Patent Application
20220266242
The invention relates to a point-of-care testing (POCT) system comprising an analyzer and a measurement cartridge having one or more detection chambers. The detection chamber of the measurement cartridge may comprise one or more electrochemical sensors and/or one or more optical chambers. The system may also comprise a calibration cartridge for calibrating at least one of the one or more electrochemical sensors.
In the clinical laboratory, a tissue substance from the body that is undergoing analysis is usually referred to as an analyte or a test. “Point-of-care Testing” (POCT) is defined as medical diagnostic testing performed in close proximity to where the patient is receiving care. Point-of-care (POC) is not restricted to laboratory tests but are more common with respect to laboratory tests. POCT is usually performed by non-laboratory personnel and the results are used for clinical decision making. An example of a non-laboratory POC device is a POC ultrasound (POCUS) device.
For the sake of convenience and rapid turnaround time, the tissue or sample of choice for POCT is whole blood (also referred to as blood). Due to the complexity of blood, certain tests can only be performed on serum or plasma. Regardless whether the sample is serum, plasma or whole blood, the quantities of analytes measured are usually measured in the plasma component of whole blood and are usually reported as a mass or molar quantity per unit volume of the whole blood used for analysis. Sometimes it is preferred to lyse the red blood cells before measurement, whereby the contents of the red blood cells become mixed with the plasma. Because the actual volume of plasma present in the blood depends on the hematocrit, some systems attempt to correct the measured values to account for hematocrit. The hematocrit is the proportion, by volume, of the blood that consists of red blood cells.
When blood is allowed to clot and the sample is centrifuged, the yellow liquid that sits on top of the blood clot is called serum. If the blood is collected in a tube containing an anticoagulant, for example heparin, and the blood centrifuged, the cells and cell fragments, referred to as formed elements, are separated from a yellow liquid called plasma, which sits on top of the formed elements. The plasma is usually about 90 percent water, in which the formed elements are usually suspended, and it transports nutrients as well as wastes throughout the body. Various analytes are dissolved in the plasma for example, glucose, electrolytes, blood gases, drugs, hormones, lipids, enzymes (e.g., ALT, which may be used for assessing liver function), and metabolites (e.g., creatinine which may be used for assessing kidney function, and lactate which may be used for detecting sepsis).
POCT involves a range of procedures of varying complexity that may include manual procedures and automated procedures conducted by portable analyzers. POCT is most efficient when the sample of interest can be applied to or loaded onto a measurement cartridge or a test cartridge at a cartridge opening (may also be referred to as a sample inlet of the cartridge), capped, and the analytical or testing steps performed automatically after the capped cartridge is inserted into a slot or receptor of an associated analyzer. Some POCT require one or more reagent that reacts with the blood sample, providing altered blood. The result of reaction between a liquid sample and one or more reagent may depend on the quantity of the one or more reagent and the volume of liquid sample. The reagent is preferably in a dry form, in order to avoid dilution of the sample.
Some blood tests, for example coagulation assays and immunoassays, require a fixed volume of sample or metered volume of sample to ensure that when mixed with a reagent, the ratio of the volume of sample to the volume (or mass) of the reagent is held constant. The term metered blood means that the blood is supplied in a measured or regulated amount. In other cases, for example the measurement of blood gases and electrolytes, a metered volume of sample is not required. In the case of electrolytes, the volume of the sample is usually not an issue if the electrolyte concentration is estimated by measuring electrical activity in the sample. The term blood gases may refer to pH, pCO2 [partial pressure of carbon dioxide] and pO2 [partial pressure of oxygen] and the term electrolytes may refer to sodium, potassium, chloride and bicarbonate ions. Other ions like calcium ions may also be referred to as electrolytes. Electrical activity is usually measured using electrochemical sensors, also referred to as biosensors. Blood gases and electrolytes are mostly measured by electrochemical sensors, but optical measurements are also possible.
There are other tests that do not require a fixed volume of sample, and cannot be measured using biosensors, for example CO-oximetry. CO-oximetry is a spectroscopic or optical technique that is used to measure the amount of different Hemoglobin (Hb) species present in a blood sample, for example, Oxy-Hb, Deoxy-Hb, Met-Hb, Carboxy-Hb and Total-Hb, and their measurements are used to assess the oxygenation status of a patient. Met-Hb and Carboxy-Hb are non-functional hemoglobin and elevated levels can be life-threatening. Although electrolytes and CO-oximetry measurements do not usually require fixed volumes of blood, the distance the blood sample travels along microfluidic channels inside some cartridges may need to be controlled or metered.
Hemoglobin is an example of an analyte that is not present in the plasma unless hemolysis has occurred. Hemoglobin is usually present in red blood cells (RBCs), and the mass or molar concentration of hemoglobin may be measured in altered blood (may be simply hemolyzed blood) or unaltered blood. Hemolyzed blood may be produced using sound waves or chemicals. Some analyzers measure hematocrit by electrical conductivity and convert the hematocrit measurement to a total hemoglobin concentration, and some analyzers measure total hemoglobin concentration by spectroscopy, and convert the total hemoglobin concentration to a hematocrit value. Spectroscopic calibration algorithms can be developed to measure both hematocrit and total hemoglobin concentration.
Another analyte that resides inside red blood cells is folic acid (˜50% localized in red blood cells, the rest is stored mostly in the liver), and the measurement of RBC folate provides useful diagnostic information. Potassium is another analyte that resides in the RBCs, at about 20 times the concentration in plasma. However, measurement of RBC potassium provides no diagnostic value, whereas plasma potassium is a commonly ordered analyte for aiding in assessing acid-base-electrolyte balance.
Applying an unmetered sample volume to test strips is well known; some test strips contain absorbing sections that can accommodate a known volume of plasma, after the RBCs are retained in another section of the test strip near the blood application site. In some cases, the hematocrit affects the plasma flow in test strips, and therefore correction for hematocrit may improve accuracy of the analyte measurement. A common analyte that is measured using a test strip is blood glucose, and the test strips play a major role in managing diabetes.
POCT has improved patient care in several areas including the Emergency Department (ED) and Intensive Care Units (ICU) of hospitals, but the ED and ICU are usually very busy and may have space limitations for implementing more than one POCT analyzer. In addition to having accurate and reliable POCT in the ED, ICU, and for use by first responders, user friendliness is a major issue.
POCT analyzers are usually pre-calibrated, with calibration information installed in a barcoded label on the test strip or test cartridge. Examples of prior art are provided below in order to discuss some calibration issues. Spectroscopic calibration, for example calibration used for CO-oximetry, are more complex and are not discussed here. One or more calibrators (or calibration standards with known amounts of one or more analytes) may be used to calibrate a system. In the simplest cases of calibration, one or two calibrators are required. Commonly used calibration equations define a straight line, with signal response on the X-axis and concentration of analyte on the Y-axis. A straight line is usually defined by a slope and a Y-intercept (also referred to as an offset). Calibration adjustment for slope may be performed using two calibrators, and calibration adjustment for offset may be performed using one calibrator, referring to two-point and one-point calibration, respectively.
U.S. Pat. No. 5,096,669 to Lauks discloses a POCT cartridge for measuring blood gases and electrolytes in whole blood. The cartridge includes a preassembled calibration liquid (also referred to as calibration fluid) blister and a spike for rupturing the blister to release the calibration fluid, which is used to perform a one-point calibration of some of the electrochemical sensors in each cartridge. A screw and wedge mechanism are used to push the blister against the spike and force the released fluid into the electrochemical sensor chamber. The cartridge also comprises a hinged cap for covering the sample inlet after depositing sample in a sample well, and the cartridge does not include an optical chamber.
U.S. Pat. No. 7,094,330 to Lauks discloses another POCT cartridge for measuring blood gases and electrolytes in whole blood. This cartridge also includes a calibration fluid blister for performing a one-point calibration of some of the electrochemical sensors in each cartridge. The method of releasing the calibration fluid includes a plug for delaminating a section of the calibration fluid blister (a breakable seal 230). Also disclosed is a fill port 221 and a vent 222 for filling the calibration fluid blister. After filling the calibration fluid, a seal element 202 is laminated to seal off ports 221 and 222. A planar element comprising a plug 282 (for delaminating breakable seal 230) and a pin element 281 compresses the calibration fluid chamber 220 to release the calibration fluid. Blood must be loaded from a syringe, and the blood ejected from the syringe displaces the calibration fluid from the sensors. The syringe remains screwed to the cartridge inlet during measurement, therefore there is no requirement for a cap, and the cartridge does not include an optical chamber.
Pat. No. CA 2,978,737 to Samsoondar discloses another POCT cartridge for measuring blood gases, and electrolytes. Also disclosed in Pat. No. CA 2,978,737 is an optical chamber for performing spectroscopic measurement, for measuring CO-oximetry and bilirubin. Details of an example of the cartridges disclosed in Pat. No. CA 2,978,737 is provided in
A major limitation of POCT blood gas and electrolyte systems disclosed in U.S. Pat. Nos. 5,096,669 and 7,094,330 is that their measurement technique is based on electrochemical sensors and therefore cannot measure CO-oximetry or Bilirubin, which can only be measured by spectroscopy. Oxygen is carried in the blood in two forms: (1) Dissolved in plasma and RBC water, which accounts for only 1-2% of the total blood oxygen content; and (2) Reversibly bound to hemoglobin, which accounts for about 98% of the total blood oxygen content. Partial pressure of oxygen (pO2) is proportional to the quantity of oxygen dissolved in blood and is related to SO2 (hemoglobin saturated with oxygen) through a sigmoidal curve (SO2 plotted on the Y-axis and pO2 plotted on the X-axis) referred to as the Oxygen-Hemoglobin Dissociation Curve. Measurement cartridges disclosed in U.S. Pat. Nos. 5,096,669, and 7,094,330 estimate SO2 from measured pO2, and estimate Hemoglobin (Hb) from measured Hematocrit. The Hb could be underestimated, possibly leading to unnecessary blood transfusion. CO-oximetry is the gold standard for measuring SO2 because it actually measures % Oxy-Hb and % Deoxy-Hb, as well as % non-functional Hb like Met-Hb and Carboxy-Hb. A finger clip-on device referred to as a Pulse Oximeter is used in the ICU to measure SO2 by a technique referred to as Pulse Oximetry, which may be inaccurate in the presence of elevated non-functional Hb. Measurement of Carboxy-Hb is essential for detecting carbon monoxide poisoning and monitoring treatment. Carbon monoxide poisoning could occur during excessive smoke inhalation. Measurement of Met-Hb is essential for detecting and treating elevated levels of Met-Hb, which could occur after ingestion of certain chemicals, in patients with certain enzyme deficiency, and in babies treated with nitric oxide for respiratory distress.
The inclusion of a calibration liquid blister within the test cartridges disclosed in U.S. Pat. Nos. 5,096,669, 7,094,330 and CA Pat. No. 2,978,737 adds significant cost to the cartridges, precluding their use in underdeveloped countries, and the calibration liquid in the blister can only perform a one-point calibration, and assumes that the slope of the calibration equation did not change. There is a need for simpler and less expensive POCT blood gas and electrolyte cartridges, and a system capable of performing more than just a one-point calibration. There is also a need for POCT cartridges that can also provide CO-oximetry and bilirubin without adding any significant cost to the cartridges. Bilirubin is a waste product of hemoglobin degradation, and elevated levels cause a condition known as jaundice. More than half of healthy neonates develop neonatal jaundice within days of birth because the baby's liver has not developed sufficiently to eliminate bilirubin from the blood. Babies with neonatal jaundice can easily be treated successfully, but if left untreated, neonatal jaundice could cause permanent brain damage and deafness.
Laboratory blood gas analyzers have evolved over the years. Since the eighties, companies began to add CO-oximetry, and later Bilirubin, to their blood gas menu. Because of the clinical need for CO-oximetry, laboratory blood gas analyzers without CO-oximetry are now virtually obsolete, and there is a need for POCT blood gas analyzers with single-use measurement cartridges to evolve like laboratory blood gas analyzers.
The invention relates to a point-of-care testing (POCT) system. In various aspects, the invention relates to a system for measuring one or more properties of a blood sample, the system comprising a measurement cartridge for measuring the one or more properties of the blood sample, the measurement cartridge comprising: a measurement cartridge body having an upper surface and a lower surface, the upper surface defining a sample storage well for receiving the blood sample; a measurement electrochemical sensor chamber located within the measurement cartridge body, the measurement electrochemical sensor chamber comprising at least one first electrochemical sensor for generating measurement electrical signals in response to the one or more properties of the blood sample; and a blood flow conduit for establishing fluid communication between the sample storage well and the measurement electrochemical sensor chamber; a calibration cartridge comprising: a calibration cartridge body having an upper surface and a lower surface; at least one sealed blister within the calibration cartridge body containing calibration liquid comprising known amounts of the one or more properties; and a calibration electrochemical sensor chamber located within the calibration cartridge body, the calibration electrochemical sensor chamber comprising at least one second electrochemical sensor for generating calibration electrical signals in response to the calibration liquid, wherein the at least one first and second electrochemical sensors generate similar electrical signals in response to the same amount of the same one or more properties; and a calibration liquid conduit for establishing fluid communication between the at least one sealed blister and the calibration electrochemical sensor chamber; and an analyzer comprising: a receptor for separately receiving the calibration cartridge and the measurement cartridge; means for releasing calibration liquid from the at least one sealed blister containing the calibration liquid; means for moving the calibration liquid from the at least one sealed blister to the at least one second electrochemical sensor of the calibration cartridge; means for moving the blood from the sample storage well to the at least one first electrochemical sensor of the measurement cartridge; an electrical receiver for receiving the calibration electrical signals generated by the at least one second electrochemical sensor and for receiving the measurement electrical signals generated by the least one first electrochemical sensor; and a processor for developing a mathematical relation between the calibration electrical signals and the one or more properties in the calibration liquid, and applying the mathematical relation to the measurement electrical signals to determine the amount of the one or more properties in the blood sample.
In various embodiments, the at least one sealed blister consists of one sealed blister containing calibration liquid, for performing one-point calibration of the at least one first electrochemical sensor.
In various embodiments, the at least one sealed blister consists of two sealed blisters containing calibration liquid, for performing two-point calibration of the at least one first electrochemical sensor.
In various embodiments, the system comprises a plurality of calibration cartridges for performing multi-point calibration, and each of the plurality of calibration cartridges comprises a single calibration liquid blister in order to provide a plurality of calibration liquid blisters, and wherein each of the plurality of calibration liquid blisters comprises a different liquid composition.
In various embodiments, the one or more properties of the blood sample is pH and the at least one first electrochemical sensor and the at least one second electrochemical sensor are potentiometric electrochemical sensors.
In various embodiments, the measurement cartridge further comprises an optical chamber having at least one of an upper optical window and a lower optical window, the optical chamber in fluid communication with the blood flow conduit, the optical chamber for facilitating interrogation of a portion of the blood sample by electromagnetic radiation, for measuring one or more other properties of the blood.
In various embodiments, the means for moving the blood sample from the sample storage well to the at least one first electrochemical sensor of the measurement cartridge comprises at least one of: an air bladder disposed in the measurement cartridge body, the air bladder in fluid communication with the sample storage well; an analyzer pump attachable to a duct of the measurement cartridge body and in fluid communication with the sample storage well; a surface of the blood flow conduit sufficiently hydrophilic to promote blood flow by capillary action; a cap for covering the sample storage well; and at least one vent defined by a surface in the cartridge body or the cap in communication with the blood flow conduit.
In various embodiments, the measurement cartridge further comprises one or more reagents and means for mixing the blood sample and the one or more reagents.
In various embodiments, the sample storage well comprises a top portion for receiving the blood sample and a bottom portion for releasing at least a portion of the blood sample to the blood flow conduit, and wherein the measurement cartridge further comprises means for mitigating blood flow out of the bottom portion of the sample storage well when blood is received in the sample storage well through the top portion.
In various embodiments, the measurement cartridge further comprises a cap, the cap selected from a hinged cap, a pivotal cap, a sliding cap, and a screw cap for covering the sample storage well.
In various embodiments, the at least one first electrochemical sensor and the at least one second electrochemical sensor are of the same type manufactured in the same batch.
In another aspect, the invention relates to a calibration cartridge for calibrating at least one electrochemical sensor used for measuring one or more properties of a blood sample, the calibration cartridge comprising: a calibration cartridge body having an upper surface and a lower surface; at least one sealed blister located within the calibration body and containing a calibration liquid, wherein the calibration liquid comprises a known amount of the one or more properties of the blood sample; means for releasing the calibration liquid from the at least one sealed blister; a first calibration liquid conduit in fluid communication with each of the at least one sealed blister for receiving the calibration liquid; a second calibration liquid conduit for receiving calibration liquid from each first calibration liquid conduit, wherein the second calibration conduit is closed off from any other liquid influx; an electrochemical sensor chamber in fluid communication with the second calibration liquid conduit, the electrochemical sensor chamber comprising at least one electrochemical sensor and at least one electrical output, when installed with an associated analyzer, the at least one electrical output is configured to make contact with at least one electrical input of the associated analyzer, used to measure the one or more properties of the blood sample; and a vent in communication with the electrochemical sensor chamber, wherein the vent is for releasing pressure and allowing the calibration liquid to make contact with the at least one electrochemical sensor.
In various embodiments, the calibration cartridge body does not include a sample storage well.
In various embodiments, the calibration cartridge comprises one sealed blister containing calibration liquid, for performing one-point calibration of the at least one electrochemical sensor.
In various embodiments, the calibration cartridge comprises two sealed blisters containing different calibration liquids, two first calibration liquid conduits, and one second calibration liquid conduit, for performing two-point calibration of the at least one electrochemical sensor. In various embodiments, the calibration cartridge may comprise a directional valve disposed at the junction of the two first calibration liquid conduits and the second calibration liquid conduit.
In various embodiments, the means for releasing calibration liquid comprise: (a) at least one spike for rupturing the at least one sealed blister; or (b) a weakened portion of each of the at least one sealed blister for rupturing the at least one sealed blister, wherein when the calibration cartridge is installed with an associated analyzer, a force on the at least one sealed blister is provided by the associated analyzer.
In another aspect, the invention relates to a measurement cartridge for measuring one or more properties of a blood sample, the measurement cartridge comprising: a cartridge body comprising an upper surface and a lower surface, the upper surface defining a sample storage well having a top portion for receiving the blood sample, and a bottom portion for releasing at least a portion of the blood sample into one or more blood conduits; one or more detection chambers for receiving blood from the one or more blood conduits and providing signals for measuring the one or more properties of the blood; a cap hingeably attached to the cartridge body and adjustable from a first position to a second position, the cap comprising a top side and an underside, the underside comprising a plunger configured to enter the sample storage well; in the cap first position the measurement cartridge is configured to receive the blood sample in the sample storage well; in the cap second position the cartridge is configured with the plunger inserted in the sample storage well, the plunger displacing at least some of the blood sample into the one or more blood conduits; and at least one vent for releasing pressure in the one or more detection chambers.
A detection chamber is a chamber containing at least some of the blood sample, wherein the analyte in the blood sample, when in the detection chamber, provides a measurable signal. In various embodiments, the signal may be: a) an electrical signal from an electrochemical sensor disposed in the detection chamber, when the blood sample makes contact with the electrochemical sensor, or b) electromagnetic radiation (EMR) emerging from the blood sample in the detection chamber, after EMR from a source in an associated analyzer impinges upon the blood sample in the detection chamber. The EMR not absorbed or scattered by the blood sample is detected by a photodetector in the associated analyzer.
In various embodiments, the one or more detection chambers comprise an electrochemical sensor chamber having at least one electrochemical sensor.
In various embodiments, the at least one electrochemical sensor is one of an amperometric sensor, a conductivity sensor and a potentiometric sensor.
In various embodiments, the one or more properties of blood is pH, and the electrochemical sensor is a potentiometric sensor.
In various embodiments, the measurement cartridge further comprises one or more reagents in communication with the one or more blood conduits and means for mixing the blood sample and one or more reagents to produce altered blood.
In various embodiments, the one or more detection chambers comprise an optical chamber having at least one of an upper optical window and a lower optical window, the optical chamber for facilitating interrogation of the blood sample or the altered blood by electromagnetic radiation.
In various embodiments, the one or more detection chambers comprise an electrochemical sensor chamber having at least one electrochemical sensor and an optical chamber having at least one of an upper optical window and a lower optical window, the optical chamber for facilitating interrogation of the blood sample by electromagnetic radiation. The measurement cartridge may further comprise one or more reagents in communication with the one or more blood conduits for mixing the blood sample and one or more reagents to produce altered blood.
In a further aspect, the invention relates to a system for measuring one or more properties of a blood sample, the system comprising a measurement cartridge as described herein and an analyzer, the analyzer comprising: a receptor for receiving the measurement cartridge; at least one source of interrogating electromagnetic radiation (EMR) for interrogating at least some of the blood sample when the blood sample is positioned within the optical chamber, or for interrogating at least some of the altered blood when the altered blood sample is positioned within the optical chamber; at least one of: a one-dimensional multi-channel detector for receiving EMR emerging from one of the blood sample in the optical chamber or the altered blood sample in the optical chamber, via an EMR dispersing element, the EMR dispersing element for providing wavelength-specific EMR and the one-dimensional multi-channel detector for generating wavelength-specific electrical signals, or a two-dimensional multi-channel detector for receiving EMR emerging from one of the blood sample in the optical chamber or the altered blood sample in the optical chamber, and generating detector-specific electrical signals; one or more analog to digital converters for receiving one or more of the wavelength-specific electrical signals for generating wavelength-specific digital information, or the detector-specific electrical signals for generating detector-specific digital information; and one or more processors for controlling the analyzer and transforming at least one of the wavelength-specific digital information and the detector-specific digital information into the one or more properties of the blood sample.
Other aspects and features of the present invention will become apparent to those having ordinary skill in the art, upon review of the following description of specific embodiments of the invention, which are provided as non-limiting examples.
A better understanding of the novel features and advantages of the present invention will be made by reading the detailed description of the preferred embodiments provided later, in conjunction with the accompanying drawings, in which:
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, and which are described in the following detailed description of preferred aspects of the invention.
POCT systems comprising an analyzer, a measurement cartridge having one or more electrochemical sensors in a detection chamber, and a calibration cartridge having one or more similar electrochemical sensors are described. Systems comprising measurement cartridges having no calibration liquid blisters, and calibration cartridges having one or two calibration liquid blisters for performing one-point calibration (for offset correction) or two-point calibration (offset and slope correction), respectively, are described. Also described are systems comprising measurement cartridges having one calibration liquid blister for performing one-point calibration and calibration cartridges having two calibration liquid blisters for performing two-point calibration. Although the examples of calibration cartridges illustrate one and two calibration liquid blisters for simplicity, any number of calibration liquid blisters are considered to be within the scope of the present application. Also described are measurement cartridges comprising one or more detection chambers, wherein the one or more detection chambers comprise one or more optical chambers.
In this application, two types of cartridges are described: 1) Calibration Cartridges, and 2) Measurement Cartridges. In the calibration cartridge, no sample storage well is required, wherein the calibration liquid conduit entering the electrochemical sensor conduit is closed off from any other liquid influx, like influx of blood. For illustration, two examples of calibration cartridges, 20a and 20b, are provided, and eight examples of measurement cartridges, 10a, 10b, 10c, 10d, 10e, 10f, 10g and 10h, are provided. Various combinations of detection chambers in the measurement cartridges are provided, in order to increase the versatility of the measurement cartridges.
As used herein, the terms “comprising,” “having,” “including” and “containing,” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, un-recited elements and/or method steps. The term “consisting essentially of” when used herein in connection with a use or method, denotes that additional elements and/or method steps may be present, but that these additions do not materially affect the manner in which the recited method or use functions. The term “consisting of” when used herein in connection with a use or method, excludes the presence of additional elements and/or method steps. A use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to. The term “plurality” as used herein means more than one, for example, two or more, three or more, four or more, and the like. Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. As used herein, the term “about” refers to an approximately +/−25% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to. The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.”
The terms “operatively connected”, “in operative communication”, “in fluid communication”, “in fluid connection” or “fluidly connected” and the like, describe elements of the cartridges, for example, channels, ducts, conduits, tunnels, passageways, that permit either fluid flow, gas flow, or both fluid and gas flow between the various compartments or elements within the cartridge that are connected by the channels, ducts, conduits, tunnels, passageways and the like.
Detailed description of features of examples of the invention is described with reference to the accompanying drawings. These examples are to be considered non-limiting, and a person having ordinary skill in the art should understand that variations are within the scope of the invention, even though they are not explicitly illustrated. The same reference numerals are used for similar elements in different examples; in some cases, letters are appended to the end of the reference numerals to denote the embodiment of the invention illustrated. For example, 10a and 10b refer to two different examples of a Measurement Cartridge, and 20a and 20b refer to two different examples of a Calibration Cartridge. To maintain the distinction between a Measurement Cartridge and a Calibration Cartridge, attempts are made to provide different reference numerals for similar structures in the two different types of cartridges. It should be noted that absence of a letter after a reference numeral may refer to a structural feature of the invention incorporated in multiple examples. For easy reference, Table 1 provides a list of the reference numerals used, and a brief description of the corresponding structural features.
Two embodiments of calibration cartridges are provided: Calibration cartridge 20a is illustrated collectively in
As an alternative to a calibration cartridge comprising two sealed calibration liquid blisters for performing two-point calibration, two calibration cartridges each comprising a single calibration liquid blister may be used, wherein each of the two calibration liquid blisters in the two calibration cartridges are located in the same position, and the liquid composition of the two calibration liquid blisters are different. An advantage to this alternative is that the analyzer only requires a single rupture mechanism. A rupture mechanism may be a stepper motor actuator, as an example, which pushes against the blister, and the same actuator may also be used to activate an air bladder, if the cartridge comprises an air bladder. Further, multi-point calibration may be performed using more than two calibration cartridges, each calibration cartridge comprising a single calibration liquid blister, wherein the single calibration liquid blisters in the more than two calibration cartridges are located in the same position, and the liquid composition of each of the single calibration liquid blisters is different. When more than one calibration cartridges, each having a single calibration blister, the calibration liquid in each calibration cartridge is released and tested sequentially.
Other measurement cartridges that may be calibrated with calibration cartridges 20a or 20b include measurement cartridge 10a (shown in
Calibration cartridge 20b, measurement cartridge 10b and analyzer 80 are used as examples to illustrate a system shown in
Calibration of one or more electrochemical sensors in electrochemical sensor array 61b of measurement cartridge 10b, using calibration cartridge 20a is described: Force from an attachment to a stepper motor, as a non-limiting example, in an associated analyzer is applied to the top portion (dome portion) of the blister 91a via blister window 291a (see
Although calibration cartridges 20a and 20b are both shown to comprise first housing members 50a and 50b attached to second housing members 60a and 60b by double-sided sticky gaskets 102a and 102b respectively, calibration cartridges comprising different housing members in terms of design and number of components are considered to be within the scope of the present application.
Calibration cartridge 20b shown collectively in
A first embodiment of a measurement cartridge 10a is illustrated collectively in
The pump probe may be a flat surface or a ball having a channel for establishing connection between an associated analyzer pump and waste receptacle 255a. After the sample storage well 51a receives blood sample, hinged cap 200a is moved from the first position to the second position shown in
Blood conduit in cartridge 10a is shown as the combination of a groove 259a in the first housing member 30a and a cutout 113a in gasket 100a, but in order to minimize sample requirement, the blood conduit may only be the gasket cutout 113a, for example 259e shown in
A third embodiment of a measurement cartridge 10c is illustrated collectively in
A second embodiment of a measurement cartridge 10b is illustrated collectively in
Measurement cartridges like 10a, 10b and 10c are discussed in PCT/CA2020/051254 filed Sep. 18, 2020. Other relevant cartridges discussed in PCT/CA2020/051254 include measurement cartridges that slide about a pivotal hinge instead of sliding along tracks.
A fourth embodiment of a measurement cartridge 10d is illustrated collectively in
A fifth embodiment of a measurement cartridge 10e illustrated collectively in
The sample storage capacity of the sample storage well 51e may be altered by changing the diameter of the well 51e. The sample storage capacity of the sample storage well 51e may also be altered without changing the diameter of the well 51e, by increasing or decreasing the depth of the well 51e. As shown in
A sixth embodiment of a measurement cartridge 10f is illustrated collectively in
Movement of altered blood from the mixing chamber 463f is facilitated by pressurized air from air bladder 417f via air bladder duct 421f and air bladder communication port 163f. Therefore, movement of unaltered blood and movement of altered blood are two separate steps, utilizing the plunger 217f and the air bladder 417f respectively. Optional use of an associated analyzer pump instead of an air bladder 417f was previously discussed.
Illustrated in
A seventh embodiment of a measurement cartridge 10g is illustrated collectively in
Shown in
Some structural features and views are illustrated for either measurement cartridge 10g or 10h and not in both. Therefore, in order to understand the cartridges functionality, references may be made to structural features and views for either measurement cartridge 10g or 10h, and the cartridges are recognized by the letters “g” and “h” respectively. After blood is placed in the sample storage well 51g shown in
In the first stage, cap 200g is adjusted from the first position to a second position, wherein in the second position the cartridge is configured so that the plunger 217g in cap 200g displaces at least some of the blood in sample storage well 51g through bottom opening 55g. The displaced blood flows through manifold 455g (see
In the second stage, positive air pressure from, for example, an air bladder 417h pushes the blood in blood conduit 402h into electrochemical sensor chamber 261h for measurement by the one or more sensors in electrochemical sensors array 61h. Other means for pushing blood into electrochemical sensor chamber 261h includes an associated analyzer pump, as described regarding measurement cartridge 10c illustrated collectively in
As mentioned before, the major difference between measurement cartridges 10g and 10h is that cartridge 10g comprises a calibration fluid blister 75g for performing a one-point calibration. An option in cartridge 10g is inclusion of a directional valve element 67g (see
Spectroscopic measurement of a blood sample is described. Other terms like spectrophotometric, photometric or optical measurement are sometimes used instead of spectroscopic measurement. A block diagram of an example of a system 70 (lower panel) for measuring one or more analyte quantities per unit volume of blood and one or more formed element quantities per unit volume of blood is provided as a non-limiting example in
With respect to the spectroscopic measurement alone, the analyzer may comprise a source of EMR (represented by 12 in
For illustration of a method for performing spectroscopic measurement of whole blood, and by way of example which is not to be considered limiting, the PDA detector may have a pixel dispersion of 2 nanometers per pixel (i.e., the pixel or digital resolution), and the PDA detector is calibrated (i.e., wavelength calibration) to read from wavelengths 300 nanometers to 812 nanometers. Two laser beams may be used to conduct wavelength calibration, which is well known by persons having knowledge in the art (see for example U.S. Pat. Nos. 6,372,503, and 6,711,516). In this example, the center of pixel 1 is assigned a wavelength of 300 nanometers (laser #1), and the center of pixel 256 is assigned a wavelength of 812 nanometers (laser #2), thereby providing a wavelength range of 300-812 nanometers. For clarity, since the center of pixel 1 is assigned 300 nanometers, the center of pixel 2 will be assigned 302 nanometers, the center of pixel 3 will be assigned 304 nanometers and so on in increments of 2 nanometers per pixel (the pixel dispersion). The two lasers may emit EMR at any wavelength within the range of 300-812 nanometers, having sufficient spacing so that linear interpolation and linear extrapolation of wavelengths can be conducted. A person skilled in spectroscopy should appreciate that the wavelength range and spectral resolution of the PDA detector depends on several factors, for example, the semiconductor material used to construct the PDA, and diffraction grating (transmission or reflective/reflection grating) and the orientation of the grating relative to the PDA detector. The source of EMR is a major determinant of the wavelength range. Each pixel is typically scanned in microseconds, which provides sufficient time to accumulate sufficient charge on the photodiode, for example to distinguish a signal from noise and dark current, without saturating the photodiode. The time the photodiode is exposed to the EMR may be referred to as “integration time”.
Saturation, or “saturating the photodiode”, means that the photodiode has reached a maximum response in current and any additional photons impinging upon the photodiode is usually converted to heat instead of current. Because the scanning time is so short, it is reasonable to say that all the photodiodes in the PDA detector are scanned simultaneously. The photons are converted to electrical current, which is measured and digitized. In this present example, absorbance (sometimes referred to as absorption, denoted by A) may be determined, where
It is well known that transmittance is defined as the fraction of incident light which is transmitted or passes through a sample. Thus:
where
Io=the intensity of light (or EMR) impinging upon or interrogating the sample (i.e. the incident light) and
I=the intensity of light (or EMR) emerging from the sample after passing through the sample.
For calculating transmittance, the amount of EMR impinging upon the optical chamber, Io, may be measured by interrogating an optical chamber containing air. The EMR impinging upon the optical chamber, Io, may be measured before or after every sample measurement, or less frequently and stored in the processor for later use.
As an example, spectroscopic measurements are used to estimate prothrombin time (PT; usually reported as PT-INR; PT-International Normalized Ratio), activated partial thromboplastin time (aPTT), or thrombin time (TT), and since a normal PT is about 10-14 seconds, a normal ACT is about 70-130 seconds, and a normal TT is about 15-19 seconds, the measurements are performed every second. An aspect of the invention with respect to coagulation measurements, e.g. PT, ACT and TT, is to use the absorbance at one or more wavelengths or pattern recognition using absorbances at a plurality of wavelengths. Techniques of pattern recognition, combined with spectroscopy are known by those having skill in the art. An example where spectroscopy, combined with pattern recognition algorithms are used and that may be applied to the methods described herein, is provided in Zhang et. al. (Mid-Infrared Spectroscopy for Coffee Variety Identification: Comparison of Pattern Recognition Methods”, J. of Spectroscopy, Volume 2016, Article ID 7927286). As blood coagulates, the blood changes from various liquid varieties to various gel varieties, with corresponding changes in spectroscopic patterns, allowing one to use similar techniques as those used by Zhang et. al. to identify different variety of coffee beans. The specific blood coagulation time measured depends on the reagents included in the cartridge. For example, thromboplastin may be used for PT, celite or kaolin may be used for ACT, and thrombin may be used for TT.
Typically, blood coagulation time is measured using mechanical methods. For spectroscopic-based assays, citrated plasma is usually used in place of whole blood, because with whole blood, a much larger fraction of the incident EMR is scattered and absorbed by the blood cells, compared with the change in emerging EMR due to gelling of the plasma. However, separating out the plasma from the whole blood requires time and centrifugation equipment. It is well known that as plasma clots or coagulates, the absorbance at a single wavelength increases. By way of example, G. O. Gogstad et. al. (1986, “Turbidimetric Determination of Prothrombin Time by Clotting in a Centrifugal Analyzer” Clin. Chem. 32/10, 1857-1862), describe the change in absorbance spectra of plasma during coagulation. However, measurement of coagulation time using whole blood instead of plasma is more representative of in vivo coagulation. Therefore, there is a need for spectroscopic measurement of the blood coagulation time employing whole blood. In order to improve the signal to noise ratio when whole blood is used with the devices as described herein, the depth of the optical chamber should be relatively small, for example about 50-200 micrometers. The use of absorbance, reflectance or transmittance at a single wavelength to generate a clotting reaction curve (for example as shown in FIG. 1 of Gogstad et. al. 1986, using absorbance), and the calculations used to compute clotting time, are considered to be within the scope of the present invention. Gogstad et. al. also provided examples of calculations use to compute clotting time that may be used according to the methods described herein.
As an example, the source of EMR may be a tungsten lamp. U.S. Pat. No. 6,651,015 describes how spectrophotometric apparatus are calibrated for measuring properties of blood, using multi-wavelength analysis. With the use of a source of EMR like a tungsten lamp, which provides multiwavelength EMR (the tungsten lamp is polychromatic, whereas a laser is monochromatic), and the use of a linear PDA detector, the analyzer has the capacity to generate full absorbance spectra in milliseconds. Several spectra may be collected over milliseconds and the absorbances averaged to minimize noise. Mathematical smoothing techniques, which are covered extensively in the literature, may be used to minimize noise. Other mathematical techniques like the use of an order derivative of absorbance are also discussed in U.S. Pat. No. 6,651,015. Even though full absorbance spectra are obtained, selected portions of the absorbance spectra, a wavelength range of the absorbance spectra, or the full absorbance spectra, may be used in order to determine a concentration of one or more than one analyte of interest. Examples of an absorbance spectrum is provided in
Any analyte that provides an absorbance, reflection or transmission spectrum change at one or more wavelengths with a change in the concentration of the analyte may be measured by spectroscopy. Other examples of analytes include bilirubin and CO-oximetry.
Electrochemical measurements are performed using electrochemical sensors installed in the detection chamber of the measurement cartridge. The electrochemical sensors may contain, without being limiting in any way, at least one of an amperometric sensor (e.g. a glucose sensor comprising an enzyme glucose oxidase or a sensor that measures pO2), a conductivity sensor (e.g. a hematocrit sensor or an electrical switch), and a potentiometric sensor (e.g. an ion-selective electrode that can measure an electrolyte or pH).
As an example, electrochemical sensor array 61b of measurement cartridge 10b, illustrated collectively in
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. Furthermore, the discussed combination of features might not be absolutely necessary for the inventive solution.
| Number | Date | Country | Kind |
|---|---|---|---|
| 3066133 | Dec 2019 | CA | national |
| 3081050 | May 2020 | CA | national |
| PCT/CA2020/051254 | Sep 2020 | CA | national |
| 3107994 | Feb 2021 | CA | national |
This application is a continuation of PCT Application No. PCT/CA2021/051289 filed Sep. 15, 2021, which claims the benefit of Canadian Patent No. 3,107,994 filed Feb. 3, 2021 and PCT Application No. PCT/CA2020/051254 filed Sep. 18, 2020. PCT Application No. PCT/CA2020/051254 claims the benefit of U.S. application Ser. No. 16/854,201 filed Apr. 21, 2020, now U.S. Pat. No. 11,161,109, and claims the benefit of Canadian Application No. 3,081,050 filed May 19, 2020, which claims the benefit of U.S. application Ser. No. 16/854,201 filed Apr. 21, 2020, now U.S. Pat. No. 11,161,109, which claims the benefit of Canadian Application No. 3,066,133 filed December 2019, which claims the benefit of U.S. application Ser. No. 16/575,645 filed Sep. 19, 2019, now U.S. Pat. No. 11,327,084. U.S. application Ser. No. 16/854,201 filed Apr. 21, 2020, now U.S. Pat. No. 11,161,109, is a continuation in part of U.S. application Ser. No. 16/575,645 filed Sep. 19, 2019, now U.S. Pat. No. 11,327,084, all of which are herein incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CA2021/051289 | Sep 2021 | US |
| Child | 17744283 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CA2020/051254 | Sep 2020 | US |
| Child | PCT/CA2021/051289 | US | |
| Parent | 16854201 | Apr 2020 | US |
| Child | PCT/CA2020/051254 | US | |
| Parent | 16575645 | Sep 2019 | US |
| Child | 16854201 | US |
