Abstract
An in-vitro diagnostic (IVD) analyzer 200 comprising an optical detection unit 217 comprising a cuvette 214 for the optical measurement of a biological sample 2, 2 is herein disclosed. The IVD analyzer 200 further comprises a piezo actuator 218 arranged on one side of the cuvette 214 configured to transmit ultrasonic waves 254, 254 through the cuvette 214, a piezo 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 operating mode (L) or an air-detection operating mode (AD). According to the lysis operating mode (L) the piezo actuator 218 is configured to transmit ultrasonic waves 254 through the cuvette 214 for disrupting cellular particles contained in the biological sample 2. According to the air-detection operating mode (AD) the piezo actuator 218 is configured to transmit ultrasonic waves 254 through the cuvette 214 and the controller 250 is configured to correlate changes in amplitude and/or shifts of phase of the ultrasonic waves 255, 255, 255 received by the piezo receiver 218 relative to reference values with an eventual presence and quantity of air 3 in the cuvette 214, in order to determine if the optical measurement of the biological sample 2, 2 is affected by the presence of air 3. A respective automated method of operating the in-vitro diagnostic analyzer 200 in order to determine if the optical measurement of the biological sample 2, 2 is affected by the presence of air is herein also disclosed.
Claims
1. An in-vitro diagnostic (IVD) analyzer comprising an optical detection unit comprising a cuvette for the optical measurement of a biological sample contained therein, the IVD analyzer further comprising a piezo actuator arranged on one side of the cuvette configured to transmit ultrasonic waves through the cuvette, a piezo receiver arranged on the opposite side of the cuvette configured to receive ultrasonic waves transmitted through the cuvette and a controller configured to operate according to either a lysis operating mode or an air-detection operating mode, wherein according to the lysis operating mode the piezo actuator is configured to transmit ultrasonic waves through the cuvette for disrupting cellular particles contained in the biological sample, and wherein according to the air-detection operating mode the piezo actuator is configured to transmit ultrasonic waves through the cuvette and the controller is configured to correlate changes in amplitude and/or shifts of phase of the ultrasonic waves received by the piezo receiver relative to reference values with an eventual presence and quantity of air in the cuvette, in order to determine if the optical measurement of the biological sample is affected by the presence of air.
2. The IVD analyzer according to claim 1, wherein the piezo actuator and the piezo receiver are ring shaped such as to form an optical window in the middle of the ring for the optical measurement of the biological sample through the cuvette.
3. The IVD analyzer according to claim 1, wherein the ultrasonic waves transmitted by the piezo actuator according to the air-detection operating mode have different amplitude and/or frequency with respect to the ultrasonic waves transmitted according to the lysis operating mode.
4. The IVD analyzer according to claim 3, wherein the amplitude is greater than about 200 V according to the lysis operating mode and smaller than about 50 V according to the air-detection operating mode.
5. The IVD analyzer according to claim 3, wherein the frequency is smaller than about 60 KHz according to the lysis operating mode and greater than about 60 KHz according to the air-detection operating mode.
6. The IVD analyzer according to claim 3, wherein, according to the air-detection operating mode, the controller is configured to scan a predetermined resonance frequency range and to correlate changes in a received wave amplitude spectrum relative to reference wave amplitude spectra and/or a shift of a wave phase profile relative to reference wave phase profiles with the presence and quantity of air in the cuvette.
7. The IVD analyzer according to claim 1, wherein the controller is configured to operate according to the air-detection operating mode before and after operation according to the lysis operating mode in order to additionally determine, by comparison, a lysis result obtained during the lysis operating mode.
8. An automated method of operating an in-vitro diagnostic analyzer comprising an optical detection unit comprising a cuvette for the optical measurement of a biological sample contained therein, a piezo actuator arranged on one side of the cuvette configured to transmit ultrasonic waves through the cuvette, a piezo receiver arranged on the opposite side of the cuvette configured to receive ultrasonic waves transmitted through the cuvette and a controller configured to operate according to either a lysis operating mode or an air-detection operating mode, wherein according to the lysis operating mode the method comprises transmitting ultrasonic waves through the cuvette by the piezo actuator for disrupting cellular particles contained in the biological sample, and wherein according to the air-detection operating mode the method comprises transmitting ultrasonic waves through the cuvette by the piezo actuator and correlating changes in amplitude and/or shifts of phase of the ultrasonic waves received by the piezo receiver relative to reference values with an eventual presence and quantity of air in the cuvette, in order to determine if the optical measurement of the biological sample is affected by the presence of air.
9. The method according to claim 8, further comprising having the piezo actuator and the piezo receiver ring shaped such as to form an optical window in the middle of the ring for the optical measurement of the biological sample through the cuvette.
10. The method according to claim 8, further comprising transmitting the ultrasonic waves according to the air-detection operating mode with different amplitude and/or frequency with respect to the ultrasonic waves transmitted according to the lysis operating mode.
11. The method according to claim 10, wherein the amplitude is greater than about 200 V according to the lysis operating mode and smaller than about 50 V according to the air-detection operating mode.
12. The method according to claim 10, wherein the frequency is smaller than about 60 KHz according to the lysis operating mode and greater than about 60 KHz according to the air-detection operating mode.
13. The method according to claim 8, wherein, according to the air-detection operating mode, the method comprises scanning a predetermined resonance frequency range and correlating changes in a received wave amplitude spectrum relative to reference wave amplitude spectra and/or a shift of a wave phase profile relative to reference wave phase profiles with the presence and quantity of air in the cuvette.
14. The method according to claim 8, further comprising performing the optical measurement of the biological sample, if it is determined that the optical measurement is unaffected by the presence of air.
15. The method according to claim 8, further comprising operating the IVD analyzer according to the air-detection operating mode before and after operating the IVD analyzer according to the lysis operating mode in order to additionally determine by comparison a lysis result obtained during the lysis operating mode.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] FIG. 1 shows schematically an IVD analyzer comprising an optical detection unit and a controller configured to operate according to either a lysis operating mode or an air-detection operating mode.
[0046] FIG. 2A shows schematically some more details of the optical detection unit and controller of FIG. 1 with the controller operating in air-detection operating mode with a non-lysed sample in absence of air bubbles.
[0047] FIG. 2B shows the same optical detection unit of FIG. 2A but with the controller operating in the lysis operating mode.
[0048] FIG. 2C is similar to FIG. 2A with the controller operating in the air-detection operating mode but with a lysed sample in absence of air bubbles.
[0049] FIG. 2D shows schematically the same optical detection unit of FIG. 2A-2C with the controller in optical measurement mode, after determining the absence of air in the lysed sample.
[0050] FIG. 2E is similar to FIG. 2C with the controller operating in the air-detection operating mode and with a lysed sample but with the presence of air bubbles.
[0051] FIG. 3A shows experimental data obtained with lysed blood sample in absence of air bubbles in the air-detection operating mode.
[0052] FIG. 3B shows in comparison to FIG. 3A the results obtained in presence of air bubbles, with all other conditions being the same as in FIG. 3A.
[0053] FIG. 4 shows other experimental data obtained with the same experimental set up of FIG. 3A-3B but with the controller configured to scan a predetermined resonance frequency range.
[0054] Skilled artisans appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements whereas other elements may have been left out or represented in a reduced number in order to enhance clarity and improve understanding of the aspects of the present disclosure.
DETAILED DESCRIPTION
[0055] FIG. 1 shows schematically an IVD analyzer 200 comprising a fluidic system 210 comprising different fluidic paths 211, 213. The fluidic path 211 is a flow-through sensor path comprising a plurality of sensors 212. The fluidic 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 the optical measurement of a biological sample brought into the cuvette 214 via the fluidic path 213.
[0056] The IVD analyzer 200 further comprises a pump 240, such as a peristaltic pump, located downstream of the of the fluidic system 210, and a fluid-supply unit 220 comprising a plurality of fluids 221, 222, 223, and a waste container 224 where fluids circulated through the fluidic system 210 may be disposed of, by the action of the pump 240. The IVD analyzer 200 further comprises a fluid-selection valve 230 for selecting between the fluids 221, 222, 223 and/or air 232.
[0057] The IVD analyzer 200 further comprises a sample input interface 201, comprising a sample input port 10 comprising an outer input-port side 11 configured for plugging-in an open end of a sample container 1 and an inner input-port side 12. The sample container 1 is in this example a capillary-like sample container. The sample input interface 201 further comprises an aspiration needle 30 comprising an upstream end 31 and a downstream end 32. The downstream end 32 of the aspiration needle 30 is fluidically connected to the fluidic system 210 via fluidic line 219 whereas the upstream end 31 is configured to alternately couple to the inner input-port side 12 in order to aspirate a sample 2 from the sample container 1 plugged in the outer input-port side 11 and to a fluid-supply unit port 40 fluidically connected to a common outlet port 231 of the fluid-selection valve 230 via a further conduit 219. The fluidic line 219 may be however directly connected to the outlet port 231 of the fluid-selection valve 230, whereas samples may be introduced via a different fluidic line separately connected to the fluid-selection valve 230, for example.
[0058] When looking at FIG. 1 in conjunction to FIG. 2A-2E, the IVD analyzer 200 further comprises a piezo actuator 218 arranged on one side of the cuvette 214 configured to transmit ultrasonic waves 254, 254 through the cuvette 214, a piezo 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 operating mode (L) or an air-detection operating mode (AD). According to the lysis operating mode (L) the piezo actuator 218 is configured to transmit ultrasonic waves 254 through the cuvette 214 for disrupting cellular particles contained in the biological sample 2. According to the air-detection operating mode (AD) the piezo actuator 218 is configured to transmit ultrasonic waves 254 through the cuvette 214 and the controller 250 is configured to correlate changes in amplitude and/or shifts of phase of the ultrasonic waves 255, 255, 255 received by the piezo receiver 218 relative to reference values with an eventual presence and quantity of air 3 in the cuvette 214, in order to determine if the optical measurement of the biological sample 2, 2 is affected by the presence of air 3.
[0059] FIG. 2A shows schematically some more details of the optical detection unit 217, partly shown also in FIG. 1, comprising the cuvette 214 arranged between the light source 215 and the photodetector 216, as well as the piezo actuator 218 and the piezo receiver 218 on each respective size of the cuvette 214. In particular, the piezo actuator 218 is electronically connected to actuation control unit 251 and the piezo receiver 218 is electronically connected to receiving control unit 252, both electronically connected to the main control unit 250.
[0060] More in particular, FIG. 2A shows schematically the controller 250 operating in the air-detection operating mode (AD) in which the piezo actuator 218 and the piezo receiver 218 cooperate with each other. In particular, the actuation control unit 251 controls the piezo actuator 218 such as to transmit ultrasonic waves 254 through the cuvette 214 with predetermined wave parameters such as predetermined amplitude and frequency whereas the receiving control unit 252 measures the actual parameters, such as actual amplitude, of the ultrasonic waves 255 received by the piezo receiver 218 with respect to those of the ultrasonic waves 254 transmitted by the piezo actuator 218 though the cuvette 214 and with respect to reference values, for the purpose of determining the eventual presence and quantity of air in the cuvette 214. In particular, the actuation control unit 251 and the receiving control unit 252 cooperate with each other by providing transmitted data and received data that are elaborated by a cross-correlation algorithm 253, while taking into account also reference values with respect to the type of optical detection unit 217 and cuvette content, e.g. type of sample, in order to determine the eventual presence and quantity of air in the cuvette 214, possibly affecting the optical measurement of the biological sample. In particular, a change and more specifically attenuations/reductions of wave amplitude and/or shifts of wave phase can be correlated to the quantity of air eventually present in the cuvette 214, and can be possibly correlated also to different statuses of the sample such as to different levels of hematocrit and/or to lysed or non-lysed sample status and/or to the presence of clots. In the schematic example shown in FIG. 2A the sample 2 contained in the cuvette 214 is a non-lysed sample (before lysis) and without the presence of air. The actual amplitude of the received wave 255 is comparable to that of a reference wave 256 under the same conditions in absence of air.
[0061] FIG. 2B shows the same optical detection unit 217 of FIG. 2A but with the controller 250 operating in the lysis operating mode (L). In this case, the piezo actuator 218 has the function of transmitting ultrasonic waves through the cuvette 214 in order to disrupt cellular particles contained in the sample, thereby obtaining a lysed sample 2, represented with a different pattern compared to the non-lysed sample 2 of FIG. 2A. The piezo receiver 218, the receiving control unit 252 and the cross-correlation algorithm 253 are not having any function in the lysis operating mode (L) and are represented with a broken line symbolizing a non-active status. In this process the membranes of cells contained in the sample, e.g. erythrocytes, are disrupted through cavitation and their content, e.g. hemoglobin, is released. Also, the transmitted ultrasonic waves 254 have a greater amplitude with respect to the ultrasonic waves 254 transmitted in the air-detection operating mode of FIG. 2A.
[0062] FIG. 2C is similar to FIG. 2A with the controller 250 operating in the air-detection operating mode (AD) but with a lysed sample 2 in the cuvette 214 as obtained in the lysis operating mode (L) shown in FIG. 2B and in the absence of air in the cuvette 214. Schematically, a reduction of amplitude of the received ultrasonic waves 255 can be observed compared to that of the transmitted ultrasonic waves 254. Also, the actual amplitude of the received wave 255 is comparable to that of a reference wave 256 under the same conditions in absence of air and slightly different from that of the reference wave 256 relative to a non-lysed sample 2 as shown in FIG. 2A. It is thus possible to distinguish also between lysed sample 2 and non-lysed sample 2 thereby confirming the effect of the lysis operation or lysis result obtained in the lysis operating mode (L).
[0063] FIG. 2D shows schematically the same optical detection unit 217 of FIG. 2A-2C with the controller 250 in an optical measurement mode (M), while optical measurement of the biological sample 2 is taking place after determining the absence of air in the lysed sample 2 in the cuvette 214. The piezo actuator 218 and the piezo receiver 218 are ring shaped such as to form an optical window 218 in the middle of the ring for the optical measurement of the biological sample 2 through the cuvette 214. The piezo actuator 218, the piezo receiver 218, the actuation control unit 251 and the receiving control unit 252 do not have any function during optical measurement.
[0064] FIG. 2E is similar to FIG. 2C with the controller 250 operating in the air-detection operating mode (AD) and with a lysed sample 2 in the cuvette 214 but with the presence of air bubbles 3 in the cuvette 214 that would affect the optical measurement of the lysed sample 2. Schematically, a larger reduction of amplitude of the received ultrasonic waves 255 can be observed compared to that of the transmitted ultrasonic waves 254. Also, the actual amplitude of the received wave 255 is smaller 257 than that of the reference wave 256 under the same conditions in absence of air. By the magnitude of the amplitude reduction it is possible to determine also the quantity of air. The controller 250 can thus determine, as in this case, that the optical measurement of the biological sample is affected by the presence of air, generating for example an alert 258. In that case the controller may terminate the analytical process, e.g. preventing the optical measurement from taking place and starting the process from the beginning with a new sample input. Another option, depending also on the quantity of air being detected, is to nevertheless continue with the optical measurement and to flag the result as possibly faulty or unreliable.
[0065] With continued reference to FIG. 2A-2E taken together an automated method of operating an IVD analyzer 200 comprising an optical detection unit 217 comprising a cuvette 214 for the optical measurement of a biological sample 2, 2 contained therein, a piezo actuator 218 arranged on one side of the cuvette 214 configured to transmit ultrasonic waves 254, 254 through the cuvette 214, a piezo 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 operating mode (L) or an air-detection operating mode (AD) is also shown. According to the lysis operating mode (L) the method comprises transmitting ultrasonic waves 254 through the cuvette 214 by the piezo actuator 218 for disrupting cellular particles contained in the biological sample 2, and wherein according to the air-detection operating mode (AD) the method comprises transmitting ultrasonic waves 254 through the cuvette 214 by the piezo actuator 218 and correlating changes in amplitude and/or shifts of phase of the ultrasonic waves 255, 255, 255 received by the piezo receiver 218 relative to reference values with an eventual presence and quantity of air (3) in the cuvette 214, in order to determine if the optical measurement of the biological sample (2, 2) is affected by the presence of air 3.
[0066] In this example, the method also comprises having the piezo actuator 218 and the piezo receiver 218 ring shaped such as to form an optical window 218 in the middle of the ring for the optical measurement of the biological sample through the cuvette 214. In this example, the method also comprises transmitting the ultrasonic waves 254 according to the air-detection operating mode (AD) with different amplitude and/or frequency with respect to the ultrasonic waves 254 transmitted according to the lysis operating mode (L). The method further comprises performing the optical measurement of the biological sample 2 if it is determined that the optical measurement is unaffected by the presence of air. The method also comprises 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) in order to additionally determine by comparison a lysis result obtained during the lysis operating mode (L).
[0067] FIG. 3A shows experimental data obtained with an arbitrary cuvette filled with a lysed blood sample in absence of air bubbles in the air-detection operating mode. The amplitude of the ultrasonic wave transmitted by the piezo actuator or excitation voltage was set at 12 V peak to peak with a frequency of about 200 KHz. The amplitude of the received ultrasonic wave 255 as measured by the receiving unit via the piezo receiver was about 160 mV peak to peak. FIG. 3B shows in comparison to FIG. 3A the results obtained with the same lysed sample but in presence of air bubbles, with all other conditions being the same as in FIG. 3A. In particular, the transmitted ultrasonic wave had the same amplitude and frequency as in FIG. 3A. The amplitude of the received ultrasonic wave 255 as measured by the receiving unit via the piezo receiver was about 90 mV peak to peak. There is thus an attenuation of about 70 mV peak to peak when compared to the amplitude of the received ultrasonic wave 255 of FIG. 3A obtained under the same conditions but in absence of air and which can be used as reference 256, therefore indicating the presence of air, the larger the attenuation the larger the quantity of air. These values are only exemplary and demonstrative of a measurable change in amplitude that can be correlated to the presence and quantity of air, as they refer to the particular experimental set up, including particular cuvette size and material used, particular piezo actuator and piezo receiver used, particular excitation voltage and frequency applied and can therefore vary under different conditions.
[0068] FIG. 4 shows other experimental data obtained with the same experimental set up of FIG. 3A-3B but with the controller configured to scan a predetermined resonance frequency range, 90-200 KHz in this example, and to correlate changes (attenuations) in a received wave amplitude spectrum 260 relative to reference spectra 261 and/or a shift of wave phase 262 relative to reference wave phases 263 with the presence and quantity of air in the cuvette. FIG. 4 also shows another embodiment of the method described above comprising scanning a predetermined resonance frequency range and correlating changes (attenuations) in a received wave amplitude spectrum 260 relative to reference spectra 261 and/or a shift of wave phase 262 relative to reference wave phases 263 with the presence and quantity of air in the cuvette. By sweeping the vibrational frequency in a frequency range more data can be collected and changes can be detected over a broader spectrum, by analyzing amplitude spectra and/or phase profiles rather than single values.
[0069] Modifications and variations of the disclosed aspects are also certainly 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 otherwise than as specifically devised in the above examples.
[0070] Particularly, it is to be understood that at least some of the drawings or parts are only schematic and provided as way of example only. Also the relationship between elements may be other than the one shown, whereas parts not relevant for the purpose of this disclosure have been omitted.
[0071] Also, reference throughout the preceding specification to one aspect, an aspect, one example or an example, one embodiment or an embodiment means that a particular feature, structure or characteristic described in connection with the aspect or example or embodiment is included in at least one aspect, example or embodiment. Thus, appearances of the phrases in one aspect, in one aspect, one example or an example, one embodiment or an embodiment, in various places throughout this specification are not necessarily all referring to the same aspect or example or embodiment.
[0072] 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.
