CA2507323A1 - Diagnostic whole blood and plasma apparatus - Google Patents
Diagnostic whole blood and plasma apparatus Download PDFInfo
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- CA2507323A1 CA2507323A1 CA002507323A CA2507323A CA2507323A1 CA 2507323 A1 CA2507323 A1 CA 2507323A1 CA 002507323 A CA002507323 A CA 002507323A CA 2507323 A CA2507323 A CA 2507323A CA 2507323 A1 CA2507323 A1 CA 2507323A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
- A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
- A61B5/14557—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases specially adapted to extracorporeal circuits
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150015—Source of blood
- A61B5/150022—Source of blood for capillary blood or interstitial fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150015—Source of blood
- A61B5/15003—Source of blood for venous or arterial blood
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
- A61B5/150213—Venting means
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
- A61B5/150236—Pistons, i.e. cylindrical bodies that sit inside the syringe barrel, typically with an air tight seal, and slide in the barrel to create a vacuum or to expel blood
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
- A61B5/150244—Rods for actuating or driving the piston, i.e. the cylindrical body that sits inside the syringe barrel, typically with an air tight seal, and slides in the barrel to create a vacuum or to expel blood
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
- A61B5/150251—Collection chamber divided into at least two compartments, e.g. for division of samples
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150343—Collection vessels for collecting blood samples from the skin surface, e.g. test tubes, cuvettes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150351—Caps, stoppers or lids for sealing or closing a blood collection vessel or container, e.g. a test-tube or syringe barrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150374—Details of piercing elements or protective means for preventing accidental injuries by such piercing elements
- A61B5/150381—Design of piercing elements
- A61B5/150389—Hollow piercing elements, e.g. canulas, needles, for piercing the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150374—Details of piercing elements or protective means for preventing accidental injuries by such piercing elements
- A61B5/150381—Design of piercing elements
- A61B5/150503—Single-ended needles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150007—Details
- A61B5/150755—Blood sample preparation for further analysis, e.g. by separating blood components or by mixing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
- A61B5/150992—Blood sampling from a fluid line external to a patient, such as a catheter line, combined with an infusion line; blood sampling from indwelling needle sets, e.g. sealable ports, luer couplings, valves
Abstract
Some embodiments of the invention provide a single apparatus that is suitable for extracting plasma from whole blood using a flow-through filtration~
chamber, and measuring the plasma and/or the whole blood using both spectroscopy and biosensors. Once the whole blood is drawn into the apparatus by capillary action, or the whole blood is injected into the apparatus, a rapid plasma separation occurs, and the apparatus can be inserted into a slot in a diagnostic measurement instrument for rapid plasma and/or blood analysis. Because the apparatus is small and no pretreatment of the fluid is necessary, the diagnostic measurement instrument may be in the form of an inexpensive instrument, which could be used at the site of patient~
care.
chamber, and measuring the plasma and/or the whole blood using both spectroscopy and biosensors. Once the whole blood is drawn into the apparatus by capillary action, or the whole blood is injected into the apparatus, a rapid plasma separation occurs, and the apparatus can be inserted into a slot in a diagnostic measurement instrument for rapid plasma and/or blood analysis. Because the apparatus is small and no pretreatment of the fluid is necessary, the diagnostic measurement instrument may be in the form of an inexpensive instrument, which could be used at the site of patient~
care.
Description
Title: DIAGNOSTIC WHOLE BLOOD AND PLASMA APPARATUS
Field Of The invention [0001] The invention relates to an apparatus that separates plasma from whole blood and the measurement of analytes in the whole blood and the plasma using spectroscopy and biosensors.
Backs~~ound Of The Invention [0002] Many medical diagnostic tests are performed on serum and plasma. Serum is the yellow liquid obtained from "whole blood" (also referred to as blood) after the blood is allowed to clot, and the clot is removed by centrifugation; plasma is the yellow liquid obtained from blood by centrifugation of blood before the blood is allowed to clot, and the packed red cells are removed by centrifugation. Plasma is usually obtained by adding an anticoagulant like heparin to the blood, to prevent clotting. In point-of-care testing or near patient testing, the preferred sample is whole blood because the time and cost required for clotting and/or centrifugation is eliminated, and less blood is usually required.
Field Of The invention [0001] The invention relates to an apparatus that separates plasma from whole blood and the measurement of analytes in the whole blood and the plasma using spectroscopy and biosensors.
Backs~~ound Of The Invention [0002] Many medical diagnostic tests are performed on serum and plasma. Serum is the yellow liquid obtained from "whole blood" (also referred to as blood) after the blood is allowed to clot, and the clot is removed by centrifugation; plasma is the yellow liquid obtained from blood by centrifugation of blood before the blood is allowed to clot, and the packed red cells are removed by centrifugation. Plasma is usually obtained by adding an anticoagulant like heparin to the blood, to prevent clotting. In point-of-care testing or near patient testing, the preferred sample is whole blood because the time and cost required for clotting and/or centrifugation is eliminated, and less blood is usually required.
[0003] Blood contains hemoglobin inside the red cells. In spectroscopic measurements, the hemoglobin absorbs a very significant portion of the incident or illuminating electromagnetic radiation (EMR), and the red cells cause significant attenuation of the incident EMR due to scattering of EMR away from the photodetector. Currently, not all diagnostic tests can be performed by spectroscopic methods (spectroscopy or spectrometry), and the use of biosensors can assist in expanding the menu of diagnostic tests.
Because serum and plasma are less viscous that blood, serum or plasma may be preferred to blood when certain biosensors are employed. Therefore, certain analytes cannot be measured accurately in blood, for example bilirubin. Also, the integrity of the plasma cannot be easily assessed in a blood sample due to the dominance of the hemoglobin color in blood. Plasma integrity may be compromised by the presence of interfering substances, such as hemoglobin released from the red cells after hemolysis. On the other hand, certain analytes can only be measured in blood because they only exist within the red cells, for example the various hemoglobin species.
Summary Of The Invention [0004] According to an aspect of an embodiment of the invention there is provided a diagnostic whole blood and plasma apparatus comprising: a) a housing; b) an inlet within the housing for receiving the whole blood; c) a flow-through filtration chamber comprising one or more than one layer of porous membrane within the housing for extracting the plasma from the whole blood;
d) a plasma measurement chamber within the housing for measuring the plasma extracted from the whole blood; and e) an outlet vent for facilitating airflow out of the apparatus. Optionally the apparatus further comprises a whole blood measurement chamber within the housing for measuring the whole blood. The measurement methods described include spectroscopy and the use of biosensors.
Because serum and plasma are less viscous that blood, serum or plasma may be preferred to blood when certain biosensors are employed. Therefore, certain analytes cannot be measured accurately in blood, for example bilirubin. Also, the integrity of the plasma cannot be easily assessed in a blood sample due to the dominance of the hemoglobin color in blood. Plasma integrity may be compromised by the presence of interfering substances, such as hemoglobin released from the red cells after hemolysis. On the other hand, certain analytes can only be measured in blood because they only exist within the red cells, for example the various hemoglobin species.
Summary Of The Invention [0004] According to an aspect of an embodiment of the invention there is provided a diagnostic whole blood and plasma apparatus comprising: a) a housing; b) an inlet within the housing for receiving the whole blood; c) a flow-through filtration chamber comprising one or more than one layer of porous membrane within the housing for extracting the plasma from the whole blood;
d) a plasma measurement chamber within the housing for measuring the plasma extracted from the whole blood; and e) an outlet vent for facilitating airflow out of the apparatus. Optionally the apparatus further comprises a whole blood measurement chamber within the housing for measuring the whole blood. The measurement methods described include spectroscopy and the use of biosensors.
[0005] Other aspects and features of the present invention will become apparent, to those ordinarily skilled in the art, upon review of the following description of the specific embodiments of the invention.
Brief Descriation Of The Drawincts [0006] For a better understanding of the present invention, and to show more clearly how it may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, which illustrate aspects of embodiments of the present invention and in which:
Brief Descriation Of The Drawincts [0006] For a better understanding of the present invention, and to show more clearly how it may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, which illustrate aspects of embodiments of the present invention and in which:
(0007] Figure 1A is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for spectroscopic measurement of whole blood and plasma separated from the blood, according to a first embodiment of the invention;
[0008] Figure 1 B is a cross-sectional view through the apparatus shown in Figure 1A along line B-B;
[0009] Figure 1 C is a cross-sectional view through the apparatus shown in Figure 1A along line C-C;
[0010) Figure 1 D is a cross-sectional view through the apparatus shown in Figure 1A along line D-D;
[0011] Figure 1 E is a cross-sectional view through the apparatus shown in Figure 1A along line E-E;
[0012] Figure 2A is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for spectroscopic measurement of whole blood and plasma separated from the blood, according to a second embodiment of the invention;
[0013] Figure 2B is a cross-sectional view through the apparatus shown in Figure 2A along line B-B;
[0014] Figure 2C is a cross-sectional view through the apparatus shown in Figure 2A along line C-C;
[0015) Figure 3 is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for spectroscopic measurement of plasma separated from the blood, according to a third embodiment of the invention;
[0016] Figure 4 is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for biosensor measurement of plasma separated from the blood, according to a fourth embodiment of the invention;
[0017) Figure 5 is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for spectroscopic measurement of plasma separated from the blood, according to a fifth embodiment of the invention;
(0018] Figure 6 is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for spectroscopic measurement of plasma separated from the blood, and biosensor measurement of whole blood, according to a sixth embodiment of the invention; and [0019] Figure 7 is a schematic drawing showing a top view of a diagnostic whole blood and plasma apparatus suitable for spectroscopic measurement of whole blood and plasma separated from the blood, and biosensor measurement of whole blood, according to a seventh embodiment of the invention.
Detailed Description Of Preferred Aspects Of The Invention [0020] Some embodiments of the invention provide a single apparatus or cartridge that is suitable for both spectroscopic and biosensor measurement of a whole blood sample, and plasma extracted within the apparatus from the whole blood. Once the blood is transferred to the apparatus, the apparatus can be inserted into a slot in a diagnostic measurement instrument for rapid plasma and/or blood analysis. Because no pretreatment of the blood is required, for example centrifugation, measurement could be made on the plasma extracted from the blood and/or the blood, and because the apparatus is also small, the diagnostic measurement instrument could be small and inexpensive, and could be used at the site of patient care.
Detailed Description Of Preferred Aspects Of The Invention [0020] Some embodiments of the invention provide a single apparatus or cartridge that is suitable for both spectroscopic and biosensor measurement of a whole blood sample, and plasma extracted within the apparatus from the whole blood. Once the blood is transferred to the apparatus, the apparatus can be inserted into a slot in a diagnostic measurement instrument for rapid plasma and/or blood analysis. Because no pretreatment of the blood is required, for example centrifugation, measurement could be made on the plasma extracted from the blood and/or the blood, and because the apparatus is also small, the diagnostic measurement instrument could be small and inexpensive, and could be used at the site of patient care.
[0021] In some very specific embodiments, the apparatus is provided with two independent flow paths for the analysis of blood and plasma: a flow path that flows through a filtration chamber (referred to as the "filtration flow path" for clarity), and a flow path, which by-passes the filtration chamber, and which includes a biosensor chamber that is specifically designed with at least one active surface, such as a chemical or ionic sensitive surface that is exposed to the blood (referred to as the "blood biosensor flow path" for clarity). The filtration flow path may include an optical chamber, which is specifically designed to reduce the average attenuation of electromagnetic radiation (EMR) due to scattering of EMR by the red blood cells in a blood sample, without having to hemolyze the red blood cells; for clarity, the flow path that includes the blood optical chamber is referred to as the "blood spectroscopic flow path", and could be included in the "filtration flow path".
The blood in the filtration flow path, which includes a filtration chamber, allows the blood to flow in contact with a first side of a hemofilter (a porous membrane). The pores in the membrane allow plasma from the blood to flow through the membrane to the second side of the membrane, but prevents cellular tissue from penetrating the membrane. Therefore, there is provided a filtration chamber where blood flows along the first side of a porous membrane, and plasma flows along the second side of the porous membrane.
The plasma flows along another flow path, which may include an optical chamber (referred to as the "plasma spectroscopic flow path" for clarity), or which may include a biosensor chamber that is specifically designed with at least one active surface, such as a chemical or ionic sensitive surface that is exposed to the plasma (referred to as the "plasma biosensor flow path" for clarity). The hemofilter in some embodiments is in the form of a hollow fiber filter (or hollow fiber membrane), where the first side could be the external surface of the hollow fiber membrane and the second side could be the internal surface of the hollow fiber membrane, or vice versa.
The blood in the filtration flow path, which includes a filtration chamber, allows the blood to flow in contact with a first side of a hemofilter (a porous membrane). The pores in the membrane allow plasma from the blood to flow through the membrane to the second side of the membrane, but prevents cellular tissue from penetrating the membrane. Therefore, there is provided a filtration chamber where blood flows along the first side of a porous membrane, and plasma flows along the second side of the porous membrane.
The plasma flows along another flow path, which may include an optical chamber (referred to as the "plasma spectroscopic flow path" for clarity), or which may include a biosensor chamber that is specifically designed with at least one active surface, such as a chemical or ionic sensitive surface that is exposed to the plasma (referred to as the "plasma biosensor flow path" for clarity). The hemofilter in some embodiments is in the form of a hollow fiber filter (or hollow fiber membrane), where the first side could be the external surface of the hollow fiber membrane and the second side could be the internal surface of the hollow fiber membrane, or vice versa.
[0022] It should be understood that the flow paths defined are non-limiting examples of flow paths that can be developed from the specific embodiments described, and other flow paths are considered to be within the scope of the present invention.
[0023] Extraction of plasma from blood using a hemofilter can be accomplished in a similar manner as described in, "Intravenous Catheter for Intracorporeal Plasma Filtration" by Handley H. H. et al (Blood Purification 2002; 20:61-69).
[0024] Those skilled in the art will appreciate that biosensors include various transducer arrangements that convert certain properties of a sample into an electrical signal. Biosensors may comprise, for example without limitations, transistors, ion-selective membranes, membrane-bound enzymes, membrane-bound antigens, and membrane-bound antibodies.
[0025] In such embodiments the optical chamber is designed to spread blood or plasma into a thin film, thereby reducing the incidences of trapped air bubbles in the blood or plasma sample in the optical chamber. Instead air bubbles are pushed through the optical chamber and guided out of the apparatus through a vent. The blood optical chamber provides spectroscopic blood measurements for determination of, for example without limitation, Hb species, and the blood biosensor chamber provides blood measurements for determination of, for example without limitation, blood pH and blood electrolytes. The plasma optical chamber provides spectroscopic blood measurements for determination of, for example without limitation, Hb (as an indicator of hemolysis), bilirubin and turbidity, and the plasma biosensor chamber provides plasma measurements for determination of, for example without limitation, plasma glucose and plasma proteins. The apparatus is particularly useful for, for example without limitation, a combination of blood gas measurement, co-oximetry, and plasma sample integrity measurement.
In a simple embodiment that includes a filtration chamber and one optical chamber, the apparatus is particularly useful for, for example without limitation, a neonatal point-of-care measurement instrument for measuring plasma bilirubin from a pin prick capillary blood sample, without having to centrifuge the blood.
In a simple embodiment that includes a filtration chamber and one optical chamber, the apparatus is particularly useful for, for example without limitation, a neonatal point-of-care measurement instrument for measuring plasma bilirubin from a pin prick capillary blood sample, without having to centrifuge the blood.
[0026] In some embodiments blood within the optical chamber is isolated from contamination by room air by providing an inlet transition chamber and an overflow chamber at a respective entrance and exit of the optical chamber. In use, blood in the inlet transition chamber and the overflow chamber serve as barriers between blood in the optical chamber and room air, thereby isolating the blood in the optical chamber from oxygen contamination. Similarly in the same embodiments, the biosensor chamber is also isolated from contamination by room air by providing an inlet transition chamber and an overflow chamber at a respective entrance and exit of the biosensor chamber. In the rare incident of a trapped air bubble, those skilled in the art will appreciate that various calibration algorithms for many specific analytes measured in the blood or plasma sample can be developed that could compensate for measurement inaccuracies caused by trapped air bubbles, except for those analytes such as the partial pressure of oxygen and oxy-hemoglobin, which become falsely elevated as a result of oxygen introduced into the blood sample from the air bubble.
[0027] The apparatus may also include at least one visible fill line or indicator serving as a marker providing a user with a visual Boolean indicator relating to the sufficiency of the blood sample in the optical chamber and biosensor chamber. Briefly, in some embodiments, the visible fill line is located in a position in and/or beyond the overflow chamber that is indicative of whether or not a volume of blood drawn into the apparatus is present in sufficient amount to: i) ensure that the blood in the optical chamber and biosensor chamber is substantially free from contaminants that may have been introduced during the filling of the apparatus with blood; and/or, ii) ensure that there is an effective amount of blood surrounding the optical chamber and biosensor chamber to isolate the blood in the optical chamber and biosensor chamber from room air; and/or, iii) ensure that sufficient blood has flown through the filtration chamber to filter out sufficient plasma.
[0028 The apparatus may also include a capillary break between the visible III lines, in the form of a bulge or increasing tube diameter, which is useful for stopping blood flow into the apparatus, particularly when the embodiment relies on capillary action as described by the inventor in US Pat.
Application (number not assigned as yet) entitled, "Blood Collection and Measurement Apparatus", filed April 12, 2005.
[0029] In accordance with an embodiment of the invention, a very specific example of an apparatus suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood is shown in Figures 1A, 1 B, 1 C, 1 D and 1 E. Specifically, Figure 1A is a schematic drawing illustrating the top view of an apparatus 100, Figure 1 B is a cross-sectional view through the apparatus 100 along line B-B in Figure 1A, Figure 1C is a cross-sectional view through the apparatus 100 along line C-C in Figure 1A, Figure 1 D is a cross-sectional view through the apparatus 100 along line D-D in Figure 1A, and Figure 1 E is a cross-sectional view through the apparatus 100 along line E-E in Figure 1A. The apparatus 100 includes a housing 103 defining an internal volume between an inlet 107 and an outlet vent 123. As shown, the housing 103 has a side dimension s, a width dimension w, and a depth dimension d. The internal volume includes several distinct portions including a blood inlet transition chamber 109a, a blood optical chamber 111a, a blood overflow chamber 113a, a filtration chamber 117, a filtration outflow chamber (or outflow tube) 121 a, a plasma collection chamber 119, a plasma inlet transition chamber 109b, a plasma optical chamber 111 b, and a plasma overflow chamber 113b. In this particular embodiment a short protruding length of capillary tube 105 defines the inlet 107 for the apparatus 100, and extends into fluid connection with the blood inlet transition chamber 109a from the inlet 107. The fluid path from the inlet 107 to the blood overflow chamber 113a defines the blood spectroscopic flow path. The overflow chamber 113a is fluidly connected between the optical chamber 111a and the filtration chamber 117. The flow path from the blood overflow chamber 113a to the outlet vent 123/123a defines the filtration flow path (In Figures 3-6, where there are no blood spectroscopic flow paths, the blood spectroscopic flow path is replaced by a filtration transition chamber 309 {309a in Figure 6}, and the filtration flow paths extend from the inlet 107 to the outlet vents 123, with the chambers fluidly connected in series). The filtration chamber 117 serves as a junction from which plasma flows, and in this specific embodiment, the hollow fiber runs approximately perpendicular to the filtration flow path where the filtration flow path crosses the hollow fiber. The flow path form the plasma collection chamber 119 to the outlet vent 123 (shown as 123b in Figure 3) defines the plasma spectroscopic flow path. The plasma spectroscopic path includes the plasma inlet transition chamber 109b, the plasma optical chamber 111 b, the plasma overflow chamber 113b, and the plasma outlet chamber 121 b, fluidly connected in series. The plasma collection chamber 119 is fluidly connected to the plasma inlet transition chamber 109b. Those skilled in the art will appreciate that depending on the relative shapes and sizes of the plasma collection chamber 119 and the plasma optical chamber 111 b, the plasma inlet transition chamber 109b could become optional.
[0030] With specific reference to Figure 1A and Figure 1 B, the blood inlet transition chamber 109a also provides a barrier between room air and blood in the blood optical chamber 111 a. The blood inlet transition path 109a is tapered towards the blood optical chamber 111 a so as to have a diminishing depth and an increasing width relative to the diameter of a tube 105 in the direction of the optical chamber 111 a from the tube 105. Moreover in use, blood remaining in the blood inlet transition path 109a serves as a barrier between room air and the blood in the blood optical chamber 111 a through which air cannot easily diffuse toward the blood in the optical chamber 111 a. Similarly blood in the blood overflow chamber 113a serves as a barrier between room air and the blood optical chamber 111 a.
[0031] With further specific reference to Figure 1 B, the interior of the blood optical chamber 111a is much thinner in depth than the average diameter of the interior of the tube 105 and the broad end of the blood inlet transition cavity 109a. In some embodiments, the depth of the optical chamber 111 a, being the internal distance between the respective interior faces of the top and bottom wall-portions 125a and 125b, ranges approximately from about 0.02 mm to about 0.2 mm, whereas the average inside diameter of the tube 105 ranges approximately from about 0.5 mm to about 2 mm, in the specific embodiment. Those skilled in the art will appreciate that the limitations regarding diameters of channels that rely on capillary action for fluid movement, are not as stringent when the fluid is forced into the apparatus. Light scattering caused by red blood cells is more prevalent when the depth of the blood optical chamber 111 a is more than 0.1 mm, and so a depth of less than 0.1 mm is preferred. If the depth is less than 0.02 mm the natural viscosity of blood may reduce how effectively blood can be spread evenly through the blood optical chamber 111 a. Specifically, the diameter in the top view, shown in Figure 1A of the blood optical chamber 119a ranges approximately, without limitation, between about 1 mm to about 70 mm. Those skilled in the art will appreciate that the circular shape of the optical chamber 111a is not essential, and as another non-limiting example, an oval shape could be just as effective.
(0032] With further specific reference to Figure 1 B and also Figure 1 C, the top and bottom wall-portions 125a and 125b of the housing 103 are preferably transparent but may be translucent, and define the blood optical chamber 111 a. Further, in this preferred embodiment, the top and bottom wall-portions 125a and 125b are recessed with respect to the corresponding top and bottom surfaces 103a and 103b of the housing 103, in order to protect the exterior faces of the top and bottom wall-portions 125a and 125b from scratches, although those skilled in the art will appreciate that this is not essential. It should be understood that the cross-sectional areas shown are non-limiting examples, and those skilled in the art will appreciate that other cross-sectional areas could be used. Those skilled in the art will also appreciate that the internal walls of the blood optical chamber 111 a do not have to be exactly parallel because the calibration algorithms for blood measurements can be developed to accommodate variability in depth of the blood optical chamber 111 a.
(0033] With further specific reference to Figure 1A, the filtration chamber 117 is fluidly connected to a blood outlet chamber 121a, which terminates at vent 123. Optionally, the blood outlet chamber 121 a includes first and second visible fill lines 125a and 125b. Between the visible fill lines 125a and 125b, the blood outlet chamber 121 a, bulge, creating volumes large enough to facilitate filling between the fill lines. In this particular embodiment, proper use requires that enough blood flows into the apparatus 100 to at least pass the first fill lines 125a. Overfilling past the second fill lines 125b will not compromise the blood sample within the blood optical chamber 111 a, but excess filling may cause blood to flow through the vent 123 onto the top surface 103a of the housing 103, thereby contaminating the housing 103 with potentially biologically hazardous material. Those skilled in the art will appreciate that the fill lines provide a guide to the user, and they should be in plain view when the apparatus is fully inserted into the slot of the diagnostic measurement instrument, particularly if the blood is injected into the apparatus 100 after the apparatus 100 is fully inserted into the slot of the diagnostic measurement instrument, as will be appreciated when other embodiments of the invention are described. Those skilled in the art will also appreciate that the fill lines could be on the surface 123a and/or 123b, depending on the orientation or the apparatus 100 in the slot of the diagnostic measurement instrument. The bulge between the visible fill lines 125a and 125b may also serve as a capillary break, whereby the blood flow slows down and may cease to flow after crossing the visible fill line 125a, when the blood flow relies on capillary action.
[0034] With further specific reference to Figure 1A, the porous membrane 115 is in the form of a hollow fiber filter (or hollow fiber membrane) with an internal chamber, which functions as the plasma collection chamber 119, which extends into fluid connection with the plasma inlet transition chamber 109b, provided to serve as a transition between the filtration chamber 117 and the plasma optical chamber 111 b. The hollow fiber is defined by the membrane 115 and the ends 114 and 116. The hollow fiber ends 114 and 116 are sealed against the walls of the filtration chamber 117, and a hole in the wall of the filtration chamber 117 at the end 116 of the hollow fiber serves to extend fluid connection with the plasma collection chamber 119 and the plasma inlet transition chamber 109b. The membrane 115 is porous and in some embodiments, the distribution of pore diameters ranges approximately from about 0.1 micrometer to about 10 micrometers.
Those skilled in the art will appreciate that the membrane 115 could be a flat piece of membrane that serves as a barrier between blood and plasma filtered through the barrier from the blood, arranged to encourage blood flow along the filtration flow path. Moreover, with respect to a flat piece of membrane that replaces membrane 115, one side of the membrane will be in contact with blood, and the other side of the membrane will be in contact with plasma.
Those skilled in the art will also appreciate that blood flow decreases the viscosity of the blood and therefore enhances separation (or filtration, or extraction) of plasma from blood; separation of plasma from blood also increases with increasing pore size, decreasing thickness of the membrane 115, and increasing membrane surface area. Although the filtration chamber 117 is illustrated using a single hollow fiber filter, those skilled in the art will appreciate that the membrane surface area can be increased by using more than one hollow fiber filter, assembled as a bundle of parallel hollow fibers.
In some embodiments, the internal diameter of the hollow fiber filter ranges approximately from about 0.1 mm to about 1 mm.
(0035] With further specific reference to Figure 1A, the plasma transition chamber 109b, the plasma optical chamber 111 b and the plasma overflow chamber 113b are arranged in the plasma spectroscopic flow path to function like the blood spectroscopic flow path, except that plasma is measured instead of whole blood. Those skilled in the art will appreciate that because plasma scatters less EMR than whole blood, the depth of the plasma optical chamber 111 b could be larger than the depth of the blood optical chamber 111 a, and also the diameter of the plasma optical chamber 111 b could be smaller than the diameter of the optical chamber 111a. The plasma overflow chamber 113b serves as a barrier between room air and plasma in the plasma optical chamber 111 b during operation. The plasma overflow chamber 113b is fluidly connected to the outlet chamber 121 b, which is fluidly connected to the vent 123. The flow path from the plasma collection chamber 119 to the vent 123 defines the plasma spectroscopic flow path. In this particular embodiment, the filtration flow path and the plasma spectroscopic flow path terminate at the same vent 123, but other embodiments show separate outlet vents for the respective flow paths.
(0036] Those skilled in the art will appreciate that the spectroscopic measurement instrument could contain one or more sources of EMR, and one or more photodetectors (or array of detectors), to illuminate the plasma and blood independently. Those skilled in the art will also appreciate that a single source of EMR can be used with a bifurcated optical fiber and a shutter that could facilitate sequential illumination of the plasma and the blood;
similarly a single photodetector (or array of detectors) can be used with a bifurcated optical fiber. Another aspect of the present invention is to optionally make the distance from the center of the blood optical chamber to the adjacent edge of the housing 103 (shown as A in Figure 1 E) and the distance from the center of the plasma optical chamber to the adjacent edge of the housing 103 (shown as B in Figure 1 E) approximately equal, and to optionally aligning the two centers approximately parallel with the axis of the width dimension. By making distance A equal to distance B, and aligning the centers, the spectroscopic measuring instrument with a single EMR path can be used to illuminate the blood first and then illuminating the plasma by rotating the apparatus 103 by 180° along the axis of the side dimension s, or vice versa.
[0037] In this particular embodiment, the blood overflow chamber 113a has a complementary design to that of the inlet transition cavity 109a. That is, the blood overflow chamber 113a is flared away from the blood optical chamber 119a so as to have an increasing depth and a decreasing width in the direction away from the blood optical chamber 111a. In this particular embodiment, the volume of the blood overflow chamber 113a is larger than that of the blood optical chamber 119a, such that during operation, filling the blood overflow chamber 113a is helpful in ensuring that blood in the optical chamber is substantially free from contamination and effectively isolated from room air that may enter via the outlet vent 123.
[0038] Once the blood is transferred into the apparatus, the blood and extracted plasma are ready for measurement by inserting the apparatus into a slot in a diagnostic measurement instrument (not shown). The end of the apparatus opposite from the end with the inlet 107 is inserted first, and the inlet 107 remains outside the slot of the diagnostic measurement instrument.
Those skilled in the art will appreciate that the outlet vent can be located in several positions in the housing 103, but it is preferably located in the housing 103, such that it will reside outside the slot of the diagnostic measuring instrument during measurement, thereby minimizing the risk of contaminating the slot of the diagnostic measurement instrument with plasma and/or blood.
[0039] Referring to Figure 2A, shown is a top view of an apparatus 200 suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood according to a second embodiment of the invention.
The apparatus 200 illustrated in Figure 2 is similar to the apparatus 100 illustrated in Figure 1, and accordingly, elements common to both share common reference numerals. For brevity, the description of Figure 1A is not repeated with respect to Figure 2A. The primary difference, illustrated in Figure 2A, is in the filtration chamber 117: the blood flows inside the hollow fiber filter, shown as 219, and the plasma collection chamber is defined by the walls of the filtration chamber 117 and the membrane 115. A second difference is an optional tube 227 that provides fluid connection between the filtration chamber 117 and the plasma transition chamber 109b. Cross section views along the lines B-B and C-C in Figure 2A are shown in Figure 2B and Figure 2C respectively.
[0040] Referring to Figure 3, shown is a top view of an apparatus 300 suitable for spectroscopic measurement of plasma extracted from a blood sample according to a third embodiment of the invention. The apparatus 300 illustrated in Figure 3 is similar to the apparatus 100 illustrated in Figure 1A, and accordingly, elements common to both share common reference numerals. For brevity, the description of Figure 1A is not repeated with respect to Figure 3. The primary difference, illustrated in Figure 3, is that the filtration fluid path does not include a blood optical chamber, which is replaced with a tube 309, whereby in some embodiments, only plasma measurement is made. Also, some embodiments may be provided with a cap 135.
(0041] The cap 135 is provided to close the inlet 107 before and after the apparatus is used. The cap 135 is optionally provided with a plunger 137, a tether 133 and a ring connector 131. The ring connector 131 is sized to fit securely around the protruding end portion of the capillary tube 105. The cap 135 is connected to the ring connector 131 by the tether 133, thereby connecting the cap 135 to the apparatus 300 even when the cap 135 is not placed on the protruding end portion of the capillary tube 105. One function of the cap 135 is to prevent contamination of the user and the diagnostic measurement instrument with blood. The plunger 137 in the cap 135 is useful for exerting positive pressure on the blood sample, thereby encouraging blood flow within the apparatus, limited by the volume of the plunger 137.
[0042] Referring to Figure 4, shown is a top view of an apparatus 400 suitable for biosensor measurement of plasma extracted from a blood sample according to the fourth embodiment of the invention. The apparatus 400 illustrated in Figure 4 is similar to the apparatus 100 illustrated in Figure 1A, and the apparatus 300 illustrated in Figure 3 and accordingly, elements common to the three apparatus share common reference numerals. For brevity, the description of Figure 1 and Figure 3 are not repeated with respect to Figure 4. The apparatus 400 is more like the apparatus 300 illustrated in Figure 3, where the plasma measurement is made by biosensors instead of spectroscopy. The biosensor chamber 211 b, the biosensor overflow chamber 213b, the biosensor outflow chamber 221 b, and the outlet vent 123d define the plasma biosensor flow path, and is comparable to the plasma spectroscopic flow path shown in Figure 3. The apparatus 400 is provided with biosensors 157a, 157b. The biosensors 157a, 157b are coupled to respective electrical contacts 159a, 159b that provide connectivity between the apparatus 400 and a diagnostic measurement instrument suitable for processing the outputs of the biosensors 157a and 157b. Such an instrument (not shown) may include a programmed general-purpose computer and/or microprocessor in combination with a suitable combination of hardware, software and firmware. Those skilled in the art will appreciate that the biosensors can be pre-calibrated and the calibration algorithms installed in the diagnostic instrument. Moreover, those skilled in the art will also appreciate that one or more biosensors may be included in an apparatus according to an embodiment of the invention, and that only two have been illustrated in Figure 4 as a non-limiting example. Additionally, the protruding open end of the inlet capillary tube 105 includes threads for connection with a correspondingly threaded cap (not shown) as an alternative to the tethered cap 135 with an optional plunger like the plunger 137 shown in Figure 3.
[0043] Referring to Figure 5, shown is a top view of an apparatus 500 suitable for spectroscopic measurement of plasma extracted from a blood sample according to the fifth embodiment of the invention. The apparatus 500 illustrated in Figure 5 is similar to the apparatus 100 illustrated in Figure and the apparatus 300 illustrated in Figure 3 and accordingly, elements common to the three apparatus share common reference numerals. For brevity, the description of Figure 1 and Figure 3 are not repeated with respect to Figure 5. The apparatus 500 is more like the apparatus 300 illustrated in Figure 3. The primary difference, illustrated in Figure 5, is that end of the inlet capillary tube 105 has been replaced with a flared capillary tube end 505, recessed within the housing 103, thereby defining an inlet 507 in place of the original inlet 107 (shown in Figures 1-4). The inlet 507 is large enough to accommodate the male end of a syringe (not shown). The apparatus 500 is well suited for scenarios where blood from a syringe is available. Because of the relatively large inlet 507, the apparatus 500 is also well suited for squeezing blood directly into the apparatus 500 by placing the flared end 505 over the pin prick.
[0044 Referring to Figure 6, shown is a top view of an apparatus 600 suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood according to a sixth embodiment of the invention.
The apparatus 600 illustrated in Figure 6 is similar to the apparatus 100 illustrated in Figure 1A, and accordingly, elements common to both share common reference numerals. For brevity, the description of Figure 1A is not repeated with respect to Figure 6. The primary differences, illustrated in Figure 6, are: i) the filtration flow path does not include a blood spectroscopic flow path as shown in Figure 1A; ii) a blood biosensor flow path is provided for biosensor measurement of the blood instead of spectroscopic measurement of the blood (Biosensor measurement was illustrated in Figure 4, but for plasma and not for blood. Those skilled in the art will appreciate that one or more biosensors may be included in an apparatus according to an embodiment of the invention, and that only two have been illustrated in Figure 6 as a non-limiting example.); and iii) the end of the inlet capillary tube has been replaced with a flared tube end 605, thereby defining an inlet 607 in place of the original inlet 107 (shown in Figures 1-4). The inlet 607 is large enough to accommodate the male end of a syringe (not shown). The apparatus 600 is well suited for scenarios where blood from a syringe is available. Because of the relatively large inlet 607, the apparatus 600 is also well suited for squeezing blood directly into the apparatus 600 by placing the flared end 605 over the pin prick. The blood entering the inlet 607 is split into the blood biosensor flow path, and the filtration flow path. The flow path from the inlet 607 to the outlet vent 123a defines the filtration flow path, and includes a filtration chamber transition tube 309a. The filtration chamber transition tube 309a fluidly connects the flared inlet tube 105 with the filtration chamber 117.
(0045] With further specific reference to Figure 6, the optional barcode pattern 677 may be marked on the apparatus to provide a means of identifying a particular apparatus 100. Additionally andlor alternatively, the barcode pattern 677 may also, without limitation, carry information relating to at least one of calibration information for the biosensors 157a, 157b, the production batch number of the biosensors 157a, 157b and/or the entire apparatus 100. Those skilled in the art will appreciate that the biosensors 157a and 157b in one apparatus 100 from a respective production batch can be calibrated, and the calibration algorithm developed can be stored in the diagnostic measurement instrument and linked to the barcode pattern 677, which could be marked on each apparatus 100 from the respective production batch. Moreover, those skilled in the art will also appreciate that by linking the calibration algorithm to a barcode pattern 677, there is no need to calibrate the biosensors 157a and 157b in each apparatus 100.
(0046] Referring to Figure 7, shown is a top view of an apparatus 700 suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood according to a seventh embodiment of the invention.
The apparatus 700 illustrated in Figure 7 is similar to the apparatus 100 illustrated in Figure 1A and the apparatus 600 illustrated in Figure 6, and accordingly, elements common to the three apparatus share common reference numerals. For brevity, the description of Figure 1A and Figure 6 are not repeated with respect to Figure 7. Apparatus 700, illustrated in Figure 7, is like a combination of apparatus 100 illustrated in Figure 1A, and apparatus 600 illustrated in Figure 6.
j0047] With respect to spectroscopic measurements, the examples shown describe an apparatus that operates in transmission mode. Those skilled in the art will appreciate that the spectroscopic apparatus can also operate in reflectance mode by placing a reflecting member on one side of the optical chamber 111 a/11 b, such that the EMR transmitted through the sample would be reflected off the reflecting member, and the reflected EMR would enter the sample for the second time. In a diagnostic measurement instrument operating in the reflectance mode, both the EMR source and the photodetector would be on the same side of the optical chamber 111 a/11 b.
Moreover, those skilled in the art will also appreciate that instead of using a reflecting member in the diagnostic measurement instrument, one side of the wall-portions (125a or 125b) of the blood optical chamber 111 a and/or one side of the wall-portions (126a or 126b) of the plasma optical chamber 111 b could be coated with a reflecting material.
[0048] Moreover, with respect to spectroscopic measurements, it should be understood that the addition of reagents, for example without limitations, anticoagulants within any portion of the internal volume of the housing 103, is considered to be within the scope of the present invention.
[0049] While the above description provides example embodiments, it will be appreciated that the present invention is susceptible to modification and change without departing from the fair meaning and scope of the accompanying claims. Accordingly, what has been described is merely illustrative of the application of aspects of embodiments of the invention.
Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
[0028 The apparatus may also include a capillary break between the visible III lines, in the form of a bulge or increasing tube diameter, which is useful for stopping blood flow into the apparatus, particularly when the embodiment relies on capillary action as described by the inventor in US Pat.
Application (number not assigned as yet) entitled, "Blood Collection and Measurement Apparatus", filed April 12, 2005.
[0029] In accordance with an embodiment of the invention, a very specific example of an apparatus suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood is shown in Figures 1A, 1 B, 1 C, 1 D and 1 E. Specifically, Figure 1A is a schematic drawing illustrating the top view of an apparatus 100, Figure 1 B is a cross-sectional view through the apparatus 100 along line B-B in Figure 1A, Figure 1C is a cross-sectional view through the apparatus 100 along line C-C in Figure 1A, Figure 1 D is a cross-sectional view through the apparatus 100 along line D-D in Figure 1A, and Figure 1 E is a cross-sectional view through the apparatus 100 along line E-E in Figure 1A. The apparatus 100 includes a housing 103 defining an internal volume between an inlet 107 and an outlet vent 123. As shown, the housing 103 has a side dimension s, a width dimension w, and a depth dimension d. The internal volume includes several distinct portions including a blood inlet transition chamber 109a, a blood optical chamber 111a, a blood overflow chamber 113a, a filtration chamber 117, a filtration outflow chamber (or outflow tube) 121 a, a plasma collection chamber 119, a plasma inlet transition chamber 109b, a plasma optical chamber 111 b, and a plasma overflow chamber 113b. In this particular embodiment a short protruding length of capillary tube 105 defines the inlet 107 for the apparatus 100, and extends into fluid connection with the blood inlet transition chamber 109a from the inlet 107. The fluid path from the inlet 107 to the blood overflow chamber 113a defines the blood spectroscopic flow path. The overflow chamber 113a is fluidly connected between the optical chamber 111a and the filtration chamber 117. The flow path from the blood overflow chamber 113a to the outlet vent 123/123a defines the filtration flow path (In Figures 3-6, where there are no blood spectroscopic flow paths, the blood spectroscopic flow path is replaced by a filtration transition chamber 309 {309a in Figure 6}, and the filtration flow paths extend from the inlet 107 to the outlet vents 123, with the chambers fluidly connected in series). The filtration chamber 117 serves as a junction from which plasma flows, and in this specific embodiment, the hollow fiber runs approximately perpendicular to the filtration flow path where the filtration flow path crosses the hollow fiber. The flow path form the plasma collection chamber 119 to the outlet vent 123 (shown as 123b in Figure 3) defines the plasma spectroscopic flow path. The plasma spectroscopic path includes the plasma inlet transition chamber 109b, the plasma optical chamber 111 b, the plasma overflow chamber 113b, and the plasma outlet chamber 121 b, fluidly connected in series. The plasma collection chamber 119 is fluidly connected to the plasma inlet transition chamber 109b. Those skilled in the art will appreciate that depending on the relative shapes and sizes of the plasma collection chamber 119 and the plasma optical chamber 111 b, the plasma inlet transition chamber 109b could become optional.
[0030] With specific reference to Figure 1A and Figure 1 B, the blood inlet transition chamber 109a also provides a barrier between room air and blood in the blood optical chamber 111 a. The blood inlet transition path 109a is tapered towards the blood optical chamber 111 a so as to have a diminishing depth and an increasing width relative to the diameter of a tube 105 in the direction of the optical chamber 111 a from the tube 105. Moreover in use, blood remaining in the blood inlet transition path 109a serves as a barrier between room air and the blood in the blood optical chamber 111 a through which air cannot easily diffuse toward the blood in the optical chamber 111 a. Similarly blood in the blood overflow chamber 113a serves as a barrier between room air and the blood optical chamber 111 a.
[0031] With further specific reference to Figure 1 B, the interior of the blood optical chamber 111a is much thinner in depth than the average diameter of the interior of the tube 105 and the broad end of the blood inlet transition cavity 109a. In some embodiments, the depth of the optical chamber 111 a, being the internal distance between the respective interior faces of the top and bottom wall-portions 125a and 125b, ranges approximately from about 0.02 mm to about 0.2 mm, whereas the average inside diameter of the tube 105 ranges approximately from about 0.5 mm to about 2 mm, in the specific embodiment. Those skilled in the art will appreciate that the limitations regarding diameters of channels that rely on capillary action for fluid movement, are not as stringent when the fluid is forced into the apparatus. Light scattering caused by red blood cells is more prevalent when the depth of the blood optical chamber 111 a is more than 0.1 mm, and so a depth of less than 0.1 mm is preferred. If the depth is less than 0.02 mm the natural viscosity of blood may reduce how effectively blood can be spread evenly through the blood optical chamber 111 a. Specifically, the diameter in the top view, shown in Figure 1A of the blood optical chamber 119a ranges approximately, without limitation, between about 1 mm to about 70 mm. Those skilled in the art will appreciate that the circular shape of the optical chamber 111a is not essential, and as another non-limiting example, an oval shape could be just as effective.
(0032] With further specific reference to Figure 1 B and also Figure 1 C, the top and bottom wall-portions 125a and 125b of the housing 103 are preferably transparent but may be translucent, and define the blood optical chamber 111 a. Further, in this preferred embodiment, the top and bottom wall-portions 125a and 125b are recessed with respect to the corresponding top and bottom surfaces 103a and 103b of the housing 103, in order to protect the exterior faces of the top and bottom wall-portions 125a and 125b from scratches, although those skilled in the art will appreciate that this is not essential. It should be understood that the cross-sectional areas shown are non-limiting examples, and those skilled in the art will appreciate that other cross-sectional areas could be used. Those skilled in the art will also appreciate that the internal walls of the blood optical chamber 111 a do not have to be exactly parallel because the calibration algorithms for blood measurements can be developed to accommodate variability in depth of the blood optical chamber 111 a.
(0033] With further specific reference to Figure 1A, the filtration chamber 117 is fluidly connected to a blood outlet chamber 121a, which terminates at vent 123. Optionally, the blood outlet chamber 121 a includes first and second visible fill lines 125a and 125b. Between the visible fill lines 125a and 125b, the blood outlet chamber 121 a, bulge, creating volumes large enough to facilitate filling between the fill lines. In this particular embodiment, proper use requires that enough blood flows into the apparatus 100 to at least pass the first fill lines 125a. Overfilling past the second fill lines 125b will not compromise the blood sample within the blood optical chamber 111 a, but excess filling may cause blood to flow through the vent 123 onto the top surface 103a of the housing 103, thereby contaminating the housing 103 with potentially biologically hazardous material. Those skilled in the art will appreciate that the fill lines provide a guide to the user, and they should be in plain view when the apparatus is fully inserted into the slot of the diagnostic measurement instrument, particularly if the blood is injected into the apparatus 100 after the apparatus 100 is fully inserted into the slot of the diagnostic measurement instrument, as will be appreciated when other embodiments of the invention are described. Those skilled in the art will also appreciate that the fill lines could be on the surface 123a and/or 123b, depending on the orientation or the apparatus 100 in the slot of the diagnostic measurement instrument. The bulge between the visible fill lines 125a and 125b may also serve as a capillary break, whereby the blood flow slows down and may cease to flow after crossing the visible fill line 125a, when the blood flow relies on capillary action.
[0034] With further specific reference to Figure 1A, the porous membrane 115 is in the form of a hollow fiber filter (or hollow fiber membrane) with an internal chamber, which functions as the plasma collection chamber 119, which extends into fluid connection with the plasma inlet transition chamber 109b, provided to serve as a transition between the filtration chamber 117 and the plasma optical chamber 111 b. The hollow fiber is defined by the membrane 115 and the ends 114 and 116. The hollow fiber ends 114 and 116 are sealed against the walls of the filtration chamber 117, and a hole in the wall of the filtration chamber 117 at the end 116 of the hollow fiber serves to extend fluid connection with the plasma collection chamber 119 and the plasma inlet transition chamber 109b. The membrane 115 is porous and in some embodiments, the distribution of pore diameters ranges approximately from about 0.1 micrometer to about 10 micrometers.
Those skilled in the art will appreciate that the membrane 115 could be a flat piece of membrane that serves as a barrier between blood and plasma filtered through the barrier from the blood, arranged to encourage blood flow along the filtration flow path. Moreover, with respect to a flat piece of membrane that replaces membrane 115, one side of the membrane will be in contact with blood, and the other side of the membrane will be in contact with plasma.
Those skilled in the art will also appreciate that blood flow decreases the viscosity of the blood and therefore enhances separation (or filtration, or extraction) of plasma from blood; separation of plasma from blood also increases with increasing pore size, decreasing thickness of the membrane 115, and increasing membrane surface area. Although the filtration chamber 117 is illustrated using a single hollow fiber filter, those skilled in the art will appreciate that the membrane surface area can be increased by using more than one hollow fiber filter, assembled as a bundle of parallel hollow fibers.
In some embodiments, the internal diameter of the hollow fiber filter ranges approximately from about 0.1 mm to about 1 mm.
(0035] With further specific reference to Figure 1A, the plasma transition chamber 109b, the plasma optical chamber 111 b and the plasma overflow chamber 113b are arranged in the plasma spectroscopic flow path to function like the blood spectroscopic flow path, except that plasma is measured instead of whole blood. Those skilled in the art will appreciate that because plasma scatters less EMR than whole blood, the depth of the plasma optical chamber 111 b could be larger than the depth of the blood optical chamber 111 a, and also the diameter of the plasma optical chamber 111 b could be smaller than the diameter of the optical chamber 111a. The plasma overflow chamber 113b serves as a barrier between room air and plasma in the plasma optical chamber 111 b during operation. The plasma overflow chamber 113b is fluidly connected to the outlet chamber 121 b, which is fluidly connected to the vent 123. The flow path from the plasma collection chamber 119 to the vent 123 defines the plasma spectroscopic flow path. In this particular embodiment, the filtration flow path and the plasma spectroscopic flow path terminate at the same vent 123, but other embodiments show separate outlet vents for the respective flow paths.
(0036] Those skilled in the art will appreciate that the spectroscopic measurement instrument could contain one or more sources of EMR, and one or more photodetectors (or array of detectors), to illuminate the plasma and blood independently. Those skilled in the art will also appreciate that a single source of EMR can be used with a bifurcated optical fiber and a shutter that could facilitate sequential illumination of the plasma and the blood;
similarly a single photodetector (or array of detectors) can be used with a bifurcated optical fiber. Another aspect of the present invention is to optionally make the distance from the center of the blood optical chamber to the adjacent edge of the housing 103 (shown as A in Figure 1 E) and the distance from the center of the plasma optical chamber to the adjacent edge of the housing 103 (shown as B in Figure 1 E) approximately equal, and to optionally aligning the two centers approximately parallel with the axis of the width dimension. By making distance A equal to distance B, and aligning the centers, the spectroscopic measuring instrument with a single EMR path can be used to illuminate the blood first and then illuminating the plasma by rotating the apparatus 103 by 180° along the axis of the side dimension s, or vice versa.
[0037] In this particular embodiment, the blood overflow chamber 113a has a complementary design to that of the inlet transition cavity 109a. That is, the blood overflow chamber 113a is flared away from the blood optical chamber 119a so as to have an increasing depth and a decreasing width in the direction away from the blood optical chamber 111a. In this particular embodiment, the volume of the blood overflow chamber 113a is larger than that of the blood optical chamber 119a, such that during operation, filling the blood overflow chamber 113a is helpful in ensuring that blood in the optical chamber is substantially free from contamination and effectively isolated from room air that may enter via the outlet vent 123.
[0038] Once the blood is transferred into the apparatus, the blood and extracted plasma are ready for measurement by inserting the apparatus into a slot in a diagnostic measurement instrument (not shown). The end of the apparatus opposite from the end with the inlet 107 is inserted first, and the inlet 107 remains outside the slot of the diagnostic measurement instrument.
Those skilled in the art will appreciate that the outlet vent can be located in several positions in the housing 103, but it is preferably located in the housing 103, such that it will reside outside the slot of the diagnostic measuring instrument during measurement, thereby minimizing the risk of contaminating the slot of the diagnostic measurement instrument with plasma and/or blood.
[0039] Referring to Figure 2A, shown is a top view of an apparatus 200 suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood according to a second embodiment of the invention.
The apparatus 200 illustrated in Figure 2 is similar to the apparatus 100 illustrated in Figure 1, and accordingly, elements common to both share common reference numerals. For brevity, the description of Figure 1A is not repeated with respect to Figure 2A. The primary difference, illustrated in Figure 2A, is in the filtration chamber 117: the blood flows inside the hollow fiber filter, shown as 219, and the plasma collection chamber is defined by the walls of the filtration chamber 117 and the membrane 115. A second difference is an optional tube 227 that provides fluid connection between the filtration chamber 117 and the plasma transition chamber 109b. Cross section views along the lines B-B and C-C in Figure 2A are shown in Figure 2B and Figure 2C respectively.
[0040] Referring to Figure 3, shown is a top view of an apparatus 300 suitable for spectroscopic measurement of plasma extracted from a blood sample according to a third embodiment of the invention. The apparatus 300 illustrated in Figure 3 is similar to the apparatus 100 illustrated in Figure 1A, and accordingly, elements common to both share common reference numerals. For brevity, the description of Figure 1A is not repeated with respect to Figure 3. The primary difference, illustrated in Figure 3, is that the filtration fluid path does not include a blood optical chamber, which is replaced with a tube 309, whereby in some embodiments, only plasma measurement is made. Also, some embodiments may be provided with a cap 135.
(0041] The cap 135 is provided to close the inlet 107 before and after the apparatus is used. The cap 135 is optionally provided with a plunger 137, a tether 133 and a ring connector 131. The ring connector 131 is sized to fit securely around the protruding end portion of the capillary tube 105. The cap 135 is connected to the ring connector 131 by the tether 133, thereby connecting the cap 135 to the apparatus 300 even when the cap 135 is not placed on the protruding end portion of the capillary tube 105. One function of the cap 135 is to prevent contamination of the user and the diagnostic measurement instrument with blood. The plunger 137 in the cap 135 is useful for exerting positive pressure on the blood sample, thereby encouraging blood flow within the apparatus, limited by the volume of the plunger 137.
[0042] Referring to Figure 4, shown is a top view of an apparatus 400 suitable for biosensor measurement of plasma extracted from a blood sample according to the fourth embodiment of the invention. The apparatus 400 illustrated in Figure 4 is similar to the apparatus 100 illustrated in Figure 1A, and the apparatus 300 illustrated in Figure 3 and accordingly, elements common to the three apparatus share common reference numerals. For brevity, the description of Figure 1 and Figure 3 are not repeated with respect to Figure 4. The apparatus 400 is more like the apparatus 300 illustrated in Figure 3, where the plasma measurement is made by biosensors instead of spectroscopy. The biosensor chamber 211 b, the biosensor overflow chamber 213b, the biosensor outflow chamber 221 b, and the outlet vent 123d define the plasma biosensor flow path, and is comparable to the plasma spectroscopic flow path shown in Figure 3. The apparatus 400 is provided with biosensors 157a, 157b. The biosensors 157a, 157b are coupled to respective electrical contacts 159a, 159b that provide connectivity between the apparatus 400 and a diagnostic measurement instrument suitable for processing the outputs of the biosensors 157a and 157b. Such an instrument (not shown) may include a programmed general-purpose computer and/or microprocessor in combination with a suitable combination of hardware, software and firmware. Those skilled in the art will appreciate that the biosensors can be pre-calibrated and the calibration algorithms installed in the diagnostic instrument. Moreover, those skilled in the art will also appreciate that one or more biosensors may be included in an apparatus according to an embodiment of the invention, and that only two have been illustrated in Figure 4 as a non-limiting example. Additionally, the protruding open end of the inlet capillary tube 105 includes threads for connection with a correspondingly threaded cap (not shown) as an alternative to the tethered cap 135 with an optional plunger like the plunger 137 shown in Figure 3.
[0043] Referring to Figure 5, shown is a top view of an apparatus 500 suitable for spectroscopic measurement of plasma extracted from a blood sample according to the fifth embodiment of the invention. The apparatus 500 illustrated in Figure 5 is similar to the apparatus 100 illustrated in Figure and the apparatus 300 illustrated in Figure 3 and accordingly, elements common to the three apparatus share common reference numerals. For brevity, the description of Figure 1 and Figure 3 are not repeated with respect to Figure 5. The apparatus 500 is more like the apparatus 300 illustrated in Figure 3. The primary difference, illustrated in Figure 5, is that end of the inlet capillary tube 105 has been replaced with a flared capillary tube end 505, recessed within the housing 103, thereby defining an inlet 507 in place of the original inlet 107 (shown in Figures 1-4). The inlet 507 is large enough to accommodate the male end of a syringe (not shown). The apparatus 500 is well suited for scenarios where blood from a syringe is available. Because of the relatively large inlet 507, the apparatus 500 is also well suited for squeezing blood directly into the apparatus 500 by placing the flared end 505 over the pin prick.
[0044 Referring to Figure 6, shown is a top view of an apparatus 600 suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood according to a sixth embodiment of the invention.
The apparatus 600 illustrated in Figure 6 is similar to the apparatus 100 illustrated in Figure 1A, and accordingly, elements common to both share common reference numerals. For brevity, the description of Figure 1A is not repeated with respect to Figure 6. The primary differences, illustrated in Figure 6, are: i) the filtration flow path does not include a blood spectroscopic flow path as shown in Figure 1A; ii) a blood biosensor flow path is provided for biosensor measurement of the blood instead of spectroscopic measurement of the blood (Biosensor measurement was illustrated in Figure 4, but for plasma and not for blood. Those skilled in the art will appreciate that one or more biosensors may be included in an apparatus according to an embodiment of the invention, and that only two have been illustrated in Figure 6 as a non-limiting example.); and iii) the end of the inlet capillary tube has been replaced with a flared tube end 605, thereby defining an inlet 607 in place of the original inlet 107 (shown in Figures 1-4). The inlet 607 is large enough to accommodate the male end of a syringe (not shown). The apparatus 600 is well suited for scenarios where blood from a syringe is available. Because of the relatively large inlet 607, the apparatus 600 is also well suited for squeezing blood directly into the apparatus 600 by placing the flared end 605 over the pin prick. The blood entering the inlet 607 is split into the blood biosensor flow path, and the filtration flow path. The flow path from the inlet 607 to the outlet vent 123a defines the filtration flow path, and includes a filtration chamber transition tube 309a. The filtration chamber transition tube 309a fluidly connects the flared inlet tube 105 with the filtration chamber 117.
(0045] With further specific reference to Figure 6, the optional barcode pattern 677 may be marked on the apparatus to provide a means of identifying a particular apparatus 100. Additionally andlor alternatively, the barcode pattern 677 may also, without limitation, carry information relating to at least one of calibration information for the biosensors 157a, 157b, the production batch number of the biosensors 157a, 157b and/or the entire apparatus 100. Those skilled in the art will appreciate that the biosensors 157a and 157b in one apparatus 100 from a respective production batch can be calibrated, and the calibration algorithm developed can be stored in the diagnostic measurement instrument and linked to the barcode pattern 677, which could be marked on each apparatus 100 from the respective production batch. Moreover, those skilled in the art will also appreciate that by linking the calibration algorithm to a barcode pattern 677, there is no need to calibrate the biosensors 157a and 157b in each apparatus 100.
(0046] Referring to Figure 7, shown is a top view of an apparatus 700 suitable for spectroscopic measurement of a blood sample and plasma extracted from the blood according to a seventh embodiment of the invention.
The apparatus 700 illustrated in Figure 7 is similar to the apparatus 100 illustrated in Figure 1A and the apparatus 600 illustrated in Figure 6, and accordingly, elements common to the three apparatus share common reference numerals. For brevity, the description of Figure 1A and Figure 6 are not repeated with respect to Figure 7. Apparatus 700, illustrated in Figure 7, is like a combination of apparatus 100 illustrated in Figure 1A, and apparatus 600 illustrated in Figure 6.
j0047] With respect to spectroscopic measurements, the examples shown describe an apparatus that operates in transmission mode. Those skilled in the art will appreciate that the spectroscopic apparatus can also operate in reflectance mode by placing a reflecting member on one side of the optical chamber 111 a/11 b, such that the EMR transmitted through the sample would be reflected off the reflecting member, and the reflected EMR would enter the sample for the second time. In a diagnostic measurement instrument operating in the reflectance mode, both the EMR source and the photodetector would be on the same side of the optical chamber 111 a/11 b.
Moreover, those skilled in the art will also appreciate that instead of using a reflecting member in the diagnostic measurement instrument, one side of the wall-portions (125a or 125b) of the blood optical chamber 111 a and/or one side of the wall-portions (126a or 126b) of the plasma optical chamber 111 b could be coated with a reflecting material.
[0048] Moreover, with respect to spectroscopic measurements, it should be understood that the addition of reagents, for example without limitations, anticoagulants within any portion of the internal volume of the housing 103, is considered to be within the scope of the present invention.
[0049] While the above description provides example embodiments, it will be appreciated that the present invention is susceptible to modification and change without departing from the fair meaning and scope of the accompanying claims. Accordingly, what has been described is merely illustrative of the application of aspects of embodiments of the invention.
Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Claims (27)
1. ~A whole blood and plasma measurement apparatus comprising:
a housing;
an inlet within the housing for receiving the whole blood to be measured;
a whole blood measurement chamber within the housing for measuring the whole blood;
a filtration chamber within the housing for extracting the plasma from the whole blood;
a plasma measurement chamber within the housing for measuring the plasma; and a vent for facilitating airflow out of the filtration chamber and the plasma measurement chamber when the inlet receives the whole blood.
a housing;
an inlet within the housing for receiving the whole blood to be measured;
a whole blood measurement chamber within the housing for measuring the whole blood;
a filtration chamber within the housing for extracting the plasma from the whole blood;
a plasma measurement chamber within the housing for measuring the plasma; and a vent for facilitating airflow out of the filtration chamber and the plasma measurement chamber when the inlet receives the whole blood.
2. ~A whole blood and plasma measurement apparatus according to claim 1, wherein the whole blood measurement chamber comprises an optical chamber having at least one optical window for performing spectrometry on the whole blood.
3. ~A whole blood and plasma measurement apparatus according to claim 1, wherein the whole blood measurement chamber comprises a biosensor chamber having at least one biosensor for performing tests on the on the whole blood.
4. ~A whole blood and plasma measurement apparatus according to claim 1, wherein the plasma measurement chamber comprises an optical chamber having at least one optical window for performing spectrometry on the plasma.
5. ~A whole blood and plasma measurement apparatus according to claim 1, wherein the plasma measurement chamber comprises a biosensor chamber having at least one biosensor for performing tests on the plasma.
6. ~A whole blood and plasma measurement apparatus according to claim 2 further comprising a reflective coating on a wall-portion of the optical chamber.
7. ~A whole blood and plasma measurement apparatus according to claim 4 further comprising a reflective coating on a wall-portion of the optical chamber.
8. ~A whole blood and plasma measurement apparatus as defined in claim 1, wherein the inlet is dimensioned to encompass a male end of a syringe to receive the whole blood therefrom.
9. ~A whole blood and plasma measurement apparatus as defined in claim 1, wherein the inlet is dimensioned to resemble the end of a capillary tube to receive the whole blood therefrom.
10. ~A whole blood and plasma measurement apparatus according to claim 1 comprising at least one visible fill line for indicating a total amount of the blood received into the apparatus.
11. ~A whole blood and plasma measurement apparatus according to claim 1 further comprising a barcode containing at least information regarding calibration of a measurement system.
12. ~A whole blood and plasma measurement apparatus according to claim 3, wherein the biosensor comprises a transducer for converting at least one property of the fluid into an electrical signal.
13. ~A whole blood and plasma measurement apparatus according to claim 12 wherein the transducer comprises at least one active surface for contacting the fluid.
14. ~A whole blood and plasma measurement apparatus according to claim 13 wherein the at least one active surface is one of a chemical sensitive surface or an ionic sensitive surface.
15. ~A whole blood and plasma measurement apparatus according to claim 3, wherein the at least one biosensor comprises, at least one of a field-effect transistor, an ion-selective membrane, a membrane-bound enzyme, a membrane-bound antigen, or a membrane-bound antibody.
16. ~A whole blood and plasma measurement apparatus according to claim 1, wherein the filtration chamber comprises one or more than one hollow fiber membrane.
17. ~A whole blood and plasma measurement apparatus according to claim 1, wherein the filtration chamber comprises a layer of membrane,~
wherein the whole blood flows along one side of the membrane and the plasma is extracted on the other side of the membrane into the plasma measurement chamber.
wherein the whole blood flows along one side of the membrane and the plasma is extracted on the other side of the membrane into the plasma measurement chamber.
18. ~A whole blood and plasma measurement apparatus according to claim 16, wherein the more than one hollow fiber membrane are arranged in a bundle of hollow fiber membranes.
19. ~A whole blood and plasma measurement apparatus according to claim 16, wherein the one or more than one hollow fiber membrane runs approximately perpendicular to the whole blood flow path.
20. ~A whole blood and plasma measurement apparatus according to claim 1 further comprising a cap for covering an opening into the inlet.
21. ~A whole blood and plasma measurement apparatus according to claim 20, wherein the cap contains a plunger for exerting pressure on the whole blood within the apparatus.
22. ~A whole blood and plasma measurement apparatus comprising:
a housing;
an inlet within the housing for receiving the whole blood to be measured;
a filtration chamber comprising one or more than one layer of membrane within the housing for extracting the plasma from the whole blood;
a plasma measurement chamber within the housing for measuring the plasma; and a vent for facilitating airflow out of the filtration chamber and the plasma measurement chamber when the inlet receives the whole blood.
a housing;
an inlet within the housing for receiving the whole blood to be measured;
a filtration chamber comprising one or more than one layer of membrane within the housing for extracting the plasma from the whole blood;
a plasma measurement chamber within the housing for measuring the plasma; and a vent for facilitating airflow out of the filtration chamber and the plasma measurement chamber when the inlet receives the whole blood.
23. ~A whole blood and plasma measurement apparatus according to claim 22, wherein the one or more than one layer of membrane is in the form of one or more than one hollow fiber.
24. ~A whole blood and plasma measurement apparatus according to claim 22, wherein the one or more than one hollow fiber membrane runs approximately perpendicular to the whole blood flow path.
25. ~A whole blood and plasma measurement apparatus according to claim 19 comprising at least one visible fill line for indicating a total amount of the blood received into the apparatus.
26. ~A whole blood and plasma measurement apparatus according to claim 22, wherein the plasma measurement chamber comprises an optical chamber having at least one optical window for performing spectrometry on~
the plasma.
the plasma.
27. ~A whole blood and plasma measurement apparatus according to~
claim 22, wherein the plasma measurement chamber comprises a biosensor chamber having at least one biosensor for performing tests on the plasma.
claim 22, wherein the plasma measurement chamber comprises a biosensor chamber having at least one biosensor for performing tests on the plasma.
Priority Applications (5)
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US11/415,284 US8206650B2 (en) | 2005-04-12 | 2006-05-02 | Joint-diagnostic spectroscopic and biosensor meter |
US11/432,616 US7816124B2 (en) | 2005-05-13 | 2006-05-12 | Diagnostic whole blood and plasma apparatus |
US11/835,631 US7807450B2 (en) | 2005-05-13 | 2007-08-08 | Plasma extraction apparatus |
US12/897,581 US8101404B2 (en) | 2005-05-13 | 2010-10-04 | Plasma extraction apparatus |
Applications Claiming Priority (1)
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CA002507323A CA2507323A1 (en) | 2005-05-13 | 2005-05-13 | Diagnostic whole blood and plasma apparatus |
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CA2507323A1 true CA2507323A1 (en) | 2006-11-13 |
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2005
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-
2006
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-
2007
- 2007-08-08 US US11/835,631 patent/US7807450B2/en not_active Expired - Fee Related
-
2010
- 2010-10-04 US US12/897,581 patent/US8101404B2/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US8206650B2 (en) | 2005-04-12 | 2012-06-26 | Chromedx Inc. | Joint-diagnostic spectroscopic and biosensor meter |
US8101404B2 (en) | 2005-05-13 | 2012-01-24 | Chromedx Inc. | Plasma extraction apparatus |
Also Published As
Publication number | Publication date |
---|---|
US7816124B2 (en) | 2010-10-19 |
US20060254962A1 (en) | 2006-11-16 |
US20070284298A1 (en) | 2007-12-13 |
US8101404B2 (en) | 2012-01-24 |
US7807450B2 (en) | 2010-10-05 |
US20110079547A1 (en) | 2011-04-07 |
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