Semi-automated patch clamp apparatus and method for performing a patch clamp procedure

Abstract

The semi-automated patch clamp apparatus (100) comprises a patch clamp plate manipulator configured to receive a patch clamp plate (1) including a plurality of patch clamp sites (10) and a computerized controller configured to define a patch clamp procedure. To enable an efficient patch clamp procedure and user interaction during the procedure, the controller is configured to define the patch clamp procedure with manual process steps assigned for manual execution by a user and automated process steps for automatic execution by the manipulator. The controller is configured to provide instructions to the user for executing the manual process steps and commands to the manipulator for automatic execution of the automated process steps, and to control the execution of the patch clamp procedure by sending commands to the manipulator for execution of the automated process steps and sending instructions to the user for manual execution of the manual process steps.

Description

[Technical field]

[0001] The present invention relates to a patch clamp apparatus including a patch clamp plate manipulator configured to receive a patch clamp plate including a plurality of patch clamp sites, the patch clamp apparatus including a computerized controller, and a method for performing a patch clamp procedure. [Background technology]

[0002] Ion channels are membrane proteins within living cells that control the flow of ions into and out of cells and are important targets for a variety of drugs.

[0003] Ion channels are commonly studied by a technique called patch clamp: cells are attached to a patch clamp plate that contains multiple patch clamp sites.

[0004] The on-cell, whole-cell, or perforated patch configurations of patch clamp are widely accepted as providing the best method for measuring ion channel activity for drug screening. In these methods, the ionic current through the ion channel is measured directly and with high resolution by sensitive current amplifiers.

[0005] A protocol specifies the pressure, potential, or current to be applied at the patch clamp site, followed by measurements such as current across ion channels, capacitance, or cell potential.

[0006] Users need efficient methods for investigating ion channels. High throughput in the screening process is important, but flexibility and freedom for users to dynamically interact with the investigation process is highly desirable.

[0007] The general idea of ​​electrically isolating a patch of membrane and studying ion channels within that patch under voltage clamp conditions has been reviewed in the literature (Neher, Sakmann, and Steinback (1978) "The Extracellular Patch-clamp, A Method For Resolving Currents Through Individual Open Channels In Biological Membranes", Pfluger Arch. 375; 219-278). Recent developments in patch clamp techniques contemplate the introduction of planar substrates (e.g., silicon chips) instead of traditional glass micropipettes (see, e.g., WO 01 / 25769 and Mayer, 2000). Additional background art includes U.S. Pat. No. 8,268,260, which is incorporated herein by reference. Summary of the Invention [Problem to be solved by the invention]

[0008] Unfortunately, current patch clamp methods and devices have shortcomings. In particular, existing methods are either manual or fully automated. Manual methods require highly skilled operators to perform time-consuming tests, and the throughput is typically insufficient for industrial testing. Automatic methods are run by large, expensive machines with little user interaction once the experimental protocol has begun. Although they offer high throughput, they do not offer the opportunity to dynamically modify an ongoing experiment, and each experiment must be planned from start to finish before it begins. [Means for solving the problem]

[0009] An objective of embodiments of the present invention is to improve patch clamping techniques, in particular to improve the balance between throughput and dynamic interaction during testing. A further objective is to effectively bridge the gap between manual and automated measurements while reducing operator error, and to enable the more robust and reproducible measurements known from automated measurements while retaining the flexibility of manual patch experiments required by experienced users.

[0010] To this and other objects, the present invention provides in a first aspect a controller comprising: Defining a patch clamp procedure that includes multiple process steps, each of which can be assigned for automatic execution by a manipulator or manual execution by a user. · Providing instructions for a user to execute a manual process step that has been assigned for manual execution. Providing commands for the manipulator with respect to the automatic process steps assigned to automatic execution. The present invention provides a semi-automatic apparatus configured to:

[0011] The controller initiates process steps assigned for automatic execution by sending commands to the manipulator, and initiates manual process steps assigned for manual execution by sending instructions to the user.

[0012] The controller has a patch clamp experiment as a predefined procedure with multiple steps, each step assigned for manual or automatic execution, allowing the controller to change between manual and automatic processing during the patch clamp procedure, thereby providing improved throughput during automatic processing and maintaining the ability to dynamically interact during the experiment.

[0013] As used herein, "semi-automatic" means that the apparatus is configured to allow certain process steps to be performed manually, while allowing other process steps to be performed automatically.

[0014] As used herein, "patch clamp procedure" refers to a selection of process steps and the particular order in which they are performed.

[0015] As used herein, a "process step" refers to a single action involved in a patch clamp procedure, which may be defined, for example, in a protocol.

[0016] As used herein, "protocol" refers to pre-specified electrical signals, pressure signals, optical signals, or combinations thereof, which can be applied to a patch clamp site by a manipulator.

[0017] The patch clamp plate manipulator is configured to perform all necessary handling of the patch clamp plate. The manipulator comprises mechanical components including inlets for facilitating the supply of solutions to the patch clamp site and for controlling the pressure at the patch clamp site. Furthermore, the manipulator comprises electronic components for performing the procedures in which electrical and / or pressure and / or optical signals are applied to and received from the patch clamp site.

[0018] The computerized controller is configured with a user interface for communication with a user and a data interface with the manipulator so that the controller can control the manipulator and control automated process steps. Additionally, the controller may have other interfaces for communicating data with, for example, an external computer.

[0019] The patch clamp procedure includes a number of predefined process steps, including manual process steps defined in the memory of the controller and executed manually by a user, and automated process steps for automated execution by a manipulator, and the controller is programmed to provide instructions relating to both the manual and automated process steps.

[0020] Instructions for the user are typically provided on a computer screen, for example in written form, and typically in graphical interactive form showing where to add solutions etc. The interface may provide feedback of results to the user during the execution of the procedure, allowing the user to modify subsequent steps taking into account the results obtained in previous steps. The controller may be configured to communicate with the user not only by the screen, but also by audio signals, or by a combination of optical and audio signals.

[0021] The controller may include, among other things, multiple patch clamp procedures, and the user may select a predefined patch clamp procedure from a procedure library, thereby allowing several predefined process steps to be loaded into the controller for execution.

[0022] The controller may also enable the user to define new patch clamp procedures. These may be defined, for example, via a computer screen or uploaded from another computer system.

[0023] To define a new patch clamp procedure, the controller may include a number of predefined process steps, each of which may be predefined as an automated process step or a manual process step.

[0024] The controller may include multiple patch clamp protocols. Each protocol defines a sequence of signals to be automatically applied by the manipulator to the patch clamp site. The protocols may be included in a protocol library from which a user may select a protocol for a particular process step. At least one of the protocols may specify at least one of a pressure, a potential, or a current to be applied by the manipulator to the patch clamp site.

[0025] Additionally, the controller may, if desired, allow the user to define and optionally save new protocols. These may, for example, be defined via a computer screen or uploaded from another computer system.

[0026] In addition to pressure and electrical signal values, the protocol may specify light signals to flash the cells with light of various wavelengths, e.g., ultraviolet light, to provide light-evoked currents recorded under voltage clamp.

[0027] The controller can include measurement steps that define how readings are automatically taken by the manipulator at the patch clamp site, at least one of the measurement steps can specify reading an electrical or optical signal from the patch clamp site.

[0028] The controller may enable the user to define new measurement steps. These may be defined, for example, via a computer screen or uploaded from another computer system.

[0029] The controller may enable a user to select a predefined protocol and / or predefined measurement steps for the patch clamp procedure, and may in particular allow such selection while a patch clamp procedure is being performed, thereby enabling the user to modify the patch clamp procedure depending on the results obtained during the procedure.

[0030] The controller can be configured to assign a manual process step to a time-critical group of manual process steps or to a non-time-critical group of manual process steps.

[0031] The instructions for the user to execute a step assigned to manual execution may be provided with a timer countdown that initiates an automatic shift to a subsequent manual process step or an automatic process step execution if the manual process step is assigned to a time-critical group of manual process steps, thereby enabling the controller to determine the timing between two subsequent process steps and thereby ensure that certain timing parameters are respected.

[0032] If the manual process step is assigned to a non-time-critical group of manual process steps, a user-initiated acknowledgment may trigger subsequent manual or automatic process step execution. This allows the user to determine timing when timing is not critical to the experiment being performed. The user-initiated acknowledgment may be the pressing of a button on a touch screen or a voice-initiated acknowledgment by the user giving a "next" command, etc.

[0033] The controller may be configured to allow a user to reassign manual process steps to automated process steps or vice versa, which may be done, for example, while a patch clamp procedure is being performed.

[0034] The controller may be configured with a user interface that allows a user to save the patch clamp procedure after modifying it and, optionally, add metadata related to the patch clamp procedure. The controller may define a data file containing metadata with data related to the patch clamp procedure and may enable such metadata to be exported to other computer systems. The user interface allows a user to add metadata individually to selected process steps or to the patch clamp procedure itself. In one example, a user may, for example, comment on the results obtained in a measurement step or comment on the procedure as a whole.

[0035] Additionally or alternatively, the controller may automatically add metadata relating to the patch clamp procedure and / or individual process steps, such as date and timestamps, or results obtained in measurement steps.

[0036] The controller can be configured to communicate to the user which process step is being performed, for example by graphically visualizing on a screen the current step, previous step and next step, or by visualizing that the current step is step number x out of a total number of y steps.

[0037] The controller may be configured to allow a user to skip a process step and jump to a subsequent process step, and to communicate the results of a process step to the user before starting the subsequent process step.

[0038] The controller may be provided with a graphical user interface and instructions for a user to perform manual process steps may include graphic illustrations relating to a patch clamp plate or multiple patch clamp sites (e.g., specifically illustrating which inlets to add particular solutions, etc.).

[0039] The controller may comprise a predefined sequence in which the process steps are performed. The sequence may for example determine that one process step is performed after another process step and before yet another process step. The sequence may determine that two process steps are performed simultaneously after another process step and before yet another process step. The controller may comprise a user interface that allows a user to change the sequence, for example by keying in a different sequence or by graphically dragging and dropping a step at a different location in the sequence of steps. Changes in the sequence may be added to the metadata automatically or manually.

[0040] In a second aspect, the present invention provides a method of performing a patch clamp procedure, comprising the steps of predefining the procedure in the form of a number of manual process steps and a number of automated process steps in a computer system, and enabling the computer system to initiate the execution of the automated process steps by electronically controlling actuators, and to initiate the manual process steps by instructing a user.

[0041] The method may include any steps that are implicit in view of the apparatus according to the first aspect of the invention.

[0042] Further details of the technique are provided in the attached dependent claims, figures and examples. [Brief description of the drawings]

[0043] The technique is illustrated by the schematic diagram below.

[0044] [Figure 1] 1 shows an apparatus according to the present invention. [Diagram 2] 1 shows a schematic of the patch clamp procedure. [Diagram 3] 1 shows the steps of the patch clamp procedure. [Figure 4] 13 illustrates user modifications of the patch clamp procedure. [Diagram 5] 3 shows various user interfaces of the controller. [Figure 6] 3 shows various user interfaces of the controller. [Figure 7] 3 shows various user interfaces of the controller. [Figure 8] 3 shows various user interfaces of the controller. [Figure 9] 3 shows various user interfaces of the controller. [Figure 10] 3 shows various user interfaces of the controller. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The patch clamp technique is used to study ionic currents within individual isolated biological cells, tissue slices, or patches of cell membrane. This technique is used to study neurons, cardiac myocytes, muscle fibers, and pancreatic beta cells, among others.

[0046] Various patch clamp techniques are used: in voltage clamp, the voltage across the cell membrane is controlled and the resulting current is recorded, and in current clamp, the current through the membrane is controlled and the resulting change in voltage is recorded.

[0047] Figure 1 shows a semi-automated patch clamp apparatus (100). The apparatus includes a slot 101 for receiving a patch clamp plate, which captures and holds cells during the patch clamp procedure.

[0048] Patch clamp plates are used in automated patch clamp (APC) measurements for high-throughput recording of ion channel currents in living cells. These patch clamp plates are assembled from multiple components with different properties that are favorable for APC measurements.

[0049] Patch clamp plates are typically "single use" (disposable). Thus, they are easily replaced by removing the used plate from slot 101 and inserting a new disposable plate into the slot, thus reducing or eliminating contamination between experiments.

[0050] The patch clamp plate comprises a plurality of intracellular (IC) inlets arranged in at least one array, each of the IC inlets being fluidly connected to an IC chamber. The patch clamp plate also comprises a plurality of extracellular (EC) inlets arranged in another array, each of the EC inlets being fluidly connected to an EC chamber.

[0051] The patch clamp plate also includes a patch clamp chip disposed between each EC chamber and each IC chamber, each patch clamp chip including one or more patch holes. At least one patch hole extends through the patch clamp chip and provides a fluid connection between the EC chamber and the IC chamber. A biological cell to be examined is captured on the patch hole during the patch clamp experiment.

[0052] Each IC chamber of the patch clamp plate is equipped with an IC electrode and each EC chamber is equipped with an EC electrode.

[0053] The patch clamp plate may further comprise a cover to seal off the testing environment and provide an inlet for fluid access to the experimental site. A flexible gasket may be present to form a fluid and electrical seal between the EC and IC chambers.

[0054] At the experimental site, a gigaohm (GΩ) hermetic seal is established between the cell membrane and the patch hole using physiological solution, allowing the user to avoid "seal-strengthening" ions, such as fluoride, which are often required in APC experiments and have been reported to modulate ion channel function.

[0055] A patch clamp plate may contain multiple measurement sites depending on the required throughput. Each "measurement site" comprises at least one patch clamp chip with an IC chamber, an EC chamber, and associated EC / IC inlets and outlets.

[0056] Microfluidic channels on the outside of the cell allow rapid fluid exchange with multiple solution additions to the same cell during an experiment. Solution exchange can be achieved with less than 10 μL of solution, significantly reducing solution consumption.

[0057] The device includes an array of inlets 102 for liquid addition, for example by manual pipetting. Any number of inlets may be provided. In the disclosed device, there is an array of eight inlets. The array includes eight inlets configured to receive eight individual pipettes.

[0058] The device comprises a patch clamp plate manipulator configured to receive a patch clamp plate and perform an automated procedure. The manipulator comprises mechanically moving components for communicating eight separate inlets with the EC and / or IC chambers of the plate. Eight different solutions can then be processed independently. The manipulator also comprises the electronics necessary to apply signals to and read signals from the patch clamp sites. Applied signals include electrical signals, pressure signals, and optionally optical signals such as flashes of light of specific wavelengths.

[0059] The apparatus includes connections for pressurized gas (eg, air, vacuum, etc.) and, if desired, connectors for water or for communication of other consumables for the experiment.

[0060] The device comprises a computerised controller configured with a user interface in the form of a computer screen 103, in this case a touch screen allowing two-way communication between the controller and the user.

[0061] The controller is implemented in a CPU with memory and computer executable code for enabling various functions, which are described in detail below. The illustrated apparatus includes a dedicated controller specially made for performing patch clamp procedures. The controller can alternatively be comprised, at least in part, of a standard computer system, such as a PC. The controller includes a data interface for external data communication, e.g., for exporting results and importing patch clamp procedures, process steps, and / or protocols.

[0062] Those skilled in the art will appreciate that the functionality of the patch clamp apparatus can be implemented using standard hardware circuitry, using software programs and data in combination with an appropriately programmed digital microprocessor or general-purpose computer, and / or using application specific integrated circuits, and / or using one or more digital signal processors. The software program instructions and data may be stored in a non-transitory computer-readable storage medium, and when the instructions are executed by a computer or other suitable processor control, the computer or processor performs the functions associated with those instructions.

[0063] Devices known in the art are fabricated for fully automated procedures where the entire procedure is pre-specified in the memory of the controller. This is efficient but results in reduced flexibility and little user interaction. The controller of the apparatus shown in Figure 1 is configured to define a patch clamp procedure that includes multiple process steps that are executed in sequence.

[0064] Some of the process steps are for manual process execution by a user and some of the process steps are for automatic execution by an apparatus.

[0065] The controller provides instructions to a user for manual process steps and controls the manipulator for automatic performance of automated process steps.

[0066] FIG. 2 shows a schematic workflow with multiple process steps illustrating an example of a patch clamp procedure defined in the memory of the controller.

[0067] The patch clamp procedure involves multiple process steps, which in this implementation of the invention are grouped into four different groups of process steps.

[0068] The first group of process steps is called "setup" or simply group S and includes eight process steps in which the experiment is set up. These process steps are numbered beginning with S, i.e., S1 to S8.

[0069] The second group of process steps is called "Priming the Patch Clamp Plate" or simply Group P and includes 9 process steps in which the patch clamp plate is primed. These process steps are numbered starting with P, i.e. P1 to P9.

[0070] The priming process may include a priming protocol to completely evacuate air from the microfluidic channels before the start of an experiment.

[0071] A cell is applied through the extracellular channel and positioned at the patch hole by low negative pressure across the patch hole. Once properly sealed, a short suction pulse forces the cell into the whole-cell configuration and is held in place by low negative pressure throughout the subsequent patch clamp experiment. The extracellular solution can be exchanged throughout the experiment, allowing for precise addition and washing of solutions.

[0072] The third group of process steps is called "Cell Positioning and Whole Cell (WC) Formation" or simply Group C, and includes five process steps in which the cells are positioned and the WCs are formed. These process steps are numbered starting with C, i.e., C1 to C5.

[0073] The fourth group of process steps is an arbitrary, freely definable set of process steps that can be a proprietary standard used by a particular user. Here, it is called "E-phys experiments" or simply group E, and it includes the 12 process steps in which E-phys experiments are performed. The numbering of these process steps starts with E, i.e., E1 to E12.

[0074] The process steps are outlined below: Process Steps: S1.[M] The user needs to insert the patch clamp plate. S2.[A] Scan the barcode. S3.[M] The user must select a site number (1-8). S4.[M] User must enter metadata (cell type, solution name, etc.). S5.[M] OPTIONAL: The user can preload a list of solutions (name + concentration) to be tested in the e-phys experiment. S6.[M] The user must select from the library the protocol to be used for WC formation. S7.[M] Optional: The user may select a fixed sequence of steps and a sequence of protocols to run in the e-phys experiment. S8.[M] The user must press Start.

[0075] Process Steps: P1.[A] The manipulator prepares the patch clamp plate for the addition of IC solution. P2.[M] The user is instructed to add IC fluid. P3.[M] User adds liquid and presses "ok". P4.[A] The manipulator seals the plate and the controller executes a pressurization step protocol to prime the plate with IC solution. P5.[A] The manipulator prepares the patch clamp plate for the addition of EC solution. P6.[M] The user is instructed to add EC solution. P7.[M] User adds liquid and presses "ok". P8.[A] The manipulator seals the plate and the controller executes a pressurization step protocol to prime the plate with EC solution. P9.[A] The controller is The electrical properties of the patch clamp plate primed with IC and EC solutions are measured individually at sites 1 to 8. If the properties are within user-defined limits, each site is cleared for further use.

[0076] Process steps: C1.[M] The user is prompted to add an amount of cell solution. A countdown timer instructs the user when to add cells, one site at a time. C2.[M] The user adds the cell solution. C3.[A] The controller initiates the applied pressure protocol at the appropriate time to position the cell at the patch hole within each of sites 1-8. The controller measures the electrical readings and determines when the cell is positioned. C4.[A] The controller initiates the applied pressure and / or potential protocol to place the cells into whole-cell formation. The controller measures the electrical readings and determines when the cells reach whole cell formation. C5.[A] 0–8 sites are prepared for e-phys experiments.

[0077] Process steps: E1.[M] The user selects the site and runs the protocol. E2.[M] The user selects the solution to be tested. E3.[M] The user selects a protocol from a library. E4.[M] The user presses "Execute". E5.[A] A countdown timer prompts the user to add the selected solution. E6.[M] The user adds the selected solution. E7.[A] The controller executes the selected protocol in a timely manner. E8.[A] The controller collects data and relevant processed data is presented to the user. E9.[A] Based on the processed data, users can choose how to proceed with the experiment. E10.[A] Steps 1 to 8 are repeated for up to eight regions according to user settings. E11.[M] Once the user confirms that the solution testing is complete, the e-phys experiment can be terminated. E12.[A] The manipulator releases the plate, allowing the user to remove it. E13.[A] The data is then exported.

[0078] Each step includes a designation of [A] for automatic or [M] for manual. This is a definition included in the controller to distinguish between manual and automatic process steps. During the execution of the patch clamp procedure, the identification of automatic and manual process steps allows the controller to execute the patch clamp procedure by sending commands to the manipulator for the execution of automatic process steps and instructions to the user for the manual execution of manual process steps.

[0079] In step S1, the corresponding instruction sent by the controller via the touch screen is "Insert a new patch clamp plate."

[0080] In step S2, the corresponding command to the manipulator is to scan the barcode on the patch clamp plate, which is an electronic command sent to a barcode reader included in the patch clamp plate manipulator, which upon receiving this instruction reads the barcode on the patch clamp plate and returns a data string representing the value read.

[0081] In step S3, the corresponding instruction sent by the controller via the touch screen is "Select the number of available sites."

[0082] In step S4, the corresponding instruction sent by the controller via the touch screen is "Add Metadata" or the instruction guides the user to add specific data. In one example, the user can benefit from pull-down menus where patch clamp procedure ID, date, user ID, and other types of predefined metadata can be selected and associated with the patch clamp procedure being started.

[0083] In step S5, the corresponding instruction sent by the controller via the touch screen is "Select a solution", and the user is guided by a pull-down menu where different solutions and concentrations can be selected and associated with the patch clamp procedure being started.

[0084] In step S6, the corresponding instruction sent by the controller via the touch screen is "Select a protocol", and the user is guided by a pull-down menu where various protocols from a library of protocols can be selected and associated with the patch clamp procedure being started.

[0085] In step S7, the corresponding instruction sent by the controller via the touch screen is "Choose a sequence", and the user is guided by a graphical user interface showing the sequence and protocol of predefined steps of the patch clamp procedure, and the user can modify the predefined sequence.

[0086] In step S8, the corresponding instruction sent from the controller via the touch screen is "Press Start to begin the patch clamp procedure," with the user having the option to wait until ready. At this point, an additional menu allows the user to abort the procedure and / or save the procedure for execution at a later time.

[0087] Figure 2 shows the procedure diagrammatically. The arrows indicate that the user can scroll between each step. Between groups of steps, the user can only move forwards, i.e. from group S to group P to group C to group E. In an alternative implementation, the user can move in both directions, e.g., after performing the steps of the Priming group, return to Setup.

[0088] Additionally, the user can cancel steps or insert additional steps between existing steps.

[0089] In Figure 2, some of the process steps are marked with an asterisk, which indicates that the process steps are time-critical manual process steps. In this case, the controller will strictly follow the time schedule and will automatically continue to the next process step when a specifically recorded time variable is exceeded (e.g. after 10 seconds).

[0090] 3 and 4 show the user interactions for the steps of groups P, C, and E.

[0091] FIG. 3 shows a table with three columns 31, 32, 33. Column 31 contains the selection of 4 out of 8 possible sites, i.e. the patch clamp procedure is reduced to the use of 4 out of 8 sites. In column 32 it is shown that the adaptive WC period has a duration that is independent for each of the 4 sites. The periods are indicated by corresponding arrows. In column 33 the selection of a predefined protocol is shown. In this example, the protocols are selected equally for the 4 different sites. Arrows 34, 35, 36 show the manual task of the user adding liquid to the 4 sites, and arrows 37, 38, 39 show the manual task of the user confirming the procedure and continuing with the next step of the predefined patch clamp procedure. Outputs 40, 41 are provided to the user during the execution of the patch clamp procedure, so that the user can obtain knowledge that can be used to modify the procedure being performed while it is being performed.

[0092] Figure 4 shows different user interactions, where during the execution of a patch clamp procedure the user modifies the protocol in terms of length, nature and timing, which can be based for example on the outputs 40, 41 obtained during the procedure and can be modified individually for selected sites.

[0093] The present invention has been described with reference to several embodiments and figures. However, those skilled in the art can select and combine various embodiments within the scope of the present invention as defined by the appended claims. All documents referenced herein are incorporated by reference.

[0094] The controller includes protocols that define a sequence of signals that are respectively automatically applied by the manipulator to the patch clamp site. Furthermore, the controller includes measurement steps that define the readings that are automatically made by the manipulator at the patch request site. Figure 5 shows a user interface presented on a computer screen 103, allowing the user to define protocols and / or measurement steps, modify predefined protocols and / or predefined measurement steps, or select predefined protocols and / or predefined measurement steps for a patch clamp procedure. In this user interface, procedures are selected in a scroll-down menu 51 in a window, protocols are selected in a scroll-down menu 52, and measurement steps are selected in a scroll-down menu 53. The selected protocols and measurement steps are automatically added to the selected patch clamp procedure according to the standards implemented in the controller. The user can then modify not only the protocols and measurement steps, but also the specific order of the process steps, and thus the order in which the protocols are performed and the measurements are performed.

[0095] The user interface shown in FIG. 5 can be activated throughout the patch clamp procedure, allowing the user to define and / or select protocols and / or measurement steps during the patch clamp procedure.

[0096] Figure 6 shows a user interface displayed on a computer screen 103, by which the controller communicates to the user the measurements, i.e. electrical, pressure or optical signals, measured at the patch clamp site. The user interface includes four windows 61, 62, 63, 64, each assigned to present a specific reading. Readings are safe, fast and easy, especially since they are always displayed in a specially assigned window. The controller allows the user to reprogram each window to match the user's personal preferences. Another number of windows can be defined depending on the need for feedback of results to the user during the patch clamp procedure.

[0097] The user interface shown in FIG. 6 can be activated throughout the patch clamp procedure, allowing the user to access the results while the procedure is being performed.

[0098] 7 shows a user interface presented on a computer screen 103, in which a user can reassign a manual process step to an automatic process step or vice versa. In window 71, the user can select each process step from a pull-down menu, and by clicking on button 72 or 73, the user can assign said process step to automatic or manual execution. The controller is configured to present the inactive state by greying out the impossible selections, thus preventing the user from assigning a process step to manual execution when only automatic execution is possible, and vice versa.

[0099] All user interfaces that allow the user to define or modify a patch clamp procedure, process step, protocol or measurement step are complemented with a save selection button that allows the user to instruct the controller to save this modification by overwriting the previous patch clamp procedure, process step, protocol or measurement step, or by creating a new patch clamp procedure, process step, protocol or measurement step.

[0100] Figure 8 shows a user interface presented on a computer screen 103. This user interface allows the user to follow the execution of a patch clamp procedure. Window 81 shows the previous process step, window 82 shows the currently active process step and window 83 shows the subsequent process steps. The process steps are shown in a sequence intended for a selected patch clamp procedure. The user interface allows the user to change this sequence by graphically dragging a process step to a new location within the row of process steps.

[0101] A simple skip command allows the user to skip a process step with the delete button 84 and jump to the subsequent process step.

[0102] Figure 9 shows a graphical user interface presented on a computer screen 103, directing the user to add a solution to a particular inlet (in this case the top four of eight inlets) of the array of inlets 102, thereby providing easy and safe guidance to the user. The particular solution type is identified in windows 91-98.

[0103] 10 shows a user interface presented on a computer screen 103, where the user can enter metadata in window 1001, by use of an on-screen keyboard in window 1002. These metadata are added to the data file and, for example, saved together with the data defining the currently selected patch clamp procedure.

Claims

1. a patch clamp plate manipulator configured to receive a patch clamp plate (101) containing a plurality of patch clamp sites; - defining a patch clamp procedure with process steps including manual process steps assigned for manual execution by a user and automatic process steps for automatic execution by a manipulator; - Providing instructions to users for performing manual process steps; Providing commands to the manipulator for automatic execution of automatic process steps; a computerized controller (103) configured to: the controller is configured to perform the patch clamp procedure by sending commands to a manipulator for execution of automatic process steps and by sending instructions to a user for manual execution of manual process steps; the patch clamp procedure includes a protocol each defining a sequence of signals to be automatically applied to the patch clamp site by a manipulator; The controller is a semi-automatic patch clamp apparatus (100) that includes a user interface that allows a user to define a protocol or modify a predefined protocol during the performance of a patch clamp procedure.

2. 10. The apparatus of claim 1, wherein the patch clamp procedure includes a measurement step that defines a reading that is automatically taken by the manipulator at the patch clamp site.

3. 3. The apparatus of claim 2, wherein the controller comprises a user interface that allows a user to define measurement steps or modify predefined measurement steps.

4. 10. The apparatus of claim 1, wherein the controller comprises a user interface that allows a user to select a predetermined protocol and / or predetermined measurement steps for the patch clamp procedure.

5. 4. The device of claim 3, wherein the user interface allows a user to define and / or select measurement steps during the execution of a patch clamp procedure.

6. The apparatus of claim 1 , wherein at least one of the protocols specifies at least one of a pressure, a voltage, a current, or an optical signal to be applied by a manipulator to the patch clamp site.

7. The apparatus of claim 1 , wherein at least one of the measuring steps specifies a reading of an electrical signal from the patch clamp site.

8. The device of claim 7 , wherein the controller is configured to communicate the electrical signal to a user.

9. The controller is configured to assign manual process steps to a time-critical group of manual process steps or a non-time-critical group of manual process steps, and instructions for a user to execute a step assigned for manual execution include: a timer countdown that initiates the execution of a subsequent manual process step or protocol if the manual process step is assigned to a time-critical group of manual process steps; and A user-triggered acknowledgment that initiates the execution of a subsequent manual process step or protocol, if the manual process step is assigned to a non-time-critical group of manual process steps; The apparatus of claim 1 , wherein:

10. 10. The apparatus of claim 1, wherein the controller is configured with a user interface that allows a user to reassign manual process steps to automated process steps or vice versa.

11. 10. The apparatus of claim 1, wherein the controller is configured with a user interface that allows a user to save the patch clamp procedure after modifying it.

12. The apparatus of claim 1 , wherein the controller is configured to communicate to a user which process step is being performed.

13. The patch clamp procedure includes the sequence in which process steps are performed, The apparatus of claim 1 , wherein the controller is configured to allow a user to skip a process step and jump to a subsequent process step in the sequence of process steps.

14. The patch clamp procedure includes the sequence in which process steps are performed, The apparatus of claim 1 , wherein the controller is configured to allow a user to change the sequence.

15. The apparatus of claim 1 , wherein the controller is configured to communicate results of a process step to a user before initiating a subsequent process step.

16. 10. The apparatus of claim 1, wherein the controller comprises a graphical user interface, and the instructions for a user to perform manual process steps include graphical illustrations relating to a patch clamp plate or a plurality of patch clamp sites.

17. the controller comprises a user interface that allows a user to add metadata associated with the patch clamp procedure; The apparatus of claim 1 , wherein the controller is configured to define a data file containing metadata with data related to the patch clamp procedure.

18. 20. The apparatus of claim 17, wherein the user interface that enables a user to add metadata associated with a patch clamp procedure enables a user to add metadata individually to selected process steps of the patch clamp procedure.

19. 20. The apparatus of claim 17, wherein the controller is configured to automatically add metadata to a patch clamp procedure or process steps of a patch clamp procedure.

20. The apparatus of claim 2 , wherein the automatically added metadata is related to a measurement step.

21. A method for performing a patch clamp procedure in an apparatus according to any one of claims 1 to 20, comprising the steps of: predefining the procedure in the form of a plurality of manual process steps and a plurality of automated process steps in a computer system; The computer system - triggering the execution of automated process steps by electronically controlling the manipulator to handle patch clamp procedures including supplying solutions to the patch clamp site, controlling pressure at the patch clamp site, and performing procedures in which electrical and / or pressure and / or optical signals are applied to and received from the patch clamp site; Initiating a manual process step by prompting a user; and enabling the

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