METHOD AND DEVICE FOR DETECTING CONTACT OF A PIPETTE TIP WITH A LIQUID AS WELL AS A LABORATORY SYSTEM WITH SUCH A DEVICE
20230191390 · 2023-06-22
Inventors
- Luca FREI (Rapperswil, CH)
- Pascal DIETERICH (Wetzikon, CH)
- Sabrina HARSCH (Zürich, CH)
- Nemanja POPOVIC (Zürich, CH)
- Benjamin DÖRNER (München, DE)
Cpc classification
B01L2300/0627
PERFORMING OPERATIONS; TRANSPORTING
B01L3/021
PERFORMING OPERATIONS; TRANSPORTING
International classification
Abstract
A method for detecting contact of a pipette tip with a surface of a liquid in a pipetting device is disclosed. The method consists of moving the pipette tip in the direction of the surface of the liquid thereby measuring an absolute capacitance between the pipette tip and a reference potential and generating a sampled output signal. A predicted momentary sample value of the output signal is generated based on a plurality of past sample values of the output signal. A contact signal indicative of the pipette tip being in contact with the surface of the liquid is generated based on comparing a momentary sample value of the output signal with the predicted momentary sample value of the output signal. A corresponding pipetting device capable of performing the method as a laboratory system, in particular an automated liquid processing system, with one or more such pipetting devices are proposed.
Claims
1. A method for detecting contact of a pipette tip (4) with a surface (7) of a liquid (6) in a pipetting device (1), the method comprising the steps of: moving (m) the pipette tip (4) in direction of the surface (7) of the liquid (6); measuring an absolute capacitance (C) between the pipette tip (4) and a reference potential (GND), such as a grounded base plate (16) upon which a container (5) with the liquid (6) is arranged, and generating a sampled output signal (s.sub.out[n]); predicting a momentary sample value of the output signal (s.sub.out[n]) based on a plurality of past sample values of the output signal (s.sub.out[n]) and generating a predicted momentary sample value of the output signal (s.sub.out[n]); generating a contact signal (D.sub.L) based on comparing a momentary sample value of the output signal (s.sub.out[n]) with the predicted momentary sample value of the output signal (s.sub.out[n]), in particular by comparing a difference between a momentary sample value of the output signal (s.sub.out[n]) and the predicted momentary sample value of the output signal (s.sub.out[n]) with a predetermined threshold (TH), in particular a user/manually selectable and/or adjustable threshold, the contact signal (D.sub.L) being indicative of the pipette tip (4) being in contact with the surface (7) of the liquid (6).
2. The method of claim. 1, wherein generating the output signal (s.sub.out[n]) comprises the step of: applying samples of the measured absolute capacitance (C) to a median filter (12), in particular a median filter (12) of order in the range from three to six, more particularly a third order median filter (12).
3. The method of claim 1, wherein measuring the absolute capacitance (C) is performed at a first sampling rate and the sampled output signal (s.sub.out[n]) is generated at a second sampling rate by means of down sampling, in particular by a factor of N in the range from 2 to 61, more particularly in the range from 2 to 8, wherein down sampling is in particular performed by determining a sum of or an average over N consecutive samples to generate a sample of a down sampled output signal (s.sub.d[n]).
4. The method of claim 1, wherein predicting comprises applying one or more of the following to the output signal: curve fitting; finite impulse response (FIR) filtering; infinite impulse response (IIR) filtering; unweighted or weighted, e.g., exponentially weighted, (windowed, recursive) moving average filtering; linear or polynomial prediction; linear or polynomial regression; Kalman filtering.
5. The method of claim 1, wherein predicting comprises applying the output signal (s.sub.out[n]) to a sliding window averaging filter, wherein the window length (L) is in particular in the range from 8 to 64, more particularly in the range from 16 to 32.
6. The method of claim 1, wherein the step of predicting comprises applying the output signal (s.sub.out[n]) to a first and a second sliding window averaging filter, wherein the window length (L.sub.1, L.sub.2) of the first and second filter is in particular identical and in particular in the range from 8 to 64, more particularly in the range from 16 to 32.
7. The method of claim 6, wherein a slope of the output signal (s.sub.out[n]) is determined based on an output of the first sliding window averaging filter and an output of the second sliding window averaging filter, in particular wherein the predicted momentary sample value is based on linearly extrapolating the output of the first sliding window averaging filter and the output of the second sliding window averaging filter.
8. The method of claim 1, further comprising the step of: predicting a further momentary sample value of the output signal (s.sub.out[n]) based on a plurality of past sample values of the output signal (s.sub.out[n]) and generating a further predicted. sample value of the output signal (s.sub.out[n]), wherein predicting the further momentary sample value is performed differently than predicting the momentary sample value, in particularly based on one or more features different than that or those used for predicting the momentary sample value, and wherein the step of generating the contact signal (D.sub.L) is further based on comparing the momentary sample value of the output signal (s.sub.out[n]) with the further predicted momentary sample value of the output signal (s.sub.out[n]), in particular by comparing a difference between the momentary sample value of the output signal with the further predicted momentary sample value of the output signal with a further predetermined threshold, in particular a user/manually selectable and/or adjustable threshold, the further predetermined threshold in particular being the same as the predetermined threshold (TH).
9. The method of claim 1, wherein the past sample values of the output signal (s.sub.out[n]) are at least older by two sampling periods of the output signal than the momentary sample value, more particular older by three sampling periods.
10. The method of claim 1, wherein measuring the absolute capacitance (C) comprises charging and discharging a capacitor formed between the pipette tip (4) and the reference potential (GND) and determining a charging time, in particular an elapsed time for charging the capacitor from a first charging state to a second charging state, the charging time in particular being determined by a time-to-digital converter, wherein a measuring frequency is equal to a charging/discharging rate, and in particular in the range from 100 kHz to 500 kHz, more particularly in the range from 200 kHz to 400 kHz.
11. The method of claim 10, wherein charging the capacitor is performed by a voltage source (U) or current source via a charging resistor (R.sub.C), and wherein discharging is in particular performed via a switch (S.sub.D), such as a transistor, in particular a field effect transistor, in particular via a discharging resistor (R.sub.D).
12. A pipetting device (1) capable of detecting contact of a pipette tip (4) with a surface (7) of a liquid (6), the pipetting device (4) comprising: a pipette (3) with the pipette tip (4) adapted to aspirate and/or dispense the liquid (6); a transport unit (2), to which the pipette (3) is attached, adapted and configured to move (m) the pipette tip (4) in direction of the surface (7) of the liquid (6); a capacitance measuring unit (8) adapted and configured to measure an absolute capacitance (C) between the pipette tip (4) and a reference potential (GND), such as a grounded base plate (16) upon which a container (5) with the liquid (6) is arranged, and to generate a sampled output signal (s.sub.out[n]); a prediction unit (13) adapted and configured to predict a momentary sample value of the output signal (s.sub.out[n]) based on a plurality of past sample values of the output signal (s.sub.out[n]) and to generate a predicted momentary sample value of the output signal (s.sub.out[n]); a detection unit (14) adapted and configured to generate a contact signal (D.sub.L) based on comparing a momentary sample value of the output signal (s.sub.out[n]) with the predicted momentary sample value of the output signal (s.sub.out[n]), in particular by comparing a difference between a momentary sample value of the output signal (s.sub.out[n]) and the predicted momentary sample value of the output signal (s.sub.out[n]) with a predetermined threshold (TH), in particular a user/manually selectable and/or adjustable threshold, the contact signal (D.sub.L) being indicative of the pipette tip (4) being in contact with the surface (7) of the liquid (6).
13. The pipetting device (1) of claim 12, further comprising, in particular as part of the capacitance measuring unit (8), a median filter (12) adapted and configured to perform median filtering on samples of the measured absolute capacitance (C) and to generate the samples of the output signal (s.sub.out[n]), in particular a median filter (12) of order in the range from three to six, more particularly a third order median filter (12).
14. The pipetting device (1) of claim 12, further comprising, in particular as part of the capacitance measuring unit (8), a down sampling unit (11) adapted and configured to perform down sampling from a first sampling rate at which measuring the absolute capacitance (C) is performed to a second sampling rate at which the sampled output signal (s.sub.out[n]) is generated, in particular by a factor of N in the range from 2 to 64, more particularly in the range from 2 to 8, wherein down sampling is in particular performed by determining a sum of or an average over N consecutive samples to generate a sample of a down sampled output signal (s.sub.d[n]).
15. The pipetting device (1) of claim 12, wherein the prediction unit (13) comprises one or more of the following to which the output signal is applied: a curve fitting unit; a finite impulse response (FIR) filter; an infinite impulse response (IIR) filter; an unweighted or weighted, e.g., exponentially weighted, (windowed, recursive) moving average filter; a linear or polynomial prediction unit; a linear or polynomial regression unit; a Kalman filter.
16. The pipetting device (1) of claim 12, wherein the prediction unit (1) comprises a sliding window averaging filter to which the output signal (s.sub.out[n]) is applied, wherein the window length (L) is in particular in the range from 8 to 64, more particularly in the range from 16 to 32.
17. The pipetting device (1) of claim 12, wherein the prediction unit (13) comprises a first and a second sliding window averaging filter in series to which the output signal is applied, wherein the window length (L.sub.1, L.sub.2) of the first and second filter is in particular identical and in particular in the range from 8 to 61, more particularly in the range from 16 to 32.
18. The pipetting device (1) of claim 17, wherein the prediction unit (13) is adapted and configured so determine a slope of the output signal (s.sub.out[n]) based on an output of the first sliding window averaging filter and an output of the second sliding window averaging filter, in particular wherein the predicted momentary sample value is based on linearly extrapolating the output of the first sliding window averaging filter and the output of the second sliding window averaging filter.
19. The pipetting device (1) of claim 12, wherein the prediction unit (13) is adapted and configured to predict a further momentary sample value of the output signal (s.sub.out[n]) based on a plurality of past sample values of the output signal (s.sub.out[n]) and generating a further predicted momentary sample value of the output signal, wherein predicting the further momentary sample value is performed differently than predicting the momentary sample value, in particularly based on one or more features different than that or those used for predicting the momentary sample value, and wherein the prediction unit (13) is adapted and configured to generate the contact signal (D.sub.L) further based on comparing the momentary sample value of the output signal (s.sub.out[n]) with the further predicted momentary sample value of the output signal (s.sub.out[n]), in particular by comparing a difference between the momentary sample value of the output signal with the further predicted momentary sample value of the output signal (s.sub.out[n]) with a further predetermined threshold, in particular a user/manually selectable and/or adjustable threshold, the further predetermined threshold in particular being the same as the predetermined threshold (TH).
20. The pipetting device (1) of claim 12, wherein the past sample values of the output signal (s.sub.out[n]) are at least older by two sampling periods of the output signal (s.sub.out[n]) than the momentary sample value, more particular older by three sampling periods.
21. The pipetting device (1) of claim 11, wherein the capacitance measuring unit (8) comprises a charging unit (9) and a discharging unit (10) adapted and configured to charge and discharge a capacitor formed between the pipette tip (4) and the reference potential (GND) and a time measurement unit adapted and configured to determine a charging time, in particular an elapsed time for charging the capacitor from a first charging state to a second charging state, the time measurement unit in particular being a time-to-digital converter, wherein a measuring frequency is equal to a charging/discharging rate, and in particular in the range from 100 kHz to 500 kHz, more particularly in the range from 200 kHz to 400 kHz.
22. The pipetting device (1) of claim 21, wherein the charging unit (9) comprises a voltage source (U) or a current source and a charging resistor (R.sub.C), and wherein the discharging unit (10) in particular comprises a switch (S.sub.D), such as a transistor, in particular a field effect transistor, and in particular a discharging resistor (R.sub.D).
23. A laboratory system, in particular an automated liquid processing system, comprising one or more pipetting devices (1) according to claim 12.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0069] The present invention is further explained below by means of non-limiting specific embodiments and with reference to the accompanying drawings, which show the following:
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[0080] In the figures, like reference signs refer to like parts.
DETAILED DESCRIPTION OF THE INVENTION
[0081]
[0082] The absolute capacitance C is measured periodically at a certain sampling rate. This can be done in a variety of different ways. The measuring capacitor can for instance be excited by a sinusoidal voltage signal whereby the magnitude and phase of the response will be dependent on the capacitance. Alternatively, the measuring capacitor can be part of an oscillator circuit which consists of a coil and the measuring capacitor and in which the resonant frequency of the oscillator circuit is dependent on the measuring capacitor. According to
[0083]
[0084] The aim of the present invention is to reliably and quickly determine when such a capacitance jump occurs to provide a contact signal indicating that the pipette tip 4 has touched the surface 7 of a liquid 6. Reliable detection of this contact event implies a low rate of false detections caused by interferences such as noise and cross coupling (e.g., due to capacitive coupling from neighbouring pipetting devices). Rapid detection of this contact event is necessary because moving of the pipette tip 4 to far into the liquid should be prevented. Thereby, the detection delay negatively impacts the (maximum) delivery speed by which the pipette tip 4 may be lowered into the container 5
[0085] According to the present invention contact detection is based on comparing a momentary (i.e., a current/present) sample value of the output signal s.sub.out[n] of the capacitance measuring unit 8 with a predicted momentary sample value of this output signal s.sub.out[n]. Hereby, the predicted momentary sample value of the output signal s.sub.out[n] is based on a plurality of past sample values of the output signal s.sub.out[n]. This prediction is performed by the prediction (or estimation) unit 13. The contact signal D.sub.L which indicates when the pipette tip 4 comes into contact with the surface 7 of the liquid 6 is for instance based on comparing a difference between the momentary sample value of the output signal s.sub.out[n] and the predicted momentary sample value of the output signal s.sub.out[n] with a predetermined threshold TH. The threshold TH may be a user/manually selectable and/or adjustable threshold. Generation of the liquid contact signal (indicator) D.sub.L is accomplished by the detection unit 14.
[0086] In order to decrease the false alarm rate of the liquid contact detection a number of optional measures may be taken. The purpose of these measures is to increase detection immunity against various sources of interference.
[0087] The samples of the measured absolute capacitance C may optionally be applied to a median filter 12, for example of order three. This median filter 12 selects the median value of three consecutive samples (i.e., the one with the middle value between the minimum and maximum value of the three sample) as its output. In this way outliers caused by erratic interference, such as electrostatic discharge (ESD) spikes, are removed from the output signal. This is clearly illustrated in
[0088] The signal-to-noise ratio (SNR) of the measured absolute capacitance C may optionally be increased by down sampling the measured absolute capacitance values, where measuring the absolute capacitance C is performed at a first sampling rate (to generate the sampled output signal s.sub.out[n′]) and the (down) sampled output signal s.sub.out[n] is generated at a second sampling rate by means of down sampling, for instance by a factor of N=4. As shown in
[0089]
[0090] A “first” exemplary prediction technique illustrated in
[0091] A problem of this prediction technique is that it is unable to take into account gradual increases of the slope of the capacitance curve which is often the case when the labware being used produces considerable capacitive coupling. In order to overcome this shortcoming of the “first” prediction technique,
[0092] As can be seen in
LIST OF REFERENCE SYMBOLS
[0093] 1 pipetting device
[0094] 2 transport unit
[0095] 3 pipette (tube)
[0096] 4 pipette tip
[0097] 5 container
[0098] 6 liquid in container
[0099] 7 surface of liquid
[0100] 8 capacitance measuring unit
[0101] 9 charging unit
[0102] 10 discharging unit
[0103] 11 down sampling unit
[0104] 12 median filter
[0105] 13 prediction/estimation unit
[0106] 14 detection unit
[0107] 15 carrier for holding container
[0108] 16 grounded base plate
[0109] C absolute capacitance (=f(C.sub.T,C.sub.L,C.sub.C)˜total series capacitance of C.sub.T, C.sub.L & C.sub.C)
[0110] C.sub.C carrier (labware) capacitance (incl. container)
[0111] C.sub.L liquid capacitance
[0112] C.sub.T tip capacitance
[0113] D.sub.L liquid contact signal
[0114] GND ground, reference potential
[0115] L, L.sub.1, L.sub.2 length of (1.sup.st/2.sup.nd) FIR/averaging filter (window length, number of taps)
[0116] m tip delivery motion
[0117] n, n′ sample index
[0118] N down sampling factor
[0119] R.sub.C charging resistor/resistance
[0120] R.sub.D discharging resistor/resistance
[0121] S.sub.D discharging switch.
[0122] s[n′] sampled output signal (at first sampling rate)˜absolute capacitance
[0123] s.sub.d[n] down sampled signal (at second sampling rate)
[0124] s.sub.in(t) input signal (applied to pipette tip)
[0125] s.sub.out(t) output signal (in response to input signal)
[0126] s.sub.out[n] sampled output signal˜absolute capacitance
[0127] t time
[0128] TH detection threshold
[0129] U voltage source