In vitro diagnostic analyzer and operation method thereof

Abstract

The present application relates to an in vitro diagnostic IVD analyzer comprising an optical detection unit comprising a cuvette for optical measurement of a biological sample. The IVD analyzer further comprises: a piezoelectric actuator for transmitting ultrasonic waves through the cuvette; a piezoelectric receiver for receiving the ultrasonic wave emitted through the cuvette; and a controller for operating according to any one of the splitting operation mode or the air detection operation mode. In accordance with the lysis mode of operation, the piezoelectric actuator emits ultrasonic waves through the cuvette for disrupting cellular particles contained in the biological sample. According to the air detection mode of operation, the piezoelectric actuator is used for transmitting ultrasonic waves through the cuvette, and the controller is used for correlating the amplitude variation and / or phase shift of the ultrasonic waves received by the piezoelectric receiver relative to a reference value with the final presence and quantity of air in the cuvette, in order to determine whether the optical measurement of the biological sample is affected by the presence of air.

Description

Technical Field

[0001] The invention relates to an in vitro diagnostic analyser comprising an optical detection unit and configured to determine the presence of air bubbles interfering with optical measurements, and to an automated method of operating an in vitro diagnostic analyser in order to determine whether optical measurements of a biological sample are affected by the presence of air. Background Art

[0002] In medicine, doctors' diagnoses and patients' treatments often rely on the measurement of patient sample parameters by in vitro diagnostic analyzers. It is important that the analyzer performs accurately by providing precise and reliable measurements. Therefore, a general requirement for in vitro diagnostic analyzers is to implement workflows that ensure analytical performance.

[0003] Some in vitro diagnostic analyzers include a fluidic system including a detection unit (including, for example, an optical detection unit), including, for example, a flow-through cuvette for optically measuring a biological sample introduced therein. The analytical workflow typically includes the use of additional fluids in addition to the sample, which are sequentially introduced into the fluidic system.

[0004] Examples of sample parameters that can be determined by optical measurements of biological samples such as blood include hemoglobin (Hb) and hemoglobin derivatives. In turn, additional sample parameters such as oxygen saturation (SO) can be derived based on previous measurements. 2 ) and total hemoglobin (tHb = sum of all hemoglobin). To perform these measurements, the blood sample in a cuvette is usually lysed (hemolyzed) by destroying cell particles (including red blood cells containing hemoglobin) to minimize light scattering caused by the cells.

[0005] Some analyzers may include a piezoelectric actuator, which essentially consists of a piston driven by a piezoelectric ceramic, typically vibrating at a frequency of 40–50 kHz, arranged on one side of the cuvette, which is configured to transmit ultrasound through the cuvette. In the process, the red blood cell membrane is disrupted by cavitation and hemoglobin is released.

[0006] A problem often encountered with this fluidic setup is that bubbles of various sizes may appear in the cuvette, which may interfere with the optical measurement. Specifically, bubbles, in addition to reducing the volume of the sample in the optical path, may cause light scattering and may reduce lysis performance due to air compression. In addition, the oxygen content in the bubbles can change the real oxygen content in the sample being measured. Summary of the invention

[0007] In contrast to the above background technology, aspects of the present disclosure provide certain non-obvious advantages and advances over the prior art. Specifically, a new in vitro diagnostic analyzer (IVD) is disclosed herein, which includes an optical detection unit, which includes a cuvette, which has minor hardware and software modifications relative to known analyzers, enabling effective lysis of biological samples in the cuvette and determining whether there is air in the cuvette that affects the optical measurement of the sample.

[0008] A corresponding automated method having the same advantages is also disclosed herein.

[0009] Specifically, the IVD analyzer of the present disclosure includes: an optical detection unit, which includes a cuvette for optically measuring a biological sample contained therein; a piezoelectric actuator arranged on one side of the cuvette, which is configured to transmit an ultrasonic wave through the cuvette; a piezoelectric receiver arranged on the opposite side of the cuvette, which is configured to receive the ultrasonic wave transmitted through the cuvette; and a controller, which is configured to operate according to either a lysis operation mode or an air detection operation mode. According to the lysis operation mode, the piezoelectric actuator is configured to transmit an ultrasonic wave through the cuvette for destroying cell particles contained in the biological sample. According to the air detection operation mode, the piezoelectric actuator is configured to transmit an ultrasonic wave through the cuvette, and the controller is configured to associate the amplitude change and / or phase shift of the ultrasonic wave received by the piezoelectric receiver relative to a reference value with the final presence and amount of air in the cuvette, so as to determine whether the optical measurement of the biological sample is affected by the presence of air.

[0010] As used herein, the term "in vitro diagnostic analyzer" or "IVD analyzer" refers to an automated or semi-automated analytical device that is configured to analyze in vitro samples to provide information for screening, diagnosis or treatment monitoring purposes. The IVD analyzer can be designed and configured according to the medical application field, the parameters to be determined and the corresponding laboratory workflow. For example, in a field care testing environment, the IVD analyzer can be changed from a handheld device with low throughput, short turnaround time and a limited number of measurable parameters to a compact desktop instrument with higher throughput and a higher number of measurable parameters. Such IVD analyzers are designed to detect certain types of parameters, such as gases, electrolytes, metabolites, clinical chemistry analytes, immunochemical analytes, coagulation parameters, hematology parameters, etc. According to the parameters of interest, a variety of different analytical methods and different detection techniques can be applied. For example, in the field of blood gas and electrolyte testing, electrochemical measurement principles and / or conductivity measurement principles and / or optical detection methods are generally used. The IVD analyzer generally includes a plurality of functional units, each of which is dedicated to a specific task and cooperates with each other to achieve automated sample processing and analysis. Such functional units may include, for example, a sample input interface for receiving a sample, a fluid system, an analytical measurement unit or a detection unit, a fluid supply unit, etc. One or more functional units may be integrated into a larger unit or module in order to simplify the operation of the IVD analyzer.

[0011] Specifically, the IVD analyzer of the present disclosure includes at least an optical detection unit, which includes a cuvette arranged between a light source and a photodetector (usually a spectrophotometer) for optically measuring a biological sample contained therein. A "cuvette" is a container or chamber that typically includes at least two parallel, straight and transparent walls at a predetermined distance from each other corresponding to the optical path between the light source and the detector, so that the intensity of light in a portion of the spectrum transmitted or emitted by a specific substance present in a sample placed therein can be measured. The optical detection unit can be embodied as a flow-through optical detection unit, which includes a flow-through cuvette or a flow-through optical path, so that fluids such as samples and possibly other fluids can flow in and out.

[0012] The IVD analyzer may further include an additional detection unit, which includes a "flow sensor path", which is a fluid conduit including one or more sensors, and the sample flowing through the sensor path contacts the one or more sensors, such as arranged in sequence along the path, such as sensors for each different parameter / analyte to be detected, and may be embodied in a replaceable box-like structure including multiple sensors, and multiple sensors may be distributed on multiple sensor paths. Alternatively, the IVD analyzer may include multiple detection units, each detection unit having a sensor path including a sensor specifically for a parameter / analyte, and may also be replaceable or non-replaceable. Therefore, the sample may flow into one or more sensing paths, and different parameters / analytes may be determined by the corresponding sensors. The term "sensor" is generally used herein to indicate a detector configured to detect sample parameters by generating a related signal output that can be quantified and digitized. The sensor may be, for example, a biosensor, a chemical sensor, or a physical sensor, and is typically a part of a functional unit (e.g., an analytical measurement unit or a detection unit) of an IVD analyzer. The sensor may be selective or specific with respect to a sample parameter of interest, or may be configured to detect and quantify a variety of different sample parameters of interest. Depending on the type of sensor, the sensor may include multiple sensing elements. Thus, the term "sensing element" refers to a portion of a sensor (e.g., a working electrode, a reference electrode, a counter electrode) that is combined with one or more other sensing elements to form a fully functional sensor. According to an embodiment, the flow sensor path includes any one or more of the following: pO 2 Sensors, pCO 2 Sensors, pH sensors, for determining electrolyte values ​​(such as Na + , K + , Ca 2 + and Cl-), one or more ion selective electrode (ISE) sensors for determining parameters such as lactate and glucose. The sensors may be, for example, based on the amperometric principle, the potentiometric principle or the conductometric principle, respectively.

[0013] The IVD analyzer may further comprise at least one pump (e.g. a peristaltic pump, a syringe pump, a diaphragm pump or any other suitable pump) for conveying, for example, a sample from a sample container, a cleaning fluid and possibly other fluids from a fluid supply unit, or ambient air through one or more detection units.

[0014] Specifically, the IVD analyzer of the present disclosure includes a piezoelectric actuator arranged on one side of the cuvette, which is configured to transmit ultrasonic waves through the cuvette, and a piezoelectric receiver arranged on the opposite side of the cuvette, which is configured to receive ultrasonic waves transmitted by the piezoelectric actuator through the cuvette. Ultrasonic waves are sound waves generated by vibrations. When propagating in a medium such as air, liquid or solid, these vibrations produce areas of more or less densely packed particles. Sound waves propagate faster in denser substances because adjacent particles are more likely to collide with each other. Therefore, the propagation speed of sound waves in liquids is much faster than in air. For example, in fresh water at room temperature, the propagation speed of sound is 4.3 times the propagation speed in air at the same temperature.

[0015] The term "piezoelectric actuator" is used herein to refer to an ultrasonic generator using a piezoelectric crystal, which is usually embodied as a film or thin layer with multiple tiny interlocking crystal domains of positive and negative charge. By applying a voltage, the crystal can undergo expansion or contraction. In particular, by applying a modulated voltage, vibration of the crystal can be obtained. Depending on the design, such as material, shape, thickness and vibration mode (e.g. radial mode or thickness mode), the crystal can vibrate in different frequency ranges and have different resonant frequencies.

[0016] Piezoelectric crystals can also operate in the opposite manner, i.e. when compressive or tensile mechanical stress is applied to the element, the crystal produces a proportional voltage and its signal can be used to measure, for example, vibration, strain and pressure, thereby operating as a sensor or detector.

[0017] The term "piezoelectric receiver" is used herein to indicate a piezoelectric crystal which may be similar or even identical in structure to the piezoelectric crystal of the piezoelectric actuator, but which acts as a detector of the ultrasonic wave emitted by the piezoelectric actuator through the cuvette, i.e. by measuring the voltage generated as a result of the vibrations induced on the piezoelectric receiver by the emitted ultrasonic wave. In particular, by measuring the generated voltage, the wave energy and, therefore, the wave amplitude can be determined. This is because the energy of a wave is closely related to the amplitude of the wave. The relationship between the energy of a wave and the amplitude of a wave is given by the formula E∝A 2 Given, where E represents the energy of the wave and A represents the amplitude of the wave. We can see that the energy of a wave is proportional to the square of the amplitude of the wave. Therefore, if there is a small change in the energy, it will result in a square change in the amplitude. When a wave travels from one medium to another, part of the wave passes through the new medium and the rest is reflected back. Therefore, changing the medium results in a decrease in energy, which directly results in a change and more accurately a decrease in the amplitude.

[0018] When an acoustic wave is transmitted from a liquid (such as a sample contained in a cuvette) into air that is ultimately also present in the cuvette, a change in the wave amplitude, in particular a reduction or attenuation of the wave amplitude, can be observed when compared to the same wave traveling only through a sample filling the cuvette in the absence of air bubbles. Specifically, the change in the received wave amplitude relative to a reference value (obtained under the same conditions of sample filling the cuvette in the absence of air bubbles) can be correlated to the presence and amount of air in the cuvette in order to determine whether optical measurements of biological samples are affected by the presence of air.

[0019] Typically, when a wave passes from a medium (e.g. a liquid medium like a sample) into another medium (such as air), a shift in the wave phase relative to a reference wave phase (observed under identical conditions with the sample-filled cuvette in the absence of bubbles) can also be observed and can therefore be correlated to the presence and amount of air in the cuvette.

[0020] In general, changes in wave amplitude and more specifically attenuation / reduction and / or shifts in wave phase may also be associated with different states of the sample, such as different levels of hematocrit and / or with a lysed or unlysed sample state and / or with the presence of a clot.

[0021] According to an embodiment, the piezoelectric actuator and the piezoelectric receiver are in a ring shape so as to form an optical window in the middle of the ring for optically measuring the biological sample through the cuvette.

[0022] The term "sample" refers to a biological material that may contain one or more target analytes and whose detection or analysis, qualitative and / or quantitative measurement may be associated with a clinical condition. The sample may be from any biological source, such as a physiological fluid, including blood, saliva, lens fluid, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. The test sample may be pretreated before use, such as preparing plasma or serum from blood, diluting viscous fluids, lysing, etc.; the treatment method may involve filtration, centrifugation, distillation, concentration, inactivation of interfering components, and addition of reagents. In some cases, the sample may be used directly as obtained from the source or may be used following a pretreatment and / or sample preparation workflow to modify the characteristics of the sample (e.g., after adding an internal standard, after diluting with another solution, or after mixing with a reagent), for example: to enable one or more in vitro diagnostic tests, or for enriching (extracting / separating / concentrating) the target analyte and / or removing matrix components that may interfere with the detection of the target analyte.

[0023] According to one aspect, the sample is blood or a blood derivative, such as plasma or serum.

[0024] According to certain aspects, the analyte of interest is hemoglobin, hemoglobin derivatives such as deoxyhemoglobin (HHb), oxyhemoglobin (OHb), or 2 Hb), carboxyhemoglobin (COHb), methemoglobin (MetHb), bilirubin, urea, creatinine. In turn, additional sample parameters such as oxygen saturation (SO 2 =O 2 Hb / (O 2 Hb+HHb)) and total hemoglobin (tHb = sum of all hemoglobin). Other analytes of interest are gases typically measured in the flow-through sensor path, such as O 2 and CO 2 ; Blood electrolytes, such as sodium (Na + ), potassium (K + ), chloride (Cl - ), calcium (Ca ++ ), proton (H + ); metabolites such as glucose and lactate, etc. However, this list is not exhaustive.

[0025] The sample typically enters the fluid system via a sample input interface different from the fluid supply unit, which is another module or component of the in vitro diagnostic analyzer, which is typically arranged at a position that is conveniently accessible to the operator and is configured to transfer the sample from the sample container brought up by the operator to the in vitro diagnostic analyzer. The sample input interface can, for example, include a sample input port, which includes an outer input port side and an inner input port side, the outer input port side being configured for coupling, attachment, connection, placement, introduction or insertion of a sample container (e.g., capillary type or syringe type), the inner input port side being coupled to or for coupling to one end of a sample input conduit, which is fluidically connected to or connectable to one or more detection units.

[0026] The term "controller" as used herein may include any physical or virtual processing device, and specifically a programmable logic controller running a computer readable program having instructions to perform operations according to an operation plan and specifically according to a method of operating an IVD analyzer as disclosed herein, so as to determine whether the optical measurement of a biological sample is affected by the presence of air. The controller may include a processor, a controller, a central processing unit (CPU), a microprocessor, a microcontroller, a reduced instruction set circuit (RISC), an application specific integrated circuit (ASIC), a logic circuit, or any other circuit or processor configured to perform one or more of the functions / methods described herein. Specifically, in addition to other possible configurations and functions, the controller is configured to associate the amplitude change and / or phase shift of the ultrasonic wave received by the piezoelectric receiver relative to a reference value with the final presence and amount of air in the cuvette, so as to determine whether the optical measurement of the biological sample is affected by the presence of air.

[0027] In particular, the controller is configured to operate according to either the lysis mode of operation or the air detection mode of operation. The term "either" is used herein to indicate that the controller is configured to operate according to both the lysis mode of operation and the air detection mode of operation, typically one mode at a time, although in principle the controller may be configured to operate according to both the lysis mode of operation and the air detection mode of operation simultaneously.

[0028] The "lysing operating mode" is a mode in which the piezoelectric actuator has the function of transmitting ultrasound through the cuvette in order to destroy (lyse) cell particles contained in the biological sample, while the piezoelectric receiver does not have any specific function in the lysing operating mode. In this process, the membranes of cells (e.g., red blood cells) contained in the sample are destroyed by cavitation and their contents (e.g., hemoglobin) are released.

[0029] An "air detection mode of operation" is a mode in which the piezoelectric actuator and piezoelectric receiver cooperate with each other to determine whether optical measurements of a biological sample are affected by the presence of air, thereby collectively performing an entirely different function relative to the lysis mode of operation.

[0030] Furthermore, the ultrasonic waves emitted by the piezoelectric actuator in accordance with the air detection mode of operation may have a different amplitude and / or frequency relative to the ultrasonic waves emitted in accordance with the lysis mode of operation.

[0031] According to an embodiment, the amplitude is greater than about 200 V (e.g., about 400-500 V or more) according to the lysis operation mode, and is less than about 50 V (e.g., about 10-20 V) according to the air detection operation mode. This is because in order to obtain lysis, higher vibration energies are generally required, while in order to detect the presence of air, much lower energies are sufficient.

[0032] According to an embodiment, the frequency is less than about 60 KHz (e.g., about 40-50 KHz) according to the lysis operation mode, and is greater than about 60 KHz (e.g., about 90-200 KHz) according to the air detection operation mode. Specifically, by increasing the frequency and thereby reducing the wavelength of the emitted ultrasonic waves (wavelength is inversely proportional to frequency according to the formula λ=v / f, where v is the velocity, λ is the wavelength and f is the frequency), the sensitivity to smaller objects (such as smaller bubbles) can be increased, given a certain cuvette thickness (i.e., the distance between the cuvette walls), typically in the range of up to several millimeters.

[0033] According to an embodiment, according to the air detection operation mode, the controller is configured to scan a predetermined resonant frequency range and associate the changes in the received wave amplitude spectrum relative to the reference wave amplitude spectrum and / or the shift of the wave phase profile relative to the reference wave phase profile with the presence and amount of air in the cuvette. Specifically, in the lysis operation mode, it may be advantageous to set the fixed frequency to the resonant frequency of the piezoelectric actuator or close to the resonant frequency of the piezoelectric actuator to maximize the vibration energy and efficiency, while in the air detection mode, due to variable conditions (which may include different bubble sizes, variable ambient temperature, etc.), it may be advantageous to scan the vibration frequency within the frequency range in order to collect more data and detect changes over a wider spectrum (e.g., by analyzing the amplitude spectrum and / or wave phase profile rather than a single value).

[0034] According to an embodiment, the controller is configured to operate the IVD analyzer according to the air detection operating mode before and after operation according to the lysis operating mode in order to additionally determine by comparison the lysis result obtained during the lysis operating mode.

[0035] The present disclosure also relates to an automated method of operating an IVD analyzer, the IVD analyzer comprising an optical detection unit, comprising a cuvette for optically measuring a biological sample contained therein; a piezoelectric actuator disposed on one side of the cuvette, configured to transmit an ultrasonic wave through the cuvette; a piezoelectric receiver disposed on an opposite side of the cuvette, configured to receive the ultrasonic wave transmitted through the cuvette; and a controller configured to operate according to either a lysis operation mode or an air detection operation mode. According to the lysis operation mode, the method comprises transmitting an ultrasonic wave through the cuvette by the piezoelectric actuator for destroying cell particles contained in the biological sample, and wherein, according to the air detection operation mode, the method comprises transmitting an ultrasonic wave through the cuvette by the piezoelectric actuator, and correlating an amplitude change and / or a phase shift of the ultrasonic wave received by the piezoelectric receiver relative to a reference value with the final presence and amount of air in the cuvette, so as to determine whether the optical measurement of the biological sample is affected by the presence of air.

[0036] According to an embodiment, the method includes forming a piezoelectric actuator and a piezoelectric receiver into a ring shape so as to form an optical window in the middle of the ring for optically measuring a biological sample through a cuvette.

[0037] According to an embodiment, the method comprises emitting ultrasonic waves according to the air detection operating mode, the ultrasonic waves having a different amplitude and / or frequency with respect to the ultrasonic waves emitted according to the lysis operating mode.

[0038] According to an embodiment, the amplitude is greater than about 200V (eg, about 400-500V or greater) according to the lysis mode of operation and less than about 50V (eg, about 10-20V) according to the air detection mode of operation.

[0039] According to an embodiment, the frequency is less than about 60 KHz (eg, about 40-50 KHz) according to the fragmentation operation mode, and is greater than about 60 KHz (eg, about 90-200 KHz) according to the air detection operation mode.

[0040] According to an embodiment, according to the air detection operating mode, the method comprises scanning a predetermined resonant frequency range and correlating changes in the received wave amplitude relative to a reference wave amplitude spectrum and / or shifts in the wave phase profile relative to a reference wave phase profile to the presence and amount of air in the cuvette.

[0041] According to an embodiment, the method comprises performing an optical measurement on the biological sample if it is determined that the optical measurement is not affected by the presence of air.

[0042] According to an embodiment, the method comprises operating the IVD analyzer according to the air detection operating mode before and after operating the IVD analyzer according to the lysis operating mode, so as to additionally determine by comparison the lysis results obtained during the lysis operating mode.

[0043] Other and further objects, features and advantages will appear from the following description of exemplary aspects and accompanying drawings, which serve to explain the principles in more detail. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 An IVD analyzer is schematically shown and includes an optical detection unit and a controller configured to operate according to either a lysis mode of operation or an air detection mode of operation.

[0045] Figure 2A Schematically shows Figure 1 Some more details of the optical detection unit and controller, where the controller is operated in an air detection operating mode and with an unlysed sample with no air bubbles present.

[0046] Figure 2B Shown with Figure 2A Same optical detection unit, but the controller is operated in the lysis mode of operation.

[0047] Figure 2C Similar to Figure 2A , where the controller is operated in an air detection mode of operation, but with a lysed sample in which no bubbles are present.

[0048] Figure 2D Schematically shows the FIG. 2A to FIG. 2C The same optical detection unit, wherein after determining that no air is present in the lysed sample, the controller is in optical measurement mode.

[0049] Figure 2E Similar to Figure 2C , where the controller is operated in an air detection mode of operation, but with a lysed sample in the presence of air bubbles.

[0050] Figure 3A Experimental data obtained with lysed blood samples in the air detection mode of operation in the absence of air bubbles are shown.

[0051] Figure 3B and Figure 3A The results obtained in the presence of bubbles are shown in comparison, all other conditions are Figure 3A Same as in.

[0052] Figure 4 Shows the use of FIG. 3A to FIG. 3B Other experimental data obtained with the same experimental setup, but the controller is configured to scan a predetermined resonant frequency range.

[0053] The skilled person will appreciate that the elements in the figures are shown for simplicity and clarity, and are not necessarily drawn to scale. For example, the sizes of some elements in the figures may be exaggerated relative to other elements, while other elements may have been omitted or represented in reduced quantities in order to enhance clarity and improve understanding of aspects of the present disclosure. DETAILED DESCRIPTION

[0054] Figure 1 Schematically illustrated is an IVD analyzer 200 comprising a fluid system 210 comprising different fluid paths 211, 213. The fluid path 211 is a flow-through sensor path comprising a plurality of sensors 212. The fluid path 213 is a flow-through optical path comprising a cuvette 214 arranged between a light source 215 and a photodetector 216, thereby forming an optical detection unit 217 for optically measuring a biological sample introduced into the cuvette 214 via the fluid path 213.

[0055] The IVD analyzer 200 further includes a pump 240 (such as a peristaltic pump) located downstream of the fluid system 210 and a fluid supply unit 220 including a plurality of fluids 221, 222, 223, and a waste container 224 in which the fluids circulated through the fluid system 210 can be processed by the action of the pump 240. The IVD analyzer 200 further includes a fluid selection valve 230 for selecting between the fluids 221, 222, 223 and / or air 232.

[0056] The IVD analyzer 200 further includes a sample input interface 201, which includes a sample input port 10, which includes an outer input port side 11 and an inner input port side 12 configured to be inserted into the open end of the sample container 1. In this example, the sample container 1 is a capillary sample container. The sample input interface 201 further includes an aspiration needle 30, which includes an upstream end 31 and a downstream end 32. The downstream end 32 of the aspiration needle 30 is fluidly connected to the fluid system 210 via a fluid line 219, and the upstream end 31 is configured to be alternately connected to the inner input port side 12, so as to aspirate the sample 2 from the sample container 1 inserted into the outer input port side 11 and aspirate to the fluid supply unit port 40 connected to the common outlet port 231 of the fluid selection valve 230 via another conduit 219' fluid. However, the fluid line 219 can be directly connected to the outlet port 231 of the fluid selection valve 230, and the sample can be introduced via, for example, different fluid lines that are separately connected to the fluid selection valve 230.

[0057] When the collection FIG. 2A to FIG. 2E Come and see Figure 1 When the IVD analyzer 200 is in operation, the IVD analyzer 200 further includes: a piezoelectric actuator 218 disposed on one side of the cuvette 214, which is configured to transmit ultrasonic waves 254, 254' through the cuvette 214; a piezoelectric receiver 218' disposed on the opposite side of the cuvette 214, which is configured to receive ultrasonic waves 255, 255', 255" transmitted through the cuvette 214, and a controller 250, which is configured to operate according to either the lysis operation mode (L) or the air detection operation mode (AD). According to the lysis operation mode (L), the piezoelectric actuator 218 is configured The piezoelectric actuator 218 is configured to transmit ultrasonic waves 254' through the cuvette 214 for destroying cell particles contained in the biological sample 2. According to the air detection operation mode (AD), the piezoelectric actuator 218 is configured to transmit ultrasonic waves 254 through the cuvette 214, and the controller 250 is configured to associate the amplitude change and / or phase shift of the ultrasonic waves 255, 255', 255" received by the piezoelectric receiver 218' relative to the reference value with the final presence and amount of air 3 in the cuvette 214, so as to determine whether the optical measurement of the biological samples 2, 2' is affected by the presence of air 3.

[0058] Figure 2A Schematically shows that Figure 1 2, and some more details of the optical detection unit 217 partially shown in FIG. 2, which includes a cuvette 214 arranged between a light source 215 and a photodetector 216, and a piezoelectric actuator 218 and a piezoelectric receiver 218' on each corresponding dimension of the cuvette 214. Specifically, the piezoelectric actuator 218 is electrically connected to an actuation control unit 251, and the piezoelectric receiver 218' is electrically connected to a receiving control unit 252, both of which are electrically connected to a main control unit 250.

[0059] More specifically, Figure 2A The controller 250 operating in an air detection operation mode (AD) is schematically shown, wherein the piezoelectric actuator 218 and the piezoelectric receiver 218' cooperate with each other. Specifically, the actuation control unit 251 controls the piezoelectric actuator 218 so as to transmit an ultrasonic wave 254 having predetermined wave parameters (such as predetermined amplitude and frequency) through the cuvette 214, and the reception control unit 252 measures the ultrasonic wave 255 received by the piezoelectric receiver 218' relative to the ultrasonic wave 254 transmitted through the cuvette 214 by the piezoelectric actuator 218 and the actual parameter (such as the actual amplitude) relative to the reference value, for determining the final presence and amount of air in the cuvette 214. In particular, the actuation control unit 251 and the reception control unit 252 cooperate with each other by providing transmission data and reception data as described in detail by the cross-correlation algorithm 253, while also taking into account reference values ​​regarding the type of optical detection unit 217 and the cuvette contents (e.g., the type of sample), in order to determine the final presence and amount of air in the cuvette 214 that may affect the optical measurement of the biological sample. In particular, the change in the wave amplitude and more particularly the attenuation / reduction and / or the shift in the wave phase can be related to the amount of air that is finally present in the cuvette 214 and may also be related to different states of the sample, such as to different levels of hematocrit and / or to a lysed or unlysed sample state and / or to the presence of a clot. Figure 2A In the illustrated exemplary embodiment, the sample 2 contained in the cuvette 214 is an unlysed sample (before lysis) and no air is present. The actual amplitude of the received wave 255 is comparable to the actual amplitude of the reference wave 256 under the same conditions without the presence of air.

[0060] Figure 2B Shown with Figure 2A The same optical detection unit 217 is used, but the controller 250 is operated in the lysis operation mode (L). In this case, the piezoelectric actuator 218 has the function of transmitting ultrasound through the cuvette 214 in order to destroy the cell particles contained in the sample, thereby obtaining a lysed sample 2', which is used to Figure 2AThe piezoelectric receiver 218', the receiving control unit 252 and the cross-correlation algorithm 253 do not have any function in the lysis operation mode (L) and are indicated by a dotted line symbolizing an inactive state. In this process, the membranes of cells (e.g., red blood cells) contained in the sample are destroyed by cavitation, and their contents (e.g., hemoglobin) are released. Moreover, the emitted ultrasonic wave 254' is relatively Figure 2A The ultrasonic waves 254 emitted in the air detection operation mode have a larger amplitude.

[0061] Figure 2C Similar to Figure 2A , wherein the controller 250 operates in an air detection mode of operation (AD), but has a Figure 2B 2 ', obtained in the lysis operation mode (L) shown, and in the absence of air in the cuvette 214. Schematically, a reduction in the amplitude of the received ultrasonic wave 255' can be observed compared to the amplitude of the emitted ultrasonic wave 254. Moreover, the actual amplitude of the received wave 255' is comparable to the amplitude of the reference wave 256' under the same conditions without the presence of air, and is similar to the amplitude of the reference wave 256 relative to the reference wave 256. Figure 2A The amplitude is slightly different for the non-lysed sample 2 shown. Therefore, it is also possible to distinguish between the lysed sample 2' and the non-lysed sample 2, thereby confirming the effect of the lysing operation or the lysing result obtained in the lysing operating mode (L).

[0062] Figure 2D Schematically shows FIG. 2A to FIG. 2C The same optical detection unit 217 of the cuvette 214 is used, wherein the controller 250 is in the optical measurement mode (M), and an optical measurement of the biological sample 2' is performed after determining that there is no air in the lysed sample 2' in the cuvette 214. The piezoelectric actuator 218 and the piezoelectric receiver 218' are ring-shaped so as to form an optical window 218" in the middle of the ring for optically measuring the biological sample 2' through the cuvette 214. The piezoelectric actuator 218, the piezoelectric receiver 218', the actuation control unit 251 and the reception control unit 252 do not have any function during the optical measurement.

[0063] Figure 2E Similar to Figure 2C, wherein the controller 250 operates in an air detection operating mode (AD) and there is a lysed sample 2' in the cuvette 214 but there is an air bubble 3 in the cuvette 214, which can affect the optical measurement of the lysed sample 2'. Schematically, a substantial reduction in the amplitude of the received ultrasonic wave 255' can be observed compared to the amplitude of the emitted ultrasonic wave 254. Moreover, under the same conditions without the presence of air, the actual amplitude of the received wave 255' is less than 257 the actual amplitude of the reference wave 256'. The amount of air can also be determined by the magnitude of the amplitude reduction. Therefore, the controller 250 can determine that, as in this case, the optical measurement of the biological sample is affected by the presence of air, thereby generating, for example, an alarm 258. In this case, the controller can terminate the analysis process, for example, to prevent the optical measurement from occurring, and restart the process from the beginning with a new sample input. Another option (also depending on the amount of air detected) is to continue with the optical measurement and mark the result as potentially erroneous or unreliable.

[0064] Continue to refer to FIG. 2A to FIG. 2E , also shows an automated method for operating an IVD analyzer 200, the IVD analyzer comprising an optical detection unit 217, which includes a cuvette 214 for optically measuring a biological sample 2, 2' contained therein; a piezoelectric actuator 218 arranged on one side of the cuvette 214, which is configured to transmit ultrasonic waves 254, 254' through the cuvette 214; a piezoelectric receiver 218' arranged on the opposite side of the cuvette 214, which is configured to receive ultrasonic waves 255, 255', 255" transmitted through the cuvette 214; and a controller 250, which is configured to operate according to either a lysis operation mode (L) or an air detection operation mode (AD). According to the lysis operation mode (L), the method includes transmitting an ultrasonic wave 254' through the cuvette 214 by the piezoelectric actuator 218 for destroying cell particles contained in the biological sample 2, and wherein, according to the air detection operation mode (AD), the method includes transmitting an ultrasonic wave 254 through the cuvette 214 by the piezoelectric actuator 218, and correlating the amplitude change and / or phase shift of the ultrasonic wave 255, 255', 255" received by the piezoelectric receiver 218' relative to the reference value with the final presence and amount of air (3) in the cuvette 214, so as to determine whether the optical measurement of the biological sample (2, 2') is affected by the presence of air 3.

[0065] In this example, the method also includes making the piezoelectric actuator 218 and the piezoelectric receiver 218' into a ring so as to form an optical window 218" in the middle of the ring for optically measuring the biological sample through the cuvette 214. In this example, the method also includes emitting an ultrasonic wave 254 according to the air detection operating mode (AD), the ultrasonic wave having a different amplitude and / or frequency relative to the ultrasonic wave 254' emitted according to the lysis operating mode (L). The method further includes performing an optical measurement of the biological sample 2' if it is determined that the optical measurement is not affected by the presence of air. The method further includes operating the IVD analyzer according to the air detection operating mode (AD) before and after operating the IVD analyzer according to the lysis operating mode (L) so as to additionally determine the lysis result obtained during the lysis operating mode (L) by comparison.

[0066] Figure 3A Experimental data obtained with an arbitrary cuvette filled with a lysed blood sample in the absence of bubbles in the air detection operating mode are shown. The amplitude of the ultrasonic wave or excitation voltage emitted by the piezoelectric actuator is set to 12V peak to peak and the frequency is about 200KHz. The amplitude of the received ultrasonic wave 255' measured by the receiving unit via the piezoelectric receiver is about 160mV peak to peak. Figure 3B and Figure 3A The results obtained with the same lysed sample but in the presence of bubbles are shown in comparison. All other conditions are the same as Figure 3A Specifically, the emitted ultrasonic wave has the same Figure 3A The amplitude of the received ultrasonic wave 255" measured by the receiving unit via the piezoelectric receiver is about 90 mV peak to peak. Therefore, when compared with the one obtained under the same conditions but without air, Figure 3A When compared to the amplitude of the received ultrasonic wave 255', there is an attenuation of about 70 mV peak to peak, and this can be used as a reference 256', thus indicating the presence of air, the greater the attenuation the greater the amount of air. These values ​​are merely examples and illustrations of the measurable changes in amplitude that can be associated with the presence and amount of air, as they relate to a specific experimental setup, including the specific cuvette size and material used, the specific piezoelectric actuator and piezoelectric receiver used, the specific excitation voltage and frequency applied, and thus can vary under different conditions.

[0067] Figure 4 Shows the use of FIG. 3A to FIG. 3BOther experimental data obtained with the same experimental setup, but the controller is configured to scan a predetermined resonant frequency range, in this example 90-200KHz, and to correlate changes (attenuation) in the received wave amplitude spectrum 260 relative to the reference spectrum 261 and / or shifts in the wave phase 262 relative to the reference wave phase 263 with the presence and amount of air in the cuvette. Figure 4 Another embodiment of the above method is also shown, which includes scanning a predetermined resonant frequency range and correlating changes (attenuation) in the received wave amplitude spectrum 260 relative to a reference spectrum 261 and / or shifts in the wave phase 262 relative to a reference wave phase 263 to the presence and amount of air in the cuvette. By scanning the vibration frequencies over a frequency range, more data can be collected and changes over a wider spectrum can be detected by analyzing the amplitude spectrum and / or phase profile rather than a single value.

[0068] Modifications and variations of the disclosed aspects are of course possible in light of the above description. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced in a manner other than that specifically designed in the above examples.

[0069] In particular, it should be understood that at least some of the drawings or parts are only schematic and are provided only as examples. In addition, the relationship between the elements may be different from the relationship shown, and parts that are not related to the purpose of the present disclosure have been omitted.

[0070] In addition, references to "one aspect", "aspect", "one example" or "example", "one embodiment" or "embodiment" throughout this specification mean that the specific features, structures or characteristics described in conjunction with the aspect, example or embodiment are included in at least one aspect, example or embodiment. Therefore, the phrases "in one aspect", "in an aspect", "one example" or "example", "one embodiment" or "embodiment" appearing in various places throughout this specification do not necessarily all refer to the same aspect, example or embodiment.

[0071] Furthermore, the particular features, structures or characteristics may be combined in any suitable combinations and / or sub-combinations in one or more aspects or examples or embodiments.

Claims

1. An in vitro diagnostic (IVD) analyzer (200) comprising an optical detection unit (217), the optical detection unit comprising a cuvette (214), the cuvette being used to perform optical measurements on a biological sample (2, 2') contained therein, the IVD analyzer (200) further comprising: A piezoelectric actuator (218) arranged on one side of the cuvette (214), configured to transmit ultrasonic waves (254, 254') through the cuvette (214); a piezoelectric receiver (218') arranged on the opposite side of the cuvette (214), configured to receive ultrasonic waves (255, 255', 255") transmitted through the cuvette (214); and a controller (250), configured to operate according to either a lysis operation mode (L) or an air detection operation mode (AD), wherein according to the lysis operation mode (L), the piezoelectric actuator (218) is configured to transmit ultrasonic waves (254') through the cuvette The invention relates to a cuvette (214) for destroying cell particles contained in the biological sample (2), and wherein according to the air detection operation mode (AD), the piezoelectric actuator (218) is configured to transmit ultrasonic waves (254) through the cuvette (214), and the controller (250) is configured to associate the amplitude change and / or phase shift of the ultrasonic waves (255, 255', 255") received by the piezoelectric receiver (218') relative to a reference value with the final presence and amount of air (3) in the cuvette (214), so as to determine whether the optical measurement of the biological sample (2, 2') is affected by the presence of the air (3).

2. The IVD analyzer (200) according to claim 1, wherein the piezoelectric actuator (218) and the piezoelectric receiver (218') are in a ring shape so as to form an optical window (218") in the middle of the ring for performing the optical measurement of the biological sample (2, 2') through the cuvette (214).

3. An IVD analyzer (200) according to claim 1 or 2, wherein the ultrasonic wave (254) emitted by the piezoelectric actuator (218) according to the air detection operating mode (AD) has a different amplitude and / or frequency relative to the ultrasonic wave (254') emitted according to the lysis operating mode (L).

4. The IVD analyzer (200) of claim 3, wherein the amplitude is greater than about 200 V according to the lysis operation mode (L) and is less than about 50 V according to the air detection operation mode (AD).

5. The IVD analyzer (200) according to claim 3 or 4, wherein the frequency is less than about 60 KHz according to the lysis operation mode (L) and is greater than about 60 KHz according to the air detection operation mode (AD).

6. The IVD analyzer (200) according to any one of claims 3 to 5, wherein: According to the air detection operating mode (AD), the controller (250) is configured to scan a predetermined resonant frequency range and associate changes in the received wave amplitude spectrum (260) relative to a reference wave amplitude spectrum (261) and / or shifts in the wave phase profile (262) relative to a reference wave phase profile (263) with the presence and amount of the air (3) in the cuvette (214).

7. An IVD analyzer (200) according to any one of claims 1 to 6, wherein the controller (250) is configured to operate according to the air detection operation mode (AD) before and after operating according to the lysis operation mode (L) so as to further determine the lysis result obtained during the lysis operation mode (L) by comparison.

8. An automated method of operating an in vitro diagnostic (IVD) analyzer (200), the IVD analyzer comprising: An optical detection unit (217) comprises a cuvette (214) for optically measuring a biological sample (2, 2') contained therein; a piezoelectric actuator (218) arranged on one side of the cuvette (214) and configured to transmit ultrasonic waves (254, 254') through the cuvette (214); a piezoelectric receiver (218') arranged on the opposite side of the cuvette (214) and configured to receive ultrasonic waves (255, 255', 255") transmitted through the cuvette (214); and a controller (250) configured to operate according to either a lysis operation mode (L) or an air detection operation mode (AD), wherein according to the lysis operation mode (L), the controller (250) is configured to operate according to either a lysis operation mode (L) or an air detection operation mode (AD), wherein according to the lysis operation mode (L), the controller (250) is configured to operate according to either a lysis operation mode (L) or an air detection operation mode (AD). The method comprises transmitting an ultrasonic wave (254') through the cuvette (214) by the piezoelectric actuator (218) for destroying cell particles contained in the biological sample (2), and wherein according to the air detection operation mode (AD), the method comprises transmitting an ultrasonic wave (254) through the cuvette (214) by the piezoelectric actuator (218), and correlating an amplitude change and / or a phase shift of the ultrasonic wave (255, 255', 255") received by the piezoelectric receiver (218') relative to a reference value with the final presence and amount of air (3) in the cuvette (214) so ​​as to determine whether the optical measurement of the biological sample (2, 2') is affected by the presence of the air (3).

9. The method according to claim 8 comprises making the piezoelectric actuator (218) and the piezoelectric receiver (218') into a ring so as to form an optical window (218") in the middle of the ring for performing the optical measurement of the biological sample (2, 2') through the cuvette (214).

10. The method according to claim 8 or 9, comprising emitting the ultrasonic wave (254) according to the air detection operating mode (AD), the ultrasonic wave having a different amplitude and / or frequency relative to the ultrasonic wave (254') emitted according to the lysis operating mode (L).

11. The method of claim 10, wherein the amplitude is greater than about 200 V according to the lysis operation mode (L) and is less than about 50 V according to the air detection operation mode (AD).

12. The method according to claim 10 or 11, wherein the frequency is less than about 60 KHz according to the splitting operation mode (L) and is greater than about 60 KHz according to the air detection operation mode (AD).

13. The method according to any one of claims 8 to 12, wherein: According to the air detection operating mode (AD), the method includes scanning a predetermined resonant frequency range and correlating changes in the received wave amplitude spectrum (260) relative to a reference wave amplitude spectrum (261) and / or shifts in the wave phase profile (262) relative to a reference wave phase profile (263) with the presence and amount of the air (3) in the cuvette (214).

14. Method according to any one of claims 8 to 13, comprising performing the optical measurement of the biological sample (2, 2') if it is determined that the optical measurement is not affected by the presence of the air (3).

15. A method according to any one of claims 8 to 14, comprising operating the IVD analyzer (200) according to the air detection operating mode (AD) before and after operating the IVD analyzer (200) according to the lysis operating mode (L) so as to further determine by comparison the lysis result obtained during the lysis operating mode (L).

Images