamber is a rigid substrate 132. The rigid substrate and connecting means form an interface that focuses ultrasound transmitted (eg, lens assembly) by a transducer into the open space of the chamber and over any biological fluid and/or reagents in the chamber. The rigid substrate of the lens may comprise a material which allows sound to pass and which may act to focus ultrasound at some level in space. Optionally, the rigid substrate comprises a styrene, such as, for example, Styrene® 666.
[0082] The lens assembly may be glued or welded to the surface 101 to secure the lens in place in an orientation that allows for the desired focusing of sound. Alternatively, the lens assembly is optionally fabricated together with the surface 101. In this regard, the rigid substrate 132 may be molded with the surface 101 and the connecting means 134 may be overmolded onto the rigid substrate. A wide variety of materials can be used to build the device. For example, plastics can be used for single-use disposable cartridges.
[0083] Each test chamber (116, 114, 112, and 110) can have a test set positioned over the large opening of the open space of each chamber. In this way, each chamber can be interrogated separately by focused ultrasound.
[0084] When placed in the analysis system 300, the connecting means 134 can be placed in acoustic communication with a transducer to deliver ultrasound through the lens assembly and into a test chamber. Optionally, an intermediate layer of an acoustically permeable material is positioned between an ultrasonic transducer and the connecting means. For example, an intermediate layer or block of Rexolite® can be used. The intermediate layer may be forced against the binding medium and may be in acoustic contact with the transducer.
[0085] Sound generated by a transducer passes through the intermediate layer, through the binding medium, through the rigid substrate, and is focused on the biological sample and reagent in the test chamber. Part of the sound directed into the chamber contacts the distal interior 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 positioned at a known distance from the ultrasound source. The distal inner surface 111 is used as a calibrated reflector, which is used to estimate sound velocity and sound attenuation in a test chamber at baseline and during the clot formation and clot dissolution process. These measurements can be used, for example, to estimate the subject's hematocrit along with hemostasis indices. The sound generated by the transducer can be focused onto the biological sample in a test chamber using a parabolic mirror that is coupled to the biological sample using an elastomer.
[0086] Figure 12A illustrates an example geometry for a parabolic mirror that can be used to focus sound into one or more test chambers, where f(x, y) is the shape of the locating reflector, zo is the height. of the reflector above the active element at the origin, and (xf, yf, zf) is the coordinate of the focal point. The focusing reflector is defined by a curve that is equidistant from the point of emission at the active acoustic element and the focal point. This can be expressed as:
where d is the total distance from the face of the acoustic source to the focus. If the distance is defined from the origin to the reflector as zo, then the total travel length is:

[0087] The shape of the reflector can be determined by solving for f(x, y) as follows:

[0088] If zo is defined, then equation 2 above can be evaluated and substituted into equation 10 above to provide an equation for the reflector surface. The reflector is a parabolic section. The example parameters are optionally an aperture of 8 mm with a focus at 16 mm laterally, 4 mm in the range and with an offset between mirror and aperture of 0.5 mm. A diagram of this geometry is shown in Figure 12B. This geometry is useful where the focusing mirror is placed in the system. The mirror can also be placed on the cartridge. In this case, the focus is optionally moved closer in the axial dimension, but additionally in the lateral dimension as shown in Figure 12C.
[0089] The cartridge 100 can be positioned in the pocket 302 of an analysis system 300. As shown in Figure 4, the pocket includes an actuator system 402 for pressing the intermediate layer, such as Rexolite®, which is acoustically coupled to a transducer in contact with connecting means 134. Thereby the pocket holds the cartridge securely in place and in an orientation such that ultrasound can be focused into each test chamber.
[0090] Figure 5 shows additional aspects of the cartridge 100 positioned in the analysis system. The cartridge is positioned such that the intermediate layer 504 is pushed into the connecting means 134, which is in communication with the rigid substrate 132 of the lens assembly 131. The ultrasonic generating means 502, including at least one ultrasonic transducer are positioned such that ultrasound is transmitted through the intermediate layer, lens assembly and into the test chamber.
[0091] At least a portion of the sound is reflected by the biological sample positioned in the chamber, and a portion of the sound transmitted into the chamber may also be reflected from the distal surface of the chamber 111. The reflected ultrasound may be received by the ultrasonic transducer and transmitted to the system for processing. In this way, the cartridge and the analysis system 300 can be in communication such that data and other operational or processing signals can be communicated between the cartridge and the analysis system.
[0092] A suitable analysis system 300 may therefore comprise one or more processing devices. Processing of the disclosed methods, devices and systems can be performed by software components. Thus, the disclosed systems, devices, and methods including the analysis system 300 may be described in the general context of computer-executable instructions, such as program modules, being executed by one or more computers or other devices. Generically, program modules comprise computer code, routines, programs, objects, components, data structures, etc., that perform specific tasks or implement specific abstract data types. For example, program modules can be used to cause transmission of ultrasound having desired transmission parameters and to receive and process ultrasound to assess hemostasis indices of a sample from the subject. The software can also be used to control the heating of the biological sample using the heat exchanger and to monitor and indicate the fill level of a given chamber. The processor can also be used to run algorithms to determine hemostatic indices and hematocrit. In some examples, the software can be used to retrieve the hematocrit determined from determined hemostatic indices. The determined hemostatic indices and hematocrit may be displayed to a medical professional or medical agent for the purpose of making medical decisions for a subject.
[0093] Accordingly, a person skilled in the art will recognize that the systems, devices and methods disclosed herein may be implemented through a general purpose computing device in the form of a computer. The computer, or portions thereof, may be located in the analysis system 300. The components of the computer may comprise, but are not limited to, one or more processors or processing units, a system memory, and a system bus that couples various system components including the processor to system memory. In the case of multiple processing units, the system can use parallel computing.
[0094] The computer typically comprises a variety of computer readable media. Exemplary readable media may be any available media that is accessible by the computer and comprises, for example, and not intended to be limiting, both volatile and non-volatile media, removable and non-removable media. System memory comprises computer-readable media in the form of volatile memory, such as random access memory (RAM), and/or non-volatile memory, such as read-only memory (ROM). System memory typically contains data such as data and/or program modules such as operating system and software that are immediately accessible to and/or are actually operated by the processing unit.
[0095] In another aspect, the computer may also comprise other removable/non-removable, volatile/non-volatile computer storage media. As an example, a mass storage device, which can provide non-volatile storage of computer code, computer readable instructions, data structures, program modules, and other data to the computer. For example, and not intended to be limiting, a mass storage device may be a hard disk, a removable magnetic disk, a removable optical disk, magnetic cassettes or other magnetic storage devices, flash memory cards, CD-ROM, digital versatile disks (DVD) or other optical storage, random access memory (RAM), read-only memory (ROM), electrically erasable programmable read-only memory (EEPROM), and the like.
[0096] Optionally, any number of program modules can be stored on the mass storage device, including, by way of example, an operating system and software. Each of the operating system and software, or some combination thereof, may comprise programming and software elements. Data can also be stored on the mass storage device. Data may be stored in any of one or more databases known in the art. Examples of such databases include DB2®, Microsoft® Access, Microsoft® SQL Server, Oracle®, mySQL, PostgresSQL, and the like. Databases can be centralized or distributed across multiple systems.
[0097] In another aspect, the user can enter commands and information into the computer through an input device. Examples of such input devices include, but are not limited to, a keyboard, pointing device (eg, a "mouse"), a touch screen, a scanner, and the like. These and other input devices can be connected to the processing unit through a human machine interface that is coupled to the system bus, but can be connected through other bus and interface structures, such as a parallel port, game port, a IEEE 1394 port (also known as a Firewire port), a serial port, or a universal serial bus (USB).
[0098] In yet another aspect, a display device 304, such as a touch screen, may also be connected to the system bus via an interface, such as a display adapter. It is understood that the computer may have more than one display adapter and the computer may have more than one display device. For example, a display device can be a monitor, an LCD (Liquid Crystal Display), or a projector.
[0099] Any of the methods disclosed may be accomplished by computer-readable instructions embedded in computer-readable media. Computer readable media can be any available media that can be accessed by a computer. By way of example and not intended to be limiting, computer readable media may comprise computer storage media and communication media. Computer storage media comprises volatile and non-volatile, removable and non-removable media implemented in any method or technology for storing information such as computer-readable instructions, data structures, program modules, or other data. Example 1
[00100] The reagents in each test chamber, also referred to as a test cavity, can include all reagents necessary to assess one or more hemostasis indices.
[00101] Optionally the cartridge is a single-use disposable cartridge with pre-filled lyophilized reagents. The cartridge can be used with whole blood from a subject. The assay cartridge or components include the following for fresh whole blood samples. Four separate wells containing lyophilized reagents to which 1.6 ml of fresh whole blood is added. Each test well uses around 300 μl of fresh whole blood along with the following reagents:Table 1:

[00102] Devices, systems and methods use the phenomenon of acoustic radiation force to measure changes in mechanical properties (eg stiffness) of a blood sample during the clotting and fibrinolysis processes. These changes are representative of the role of the four major components of hemostasis: (i) plasma clotting factors, (ii) platelets, (iii) fibrinogen, and (iv) plasma fibrinolytic factors. The basic approach is shown in Figures 6A-C.
[00103] A series of focused ultrasound pulses N is sent into a blood sample at short intervals ΔT (ΔT is on the order of microseconds), as shown schematically in panel A. each pulse generates a small, localized force in the blood as acoustic energy is absorbed and reflected during propagation. This force, which is concentrated around the focus of the ultrasound beam, induces a small displacement in the blood sample that depends on local mechanical properties. These shifts are on the order of 40 microns or less at the focus of the ultrasound beam.
[00104] Each pulse also returns an echo, as a portion of its energy is reflected from within the blood sample. As the sample moves slightly from one pulse transmission to the next, the path length between the fixed ultrasound emitter and any given region on the target increases with the number of pulses. This change in run length can be estimated from differences in the arrival times of echoes from the same region. The set of these delays forms a time displacement curve that retains combined information about the viscoelastic properties of the sample. These time displacement curves are shown in Figure 6B. These time displacement curves are measured every 6 seconds to fully characterize the coagulation and fibrinolysis dynamics, representing the entire hemostatic process.
[00105] When the blood sample is in a viscous fluid state, the application of acoustic force generates large displacements. As clotting is activated and fibrinogen is cross-linked to fibrin filaments, the sample behaves like a viscoelastic solid and the induced displacement reduces as the sample stiffness increases. The interaction of platelets and the fibrin mesh also further reduces induced displacements as clot stiffness increases. As the clot progresses to the fibrinolysis phase, the fibrin mesh is dissolved by fibrinolytic enzymes and the sample returns to viscous fluid, showing increasing displacements.
[00106] The evolution of the magnitude of induced displacements over time is therefore directly related to changes in mechanical properties of the blood sample during hemostasis. A curve obtained with this method is shown in Figure 6. Functional data highlighting the role of clotting factors, platelets, fibrinogen, and fibrinolysis can be extracted from the curve, as labeled in Figure 6.
[00107] The acoustic radiation force results from the transfer of momentum that occurs when a propagating acoustic wave is absorbed or reflected. This body force acts in the direction of the propagating wave, and can be approximated by the following expression:
where α[m-1] is the acoustic attenuation coefficient, c[m/s] is the speed of sound, I(t) [W/m2] is the instantaneous intensity of the ultrasound beam, PII is the intensity integral pulse, ΔT [s] is the time interval between successive ultrasound pulse transmissions, and <> indicates a measured amount of time.
[00108] The acoustic energy used by the instrument to generate acoustic radiation force is comparable with the acoustic energy typically used for common medical ultrasound procedures such as color Doppler imaging. The estimated maximum acoustic intensity is on the order of 2.5 W/cm2 (time average), which results in a blood sample temperature rise of 0.01°C for each measurement set (performed approximately every 6 seconds). ).
[00109] As the blood sample rapidly changes from viscous fluid to viscoelastic solid during coagulation and back to viscous fluid after clot lysis, the applied acoustic radiation force is adaptively altered to induce displacements above the noise threshold, however below levels that could induce mechanical breakdown (typically below 40 microns).
[00110] The magnitude of the force is adjusted to follow changes in mechanical properties of the blood sample by varying the time interval ΔT between successive pulses, as shown in equation 1. The maximum displacement induced during (m-1) acquisition is used to determine whether the force should be increased or decreased for the acquisition, based on predetermined threshold values. This adaptable process allows characterization of five orders of magnitude in stiffness without generating high stress on the blood sample that could alter the dynamics of coagulation and fibrinolysis.
[00111] As shown in equation (1), the applied acoustic radiation force changes as a function of acoustic attenuation and sound velocity, which change as a function of coagulation. The system uses the echoes that return from inside the cartridge to estimate changes in these parameters and normalize the strength of acoustic radiation.
[00112] Acoustic radiation force is generated using conventional piezoelectric materials that act as acoustic emitters and receivers. These materials deform when a voltage is applied across them, and conversely generate a voltage when they are deformed. Similar to optics, an acoustic lens can be placed in front of the piezoelectric material to focus acoustic energy into a single focal point.
[00113] In the example systems, method and devices piezoelectric disks are used which have an active diameter of 7.5 mm. The acoustic lens is provided by the curved shape of the disposable cartridge. Four discs are placed side by side to send sound to the four test cavities in a disposable. The vibration frequency of these piezoelectric disks is centered at 10 MHz, well understood in the frequency range used in conventional ultrasound imaging.
[00114] Ultrasound echo signals returning to transducers from blood samples are first filtered to remove electronic noise, digitized and further processed in a processor built into the system. A flowchart of the data analysis steps performed by the system is shown in Figure 7 where one starts at block 700. Ultrasound pulses are transmitted on a target sample into a test cavity at 702. The echoes are received, filtered and digitized into 704. After a short wait 706, steps 702 to 704 can be repeated. A time delay estimation is applied at 708 and a curve fit at 710. The system then determines whether enough data has been acquired to estimate the desired hemostasis rates at 712. If there is sufficient data to estimate a hemostasis rate, the rate of hemostasis is estimated at 714 and displayed at 716. If at 712 it is determined that not enough data has been acquired to estimate a hemostasis index, the system determines whether the test should be stopped at 718 and, if so, an output summary is generated at 722. If the test is to continue, after a long wait 770, one or more steps 702-770 are optionally repeated. Time Delay Estimation
[00115] After a set of N pulses is sent in the blood sample and the return echoes are obtained, time delay estimation (TDE) is performed to estimate a local time displacement curve, similar to that shown in Figure 6B. TDE encompasses measuring the relative time shift from one received echo to the next; the known value of the speed of sound in blood allows conversion of time changes into displacements. TDE is performed around the focus of the ultrasound beam. This process is repeated every 6 seconds (arbitrary fixed wait) to obtain time displacement curves throughout the coagulation and fibrinolysis process.
[00116] A variety of "storage" algorithms are available to perform this operation. TDE is a common signal processing step in application fields ranging from RADAR, SONAR and medical ultrasound (Doppler) imaging. curve fit
[00117] The viscoelastic properties of the blood sample during hemostasis are modeled using a modified model consisting of the well-known mechanical Voigt-Kelvin model with the addition of inertia. While the dynamic changes in blood viscoelasticity during hemostasis are certainly complex, the modified Voight-Kelvin model is simple and robust, and has been well validated in the past.
[00118] Each time displacement curve is fitted to the characteristic equation of the modified Voight - Kelvin model to estimate a variety of parameters referring to the viscoelastic properties of the sample. These parameters include relative elasticity, relative viscosity, time constant, and maximum displacement. The mathematical expression of the equation of motion for the modified Voigt-Kelvin model is
Where
is the damping ratio, ® is the natural frequency, and s is the static sensitivity.
[00119] Among the parameters obtained by the curve fitting, the system uses the magnitude of displacement estimated in 1 second with a qualitative measure of the sample stiffness. When blood is in a viscous fluid state, the displacement in 1 second is high. As the blood clots, this shift decreases in proportion to the generation of fibrin mesh and platelet activity. The value increases again during the fibrinolysis process. Estimate Hemostatic Function Indices
[00120] The displacement values obtained in 1 second for each data acquisition are compiled to form a curve showing relative stiffness as a function of time (Figure 6C). This curve, shown above, fully characterizes hemostasis and can be further processed to estimate direct indices of hemostatic function.
[00121] Hemostasis indices are calculated by fitting a sigmoidal curve to the time-stiffness curve (Figure 6C) and evaluating the first derivative of the curve. The times to clot TC1 and TC2 are calculated based on a threshold value of the derived curve (20% of the minimum value) and are indicative of the beginning and end of the fibrin polymerization phase. The CFR coagulation slope is the maximum of the drift curve and is indicative of the fibrin polymerization rate. Stiffness S is estimated from the stiffness curve 3 minutes after TC2. S depends on platelet function and the final stiffness of the fibrin network. Identical methods and indices are calculated for the fibrinolytic process. In particular the times TL1 and TL2 can be defined to represent the initial and final phases of the fibrinolytic process and the consequent dissolution of the fibrin network (time to lysis).
[00122] A summary of the parameters generated for each test chamber is presented in table 2:


[00123] To isolate the four main components of hemostasis, four measurements are performed in parallel on the disposable cartridge using a combination of agonists and antagonists in each of four wells. Measurements in each well are combined to form hemostasis indices as shown in Table 3:

[00124] Many modifications and other embodiments of the invention set forth herein will come to the mind of a person skilled in the art to which the present invention pertains having the benefit of the teachings presented in the above description. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are used, they are used in a generic and descriptive sense only and not for purposes of limitation.

权利要求:
Claims (10)
[0001]
1. Device for evaluating hemostasis characterized in that it comprises: a housing; a plurality of test chambers (110, 112, 114 and 116) each configured to receive a test sample of blood, each test chamber comprising a reagent or a combination of reagents, wherein the plurality of test chambers (110) , 112, 114 and 116) includes at least a first test chamber and a second test chamber that are each at least partially defined by the housing, wherein the reagent or combination of reagents is mixed before the test is started and the mixing is performed outside the test chamber in a portion of the housing; wherein the first chamber of the plurality comprises a first reagent or a combination of reagents that interact with the blood test sample; wherein the second chamber of the plurality comprises a second reagent or a combination of reagents that interact with the blood test sample; and wherein the first and second chambers are configured to be interrogated to determine a hemostatic parameter of the test sample that is received therein and a reagent or combination of reagents, wherein a first reagent or combination of reagents in the first test chamber is different than a second reagent or combination of reagents in the second test chamber; and a fluid path comprising a plurality of channels (202, 204, 206, 208, 210, 212, 214), each defined at least in part by the housing, wherein the fluid path includes an inlet (102) defined at least in part by the housing through which the test sample is introduced into the device, wherein at least one channel of the plurality of channels (202, 204, 206, 208, 210, 212, 214) is in communication with the inlet (102) and with the first test chamber and the second test chamber for dispensing a portion of the test sample to each of the first test chamber and the second test chamber, and wherein the fluid path includes a first orifice (106), defined at least in part by the housing, in communication with a channel of the fluid path and from which a pressure gradient when applied from an external source to the first orifice (106) draws the test sample through of the fluid path and to at least one of the test chambers wherein the at least one channel of the fluid path includes an inlet channel, a first channel, and a second channel, wherein the inlet channel is in communication with the inlet (102), wherein the first channel is in communication with the inlet channel and at least with the first test chamber, and wherein the second channel is in communication with the inlet channel and at least with the second test chamber, wherein at least a portion of the housing is thermally conductive to allow the test sample to be heated, wherein the first reagent or combination of reagents activates the test sample through an intrinsic clotting pathway, an extrinsic clotting pathway, or a combination thereof; wherein the second reagent or combination of reagents activates the test sample through an intrinsic clotting pathway, an extrinsic clotting pathway, or a combination thereof; at least one of the first reagent or reagent combination and the second reagent or reagent combinations activates the test sample through the extrinsic clotting pathway, wherein the second reagent or reagent combination further includes one or both of abciximab and cytochalasin D; wherein the device can be used with an interrogation device to measure at least one viscoelastic property of the test sample.
[0002]
2. Device, according to claim 1, characterized in that it further comprises: a. a third chamber comprising a third reagent or combination of reagents that interact with the blood test sample received therein; B. a fourth chamber comprising a fourth reagent or a combination of reagents that interact with the blood test sample received therein; and c. wherein the third and fourth chambers are configured to be interrogated to determine a hemostatic parameter of the test samples.
[0003]
3. Device according to claim 1 or 2, characterized in that the interrogation comprises the transmission of sound to one or more test chambers.
[0004]
4. Device according to any one of claims 1 to 3, characterized in that the reagents are selected from the group comprising kaolin, celite, glass, abciximab, cytochalasin D, thrombin, recombinant tissue factor, ADP, arachidonic acid, reptilase and combinations thereof.
[0005]
5. Device according to claim 4, characterized in that the reagents are lyophilized before interacting with the test samples.
[0006]
6. Device according to claim 1, characterized in that the device is configured for use with a single test sample.
[0007]
Device according to any one of claims 1 to 6, characterized in that it further comprises a fluid path having an inlet (102) for receiving a test sample, wherein the fluid path is in communication with at least one test chamber for dispensing the test sample, or a portion thereof, to one or more of the test chambers.
[0008]
8. Method for the evaluation of hemostasis in a subject characterized by the fact that it comprises: providing at least one accommodation; providing at least two test chambers, each test chamber including a reagent or a combination thereof, wherein the at least two test chambers include at least a first test chamber and a second test chamber which are each at least partially defined by the housing, where the reagent or combination of reagents is mixed before the test is started and the mixing is carried out outside the test chamber in a portion of the housing; B. introducing the subject's blood into the test chambers to mix with the reagent or reagents; ç. interrogating the mixed blood and reagent in the test chamber to determine a hemostatic parameter of the test samples that is received therein and a reagent or combination of reagents, where a first reagent or combination of reagents in the first test chamber is different than the one a second reagent or combination of reagents in the second test chamber; and a fluid path comprising a plurality of channels (202, 204, 206, 208, 210, 212, 214), each defined at least in part by the housing, wherein the fluid path includes an inlet (102) defined at least in part by the housing through which the test sample is introduced into the device, wherein at least one channel of the plurality of channels (202, 204, 206, 208, 210, 212, 214) is in communication with the inlet (102) and with the first test chamber and the second test chamber for dispensing a portion of the test sample to each of the first test chamber and the second test chamber, and wherein the fluid path includes a first orifice (106), defined at least in part by the housing, in communication with a channel of the fluid path and from which a pressure gradient when applied from an external source to the first orifice (106) draws the test sample through of the fluid path and to at least one of the test chambers wherein the at least one channel of the fluid path includes an inlet channel, a first channel, and a second channel, wherein the inlet channel is in communication with the inlet (102), wherein the first channel is in communication with the inlet channel and at least with the first test chamber, and wherein the second channel is in communication with the inlet channel and at least with the second test chamber, wherein at least a portion of the housing is thermally conductive to allow the test sample to be heated, wherein the first reagent or combination of reagents activates the test sample through an intrinsic clotting pathway, an extrinsic clotting pathway, or a combination thereof; wherein the second reagent or combination of reagents activates the test sample through an intrinsic clotting pathway, an extrinsic clotting pathway, or a combination thereof; at least one of the first reagent or reagent combination and the second reagent or reagent combinations activates the test sample through the extrinsic clotting pathway, wherein the second reagent or reagent combination further includes one or both of abciximab and cytochalasin D; wherein the device can be used with an interrogation device to measure at least one viscoelastic property of the test sample.
[0009]
9. Method according to claim 8, characterized in that the parameters are selected from the group comprising TC1, TC2, clot stiffness, clot formation rate (CFR), TL1 and TL2.
[0010]
10. Method, according to claim 8, characterized in that it further comprises determining an intrinsic pathway coagulation factor index, an extrinsic pathway coagulation factor index, a platelet index, a fibrinogen index and a fibrinolysis index.

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法律状态:
2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-11-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-01-25| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/02/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161443088P| true| 2011-02-15|2011-02-15|

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US61/443,088|2011-02-15|

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PCT/US2012/025270|WO2013105986A2|2011-02-15|2012-02-15|Devices, systems and methods for evaluation of hemostasis|

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