Patent Application
20200290035
The invention relates to a disposable cartridge and an analyzer for point-of-care testing (POCT) of a patient's blood, using a combination of spectroscopic and biosensor measurements. In particular, the invention relates to POCT of blood gases and CO-oximetry.
There are many medical diagnostic tests that require a fluid, for example, blood (sometimes referred to as whole blood), serum, plasma, cerebrospinal fluid, synovial fluid, lymphatic fluid, calibration fluid, and urine. With respect to blood, a blood sample is typically withdrawn in either an evacuated tube containing a rubber septum, or a syringe, and sent to a central laboratory for testing. The eventual transfer of blood from the collection site to the testing site results in inevitable delays. Moreover, the red blood cells are alive and continue to consume oxygen during any delay in testing, which in turn changes the chemical composition of the blood sample, from the time the blood sample is collected to the time the blood sample is analyzed, also referred to as measured or tested.
One example of a blood analysis technique that is affected by delay in testing and transfer of blood from the blood collection device to the analyzer, is CO-oximetry. CO-oximetry is a spectroscopic technique that is used to measure the different Hemoglobin (Hb) species present in a blood sample, for example, Oxy-Hb, Deoxy-Hb, Met-Hb, Carboxy-Hb and Total-Hb. Some Co-oximeters can also measure Sulf-Hb and Fetal-Hb. The results of CO-oximetry are used to provide Hb Oxygen Saturation (sO2) measurements in two ways: 1) functional sO2 is defined as the ratio of Oxy-Hb to the sum of Oxy-Hb and Deoxy-Hb; and 2) fractional sO2 is defined as the ratio of Oxy-Hb to the Total-Hb.
If the blood sample is exposed to air, the sO2 measurements may become falsely elevated, as oxygen from the air is absorbed into the blood sample. CO-oximetry usually requires hemolyzing the red blood cells (hemolysis) using a sound generator, in order to make the blood sample more transparent for spectroscopic measurement; blood with intact red cells scatter significantly more electromagnetic radiation (EMR) than hemolyzed blood. Hemolysis can also be accomplished by mixing a chemical, for example, a detergent, with the blood. Parameters that can be measured in blood by spectroscopic techniques (or spectroscopy, sometimes referred to as spectrometry) are limited by the amount of EMR absorbed by the analytes measured. In contrast, for example, without limitation, hydrogen ions (which determine pH) and electrolytes (e.g., sodium, potassium, and chloride) do not absorb EMR in the approximate wavelength range of about 300 nm to 2500 nm. Therefore, if this wavelength range is used to conduct spectroscopic measurements of Hb species, then these important parameters, i.e., hydrogen ions and electrolytes, must be measured by another means.
Another example of a blood analysis technique that is affected by the aforementioned sources of error is blood gases. Traditionally, blood gas measurement includes the partial pressure of oxygen (pO2), the partial pressure of carbon dioxide (pCO2), and pH. From these measurements, other parameters can be calculated, for example, sO2, bicarbonate, base excess and base deficit. Blood gas and electrolyte measurements usually employ biosensors, also referred to as electrochemical sensors or electrochemical detectors. Bench-top analyzers are available, which perform the following: (1) measurement of blood gases, (2) CO-oximetry, or (3) combined measurement of blood gases and CO-oximetry. Some combinations of diagnostic measurement instruments also include electrolytes, and other measurements, for example, lactate and creatinine. Because these instruments are large and expensive, they are usually located in central laboratories. Biosensor technology is also limited by the blood parameters biosensors can measure. To the inventor's knowledge, biosensors are not currently available for performing CO-oximeters. U.S. Pat. Nos. 5,096,669 and 7,094,330 to Lauks et al., as examples, describe in details cartridges that employ biosensor technology for POCT. In particular, they teach about pH measurement (a potentiometric measurement), blood gas measurement (a potentiometric and an amperometric measurement for pCO2 and pO2, respectively), and hematocrit measurement (a conductivity measurement). U.S. Pat. No. 7,740,804 to Samsoondar (the present inventor) teaches disposable cartridges for spectroscopic measurement (e.g., CO-oximetry) for POCT using unaltered blood. U.S. Pat. Nos. 5,430,542 and 6,262,798 to Shepherd describes a method for making disposable cuvettes having a path length in the range of 80 to 130 micrometers for performing CO-oximetry measurement on unaltered blood.
Blood tests for assessing a patient's oxygenation and acid-base status may include pH, sO2, CO2, and Total Hb. The leading POCT analyzers used to assess a patients acid-base status estimate sO2 from a measured partial pO2, and estimate Total Hb from a measured hematocrit. Both hematocrit and pO2 are measured using biosensors.
sO2 calculated from pO2 is criticized in the literature because: 1) pO2 measures the O2 dissolved in the blood plasma, which accounts for only about 1% of the total oxygen in blood—the remaining 99% of blood oxygen is bound to Hb; 2) it is assumed that the patient's red blood cells (RBC) contain normal levels of 2,3-diphosphoglycerate; and 3) the patient has normal levels of dyshemoglobins, e.g., Carboxy-Hb and Met-Hb. Dyshemoglobins are non-functional Hbs. Temperature and pH, which are also sources of error, are usually corrected for.
Total Hb estimated from hematocrit measurement by conductivity is criticized in the literature because: 1) a certain RBC Hb concentration is assumed for all patients; and 2) alteration in plasma protein, electrolytes, white cells, and lipids are sources of errors in hematocrit measurement. These assumptions can lead to significant errors in managing seriously ill patients. Moreover, Hb measurement is preferred over hematocrit measurement for evaluating chronic anemia and blood loss. Unnecessary blood transfusion due to underestimation of Hb from hematocrit is a major concern.
In choosing a POCT analyzer, a user must understand clearly the parameters that are actually measured and the parameters that are calculated from measured parameters. Measurement of Total Hb and sO2 performed by spectroscopy provide the best measurement of a patient's oxygenation status, because they are more accurate than results calculated from hematocrit and pO2, respectively. Lab analyzers can easily combine biosensor and spectroscopic technologies because analyzer size is not a limitation. Currently, no small POCT analyzer is available that provides blood gases (includes pH) and CO-oximetry. Some POCT vendors provide a solution in the form of a separate POCT analyzer just for performing CO-oximetry, which complements their blood gas POCT analyzer.
Since CO-oximetry measures functional Hb species, and non-functional Hb species like Carboxy-Hb and Met-Hb, a physician can continue to confidently monitor a patient's oxygenation status non-invasively using a Pulse Oximeter. According to best practice, pulse oximetry should only be used after verifying that the patient's blood does not contain significant amount of non-functional Hb. The presence of elevated non-functional hemoglobin species is a source of error in pulse oximetry. The present invention can use capillary blood as well as arterial blood, which provides a major advantage for babies. Obtaining arterial blood is painful, can cause nerve damage, must be performed by a qualified person like a physician, and the resulting blood loss in babies is clinically significant. The cartridge of the present invention can also facilitate monitoring Met-Hb in neonates during treatment with nitric oxide for respiratory distress, and facilitate measuring bilirubin for assessing neonatal jaundice. The use of capillary blood also makes the present invention an attractive tool for monitoring sO2, Carboxy-Hb (increased due to carbon monoxide poisoning resulting from smoke inhalation) and pH in firefighters and other victims of smoke inhalation. Most of these victims will be treated with oxygen, which elevates the pO2, therefore pO2 cannot be used to assess the blood oxygen content. CO-oximetry is therefore essential to victims of smoke inhalation. Capillary blood is usually obtained from a finger, heel or ear lobe prick. The capillary blood can be altered (“arterialized”) to more closely resemble arterial blood by applying a heating pad to the site that will be pricked.
U.S. Pat. No. 8,206,650 to Samsoondar (the present inventor) teaches the combination of spectroscopy and biosensor technologies in one disposable cartridge, and can therefore provide pH, blood gases and CO-oximetry on a small POCT analyzer. The users are provided with the convenience of applying the sample once, as opposed to using a first analyzer that employs biosensor technology alone, and a second analyzer that employs spectroscopy alone. However, U.S. Pat. No. 8,206,650 does not provide details required by a person with ordinary skill in the art, for making a functional cartridge, and further does not provide details that can be applied to a cartridge manufacturing process.
U.S. Pat. No. 8,206,650 provides a single cartridge option that can be used to test blood from a syringe like arterial blood, and capillary blood at the surface of a body part, which is a very important consideration when the patient is a neonate. However, the option for obtaining capillary blood is limited. A person of ordinary skill in the art of blood gases will appreciate that the pO2 will be overestimated significantly due to atmospheric contamination; current practice includes inserting the open end of a capillary tube inside the drop of blood, quickly sealing the ends of the capillary tube, and taking the sample to an analyzer.
U.S. Pat. No. 9,470,673. to Samsoondar (the present inventor), the contents of which are hereby incorporated in entirety by reference, provides improvements to the teachings of U.S. Pat. No. 8,206,650, for example, the design of a capillary adaptor for drawing capillary blood into the cartridge, the design of a more efficient capillary break, the design of the delivery system for calibration fluid, and the design of the analyzer cartridge receptor. Other limitations of the cartridge described in U.S. Pat. No. 9,470,673 will become apparent as different embodiments of the present invention are described.
In accordance with an aspect of an embodiment of the present invention there is provided a disposable cartridge for operation with a joint spectroscopic and biosensor blood analyzer for measurement of at least two hemoglobin species in a patient's blood sample by spectroscopy, and measurement of at least pH of the blood sample by biosensor, for assessing the patient's oxygenation and acid-base status. The cartridge comprises a housing having at least a first housing member and a second housing member bonded together by a gasket. The housing comprises a cartridge inlet; a blood storage conduit within the housing having a proximal end close to the cartridge inlet and a distal end away from the cartridge inlet; an optical chamber within the housing for receiving the blood from the distal end of the blood storage conduit and for measuring the at least two hemoglobin species; an optical chamber overflow chamber for receiving the blood from the optical chamber; a biosensor conduit within the housing for receiving the blood from the optical chamber overflow chamber, the biosensor conduit comprising a proximal end, a distal end and at least a portion of a pH biosensor; a waste receptacle for receiving liquid waste from the biosensor conduit; a vent for relieving pressure in the waste receptacle; an air bladder and an air bladder exit port within the housing for providing pressurized air for urging blood from the blood storage conduit into the biosensor conduit; and, an optical window and an aligned optical member, the first housing member comprising one of the optical window and the aligned optical member, and the second housing member comprising the other of the optical window and the aligned optical member; the aligned optical member being one of a reflecting member or a second optical window, and being positioned to align with at least a portion of the optical chamber and at least a portion of the optical window. The gasket has at least one gasket cut-out positioned to provide fluid connection between the blood storage conduit and the optical chamber, wherein at least a portion of the at least one gasket cut-out is positioned to align with at least a portion of the optical chamber for collecting spectroscopic data from blood in that portion of the optical chamber.
In some embodiments, the at least one gasket cut-out has a second portion positioned to align with the active area of the pH biosensor.
In some embodiments, the disposable cartridge is insertable into a receptor of the joint spectroscopic and biosensor analyzer, and at least one of the first and second optical window is positioned to align with at least a portion of the optical chamber for collecting spectroscopic data from blood in that portion of the optical chamber. In these embodiments, the housing further comprises a blood shunt for providing fluid connectivity between the distal end of the blood storage conduit and the optical chamber overflow chamber. The optical chamber overflow chamber comprises: a first duct fluidly connected with the blood shunt and traversing a thickness of the second housing member; a recess disposed at the bottom of the second housing member and fluidly connected to the first duct; and, a second duct having a first cross-sectional area, and fluidly connected to the recess. In addition to that blood shunt, the housing further comprises an enlarged cavity having a second cross-sectional area parallel to the first cross-sectional area; wherein, the second cross-sectional area is substantially larger than the first cross-sectional area, whereby blood flow by capillary action slows down as the blood reaches the end of the second duct, and wherein the enlarged cavity is simultaneously in fluid connection with the optical chamber and the second duct.
In some embodiments, this disposable cartridge is insertable along a plane substantially defined by a surface of the gasket, into the receptor of the joint spectroscopic and biosensor analyzer, the optical chamber comprising an optical depth dimension orthogonal to the plane, the blood shunt having a maximum shunt depth dimension orthogonal to the plane, the maximum shunt depth dimension being substantially larger than the optical chamber depth dimension, and the first cross-sectional area being along the place.
In some embodiments of this disposable cartridge, the optical chamber overflow chamber is fluidly connected with the optical chamber, and the housing further comprises: a calibration fluid pouch for storing and releasing calibration fluid; a spike disposed in the second housing member of the cartridge for rupturing the calibration fluid pouch; a recess disposed in the opposite side of the second housing member; and a hole in the spike for permitting flow of the calibration fluid from the calibration fluid pouch to the recess for channeling the calibration fluid to the biosensor conduit.
In some embodiments, this cartridge further comprises a compressible member surrounding the spike, for supporting the calibration fluid pouch.
In accordance with another aspect of another embodiment of the present invention, there is provided a system for transferring capillary blood from a puncture site of a body part of a patient, the system comprising a capillary adaptor; and a disposable cartridge according to any of the embodiments described above. The cartridge inlet further comprises: an internal wall for receiving the capillary adaptor, the internal wall defining an airflow path for airflow between an exterior of the disposable cartridge and the blood storage conduit when the capillary adaptor is being removed from the cartridge inlet; an external wall having a cartridge inlet thread; a blood storage conduit entrance at the base of the cartridge inlet, the blood storage conduit beginning at the blood storage conduit entrance; and a cartridge inlet inner face surrounding the blood storage conduit entrance. The capillary adaptor comprises a capillary adaptor inlet member comprising a capillary adaptor tube, the capillary adaptor inlet member having a capillary adaptor inlet port for receiving the blood sample; a capillary adaptor outlet member sized to fit into the cartridge inlet; a capillary adaptor outlet port disposed at the end of the capillary adaptor outlet member; a capillary adaptor face surrounding the capillary adaptor outlet port; a capillary adaptor lumen extending from the capillary adaptor inlet port to the capillary adaptor outlet port; a handgrip for handling the capillary adaptor; and an internal wall in the hand grip having a capillary adaptor thread for engaging the cartridge inlet thread in the cartridge inlet. When the capillary adaptor thread is properly engaged with the cartridge inlet thread, the capillary adaptor face mates with the cartridge inlet inner face, sufficiently to permit flow of blood from the patient to the blood storage conduit by capillary action.
In some embodiments of this system, the position of the capillary adaptor face relative to the cartridge inlet inner face, when the capillary adaptor is fully engaged with the cartridge inlet, is one of no gap between the capillary adaptor face.
In some embodiments of this system, the cartridge inlet thread is an abbreviated thread.
In some embodiments of this system, the capillary adaptor thread is an abbreviated thread.
In some embodiments of this system, the volume of the capillary adaptor lumen is in the approximate range of about 5 microliters to about 20 microliters.
In some embodiments of this system, the volume of the capillary adaptor lumen is in the approximate range of about 5 microliters to about 10 microliters.
In some embodiments of this system, the length of the capillary adaptor inlet member is in the approximate range of about 2 millimeters to about 5 millimeters.
In accordance with another aspect of an embodiment of the present invention, there is provided a system for transferring blood from a syringe containing the blood. The system comprises the disposable cartridge according to any of the embodiments described above, wherein the cartridge inlet engages the syringe. The cartridge inlet further comprises an internal wall for receiving the syringe, the internal wall defining an airflow path for airflow between an exterior of the disposable cartridge and the blood storage conduit when the syringe is being removed from the cartridge inlet; an external wall; a blood storage conduit entrance at the base of the cartridge inlet, the blood storage conduit beginning at the blood storage conduit entrance; and a cartridge inlet inner face surrounding the blood storage conduit entrance.
In accordance with yet another aspect of an embodiment of the present invention, there is provided a joint spectroscopic and biosensor system for measurement of at least two hemoglobin species in a patient's blood sample by spectroscopy, and measurement of at least pH of the blood sample by biosensor, for assessing the patient's oxygenation and acid-base status. The system comprises the disposable cartridge according to any of the embodiments described above, wherein the first optical window and the second optical window are part of the optical chamber; the optical chamber overflow chamber is fluidly connected with the optical chamber, and the housing further comprises: a pH biosensor electrical output element; and a calibration fluid pouch containing calibration fluid for at least calibrating the pH biosensor; and an analyzer comprising an analyzer housing. The analyzer housing comprises: a receptor comprising a first opening for receiving and aligning the cartridge in an operational position; a source of electromagnetic radiation; at least one photodetector; a power supply; and a processor for controlling the analyzer. The receptor further comprises: a second opening for directing the electromagnetic radiation to the first optical window when the cartridge is in the operational position; a third opening for directing electromagnetic radiation emerging from the second optical window to the at least one photodetector when the cartridge is in the operational position; a physical interface for providing electrical contact between the pH biosensor electrical output element and the processor; and a bracket mounted on the receptor for at least supporting a first stepper motor for applying force to the calibration fluid pouch against a spike for rupturing the calibration fluid pouch to release the calibration fluid, and a second stepper motor for forcing air from the air bladder through the air bladder exit port, for pushing the blood into the biosensor conduit.
In some embodiments of this system, the receptor further comprises a top portion and a bottom portion, and the bottom portion comprises at least one heating element layered on a surface of the bottom portion, for heating the cartridge, and the top portion comprises a spring-loaded locating element for engaging with a notch disposed at a top of the cartridge, for forcing the cartridge against the at least one heating element.
In some embodiments of the system, whether comprising a capillary adapter or for use with the syringe, the system further comprises a cap for covering the cartridge inlet when one of the capillary adaptor and the syringe is withdrawn from the cartridge inlet. The cap comprises a cap airflow path for airflow between an exterior of the disposable cartridge and the blood storage conduit when the cap is being engaged to impede blood in the blood storage conduit being disturbed by compression of air within the cartridge inlet during engagement of the cap.
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 the specific embodiments of the invention.
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:
The invention provides a system for joint spectroscopic and biosensor measurement of at least two hemoglobin species in a patient's blood sample by spectroscopy, and measurement of at least the blood pH by biosensor. The terms biosensor, electrochemical sensor and electrochemical detector are sometimes used interchangeably, and they have the same meaning in this description. The system comprises a disposable cartridge adapted for insertion into a receptor of an analyzer, a cap for capping the cartridge when it is inserted into the analyzer, and a capillary adaptor for drawing blood directly from the puncture site of the skin of a patient, into the cartridge. The results are used for assessing a patient's oxygenation and acid-base status. This system allows for the use of capillary blood instead of arterial blood, which is particularly useful for neonatal care.
Some embodiments of an analysis system include at least some of the following: an analyzer described in part in U.S. Pat. Nos. 8,206,650 and 9,470,673, the analyzer having some of the following: i) a power supply, which is optionally in the form of disposable or rechargeable batteries; ii) a source of electromagnetic radiation (EMR), for example, one or more LEDs, a tungsten lamp, one or more lasers, or any combination thereof; iii) a receptor in the analyzer housing for receiving a disposable cartridge; iv) a photodetector for measuring EMR transmitted through or reflected from a blood sample within the optical chamber of the cartridge and for providing an EMR-based signal derived from the EMR transmitted through or reflected from the blood sample; v) a processor for controlling the analyzer and in communication with the photodetector for receiving the EMR-based signal, and at least one calibration algorithm installed in the processor for transforming the EMR-based signal into a hemoglobin specie concentration; vi) a physical interface attached to the receptor for connecting with an analyzer processor and for connecting with the biosensor; vii) means for releasing the calibration fluid from the calibration fluid pouch and transporting released calibration fluid to the biosensor conduit for calibrating at least the pH biosensor prior to measuring the pH of the blood sample; viii) means for maintaining the active area of the biosensor at a pre-determined temperature; and ix) means for preheating the blood sample.
When the biosensor electrical contact of the cartridge is inserted into the physical interface of the receptor, the optical chamber of the cartridge becomes positioned to receive the EMR from the EMR source.
Some embodiments of the system also include: x) means for handling the blood sample, for example, a) a syringe containing the blood, and b) a capillary adaptor capable for transferring capillary blood directly from punctured skin of the body part of a patient to the cartridge; and xi) a cap for sealing the cartridge inlet. A syringe is required for collecting arterial blood, but capillary blood can be obtained by puncturing a body part with a lancet, and transferring the capillary blood that accumulates at the surface of the skin, to the cartridge via a capillary adaptor. In certain situations, for example when the patient is a baby, and under certain conditions, capillary blood may be used as a substitute for arterial blood. Moreover, collection arterial blood is painful, may cause nerve damage, and is usually performed by a physician.
The means for calibrating the at least one biosensor includes: a) a pouch within the housing containing calibration fluid; b) means for releasing fluid from the calibration pouch; and c) a calibration fluid conduit for transporting the released calibration fluid to the biosensor conduit. Those skilled in the art will appreciate that the electrical signals generated from the biosensor after it comes in contact with a calibration fluid of known composition, and the known concentration of the analyte in the calibration fluid, can be used to generate a calibration algorithm for the analyte, and therefore for the sake of brevity, the mathematics involved in biosensor calibration will not be discussed here. Some embodiments of the present invention provide biosensor calibration algorithms installed in the analyzer processor, and therefore do not require the calibration fluid.
The current practice when testing capillary blood on a blood gas analyzer or a CO-oximeter is to collect the capillary blood in a capillary tube, and subsequently transfer the blood from the capillary tube to the analyzer. This transfer of the blood from the capillary tube to the analyzer presents sources of error, for example: a) cellular metabolism continues after blood is collected, and the error is proportional to the delay in testing; and b) opportunity for atmospheric contamination by incorporation of air bubbles in the capillary tube, which is subsequently mixed into the blood. An external magnet is used to move a piece of wire located inside the capillary tube, forward and backward along the capillary tube, in order to mix the sample with anticoagulant deposited on the internal wall of the capillary tube. The present invention provides a capillary adaptor designed to eliminate this step of sample transfer. The atmosphere contains about 21% oxygen; therefore for direct measurement (CO-oximetry) or indirect measurement (i.e., calculating sO2 from measured pO2) of oxygen saturation, the blood must be protected from atmospheric contamination in order to minimize errors, and delay in testing must be minimized.
When a cartridge is inserted properly in the receptor of the analyzer, the cartridge biosensor electrical contact mates with the analyzer electrical contact (see
In some embodiments, the joint-diagnostic spectroscopic and biosensor analyzer further comprises a display screen for viewing the results and aiding the operator in use of the analyzer, as well as buttons for manipulating the display function. Those skilled in the art will appreciate that the analyzer could be connected to a host computer. Therefore, some embodiments of the system also comprise at least one communication port for interfacing with other instruments. Other non-limiting examples of other instruments are a printer, and diagnostic testing instruments like a pulse oximeter or some other non-invasive testing instrument. The optional communication port is also used to upgrade information in the analyzers processor, as well as to upload information from the analyzers processor. Another optional port in the housing of some embodiments of the joint-diagnostic spectroscopic and biosensor analyzer is provided for charging the power supply within the analyzer. Those skilled in the art will appreciate that a single port can be used for both data transfer and a power supply, for example, without any limitation, a USB (Universal Serial Bus) port. In some embodiments of a system, data transfer to and from the analyzer is accomplished by wireless means that are known by one of skill in the art, and therefore, for the sake of brevity, wireless communication means will not be discussed here.
Some embodiments of the joint-diagnostic spectroscopic and biosensor analyzer comprise one photodetector (photodiode), or more than one photodetector assembled as an array of detectors in a spectrometer, wherein the spectrometer comprises a grating for dispersing EMR emerging from the fluid sample, into wavelength components. The analyzer optionally comprises one or more focusing lenses between the disposable cartridge and the spectrometer. A person of ordinary skill in the art will appreciate that other forms of optical detection, for example, CCD (charged-coupled device), can be used, and are therefore considered to be within the scope of the invention.
In some embodiments, the interior walls of the cartridges are treated with a hydrophilic coating to promote even spreading of the blood within the optical chamber, and to promote movement of blood along the flow path by capillary action. An alternative to a hydrophilic coating is plasma or corona treatment of a surface for making the surface more hydrophilic.
The optical chamber is located along a flow path, and the optical chamber has at least one optical window for spectroscopic analysis of the blood. The at least one optical window is in alignment with at least a portion of the optical chamber. A flow path may also contain one or more reagents, anywhere along the flow path, for example, without limitation, an anticoagulant, a hemolyzing reagent, or a reagent that reacts with an analyte to enhance the absorbance of EMR. The optical chamber is specifically designed to reduce the average attenuation of EMR due to scattering of EMR by the intact red blood cells in a blood sample, without having to hemolyze the red blood cells using sound waves or hemolyzing chemicals. Preferably, the depth of the optical chamber, i.e., the internal distance between the optical windows, is in an approximate range of about 50 microns to about 200 microns. In a preferred embodiment, the depth of the optical chamber is substantially uniform across the optical windows. In some embodiments, the depth of the optical chamber is not uniform across the optical windows, and is within the scope of the present invention. A person of ordinary skill in the art will appreciate that although the optical windows are illustrated as circular elements, they can have other shapes, for example, without being limited, oval and square shapes. In some embodiments, the area of an optical window that is in alignment with an optical chamber is in an approximate range of about 1 sq. millimeter to about 100 sq. millimeters. For the sake of minimizing sample volume, a more preferred optical window area that is in alignment with the optical chamber is in an approximate range of about 1 sq. millimeter to about 10 sq. millimeters.
The biosensor conduit is located along a flow path, and the biosensor conduit may have one or more than one biosensors for analyzing the blood. Those skilled in the art will appreciate that biosensors may include various transducer arrangements that convert at least one property of the fluid sample into an electrical signal, wherein the transducer comprises at least one active surface for contacting the fluid sample. In some embodiments, the active surface is one of a chemical sensitive surface, or an ionic sensitive surface, and wherein the biosensor comprises at least one of a transistor, an ion-selective membrane, a membrane-bound enzyme, a membrane-bound antigen, a membrane-bound antibody, or a membrane-bound strand of nucleic acid. The disposable cartridge also comprises at least one biosensor electrical contact, and the cartridge receptor of the analyzer also comprises at least one analyzer electrical contact. Although the examples illustrated show the cartridge electrical output contact as flat pins in an array, those skilled in the art will appreciate that the electrical contacts can mate in other ways, for example, the electrical contacts described in U.S. Pat. No. 8,206,650.
Some embodiment of a joint-diagnostic spectroscopic and biosensor analyzer optionally comprises a barcode reader for reading a barcode on the disposable cartridge, the barcode containing at least information regarding calibration of a biosensor. The barcode also optionally contains information about the joint-diagnostic spectroscopic and biosensor analyzer. Some embodiments of disposable cartridges comprise radio frequency identification (RFID) tags. In some embodiments, the disposable cartridge further comprises a calibration fluid pouch containing a calibration fluid that is arranged in fluid connection with a biosensor conduit. For cartridges with calibration fluid pouches, the joint-diagnostic spectroscopic and biosensor system further comprises means for rupturing the calibration fluid pouches, for example, which should not be considered limiting in any way, a rotating cam, a reciprocating plunger, or a stepper motor linear actuator, and a spike in the cartridge housing. In some embodiments, the pouch itself contains an object with multiple spikes, which ruptures the calibration fluid pouch when pressure is applied to the calibration fluid pouch. In some embodiments, a portion of the seal of the calibration pouch is substantially weaker by design, than the rest of the seal, for easy rupture after pressure is applied. These weaker seal portions are sometimes referred to as frangible seals.
Some embodiments of cartridges also include at least one visible fill line or indicator serving as a marker providing a user with a visual indicator relating to the sufficiency of the blood sample in the optical chamber. Preferably the cartridge housing is made of transparent plastic for easy viewing of the blood inside the cartridge.
The means for calibrating the at least one biosensor includes a calibration fluid pouch 90 within the cartridge containing calibration fluid, means for rupturing the calibration pouch, and a calibration fluid conduit for transporting the calibration fluid from the pouch 90 to the biosensor conduit 54. U.S. Pat. No. 5,096,669 describes analyzer means for depressing and rupturing a calibration pouch. Although the cartridge embodiments shown comprise means for calibrating the biosensors, some cartridge embodiments have factory-calibrated biosensors, and therefore do not require means for calibrating the biosensors. These cartridge embodiments are also within the scope of the invention.
In some embodiments of a disposable cartridge, the blood storage conduit begins at a the blood storage conduit entrance and terminates at the optical chamber, and the volume of the blood storage conduit is in an approximate range of about 50 microliters to about 100 microliters. A small sample size is preferred for babies, but for pO2 measurement, air bubbles can create greater errors in smaller samples. Therefore the size of the samples must be balanced between allowable errors and the amount of blood the patient can provide without causing the patient harm.
An air bladder is used for the purpose of urging blood along a path, and means for activating the air bladder is provided.
In some embodiments, the blood storage conduit has a length dimension measured from the proximal end (i.e., near the inlet) to the distal end (i.e., near the optical chamber) and has a cross-sectional area orthogonal to the length dimension, the size of the cross-sectional area being sufficiently small to receive the blood by capillary action, and the size being substantially uniform throughout a substantial portion of the length dimension. Cross-sectional areas are shown as semi-circular and rectangular, but a person with ordinary skill in the art will appreciate that other shapes can be used, and are therefore considered to be within the scope of the present invention.
The optical chamber of an embodiment of the cartridge has a depth dimension orthogonal to a plane of insertion of the cartridge into the receptor of the analyzer, wherein the depth dimension is in an approximate range of about 50 microns to about 200 microns. In the embodiments described in details later, the optical chamber is defined by a cut-out in the gasket 100. In some embodiments (not shown), the depth dimension of the optical chamber is greater than the thickness of the gasket.
Another aspect of an embodiment of a disposable cartridge (the first embodiment 10) for operation with a joint spectroscopic and biosensor blood analyzer for measurement of at least two hemoglobin species in blood by spectroscopy, and measurement of at least blood pH by biosensor, is a housing comprising: A) a first housing member 20; B) a second housing member 30; and C) a double-sided sticky gasket 100, are illustrated. U.S. Pat. No. 9,470,673 to the present inventor, the contents of which are hereby incorporated in entirety by reference, describes several other embodiments of the cartridge. Although the embodiments of a disposable cartridge illustrated in U.S. Pat. No. 9,470,673 comprise a single double-sided sticky gasket, some cartridge embodiments comprise more than two housing members, and therefore require more than one double-sided sticky gasket for bonding the additional housing members, for example, the second embodiment 10a.
In some embodiments of a cartridge, the double-sided sticky gasket has a thickness in the approximate range of about 50 microns to about 200 microns. Although the gaskets are described as sticky gaskets, non-sticky gaskets are considered within the scope of the invention. In embodiments using non-sticky gaskets, some form of adhesive is applied directly to the housing members at the areas where the gasket makes contact with the housing members, or some other means are used for sandwiching the gasket between the housing members.
The gaskets shown are flat and therefore each side of the gasket defines a plane, wherein both planes are parallel to each other. In some embodiments, the gasket is substantially flat, wherein each side substantially defines a plane, and wherein the two planes are not parallel. Therefore, it should be understood that reference to a plane orthogonal to the gasket means a plane orthogonal to either of the two planes substantially defined by the respective sides of a substantially flat gasket. As an example, a substantially flat gasket is one where most of the gasket is flat, but some sections comprise dimples and or bumps.
The gaskets illustrated comprise several gasket cut-outs but some embodiments of the cartridges comprise one or more than one gasket cut-out. As an example, consider gaskets 100 (according to a first embodiment of a cartridge) and 100a (according to a second embodiment of a cartridge) illustrated in cartridge embodiments 10 and 10a respectively, disclosed as examples. Cut-outs 101 and 102 in cartridge 10 are illustrated in cartridge 10a as a single cut-out labeled 101a, an embodiment vented through a groove in housing (not shown) does not have cut-out 107a; an embodiment comprising pre-calibrated biosensors (not shown) does not have cut-out 105a; and a cartridge embodiment in which there is no concern about contact between the calibration fluid and the gasket (not shown) does not have cut-out 106a. Moreover, in some embodiments cut-outs 101a is joined with cut-out 103a, and in some embodiments cut-out 103a is further joined to cut-out 104a (not shown). In order to minimize contact between the sample and the adhesive in the gasket some embodiments of cartridges comprise a single gasket cut-out, wherein a first portion of the cut-out is positioned to align with at least a portion of the optical chamber, and a second portion is positioned to at least align with the active area of the pH biosensor. In some embodiments, the single gasket is transformed into two separate gasket cut-outs: a first gasket cut-out is positioned to align with at least a portion of the optical chamber, and a second gasket cut-out is positioned to at least align with the active area of the pH biosensor. It is well known that adhesives are available that are compatible with the blood sample and the calibration fluids, and more cut-outs may be desired depending on the assembly process. Therefore at least one gasket cut-out is within the scope of the present invention.
With respect to spectroscopic measurements, those skilled in the art will appreciate the various ways a spectroscopic measurement apparatus can be constructed, and various elements that make up such apparatus. Accordingly, for the sake of brevity, description of basic spectroscopy and a list and function of the elements that make up a spectroscopic apparatus will not be discussed here. Those skilled in the art will appreciate that when the source of EMR is a single source, the single source could be split by a multi-channel optical fiber for providing more than one light paths. An example of a system for detecting the EMR transmitted through or reflected from a sample is an array of photodiodes, but those skilled in the art will appreciate that these spectroscopic elements are just examples and should not be considered limiting for the present invention.
Still 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 of a joint-diagnostic spectroscopic and biosensor analyzer can also operate in reflectance mode by placing a reflecting member in the analyzer receptor designed for receiving the cartridge, on one side of the optical chamber, such that the EMR transmitted through the sample would be reflected off the reflecting member, whereby the reflected EMR would enter the sample for the second time. In some embodiments of diagnostic measurement instruments or analyzers operating in the reflectance mode, both the EMR source and the photodetector are on the same side of the optical chamber. Moreover, those skilled in the art will also appreciate that instead of installing a reflecting member around the receptor in the housing of the analyzer, one side of the wall-portions of the optical chamber of the cartridge could be coated with a reflecting material.
A blood storage conduit is defined by a first blood storage conduit groove in one of the housing members, and either the gasket or the other housing member with or without a second blood storage conduit groove. In the embodiments where the blood storage conduit allows the blood to make contact with a surface of the gasket, the gasket is preferably made of hydrophilic material for enhancing wetting of the gasket, and the gasket adhesive is compatible with the sample. The blood storage conduit in some embodiments is simply a cut-out in the gasket with no grooves in either of the housing members. For clarity, the blood storage conduit in some embodiments, comprise a groove in the first housing member aligned with the gasket cut-out, or a groove in the second housing member alignment with the gasket cut-out. In yet other embodiments, the gasket cut-out is aligned with a first groove in the first housing member and a second groove in the second housing member. The illustration of the various embodiments of the blood storage conduit can be applied to other conduits, for example, the biosensor conduit, the blood shunt and the calibration fluid conduit, and are considered to be within the scope of the invention.
The housing of some embodiments of the disposable cartridge comprises a blood shunt (for example, 45 in
The details of the drawings are discussed next, to further describe specific embodiments of the invention not completely described in U.S. Pat. No. 9,470,673, filed by the inventor. Two different cartridge embodiments are described in details, as examples only, and a person of ordinary skill in the art will appreciate that other embodiments that are not explicitly illustrated are implied. For easy reference, Table 1 provides a list of the reference numerals used, and a brief description of the structural features referred to. Attempts are made to use the same reference numerals for similar elements and, in some cases, the letter “a” is appended to the end of the number to refer to the second embodiment of the cartridge.
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All the previous Figures are illustration of a first embodiment of a cartridge 10, and all subsequent Figures are illustration of various aspects of a second embodiment of a cartridge 10a,
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The advantage of the rupture mechanism described for cartridge embodiment 10a for releasing calibration fluid, over the rupture mechanism described for cartridge embodiment 10 and the embodiments described in U.S. Pat. No. 9,470,673, is the decreased force required to rupture the calibration fluid pouch, by direct observation.
The advantage of the fluid connection between the shunt 45a and the enlarged cavity 56a described for cartridge embodiment 10a for slowing down blood flow by capillary action, over the fluid connection between the shunt 45 and the enlarged cavity 56 described for cartridge embodiment 10 for slowing down blood flow by capillary action for cartridge embodiment 10 and the embodiments described in U.S. Pat. No. 9,470,673, is the efficiency of enlarged cavity 56a as a capillary break.
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A block diagram of an embodiment of an analyzer for measurement of at least two hemoglobin species in a patient's blood sample by spectroscopy, and measurement of at least pH of the blood sample by biosensor, for assessing the patient's oxygenation and acid-base status, is provided in
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Another embodiment of a disposable cartridge for operation with a joint spectroscopic and biosensor blood analyzer for measurement of at least two hemoglobin species in a patient's blood sample by spectroscopy, and measurement of at least pH of the blood sample by biosensor, for assessing the patient's oxygenation and acid-base status, comprises a housing having at least a first housing member and a second housing member bonded together by a gasket, wherein the housing comprises: a) a cartridge inlet; b) a blood storage conduit within the housing having a proximal end close to the cartridge inlet and a distal end away from the cartridge inlet; c) an optical chamber within the housing for receiving the blood from the distal end of the blood storage conduit and for measuring the at least two hemoglobin species; d) an optical chamber overflow chamber fluidly connected with the optical chamber; e) a biosensor conduit within the housing for receiving the blood from the optical chamber overflow chamber, the biosensor conduit comprising a proximal end, a distal end and at least a portion of a pH biosensor; f) a calibration fluid pouch for storing and releasing calibration fluid, a spike disposed in the second housing member of the cartridge for rupturing the pouch, a recess disposed in the opposite side of the second housing member, a hole in the spike for permitting flow of the calibration fluid from the pouch to the recess for channeling the calibration fluid to the biosensor conduit; g) a waste receptacle for receiving liquid waste from the biosensor conduit; h) a vent for relieving pressure in the waste receptacle; and i) an air bladder and an air bladder exit port within the housing for providing pressurized air for urging blood from the blood storage conduit into the biosensor conduit. The cartridge further comprises a compressible member surrounding the spike, for supporting the calibration fluid pouch.
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An embodiment of a joint spectroscopic and biosensor system for measurement of at least two hemoglobin species in a patient's blood sample by spectroscopy, and measurement of at least pH of the blood sample by biosensor, for assessing the patient's oxygenation and acid-base status comprises a disposable cartridge and an analyzer. The cartridge comprises a cartridge housing and the cartridge housing comprises: a) cartridge inlet; b) a blood storage conduit having a proximal end close to the cartridge inlet and a distal end away from the cartridge inlet; c) an optical chamber for receiving the blood from the distal end of the blood storage conduit and for measuring the at least two hemoglobin species, the optical chamber comprising a first optical window and a second optical window; d) an optical chamber overflow chamber fluidly connected with the optical chamber; e) a biosensor conduit for receiving the blood from the optical chamber overflow chamber, the biosensor conduit comprising a proximal end, a distal end and at least a portion of a pH biosensor; f) a pH biosensor electrical output element; g) a calibration fluid pouch containing calibration fluid for at least calibrating the pH biosensor; and h) an air bladder and an air bladder exit port.
The analyzer comprises an analyzer housing, the analyzer housing comprising: a) a receptor comprising a first opening for receiving and aligning the cartridge in an operational position; b) a source of electromagnetic radiation; c) at least one photodetector; d) a power supply; and e) a processor for controlling the analyzer. The receptor further comprises: i) a second opening for directing the electromagnetic radiation to the first optical window when the cartridge is in the operational position; ii) a third opening for directing electromagnetic radiation emerging from the second optical window to the at least one photodetector when the cartridge is in the operational position; iii) a physical interface for providing electrical contact between the pH biosensor electrical output element and the processor; and iv) a bracket mounted on the receptor for at least supporting a first stepper motor for applying force to the calibration fluid pouch against a spike for rupturing the spike and releasing calibration fluid, and a second stepper motor for forcing air from the air bladder through the air bladder exit port, for pushing the blood into the biosensor conduit.
In some embodiments, the receptor further comprises a top portion and a bottom portion, and the bottom portion comprises at least one heating element layered on the surface of the bottom portion, for heating the cartridge, and the top portion comprises a spring-loaded locating element for engaging with a notch disposed at the top of the cartridge, for forcing the cartridge against the at least one heating element.
The procedures for operating a joint spectroscopic and biosensor system comprising the analyzer illustrated in
An air bubble created in the enlarged cavity 56a and the conduit formed by connecting groove 57a positioned to provide fluid connection between enlarged cavity 56a and biosensor conduit groove 55a of cartridge 10a (see
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.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CA2017/050379 | 3/27/2017 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62316653 | Apr 2016 | US |
