PIPETTING TIP SCANNER

Abstract

A method of measuring the alignment of one or more pipetting tips in an automated pipetting system where the one or more pipetting tips are mounted on one or more adapters of a pipetting head approximately perpendicular to the pipetting head mounting surface is disclosed. The orifices at the end of the one or more pipetting tips are mapped with an image capture device having a sensor placed in face and distant of the orifices. The method sends the acquired data from mapping the orifices of the one or more pipetting tips to the data processor, generating an image of the orifices of the one or more pipetting tips, determining the center positions of orifices, and delivering alignment information for the one or more pipetting tips.

Claims

1. A method of measuring the alignment of one or more pipetting tips (2) in relation to a pipetting head (4) in an automated pipetting system (1) comprising: mounting the one or more pipetting tips (2) on one or more adapters (3) of the pipetting head (4) approximately perpendicular to the pipetting head (4) mounting surface, mapping the orifices (21) at the protruding end of the one or more pipetting tips (2) with an image capture device (5) comprising a sensor (6) placed in face and distant of the orifices (21), sending the acquired data from mapping the orifices (21) of the one or more pipetting tips (2) to a data processor (7), generating an image of the orifices (21) of the one or more pipetting tips (2) from said acquired data, determining the center positions of orifices (21) relative to the pipetting head (4), and calculating alignment information for the one or more pipetting tips (2) with respect to a virtual regular grid assumed to the pipetting head (4) mounting surface.

2. The method according to claim 1, whereas mapping the orifices (21) comprises scanning the orifices (21) by moving the pipetting head (4) and/or the sensor (6) relative to one another.

3. The method according to claim 1, further comprising: determining the center positions of orifices (21) relative to the pipetting head (4) by sub-pixel interpolation of peaks or a pattern found in said image of the orifices (21) generated.

4. The method according to claim 1, further comprising: moving the pipetting head (4) and/or the sensor (6) relative to one another with a known temporal profile of relative positions.

5. The method according to claim 1, whereas calculating alignment information for the one or more pipetting tips (2) comprises converting the sub-pixel positions into positions in a measure of length.

6. The method according to claim 1, whereas calculating alignment information for the one or more pipetting tips (2) comprises calibrating the sensor (6) with a calibrated image on an axis parallel to the pipetting head (4) and perpendicular to the movement axis of the pipetting head (4) and/or the sensor (6) relative to one another.

7. The method according to claim 1, further comprising: creating a cross-correlation matrix from the scanned image and a template of a pipetting tip (2), and determining the center positions of orifices (21) of the one or more pipetting tips (2) by sub-pixel interpolation of peaks in the cross-correlation matrix.

8. The method according to claim 1, further comprising: scanning the one or more adapters (3) of the pipetting head (4) with an image capture device (5) comprising a sensor (6) by moving the pipetting head (4) and/or the sensor (6) relative to one another, sending the acquired data from scanning the one or more adapters (3) to the data processor (7), calculating positions of the one or more adapters (3) in relation to the pipetting head (4), and using this information to calculate the alignment of the one or more pipetting tips (2) with respect to the one or more adapters (3) of the pipetting head (4).

9. A computer program comprising instructions which, when the program is executed by a data processor (7), cause an automated pipetting system (1) to mount one or more pipetting tips (2) on one or more adapters (3) of a pipetting head (4) mounting surface, map the orifices (21) at the protruding end of the one or more pipetting tips (2) with an image capture device (5) comprising a sensor (6) placed in face and distant of the orifices (21), send the acquired data from mapping the orifices (21) of the one or more pipetting tips (2) to a data processor (7), generate an image of the orifices (21) of the one or more pipetting tips (2) from said acquired data, determine the center positions of orifices (21) relative to the pipetting head (4), and calculate alignment information for the one or more pipetting tips (2) with respect to a virtual regular grid assumed to the pipetting head (4) mounting surface.

10. The computer program according to claim 9, further comprising instructions which, when the program is executed by a data processor (7), cause an automated pipetting system (1) to scan the orifices (21) at the protruding end of the one or more pipetting tips (2) with the image capture device (5) comprising a sensor (6) placed in face and distant of the orifices (21) by moving the pipetting head (4) and/or the sensor (6) relative to one another.

11. The computer program according to claim 9, further comprising instructions which, when the program is executed by a data processor (7), cause an automated pipetting system (1) to determine the center positions of orifices (21) relative to the pipetting head (4) by sub-pixel interpolation of peaks or a pattern found in said image of the orifices (21) generated, and convert the sub-pixel positions into positions in a measure of length.

12. The computer program according to claim 9, further comprising instructions which, when the program is executed by a data processor (7), cause an automated pipetting system (1) to create a cross-correlation matrix from the scanned image and a template of a pipetting tip (2), and determine the center positions of orifices (21) of the one or more pipetting tips (2) by sub-pixel interpolation of peaks in the cross-correlation matrix.

13. The computer program according to claim 9, further comprising instructions which, when the program is executed by a data processor (7), cause an automated pipetting system (1) to scan the one or more adapters (3) of the pipetting head (4) with an image capture device (5) comprising a sensor (6) by moving the pipetting head (4) and/or the sensor (6) relative to one another, send the acquired data from scanning the one or more adapters (3) to the data processor (7), calculate positions of the one or more adapters (3) in relation to the pipetting head (4), and use this information to calculate the alignment of the one or more pipetting tips (2) with respect to the one or more adapters (3) of the pipetting head (4).

14. A contactless measurement system (10) for measuring the alignment of one or more pipetting tips (2) in an automated pipetting system (1) comprising: one or more adapters (3) on a pipetting head (4) connected to a robotic pipetting arm (11) for mounting the one or more pipetting tips (2), an image capture device (5) comprising a sensor (6) joined to a worktable (9) for capturing an image of the orifices (21) of the one or more pipetting tips (2) or of the one or more adapters (3) of the pipetting head (4), a data processor (7) for receiving the image data acquired by the sensor (6) and for calculating alignment information for the one or more pipetting tips (2) with respect to a virtual regular grid assumed to the pipetting head (4) mounting surface.

15. The contactless measurement system (10) according to claim 14, further comprising: a mechanism for moving the pipetting head (4) and/or the sensor (6) relative to one another for scanning the orifices (21) at the protruding end of the one or more pipetting tips (2) or of the one or more adapters (3) of the pipetting head (4).

16. The contactless measurement system (10) according to claim 14, whereas the image capture device (5) comprises a light source (8) for illuminating the object to be scanned, and an optical subsystem reflecting the object to be scanned onto the sensor (6).

17. The contactless measurement system (10) according to claim 14, whereas the image capture device (5) is a flatbed document scanner.

18. The contactless measurement system (10) according to claim 14, whereas the contactless measurement system has an application for pipetting liquid samples, whereas the contactless measurement system (10) assists in analyzing the position of one or more pipetting tips (2) in an automated pipetting system (1).

19. An automated pipetting system (1) comprising a contactless measurement system (10) according to claim 14.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0060] The invention will be described in detail with respect to the drawings schematically depicting embodiments of the invention. These are for illustrative purposes only and are not to be construed as limiting. In detail:

[0061] FIG. 1 shows a schematic full sectional view of an embodiment of a contactless measurement system for analyzing the position of pipetting tips in an automated pipetting system, and

[0062] FIG. 2 shows a schematic full sectional view of an embodiment of a contactless measurement system comprising an image capture device with a scan head and movement mechanism on a worktable, and

[0063] FIG. 3 shows a schematic full sectional view of an embodiment of a contactless measurement system comprising a laser profiler emitting a laser light, and a laser displacement sensor, and

[0064] FIG. 4 shows a schematic full sectional view of an embodiment of a contactless measurement system comprising a scan head and a movement mechanism, and

[0065] FIG. 5 shows a schematic full sectional view of an automated pipetting system comprising a contactless measurement system with a data processor for calculating the position of one or more pipetting tips, and

[0066] FIG. 6 shows a series of images that may be created by the data processor in the process of measuring the alignment of pipetting tips in an automated pipetting system.

DETAILED DESCRIPTION OF THE FIGURES

[0067] FIG. 1 shows a schematic full sectional view of an embodiment of a contactless measurement system 10 for measuring the alignment of one or more pipetting tips 2 in an automated pipetting system 1 comprising one or more adapters 3 on a pipetting head 4 connected to a robotic pipetting arm 11 for mounting the one or more pipetting tips 2 approximately perpendicular to the pipetting head 4, an image capture device 5 comprising a sensor 6 for capturing an image of the orfices 21 of the one or more pipetting tips 2 or of the one or more adapters 3 of the pipetting head 4. The sensor 6 may be a charge-coupled device image sensor (CCD) or contact image sensor (CIS), or any other appropriate sensor.

[0068] The contactless measurement system 10 further comprises a data processor 7 for receiving the image data acquired by the sensor 6 and for calculating alignment information for the one or more pipetting tips 2 with respect to a virtual regular grid assumed to the pipetting head 4 mounting surface.

[0069] The pipetting head 4 and/or the sensor 6 can move relative to one another so that the orfices 21 of the one or more pipetting tips 2 or of the one or more adapters 3 of the pipetting head 4 can be scanned by the image capture device 5.

[0070] The stream of numbers, i.e. the image data captured, is transmitted to the data processor 7. The figure schematically shows a wire connection between the image capture device 5 and the data processor 7, however any means for data transfer, including wireless technology may be applied in any embodiment according to the invention. The data processor 7 comprises an operating system which installs the appropriate drivers for the image capture device 5. An application program receives the image data from the image capture device 5 and performs calculation processes. The data processor 7 generates an image of the orfices 21 of the one or more pipetting tips 2, determines the center positions of orfices 21, and delivers alignment information for the one or more pipetting tips 2. The data processor 7 may additionally create a cross-correlation matrix from the scanned image and a template of a pipetting tip, and determine the center positions of orfices 21 of the one or more pipetting tips 2 by sub-pixel interpolation of peaks in the cross-correlation matrix. The sub-pixel positions may be converted into positions in a measure of length, and the data processor 7 may calculate alignment information for the one or more pipetting tips 2 with respect to a virtual regular grid assumed to the pipetting head 4 mounting surface.

[0071] FIG. 2 shows a schematic full sectional view of an embodiment of a contactless measurement system 10 for measuring the alignment of one or more pipetting tips 2 in an automated pipetting system 1 comprising a scan head 52 and a movement mechanism 53 for progressively repositioning the sensor 6 across the one or more pipetting tips 2 to capture an image. Also, the embodiment shown comprises a worktable 9 on which an image capture device 5 is arranged. According to the invention any form of connection to a worktable 9 may be possible. The image capture device 5 may be placed on top of the worktable 9 as shown or may be attached in an opening of the worktable 9 or be fastened underneath the worktable 9 with an opening in the worktable 9 allowing the robotic pipetting arm 11 to access the image capture device 5.

[0072] In the embodiment of a contactless measurement system 10 shown, adapters 3 for mounting the one or more pipetting tips 2 approximately perpendicular to a pipetting head 4 are connected through the pipetting head 4 to a robotic pipetting arm 11. The image capture device 5 comprises a sensor 6 for capturing an image of the orfices 21 of the pipetting tips 2 or of the adapters 3 of the pipetting head 4. The sensor 6 may be a CCD array or CIS, or any other appropriate sensor. The sensor 6 is part of the scan head 52 and rolls or moves over the object. The scan head 52 may be fixed to the movement mechanism 53, which may be a bar that acts like a stabilizer and moves the scan head 52 progressively across the one or more pipetting tips 2. The movement mechanism 53 may comprise a belt that is attached to a DC electric motor (e.g., a stepper motor) or may be any other mechanism for progressively moving the scan head 52 across an object. The scan head 52 may finish a complete scan of the document or object in a single pass (single pass method). The image capture device 5 may comprise an optical subsystem (not shown) reflecting the object to be scanned onto the sensor 6. Angled mirrors 63 may reflect the image of the object on other mirrors 63 (not shown). In some scanners, there are only two mirrors 63 while others use three or more mirror approaches. Each mirror 63 is slightly curved to focus the image it reflects onto a smaller surface, up to the last mirror 63 that reflects the image onto a lens. The lens focuses the image through a filter on the sensor 6 (e.g., a CCD array). A digitizer (not shown) processes the sensor signal, turning it into a stream of numbers that indicate the brightness or darkness of points on the object.

[0073] The stream of numbers, i.e. the image data captured, is transmitted to the data processor 7. The figure schematically shows a wire connection between the image capture device 5 and the data processor 7, however any means for data transfer, including wireless technology may be applied in any embodiment according to the invention. The data processor 7 comprises an operating system which installs the appropriate drivers for the image capture device 5. An application program receives the image data from the image capture device 5 and performs calculation processes. The data processor 7 generates an image of the orfices 21 of the one or more pipetting tips 2, determines the center positions of orfices 21, and delivers alignment information for the one or more pipetting tips 2. The data processor 7 may additionally create a cross-correlation matrix from the scanned image and a template of a pipetting tip 2, and determine the center positions of orfices 21 of the one or more pipetting tips 2 by sub-pixel interpolation of peaks in the cross-correlation matrix. The sub-pixel positions may be converted into positions in a measure of length, and the data processor 7 may calculate alignment information for the one or more pipetting tips 2 with respect to a virtual regular grid assumed to the pipetting head 4 mounting surface.

[0074] FIG. 3 shows a schematic full sectional view of an embodiment of a contactless measurement system 10 comprising a laser profiler 51 with a light source 8 emitting a laser light 81, and a laser displacement sensor 61. The image capture device 5 in the embodiment shown here comprises a laser profiler 51. The laser profiler 51 comprises a light source 8 for emitting a laser light 81 in the direction of the one or more pipetting tips 2. The reflection is recorded by a laser displacement sensor 61, which transfers the data to a data processor 7. The data processor 7 calculates the position of the one or more pipetting tips 2 in an automated pipetting system 1. The pipetting head 4 and/or the laser displacement sensor 61 in the laser profiler 51 can move relative to one another so that the orfices 21 of the one or more pipetting tips 2 or of the one or more adapters 3 of the pipetting head 4 can be scanned by the image capture device 5.

[0075] In this embodiment, one or more laser displacement sensors 61 apply triangulation by combining the emitting element and the position sensitive device (PSD) to detect the amount of displacement. Data enabling 2D and 3D measurements, such as height difference, width, or angle, is collected across a laser line that is focused through the emitting lens and projected on an object, e.g. pipetting tips 2 or adapters 3. The contactless measurement system 10 additionally comprises a data processor 7 for calculating the position of the one or more pipetting tips 2. The data enabling 2D and 3D measurements, i.e. the image data captured, is transmitted to the data processor 7. An application program receives the image data from the image capture device 5 and performs calculation processes. The figure schematically shows a wire connection between the image capture device 5 and the data processor 7, however any means for data transfer, including wireless technology may be applied in and embodiment according to the invention.

[0076] FIG. 4 shows a schematic full sectional view of an embodiment of a contactless measurement system 10 for measuring the alignment of one or more pipetting tips 2 in an automated pipetting system 1 comprising a scan head 52 and a movement mechanism 53 for progressively repositioning the scan head 52 across the one or more pipetting tips 2 to capture an image. Also, the embodiment shown comprises a worktable 9 on which an image capture device 5 is arranged. According to the invention any form of connection to a worktable 9 may be possible. The image capture device 5 may be placed on top of the worktable 9 as shown or may be attached in an opening of the worktable 9 or be fastened underneath the worktable 9 with an opening in the worktable 9 allowing the robotic arm 11 to access the image capture device 5.

[0077] In the embodiment of a contactless measurement system 10 shown, adapters 3 for mounting the one or more pipetting tips 2 approximately perpendicular to a pipetting head 4 are connected through the pipetting head 4 to a robotic pipetting arm 11. The image capture device 5 comprises a sensor 6 for capturing an image of the orfices 21 of the pipetting tips 2 or of the adapters 3 of the pipetting head 4. The sensor 6 may be a CCD array or CIS, or any other appropriate sensor. The sensor 6 is part of the scan head 52 and rolls or moves over the object. A beam-splitter 62 is arranged in the image capture device 5 such that a common optical path for illumination and light detection within the scanner is obtained. Angled mirrors 63 reflect the image of the object on other mirrors 63. In some scanners, there are only two mirrors 63 while others use three or more mirror 63 approaches. Each mirror 63 is slightly curved to focus the image it reflects onto a smaller surface, up to the last mirror 63 that reflects the image onto a lens (not shown). The lens focuses the image through a filter on the sensor 6. A digitizer (not shown) processes the sensor signal, turning it into a stream of numbers that indicate the brightness or darkness of points on the object.

[0078] The scan head 52 may be fixed to the movement mechanism 53, which may be a bar that acts like a stabilizer and moves the scan head 52 progressively across the one or more pipetting tips 2. The movement mechanism 53 may comprise a belt that is attached to a DC electric motor (e.g., a stepper motor), or may be any other mechanism for progressively moving the scan head 52 across an object. The scan head 52 may finish a complete scan of the document or object in a single pass (single pass method).

[0079] The stream of numbers, i.e. the image data captured, is transmitted to the data processor 7. The figure schematically shows a wire connection between the image capture device 5 and the data processor 7, however any means for data transfer, including wireless technology may be applied in any embodiment according to the invention. The data processor 7 comprises an operating system which installs the appropriate drivers for the image capture device 5. An application program receives the image data from the image capture device 5 and performs calculation processes. The data processor 7 generates an image of the orfices 21 of the one or more pipetting tips 2, determines the center positions of orfices 21, and delivers alignment information for the one or more pipetting tips 2. The data processor 7 may additionally create a cross-correlation matrix from the scanned image and a template of a pipetting tip, and determine the center positions of orfices 21 of the one or more pipetting tips 2 by sub-pixel interpolation of peaks in the cross-correlation matrix. The sub-pixel positions may be converted into positions in a measure of length, and the data processor 7 may calculate alignment information for the one or more pipetting tips 2 with respect to a virtual regular grid assumed to the pipetting head 4 mounting surface.

[0080] FIG. 5 shows a schematic full sectional view of an automated pipetting system 1 comprising a contactless measurement system 10 according to the invention. The contactless measurement system 10 as shown comprises a data processor 7 for calculating the position of one or more pipetting tips 2. It further comprises pipetting tips 2 mounted on a robotic pipetting arm 11, a worktable 9 for holding labware and equipment, and an image capture device 5 arranged on said worktable 9. The worktable 9 according to the invention may hold the image capture device 5 by any means of connection. The image capture device 5 may be placed on top of the worktable 9 as shown or may be attached in an opening of the worktable 9 or be fastened underneath the worktable 9 with an opening in the worktable 9 allowing the robotic arm to access the image capture device 5.

[0081] The image capture device 5 shown comprises a light source 8, a sensor 6, and a movement mechanism 53 for progressively repositioning the light source 8 and the sensor 6 across the one or more pipetting tips 2 to capture an image. The movement mechanism 53 may be a bar that acts like a stabilizer applying a belt that is attached to a DC electric motor (e.g., a stepper motor) or may be any other mechanism for progressively moving the scan head 52 across an object.

[0082] The contactless measurement system 10 comprises a data processor 7 for calculating the position of the one or more pipetting tips 2. The stream of numbers, i.e. the image data captured, is transmitted to the data processor 7. An application program receives the image data from the image capture device 5 and performs calculation processes. The figure schematically shows a wire connection between the image capture device 5 and the data processor 7, however any means for data transfer, including wireless technology may be applied in any embodiment according to the invention.

[0083] FIG. 6 shows a series of images that may be created by the data processor 7 in the process of measuring the alignment of one or more pipetting tips 2 in an automated pipetting system 1. A computer program according to the invention may initiate the generation of images as shown. The automated pipetting system 1 comprising a contactless measurement system 10 according to the invention scans the orfices 21 of the one or more pipetting tips 2 or scans the one or more adapters 3 of a pipetting head 4 with an image capture device 5 comprising a sensor 6 by moving the pipetting head 4 and/or the sensor 6 relative to one another. The acquired data is sent to the data processor 7, which generates an image of the orfices 21 of the one or more pipetting tips 2 as shown in FIG. 6A.

[0084] A template of the pipetting tip 2 that will be detected is generated e.g. by reading the outside and inside diameters of the orfice 21 off the technical drawing of the corresponding pipetting tip 2, or by directly reading the diameters off the scanned image of the orfices 21 of several pipetting tips 2 as shown in FIG. 6A. Thereby, an image as shown in FIG. 6B is created, with a white ring on a black background representing the outer and inner diameters of the orfice 21. The image is converted into pixels, whereas the center of the orfice 21 may correspond to the center of the image. The example shown in FIG. 6B represents the orifice 21 of a standard disposable pipetting tip 2.

[0085] A cross-correlation matrix from the scanned image as shown in FIG. 6A and the template of a pipetting tip 2 as shown in FIG. 6B may then be created, resulting in an image corresponding to FIG. 6C. Alternatively, a protocol recognizing the circles stemming from the orfices 21 may be applied without the use of a cross-correlation matrix. The center positions of orfices 21 of the one or more pipetting tips 2 may be determined by sub-pixel interpolation of peaks in the cross-correlation matrix (FIG. 6C) or corresponding image. The data processor 7 may convert the sub-pixel positions into positions in a measure of length. A measure of length according to the invention may be any unit of length measurement in the metric (international system, SI) or non-metric system (e.g., imperial system). A measure of length according to the invention may be millimeters (mm).

[0086] The data processor 7 may estimate a grid by using this data together with information on the number and arrangement of adapters 3 on the pipetting head 4. For pipetting into a 96-well microplate the arrangement of adapters 3 on the pipetting head 4 may be an array or grid with 96 positions whereas the spacing of adapters 3 (point-to-point distance) is 9 mm, corresponding to a certain number of pixels, depending on the resolution chosen.

[0087] The data processor 7 may then calculate alignment information for the one or more pipetting tips 2 with respect to the virtual regular grid assumed to the pipetting head 4 mounting surface. As shown in FIG. 6D the data processor 7 may represent the detected peaks (dots) next to the estimated grid (+ signs) in a nearest neighbor assignment, whereas the x- and y-positions are represented on a scale of pixels (px). The alignment information for the one or more pipetting tips 2 may also be shown after multiple sets of pipetting tips 2 have been analysed. The results of these multiple runs may be stacked and the result may be presented on top of the outline of a multiwell plate as shown in FIG. 6E. The plot of a multiple plate analysis shown in FIG. 6E includes the calculated maximum deviation (max, lower number) and mean (upper number) or median deviation. The circles shown correspond to wells A1 to A6, B1 to B6, and C1 to C6 of a 96-well plate.

[0088] Instead of estimating a grid by using the data generated by scanning the one or more pipetting tips 2, the one or more adapters 3 of the pipetting head 4 may be scanned by the image capture device 5. The acquired data from scanning the one or more adapters 3 is transferred the to the data processor 7, which may generate an image of the array of adapters 3 on the pipetting head 4 as shown in FIG. 6F. This image then serves as the basis for calculating positions of the one or more adapters 3 and for determining the center positions of orfices 21 of the one or more pipetting tips 2.

[0089] Incidentally it is also possible to implement the invention in a variety of variations in hereby shown examples and aspects of the invention highlighted above.

TABLE-US-00001 LIST OF REFERENCE SIGNS 1 automated pipetting system 10 contactless measurement system 11 robotic pipetting arm 2 pipetting tips 21 orifice 3 adapter 4 pipetting head 5 image capture device 51 laser profiler 52 scan head 53 movement mechanism 6 sensor 61 laser displacement sensor 62 beam-splitter 63 mirror 7 data processor 8 light source 81 laser light 9 worktable