WO2026022367A1 - Système et procédé d'analyse de tissu cellulaire contractile in vitro - Google Patents

Système et procédé d'analyse de tissu cellulaire contractile in vitro

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Publication number
WO2026022367A1
WO2026022367A1 PCT/EP2025/071508 EP2025071508W WO2026022367A1 WO 2026022367 A1 WO2026022367 A1 WO 2026022367A1 EP 2025071508 W EP2025071508 W EP 2025071508W WO 2026022367 A1 WO2026022367 A1 WO 2026022367A1
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WO
WIPO (PCT)
Prior art keywords
well plate
data
input
controller
defined position
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/071508
Other languages
English (en)
Inventor
Miguel HERMANN
Sandra WILSON
Jens HENNEKE
Rujing Zhang
Torben Trindkær NIELSEN
Patrick Martin JUHL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sophion Bioscience AS
Original Assignee
Sophion Bioscience AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sophion Bioscience AS filed Critical Sophion Bioscience AS
Publication of WO2026022367A1 publication Critical patent/WO2026022367A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/48—Automatic or computerized control
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
    • C12M21/08—Bioreactors or fermenters specially adapted for specific uses for producing artificial tissue or for ex-vivo cultivation of tissue
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
    • C12M35/02—Electrical or electromagnetic means, e.g. for electroporation or for cell fusion

Definitions

  • the present invention relates to a system for carrying out cell experiments with 3D in-vitro contractile cells such as for carrying out experiments with muscle tissue.
  • the system to which the invention relates comprises at least one well plate forming a plurality of wells configured for receiving in-vitro contractile cells.
  • the invention further relates to a method of carrying out experiments with contractile cells, to well plates for the system, and to a computer system configured to plan and execute experiments, and to collect and analyze data automatically with user defined parameters and timepoints.
  • Biological samples are commonly analyzed in well plates. Often, the processing of the samples can be performed automatically using a robotic device that can add various substances automatically during the cause of an experiment. Sometimes, the process can be observed via a camera. The samples must be positioned in the field of view of the camera, and robotized means for adding liquid substances must be programmed to reach the specific position. Particularly when conducting multiple cell experiments of different nature, data handling and physical handling of the equipment can be challenging.
  • the large amount of generated data can be difficult to manage, not least because the data should be handled and assigned systematically over extended periods of time, and often by different users of the system.
  • the invention in a first aspect provides a system according to claim 1. Since the controller is configured to determine the data-input defined by the active well plate, to associate the data-input with the at least one procedural step, and to carry out the at least one procedural step as part of the experiment with respect to the active well plate, different cell experiments can be carried out efficiently by the same or different users.
  • the user defines the configuration of the well plate and the data which is required and sets the frequency of measurement.
  • the system then takes this information and schedules timepoints considering the entirety of the system and other users measurement frequencies and measurement durations.
  • controller refers to the computerized means included in the system for carrying out all data handling and for controlling the experiment e.g., by controlling image capturing, addition of reagents, or other processes which may be included in the experiment.
  • a user which is to carry out a specific experiment assigns a well plate to that experiment, and the system will then automatically, i.e. by use of its controller, determine the data-input of the well plate and assign the corresponding procedure. That allows efficient use particularly in environments with many different cell experiments being carried out in the same system. This is often the case inter alia in university laboratories and industrial laboratories etc.
  • Data-input when used herein, refers to information related to the experiment. Due to the data-input of each well plate, the entire experiment can be preplanned on a computer e.g., away from the system and without utilizing the system. Herein, reference is made generally to an "external computer” when describing that it is away from the system and without occupying the system.
  • the external computer system may assign the preplanned experiment to the well plate. Subsequently, the preplanned experiment and the corresponding data-input of the well plate is communicated to the system, and when that well plate is inserted on the base of the system, the data-input of the well plate may associate the well plate with the preplanned experiment which can then be carried out automatically.
  • the term “experiment” refers to a process for evaluating contractile conditions during different external stimuli, e.g., including electrical and chemical cell stimuli.
  • the in-vitro contractile cell tissue could e.g., be muscle tissue and the well plates may facilitate suspension of the cell tissue in each well.
  • the system may be stored in an incubator providing predictable ambient conditions, i.e., temperature, light, or humidity etc.
  • the well plates could be constituted by well plates known in the art, i.e. forming a plurality of wells arranged in a matrix form.
  • each well plate further defines data-input.
  • data-input means any kind of information related to the cell tissue analysis. It could be contained in a data repository, i.e., a structure capable of carrying information with the well plates. Such information forms input for the experiment when the data-input is determined by the controller of the system.
  • the data-input may be defined by marking an external surface of the well plate, e.g., by sticker or an attached data-chip, or it could be defined by the entire surface or structure of the well plate.
  • the data-input is defined by a color of or color mark on the well plate, by plain text on the outer surface of the well plate, by a magnetic label, or a readable chip, e.g., an RFID chip etc.
  • the following non-exhaustive list contains examples of the data-input which could be a : a unique ID of the well plate, a unique ID of a person, e.g. a person being responsible for an experiment, a list process steps related to an experiment, process settings for an experiment, date or time, or types of tissue cells etc.
  • the data-input is configured for being communicated with the controller via a communication interface between the well plate and the controller.
  • the data-input may be carried by a data repository of the well plate.
  • a data repository could be a chip or a tag, e.g., configured for wireless communication or wired communication.
  • the data repository may facilitate amendments of the input-data such that a user can assign new information to the data-input. This could be done e.g., by the external computer in order not to occupy the system.
  • the base comprises at least one defined position on which the well plate can be placed. Each defined position is configured to removably hold one of the at least one well plate in a defined position on the base.
  • the base may, e.g., define the positions in a row or matrix of positions.
  • the base may be made like a drawer allowing it to be slid out of the system for easy user access. This may be particularly advantageous if the system is placed in an incubator, or when several systems are stacked above each other in a shelving unit.
  • the base may include illumination for illuminating wells of well plates arranged at the defined positions, and the well plates may correspondingly allow light to pass through each well to thereby facilitate image capturing of the cell tissue in the wells. Additionally, the base may include different connections for connecting each well plate to an electrical supply, e.g. for providing an electrical signal to the electrodes in the wells and/or for communication of the data-input from a data repository of the well plate. Additionally, the base may include a pacing unit or at least a part of a pacing unit for applying an electrical signal to the wells of well plates located in the defined positions.
  • the system further comprises a processing structure configured for carrying out an experiment with respect to each well plate held by the defined positions.
  • the processing structure may e.g., comprise one or more of the following features:
  • the above mentioned pacing unit that initiates electrical impulses that trigger muscle contraction. These impulses are generated based on a specific pattern, e.g. predefined in the pacing unit or programmed into the pacing unit. The impulses travel through the tissue and cause the cells to contract in a coordinated manner.
  • an image capturing structure configured for taking pictures in each well of the well plates arranged at the predetermined positions on the base.
  • the system may e.g., comprise a pacing unit and an image capturing structure such that images can be captured while the cells are triggered to contract by the electrical impulses from the pacing unit.
  • the system may comprise only a pacing unit and/or a liquid reagent structure and therefore trigger the contraction without the ability to capture images.
  • a system could particularly be relevant e.g., in a setup comprising a plurality of systems where one or more of the systems only comprises the pacing unit and/or the liquid reagent structure and at least one system also comprises the image capturing structure. In that case, an experiment could be carried out as follows:
  • One or more well plates are prepared and arranged in a system which only comprises the pacing unit and/or the liquid reagent structure.
  • the well plates are left in this system for incubation in a first period of time, e.g., extending over 2-3 weeks.
  • the well plates are moved to another system which comprises an image capturing structure in addition to the pacing unit and/or the liquid reagent structure.
  • the well plates could be moved one by one from the base of one system to the base of the other system, or the entire base could form a removable drawer which could be moved with the well plates from one system to the other system.
  • pictures may be captured while the contraction takes place, and visual analysis could be carried out.
  • Both the initial system without the image capturing structure and the subsequent system including the image capturing structure could be contained in an incubator, and since only a subset of the total amount of systems comprises the image capturing structure, the total setup including the plurality of systems may take less space than a corresponding setup where all systems comprise an image capturing structure.
  • the systems not including the image capturing structure are contained in one incubator and the systems including the image capturing structure are contained in another incubator.
  • the processing structure may comprise a liquid reagent structure configured to add liquid reagents to each well of the well plates held by the defined positions.
  • the processing structure may, e.g., comprise a manipulator, e.g., a Scara robot, or a cartesian robot configured to reach all wells of the well plates in the system, e.g. for bringing a camera or a pipette to the wells for taking pictures or adding liquids.
  • the system comprises an electronic controller configured to control the processing structure and comprising at least one preprogrammed procedure defining at least one procedural step of the experiment.
  • the preprogrammed procedure may e.g., define a plurality of procedural steps forming a library from procedure steps for a specific procedure can be selected; define a plurality of procedural parameters, e.g. electrical signals to be applied to the electrodes in the wells, temperatures, reagents, or light etc.; define a specific surveillance of the analysis, e.g. settings for the camera, for the illumination of the wells, for frequency of image capturing, or for other settings relevant for surveillance, e.g., alarm settings for temperature, humidity, or liquid level in the wells etc.; define identification of personnel involved in the analysis.
  • the controller is configured to determine one of the at least two defined positions in which an active one of the at least one well plate has been inserted. This could be by use of a physical contact switch, it could be by determining an electrical connection between electrodes of the base and electrodes of the well plate(s), or it could be determined visually or otherwise.
  • the controller is configured to determine the data-input of the active well plate by communication via a communication interface between the controller and the well plate.
  • a communication interface may be based on physical contact between electrodes of the base and electrodes of the well plate(s), or by visually determining the data-input, e.g. as character recognition, it could be by wireless signal transmission, e.g. LoRATM, or BluetoothTM communication, or visually etc., which herein is considered as a wireless signal transmission.
  • the visual detection could be reading data-input which is written visually on an exterior surface of the well plate either as a code, e.g. a bar-code etc., or in plane letters or digits.
  • the controller is configured to associate the data-input with at least one procedural step. This may e.g., imply using the data-input as an input in defining a specific experiment.
  • the data-input may be an ID of the well plate, and the controller may have information linking that ID with a specific set of procedure steps, e.g. a subset selected from said library of procedure steps.
  • the data-input may contain a specific set of procedure steps to be carried out by the processing structure.
  • the controller is configured to carry out at least one procedural step as part of the experiment with respect to the active well plate. That implies controlling the processing structure in accordance with the procedural steps.
  • the processing structure may comprise an image capturing structure arranged to capture images of the wells and control of the image capturing structure may form part of the preprogrammed procedure.
  • the image capturing structure may e.g., be movable between the wells by said manipulator, or the image capturing structure may cover all wells, or the processing structure may comprise a plurality of image capturing structures.
  • the image capturing structure may be configured to capture single images or videos, e.g., high speed video, and it may particularly be configured to either capture high resolution images or high-speed videos, or both.
  • the image capturing structure may include different cameras, where at least one is suitable for high resolution, and one is suitable for high speed.
  • the preprogrammed procedure may define a frequency at which images are captured, and/or a point in time when images are captured, and/or a type of image being captured with the image capturing structure, and/or a resolution of the images etc.
  • Each well plate may comprise a first set of electrically conductive contact pads each being electrically connected to at least one electrode in one of the plurality of wells.
  • Each contact pad of the first set of contact pads may be electrically connected to a plurality of electrodes located in different wells of the plurality of wells. This may allow the electrodes to be connected to an electronic pacing unit providing a predefined electrical signal to each well via the electrodes.
  • Each defined position may comprise a first set of contact points arranged to electrically connect to the contact pads of the first set of contact pads of a well plate located in the defined position. This may allow the predefined electrical signal to be distributed to each well via the base and it may provide a fast way of connecting the well plate with said pacing unit.
  • the pacing unit may e.g., be located away from the system.
  • the system is in an incubation chamber and the pacing unit is located outside the incubation chamber.
  • the pacing unit may e.g., be located near the system.
  • the system is in an incubation chamber and the pacing unit is also located in the incubation chamber.
  • the pacing unit may, e.g., be integrated into the system.
  • the pacing unit is in the base.
  • Each contact point of the first set of contact points may be configured to apply the predefined electrical signal to the contact pads of the first set of contact pads and the predefined electrical signal may be defined by the preprogrammed procedure.
  • the pacing unit may e.g., be controlled by the electronic controller based on the procedural steps assigned to the experiment based on the data-input of the well plate.
  • the definition of the electrical signal may comprise a definition of current or voltage, frequency, amplitude, and/or duration of the electrical signal. These different definitions of the electrical signal may be stored/or continuously transferred in the pacing unit and the preprogrammed procedure may define which of the stored definitions should be applied during an experiment.
  • Each well plate may comprise a second set of electrically conductive contact pads and each defined position of the base may comprise a second set of electrically conductive contact points arranged to engage the contact pads of the second set of contact pads of a well plate held by the defined position.
  • the contact pads and contact points of the second set of contact pads and contact points may form part of the communication interface which facilitates communication of the data-input with the controller.
  • the system may comprise an interface to a user of the system.
  • the user interface may be configured to identify a user based on the data-input of the active well plate and to send data related to the preprogrammed procedure carried out on the at least one well plate to the identified user.
  • the user interface may e.g., utilize mail communication, or GSM communication to a mobile device of the user.
  • a user interface may inform the user about irregular procedure steps, e.g., whenever a step is not in compliance with the preprogrammed procedure.
  • the user interface includes a web interface.
  • the user interface may also, or alternatively, communicate when the experiment is finalized, the user interface may inform the user if other users carry out similar experiment processes in the system, or other users may use the user interface to inform the user about aspects of the experiment.
  • the user interface may be a communication platform between different users of the system.
  • the well plates could form a plurality of wells arranged in a matrix form, e.g., a 24, 48, 96, or 384 wells, i.e. if it is a 96 well plate, the wells could be arranged in 8 rows and 12 columns.
  • Each well comprises one or more spaces for holding a liquid reagent, thereby allowing the contractile cell tissue to be submerged in the reagent.
  • each well comprises two spaces having a shape like a small enclosure. Elastic elements may extend into each space and define upright poles in the space. This allows suspension of the tissue, and due to the elasticity, the tissue is allowed to contract.
  • each well may comprise an electrode structure with at least one electrode-pair for providing an electrical signal in the well and thereby for stimulating contractile activity of the cells.
  • the at least one preprogrammed procedural step may define at least one of a type of liquid to be applied to the space by the liquid handling module, and/or a frequency at which the liquid is applied, and/or an amount of the liquid to be applied by the liquid handling module.
  • Each well may have a translucent or transparent bottom and an open top allowing light to illuminate the well from below and allowing cell tissue and reagents to be added from above.
  • the open top further allows images to be taken through the open top.
  • the well plate may comprise a removable lid covering the open top of the wells. Such a lid may be transparent to allow images to be captured through the lid.
  • the system may comprise a temperature control structure configured to provide a specific temperature at the wells.
  • the temperature control structure may e.g., be controlled by at least one of the at least one preprogrammed procedural step. Such temperature control may allow cell experiments where temperature control is relevant.
  • the temperature control structure may, e.g., be configured to control the flow of a cooling liquid entering the system, e.g., the flow of a cooling liquid entering an incubator in which the system is placed.
  • the temperature control structure may control an electrical cooling appliance, e.g. based on Peltier elements etc.
  • the cooling liquid may cool the base and/or the camera(s) and/or other parts of the system if needed.
  • the at least one preprogrammed procedural step may define a type of liquid to be applied, a frequency at which the liquid is applied, an amount of the liquid to be applied by the liquid handling module, or combinations thereof.
  • the invention provides a method for the analysis of in-vitro contractile cell tissue by use of the system according to the first aspect.
  • the method comprises: a. a first user selecting a first well plate with at least one first data-input, b. the first well plate being inserted into a defined position of the base layer, c. the first defined position is identified by the controller and the first data-input is extracted, d. the data-input is associated with at least one preprogrammed first procedural step, e. the controller carrying out the first procedural steps on the first defined position.
  • the method may further comprise: f. the first user or a second user selecting a second well plate with at least one second data-input being assigned, g. the second well plate being inserted into a second defined position of the base layer that is not the same as the first defined position, h. the controller determining the second defined position that the second well plate is inserted into and reading the at least one second data-input associated with the second well plate, i. the controller associating the at least one second data-input with at least one second procedural step, j. the controller carrying out the first procedural steps on the first defined position and second procedural steps on the second defined position simultaneously.
  • the controller may generate a first set of updates based on the first procedural steps and send them to the first user identified by the first data-input. Subsequently, the controller may generate a second set of updates, based on the second procedural steps and send them to the second user identified by the second data-inputs.
  • the method is not limited to a first and a second user but may encompass any number of users, e.g. also a third, fourth, fifth, sixth, seventh, eighth, or ninth user.
  • the base may e.g., include 9 defined positions for nine different well plates, and the method may apply to different users for each defined position such that each well plate can be associated with individual users.
  • the invention provides a computer system for facilitating in-vitro contractile cell tissue analysis in the system of the first aspect.
  • the computer system comprises a CPU and a computer program configured, when loaded into the CPU, to read the data-input of the active well plate, associate data-input with the at least one procedural step, and export the data-input with the at least one procedural step to the controller of the system.
  • the invention provides a well plate for a system according to the first aspect.
  • the well plate comprises a data-input related to at least one procedural step of an experiment and being configured to exchange information with the controller of the system.
  • the invention provides a system setup comprising a plurality of systems according to the first aspect of the invention.
  • Each of the systems comprises a processing structure with a pacing unit but at least one of the plurality of systems does not comprise an image capturing structure.
  • Fig. 1 illustrates a system for cell tissue analysis
  • Fig. 2 illustrates a base of the system configured as a drawer
  • Fig. 3 illustrates a well plate for the system
  • Fig. 4 illustrates details of a well of the well plate
  • Fig. 5 illustrates details of pads and contact points
  • Fig. 6 illustrates a camera forming part of a working module
  • Fig. 7 illustrates a base
  • Figs. 8 and 9 illustrate method steps
  • Figs. 10-13 illustrate procedure steps.
  • Fig. 1 illustrates system 1 for carrying out cell experiments where contractile cell tissue is analyzed.
  • the system comprises a plurality of well plates 2 each comprising a plurality of wells.
  • a well plate is illustrated in detail in Fig. 5.
  • Well plates 2 are removably held on a base 3, at defined positions 4-12.
  • Fig 2 illustrates base 3 where one well plate is removed leaving an empty position 12 and Fig. 2 thereby illustrates that the base 3 defines 9 positions 4-12. Any number of positions could be considered depending on the size of the system.
  • the processing structure 15, schematically illustrated by a CPU is configured for carrying out an experiment with respect to each well plate held at the defined positions, and particularly for carrying out individual cell experiments such that each of the positions 4-12 can be treated differently. This allows different cell experiments to be carried out in each position and/or it allows different users to use different positions for individual cell experiments to be carried out by each user.
  • the processing structure may communicate with the controller 19, indicated by the dotted connection, or it could form an integrated part of the controller 19, or it may be constituted by a separate computer unit.
  • the processing structure may further comprise a working module 16 movable by a gantry 17 in x, y, and z directions of a cartesian space above the base 3.
  • Base 3 is made as a drawer which can be pulled horizontally away from the processing structure and thereby allows easier access to insert or remove a well plate from the base.
  • Working module 16 comprises at least one camera module 60 with optics (lenses) and may include an automated pipetting system. The working module 16 including the camera module 60, pipetting system or other features are controlled via the controller.
  • Electronic controller 19 is configured to control the processing structure.
  • the electronic controller includes hardware and/or software to control the x, y, and z movement of the gantry. This includes motion planning and execution of specific commands to a servo system arranged for effectuating the specific movement.
  • the experiment which is to be performed comprises a plurality of steps. These steps may inter alia relate to: applying an electrical signal to the tissue being analyzed; capturing images, e.g. in the form of video, of the tissue being analyzed, e.g. while the electrical signal is applied; and/or adding substances to the wells of the well plate
  • the electronic controller is programmed to execute a procedure which defines at least one step of the experiment which is to be performed.
  • the procedure may define a step of applying an electrical signal to a specific well while capturing images of that well with a certain frequency and/or while adding a specific substance to that specific well.
  • the controller may be implemented using standard hardware circuits, using software programs and data in conjunction with a suitably programmed digital microprocessor or a general-purpose computer, and/or using application specific integrated circuitry, and/or using one or more analog or digital signal processors.
  • Software program instructions and data may be stored on a non-transitory, computer-readable storage medium, and when the instructions are executed by a computer or by another suitable processor, the computer or processor performs the functions associated with those instructions for performing the desired functions of the control system.
  • the controller may, e.g., be implemented in a standard microcontroller, e.g., a processor programmed with suitable computer code for enabling the functions described herein.
  • an active well plate at well plate being attached to one of the defined positions is referred to as an active well plate and a well plate not being placed at one of the defined positions is referred to as a passive well plate.
  • the following description will generally refer to one single of either active or passive well plates even though the disclosure encompasses simultaneous cell experiments with a plurality of well plates, e.g. as illustrated in Fig. 1 where nine well plates are processed simultaneously.
  • the controller is programmed to determine one of the at least two defined positions in which an active one of the at least one well plate has been inserted. This could be determined by use of the camera module 60 or, as will be described in following, by use of electrical connections between the base and each well plate attached to the positions 4-12.
  • the controller is configured to determine the data-input of the active well plate.
  • the data- input may be determined by the use of a communication interface between the controller and the well plate.
  • This communication interface may include use of the camara module 60 by which the controller may visually read a code on the external surface of the well plate, and/or it may include use of electrical connections which will be discussed in further detail later.
  • the controller is configured to associate the data-input with at least one procedural step.
  • the term "associate with” encompasses a step of defining the at least one procedural step based on the data-input, or the step of selecting the step from a library of steps. Below we provide different examples of such associating steps.
  • the data-input of the well plate could be a unique code identifying the well plate in question.
  • the controller may include or have access to a database, herein referred to as the "procedural step database".
  • the procedural step database may include a list of unique codes, i.e. data-inputs of different well plates and a corresponding list of procedural steps which are to be included in the preprogrammed procedure for each well plate. The below example illustrates how the procedural step database could be defined :
  • Table 1 example of a procedural step database
  • Table 1 contains three columns. Column 1 identifies the data-input and thereby identifies the specific well plate for which a experiment is carried out.
  • Column 2 identifies the procedural steps of the preprogrammed procedure.
  • Well plate #1 is assigned to steps 1, 3, 5, 7 and 9 etc. In this example, the steps are part of the preprogrammed procedure, and the table needs only to refer to the numbers of the predefined steps. In other examples, the data-input in question may define details of the procedural steps.
  • Column 3 identifies parameters to be associated with selected procedural steps.
  • well plate #1 is to be associated with procedural step 1 with parameter 10 and with procedural step with the parameter 17.
  • Procedural step 1 could be application of a certain electrical signal to the tissue being analyzed and the parameter could be a frequency, a voltage or a current amplitude of the signal.
  • procedural step 5 could be addition of a substance to the well, and the parameter 17 could refer to the well number of the well plate #1 which is to receive the substance.
  • the data-input of the well plate could be a unique code identifying a user which is in charge with the experiment of the well plate in question.
  • the controller may include or have access to a database, herein referred to as the "user database".
  • the user database may include a list of unique codes, i.e. data-inputs identifying different users and a corresponding list of procedural steps which are to be included in the preprogrammed procedure for cell experiments carried out by that specific user.
  • the below example illustrates how the user database could be defined :
  • Table 2 example of a user database
  • Table 2 contains three columns. Column 1 identifies the user and thereby identifies the specific user to which a well plate refers, i.e. the user overseeing cell experiments carried out for a specific well plate.
  • Column 2 identifies the procedural steps of the preprogrammed procedure.
  • each step may be well defined in the preprogrammed procedure and the data-inputs to be associated with each procedural step may be predefined.
  • the user database may comprise an additional column corresponding to column 3 of the procedural step database, i.e. identifying specific parameters applied to each procedural step.
  • the third column named "communication" provides a communication link to which the system may send results of the experiment.
  • the example illustrates different e-mail addresses, but the column should be seen as links to the user, and it could be telephone numbers, Ip- addresses or other kinds of links.
  • the link provides direct access for the user to communicate back to the system.
  • the system may be configured such that communication received from a user by use of the communication form identified in the third column may access a certain experiment directly, i.e., with or without a password but at least without further identification.
  • the data-input of the well plate could define a predefined procedure, e.g., in combination with what is illustrated in the third column of example 1, i.e. the procedural step parameters.
  • the controller may include or have access to a database, herein referred to as the "procedure database".
  • the procedure database may include a list of procedural steps to be included in a predefined procedure. The below example illustrates how the procedure database could be defined :
  • Table 3 contains two columns. Column 1 identifies a preprogrammed procedure and Column 2 identifies the procedural step parameters to be assigned to the procedure.
  • any of the above examples illustrate the efficiency of the procedure, particularly when different users carry out different cell experiments with different well plates.
  • the controller When the controller has received a well plate, has identified the data-input, and has associated the data-input with at least one procedural step, it is ready to carry out the experiment automatically. Accordingly, the system facilitates a procedure where different users may carry out different cell experiments simply by inserting a well plate with a data-input in one of the positions and allowing the system to automatically identify that data-input and carry out the corresponding procedure.
  • the different databases could be defined locally in the controller, they could be defined in the cloud, or they could be defined by a central server system of the laboratory hosting the system etc.
  • the data in the databases could either be statically defined by an administrator of the system, or user, e.g., selected users, may be allowed to amend specific databases or to amend all databases depending on the need for variations in the cell experiments.
  • the specifically exemplified databases are only to be considered as different examples of how the controller may carry out the at least one procedural step as part of the experiment based on the data-input of the well plate.
  • Figs. 3 - 4 illustrate details of a well plate 2.
  • the specifically illustrated well plate is a 96-well plate comprising a well frame 30 defining 96 wells 31.
  • the well plate comprises a data repository defining data-input.
  • the data repository is in the form of an RFID tag 32 attached to an outer surface of the well plate or molded into frame 30.
  • the repository is a chip which can be reprogrammed to allow a user to amend the data-input.
  • Fig. 4 illustrates an enlarged view of one of the wells.
  • Each well houses two spaces 40 for holding liquid.
  • Two elastic elements 41 project into each of the two spaces and facilitate suspension of contractive cell tissue between the elements.
  • Figure 4 also shows a pair of electrodes 42 for providing an electrical signal in the well and thereby for stimulating contractile activity of the cells.
  • the well plates 2 may be formed of plastic, or glass etc.
  • the glass substrate is translucent or transparent and therefore allows light to pass from underneath through the glass substrate.
  • each well can be inspected from above by illumination from below, vice versa.
  • Each well plate 2 comprises data-input.
  • the data-input may relate to the experiment that is to be carried out.
  • the data-input may define one or more of the following which should be considered a non-exhaustive list: an identifier of the well plate, an identifier of a user, e.g. a person responsible for the experiment, parameters of the experiment, and/or procedural steps of the experiment etc.
  • the data-input may be written visually on an exterior surface of the well plate either as a code, e.g. a bar-code etc., or in plane letters or digits.
  • the data-input could be stored on an electronically readable tag affixed to the well plate.
  • a tag could e.g., be an RFID tag, a Bluetooth tag, or any similar kind of machine-readable tag.
  • Fig. 5 illustrates a cross section of the well plate 2, and particularly illustrates a plurality of electrical contact pads 50.
  • Each contact pad is electrically connected to a plurality of electrodes arranged in the wells of one of the rows of wells of the well plate.
  • the contact pads are exposed on the outer surface of the well plate, more particularly on a lower surface of the glass substrate.
  • electrical contact points of the base will contact the pads of the well plate and allow transmission of an electrical signal from the base to the electrodes in the wells.
  • a first set of the contact pads may be adapted to join the contact points of the base, and a second group of pads may be used for connecting to contact points of the base for the purpose of communicating the data-input between the well plate and the electronic controller.
  • Fig. 6 illustrates an image capturing structures 16 forming part of processing structure 15.
  • the image capturing structure comprises one or more camera modules 60 arranged to form a matrix of cameras.
  • the camera can be brought to a position above one or more of the active well plates and capture images of the contractile cell tissue in the wells.
  • Fig. 7 illustrates a top view of base 3 without well plates.
  • Base 3 comprises a plurality of LEDs 70 or other kinds of light emitters arranged to emit light upwardly from an upper surface of the base, i.e. through that surface carrying the well plates. The light emitters thereby emit light into each well of the well plates through the transparent or translucent glass substrate.
  • a row of conductive contact points 71 is arranged along an edge of the base. The contact points join the contact pads of the well plates.
  • a first set of the contact points may be adapted to join the pads of the well plate which are connected to the electrodes in each well and thereby be used for applying an electrical signal to each well.
  • a second group of contact points may be used for connecting the second group of contact pads and thereby be used for communication of the data-input between the well plate and the electronic controller.
  • Figs 8-9 illustrate by block diagrams, different cell experiments including different procedural steps of an in-vitro contractile cell tissue analysis process.
  • a first user selects a first well plate with at least one first data-input in step A.
  • the first well plate is inserted into a first defined position of the base layer.
  • the first defined position is identified by the controller and the first data-input is extracted.
  • the data-input is associated with at least one preprogrammed first procedural step.
  • the controller carries out the first procedural steps on the first defined position.
  • Fig. 9 illustrates the procedure carried out by multiple users.
  • the procedure is like the one in Fig. 8, and Steps A through E are not repeated. These are set prior to the further step F of a second user selecting a second well plate with at least one second data-input being assigned.
  • step G the second well plate is inserted into a second defined position of the base layer that is not the same as the first defined position.
  • the controller determines in step H, the second defined position that the second well plate is inserted into and in step I, the controller determines the at least one second data-input associated with the second well plate.
  • step J the controller associates the at least one second data-input with at least one second procedural step
  • step K the controller carries out the first procedural steps on the first defined position and second procedural steps on the second defined position, e.g., simultaneously.
  • step L the controller generates a first set of updates based on the first procedural steps and sends them to the first user identified by the first data-inputs and in step M, the controller generates a second set of updates, based on the second procedural steps and sends them to the second user identified by the second data-inputs.
  • Figs. 10-13 illustrate an example of an experimental workflow comprising four distinct procedural steps.
  • Step 1 (Pre-Casting preparation) : Mix freshly thawed isogenic human induced pluripotent stem cells Cardiomyocytes and Cardiac Fibroblast with gel matrix and pipette into a standard 96-well plate.
  • Step 2 engineered heart tissues (EHT) casting preparation: Load the prepared well plate into the pipetting robot and initiate the EHT casting protocol in the electronic controller.
  • the cell/gel mixture could be automatically pipetted into each well in the well plate.
  • Step 3 EHT formation and maturation: The seeded well plate is manually placed onto a slot of the optical measurement system to automatically run user defined assays with planned scheduled events which include timely recording of videos of tissues and pacing of the tissues.
  • Step 4 Endpoint analysis: Once the tissue has achieved desired maturity, various functional, pharmacological or molecular studies can be carried out on the EHTs. Analyze and plot the generated data using the system, e.g. with an image capturing structure.
  • Fig. 10 cell and gel matrix is seeded into the wells for a pipetting robot to dispense.
  • the pipetting robot dispenses the cell-gel matrix mix into the wells in the well plate for EHT formation.
  • optical measurement tracks the EHT formation and maturation with user defined scheduled assay plan.
  • Fig. 13 illustrates schematically, an analyzer which automatically tracks the concentration of the EHT and plots the data for interpretation and presentation.

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Abstract

L'invention concerne un système (1) pour l'analyse de plaques à puits de tissu cellulaire contractiles in vitro. Les plaques à puits sont logées sur une base (3) dotée d'au moins deux positions définies (4-12). Une structure de traitement (15) est conçue pour réaliser une expérience sur chaque plaque à puits maintenue dans les positions définies, et un dispositif de commande électronique (19) est conçu pour commander la structure de traitement et inclut au moins une procédure préprogrammée définissant au moins une étape procédurale de l'expérience. Afin d'offrir des conditions optimales pour plusieurs utilisateurs ou différentes expériences cellulaires simultanées, le dispositif de commande est conçu pour déterminer un paramètre d'une plaque à puits, associer ce paramètre à une étape procédurale et exécuter les étapes procédurales dans le cadre de l'expérience relative à la plaque à puits active.
PCT/EP2025/071508 2024-07-25 2025-07-25 Système et procédé d'analyse de tissu cellulaire contractile in vitro Pending WO2026022367A1 (fr)

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EP24190883.9 2024-07-25
EP24190883 2024-07-25
EP25181401.8 2025-06-06
EP25181401 2025-06-06

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016069142A2 (fr) * 2014-09-24 2016-05-06 President And Fellows Of Harvard College Dispositifs de mesure de la fonction contractile, systèmes associés et procédés d'utilisation correspondants
WO2019200042A1 (fr) * 2018-04-11 2019-10-17 Trustees Of Boston University Plate-forme modifiée pour générer des tissus cardiaques 3d
EP4321607A1 (fr) * 2022-08-09 2024-02-14 Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNO Dispositifs de lecture optique comprenant des unités de culture cellulaire dans lesquelles un tissu contractile peut être cultivé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016069142A2 (fr) * 2014-09-24 2016-05-06 President And Fellows Of Harvard College Dispositifs de mesure de la fonction contractile, systèmes associés et procédés d'utilisation correspondants
WO2019200042A1 (fr) * 2018-04-11 2019-10-17 Trustees Of Boston University Plate-forme modifiée pour générer des tissus cardiaques 3d
EP4321607A1 (fr) * 2022-08-09 2024-02-14 Nederlandse Organisatie voor toegepast-natuurwetenschappelijk Onderzoek TNO Dispositifs de lecture optique comprenant des unités de culture cellulaire dans lesquelles un tissu contractile peut être cultivé

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