Parallel dipping phases enabled by robotic actuator for dipping electrical sensors for measuring properties of molecules

Abstract

Techniques for performing an electrical measurement of one or more properties of molecules by dipping electrical sensors into wells of the multi-will plate are disclosed. Techniques are disclosed that enable to parallelize dipping phases (340, 341, 342, 350, 351, 352) for multiple sensor heads (305, 306), thereby increasing the measurement throughput.

Description

[0001] D E S C R I P T I O N

[0002] PARALLEL DIPPING PHASES ENABLED BY ROBOTIC ACTUATOR FOR DIPPING ELECTRICAL SENSORS FOR MEASURING PROPERTIES OF MOLECULES

[0003] TECHNICAL FIELD

[0004] Various examples of the disclosure generally relate to measuring properties of molecules. For this, a robotic actuator is used to dip electrical sensors into wells of a multi-well plate. Various examples of the disclosure specifically relate to enabling time-parallel dipping phases for multiple sensor heads, each including one or more electrical sensors.

[0005] BACKGROUND

[0006] Properties of molecules, in particular interactions between molecules, are investigated in various use cases. For instance, for drug discovery and process monitoring, there is a need for low cost, rapid, accurate methods for analysing interactions between molecules. Examples are numerous and include studying binding kinetics of analyte molecules (e.g., representing future drugs) to target molecules; screening for the quantity and quality of a valuable protein molecule (e.g., monoclonal antibody) during various developmental and production steps; or mapping antigen epitopes to characterise and optimise antibody binding.

[0007] Label-based and label-free measurements enable to measure properties of molecules. One measurement technique relies on an electrical measurement. An example technique is disclosed in WO 2023 / 275373. It has been found that measurements require a significant time duration. This limits the overall measurement throughput. SUMMARY

[0008] Accordingly, there is a need for advanced techniques of measuring properties of molecules. Specifically, there is a need for techniques that facilitate fast, reliable, quantitative, and reproducible measurements.

[0009] This need is met by the features of the independent claims. The features of the dependent claims define embodiments.

[0010] Hereinafter, techniques of automating measurements for determining properties of molecules will be disclosed. Label-based or label-free measurements can be used. For instance, binding properties between molecules of a first type and molecules of a second type can be determined. Binding properties between target molecules and analyte molecules can be determined.

[0011] Such measurements are implemented using electrical sensors. The electrical sensors are configured for being dipped into wells of a multi-well plate (MWP). The electrical sensors may be functionalized. More specifically, a sensitive surface of the electrical sensors may be functionalized using sensor-side molecules.

[0012] According to various examples, a robotic actuator is employed to automate the measurements.

[0013] The robotic actuator can handle sensor heads including one or more of the electrical sensors. The robotic actuator can dip the electrical sensors into wells of the MWP. Each of the multiple sensor heads includes one or more electrical sensors. Upon the robotic actuator engaging a sensor head, the robotic actuator can dip the respective one or more electrical sensors into one or more wells of the MWP. The one or more electrical sensors, and specifically a sensitive region of each sensor, can thus be immersed in a liquid. The liquid can be a solution of molecules of a certain type. Molecules could also be included as a dispersion. Liquid-side molecules can thus interact with the electrical sensor, e.g., with sensor-side molecules.

[0014] By dipping the electrical sensor into liquids including the molecules, it is possible to reliably bring the molecules into contact with a sensitive region of the electrical sensor. Further, a timing of exposure of the sensitive surface to the molecules can be precisely captured based on the dipping process. The duration of a dipping phase can be predefined. Complex measurement protocols can be automated, e.g., using a multi-well plate including multiple wells including different liquids. Different dipping phases of a measurement protocol can be implemented. One or more properties can be quantified accurately.

[0015] The robotic actuator may handle multiple sensor heads, to thereby execute multiple measurements in parallel. A user may trigger multiple measurements jointly and then multiple sensor heads are handled by the robotic actuator to execute the multiple measurements in parallel. This increases the overall measurement throughput, i.e., the number of measurements per time unit (each individual measurement may still require the same time as in reference techniques according to which the robotic actuator only handles a single sensor head).

[0016] A system includes a robotic actuator if the robotic actuator is configured to releasably engage a plurality of sensor heads. Each of the plurality of sensor heads includes one or more electrical sensors. Each electrical sensor includes a sensitive region. The sensitive regions can be functionalized using molecules (sensor-side molecules).

[0017] The system also includes a platform. The platform is configured to retain a MWP. The MWP includes multiple wells that may be filled with liquids. Further molecules can be dissolved in the liquids (liquid-side molecules).

[0018] The system also includes at least one processor. The at least one processor is configured to control the robotic actuator to sequentially engage different ones of the plurality of sensor heads, to dip the respective one or more electrical sensors into different wells of the MWP.

[0019] Thus, a single robotic actuator can be used to handle multiple sensor heads. Electrical sensors of different sensor heads can be dipped into different wells of the MWP, by engaging and disengaging the respective sensor heads using the robotic actuator. Thereby, parallel dipping phases can be implemented. I.e., during the dipping phase of a first one of the plurality of sensor heads, a second one of the plurality of sensor heads can be engaged, repositioned, dipped, and then released. I.e., the wait time available during the dipping phase of a first one of the plurality of sensor heads can be used for handling one or more second ones of the plurality of sensor heads. This enables to parallelize the handling of multiple sensors heads, thereby parallelizing multiple measurements. The overall measurement throughput can be increased.

[0020] A method of operating a robotic actuator of a system is disclosed. The method includes engaging a first sensor head in dipping one or more electrical sensors of the first sensor head into one or more first wells of a multi-well plate. The method also includes releasing the first sensor head while the one or more electrical sensors of the first sensor head are dipped into the one or more first wells. The method further includes, while the one or more electrical sensors of the first sensor head are dipped into the one or more first well: engaging a second sensor head and dipping one or more electrical sensors of the second sensor head into one or more second wells of the multi-well plate.

[0021] It is to be understood that the features mentioned above and those yet to be explained below may be used not only in the respective combinations indicated, but also in other combinations or in isolation without departing from the scope of the invention. For illustration, the method of operating the robotic actuator can be modified based on aspects disclosed in connection with the robotic actuator or system above.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 schematically illustrates a system for performing measurements on molecules according to various examples.

[0024] FIG. 2 schematically illustrates a sensor head including a single electrical sensor according to various examples.

[0025] FIG. 3 and FIG. 4 schematically illustrates a sensor head including multiple electrical sensors according to various examples.

[0026] FIG. 5 and FIG. 6 schematically illustrates a sensor head including multiple electrical sensors according to various examples.

[0027] FIG. 7 schematically illustrates an MWP according to various examples. FIG. 8 schematically illustrates sequential handling of multiple sensor heads according to various examples.

[0028] FIG. 9 is a perspective view of an example implementation of a fixture configured to cooperate with a multi-well plate to releasably retain sensor heads when the respective electrical sensors are dipped into wells of the multi-well plate.

[0029] FIG. 10 is a further perspective view of an example implementation of a fixture configured to cooperate with a multi-well plate to releasably retain sensor heads when the respective electrical sensors are dipped into wells of the multi-well plate.

[0030] DETAILED DESCRIPTION OF EMBODIMENTS

[0031] Some examples of the present disclosure generally provide for a plurality of circuits or other electrical devices. All references to the circuits and other electrical devices and the functionality provided by each are not intended to be limited to encompassing only what is illustrated and described herein. While particular labels may be assigned to the various circuits or other electrical devices disclosed, such labels are not intended to limit the scope of operation for the circuits and the other electrical devices. Such circuits and other electrical devices may be combined with each other and / or separated in any manner based on the particular type of electrical implementation that is desired. It is recognized that any circuit or other electrical device disclosed herein may include any number of microcontrollers, a graphics processor unit (GPU), integrated circuits, memory devices (e.g., FLASH, random access memory (RAM), read only memory (ROM), electrically programmable read only memory (EPROM), electrically erasable programmable read only memory (EEPROM), or other suitable variants thereof), and software which co-act with one another to perform operation(s) disclosed herein. In addition, any one or more of the electrical devices may be configured to execute a program code that is embodied in a non-transitory computer readable medium programmed to perform any number of the functions as disclosed.

[0032] In the following, embodiments of the invention will be described in detail with reference to the accompanying drawings. It is to be understood that the following description of embodiments is not to be taken in a limiting sense. The scope of the invention is not intended to be limited by the embodiments described hereinafter or by the drawings, which are taken to be illustrative only.

[0033] The drawings are to be regarded as being schematic representations and elements illustrated in the drawings are not necessarily shown to scale. Rather, the various elements are represented such that their function and general purpose become apparent to a person skilled in the art. Any connection or coupling between functional blocks, devices, components, or other physical or functional units shown in the drawings or described herein may also be implemented by an indirect connection or coupling. A coupling between components may also be established over a wireless connection. Functional blocks may be implemented in hardware, firmware, software, or a combination thereof.

[0034] Hereinafter, techniques of performing, in parallel, multiple measurements of one or more properties of one or molecules will be described. Specifically, properties of analyte molecules may be determined. Such measurements may facilitate various use cases. Surface science can be facilitated where properties of a surface formed by certain molecules is investigated. For instance, proteins or small molecules for research of pharmaceutical drugs may be facilitated. Ribonucleic acid (RNA) or Deoxyribonucleic acid (DNA) can be investigated. Molecule-binding assays could be implemented. Antibody-antigen kinetics could be measured. The quantity and / or quality of a protein molecule such as a monoclonal antibody could be measured. Antigen epitopes could be mapped to characterize and optimize antibody binding.

[0035] As a general rule, different kinds of measurements can be implemented and, along with different kinds of measurements, different properties can be determined. For instance, it would be possible to determine a property of a binding / adsorption between target molecules and analyte molecules. Binding parameters may include binding kinetics or a binding affinity. The binding kinetics can specify how fast the target and analyte molecules bind. Binding affinity can specify a strength of the binding. Another option would be to determine a concentration of the analyte molecules in an analyte liquid. Yet another option be to determine a conformality structure of analyte molecules.

[0036] Electrical sensing is employed for implementing measurements of properties of molecules. Specifically, electrical sensors are used. This means that electrical sensor signals are used to determine one or more properties as identified above. For instance, a time-dependency of an electrical sensor signal may be determined while a respective electrical sensor is dipped in a liquid.

[0037] A sensitive region of the electrical sensors may be pre-coated with certain molecules, e.g., proteins. It would also be possible to coat the sensitive region with certain target molecules by dipping the electrical sensors into a respective liquid including such molecules (preparation dipping phase). In a capture dipping phase, analyte molecules binds to molecules on the surface of the electrical sensor. In the capture dipping phase, the electrical sensor is lowered into a liquid including the analyte molecules. It would also be possible that the surface of the electrical sensor is coated with analyte molecules and then target molecules are binding to the analyte molecules in the capture dipping phase.

[0038] For readout, it is optionally possible to bind such analyte molecule with a label, e.g., Horseradish peroxidase (HRP) or another detection antibody. For this, the electrical sensor is dipped into a liquid including the label molecules (labeling dipping phase). In a subsequent readout phase, and enzymatic reaction of the label molecules is triggered, by dipping the electrical sensor into a liquid that triggers the enzymatic reaction. For a label-free measurements, it would be possible to monitor electric signals at the electrical sensors during the capture dipping phase. In other words, the capture dipping phase also implements data readout.

[0039] According to various examples, an electrical sensor is dipped into one or more wells of an MWP. Dipping of electrical sensors is automated using a robotic actuator. The robotic actuator is configured to engage sensor heads that each include one or more electrical sensors.

[0040] To enable the robotic actuator to physically engage sensor heads, the sensor heads may include one or more engagement features. Such engagement features can facilitate reliable and releasable contact between an engagement section of the robotic actuator (e.g., a clamp or gripper) and the sensor head. Different kinds and types of engagement features are conceivable, including mechanical and magnetic engagement features. For instance, protrusions or indentations may be provided that can be engaged with corresponding features of the engagement section of the robotic actuator. A clamp may be used to grip a respective portion of a sensor heads. Magnetic material may be provided at the sensor heads so that a magnetic force can be used in order to selectively engage the sensor heads.

[0041] Physical engagement of a sensor head is accompanied by electrically contacting a sensor head, to read electrical signals provided by the one or more electrical sensors of the sensor head. In particular, during readout, electrical signals are collected from the electrical sensor that are indicative of one or more properties of molecules such as analyte molecules.

[0042] The capability of the system to control the robotic actuator to engage and release sensor heads enables parallelization of measurements of properties of molecules using multiple sensor heads. This is explained in further detail hereinafter.

[0043] Various techniques are based on the finding that the chemical processes taking place when dipping an electrical sensor into a liquid can require significant time (process time). For instance, binding / adsorption between target molecules and analyte molecules may require minutes or even tens of minutes. For instance, the capture dipping phase may include such binding of target molecules to analyte molecules. Similarly, a detection dipping phase including binding of label molecules may require minutes or tens of minutes. Thus, an electrical sensor may have to remain dipped in a well of the MWP for minutes or tens of minutes. Such process times are limited by the underlying chemical processes and cannot be accelerated. During this process time, the respective sensor head must remain stationary so that the one or more electrical sensors are dipped in the respective one or more wells. The robotic actuator does not need to handle the sensor head during the process time.

[0044] The significant process time limits the measurement throughput in conventional systems. In view of the significant process times, there is a need to accelerate the measurement throughput. Hereinafter, techniques are disclosed to accelerate the measurement throughput, i.e. , the number of measurements taken per time unit. The measurement throughput can be accelerated using parallelization.

[0045] To achieve a first layer of parallelization, multiple electrical sensors may be combined in a single sensor head. A sensor head is the unit that can be engaged and handled by the robot actuator. The sensor head is designed such that the multiple electrical sensors can be jointly dipped into adjacent wells of the MWP, by a single movement of the robotic actuator. In other words, a spacing in between the electrical sensors of the sensor head can correlate with a spacing of the wells of the MWP.

[0046] To achieve a second layer of parallelization, the robotic actuator may be configured to sequentially engage different ones of a plurality of sensor heads to dip the respective one or more electrical sensors into different wells of the MPW. In other words, the robotic actuator can be configured to engage, reposition, and dip and release (handle) a given sensor head while one or more electrical sensors of another sensor head previously handled by the robotic actuator are currently dipped into one or more wells of the MWP. Thus, dipping phases - e.g., capture dipping phases or detection dipping phases - can be parallelized. Typically, readout may not be parallelized, because the electrical connection to the electrical sensors is also established via the robotic actuator so that at any given point in time only a single sensor head can be electrically connected for readout.

[0047] FIG. 1 schematically illustrates a system 100 according to various examples. The system 100 is configured for performing parallel measurements (“measurement” as used herein is not limited to readout, but also includes calibration, capture, detection, labelling, etc.) using multiple sensor heads, to determine properties of molecules. Specifically, properties of analyte molecules can be determined. The analyte molecules can be in a liquid, i.e., liquid-side molecules; but it would also be possible that the analyte molecules are attached to a sensor surface, i.e., sensor side molecules.

[0048] The system 100 includes multiple sensor heads, wherein in FIG. 1 , for sake of simplicity, a single sensor head 305 is illustrated. The sensor head 305 includes multiple electrical sensors 111 , 112. As a general rule, each sensor head used in the present disclosure may include one or more electrical sensors.

[0049] A sensor head, such as the sensor head 305, is configured so that it can be engaged by a robotic actuator 102. This includes a mechanical engagement. The robotic actuator 102 can be controlled to reposition the sensor head 305 in an XY-plane that is parallel to a platform 170 onto which an MWP 130 including multiple wells 131-136 is mounted. Thereby, the electrical sensors 111 , 112 of the sensor head 305 can be positioned above certain wells of the MWP 130. Then, the robotic actuator 102 can be controlled to dip the electrical sensors 111 , 112 into these wells 133, 134 by performing a respective movement of the sensor head 305 along a Z-direction perpendicular to the XY-plane.

[0050] As a general rule, various implementations are available for the robotic actuator 102. For instance, a robotic arm may be used. It would be possible to use a belt-based XYZ-system (three degrees of freedom).

[0051] For controlling the robotic actuator 102, the system 100 includes a control device 101. The control device 101 can communicate with the robotic actuator 102. The control device 101 can also communicate with each of the electrical sensors 111 , 112.

[0052] The control device 101 can include at least one processor 801 (labelled “PU” in FIG. 1 , processor unit) and a memory 802. The at least one processor 801 could be implemented by a general-purpose processing unit, and an application-specific integrated circuit, or a field-controlled gated array, to give just a few examples. The at least one processor 801 could load program code from the memory 802 and execute the program code. Upon loading and executing the program code, the at least one processor 801 can perform techniques as described herein, e.g., control the robotic actuator to move, e.g., to position the sensor head 119 and thereby the electrical sensors 111 , 112 in or above certain wells 131 -136 of a MWP 130 that is arranged on a platform 170 or to dip the electrical sensors 111 , 112 into respective wells 131- 136, perform a readout of electrical signals from one or more electrical sensors of a sensor head that is engaged by the robotic actuator, determine one or more properties of analyte molecules, read one or more measurement scripts 185 and control the robotic actuator 102 and / or the electrical sensor 111 , 112 based on the one or more measurement scripts 185, etc..

[0053] FIG. 2 schematically illustrates an example implementation of the sensor head 305 (other sensor heads can be configured similarly). The sensor head 305 includes a single electrical sensor 111.

[0054] The electrical sensor 111 has generally an elongated shape, i.e. , extends along a longitudinal direction 51 . A respective longitudinal center axis 6055 (arranged in the middle of the sensor 111 along a width direction 52) of the electrical sensor 111 extending between a distal end 6191 and a proximal end 6192 is illustrated (dashed dotted line).

[0055] An elongated base 6101 extends between the distal end 6191 and the proximal end 6192.

[0056] The base 6101 has a top surface 6102 and a bottom surface (obstructed from view in FIG. 1 ). The top surface 6102 is plane and extends in a plane defined by the longitudinal direction 51 and a width direction 52.

[0057] The base 6101 includes a narrow sensing region 6105 (for dipping into a well) at the distal end 6191 and a wider connection region 6106 for enabling electrical and mechanical contact.

[0058] An engagement section (e.g., a mounting bracket) of the robotic actuator 102 can engage the connection region 6106 to firmly grip the sensor head 305. Electrical contacts may establish an electrical contact with multiple electrodes 6150, 6155, 6130 of the electrical sensor 100. For this, landing pads 6152, 6157, 6134 are provided.

[0059] The metal electrodes 6150, 6155 are arranged on the top surface 6102 of the base 6101 and extend between the distal end 6191 and the proximal end 6192. The metal electrode 6130 is arranged on a top surface 6122 of an elongated substrate slab 6121 that is attached, at its bottom surface (obstructed from view in FIG. 1), to the top surface 6102 of the base 6101. The elongated substrate slab 6121 extends along the metal electrodes 6150, 6155 between the distal end 6191 and the proximal end 6192.

[0060] Arranged on the top surface 6122 of the elongated substrate slab 6121 is the electrode 6130, e.g., a thin metal film possibly including gold.

[0061] An electrochemical measurement may be executed by determining a current or a voltage in-between the pair of electrodes 6130, 6150 or between the pair of electrodes 6155, 6130. For this, a sensing region 6131 of the electrode 6130 can be bio-functionalized (not shown).

[0062] While FIG. 2 illustrates a scenario in which the sensor head 305 includes a single electrical sensor 111 , other scenarios are conceivable in which a sensor head includes multiple electrical sensors, e.g., to thereby achieve a first layer of parallelization of multiple measurements. Respective examples are illustrated next.

[0063] FIG. 3 is a top perspective view of a sensor head 305 including multiple electrical sensors 111-114. The multiple electrical sensors 111-114 - here four electrical sensors 111-114, but a larger or smaller count would be equally possible - are arranged in a row. An inter-sensor offset between adjacent electrical sensors H I- 114 along the axis 52 corresponds to the inter-well offset of the MWP 130 (not shown).

[0064] The sensor head 305 also includes a dedicated mounting structure 49 that can be engaged by the robotic actuator 102. For this, the mounting structure 49 includes engagement features 989 - here elongated through holes - that can be engaged by pins of a mounting bracket of the robotic actuator 102.

[0065] The bases 6101 of the sensors 111-114 are attached to the mounting structure 49, e.g., by adhesive. The mounting structure 49 includes a through hole that enables contacting the connection region 6134. This is visible in FIG. 4 which is the bottom perspective view corresponding to the top perspective view of FIG. 3.

[0066] In scenarios in which sensor head 305 includes multiple sensors, as illustrated in the example of FIG. 3 and FIG. 4, it is also possible that a single base 6101 is used for the multiple sensors. This is illustrated in the schematic top view of FIG. 5 and the schematic bottom view of FIG. 6.

[0067] FIG. 5 and FIG. 6 illustrate a variant of the sensor head 305. The sensor head 305 includes four sensors 111-114 but could equally include a larger or smaller amount of sensors 111-114. In FIG. 5 and FIG. 6 the base 6101 also implements a mounting structure including the through holes 989 (cf. FIG. 3 and FIG. 4). Other engagement features for facilitating engagement of the sensor head 305 by the robotic actuator 102 may be used.

[0068] Such and other sensor heads can be engaged and released by the robotic actuator 102. Thus, multiple sensor heads can be sequentially handled. Multiple sensor heads can be sequentially engaged and dipped into different wells of an MWP. This enables implementing parallel dipping phases. This is illustrated in FIG. 7. FIG. 7 is a top view of the MWP 130 mounted on the platform 170. The MWP 130 extends in the XY-plane (of. FIG. 1). The platform 170 includes two holders 176, 177 configured to fix each of two sensor heads 305, 306 in a respective predefined rest position. For instance, such holders 176, 177 could be formed as recesses or cavities in the platform 170 such that a user can manually place each sensor head 305, 306 in the respective recess. The sensor heads can then be mounted in an orientation which enables the robotic actuator 102 to engage the respective sensor head 305, 306 when being positioned at the rest position. Then, upon engaging a sensor head 305, 306 in its respective rest position, the robotic actuator 102 can laterally reposition the sensor head 305, 306 (xy-movement) to be positioned above certain wells of the MWP 130.

[0069] FIG. 7 schematically illustrates which wells of the MWP 130 (the wells are shown using circles in FIG. 7) are associated with which sensor head 305, 306. As illustrated in FIG. 7, the first sensor head 305 is associated with 2x2 wells 391 , 392, 393, 394 (dashed line); and the second sensor head 306 is associated with 2x2 further wells 395, 396, 397, 398 (dashed-dotted line). Next, operation of the robotic actuator 102 in such an example scenario is discussed in connection with FIG. 8.

[0070] FIG. 8 schematically illustrates handling of multiple sensor heads using a robotic actuator. In the example of FIG. 8, a first sensor head 305 and a second sensor head 306 are handled subsequently by the robotic actuator 102 (also cf. FIG. 7). FIG. 8 illustrates a sequence of actions executed by the robotic actuator 102.

[0071] The robotic actuator 102 can be controlled by the control device 101 to execute the sequence of actions as discussed hereinafter in connection with FIG. 8. More specifically, it would be possible that the processor 801 controls the robotic actuator 102 accordingly, e.g., by executing multiple measurement scripts. For instance, it would be possible that multiple measurement scripts are available; there may be a measurement script provisioned for each of the plurality of sensor heads, here the sensor head 305 in the sensor head 306. Then, these multiple measurement scripts can be executed synchronized and in parallel, to enable the parallel handling of the multiple sensor heads.

[0072] Before explaining details, it is noted that FIG. 8 is only an example implementation of the parallelization of dipping phases. Multiple variations are possible. In particular, it would be possible to handle more than two sensor heads in parallel. Here, further actions can be executed, e.g., in between timestamp 26 and 27 and / or in between timestamp 30 and timestamp 31 .

[0073] At timestamp 20 a trigger signal may be obtained, a user may trigger multiple measurements associated with the first and second sensor heads 305, 306. The user may thereby conveniently trigger multiple measurements to take place in parallel.

[0074] At timestamp 21 the robotic actuator 102 engages the first sensor head 305. A mechanical contact and an electrical connection is made.

[0075] As a general rule, it is possible to determine whether a given sensor head is engaged by measuring an electrical test signal. For instance, current flow in between multiple pins nominally landed on the same landing pad may be measured and the amplitude of the current flow measured may be compared to a given threshold. Engagement of the given sensor head may be confirmed if the current flow exceeds a certain threshold. For instance, referring to FIG. 2, the mounting structure of the robotic actuator can include two pins that are both arranged to land on the landing pad 6152 or the landing pad 6157. Then, a current flow in between those two pins can be measured to determine whether the first sensor head 305 has been reliably engaged. More generally, it is possible to determine whether a given one of the plurality of sensor heads is engaged based on an electrical signal

[0076] At timestamp 21 , the first sensor head 305 is in a rest position. For instance, a user can have placed the first sensor head 305 in the rest position. The rest position may be defined by a respective holder at a predefined position in a machine coordinate system accessible by the robotic actuator 102 (cf. FIG. 7: holder 176).

[0077] Then, the robotic actuator 102 repositions the first sensor head 305, e.g., in the XY- plane (cf. FIG. 7) in which the MWP 130 extends.

[0078] Then, at timestamp 22, the robotic actuator 102 dips the one or more electrical sensors of the first sensor head 305 into respective one or more wells of the MWP 130 (e.g., in the scenario of FIG. 7, the wells 391 , 392). This is achieved by repositioning the first sensor head 305 along the z-position (“lowering into the well”). This triggers a dipping phase 340. Then, at timestamp 23, the robotic actuator 102 disengages the first sensor head. The mechanical contact and the electrical connection are released. This occurs while the one or more electrical sensors of the first sensor head 305 are dipped in the respective wells. I.e. , the dipping phase 340 continues beyond the timestamp 23.

[0079] To ensure that the first sensor head 305 remains stable in this position upon being released (so that it can be later on retrieved by re-engaging the second sensor head 305 at that position), a fixture may be provided. Such fixture may be attached to the MWP 130 or the platform 170. The fixture may extend along the MWP 130 (XY- plane, cf. FIG. 1 ). The fixture 130 may include recesses or other engagement features configured to fix, retain, or otherwise stabilize sensor heads in relevant positions suitable for dipping the electrical sensors into the wells. For instance, such fixture may include recesses configured to engage lower edges 980 of the sensor heads (cf. FIG. 2, FIG. 3, FIG. 4, FIG. 5 where the lower edges 980 adjacent to the MWP 130 are shown). Thereby, tilt of the sensor heads can be prevented.

[0080] For instance, the dipping phase 340 may be a capture phase. Here, target molecules may bind to analyte molecules. Either the target molecules or the analyte molecules may be coated on a bio-functionalized region of the one or more electrical sensors of the first sensor head 305. This binding I association may require a significant process time to complete; so the dipping phase 340 may have a duration of minutes or tens of minutes. Thus, it is beneficial to proceed to handling the second sensor head 306 while the dipping phase 340 is still ongoing, to increase the measurement throughput. Throughout the dipping phase 340, data readout may not be required.

[0081] Accordingly, the robotic actuator 102 repositions to then engage the second sensor head 306 in a respective rest position, at timestamp 24. Again, that rest position could be defined by a holder allocated to the second sensor head 306. The rest position is predefined in the machine coordinate system of the robotic actuator 102. This enables the robotic actuator 102 to grab I engage the second sensor head 306, at timestamp 24.

[0082] The robotic actuator 102 then replaces the second sensor head 306 above the MWP

[0083] 130. For instance, as illustrated in FIG. 7, it would be possible that the robotic actuator 102 replaces the second sensor head 306 so that it is positioned above the wells 395, 396 of the MWP 130. All this happens while the first sensor head 305 is still arranged so that the electrical sensors thereof are dipped in the wells 391 , 392.

[0084] At timestamp 25, the robotic actuator 102 dips the one or more electrical sensors of the second sensor head 306 into respective wells of the MWP. This triggers the dipping phase 350. For instance, the dipping phase 350 may also be a capture dipping phase, as the dipping phase 340. Different analyte molecules and / or different target molecules may be used in the dipping faces 340, 350, respectively.

[0085] As is apparent from FIG. 8, the dipping phase 350 and the dipping phase 340 partially overlap in time domain. This time-domain overlap increases the overall measurements throughput.

[0086] For example, as explained above in connection with timestamp 23, the capture dipping phase 340 (at which target molecules bind with analyte molecules) partially overlaps with the capture dipping phase 350. However, various variations are conceivable. For example, it would be possible that a capture dipping phase partially overlaps with a detection dipping phase (in which a label binds to the target or analyte molecules).

[0087] This concept of (partially) overlapping dipping phases can be implemented in various manners. To further illustrate this concept, the further actions of the robotic actuator 102 are presented in FIG. 8. However, multiple variations of the sequence of actions are conceivable.

[0088] At timestamp 26, the robotic actuator 102 disengages the second sensor head 306 while its electrical sensors remain dipped in the respective wells of the MWP 130. Thus, the dipping phase 350 continues.

[0089] At timestamp 27, the robotic actuator 102 engages the first sensor head 305. The first sensor head 305 is engaged at the same position at which it has been previously released at timestamp 23. Using a fixture can ensure that the first sensor head 305 does not move in-between timestamps 23 and 27.

[0090] At timestamp 28, the robotic actuator 102 lifts the first sensor head 305 so that its electrical sensors are retrieved from the respective wells of the MWP 130. Timestamp 28 can be triggered by expiry of a predefined timer that is initialized by timestamp 22. In other words, it would be possible that a dipping phase has a predefined length. It would also be possible that a dipping phase has a dynamic length. In such a scenario, timestamp 28 is triggered based on one or more electrical signals measured using one or more electrical sensors of the sensor head associated with the respective dipping phase. For instance, it would be possible to monitor electrical signals in between timestamp 27 and timestamp 28 (upon establishing the electrical contact with the first sensor head 305 and its electrical sensors) to determine whether the electrical signals exceed or fall below a certain predefined threshold and / or fulfill further requirements. Responsive to one or more such trigger events, it would then be possible to lift the first sensor head 305 so that the one or more electrical sensors thereof are retrieved from wells of the MWP.

[0091] The robotic actuator 102 then repositions the engaged first sensor head 305 so that it is positioned above further wells of the MWP (e.g., referring to the scenario of FIG. 7, above the wells 393, 394 of the MWP 130).

[0092] At timestamp 29, the robotic actuator 102 dips the first sensor head 305 into the further wells of the MWP so that a further dipping phase 341 commences. For instance, the further dipping phase 341 could be a detection dipping phase in which label molecules bind to the analyte or target molecules.

[0093] At timestamp 30, after the dipping phase 341 has commenced, the robotic actuator disengages the first sensor head 305 while the dipping phase 341 is ongoing. The first sensor head 305 is retained in its position by the fixture.

[0094] The robotic actuator 102 repositions to then engage, at timestamp 31 , the second sensor head 306. The second sensor head 306 is engaged at the position at which it has been previously released at timestamp 26; the second sensor head 306 is retained in this position in-between timestamps 26 and 31 by means of the fixture.

[0095] At timestamp 32, the second sensor head 306 is then lifted from the respective wells and repositioned with respect to the MWP.

[0096] At timestamp 33, the one or more electrical sensors of the second sensor head 306 are dipped into further wells of the MWP. Another dipping phase 351 commences, e.g., a further detection dipping phase. At timestamp 34, the second sensor head 306 can be disengaged.

[0097] At timestamp 35, the first sensor head 305 is engaged by the robotic actuator and lifted from the respective well at timestamp 36, thereby ending the dipping phase 341.

[0098] At timestamp 37, the first sensor head 305 is placed in its rest position. This enables the robotic actuator to engage the second sensor head 306 at timestamp 38 and lifts the second sensor head 306 from the respective well at timestamp 39.

[0099] At timestamp 40, after repositioning, the second sensor head 306 is dipped into a further well, to thereby trigger the dipping phase 352. During the dipping phase 352, data readout is performed. For instance, the second sensor head 306, at timestamp 40, can be dipped into a well that triggers an enzymatic reaction of the label molecules previously attached to the analyte or target molecules in the detection dipping phase 351 .

[0100] Typically, data readout requires a comparatively short time so that the readout dipping phase 352 is shorter than the previous dipping phases 350, 351. At timestamp 41 , the robotic actuator lifts the second sensor head 306 from the respective well in places that, at timestamp 42, in a rest position. The robotic actuator disengages the second sensor head 306 and, after repositioning, at timestamp 43, engages the first sensor head 305. At timestamp 44, the robotic actuator places the first sensor head 305 and a respective well to trigger a readout dipping phase 342. At timestamp 45, the robotic actuator lifts these first sensor head 305 from the respective well.

[0101] FIG. 8 is only an example implementation of the parallelization of dipping phases. Multiple variations are possible. In particular, it would be possible to handle more than two sensor heads in parallel. Here, further actions can be executed, e.g., in between timestamp 26 and 27 and / or in between timestamp 30 and timestamp 31.

[0102] As will be appreciated from the above, parallelization of dipping phases is achieved by releasably engaging multiple sensor heads. Such releasable engagement of multiple sensor heads each including one or more electrical sensors is enabled by an appropriate mechanical contact and electrical connection between the sensor heads and a respective engagement section of the robotic actuator. For instance, open-loop control of the positioning of the robotic actuator to engage a given sensor head would be possible. A list of predefined positions including a rest position and multiple dipping positions may be provisioned and the robotic actuator can be controlled to move to these predefined positions and then engage the given sensor head at these positions. Alternatively, it would also be possible to implement closed-loop positioning of the robotic actuator. Positioning means may be available to determine a position of the given sensor head in a machine coordinate system of the robotic actuator. For instance, a camera may be used, and image processing may be executed to determine the position of the given sensor head in the machine coordinate system of the robotic actuator. Other positioning means are conceivable, e.g., based on distance sensors, other image sensors, or active positioning beacons.

[0103] FIG. 9 illustrates a fixture 900. The fixture 900 has a plate-shaped element 995 having lateral dimensions (XY-plane) slightly larger than the lateral dimensions of a MWP. The plate-shaped element 995 has a top surface 990 and a bottom surface 991 (hidden from view in the perspective view of FIG. 9). Pillars or feet 901 extend from the bottom surface 991 along the z-direction so that the MWP can be placed below the plate-shaped element 995 (in FIG. 9, the MWP is not shown).

[0104] Longitudinal ridges 920 are formed in the top surface 990 of the fixture 900. The longitudinal ridge 920 extend along the Y-direction. In between adjacent longitudinal ridge 920, through holes 920 are formed through which the electrical sensors can extend. Also shown in FIG. 9 are grooves 911 formed in the ridges 920 and extending along the X-direction. The grooves 911 are shaped so as to retain a sensor head 305, 306. Accordingly, the grooves 911 and the ridges 910 form engagement features that can releasably retain the sensor heads 305, 306 when the respective electrical sensors are dipped into the wells of the MWP. The dimensions of the various elements of the fixture 900 are chosen so that the electrical sensors are dipped into the wells of the MWP when the sensor heads 305, 306 are retained by the grooves 911 formed in the ridges 910.

[0105] In FIG. 9 the sensor heads 305, 306 each include four electrical sensors indicated by dashed line; only the electrical sensors 111 , 114 are labeled for sake of simplicity; the number of electrical sensors per sensor head is generally variable, e.g., it would be possible that each sensor had only includes two electrical sensors, e.g., is schematically shown in FIG. 7. FIG. 10 is a further perspective view of the fixture 900 illustrated in FIG. 9 (without the sensor heads 305, 306).

[0106] Although the invention has been shown and described with respect to certain preferred embodiments, equivalents and modifications will occur to others skilled in the art upon the reading and understanding of the specification. The present invention includes all such equivalents and modifications and is limited only by the scope of the appended claims.

[0107] For illustration, above a scenario has been disclosed in which an electrical sensor is configured for measuring a current flow through a liquid in-between electrodes. Other electrical sensors may be used, e.g., field-effect transistors, etc.

Claims

C L A I M S1. A system (100), comprising:- a robotic actuator (102) configured to releasably engage a plurality of sensor heads (305, 306), each of the plurality of sensor heads (305, 306) comprising one or more electrical sensors (111 , 112, 113, 114),- a platform (170) configured to retain a multi-well plate (130), and- at least one processor (801 ) configured to control the robotic actuator (102) to sequentially engage different ones of the plurality of sensor heads (305, 306) to dip the respective one or more electrical sensors (111 , 112, 113, 114) into different wells (131-136, 391-398) of the multi-well plate (130).

2. The system (100) of claim 1 , wherein the at least one processor is configured to implement, for each of the plurality of sensor heads (305, 306), at least one respective dipping phase (340, 341 , 350, 351 ) during which the respective one or more electrical sensors (111 , 112, 113, 114) are dipped into one or more wells (131-136, 391 -398) of the multi-well plate (130), wherein dipping phases (340, 341 , 350, 351 ) associated with different ones of the plurality of sensor heads (305, 306) at least partially overlap in time domain.

3. The system (100) of claim 2, wherein a capture dipping phase (340) associated with a first one (305) of the plurality of sensor heads (305, 306) partially overlaps in time domain with the capture dipping phase (350) associated with second one (306) of the plurality of sensor heads (305, 306).

4. The system (100) of claim 2 or 3, wherein a capture dipping phase associated with a first one of the plurality of sensor heads partially overlaps in time domain with a detection dipping phase associated with second one of the plurality of sensor heads.

5. The system (100) of any one of the preceding claims, wherein the at least one processor is configured to control to the roboticactuator to sequentially perform the following actions: a) engage (21) a first one (305) of the plurality of sensor heads (305, 306) in a first rest position, b) reposition and then dip (22) the one or more electrical sensors associated with the first one (305) of the plurality of sensor heads (305, 306) into one or more first wells (391 , 392) of the multi-well plate (130), c) disengage (23) the first one (305) of the plurality of sensor heads (305, 306) while the one or more electrical sensors associated with the first one (305) of the plurality of sensor heads (305, 306) are dipped in the one or more first wells (391 , 392), d) engage (24) a second one (306) of the plurality of sensor heads (305, 306) in a second rest position, e) reposition and then dip (25) the one or more electrical sensors associated with the second one (306) of the plurality of sensor heads (305, 306) into one or more second wells (395, 396) of the multi-well plate (130), f) disengage (26) the second one of the plurality of sensor heads while the one or more electrical sensors associated with the second one (306) of the plurality sensor heads (305, 306) are dipped in the one or more second wells (395, 396).

6. The method of claim 5, wherein the at least one processor is further configured to control to the robotic actuator to sequentially perform the following actions, after executing f): g) engage (27) the first one (305) of the plurality sensor heads (305, 306) while the one or more electrical sensors associated with the first one (305) of the plurality sensor heads (305, 306) are dipped in the one or more first wells, h) reposition (28) and then dip (29) the one or more electrical sensors associated with the first one (305) of the plurality of sensor heads (305, 306) into one or more third wells (393, 394) of the multi-well plate (130), i) disengage (30) the first one (305) of the plurality of sensor heads (305, 306) while the one or more electrical sensors of the first one (305) of the plurality of sensor heads (305, 306) are dipped into the one or more third wells (393, 394), j) engage (31 ) the second one (306) of the plurality of sensor heads (305, 306) while the one or more electrical sensors associated with the second one (306) of theplurality of sensor heads (305, 306) are dipped in the one or more second wells (395, 396), k) reposition (32) and then dip (33) the one or more electrical sensors associated with the second one (306) of the plurality of sensor heads (305, 306) in one or more fourth wells (397, 398) of the multi-well plate (130), and l) disengage (34) the second one (306) of the plurality of sensor heads (305, 306) while the one or more electrical sensors of the second one (306) of the plurality of sensor heads (306) are dipped into the one or more fourth wells (397, 398).

7. The system (100) of any one of the preceding claims, wherein the platform (170) comprises holders (176, 177) to fix each of the plurality of sensor heads (305, 306) in a respective predefined rest position, wherein the at least one processor (801 ) is configured to engage each of the plurality of sensor heads (305, 306) in the respective predefined rest position.

8. The system (100) of any one of the preceding claims, further comprising:- a fixture extending along the multi-well plate (130) and comprising engagement features (910, 911 ) configured to releasably retain each of the plurality of sensor heads (305, 306) when the respective one or more electrical sensors (111 , 112, 113, 114) are dipped into wells of the multi-well plate (130).

9. The system (100) of any one of the preceding claims, wherein the at least one processor is further configured to determine whether a given one of the plurality of sensor heads is engaged based on an electrical signal flowing through a current path supported by the given one of the plurality of sensor heads.

10. A method of operating a robotic actuator (102) of a system (100), the method comprising:- engaging a first sensor head (305) and dipping one or more electrical sensors of the first sensor head (305) into one or more first wells of a multi-well plate,- releasing the first sensor head (305) while the one or more electrical sensors of the first sensor head are dipped into the one or more first wells, and- while the one or more electrical sensors of the first sensor head are dipped into the one or more first wells: engaging a second sensor head (306) and dipping one or more electrical sensors of the second sensor head (306) into one or more second wells of the multi-well plate.

11. The method of claim 10, wherein the method is executed by the system (100) of any one of claims 1 to 9.

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