Apparatus and method for determining settling velocity

Abstract

The apparatus for determining sedimentation rate comprises at least one member (8) for sampling a blood sample, and a sensor (20) having an infrared light source (12) and an optical sensor (14), the infrared light source (12) and the optical sensor (14) being arranged substantially opposite each other around the substantially transparent portion (16) of the sampling member (8) such that light emitted by the infrared light source (12) reaches the optical sensor (14) after passing through the substantially transparent portion (16). The optical sensor (14) is arranged to perform blank measurements, the apparatus further comprising a converter arranged to receive one or more light transmission measurements from the optical sensor (14), calculate a ratio between the blank measurement and the one or more light transmission measurements, and return the sedimentation rate.

Description

[Technical field]

[0001] The present invention relates to the field of hematology, and more particularly to the measurement of sedimentation rate (hereinafter also called "ESR", in English "erythrocyte sedimentation rate" or "ESR"). [Background technology]

[0002] Sedimentation rate is a routine part of the complete blood count (CBC) performed in blood tests and can detect the presence of inflammatory or infectious pathologies, such as rheumatism, cancer, and other diseases that cause changes in the protein concentration in the blood. A high ESR indicates an inflammatory state, without prejudging its nature. However, the ESR may remain low during the presence of an inflammatory syndrome. Therefore, a high ESR generally indicates the presence of a pathology. Combining this nonspecific test with complementary tests allows for a more accurate diagnosis.

[0003] The standard method for ESR measurement is the Westergren method. Thin tubes with standardized dimensions are filled with blood samples sampled with an anticoagulant, e.g. EDTA, and diluted with sodium citrate, and placed vertically. The ESR measurement is the height (in millimeters) of the plasma column after one hour of sedimentation. For example, for an adult male, a height of less than 10 mm after the first hour of sedimentation is considered normal. The normal limits are not absolute and depend on the age and sex of the patient.

[0004] ESR is the result of three steps: aggregation, sedimentation, and roll sedimentation of hemocytes.

[0005] The phenomenon of red blood cell aggregation is caused by proteins in particular in blood, the higher their concentration, the greater the force they exert. The formation of aggregates means that red blood cells pile up in a "roll-like" manner, forming a three-dimensional structure. The rate of sedimentation depends on the size of the aggregate and on the viscosity of the plasma.

[0006] In the final step, the aggregates settle, i.e., they slowly fall to the bottom of the tube and are then compressed, separating the sample into a clear translucent portion at the top (plasma) and a much darker portion at the bottom (red blood cells). The ESR is measured by the height of the translucent portion.

[0007] The most important inflammatory parameter is the aggregation phenomenon, which is directly dependent on the concentration of plasma proteins. It is this phenomenon that the present invention measures to return an ESR value. It is also a non-specific parameter, but it suppresses the interferences arising from the last two steps of the ESR. There are no standardized parameters that can express this aggregation rate or kinetics / dynamics. It is therefore important to translate the aggregation measurement to ESR.

[0008] Due to the volume of blood (1.6 ml) and the time required for completion (1 hour), the Westergren method is not compatible with hematology instruments for CBC analysis. To overcome these problems, research has been conducted using extinction optical measurements (absorption and scattering) to determine sedimentation velocity, such as in patent US 6,632,679.

[0009] Some patents have proposed incorporating an improved ESR measurement into a hematology testing device, as described in EP2921862, in which a certain amount of blood is taken and separated into two parts, one for the count (CBC) and one for the sedimentation rate measurement.

[0010] This device therefore links the counting and sedimentation velocity measurements and is disadvantageous because it requires complex equipment to dispense portions of two blood samples, one via a single sample, towards the counting portion on one side and towards the sedimentation velocity measurement portion on the other side, and further because the CBC and ESR measurement operations do not have similar requirements in sample preparation.

[0011] Others, such as the patent described in WO2011 / 101815, have proposed a portable device that can measure sedimentation velocity by measuring transmittance. This device uses a disposable capillary, but requires a blood suction system for the measurement. In addition, the method of inserting the capillary does not make the device ergonomic. Furthermore, transmittance measurement uses a capillary, which causes accuracy problems.

[0012] Document ITUA20163693A1 describes an apparatus that makes it possible to carry out hematological analyses on blood samples and to integrate the detection of the blood sedimentation rate (ESR) with the detection of other chemical and physical parameters of the blood.

[0013] Document FR2955392 describes an agglutination rate measuring device comprising a removable nozzle support, suction means connected to the support, capture means facing the support for picking up at least one physical quantity representative of the agglutination of blood components, and means for determining the agglutination rate depending on the at least one physical quantity.

[0014] There is no known device capable of determining sedimentation velocity measurements quickly, reproducibly and with a simple structure. Summary of the Invention

[0015] The present invention remedies this situation by providing an apparatus for determining sedimentation rate, the apparatus comprising at least one member for sampling a blood sample and a sensor having an infrared light source and an optical sensor arranged substantially opposite each other around a substantially transparent portion of the sampling member such that light emitted by the infrared light source reaches the optical sensor after passing through the substantially transparent portion of the sampling member, the optical sensor arranged to perform a blank measurement, the apparatus further comprising a converter arranged to receive one or more light transmission measurements from the optical sensor, calculate a ratio between the blank measurement and the one or more light transmission measurements and return the sedimentation rate.

[0016] This device is particularly advantageous as it allows reproducible determination of sedimentation velocity measurements.

[0017] According to various embodiments, the invention may have one or more of the following features. the converter is arranged to determine the time of the lowest light transmission measurement and the time of the final light transmission measurement; the optical sensor is arranged to perform a maximum gain between the time of the lowest light transmission measurement and the time of the final light transmission measurement, and a minimum gain at other times; the converter is arranged to calculate the settling velocity on the basis of the ratio between the empty measurement and the measurement at the time of the final light transmittance measurement, on the one hand, and the ratio between the empty measurement and the measurement at the time of the lowest light transmittance measurement, on the other hand; The optical sensor is controlled at a low gain before the blood passes through the substantially transparent portion and at a high gain after the blood passes through the substantially transparent portion; the sampling member being a needle that can be controlled for sampling a blood sample, to which a tube formed with a substantially transparent portion is connected, the infrared light source and the optical sensor are positioned less than 10 cm from the sampling end of the needle; the device is arranged to carry out a rinsing of the needle and the tube between two sedimentation velocity measurement determinations, the sampling member is a capillary, the sensor having a bore arranged to receive the capillary; The capillary has a lug arranged to abut against the sensor.

[0018] The present invention also relates to a method for determining sedimentation velocity, the method comprising: a) taking a blood sample; b) passing the blood sample through a substantially transparent portion disposed between the infrared light source and the optical sensor; c) measuring one or more light transmittances during operation b); and d) performing a blank measurement in the absence of a blood sample; and e) calculating a ratio between the blank measurement and the one or more light transmittance measurements and inferring therefrom the settling velocity; Includes operations.

[0019] Operation d) may be performed before operation c).

[0020] Other characteristics and advantages of the invention will appear better on reading the following description with reference to embodiments given for illustrative and non-limiting purposes and with reference to the drawings, in which: [Brief description of the drawings]

[0021] [Figure 1] Overall schematic diagram of the device according to the present invention [Diagram 2] Detailed view of the creation of the elements in Figure 1 [Diagram 3] Measurement diagram of the device in Figure 1 [Figure 4] 2 is a schematic diagram of a first embodiment of the device of FIG. 1; [Diagram 5] Schematic diagram of a second embodiment of the device of FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The drawings and the description below contain elements of an essentially constant nature, which therefore serve not only to better understand the invention but also, where appropriate, to contribute to its definition.

[0023] 1 is a general schematic diagram of an apparatus 2 for performing a complete blood count and determining a sedimentation velocity measurement according to the present invention. The apparatus 2 comprises a first group 4, a second group 6, a sampling member 8 and a converter 10.

[0024] The first group 4 is arranged to sample the blood sample in the tube and mainly perform a complete blood count on this sample. This measurement can be performed in a conventional manner and is known elsewhere. There are many blood testing devices that specialize in this measurement. Other blood analyses than CBC can also be performed in group 4, such as glycosylated hemoglobin (HbA1c) measurement, C-reactive protein (CRP), etc.

[0025] The second group 6 is arranged to determine an ESR measurement, and it is to this second group that the present invention is primarily directed. Indeed, as mentioned at the beginning, this test, whether carried out according to the conventional method or by measuring the change in absorbance, is either cumbersome or coupled with a CBC measurement, slowing down the operation of the whole device.

[0026] The implementation of the second group 6 according to the invention allows for the extrapolation of sedimentation velocity measurements by varying the absorbance in a manner that is decoupled from the CBC or other blood measurements. For this purpose, the second group 6 is arranged to control the sampling member 8, here a needle, independently of the first group 4, i.e. the samples sampled by the first group 4 are used only for the CBC or other blood measurements and the samples sampled by the second group 6 are used only for the ESR measurements.

[0027] Thus, as shown in Figure 1, the first group 4 or the second group 6 controls a needle 8 to sample a blood sample in a blood tube 11. This sample is then brought to the first group 4, where a blood measurement, such as a CBC measurement, is performed, or to the second group 6, where a measurement of the change in absorbance is performed. In the last case, the measurement is sent to the converter 10, which returns an ESR signal and / or an ESR measurement.

[0028] 2 shows an embodiment of the second measuring group 6. According to this embodiment, the second measuring group 6 is made up of a light source 12 and an optical sensor 14 assembled opposite each other around a tube 16 intended to transport the blood sample sampled by the needle 8 from the blood tube 11 towards the interior of the device 2.

[0029] In the embodiment described herein, the light source 12 is of the LED type, preferably with an infrared wavelength in the range of 700-980 nm, in particular 800 nm, which is the iso-saturation point between oxyhemoglobin and deoxyhemoglobin, making the measurement less sensitive to blood oxygen saturation. In the embodiment described herein, the optical sensor 14 is of the photodiode type and may be selected among PMT, PDA, CMOS, etc. sensors. In the embodiment described herein, the tube 16 is made of Teflon and is connected to the needle 8. Alternatively, the tube 16 may be made of glass or plastic and should be selected to provide good transparency for the wavelength of the light source 12.

[0030] The light source assembly 12 and the optical sensor 14 can be seen as one sensor 20 of the second group 6. As in the example described here, they may be made as two parts that are assembled to sandwich the needle 8 (e.g. made of metal) and the tube 16. Alternatively, the light source 12 and the optical sensor 14 may be integrated. Preferably, the sensor 20 is placed fairly close to the tip of the needle 8, less than 10 cm, to optimize the shearing of the red blood cells. Preferably, this distance is about 5 cm for best results. In a variant, the sensor 20 may be placed directly at the exit of the needle 8.

[0031] Whatever its configuration, the second group 6 can advantageously use needle 8 diameters conventionally in the range of 1 mm. Indeed, during sampling by the needle 8, the red blood cells undergo continuous deformations, as will be explained below and shown in FIG.

[0032] Thus, when the needle 8 is immersed in the blood tube 11, the second group 6 controls the aspiration by the needle 8, already primed with diluent, in order to sample blood. This is achieved by automated control means, preparation trays, solenoid valves and syringes, which are known and are not shown for simplicity. These means cause the movement of the diluent occupying the tube 16. In this step, the sensor 20 measures a constant light signal, since the tube 16 and the diluent contained therein are translucent.

[0033] An aliquot of blood is then moved by suction to the sensor 20. The red blood cells are sheared and clumps are broken. At this step, the optical signal remains at a maximum because the blood has not yet faced the sensor 20. In Figure 3, this is indicated by reference numeral 30.

[0034] When blood reaches the sensor, the optical signal represents the blood shear state, during which red blood cells have an elongated shape, as shown by reference numeral 31.

[0035] When the suction is stopped to stop the shearing, the light transmission signal drops as the red blood cells return to their biconcave disk relieved form, shown as 32 in FIG. 3. The light signal then increases according to a pseudo-logarithmic progression. The progressive increase in the optical signal measured by the optical sensor 14 is associated with the progressive aggregation of the free red blood cells. Aggregation occurs by the red blood cells stacking into rolls and then forming three-dimensional structures shown as 34 and 36 in FIG. 3.

[0036] Beyond about 40 s, depending on the blood, clumping slows considerably and sedimentation begins, which prevents the correlation of clumping with sedimentation velocity, the measurement of interest. After t4, an aliquot of blood is drained, for example by moving needle 8 over the tray, thus draining the blood and rinsing tube 16 with diluent, and at the end of this step tube 16 is completely filled with diluent as at the start of the procedure described herein above.

[0037] The four time points are shown in FIG. Before time t1, the tube 16 is filled with diluent. - Time t1 indicates the time when blood reaches the level of the sensor 20 by suction. - Time t2 indicates the time when suction stops. - Time point t3 marks the point from which the red blood cells regain their relaxed shape and aggregation begins. - Time point t4 marks the end of the treatment with the blood being drained and replaced again by diluent as before time point t1.

[0038] 3, it may seem paradoxical that after time t4, while tube 16 is filled with diluent, the optical signal is less significant than when tube 16 is filled with blood, which is explained in the embodiment described herein by the fact that optical sensor 14 is conditioned differently before time t1 and after time t4 in FIG.

[0039] Therefore, before time t1 and after time t4, the measurements are determined to correspond to "blank" measurements. During this period, the optical sensor 14 is adjusted by the converter 10 with a minimum measurement gain.

[0040] Time t3 corresponds to the lowest point of the period t1-t4, beyond which the optical signal begins to increase, which indicates the onset of the phenomenon that the present invention seeks to measure, as described herein above. For this reason, and because the variations in the optical signal remain small between times t0 and t1, in the embodiment described herein, the optical sensor 14 is conditioned at minimum gain until time t1, at maximum gain between times t1-t4, and again at minimum gain after time t4 for the next measurement.

[0041] This is further advantageous since in the embodiment described herein the converter 10 is arranged to determine the measurement based on the optical density of the signal measured by the optical sensor 14, where the optical density is defined by the formula DO(t)=log(KI / I(t)), where I(t) is the measurement of the optical sensor at time t and K is the maximum gain / minimum gain ratio. More specifically, the converter 10 is arranged to return a sedimentation velocity measurement based on the ratio DO(t3) / DO(t4). The applicant has carried out a large number of sedimentation velocity measurements using the Westergren criteria method, which allows the converter 10 to relate the measurement thus calculated to an ESR value.

[0042] The applicant has found it particularly advantageous to use optical density, which allows independence from the variability of the transmission measurements. The applicant has also found that the converter 10 can also operate on the basis of the ratio I(t4) / I(t3), without taking into account optical density in the Beer-Lambertian sense and without using I0 differently in the calculation.

[0043] The converter 10 may be created in various ways, for example in the form of a suitable computer code executed on one or more processors. By processor, we mean any processor suitable for the calculations described herein. Such a processor may be made in any known manner in the form of a microprocessor for a personal computer, laptop, tablet or smartphone, a dedicated chip of FPGA or SoC type, a computing resource on a grid or on the cloud, a cluster of graphical processors (GPUs), a microcontroller, or any other form capable of providing the computing power required for the completion of the processes described herein. One or more of these elements may be made in the form of a specialized electronic circuit, such as an ASIC. A combination of a processor and an electronic circuit is also conceivable. In the case of a machine learning unit based on gradient boosting, a processor dedicated to machine learning is also conceivable. Alternatively, the converter 10 may be an analog computer without programming or computer code.

[0044] As a further alternative, the converter 10 can use machine learning algorithms (in English "machine learning"), which may or may not include neural networks (deep or not). This involves correlating the intensity measurements of the optical sensor 14 with values ​​of the sedimentation velocity. This variant may be particularly useful to implement without optical density. As a further alternative, the gain of the optical sensor 14 can be the same for all measurements at any one time.

[0045] Figure 4 is a schematic diagram showing an embodiment of the device of Figure 1. As shown in this figure, device 2 is a conventional blood testing device that includes a syringe 40 with a diameter of 1.5 mm and a syringe 42 with a diameter of 16 mm, both of which are connected to a needle 8. Sensor 20 is integrated into needle 8 so as to cover the end of tube 16 connected to needle 8.

[0046] The apparatus 2 of FIG. 4 is adapted to perform CBC measurements, ESR measurements, or both.

[0047] For the CBC measurement, the whole circuit is primed with diluent, the needle 8 hits the blood tube 11 and samples 10 μl with the syringe 40. The needle 8 is then lifted and placed on the preparation tray, the outside of the latter is washed on this tray and drained to waste. Finally, a mixture of 10 μL of sample and 1 mL of diluent (for example) is dispensed immediately after sampling with the syringe 42 into the preparation tray. This initial diluent is then used for the various preparations to perform the CBC measurement.

[0048] For the ESR measurement, the procedure proceeds as described herein with reference to Figures 1 to 3. The entire circuit is primed with diluent pumped from the reservoir 44 and a few μL of air bubble is created at the tip of the needle 8. The needle 8 is lowered into the blood tube 11 and an aliquot of 50 μL to 100 μL is sampled with the syringe 42. The needle 8 is raised and the aliquot is transferred to the sensor 20 and an optical measurement of agglutination is made. Finally, the needle 8 is rinsed internally and externally in a tray and drained to waste. An empty measurement (I0) may be taken before sampling or at the end of the rinse. An optional before and after comparison of the empty measurement allows exception handling, e.g. control of the rinse.

[0049] The CBC and ESR cycles are performed independently of each other, in particular with separate sampling by needle 8. An aliquot for a CBC measurement cannot be used for an ESR measurement and vice versa.

[0050] A mixture of 10 μL of sample and 1 mL of diluent (for example) is dispensed immediately after sampling in the preparation tray with a syringe 42. This initial diluent is then used for the various preparations for performing the CBC measurement.

[0051] This allows the two measurements to be decoupled without problematic blood sampling if both measurements are required. This independence means that the ESR measurement does not significantly impact the work rate of device 2, allowing for low-cost integration in terms of both equipment and personnel.

[0052] FIG. 5 is a schematic diagram illustrating another embodiment suitable for implementation in a portable device for determining ESR.

[0053] In this embodiment, the sampling member 8 is implemented by a disposable capillary 54. This allows sampling of just one drop of blood from the patient's finger, avoiding blood collection by venipuncture.

[0054] The device 2 thus comprises a case 50 housing the converter 10 and the sensor 20. The case 50 thus encloses the light source 12 and the optical sensor 14 which are received opposite each other around a bore 52 in the case 50.

[0055] As before, the light source 12 is preferably of the LED type with an infrared wavelength in the range of 700-980 nm, in particular 800 nm, and the optical sensor 14 is of the photodiode type and may be chosen among PMT, PDA, CMOS sensor etc.

[0056] As shown in FIG. 6, when capillary 54 is inserted into bore 52, blood contained therein can rise up into case 50 by capillary action.

[0057] In the example described herein, the capillary 54 is made of Teflon and has a diameter of 0.8 mm. Alternatively, the capillary 54 may be made of glass or plastic and should be selected to provide good transparency to the wavelength of the light source 12. As a further alternative, the diameter of the capillary 54 may be configured between 0.5 mm (lower values ​​may prevent the formation of large aggregate structures and make the optical measurement window too small) and 1.5 mm (higher values ​​may result in insufficient capillary forces).

[0058] In the embodiment described herein, the capillary has a lug 56 that butts against the case 50 to control the entry of the tube 14 into the bore 52. The distance from the lug 56 to the end of the capillary 54 is set at 15 mm in the embodiment described herein. The upper and lower limits are determined by the following constraints: too close and the sensor 20 will interfere with the finger blood sampling, too far and too much capillary force will be required. Alternatively, the tube 54 can be provided with markings or other means by which the placement of the tube 54 in the bore 52 can be monitored. Alternatively, none is provided.

[0059] In this embodiment, the shape of the signal is slightly different, since the suction is performed by capillary action.Figure 7, which is also comparable to figure 3, shows the course of the measured signal at the output of the optical sensor 14.

[0060] As shown in this figure, the portion before time t1 and the portion after time t4 do not exist because the capillary is intended for one-time use. - Reference 1 corresponds to the period before time t1 in Figure 3. The measurement is made through an empty capillary 54 and constitutes I0 for the low gain calculation. The transmittance of the empty capillary 54 is 30 times that of blood. Under these conditions it is preferable to maintain the high gain / low gain mode. - Criterion 2 corresponds to time t2-t3 in Figure 3. Blood reaches the sensor and the transmittance drops instantly to 0. This edge can be detected and used to control a flip-flop from low gain to high gain. - Reference 3 corresponds to a point after time t3 in Figure 3. Blood flows through the capillary. It is in a sheared state. This slight slope is due to the blood slowing down and shearing occurring. - Criterion 4 corresponds to the end of sampling. When the blood passes the sensor, the user removes the system. The separation of the capillary and the blood drop causes an "abrupt" stop of the capillary rise. This is reflected by a peak and then a drop (pointed out by criterion 4). - Criterion 5 corresponds to the cohesion stage.

[0061] The converter 10 may be connected to any type of interface, for example a laptop computer, a notebook computer. It may also be a smartphone type interface equipped with a dedicated application. In this case, the sensor 20 incorporates optical components and electronic resources that allow interfacing with standard means of communication, for example USB. The interface may also be a proprietary system. This solution allows a strict reduction of the components integrated in the sensor (LEDs and photodiodes), but also a human-machine interface perfectly suited to the needs. Preferably, a touch screen is used, which by use can provide, in particular, a virtual keyboard for entering identifiers and other information related to the analysis performed.

Claims

1. 1. An apparatus for determining sedimentation velocity, comprising: At least one member (8) for sampling a blood sample, a sensor (20) having an infrared light source (12) and an optical sensor (14); the infrared light source (12) and the optical sensor (14) are disposed substantially opposite each other around the substantially transparent portion (16) of the sampling member (8) such that light emitted by the infrared light source (12) reaches the optical sensor (14) after passing through the substantially transparent portion (16); The optical sensor (14) is arranged to perform a blank measurement; The apparatus further comprises a converter (10) arranged to receive one or more light transmission measurements from said optical sensor (14), calculate a ratio of a blank measurement to the one or more light transmission measurements, and return a sedimentation velocity.

2. 2. The device according to claim 1, wherein the converter (10) is arranged to determine the time of the lowest light transmission measurement (t3) and the time of the final light transmission measurement (t4).

3. 3. The apparatus of claim 2, wherein the optical sensor (14) is positioned to implement a maximum gain between the time of the lowest light transmittance measurement (t3) and the time of the final light transmittance measurement (t4), and to implement a minimum gain at other times.

4. 4. The device according to claim 2 or 3, wherein the converter (10) is arranged to calculate the sedimentation velocity based on the ratio between the empty measurement and the measurement at the time (t4) of the final transmittance measurement, on the one hand, and the ratio between the empty measurement and the measurement at the time (t3) of the lowest light transmittance measurement, on the other hand.

5. 5. The apparatus of claim 1, wherein the optical sensor (14) is controlled at a low gain before blood passes through the substantially transparent portion and at a high gain after blood passes through the substantially transparent portion.

6. 6. The device according to claim 1, wherein the sampling member is a needle (8) that can be controlled for sampling a blood sample to which a tube (16) having the substantially transparent portion (16) is connected.

7. 7. The apparatus of claim 6, wherein the infrared light source (12) and the optical sensor (14) are positioned less than 10 cm from the sampling end of the needle (8).

8. 8. An apparatus according to claim 6 or 7, arranged to carry out a rinsing of the needle (8) and the tube (16) between two determinations of sedimentation velocity measurements.

9. The sampling member (8) is a capillary (54), The apparatus of any one of claims 1 to 5, wherein the sensor (20) has a bore (52) positioned to receive the capillary (54).

10. The apparatus of claim 9, wherein the capillary (54) has a lug (56) positioned to abut the sensor (20).

11. 1. A method for determining sedimentation velocity comprising the steps of: a) taking a blood sample; b) passing the blood sample through a substantially transparent portion disposed between the infrared light source and the optical sensor; c) measuring one or more light transmittances during operation b); and d) performing a blank measurement in the absence of a blood sample; e) calculating a ratio between said blank measurement and said one or more light transmittance measurements and inferring a settling velocity from said ratio.

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