Multi-receptacle micro-electrode array device

Abstract

Disclosed is a multi-receptacle micro-electrode array device (1) comprising: a plurality of receptacles (13), the receptacles (13) arranged in an array, wherein a micro-electrode array (11) is arranged in each receptacle (13), a carrier (12), wherein the receptacles (13) are arranged on the carrier (12), a thermal control device interface (16) configured for coupling the multi-receptacle micro-electrode array device (1) to a thermal control device (22), and a thermal energy balancing device (14), the thermal energy balancing device (14) being thermally connected to at least a subset of the micro-electrode arrays (11), the thermal energy balancing device (14) being configured to balance a temperature across at least two micro-electrode arrays (11).

Description

[0001] MULTI-RECEPTACLE MICRO-ELECTRODE ARRAY DEVICE

[0002] FIELD OF THE DISCLOSURE

[0003] The present invention relates to a multi-receptacle micro-electrode array device.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] A multi-receptacle micro-electrode array device is a device that includes multiple microscopic electrodes arranged in a grid pattern at the bottom of each receptacle (also known as a well). The receptacles are typically also arranged in an array on a plate. The device can be used to measure the electrical activity of one or more cells, for example neurons, that are cultured over the electrodes. The device may also deliver electrical stimulation to the cells to modulate their activity. The device can be used for various purposes, such as electrophysiology, safety pharmacology, toxicity screening, neuroscience research, and drug discovery.

[0006] To reliably study the cells for the aforementioned purposes, it is preferable to study a large number of replicas of cell cultures. Therefore, multi-receptacle micro-electrode array devices have been proposed which include 6, 12, 24, 48, 96, or 384 receptacles, such that a large number of cell cultures can be studied simultaneously. This provides for many different data points which can be compared against each other, improving the reliability of any measurements made and analyses performed.

[0007] T o ensure that results for different cells are comparable, the cells must be cultured under similar environmental conditions. Cultured cells are living organisms that need very specific environmental conditions to thrive. One of the most important factors is temperature, which affects the cell membrane, the metabolism, and the growth rate of the cells. For example, the lipids and proteins of the cell membrane have a different permeability depending on the temperature. If the temperature is too high, the cell membrane can become too permeable, allowing unwanted substances to enter or exit the cell. If the temperature is too low, the cell membrane can become too rigid and brittle, preventing essential molecules from crossing the membrane. Temperature also affects the growth rate of cells. Generally speaking, higher temperatures tend to increase the growth rate of cells, while lower temperatures tend to decrease it. Some cells may have a specific temperature range that is optimal for their growth, while others may be more tolerant or adaptable to temperature variations. For example, most mammalian cells grow best at around 37 °C, which is close to their body temperature in vivo. Even small temperature changes can have a comparatively large effect on mammalian cells.

[0008] Multi-receptacle micro-electrode array devices are therefore heated to a defined temperature of around 37 °C. A short-coming of known multi-receptacle micro-electrode array devices is that there may be deviations in the temperature between receptacles. This leads to the cells in different receptacles potentially being subject to different environmental conditions which ultimately makes comparing the behavior of cells in different receptacles more challenging and fraught with uncertainty.

[0009] SUMMARY OF THE DISCLOSURE

[0010] It is an object of embodiments disclosed herein to provide a multi-receptacle microelectrode array device. In particular, it is an object of the embodiments disclosed herein to provide a multi-receptacle micro-electrode array device and a multi-receptacle microelectrode array docking device which does not have one or more disadvantages of the prior art. In an aspect, the overall objective is achieved by a multi-receptacle micro-electrode array device. The multi-receptacle micro-electrode array device comprises a plurality of sample receptacles which are preferably circumferentially closed, for example in that the receptacles form a circular wall. The sample receptacles are arranged in an array, respectively a matrix, side-by-side. Typically, all sample receptacle are of identical design.

[0011] In each sample receptacle, a micro-electrode array (MEA) is arranged, in particular in a bottom area thereof. The micro-electrodes of the MEAs are in each case generally arranged in a matrix. Typically, all MEAs are of identical design.

[0012] The multi-receptacle micro-electrode array device further comprises a carrier. The sample receptacles may be arranged on the carrier. Alternatively or additionally, a bottom surface of sample receptacles is in each case formed, at least in part, by the carrier.

[0013] The multi-receptacle micro-electrode array device further comprises a thermal control device interface. The thermal control device interface is configured for coupling the multireceptacle micro-electrode array device to an external thermal control device, in particular for heating and / or cooling the multi-receptacle micro-electrode array device by heat conduction to and / or from the multi-receptacle micro-electrode array device.

[0014] The multi-receptacle micro-electrode array device further comprises a thermal energy balancing device. The thermal energy balancing device is thermally connected to at least a subset of the micro-electrode arrays and is configured to balance a temperature across at least two of the MEAs.

[0015] By way of example, the number of sample receptacles may be 6, 12, 24, 48, 96, or 384. The outer dimensions of the array device may be in the range of 100 mm - 150 mm by 60 mm to 100 mm. For example, the outer dimensions are 127.8 mm x 85.5 mm. The sample receptacles may be wells. A cross sectional contour respectively footprint of the sample receptacles is typically circular and an inner room of the sample receptacles may accordingly be generally cylindrical for a flat respectively planar bottom surface. An inner diameter of such sample receptacles may depend on the total number of well and is typically in a range from 3 mm to 40 mm, in particular 3.30 mm, 19 mm, or 32 mm. A height of the sample receptacle as measured from the bottom surface is typically in the mm-range, e.g. 8 mm. Other designs and dimensions may be foreseen as appropriate. At a side opposite to the bottom surface, the sample receptacles are generally open. In other words, the sample receptacles are open at the top, allowing for cells to be placed into the sample receptacle, for example by pipette. The multi-receptacle micro-electrode array device may have an overall plate-shaped design and the device may accordingly in particular be a multi-receptacle micro-electrode array device, respectively well plate.

[0016] The micro-electrode arrays (MEAs) typically have up to several thousand individual electrodes, e.g. 26’400 electrodes, for example in a rectangular arrangement, with 3.85 mm x 2.10 mm as exemplary dimensions. Alternatively, the MEAs may have a different number of electrodes, for example 3, 9, 16, 64, or 4000 electrodes per well, including values in the ranges between those examples.

[0017] While other designs may be used as well, the carrier is typically sheet-shaped respectively plate shaped having, for example, a rectangular footprint and a parallel spaced apart even, respectively planar, top surface and bottom surface. In a particular design, the carrier comprises or is realized as printed circuit board (PCB) as discussed further below in more detail. In another design, the carrier is a glass plate.

[0018] In an embodiment, the sample receptacles have themselves a bottom surface and are connected to, respectively mounted on, the carrier, e.g., by way of adhesive bonding. In designs where the bottom surfaces of the sample receptacles are formed by the carrier, the sample receptacles may in each case have a circumferentially closed, e.g., ring shaped or hollow cylindrical wall member, which is connected to, respectively mounted on, the carrier, e.g., by way of adhesive bonding. Instead of separate, e.g., shaped wall members for each sample, receptacles, the wall elements may be realized in a structurally integral manner for some or all sample receptacles, e.g. in form of a plate with a respective cylindrical through-hole for each sample receiving cavity. The material of the sample receptacles may be, e.g., a suitable plastic material such as polycarbonate. The sample receptacles may be formed by injection molding.

[0019] The thermal control device can be provided for heating and / or cooling the sample receptacles, including the MEAs as well as the samples (the samples including cells and cell media, for example) received in the sample receptacles as well as for electrically interfacing the MEAs respectively electronic chips comprising the MEAS as discussed further below. In an example, the thermal control device is interface is made from material of good thermal conductivity, in particular metal and may, e.g., have a flat respectively planar surface for placement on the temperature control device, e.g. a contact surface thereof. It is important to ensure good thermal contact between the thermal control device interface and the thermal control device.

[0020] To achieve good thermal contact, the weight of the multi-receptacle micro-electrode array device may be sufficient. An additional contact force may, however, also be provided. The multi-receptacle micro-electrode array device may be connected to the temperature control device and the contact force may be improved, e.g., by one or more of clamping, suction coupling and / or magnetic attraction between the multi-receptacle micro-electrode array device and the thermal control device. Typically, the carrier is thermally arranged between the sample receptacles, particularly the micro-electrode arrays, and the thermal control device interface.

[0021] The thermal energy balancing device serves the purpose of balancing a temperature difference between different MEAs respectively sample receptacles or wells. Balancing is to be understood as reducing and minimizing, ideally eliminating, temperature differences respectively ensuring a uniform and substantially constant temperature. The balancing may concern two sample receptacles, a subset of sample receptacles or, in a particular design, all sample receptacles and therein arranged MEAs. The balancing may be achieved via the thermal energy balancing device in various ways as discussed further below by way of thermal conduction. For example, if one of the two MEAs is hotter than the other, then balancing the temperature may include reducing the temperature of the hotter MEA, increasing the temperature of the cooler MEA, or both, such that the temperature difference is minimized or, preferably, eliminated. The temperature between two MEAs may be considered balanced if a temperature difference between two MEAs is below a defined temperature difference threshold. The temperature difference threshold may be, for example, less than 0.5 °C, less than 0.3 °C, or less than 0.1 °C.

[0022] Throughout this document, a direction in which the sample receptacles and the thermal control device interface, respectively in application the thermal control device, are arranged is referred to as the vertical direction, corresponding to the general configuration in use, with the sample receptacles being arranged above the thermal control device. Directions transverse to the vertical direction are referred to as lateral directions and generally span a horizontal plane in application. The sample receptacles are accordingly arranged laterally beside each other in the array.

[0023] In an embodiment, the sensor electrode arrangement is in each case part of a respective electronic chip, in particular a semiconductor chip. The electronic chip is in each case arranged in the respective sample receptacle. For such a design, the carrier is implemented as, or may include, a PCB on which the electronic chips are mounted, e.g. by way of adhesive bonding, wire bonding, and / or soldering, and which may further serve for electrically contacting the electronic chips. The electronic chips may be based on any suitably technology, in particular CMOS. The electronic chips may, in addition to the MEA, include additional circuitry and / or micro-electromechanical systems, such as solidstates switches, amplifiers, filters, analogue-to-digital (A / D) conversion, multiplexers and general interface circuitry.

[0024] It is noted that that for embodiments where the MEAs are in each case part of a respective electronic chip as mentioned, the complete chip, including the MEA, preferably has a common defined temperature across the whole chip. This is due to the high thermal conductivity of the chip itself owing to the plurality of metal electrical connections, as well as the relatively small size scale of the chip. Therefore, references to heat transfer, thermal coupling, thermal balancing and the like of an MEA are to be understood as referring to the respective electronic chip as a whole, and vice versa. It is further noted that any material that is present between the carrier and the electronic chips, in particular adhesives and / or electrical conductors such as leads and wires, influences the thermal design and should be taken into account accordingly.

[0025] In alternative designs, the carrier is made from glass. In such a design, the MEAs and corresponding connection traces are realized by a structured metal layer on the glass carrier, which structural metal layer is typically planar. In a variant, the carrier is made from a plastic material, e.g., a polycarbonate and the electrodes and corresponding connection traces are realized as a structured metal layer using Molded Interconnected Device (MID) technology.

[0026] In an embodiment, the thermal energy balancing device is configured for lateral heat transport and / or heat transport between the sample receptacles and the thermal control device interface. The thermal conductivity in a direction between the sample receptacles and the thermal control device interface generally varies laterally. Laterally varying thermal conductivity in a vertical direction respectively between the thermal control device interface and the sample receptacles may be used to provide, e.g., more thermal energy respectively heat to the sample receptacles in a region of good thermal conductivity, and less thermal energy in a region of lower thermal conductivity, thereby providing thermal balancing. A laterally varying lateral thermal conductivity may be used for balancing by lateral thermal energy distribution. For cooling, the same principles apply in an analogous manner.

[0027] In an embodiment, the thermal energy balancing device includes a structured thermally conductive layer. By way of the structure of the thermally conductive layer, the thermal conductivity over the thermal energy balancing device varies laterally. By appropriate design of the structure, the thermal conductivity can be adjusted for achieving a balancing of the temperature. The thermally conductive layer generally extends in the lateral plane. The structure may in particular apply to the thermally conductive material of the layer, e.g., metal not being equally present over the whole lateral extension of the thermally conductive layer, and / or by the thermally conductive layer having a laterally non- uniform thickness.

[0028] In an embodiment, the carrier includes a printed circuit board. The thermal energy balancing device is formed, at least in part, by at least one metal layer of the printed circuit board. The metal layer may be electrically connected to one or more of the MEAs. The metal layer may form a ground plane. The metal layer may be a structured layer in which the structure is designed to balance a temperature across two or more of the MEAs.

[0029] In an embodiment, the thermal energy balancing device is areally connected to the carrier, in particular a bottom side of the carrier. An areal connection is a connection extending in two dimensions, such that a surface of the thermal energy balancing device at least partially contacts a surface of the carrier, in particular the bottom side of the carrier.

[0030] In an embodiment, the thermal energy balancing device is applied to the carrier as a coating, in particular by way of painting, spraying, and / or printing, in particular screen printing. Alternatively, the thermal energy balancing device is attached, in particular adhesively attached, to the carrier.

[0031] In an embodiment, the thermal energy balancing device includes a thermal pad, the thermal pad being in particular flexible and / or soft (respectively compressible). The thermal pad may include, or be made of, a carbon material. The thermal pad may also be at least partially rigid and include a metallic material, in particular a metal having high thermal conductivity, such as copper or aluminium. The thermal pad may be applied or attached by way of a thermally conductive adhesive, for example a thermally conductive epoxy.

[0032] In an embodiment, the thermal energy balancing device includes a thermal filler, the thermal filler being arranged between at least some of the sample receptacles. The thermal filler may be, for example, a potting compound, preferably a thermally conductive potting compound, such as a thermally conductive epoxy resin. A material may be considered thermally conductive if it has a thermal conductivity of greater than 0.5 W / m.K., preferably greater than 1 W / m.K. . The thermal filler may be a curable thermal filler. The thermal filler may provide additional structural support and / or rigidity to the multi-receptacle micro-electrode array device, in by supporting the outside of the sample receptacles.

[0033] In an embodiment, a material, composition, and / or thickness of the thermal filler varies laterally. By varying the material, composition and / or thickness, the thermal conductivity of the thermal filler laterally varies, that is, the thermal conductivity is different for different lateral positions. The material, composition, and / or thickness is designed to vary such that the temperature between at least two of the sample receptacles, in particular two MEAs, is balanced.

[0034] In an embodiment, the thermal energy balancing device has a laterally varying thermal conductivity. In an embodiment, the thermal energy balancing device includes a pattern of separate and laterally distributed thermal balancing members, the thermal balancing members being in particular adhesive patches. The adhesive patches may be formed of the same material as the thermal pad described herein.

[0035] In an embodiment, the thermal energy balancing device is configured for lateral heat transport and / or heat transport between the sample receptacles and the thermal control device interface.

[0036] In an embodiment, the thermal energy balancing device includes at least one of metal, in particular copper, a thermally conductive plastic, carbon, or a thermally conductive liquid.

[0037] In addition to the multi-receptacle micro-electrode array device, the present disclosure also relates to a multi-receptacle micro-electrode array docking device. The multi-receptacle micro-electrode array docking device is configured to connect to a multi-receptacle micro-electrode array device, for example a multi-receptacle micro-electrode array device as known in the prior art. In particular, the multi-receptacle micro-electrode array described with reference to the docking device may be a conventional multi-receptacle micro-electrode array which does not necessarily need to have a thermal energy balancing device as described herein. The multi-receptacle micro-electrode array docking device is designed for electrical contact and temperature control of the multi-receptacle micro-electrode array device. The multi-receptacle micro-electrode array docking device includes a support pad comprising a plurality of electrical contacts configured for electrical connection with the multi-receptacle micro-electrode array device. The docking device includes a temperature control device, the temperature control device being thermally connected to the support pad. The temperature control device is configured for controlling a temperature of the multi-receptacle micro-electrode array device by way of heating and / or cooling. The docking device includes a thermal balancing device, the thermal energy balancing device being thermally connected to the support pad and the temperature control device and being configured to balance a temperature across the support pad.

[0038] Thereby, by balancing the temperature across the support pad, the docking device is configured to balance the temperature across a convention (prior art) multi-receptacle micro-electrode array device.

[0039] In an embodiment, the temperature control device includes a number of separately controllable temperature control zones.

[0040] In an embodiment, the temperature control zones include a central temperature control zone and one or more peripheral temperature control zones. The one or more peripheral temperature control zones are arranged laterally around the central control zone, in particular in a concentric manner. In particular, the peripheral zones may be nested peripheral zones, in which an outer peripheral zone encompasses an inner peripheral zone and / or the central control zone.

[0041] In an embodiment, the multi-receptacle micro-electrode array docking device is configured to control heating and / or cooling of each of the temperature control zones in a substantially uniform manner.

[0042] In an embodiment, the temperature control device includes a resistive electric heater and / or a Peltier element.

[0043] In an embodiment, the temperature control device includes a fluid conduit arrangement filled with heat transport fluid, and a fluid heating and / or cooling device for heating and / or cooling the heat transport fluid. In an embodiment, the thermal energy balancing device includes a thermal pad. The thermal pad is thermally connected to the support pad and / or is integral with the support pad. The thermal pad may be implemented as described herein with reference to the disclosed multi-receptacle micro-electrode array device.

[0044] In an embodiment, the thermal pad is adhesively connected to the support pad.

[0045] BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The herein described disclosure will be more fully understood from the detailed description given herein below and the accompanying drawings which should not be considered limiting to the invention described in the appended claims. The drawings in which:

[0047] Fig. 1 shows a top view illustrating schematically a multi-receptacle micro-electrode array device having 24 wells according to the prior art, in which the shading of the wells is indicative of their temperature and the central wells have a higher temperature than the peripheral wells;

[0048] Fig. 2 shows a top view illustrating schematically a multi-receptacle micro-electrode array device having 6 wells according to the prior art, in which the shading of the wells is indicative of their temperature and the central wells have a higher temperature than the peripheral wells;

[0049] Fig. 3 shows a block diagram of a multi-receptacle micro-electrode array device according to an embodiment;

[0050] Fig. 4 shows a block diagram of a multi-receptacle micro-electrode array docking device according to an embodiment;

[0051] Fig. 5 shows a lateral section view illustrating schematically a multi-receptacle micro-electrode array device according to an embodiment; Fig. 6 shows a lateral section view illustrating schematically a multi-receptacle micro-electrode array device according to an embodiment;

[0052] Fig. 7 shows a bottom view illustrating schematically a multi-receptacle micro-electrode array device including a thermal pad according to an embodiment;

[0053] Fig. 8 shows a bottom view illustrating schematically a multi-receptacle micro-electrode array device including a plurality of thermal patches of differing sizes according to an embodiment;

[0054] Fig. 9 shows a top section view and a side section view along the line D illustrating schematically a multi-receptacle micro-electrode array device including a patterned layer in the printed circuit board according to an embodiment;

[0055] Fig. 10 shows a top section view illustrating schematically a multi-receptacle microelectrode array device including a patterned layer in the printed circuit board according to an embodiment;

[0056] Fig. 11 shows a top view illustrating schematically a multi-receptacle micro-electrode array device including thermal filling material between the wells according to an embodiment, in particular having at least two regions with different thermal filling materials;

[0057] Fig. 12 shows a perspective view and a section view illustrating schematically a multi-receptacle micro-electrode array docking device including a thermal energy balancing device according to an embodiment;

[0058] Fig. 13 shows a plot of temperature inside the wells of a multi-receptacle micro-electrode array device over time according to the prior art, highlighting the difference in temperatures between wells at the center and wells at the edge of the plate; and Fig. 14 shows a plot of temperature inside the wells of a multi-receptacle micro-electrode array device over time according to the present disclosure, highlighting the substantial uniformity in temperatures between wells at the center and wells at the edge of the plate.

[0059] DESCRIPTION OF THE EMBODIMENTS

[0060] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying drawings, in which some, but not all features are shown. Indeed, embodiments disclosed herein may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Whenever possible, like reference numbers will be used to refer to like components or parts. For the sake of improved clarity in the drawings, where multiple of the same features are shown, not all instances of the same features may be labeled with reference numbers to reduce clutter.

[0061] Figure 1 shows a top view illustrating schematically a multi-receptacle micro-electrode array device having 24 wells respectively receptacles according to the prior art, in which the shading of the wells is indicative of their temperature and the central wells have a higher temperature than the peripheral wells. The 24 wells are arranged in a 4 x 6 grid layout. The four central wells have a relatively higher temperature as indicated by the closer spaced hatching than the other wells. The peripheral wells have a relatively lower temperature. For an exemplary measured temperature difference between the wells in the center and the wells at the edge, we refer to Fig. 13.

[0062] The temperature difference arises primarily due to the edges of the multi-receptacle micro-electrode array device, at which heat is lost due to conduction and radiation into the environment. By contrast, the center of the plate, in which the central wells are arranged, do not lose any heat to the environment laterally and also do not overheat due to the surrounding wells.

[0063] Depending on whether the MEAs arranged in the wells are implemented as passive electrode arrays, or are implemented as active chips which also represent a heat source due to resistive losses within the chip, the wells at the center of the plate may also be cooler than peripheral wells. The same applies to the configuration shown in Figure 2, or other well-plate configurations of 24, 96 or more wells, for example.

[0064] Figure 2 shows a top view illustrating schematically a multi-receptacle micro-electrode array device having 6 wells according to the prior art, in which the shading of the wells is indicative of their temperature and the central wells have a higher temperature than the peripheral wells. The wells are arranged in a 2 x 3 arrangement. The central column of two wells has a higher temperature than the lateral columns of wells for the same reasons as described above with reference to Figure 1 , namely the larger edge length which provides for heat loss to the environment.

[0065] Figure 3 shows a block diagram of a multi-receptacle micro-electrode array device 1 according to an embodiment of the present disclosure.

[0066] The multi-receptacle MEA 1 includes a plurality of MEAs 11 . The MEAs 1 1 are preferably implemented as individual electronic chips, which may also be referred to as “active” MEAs 11 . The MEAs 11 may alternatively be implemented as electrode arrays without any further integrated circuitry, and may also be referred to as “passive” MEAs 1 1 . The MEAs 11 include a plurality of electrical contacts (i.e. electrodes) arranged in an array. Cells may be placed onto the MEAs 11 such that electrical measurements on the cells, in particular neural cells, may be performed. The electrical contacts may also be used to electrically stimulate the cells. MEAs 1 1 implemented as electronic chips may generate heat, for example due to resistive losses. The MEAs 1 1 may, in some variants, also include an integrated or directly connected controllable heating element, such as a resistive or Peltier element.

[0067] The multi-receptacle MEA 1 includes a carrier 12 on which the MEAs 11 are formed, or onto which the MEAs 11 are attached. The carrier 12 may provide, or contribute to, a structural frame to the multi-receptacle MEA device 1 . In other words, the carrier 12 may provide a certain amount of structural rigidity to the multi-receptacle MEA 1 . The carrier 12 may be implemented or include a PCB. The carrier 12 may also be implemented as a glass, metal, or composite carrier. The carrier 12 may have a substantially planar, plate-like, and / or flat, rectangular shape as is known in the field of MEAs.

[0068] Each of the MEAs 11 is arranged in a receptacle 13. The receptacles 13, also known as wells in the art, are each designed to receive a sample, in particular a sample including one or more cells. The receptacles 13 further serve to separate each MEA 11 from other MEAs 1 1 , such that the samples containing the cells are held separate from each other for the duration of the experiments. Further details are shown in other Figures, in particular Figures 5 and 6.

[0069] The multi-receptacle MEA 1 includes a thermal energy balancing device 14. The thermal energy balancing device 14 is a device, in particular a part or component of the multireceptacle MEA device 1 which is configured to balance the temperature between two or more of the MEAs 11. The thermal energy balancing device 14 may be realized or implemented by a dedicated component or part of the multi-receptacle MEA 1 , i.e. a component or part which has no other significant function or purpose. Alternatively or additionally, the thermal energy balancing device 14 may be realized or implemented by the particular design or configuration of another part or component of the multi-receptacle MEA 1 , specifically a part or component of the multi-receptacle MEA 1 which may have an additional function or purpose. The thermal energy balancing device 14 is designed to ensure that the temperature of at least two of the MEAs 1 1 are similar, specifically that a difference in temperature between at least two of the MEAs 11 , preferably between all of the MEAs 1 1 , is lower than a defined temperature difference. The defined temperature difference is lower than 0.5 °C, preferably lower than 0.3 °C, more preferably lower than 0.1 °C. Thereby, the temperature of the MEAs 1 1 may be considered substantially identical, in particular when considering the temperature related effects on the cells under study.

[0070] The thermal energy balancing device 14 may balance the temperature by providing one or more thermal energy conduits between two or more MEAs 11 , such that a relatively warmer MEA 1 1 transfers thermal energy to a relatively cooler MEA 1 1 .

[0071] The thermal energy balancing device 14 may, alternatively or additionally, heat and / or cool particular MEAs 1 1. For example, the thermal energy balancing device 14 may include one or more Peltier elements. The one or more of the MEAs 1 1 may be connected to the one or more Peltier elements, thereby heating the connected MEAs 11 such as to balance the temperature of the MEAs 11 .

[0072] The thermal energy balancing device 14 may include a sensor system including one or more temperature sensors configured to measure a temperature of one or more MEAs 1 1 , either directly or indirectly. The sensor system may be integrated at least partially into the MEAs 11 themselves, for example, each MEA 1 1 may be provided with a temperature sensor communicatively connected to the thermal energy balancing device 14. The thermal energy balancing device 14 may be configured to control one or more heating elements, e.g., the Peltier elements, using a temperature signal received from the one or more temperature sensors.

[0073] In an embodiment where the MEAs 1 1 are implemented as electronic chips, the MEAs

[0074] 1 1 themselves may produce heat contributing to their temperature. In fact, the MEAs 1 1 may produce a significant proportion, for example even the majority, of heat required for the MEAs 11 to reach their desired set point temperature, for example of 37 °C. In such scenarios, the MEAs 11 in the center of the multi-receptacle MEA device 1 may have a lower temperature than those MEAs 1 1 on the periphery of the multi-receptacle MEA device 1 due to greater heat losses to a docking device onto which the multi-receptacle MEA device 1 is placed in use. Therefore, the thermal energy balancing device 14 may be designed such that heat is transferred from peripheral MEAs 11 to central MEAs 11 .

[0075] The multi-receptacle MEA device 1 may further include a thermal control interface device 16. The thermal control interface device 16 is configured to receive thermal energy from a thermal control device. The thermal control interface device 16 may be integrated into another part of the multi-receptacle MEA device 1 , for example it may be integrated into the carrier 12 and / or the thermal energy balancing device 14. The thermal control interface device 16 may, additionally or alternatively, be a separate part or component of the multi-receptacle MEA device 1 , in particular separate from the carrier 12 and / or the thermal energy balancing device 14. The thermal control interface device 16 is thermally connected to the MEAs 11 , for example by direct contact and / or by way of a thermally conductive material.

[0076] The thermal control interface device 16 may be arranged on or integrated into a bottom surface of the multi-receptacle MEA device 1 . For example, the thermal control interface device 16 may be implemented as a planar device, for example in the form of a plate. The plate may be made of a suitable material, for example a metal, a ceramic, or a polycarbonate. Preferably, the thermal control interface device 16 has a shape substantially corresponding to the overall shape of the multi-receptacle MEA device 1 . For example, the thermal control interface device 16 may be attached directly to the carrier 12 implemented as a PCB, or the carrier 12 implemented as PCB may form the thermal control interface device 16. The thermal control interface device 16 is thermally connected to the thermal energy balancing device 14, for example by direct contact and / or by way of an intermediary thermally conductive material.

[0077] In an embodiment, both the thermal energy balancing device 14 and the thermal control interface device 1 are implemented as a single thermal pad applied to the bottom of the multi-receptacle MEA device 1 .

[0078] The thermal control device may include a heater and / or a cooler. The thermal control device may include a heating plate which is placed into thermal contact with the thermal control interface device 16.

[0079] The thermal control device may be integrated into a docking device configured to electrically connect to the multi-receptacle MEA device 1 and may be configured to perform experiments by controlling the multi-receptacle MEA device 1 , for example by measuring and / or stimulating the cells during an experiment.

[0080] Figure 4 shows a block diagram of a multi-receptacle MEA docking device 2 according to an embodiment. The multi-receptacle MEA docking device 2 is a device suitable for use with a multi-receptacle MEA device, in particular a multi-receptacle MEA device as known from the prior art. The multi-receptacle MEA docking device 2 may, of course, also be used with the multi-receptacle MEA device 1 described herein. The multi-receptacle MEA docking device 2 is configured to electrically contact a multi-receptacle MEA device and further to heat the multi-receptacle MEA device, such that experiments on cells included in samples placed on the multi-receptacle MEA device may be performed.

[0081] The multi-receptacle MEA docking device 2 includes a support pad 21 . The support pad is a structure configured to receive and hold a multi-receptacle MEA device placed on or into the multi-receptacle MEA docking device 2. The support pad 21 has a shape which is configured to correspond, at least in part, to a shape of the multi-receptacle MEA device. For example, the support pad 21 may have a substantially flat rectangular shape, for example in the form of a rectangular plate, designed to support a correspondingly shaped flat and rectangular multi-receptacle MEA device.

[0082] The support pad 21 may include one or more holding members configured to releasably engage with the multi-receptacle MEA device to physically hold it in place. The support pad 21 may include one or more alignment members configured to engage with the multireceptacle MEA device to align it such that it rests on the support pad 21 in a pre-defined position. The support pad 21 may provide a plurality of electrical contacts configured to engage with corresponding electrical contacts of the multi-receptacle MEA device, for the purposes of performing experiments on samples placed on the MEAs of the multireceptacle MEA device.

[0083] The multi-receptacle MEA docking device 2 further includes a thermal control device 22. The thermal control device 22 may be implemented as part of the support pad 21 , or may be a separate part or component of the multi-receptacle MEA docking device 2. The thermal control device 22 is configured to heat and / or cool a multi-receptacle MEA device placed on the support pad 21 . The thermal control device 22 may include one or more heating elements.

[0084] The multi-receptacle MEA docking device 2 further comprises a thermal energy balancing device 23. The thermal energy balancing device 23 is configured to balance a temperature between at least two MEAs of the multi-receptacle MEA device placed on the support pad 21.

[0085] Figure 5 shows a lateral section view illustrating schematically a multi-receptacle MEA device 1 according to an embodiment. The multi-receptacle MEA device 1 includes a plurality of receptacles 13. Shown are four receptacles 13. The receptacles 13 are arranged on the carrier 12, which may be implemented, at least in part, as a PCB.

[0086] The receptacles 13 have a bottom area 131 , in or on which the MEAs 13 are arranged. The bottom area 131 has a lateral extension, i.e. in the plane of the multi-receptacle MEA device 1. The receptacles 13 further have a wall 132, extending from the bottom area 131 in the vertical direction by a defined distance. The wall 132 preferably circumferentially encloses the bottom area 131 and thereby the MEA 1 1. The receptacles 13 form an opening 133 opposite to the bottom area 131.

[0087] The MEAs 1 1 may be implemented as electronic chips, in particular semiconductor chips. The MEAs 11 are electrically connected to the carrier 12, in particular by way of electrical leads and / or soldered connections.

[0088] The thermal energy balancing device 14 is depicted as being implemented in the area of the carrier 12, and may be integrated into the carrier 12. The thermal energy balancing device 14 as shown is laterally connected all the MEAs 11 .

[0089] The thermal control interface device 16 is shown as being arranged on a bottom surface of the multi-receptacle MEA device 1. It may be integrated into the thermal energy balancing device 14 and / or the carrier 12.

[0090] Figure 6 shows a lateral section view illustrating schematically a multi-receptacle MEA device 1 according to an embodiment, in particular it shows the multi-receptacle MEA device 1 as described above with reference to Figure 5 in more detail in the area of the thermal energy balancing device 14 and the carrier 12. The carrier 12 is shown as a flat member extending laterally underneath the receptacles 13. The carrier 12 may be implemented as a PCB to which the MEAs 1 1 are electrically connected. The thermal energy balancing device 14 is arranged underneath the carrier 12. The thermal energy balancing device 14 does not extend across the entire bottom surface of the multi-receptacle MEA device 1 , rather, it is arranged in a central area with a reduced peripheral area with respect to the multi-receptacle MEA device 1 , in particular with respect to the carrier 12. The thermal energy balancing device 14 may be implemented as a thermal pad, more precisely a thermally conductive layer. The thermal energy balancing device 14 is preferably implemented as a flexible and adhesive pad containing carbon such that it can be readily applied to the carrier 12 during manufacture. Additionally, the flexible nature of the thermal energy balancing device 14 means that good thermal contact is established between the thermal energy balancing device 14 and the (external) thermal control device 15, in particular an areal (in particular planar) and conformal contact. The thermal control interface device 16 is implemented in part by the thermal energy balancing device 14 and in part by the carrier 12.

[0091] The thermal control device 15, which is not part of the multi-receptacle MEA device 1 , is shown. The thermal control device 15 is configured to provide heat energy to the multireceptacle MEA device 1 . The thermal energy balancing device 14, i.e. the thermal pad in this particular embodiment, is configured such that the MEAs 11 are evenly heated and have a substantially uniform temperature.

[0092] Figure 7 shows a bottom view illustrating schematically a multi-receptacle MEA array device 1 including a thermal energy balancing device 14 implemented as a thermal pad according to an embodiment. In particular, Figure 7 is a bottom view of the embodiment shown in Figure 6. It can be seen that the thermal energy balancing device 14 has a rectangular shape similar in aspect ratio to the aspect ratio of the overall shape of the multi-receptacle MEA array device 1 , in particular with respect to the overall shape of the carrier 12. The thermal energy balancing device 14 is centrally arranged and designed such that the thermal conductivity between the multi-receptacle MEA array device 1 and the docking device (not shown) onto which the multi-receptacle MEA array device 1 is placed is increased, in particular in a central region of the multi-receptacle MEA array device 1. Further, the thermal energy balancing device 14 increases the lateral thermal conductivity in a central region of the multi-receptacle MEA array device 1 , such that peripheral MEAs 1 1 , i.e. MEAs 1 1 arranged on the periphery of the multi-receptacle MEA array device 1 , draw heat via the thermal energy balancing device 14 from centrally arranged MEAs 1 1 .

[0093] Figure 8 shows a bottom view illustrating schematically a multi-receptacle MEA array device 1 including a thermal energy balancing device 14 implemented using a plurality of thermal patches 14. The thermal patches are arranged on the bottom of the carrier 12 in positions corresponding to the positions of the MEAs 1 1 (not shown). The thermal patches are circular in shape and have differing sizes according to their position. In particular, thermal patches closer to the center of the carrier 12 are larger in size than thermal patches at the periphery. The thermal patches may be made similarly to the thermal pad described herein, for example as a flexible and adhesive patch made of a thermally conductive material. The central thermal patches are higher, thereby the thermal conductivity between the MEAs 11 arranged above a respective central thermal patch is heated more easily by a thermal control device onto which the multi-receptacle MEA array device 1 is placed. The size of the thermal patches is designed such that, during use, the MEAs 11 of the multi-receptacle MEA array device 1 have a balanced, i.e. the same or substantially the same, temperature.

[0094] Figures 9 and 10 show a top section view and a side section view along line D illustrating schematically a multi-receptacle MEA device 1 including a patterned layer in the carrier according to two similar embodiments. In particular, the thermal energy balancing device 14 implemented as a patterned or otherwise structured layer within the carrier 12. The layer is structured in that the thermal energy balancing device 14 is not present in all lateral positions of the carrier 12. In particular, as seen in the top view, the thermal energy balancing device 14 is patterned such that it is present underneath the central 8 receptacles 14 of the 4 x 6 receptacle arrangement of the multi-receptacle MEA device 1. Additionally, the thermal energy balancing device 14 is present underneath the receptacles 13 arranged in the corner of the multi-receptacle MEA device 1 . It is noted that the receptacles 13 are depicted on top of the thermal energy balancing device 14 to indicate the positions of the receptacles 13 relative to the thermal energy balancing device 14, such that it appears that the thermal energy balancing device 14 has circular holes. This is not the case, the thermal energy balancing device 14 is whole underneath the receptacles 131 , as shown in the section side view.

[0095] The difference in the thermal energy balancing device 14 between Figures 9 and 10 lies in that, in the embodiment depicted in Figure 9, there are two relatively narrow cut-out sections between the second and third rows of receptacles 13, in particular in the second and fifth column. These cut-out sections do not exist in the embodiment depicted in Figure 10.

[0096] Figure 11 shows a top view illustrating schematically a multi-receptacle micro-electrode array device including thermal filling material between the receptacles 13 according to an embodiment. In particular, two different thermal filling materials 14A, 14B are used. The thermal filling material 14A has a different thermal conductivity to the thermal filling material 14B. In one example, the thermal filling material 14A has a higher thermal conductivity than the thermal filling material 14B. The thermal filling materials 14A, 14B, in particular the thermal filling material 14A balances the temperature between the receptacles 13, in particular by conducting heat from hotter receptacles 13 to cooler receptacles 13. Figure 12 shows a perspective view and a section view illustrating schematically a multireceptacle MEA docking device 2 including a thermal energy balancing device 23 according to an embodiment. The thermal energy balancing device 23 is implemented as part of the thermal control device 2. The support pad 21 is also implemented as part of the thermal control device 2.

[0097] The thermal energy balancing device 23 includes several zones 231 , 232, 233 which are concentrically arranged, in other words nested within each other. In particular, the central zone 233, also referred to in the Figure as zone 3, is surrounded by two peripheral zones 231 , 232, in which zone 2 completely surrounds zone 3 and zone 1 completely surrounds zone 2. The zones have a rectangular shape with the same aspect ratio as the overall multi-receptacle MEA docking device 2.

[0098] The thermal energy balancing device 23 is designed to control the heating and / or cooling of a multi-receptacle MEA device placed on top of the multi-receptacle MEA docking device 2. Specifically, the thermal energy balancing device 23 is designed to individually control the zones 231 , 232, 233 such as to achieve a balanced temperature across the MEAs of the multi-receptacle MEA device. For example, it may heat the peripheral zones 231 , 232 more or less than the central zone 233.

[0099] The thermal energy balancing device 23 may be implemented by one or more passive layers of thermally conductive material, thermal pad(s), or the like. Alternatively or additionally, the thermal energy balancing device 23 may be implemented using active heating and / or cooling elements. The overall heating and / or cooling provided by the multireceptacle MEA docking device 2 is typically achieved in conjunction with the thermal control device 2.

[0100] Thereby, a multi-receptacle MEA device placed on top of the multi-receptacle MEA docking device 2 achieves a balanced temperature across at least two of the MEAs, without the multi-receptacle MEA device having to be specifically configured to balance the temperature between two or more MEAs.

[0101] Figure 13 shows a plot of temperature inside the receptacles or wells of a multi-receptacle MEA device according to the prior art, highlighting the difference in temperatures between receptacles or wells at the center (well center) and receptacles or wells at the edge of the device (well edge). In particular, “well edge” refers to wells or receptacles arranged at the edge or periphery of the multi-receptacle MEA device. The MEAs of the multi-receptacle MEA device are, in this case, passive MEAs. It can be seen that the wells at the center of the device are relatively close to the set point (optimal) temperature, with a small drift evident over time. The wells at the edge, however, have a significantly lower temperature than the optimal temperature and the well also has a larger drift / variation over time. Thereby, the cells cultured in wells at the edge experience different environmental conditions than wells in the center, meaning that experimental results may not always be directly comparable.

[0102] It is understood that for prior art multi-receptacle MEA devices in which the MEAs are active devices, such as electronic semiconductor chips, the MEAs in central wells may have a lower temperature than those arranged at the edge due to the greater outflow of heat from the central wells into the docking device.

[0103] Figure 14 shows a plot of temperature inside the wells of a multi-receptacle MEA device 1 over time according to the present disclosure, highlighting the substantial uniformity in temperatures between wells at the center and wells at the edge of the plate. In particular, it can be seen that, while wells in the center have a higher temperature than wells at the edge, that the temperature difference much smaller than in the prior art. According to the present disclosure, temperature differences of less than 0.3 °C or preferably less than 0.2 °C may be considered as insignificant and essentially balanced. The above-described embodiments of the disclosure are exemplary and the person skilled in the art knows that at least some of the components and / or steps described in the embodiments above may be rearranged, omitted, or introduced into other embodiments without deviating from the scope of the present disclosure.

Claims

CLAIMS1. A multi-receptacle micro-electrode array device (1 ) comprising: a plurality of circumferentially closed sample receptacles (13), the sample receptacles (13) being arranged side-by-side in an array, wherein a micro-electrode array (1 1 ) is arranged in each sample receptacle (13), in particular in a bottom area thereof; a carrier (12), wherein the sample receptacles (13) are arranged on the carrier (12) and / or a bottom surface (131 ) of the sample receptacles (13) is in each case formed by the carrier (12); a thermal control device interface (16), the thermal control device interface (16) being configured for coupling the multi-receptacle micro-electrode array device (1 ) to a thermal control device; and a thermal energy balancing device (14), the thermal energy balancing device (14) being thermally connected to at least a subset of the micro-electrode arrays (1 1 ), the thermal energy balancing device (14) being configured to balance a temperature across at least two micro-electrode arrays (1 1 ).

2. The multi-receptacle micro-electrode array device (1 ) according to claim 1 , wherein each micro-electrode array (1 1 ) is part of an electronic chip, the electronic chip being arranged on the carrier (12) inside the sample receptacle (13).

3. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) includes a structured thermally conductive layer.

4. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the carrier (12) includes a printed circuit board (12), whereinthe thermal energy balancing device (14) is formed, at least in part, by at least one metal layer of the printed circuit board (12).

5. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) is areally connected to the carrier (12), in particular a bottom side of the carrier (12).

6. The multi-receptacle micro-electrode array device (1 ) according to claim 5, wherein the thermal energy balancing device (14) is applied to the carrier (12) as a coating, in particular by way of painting, spraying, or printing, in particular screen printing, or wherein the thermal energy balancing device (14) is attached, in particular adhesively attached, to the carrier (12).

7. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) includes a thermal pad, the thermal pad being in particular flexible.

8. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) includes a thermal filler, the thermal filler being arranged between at least some of the sample receptacles (13).

9. The multi-receptacle micro-electrode array device (1 ) according to claim 8, wherein a material, composition, and / or thickness of the thermal filler varies laterally.

10. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) has a laterally varying thermal conductivity.

11. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) includes a pattern of separate and laterally distributed thermal balancing members, the thermal balancing members being in particular adhesive patches.

12. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) is configured for lateral heat transport and / or heat transport between the sample receptacles (13) and the thermal control device interface (16).

13. The multi-receptacle micro-electrode array device (1 ) according to one of the preceding claims, wherein the thermal energy balancing device (14) includes at least one of metal, in particular copper, thermally conductive plastics, carbon, or liquid.

14. A multi-receptacle micro-electrode array docking device (2) for electrical contact and temperature control of a multi-receptacle micro-electrode array device (1 ), the multi-receptacle micro-electrode array docking device (2) including: a support pad (21 ), the support pad (21 ) comprising a plurality of electrical contacts configured for electrical connection with a multi-receptacle micro-electrode array device; a temperature control device (22), the temperature control device (22) being thermally connected to the support pad (21 ), the thermally control device being configured for controlling a temperature of the multi-receptacle micro-electrode array device (1 ) by way of heating and / or cooling; and a thermal energy balancing device (23), the thermal energy balancing device (23) being thermally connected to the support pad (21 ) and the temperature control device (22) and being configured to balance a temperature across the support pad (21 ).

15. The multi-receptacle micro-electrode array docking device (2) according to claim14, wherein the temperature control device (22) includes a number of separately controllable temperature control zones (231 , 232, 233).

16. The multi-receptacle micro-electrode array docking device (2) according to claim15, wherein the temperature control zones include a central temperature control zone (233) and one or more peripheral temperature control zones (231 , 232), wherein the one or more peripheral temperature control zones (231 , 232) are arranged laterally around the central temperature control zone (233), for example in a concentric manner.

17. The multi-receptacle micro-electrode array docking device (2) according to one of claims 15 or 16, wherein the multi-receptacle micro-electrode array docking device (2) is configured to control heating and / or cooling of each of the temperature control zones (231 , 232, 233) in a substantially uniform manner.

18. The multi-receptacle micro-electrode array docking device (2) according to one of claims 14 to 17, wherein the temperature control device (22) includes at least one of a resistive electric heater and a Peltier element.

19. The multi-receptacle micro-electrode array docking device (2) according to one of claims 14 to 18, wherein the temperature control device (22) includes a fluid conduit arrangement filled with heat transport fluid, and a fluid heating and / or cooling device for heating and / or cooling the heat transport fluid.

20. The multi-receptacle micro-electrode array docking device (2) of according to one of claims 14 to 19, wherein the thermal energy balancing device (23) includes a thermal pad, the thermal pad being thermally connected to the support pad (21 ) or is integral with the support pad (21 ).

21. The multi-receptacle micro-electrode array docking device (2) of according claim20, wherein the thermal pad is adhesively connected to the support pad (21 ).

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