Patent Grant
7906338
The present invention relates generally to methods for measuring fluid properties, such as fluid suspension properties. More particularly, in one embodiment, the present invention relates to measuring blood platelet function.
Currently, there are over 2 million hospitalizations and nearly 10 million visits to physicians that are associated with coronary heart disease in the United States every year. A majority of these patients receive some form of antiplatelet therapy, e.g. Aspirin, Plavix, etc., to prevent acute thrombosis and clotting associated with vascular interventions, such as angioplasty, or implants, such as coronary stents. Excess dosage of the antiplatelet drugs can result in bleeding complications because the platelet function is over-suppressed, while insufficient dosage can fail to prevent acute thrombosis and clotting due to insufficient suppression of platelet function. Thus, it would be valuable to assess platelet function in patients at certain points of care and adjust the antiplatelet drug dosage to the specific needs of each individual. The relevance of such a point-of-care approach is becoming increasingly important in the context of platelet GP IIb/IIIa antagonists, e.g. Abciximab, Tirofiban, Eptifibatide, etc., with short half-lives (typically about 1 hour) that can be adjusted carefully and quickly to meet the needs of each patient. Thus, an effective point-of-care platelet function assay that enables management of therapeutic regimen has considerable clinical value.
A platelet aggregometer is an instrument that can assess certain aspects of platelet function. This device can be used by starting with a platelet suspension, such as blood or platelet rich plasma, which can be collected from a patient and dispensed into a disposable sample holder of the platelet aggregometer. A chemical stimulus, such as collagen, can be added to the platelet suspension in the sample holder, and subsequent agitation/mixing of the platelet suspension with the stimulus can cause the platelets to aggregate. The characteristics of this aggregation can be measured by various methods known by those skilled in the art, and the degree of aggregation measured can be directly related to the function of the platelets.
Currently available methods in the field of platelet aggregometers include sample holders that provide thorough mixing and agitation of the platelet suspension to cause platelet aggregation. However, most of these methods and devices create flow that is not conducive to enabling certain detection modalities of platelet aggregation, particularly for light scattering methods.
Many methods utilize mechanical mixing which often damages or otherwise alters fluid characteristics. For example, the use of a roller pump has been one proposed method for moving blood. However, the compression of a flow conduit containing blood by means of rollers often disfigures platelet aggregates, damages red cells, and alter their characteristics. Thus, the ergonomics of such designs can be undesirable, and loading of the blood sample and/or the chemical stimulus that causes platelet aggregation can be cumbersome. These limitations detrimentally influence the quality and consistency of platelet aggregation, which in turn adversely affects the reproducibility and reliability of the measurement of platelet function. Other methods include designs that present relatively good flow patterns for measurement using light scattering techniques, but do not provide significant mixing that induces more thorough and consistent platelet aggregation.
It has been recognized that there is a need to develop systems and methods that provide good mixing properties, without substantial damage to blood aggregates or other fluid properties to be measured. At the same time, such a system can also provide streamlined flow in a distinct region for accurate measurement of a fluid property. The present invention addresses the limitations of previous methods and presents fluid measurement devices and methods that enable more reliable assessment of platelet function, or in the case of other fluids, more reliable assessment of a desired fluid property.
In a first embodiment, a fluid property measurement system for measuring free stream particulates can include a fluid movement device positioned within a fluid container to cause fluid flow within the fluid container along a fluid flow path. The fluid movement device can often be a rotor although other devices can also be suitable. The system can further include a constricted region along the fluid flow path which generates a region of concentrated streamlined flow within the constricted region and mixing of the fluid outside of the constricted region. A property measuring device can also be functionally positioned with respect to the constricted region to measure fluid properties in the region of streamlined flow. In one detailed aspect of the present invention, the constricted region can be formed by a stenotic baffle system. The constricted region and fluid movement device can advantageously be configured to provide free stream aggregation of material such that measurement of aggregation can be based on free stream properties.
In another embodiment of the present invention, a method for measuring free stream properties of a fluid can include placing a quantity of fluid in a container and inducing flow in the fluid. The induced flow can be substantially streamlined in at least a measuring region of the container by constricting flow. Further, the fluid can be recirculated through the measuring region. A mixing region can be created separate from the measuring region sufficient to substantially mix the fluid and a property of the fluid can be measured in the measuring region. The systems and methods of the present invention provide an improved aggregation measurement of biological fluids while also minimizing adverse affects on the fluid properties such as platelet function.
Additional features and advantages of the invention will be apparent from the detailed description which follows, taken in conjunction with the accompanying drawings, which together illustrate, by way of example, features of the invention.
The drawings are intended to illustrate several specific embodiments of the present invention and are not intended to be unnecessarily limiting. As such, departure may be had in dimensions, materials, and features while still falling within the scope of the invention.
Reference will now be made to the exemplary embodiments illustrated in the drawings, and specific language will be used herein to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the inventions as illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention.
In describing and claiming the present invention, the following terminology will be used.
The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a rotor” includes reference to one or more of such structures, and reference to “a stimulus” includes reference to one or more of such factors.
As used herein, “recirculating,” “recirculated,” or “recirculation” refers to fluid flow along a path that is primarily related to a measuring region where fluid recirculation occurs, though recirculation can also occur in other non-measuring regions. By recirculating in the measuring region, a better measurement sample over a predetermined time can be taken as to the properties of the fluid. For example, in one embodiment, recirculation can occur by circumferential recirculation, and in another embodiment, the recirculation can be by bi-directional recirculation.
As used herein, “fluid” refers to a flowable composition and can include liquid, gas, suspended solid or other flowable mass. Fluids can be in the form of suspensions, emulsions, solutions, mixtures, or the like.
As used herein, “mixing” refers to disturbed flow or separated flow of a fluid. In one embodiment, the addition of a chemical stimulus can be accompanied by mixing in order to facilitate distribution of the stimulus sufficient to affect the bulk properties of the fluid. As used herein, mixing does not include mixing that is merely the result of intermolecular, intercellular, or structural forces exerted within a fluid under substantially streamlined flow, or which is solely the result of diffusion due to concentration gradients.
As used herein, “streamlined” refers to a fluid flow state that is more streamlined than is present in a mixing region acting on the same fluid. Additionally, a streamlined flow is capable of providing fluid flow dynamics such that at least a substantially accurate measurement can be taken, such as by use of a light scattering device or other fluid property measuring device. Further, streamlined flow typically refers to minimally disturbed flow that can be predominantly laminar, including arcuate flow in case of a cylindrical container. Such flow is suitable for testing using methods such as light scattering, etc. Although a common definition of the term “streamlined” can define a path or paths characterized by a moving particle in a fluid such that the tangent to the path at every point is in the direction of the velocity flow, the term as used herein is intended to be broader in scope to include flow that is minimally disturbed such that more accurate readings using fluid measuring equipment can be used, e.g., light scattering particle detection devices.
As used herein, “free stream particulates” refers to masses which are non-liquid materials contained within a fluid which are not attached to a fixed structure such as a container wall or other solid member. Free stream particulates can include, but are not limited to, platelet aggregates, solid debris, air bubbles, clots, and the like.
As used herein, “stenotic” refers to any constriction or narrowing of a fluid flow path. Typically, stenotic baffles can have a gradually narrowing portion which leads to a flow path portion having substantially constant cross-sectional area, and a subsequent expanding portion where cross-sectional area gradually increases to an unobstructed flow.
As used herein, the term “concentrated” when referring to streamlined flow, indicates that a greater number of streamlines per unit area are present than are present in other areas of the system in accordance with embodiments of the present invention. Areas outside of where there is “concentrated” streamline flow can be from streamlined (though less concentrated) to chaotic.
As used herein “fluid dynamic focus,” “fluid dynamically focused,” or the like, refers to fluid conditions where elements of the fluid are can become concentrated in a smaller cross-sectional area of controlled volume of flow.
Concentrations, amounts, and other numerical data can be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described.
As illustrated in
In accordance with one aspect of the present invention, a fluid container 12 is configured for recirculating fluid. The fluid container can be shaped so as to allow fluid to circulate within the container recursively. The fluid flows unidirectionally in a substantially circular pattern in
Returning to discussion of
In another aspect of the present invention, a measuring region or streamlined flow region 28 is provided distinct from a mixing region 26. The measuring region 28 is configured for providing substantially streamlined flow of the fluid within the fluid container 12. Flow of fluid within the container 12 can be induced by a method that is non-destructive of the fluid or its properties. Such methods include the use of a rotor 20a, other mixer (not shown), stir bar (not shown), forced flow device (not shown), or an external drive (not shown). These and other means for inducing flow can also be suitable for use in the present invention, but should provide a streamlined region 28, and should not adversely affect the fluid properties. Preferred methods for inducing flow in a blood component-containing fluid will not damage aggregates, destroy coagulated masses, or otherwise adversely affect the blood components, such as by causing significant hemolysis.
In this embodiment, the rotor 20a is a cylindrical body having a conical portion at a bottom end. The rotor can be rotated and secured using shaft 22a and cavity 22b system. The shaft 22a can be coupled to a constant or variable speed motor 24 that can be used to adjust the rotational speed based on the fluid properties, such as viscosity or fragility. Depending on the viscosity of the fluid, the rotor speed can vary from one medium to another, while the rotor 20a is being driven by non-varying force. In some scenarios, it may be desirable to maintain the rotor speed at a particular value. This can be accomplished by either using a large driving force to drive the rotor 20a, or by providing a motor 24 equipped with a feedback control to either increase or decrease the rotor driving force by means of monitoring the rotor speed. This embodiment generates general circumferential recirculation of the fluid within the system.
As mentioned, the fluid container 12 includes a mixing region 26 configured for substantial mixing of the fluid in the fluid container. The mixing region 26 is a region within the container 12 in which the fluid is mixed, and which is separate from a measuring or streamlined flow region 28. The mixing that can occur in the mixing region 26 can be turbulent or more gentle in action, but should be sufficient to substantially mix or homogenize the composition of the entire fluid. Thus, the measurement of fluid properties in the separate measuring region 28 can be representative of the bulk properties of the fluid. The separation of mixing region 26 and measuring region 28 allows for increased control of the fluid flow environment, and improves the ability to prevent damage to the fluid. The mixing region 26 can be produced using a variety of disruption members 14a, 14b, and/or 14c, such as a stationary obstruction, movable obstruction, rotating mixer, vagile object, or combinations thereof. These disruption members can cause a local disruption or turbulence in the streamline flow of the fluid sufficient to mix the fluid.
In one aspect of the present invention, the disruption members 14a, 14b, 14c protrude from an inside surface 16 of the fluid container 12. The disruption members 14a, 14b, 14c can be molded as an integral part of the container, or can be separately formed members. Additionally, the disruption members 14a, 14b, 14c can be attached to the inner surface 16 in a permanent or removable manner.
One or more disruption member 14a, 14b, 14c can affect mixing in the mixing region 26 in the vicinity of the one or more member 14a, 14b, 14c. Three different disrupting members are shown for exemplary purposes only. One disrupting member is typically sufficient to provide disturbed flow, or even turbulent flow, though more than one can be present at or near the mixing region 26 in some embodiments.
The mixing region 26 can vary in size depending on such variables as the fluid flow velocity approaching the disruption members, fluid viscosity, and the particular shape of the disruption member(s). Often a single disruption member and mixing region is sufficient to produce substantial mixing of the fluid. However, as shown in
In one embodiment, the surfaces that contact the fluid, i.e., rotor 20a and/or inside surface 16, can be configured to be highly compatible with the introduced fluid, and can also be configured to avoid contamination of the fluid and/or deterioration of the surfaces. For example, the fluid container 12, if made for use with platelet suspensions, can be made of materials that are generally compatible with the platelet suspension. Additionally, it may be desirable for aggregates not to adhere to surfaces within the apparatus or system 10a, such as the inner surface 16 of the fluid container 12, the rotor 20a, the disruption member(s) 14a, 14b, 14c, or other parts of the apparatus. This can be accomplished by using smooth geometries in the apparatus and/or coatings, such as lubricious, hydrophilic, or hydrophobic coatings on the apparatus components. Such coatings, if used, can increase biocompatibility and/or decrease friction and associated adherence to the coated surfaces. Coatings suitable for use in the present invention can include, but are not limited to, hydrophilic, hydrophobic, lubricious, heparin, carbon-diamond, or ceramic coatings.
In addition to the above components, the fluid container 12 can have a cap 34 to hold the fluid within the fluid container 12 and prevent spillage of the contents. The cap 34 can be made of a material that has similar properties to that of the fluid container 12, e.g. sufficient mechanical strength and compatibility with the fluid. The cap 34 can also be formed as an integral part of the fluid container 12. Optionally, the cap can also contain self-sealing ports through which the fluid and/or additional material, such as stimuli, can be introduced. In one embodiment, fluid can be introduced through an inlet line 36, or through depositing the fluid into the fluid container 12 prior to securing the cap 34. The inlet line 36 can be configured as shown in
In another aspect of the present invention, a property measuring device 32 can be operatively associated with the measuring region. The property measuring device 32 can be a light scattering whole blood platelet aggregometer (LSWBPA), or another known light scattering device, optical device, ultrasound, electro-magnetic device, or mechanical device.
The above-described device can be used to measure a variety of fluid properties such as, but not limited to, platelet and leukocyte aggregation, degree of coagulation, particle count, density, viscosity, temperature, hematocrit, chemical composition, fluorescence, refractive index, absorption, attenuation, elasticity, compressibility, dielectric strength, impedance, echogenecity, specific heat, heat conductivity, osmolarity, diffusivity, and/or pH. A currently recognized use of the present invention is in the measurement of platelet aggregation of blood component-containing fluids. In this embodiment, the blood component-containing fluid can be introduced into the fluid container 12 through inlet 36 (or inlet 18). A stimulus, such as an aggregating agent, can be introduced into the blood component-containing fluid, which can cause a change in the blood component-containing fluid properties. The desired fluid properties can be measured and recorded using the property measuring device 32, which is typically operatively associated with the measuring region 28 of the fluid. Additionally, a baseline measurement of the property of interest can be taken prior to or shortly after introduction of the stimulus in order to quantify the effect of the stimulus on the fluid. The fluid container 12 with its contents can then be disposed of or recycled for future use.
Regarding the above and other embodiments, with respect to the stimulus that can be used, the stimulating agent that is introduced into the fluid to elicit response can be mechanical, electromagnetic, biological, chemical, or other stimulus. For example, in a platelet suspension, the platelets in the fluid container can be subjected to certain fluid dynamic forces in order to activate them via mechanical stimulus. Alternatively, the fluid can be subjected to electromagnetic stimulus using an electromagnetic field to elicit a response. In yet another alternative embodiment, the fluid can be subjected to biological agents such as bacteria, viruses, other platelets or white cells, or similar agents that cause a measurable biological response in the fluid. The response to the stimulus is usually the aggregation, agglutination, coagulation, or other types of clumping of the platelets within the fluid. Although introduction of a single stimulus is usually sufficient, several stimuli can also be introduced either simultaneously or sequentially. A pre-stimulus baseline measurement of the platelet suspension can be established while flow is induced in the fluid inside the container at an initial time prior to introducing the stimulus.
Specific stimuli that can be used for specific types of fluid are included by way of example, as follows. If a platelet-containing fluid is being used to measure platelet function, various activating/aggregating agents can be used alone or in combination, including adenosine di-phosphate (ADP), collagen, thrombin, epinephrine, ristocetin, calcium ionophore, thrombin receptor agonist protein (TRAP), arachidonic acid, and combinations thereof. If leukocyte function is to be measured, to a leukocyte-containing fluid can be added effective amounts of a leukocyte aggregating agent. Such leukocyte aggregating agents can include calcium ionophore, formyl-methyl-l-phenylalanine, or combinations thereof. Plasma or blood activating agents can include thrombin, diatomaceous earth, kaolin, celite, glass particulates, trypsin, pepane, phospholipids, or combinations thereof.
In keeping with the present invention, there are several mechanisms by which the stimulus can be introduced into the fluid. Chemical and/or biological stimuli can be injected into the fluid by a pipette, a needle, or other types of injection devices. Alternatively, the stimulus can be pre-dispensed onto an interior surface (e.g. by coating) within the container such as a disruption member, baffle, rotor, or inner surface of the container. In keeping with the present invention, the stimulus can also be dispensed into the fluid container prior to the introduction of the fluid into the container, in which case, a baseline can be quickly established before the onset of the response. In yet another optional embodiment, the stimulus can be introduced into the fluid after placing the fluid into the container.
The fluid response can be measured as the fluid components react to the stimulus. Such a response can be a change in viscosity, luminescence, conductivity, or other properties of the fluid. For example, with platelet containing fluids, the measured response is the number of the platelet aggregates of a minimum size as they form and disintegrate. The size of these platelet aggregates can also be measured as another type of response. Other combinations of number and size can also be measured. Further, an overall change in scattered light can be measured to reflect a change in bulk properties. These responses are recorded and subsequently analyzed so as to assess the functions of the platelet under investigation. At the conclusion of the test the fluid and the fluid container can be discarded. Alternatively, parts of the apparatus can be salvaged and recycled. The process of the present invention can also be considered essentially a batch process or closed system for the period between introduction of the stimulus and the final measurement of the target property.
Turning now to
Other suitable shapes for use in the rotor aspect of the present invention include, but are not limited to, spherical, elliptical, quadrilateral, and combinations of these shapes. Alternatively, flow of the fluid can be induced using magnetic stir bars or other known mixers that produce a measuring region suitable for use in the present invention. A variety of methods can be employed to induce flow in the fluid consistent with the methods of the present invention. Suitable methods for platelet-containing fluids will expose the fluid to relatively low shear stresses and minimize and/or avoid damage to fluid components. Alternatively, the rotation can be powered by electromagnetic force. If the rotor is driven electromagnetically, a magnetic stir bar could be used or a bar made of magnetic material such as iron would be embedded within the rotor.
In
In an alternative embodiment of the present invention, flow of the fluid can also be induced using forced flow.
In addition to that described above, the mixing regions can take various shapes and dimensions consistent with the methods of the present invention. For example, a region of narrowing geometry in the mixing region, where the mixing region begins to narrow toward the measuring region 36, is an area of vortex formation. There, sufficient mixing can occur to facilitate aggregation and homogenization of the fluid. The region of converging geometry is also an area where there are significant inter-platelet collisions, which also aids aggregation and accurate measurement. Stir bars 38a, 38b can also be incorporated in the narrowing areas of the reservoirs to further enhance mixing if desired, as shown in
In another aspect of the present invention, streamlined flow can be induced in a fluid by an external drive, such as by rotating the fluid container while holding a rotor stationary (or rotating at a different rate or direction), or by otherwise moving the fluid container to cause fluid flow having the above described characteristics of a mixing and a measuring region within the container.
In yet another aspect of the present invention consistent with the above description,
The measuring region can be a constricted region where fluid flow passes through a volume having a smaller cross-sectional area than neighboring volumes along the fluid flow path.
The constricted region shown in
In each of the embodiments described above, the fluid container includes a region(s) where the local flow patterns of the fluid are such that there is substantial mixing of the fluid. Further, the fluid container includes another region(s) separate from the mixing region(s) where the flow characteristics are substantially streamlined. Such streamlined flow is steady enough that the entities of interest in the fluid, e.g. platelet aggregates in a blood component-containing fluid, carried in it can be detected more accurately by certain detection methods, such as light scattering. As recirculation occurs in the measuring region, a more complete sample of fluid can also be measured. Moreover, the above mixing and streamlined flow characteristics are induced using methods that minimize damage to, or alteration of entities of interest, e.g., platelet aggregates and coagulated masses. In addition, the present invention can be incorporated into a compact, disposable, and ergonomic design that further enables more reliable assessments of platelet function.
Further, the systems and devices of the present invention are designed to measure of free stream particulates such as platelet aggregates. The fluid flow velocity, disruption member designs such as constricted regions or baffles, and other variables can be adjusted to encourage aggregation of platelets while in the fluid rather than impact and agglomeration on an interior surface of the device. For example, a relatively high shear rate, e.g. 200 s−1 to 2000 s−1 can be maintained in order to prevent platelet aggregates from adhering to walls or baffles. Thus, in one embodiment, the systems of the present invention can measure free stream aggregation with significantly reduced concerns and affects associated with clogging and blockage which can occur as masses of material build up on moving parts or other surfaces.
The following examples illustrate embodiments of the invention that are presently known. Thus, these examples should not be considered as limitations of the present invention, but are merely in place to teach how to make the best-known systems and methods of the present invention based upon current experimental data. As such, a representative number of systems and methods are disclosed herein.
A cylindrically shaped fluid container having an inner diameter of 11 mm, a height of 20 mm, and a wall thickness of 2 mm was obtained. The fluid container is formed of a polycarbonate, coated on the inner surface with a non-tacky coating to increase compatibility with blood. A cylindrical cap, having an 11 mm inner diameter and 20 mm height made of the material DELRIN™ was fitted to substantially seal the inner diameter of the fluid container. The cap had a 4 mm diameter hole in the center, extending entirely through the height of the cap, i.e., 20 mm, and includes a side notch measuring 5 mm by 5 mm (also extending the entire length of the cap). The rotor included a cylindrical shaft 24 mm in length and 4 mm in diameter, and a rotor body that was 6 mm in diameter and 6 mm in length. The bottom of the rotor body included a sharp pointed tip with a 30° angle similar to rotor 20a shown in
The apparatus was then used to measure platelet aggregation of whole blood as follows: Blood (0.2 ml) was injected into the fluid container. A rotational speed of about 600 RPM was set for the rotor. A differential light-scattering detector was positioned externally on a side opposite the disruption member. A blood baseline was measured with the detector for a period of 5 seconds to set the platelet aggregate threshold. After the measurement of the baseline and the establishment of the threshold, a platelet-aggregating agent of 10 μl ADP solution was injected into the moving blood resulting in a final concentration of ADP in blood of 50 μM. Platelet aggregates formed under the stimulation of the ADP and the flow and mixing induced by the rotor and disrupting member. In regions opposite the mixer, i.e., the streamlined flow or measuring region, where the detector was located, the blood flow is essentially streamline. Hence, the detector measured the platelet aggregates that were entrained inside the blood flow as distinctive spiked signals above or below the baseline. As these signals developed beyond the threshold, they were recorded. After 2 minutes of measurement, the recording was terminated and the entire fluid container with the blood inside was discarded.
A fluid container including two identical reservoirs connected by an elongated conduit was formed, similar to the embodiment shown in
A volume of 1 ml of whole blood was transferred into one of the two reservoirs prior to attachment of the piston. The piston was then attached to the base of that reservoir to seal in the blood. The two pistons were moved up and down oppositely in synchrony so that the blood was transferred between the two reservoirs through the conduit. Average flow velocity inside the conduit was 20 mm per second. After the establishment of the baseline and threshold, a platelet-aggregating agent was injected into one reservoir through the self-sealing diaphragm port. Under the stimulation of the agent and with the help of the mixing brought on by the contraction-expansion of blood flow, platelet aggregates formed inside the sample holder. As these platelet aggregates were carried by the blood through the conduit, they were measured by a detector placed along the conduit and recorded. After 2 minutes of measurement, the recording was stopped, and the whole sample holder was retrieved for recycling.
A cylindrically shaped fluid container having an inner diameter of 10 mm, a height of 8 mm, and a wall thickness of 1 mm was obtained. The fluid container is formed of a polycarbonate, coated on the inner surface with a non-tacky coating to increase compatibility with blood. A cylindrical cap, having a 10 mm inner diameter and 4 mm height made of the material DELRAN™ was fitted to substantially seal the inner diameter of the fluid container. The rotor included a cylindrical shaft 24 mm in length and 4 mm in diameter, and a rotor body that was 6 mm in diameter and 6 mm in length. The bottom of the rotor body included a plug tip which fit into a recess in the bottom of the fluid container similar to rotor 54 shown in
The apparatus was then used to measure platelet aggregation of whole blood as follows: Blood (0.2 ml) was placed into the fluid container. A rotational speed of about 600 RPM was set for the rotor. A differential light-scattering detector was positioned externally on a side opposite the disruption member. A blood baseline was measured with the detector for a period of 3 seconds to set the platelet aggregate threshold. After the measurement of the baseline and the establishment of the threshold, a platelet-aggregating agent of 0.2 mM solution was injected into the moving blood resulting in a final concentration of ADP in blood of 10 μM. Platelet aggregates formed under the stimulation of the ADP and the flow and mixing induced by the rotor and constricting region. In the constricting region, the streamlined flow or measuring region, where the detector was located, the blood flow is essentially streamline. Hence, the detector measured the platelet aggregates that were entrained inside the blood flow as distinctive spiked signals above or below the baseline. As these signals developed beyond the threshold, they were recorded. After 2 minutes of measurement, the recording was terminated and the entire fluid container with the blood inside was discarded.
The above description and examples are intended only to illustrate certain potential uses of this invention. It will be readily understood by those skilled in the art that the present invention is susceptible of a broad utility and applications. Many embodiments and adaptations of the present invention other than those herein described, as well as many variations, modifications, and equivalent arrangements will be apparent from or reasonably suggested by the present invention and the forgoing description thereof without departing from the substance for scope of the present invention. Accordingly, while the present invention has been described herein in detail in relation to its preferred embodiment, it is to be understood that this disclosure is only illustrative and exemplary of the present invention and is made merely for purpose of providing a full and enabling disclosure of the invention. The forgoing disclosure is not intended or to be construed to limit the present invention or otherwise to exclude any such other embodiment, adaptations, variations, modifications and equivalent arrangements, the present invention being limited only by the claims appended hereto and the equivalents thereof.
This application is a continuation of U.S. patent application Ser. No. 11/504,970, filed Aug. 15, 2006, and now U.S. Pat. No. 7,393,690, issued Jul. 1, 2008, which is a continuation-in-part of U.S. patent application Ser. No. 10/431,358, filed on May 6, 2003, and now U.S. Pat. No. 7,262,059, issued Aug. 28, 2007, each of which is hereby incorporated herein by reference in its entirety.
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