System for measuring multiple electrical resistance of living tissue

Abstract

A transepidermal electrical resistance measuring device according to one embodiment of the present invention comprises: a plurality of cell culture chips having a medium input space formed for introducing a medium, a receiving space formed for accommodating the medium and a cell surrounded by the medium, a first electrode for applying a resistance measuring current to the medium accommodating the receiving space, a first terminal for measuring a first potential from the medium to which a voltage is applied due to the resistance measuring current, and a membrane that supports the cell within the receiving space so that the cell is spaced apart from the first electrode and the first terminal, and through which the medium passes; and a first substrate disposed on top of the plurality of cell culture chips and electrically connected to each of the first electrode and the first terminal provided on each of the plurality of cell culture chips. It includes a plurality of second electrodes for applying the resistance measurement current to each of the medium and each of the cells contained in the receiving space of each of the plurality of cell culture chips, and a plurality of second terminals for measuring a second potential from each of the medium and the cells contained in the receiving space of each of the plurality of cell culture chips and to which a voltage is applied due to the resistance measurement current; and a resistance measurement voltage, which is a potential difference between the first potential and the second potential, can be applied to the medium and the cells due to the resistance measurement current applied through the first electrode and the second electrode.

Description

Technology Field

[0001] The present invention relates to a multi-electrical resistance measurement system for biological tissues, comprising a plurality of cell culture chips in which cells are cultured, and capable of calculating the electrical resistance of the cells cultured in each cell culture chip from the first potential and second potential of the cells after applying a resistance measurement current to each cell culture chip. Background Technology

[0003] Transepithelial electrical resistance (TEER) is a value representing electrical resistance due to a membrane and is a method that can be used to measure the resistance formed by tight junctions of cells.

[0004] Currently, TEER measurement requires dispensing cell results from a biochip for external verification or measuring in an open system, and even when measured on the same chip, there was a problem where electrodes made of metallic materials reacted with water-soluble biomaterials and oxidized.

[0005] Accordingly, there is an urgent need for the development of electrodes and biochips that have excellent biocompatibility, allowing for measurement as a closed system within the biochip, and have high conductivity, enabling excellent TEER measurement.

[0006] In addition, the current TEER measurement method involves the operator immersing a chopstick-shaped electrode in the culture medium, which causes errors in the measurement value if the position of the immersed electrode is changed by the operator, and there is a problem that TEER can only be measured if the electrode is kept immersed in the culture medium. Prior art literature

[0008] Korean Patent Publication No. 10-2010-0136181 The problem to be solved

[0009] The objective of the present invention is to provide a system for measuring multiple electrical resistances of biological tissues that can simultaneously measure the electrical resistance of multiple cells by applying a resistance measurement current to multiple cells through a current source and then measuring a first potential and a second potential.

[0010] In addition, the objective of the present invention is to provide a multi-electrical resistance measurement system for biological tissues capable of continuously measuring the transepithelial electrical resistance of cells in real time.

[0011] The objects of the present invention are not limited to those mentioned above, and other unmentioned objects and advantages of the present invention may be understood from the following description and will be more clearly understood by the embodiments of the present invention. Furthermore, it will be readily apparent that the objects and advantages of the present invention can be realized by the means and combinations thereof set forth in the claims. means of solving the problem

[0013] A transepidermal electrical resistance measuring device according to one embodiment of the present invention comprises: a plurality of cell culture chips having a medium input space formed for introducing a medium, a receiving space formed for accommodating the medium and a cell surrounded by the medium, a first electrode for applying a resistance measuring current to the medium accommodating the receiving space, a first terminal for measuring a first potential from the medium to which a voltage is applied due to the resistance measuring current, and a membrane that supports the cell within the receiving space so that the cell is spaced apart from the first electrode and the first terminal, and through which the medium passes; and a first substrate disposed on top of the plurality of cell culture chips and electrically connected to each of the first electrode and the first terminal provided on each of the plurality of cell culture chips. It includes a plurality of second electrodes for applying the resistance measurement current to each of the medium and each of the cells contained in the receiving space of each of the plurality of cell culture chips, and a plurality of second terminals for measuring a second potential from each of the medium and the cells contained in the receiving space of each of the plurality of cell culture chips and to which a voltage is applied due to the resistance measurement current; and a resistance measurement voltage, which is a potential difference between the first potential and the second potential, can be applied to the medium and the cells due to the resistance measurement current applied through the first electrode and the second electrode.

[0014] According to one embodiment of the present invention, the plurality of cell culture chips may comprise: a culture medium input hole formed through in the vertical direction and forming part of a culture medium input space into which the culture medium is introduced, and a cell input hole formed through in the vertical direction into which the cell is introduced or into which the cell and the culture medium are introduced and which forms part of a receiving space; a biomimetic tissue chip disposed on the upper part of the wafer below in which the culture medium is moved between the culture medium input hole and the cell input hole; a membrane disposed inside the cell input hole that supports the culture medium by allowing it to pass through the receiving space in the vertical direction, but prevents the cell from passing through the receiving space in the downward direction; the first electrode disposed below the culture medium input hole; an electrode extension line formed integrally with the first electrode and electrically connected to the first electrode; the first terminal disposed below the culture medium input hole; a terminal extension line formed integrally with the first terminal and electrically connected to the first terminal; and a wafer on which the first electrode, the electrode extension line, the first terminal, and the terminal extension line are formed on the upper part.

[0015] According to one embodiment of the present invention, the first substrate may comprise: a first base substrate; a first input / output terminal disposed on the upper portion of the first base substrate, to which the resistance measurement current is input / output and the first potential is output; a plurality of first current wires disposed on the upper portion of the first base substrate, one end of which is electrically connected to the first input / output terminal; a plurality of current connection wires that electrically connect the plurality of first current wires to each of the first electrode or the electrode extension line provided on each of the plurality of cell culture chips; a plurality of first voltage wires disposed on the upper portion of the first base substrate, one end of which is electrically connected to the first input / output terminal; a plurality of voltage connection wires that electrically connect the plurality of first voltage wires to each of the first terminal or the terminal extension line provided on each of the plurality of cell culture chips; and a first mask layer that covers the upper portion of the first base substrate such that only the plurality of current connection wires, the plurality of voltage connection wires, and the first input / output terminal are exposed to the outside.

[0016] According to one embodiment of the present invention, the second substrate may comprise: a second base substrate; a second input / output terminal disposed at the bottom of the second base substrate, to which the resistance measurement current is input / output and the second potential is output; a plurality of second current wires disposed at the bottom of the second base substrate, one end of which is electrically connected to the second input / output terminal; a plurality of second electrodes formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of second current wires, and inserted into the upper part of the receiving space from the other end; a plurality of second voltage wires disposed at the bottom of the second base substrate, one end of which is electrically connected to the second input / output terminal; a plurality of second terminals formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of second voltage wires, and inserted into the upper part of the receiving space from the other end; and a second mask layer covering the bottom of the second base substrate such that only the plurality of second electrodes, the plurality of second terminals, and the second input / output terminal are exposed to the outside among the bottom of the second base substrate.

[0017] A cell culture chip according to one embodiment of the present invention may have a medium input space formed for introducing a medium, a receiving space formed for receiving the medium and a cell surrounded by the medium, a first electrode for applying a resistance measuring current to the medium and the cell received in the receiving space, a first terminal for measuring a first potential from the medium and the cell to which a voltage is applied due to the resistance measuring current, and a membrane that supports the cell within the receiving space so that the cell is spaced apart from the first electrode and the first terminal, and through which the medium passes.

[0018] A cell culture chip according to one embodiment of the present invention comprises: a biomimetic tissue chip having a culture medium input hole formed through in the vertical direction for introducing the culture medium, and a cell input hole formed through in the vertical direction for introducing the cell or introducing the cell and the culture medium and forming a part of the receiving space; a membrane disposed below the cell input hole for supporting the culture medium introduced into the cell input hole, allowing the culture medium introduced into the cell input hole to pass to the outside of the cell input hole, while preventing the cell introduced into the cell input hole from passing to the outside of the cell input hole; a second biomimetic tissue chip having a culture medium channel formed through in the vertical direction for introducing the culture medium introduced into the culture medium input hole, communicating with the culture medium input hole, and a culture medium input hole formed through in the vertical direction for introducing the culture medium that has passed through the membrane, communicating with the culture medium channel for introducing the culture medium introduced into the culture medium channel, and forming a receiving space other than the receiving space formed by the cell input hole; and the first electrode disposed below the culture medium input hole. The apparatus may comprise an electrode extension line formed integrally with the first electrode and electrically connected to the first electrode; and a wafer having the first electrode and the electrode extension line formed on its upper surface.

[0019] A transepidermal electrical resistance measuring device according to another embodiment of the present invention comprises a plurality of cell culture chips having a medium input space formed for introducing a medium, a receiving space formed in communication with the medium input space and receiving the medium and a cell surrounded by the medium, and a membrane that supports the cell within the receiving space and through which the medium passes; The apparatus comprises: a plurality of first electrodes for applying a resistance measurement current to each of the medium and each of the cells contained in the receiving space of each of the plurality of cell culture chips; a plurality of second electrodes for applying the resistance measurement current to each of the medium introduced in the medium introduction space of each of the plurality of cell culture chips; a plurality of first terminals for measuring a first potential from the medium and the cells contained in the receiving space of each of the plurality of cell culture chips to which a voltage is applied due to the resistance measurement current; and a plurality of second terminals for measuring a second potential from the medium introduced in the medium introduction space of each of the plurality of cell culture chips to which a voltage is applied due to the resistance measurement current; wherein a resistance measurement voltage, which is a potential difference between the first potential and the second potential, can be applied to the medium and the cells due to the resistance measurement current applied through the first electrode and the second electrode.

[0020] According to another embodiment of the present invention, the plurality of cell culture chips may comprise: a wafer; a culture medium input hole formed through in the vertical direction and forming part of the culture medium input space into which the culture medium is introduced, and a cell input hole formed through in the vertical direction into which the cell is introduced or into which the cell and the culture medium are introduced and which forms part of the receiving space, and a biomimetic tissue chip disposed on the upper part of the wafer in which the culture medium is moved between the culture medium input hole and the cell input hole; and a membrane disposed inside the cell input hole that allows the culture medium to pass through in the vertical direction in the receiving space, but supports the cell without allowing it to pass through in the downward direction in the receiving space.

[0021] According to another embodiment of the present invention, the second substrate comprises: a second base substrate; a second input / output terminal disposed below the second base substrate, to which the resistance measurement current is input / output and to which the first potential and the second potential are output; a plurality of first current wires disposed below the second base substrate, one end of which is electrically connected to the second input / output terminal; the plurality of first electrodes formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of first current wires, and inserted into the upper part of the receiving space from the other end; a plurality of first voltage wires disposed below the second base substrate, one end of which is electrically connected to the second input / output terminal; the plurality of first terminals formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of first voltage wires, and inserted into the upper part of the receiving space from the other end; and a plurality of second current wires disposed below the second base substrate, one end of which is electrically connected to the second input / output terminal. The plurality of second electrodes formed in a bar shape, with one end electrically connected to the other end of each of the plurality of second current wires and inserted into the upper part of the culture medium input space from the other end; a plurality of second voltage wires disposed on the lower part of the second base substrate, with one end electrically connected to the second input / output terminal; a plurality of second terminals formed in a bar shape, with one end electrically connected to the other end of each of the plurality of second voltage wires and inserted into the upper part of the culture medium input space from the other end; and a second mask layer covering the lower part of the second base substrate such that only the plurality of first electrodes, the plurality of first terminals, the plurality of second electrodes, the plurality of second terminals, and the second input / output terminal are exposed to the outside among the lower part of the second base substrate.

[0022] A cell culture chip according to another embodiment of the present invention may have a medium input space formed for introducing a medium, a receiving space formed in communication with the medium input space and receiving the medium and a cell surrounded by the medium, and may have a membrane that supports the cell within the receiving space and through which the medium passes.

[0023] A cell culture chip according to another embodiment of the present invention may comprise: a wafer; a culture medium input hole formed through in the vertical direction and forming part of the culture medium input space into which the culture medium is introduced, and a cell input hole formed through in the vertical direction into which the cell is introduced or into which the cell and the culture medium are introduced and which forms part of the receiving space, and a biomimetic tissue chip disposed on the upper part of the wafer in which the culture medium is moved between the culture medium input hole and the cell input hole; and a membrane disposed inside the cell input hole that allows the culture medium to pass through in the vertical direction in the receiving space, but supports the cell without allowing it to pass through in the downward direction in the receiving space.

[0024] The transepithelial electrical resistance calculation device according to the present invention comprises: an output unit that outputs a resistance measurement current to a transepithelial electrical resistance measuring device according to the present invention; an input unit that receives a first potential and a second potential output from the transepithelial electrical resistance measuring device; and a processor that calculates transepithelial electrical resistance based on the resistance measurement current, the first potential, and the second potential, wherein the processor can calculate a cell culture degree indicating the degree of cell culture based on the resistance change rate of the transepithelial electrical resistance.

[0025] A multi-electrical resistance measurement system for biological tissue according to the present invention may include a transepithelial electrical resistance measurement device according to the present invention; and a transepithelial electrical resistance calculation device according to the present invention. Effects of the invention

[0027] The present invention can simultaneously measure transepithelial electrical resistance for a plurality of cells.

[0028] In addition, the present invention can continuously measure the transepithelial electrical resistance of a cell in real time.

[0029] In addition, the present invention can improve the accuracy of the measurement of transepithelial electrical resistance by measuring the transepithelial electrical resistance from the first and second potentials of a cell measured while applying a resistance measurement current through a current source. Brief explanation of the drawing

[0031] FIG. 1 is a diagram illustrating the connection configuration of a multi-electrical resistance measurement system for biological tissue according to an embodiment of the present invention. FIG. 2 is a block diagram of a multi-electrical resistance measurement system for biological tissue according to an embodiment of the present invention. FIG. 3 is a block diagram of a transepithelial electrical resistance measurement device according to an embodiment of the present invention. FIG. 4 is a perspective view of a transepithelial electrical resistance measurement device according to an embodiment of the present invention with the housing open. FIG. 5 is an exploded perspective view of a transepithelial electrical resistance measurement device according to an embodiment of the present invention. FIG. 6 is a perspective view of a cell culture chip according to one embodiment of the present invention. FIG. 7 is an exploded perspective view of a cell culture chip according to one embodiment of the present invention. FIG. 8 is a cross-sectional view along A1-A1' of FIG. 6. FIG. 9 is a cross-sectional view along A2-A2' of FIG. 6. FIG. 10 is a cross-sectional view along A3-A3' of FIG. 6. FIG. 11 is an exploded perspective view of a first substrate included in a transepithelial electrical resistance measuring device according to one embodiment of the present invention. FIG. 12 is a perspective view of a second substrate included in a transepithelial electrical resistance measuring device according to one embodiment of the present invention. FIG. 13 is an exploded perspective view of a second substrate included in a transepithelial electrical resistance measuring device according to one embodiment of the present invention. FIG. 14 is a block diagram of a transepithelial electrical resistance measuring device according to another embodiment of the present invention. FIG. 15 is a perspective view of a transepithelial electrical resistance measuring device according to another embodiment of the present invention with the housing open. FIG. 16 is an exploded perspective view of a transepithelial electrical resistance measuring device according to another embodiment of the present invention. FIG. 17 is a perspective view of a cell culture chip according to another embodiment of the present invention. FIG. 18 is an exploded perspective view of a cell culture chip according to one embodiment of the present invention. FIG. 19 is a cross-sectional view along A4-A4' of FIG. 17. FIG. 20 is a perspective view of a second substrate included in a transepithelial electrical resistance measuring device according to another embodiment of the present invention. FIG. 21 is an exploded perspective view of a second substrate included in a transepithelial electrical resistance measuring device according to another embodiment of the present invention.FIG. 22 is a block diagram of a device for calculating transepidermal electrical resistance according to one embodiment of the present invention. Specific details for implementing the invention

[0032] Hereinafter, various embodiments of the present invention are described with reference to the accompanying drawings. However, this is not intended to limit the present invention to specific embodiments and should be understood to include various modifications, equivalents, and / or alternatives of the embodiments of the present invention. In connection with the description of the drawings, similar reference numerals may be used for similar components.

[0033] In this document, expressions such as "have," "may have," "include," or "may include" refer to the existence of the relevant feature (e.g., numerical values, functions, operations, or components, etc.) and do not exclude the existence of additional features.

[0034] In this document, expressions such as “A or B”, “at least one of A or / and B”, or “one or more of A or / and B” may include all possible combinations of items listed together. For example, “A or B”, “at least one of A and B”, or “at least one of A or B” may refer to cases including (1) at least one A, (2) at least one B, or (3) both at least one A and at least one B.

[0035] Expressions such as "first," "second," "first," or "second" used in this document may modify various components regardless of order and / or importance, and are used merely to distinguish one component from another without limiting such components. For example, the first user device and the second user device may represent different user devices regardless of order or importance. For example, without departing from the scope of rights set forth in this document, the first component may be named the second component, and similarly, the second component may be renamed the first component.

[0036] When it is stated that a component (e.g., a first component) is "connected" to another component (e.g., a second component), it should be understood that the component is directly connected to the other component or is composed of a single material. On the other hand, when it is stated that a component (e.g., a first component) is "fastened" to or "bonded" to another component (e.g., a second component), it should be understood that the component is fastened or bonded to the other component using a mechanical structure.

[0037] The terms used in this document are used merely to describe specific embodiments and are not intended to limit the scope of other embodiments. Singular expressions may include plural expressions unless the context clearly indicates otherwise. Terms used herein, including technical or scientific terms, may have the same meaning as generally understood by those skilled in the art described in this document. Terms used in this document that are defined in general dictionaries may be interpreted as having the same or similar meaning as they have in the context of the relevant technology, and are not to be interpreted in an ideal or overly formal sense unless explicitly defined in this document. In some cases, even terms defined in this document may not be interpreted to exclude the embodiments of this document.

[0038] FIG. 1 is a diagram illustrating the connection configuration of a multiple electrical resistance measurement system for biological tissue according to one embodiment of the present invention, and FIG. 2 is a block diagram of a multiple electrical resistance measurement system for biological tissue according to one embodiment of the present invention.

[0039] Referring to FIGS. 1 and 2, a multi-electrical resistance measurement system (10) for biological tissue according to one embodiment of the present invention may include a transepithelial electrical resistance measurement device (100) and a transepithelial electrical resistance calculation device (200) according to one embodiment of the present invention.

[0040] The transepidermal electrical resistance measuring device (100) includes a plurality of cell culture chips that accommodate cells cultured in a medium, and after applying a resistance measuring current to each of the cells surrounded by the medium through the plurality of cell culture chips, it can output a first potential measured at one side of the cell and a second current measured at the other side of the cell.

[0041] At this time, the transepidermal electrical resistance calculation device (200) outputs a resistance measurement current applied to a plurality of cell culture chips included in the transepidermal electrical resistance measuring device (100), and can receive a first potential and a second potential output from the transepidermal electrical resistance measuring device (100).

[0042] Subsequently, the transepithelial electrical resistance calculation device (200) can calculate the transepithelial electrical resistance for a cell contained in each of a plurality of cell culture chips based on the resistance measurement current, the first potential, and the second potential.

[0043] Specifically, the transepidermal electrical resistance calculation device (200) can calculate the voltage value of the resistance measurement voltage, which is the potential difference between the first potential and the second potential output from the transepidermal electrical resistance measuring device (100), and calculate the transepidermal electrical resistance by dividing the calculated voltage value by the current value of the resistance measurement current output to the transepidermal electrical resistance measuring device (100).

[0044] Hereinafter, a transepidermal electrical resistance measuring device (100) according to one embodiment of the present invention will be described in detail.

[0045] FIG. 3 is a block diagram of a transepidermal electrical resistance measuring device according to one embodiment of the present invention, FIG. 4 is a perspective view of a transepidermal electrical resistance measuring device according to one embodiment of the present invention with the housing open, and FIG. 5 is an exploded perspective view of a transepidermal electrical resistance measuring device according to one embodiment of the present invention.

[0046] Referring further to FIGS. 3 to 5, a transepidermal electrical resistance measuring device (100) according to one embodiment of the present invention may include a plurality of cell culture chips (110), a first substrate (120), a second substrate (130), and a housing part (140).

[0047] A plurality of cell culture chips (110) are disposed on the upper surface of the first substrate (120), and a second substrate (130) may be disposed on the upper surface of the plurality of cell culture chips (110) disposed on the upper surface of the first substrate (120).

[0048] At this time, a second substrate (130) may be arranged so that the second electrode and the second terminal of the second substrate (130) are inserted into each of the receiving spaces of the plurality of cell culture chips (110).

[0049] Meanwhile, the first substrate (120) and the second substrate (130) can each be accommodated in the first housing (141) and the second housing (142) respectively included in the housing part (140).

[0050] The first housing (141) and the second housing (142) can be joined by a hinge on one side to form an opening and closing structure.

[0051] When the second housing (142) is covered and closed on the first housing (141), as described above, the second substrate (130) is placed on top of the plurality of cell culture chips (110), and the second electrode and the second terminal of the second substrate (130) can be inserted into the receiving space of each of the plurality of cell culture chips (110).

[0052] At this time, a second electrode and a second terminal can be inserted into each of the receiving spaces of the plurality of cell culture chips (110).

[0053] Hereinafter, a cell culture chip (110) according to one embodiment of the present invention will be described in detail.

[0054] FIG. 6 is a perspective view of a cell culture chip according to one embodiment of the present invention, FIG. 7 is an exploded perspective view of a cell culture chip according to one embodiment of the present invention, FIG. 8 is a cross-sectional view along A1-A1' of FIG. 6, FIG. 9 is a cross-sectional view along A2-A2' of FIG. 6, and FIG. 10 is a cross-sectional view along A3-A3' of FIG. 6.

[0055] Referring further to FIGS. 6 to 10, a transepithelial electrical resistance measuring device (100) according to one embodiment of the present invention may include a plurality of cell culture chips (110) according to one embodiment of the present invention. For example, a transepithelial electrical resistance measuring device (100) according to one embodiment of the present invention may include eight cell culture chips (110) according to one embodiment of the present invention.

[0056] In this cell culture chip (110) according to one embodiment of the present invention, a medium input space (ER) into which a medium (M) is introduced is formed, and a receiving space (MR) into which a medium (M) and a cell (C) surrounded by the medium (M) are received is formed.

[0057] Additionally, a cell culture chip (110) according to one embodiment of the present invention may have a first electrode (114a) for applying a resistance measuring current to a medium (M) and a cell (C) contained in a receiving space (MR), a first terminal (114b) for measuring a first potential from the medium (M) and the cell (C) to which a voltage is applied due to the resistance measuring current, and a membrane (112) for supporting the cell (C) within the receiving space (MR) so that the cell (C) is spaced apart from the first electrode (114a) and the first terminal (114b).

[0058] The cell culture chip (110) according to one embodiment of the present invention may further comprise a biomimetic tissue chip (111), an electrode extension line (115a), a terminal extension line (115b), and a wafer (116).

[0059] A biomimetic tissue chip (111) is placed on the top of a cell culture chip (110) and may have a through-formed culture medium input hole (111a) and a through-formed cell input hole (111b).

[0060] At this time, the culture medium insertion hole (111a) is formed by penetrating the biomimetic tissue chip (111) in the vertical direction and may be a hole into which the culture medium (M) is inserted.

[0061] The cell insertion hole (111b) is formed by penetrating the biomimetic tissue chip (111) in the vertical direction and may be a hole into which a culture medium (M) and a cell (C) are inserted, or into which only a cell (C) is inserted.

[0062] Meanwhile, the culture medium input hole (111a) can be formed in a rectangular shape, and the cell input hole (111b) can be formed in a cylindrical shape.

[0063] Additionally, the medium input hole (111a) may be formed to a predetermined depth to accommodate the medium (M), and the cell input hole (111b) may be formed to a predetermined depth to accommodate the medium (M) and the cell (C).

[0064] Meanwhile, the inner space of the culture medium insertion hole (111a) may form part of the culture medium insertion space (ER). That is, part of the culture medium insertion space (ER) described above may be the inner space of the culture medium insertion hole (111a).

[0065] Meanwhile, the inner space of the cell insertion hole (111b) may form part of the receiving space (MR) described above. That is, part of the receiving space (MR) described above may be the inner space of the cell insertion hole (111b).

[0066] Preferably, two culture medium input holes (111a) may be formed, and a cell input hole (111b) may be formed between the two culture medium input holes (111a).

[0067] At this time, among the bottom surfaces of the biomimetic tissue chip (111), the bottom surface between the culture medium input hole (111a) and the cell input hole (111b) may be recessed compared to other bottom surfaces.

[0068] Accordingly, when the biomimetic tissue chip (111) is placed in contact with the upper surface of the wafer (116), the bottom surface between the culture medium input hole (111a) and the cell input hole (111b) is spaced apart from the upper surface of the wafer (116), thereby forming a spaced-apart space, and the culture medium (M) can move between the culture medium input hole (111a) and the cell input hole (111b) through this spaced-apart space.

[0069] The material of such a biomimetic tissue chip (111) may be made of any one of polydimethylsiloxane (PDMS), epoxy, polymer, polycarbonate (PC), polymethylmethacrylate (PMMA), polystyrene (PS), and cycloolefin copolymer (COC), or a mixture of two or more of these materials.

[0070] Preferably, the material of the biomimetic tissue chip (111) can be made of polydimethylsiloxane (PDMS).

[0071] Additionally, the biomimetic tissue chip (111) can be made of a transparent material to observe the inside of the culture medium input hole (111a) and the inside of the cell input hole (111b).

[0072] A membrane (112) is placed inside the cell insertion hole (111b) so that the cell insertion medium (M) passes up and down in the receiving space (MR), but the cell (C) inserted into the cell insertion hole (111b) is supported without passing down in the receiving space (MR).

[0073] That is, the culture medium (M) freely passes through the membrane (112), but the cell (C) introduced into the upper part of the membrane (112) in the receiving space (MR) is supported by the membrane (112) and cannot pass through the membrane (112) and cannot move to the lower part of the membrane (112).

[0074] Such a membrane (112) can be formed to a size corresponding to the cross-section in the horizontal direction of the cell insertion hole (111b).

[0075] Meanwhile, the membrane (112) is formed porously so that the secreted substances of the cell (C) and the medium (M) pass through, but the cell (C) does not pass through.

[0076] The material of the membrane (112) may be made of any one of PC (polycarbonate), PET (Polyester, Polyethylene, Terephthalate), PTFE (Polytetrafluoroethylene), and Cellulose, or a mixture of two or more of these materials, but is not limited thereto, and preferably may be a transparent material for cell observation.

[0077] The first electrode (114a) can be formed on the upper part of the wafer (116) so as to be placed below the cell insertion hole (111b).

[0078] Such a first electrode (114a) can apply a resistance measurement current to a badge (M) accommodated in a receiving space (MR).

[0079] In particular, the first electrode (114a) is located at the bottom of the membrane (112) in the receiving space (MR) and can apply a resistance measurement current to the medium (M) contained in the receiving space (MR receiving space (MR).

[0080] This first electrode (114a) can be formed by depositing titanium on the upper surface of the wafer (116) and depositing gold on the deposited titanium. Additionally, the first electrode (114a) can be formed in an open ring shape surrounding the disc.

[0081] The electrode extension line (115a) is formed integrally with the first electrode (114a) and is electrically connected to the first electrode (114a). A portion of the extension line may be formed on the upper surface of the wafer (116) so as to be placed below the biomimetic tissue chip (111), while the remainder may be formed on the upper surface of the wafer (116) so as not to be placed below the biomimetic tissue chip (111). That is, the terminal extension line (115b) may be formed on the upper surface of the wafer (116), with a portion placed below the biomimetic tissue chip (111) and the remainder not placed below the biomimetic tissue chip (111).

[0082] These electrode extension lines (115a) can be formed of copper and then coated with gold, and the width of the end furthest from the first electrode (114a) can be formed wide.

[0083] The first terminal (114b) can be formed on the upper part of the wafer (116) so as to be positioned below the cell insertion hole (111b).

[0084] The first terminal (114b) is accommodated in the receiving space (MR) and can measure the first potential from the badge (M) to which a voltage is applied due to the resistance measurement current.

[0085] In particular, the first terminal (114b) is located at the bottom of the membrane (112) in the receiving space (MR) and can measure the first potential from the medium (M) received in the receiving space (MR).

[0086] Such a first terminal (114b) can be formed by depositing titanium on the upper surface of a wafer (116) and depositing gold on the deposited titanium. Additionally, the first terminal (114b) can be surrounded by a first electrode (114a) and can form a disc shape.

[0087] The terminal extension line (115b) is formed integrally with the first terminal (114b) and is electrically connected to the first terminal (114b). A portion of the terminal extension line (115b) may be formed on the upper surface of the wafer (116) so as to be placed below the biomimetic tissue chip (111), while the remainder may not be placed below the biomimetic tissue chip (111). That is, the terminal extension line (115b) may be formed on the upper surface of the wafer (116), with a portion placed below the biomimetic tissue chip (111) and a remainder not placed below the biomimetic tissue chip (111).

[0088] Such terminal extension lines (115b) can be formed of copper and then coated with gold, and the width of the end furthest from the first terminal (114b) can be formed wide.

[0089] A wafer (116) may have a first electrode (114a), an electrode extension line (115a), a first terminal (114b), and a terminal extension line (115b) formed on its upper surface. Such a wafer (116) may be formed of glass.

[0090] Meanwhile, a second electrode (134a) and a second terminal (134b) can be inserted from the open top into the receiving space (MR) formed by the inner space of the cell insertion hole (111b).

[0091] At this time, the second electrode (134a) and the second terminal (134b) can be inserted into the receiving space (MR) and positioned and fixed so as not to come into contact with the cell (C) contained in the receiving space (MR).

[0092] Below, the first substrate (120) will be described.

[0093] FIG. 11 is an exploded perspective view of a first substrate included in a transepidermal electrical resistance measuring device according to one embodiment of the present invention.

[0094] Referring further to FIG. 11, a plurality of cell culture chips (110) are arranged on the upper surface of the first substrate (120) at a predetermined interval, and a resistance measurement current can be transmitted to each of the first electrodes (114a) provided on each of the plurality of cell culture chips (110).

[0095] To this end, the first substrate (120) may have a first base substrate (121), a first input / output terminal (122), a plurality of first current wires (123a), a plurality of current connection wires (124a), a plurality of first voltage wires (123b), a plurality of voltage connection wires (124b), and a mask layer (125).

[0096] The first base substrate (121) may be a base substrate of a conventional PCB.

[0097] The first input / output terminal (122) is positioned on the upper part of the first base substrate (121) and can receive a resistance measurement current from an external current source and output it to a plurality of first current wires (123a), or output a resistance measurement current input from a plurality of first current wires (123a).

[0098] Specifically, the first input / output terminal (122) receives a resistance measurement current output from the output section (210) of the electrical resistance calculation device (200) and can output it to a plurality of first current wires (123a).

[0099] Conversely, the first input / output terminal (122) can output a resistance measurement current flowing through a plurality of first current wires (123a) to the input section (220) of the transverse electrical resistance calculation device (200). Meanwhile, the first input / output terminal (122) can output a first potential input from a plurality of first voltage wires (123b).

[0100] Specifically, the first input / output terminal (122) can output the first potential applied to a plurality of first voltage wires (123b) to the input section (220) of the transepidermal electrical resistance calculation device (200).

[0101] There may be two first input / output terminals (122), and each of the first input / output terminals (122) may be provided with eight input / output pins, each of the eight input / output pins may be electrically connected to one end of each of the plurality of first current wires (123a), and each of the remaining eight input / output pins may be electrically connected to one end of each of the plurality of first voltage wires (123b).

[0102] A plurality of first current wires (123a) are disposed on the upper part of the first base substrate (121), one end of which is electrically connected to each of the plurality of input / output pins of the first input / output terminal (122), and the other end of which can be electrically connected to each of the plurality of current connection wires (124a).

[0103] A plurality of current connection wires (124a) can electrically connect a plurality of first current wires (123a) to each of a first electrode (114a) or electrode extension line (115a) provided on each of a plurality of cell culture chips (110).

[0104] A plurality of first voltage wires (123b) are disposed on the upper part of the first base substrate (121), one end of which is electrically connected to each of the plurality of input / output pins of the first input / output terminal (122), and the other end of which can be electrically connected to each of the plurality of voltage connection wires (124b).

[0105] A plurality of voltage connection wires (124b) can electrically connect a plurality of first voltage wires (123b) to each of a first terminal (114b) or terminal extension line (115b) provided on each of a plurality of cell culture chips (110).

[0106] Meanwhile, the plurality of input / output pins of each of the first input / output terminals (122), the plurality of first current wires (123a), the plurality of current connection wires (124a), the plurality of first voltage wires (123b), and the plurality of voltage connection wires (124b) may not be particularly limited in the type of material as long as they are made of a conductive material.

[0107] The first mask layer (125) may be formed to cover the upper portion of the first base substrate (121) such that only a plurality of current connection wires (124a), a plurality of voltage connection wires (124b), and a first input / output terminal (122) are exposed to the outside.

[0108] The first mask layer (125) may not be limited in the type of material as long as it is made of an insulating material.

[0109] FIG. 12 is a perspective view of a second substrate included in a transepidermal electrical resistance measuring device according to one embodiment of the present invention, and FIG. 13 is an exploded perspective view of a second substrate included in a transepidermal electrical resistance measuring device according to one embodiment of the present invention.

[0110] Referring further to FIGS. 12 and 13, the second substrate (130) may have a plurality of second electrodes (134a) for applying a resistance measurement current to each of the medium (M) and cells (C) accommodated in each of the receiving spaces (MR) of the plurality of cell culture chips (110), and a plurality of second electrodes (134a) for measuring a second potential from each of the medium (M) and cells (C) accommodated in the receiving spaces (MR) of the plurality of cell culture chips (110) and to which a voltage is applied due to the resistance measurement current.

[0111] To this end, the second substrate (130) may be provided with a second base substrate (131), a second input / output terminal (132), a plurality of second current wires (133a), a plurality of second electrodes (134a), a plurality of second voltage wires (133b), a plurality of second terminals (134b), and a mask layer (135).

[0112] The second base substrate (131) may be a base substrate of a conventional PCB.

[0113] The second input / output terminal (132) is positioned at the bottom of the second base substrate (131) and can receive a resistance measurement current from an external current source and output it to a plurality of second current wires (133a), or output a resistance measurement current that is input from a plurality of second current wires (133a).

[0114] Specifically, the second input / output terminal (132) receives a resistance measurement current output from the output section (210) of the electrical resistance calculation device (200) and can output it to a plurality of second current wires (133a).

[0115] Conversely, the second input / output terminal (132) can output the resistance measurement current flowing through the plurality of second current wires (133a) to the input section (220) of the electrical resistance calculation device (200).

[0116] Meanwhile, the second input / output terminal (132) can output a second potential input from a plurality of second voltage wires (133b).

[0117] Specifically, the second input / output terminal (132) can output the second potential applied to a plurality of second voltage wires (133b) to the input section (220) of the transverse epithelial electrical resistance calculation device (200).

[0118] There may be two such second input / output terminals (132), and each of the second input / output terminals (132) may be equipped with eight input / output pins, each of the eight input / output pins may be electrically connected to one end of each of the plurality of second current wires (133a), and each of the remaining eight input / output pins may be electrically connected to one end of each of the plurality of second voltage wires (133b).

[0119] A plurality of second current wires (133a) are disposed on the lower part of the second base substrate, one end of which is electrically connected to each of the plurality of input / output pins of the second input / output terminal (132), and the other end of which can be electrically connected to each of the plurality of second electrodes (134a).

[0120] A plurality of second electrodes (134a) are formed in a bar shape, one end of each of the plurality of second current wires (133a) is electrically connected to the other end of each, and can be inserted into the upper part of the receiving space (MR) from the other end.

[0121] A plurality of second voltage wires (133b) are disposed on the lower part of the second base substrate, and one end is electrically connected to each of the plurality of input / output pins of the second input / output terminal (132), and the other end can be electrically connected to each of the plurality of second terminals (134b).

[0122] A plurality of second terminals (134b) are formed in a bar shape with a length longer than that of a plurality of second electrodes (134a), one end of which is electrically connected to the other end of each of a plurality of second voltage wires (133b), and can be inserted into the upper part of the receiving space (MR) from the other end.

[0123] Meanwhile, the plurality of input / output pins, plurality of second current wires (133a), plurality of second electrodes (134a), plurality of second voltage wires (133b), and plurality of second terminals (134b) of each of the second input / output terminals (132) may not be particularly limited in the type of material as long as they are made of a conductive material.

[0124] Accordingly, when the resistance measurement current output from the output section (210) of the transepidermal electrical resistance calculation device (200) is input to the first input / output terminal (122), the resistance measurement current flows in the order of a plurality of first current wires (123a), a plurality of current connection wires (124a), an electrode extension line (115a), and a first electrode (114a), then flows through the medium (M) and cell (C) contained in the receiving space (MR), and then flows again in the order of a plurality of second electrodes (134a) and a plurality of second current wires (133a), and then is output through the second input / output terminal (132) and can be input to the input section (220) of the transepidermal electrical resistance calculation device (200).

[0125] Conversely, when a resistance measurement current output from the output section (210) of the transepithelial electrical resistance calculation device (200) is input to the second input / output terminal (132), the resistance measurement current flows through a plurality of second current wires (133a) and a second electrode (134a) in sequence, then flows through a medium (M) and a cell (C) contained in a receiving space (MR), and then flows through a plurality of first electrodes (114a), an electrode extension line (115a), a plurality of current connection wires (124a), and a plurality of first current wires (123a) in sequence, and then is output through the first input / output terminal (122) and can be input to the input section (220) of the transepithelial electrical resistance calculation device (200).

[0126] Meanwhile, due to the resistance measurement current, a resistance measurement voltage, which is the potential difference between the first potential and the second potential, can be applied to the medium (M) and cell (C) contained in the receiving space (MR).

[0127] Meanwhile, the first potential applied to the first terminal (114b) from the medium (M) located at the bottom of the membrane (112) in the receiving space (MR) is applied in the order of the terminal extension line (115b), the plurality of voltage connection wires (124b), and the plurality of first voltage wires (123b), and finally the first potential is output through the first input / output terminal (122) and can be input to the input section (220) of the transepidermal electrical resistance calculation device (200).

[0128] Additionally, the second potential applied to the second terminal (134b) from the medium (M) and cell (C) located above the membrane (112) in the receiving space (MR) is applied to a plurality of second voltage wires (133b), and then the second potential is finally output through the second input / output terminal (132) and can be input to the input section (220) of the transepithelial electrical resistance calculation device (200).

[0129] The second mask layer (135) may be formed to cover the lower part of the second base substrate (131) such that only a plurality of second electrodes (134a), a second terminal (134b), and a second input / output terminal (132) are exposed to the outside.

[0130] The second mask layer (135) may not be limited in the type of material provided that it is made of an insulating material.

[0131] A receiving space (MR below) will be described in detail regarding a transepidermal electrical resistance measuring device (100) according to another embodiment of the present invention.

[0132] FIG. 14 is a block diagram of a transepidermal electrical resistance measuring device according to another embodiment of the present invention, FIG. 15 is a perspective view of a transepidermal electrical resistance measuring device according to another embodiment of the present invention with the housing open, and FIG. 16 is an exploded perspective view of a transepidermal electrical resistance measuring device according to another embodiment of the present invention.

[0133] Referring further to FIGS. 14 to 16, a transepidermal electrical resistance measuring device (100) according to another embodiment of the present invention may include a plurality of cell culture chips (110), a second substrate (130), and a housing part (140).

[0134] A plurality of cell culture chips (110) can be accommodated in a first housing (141) included in a housing part (140).

[0135] A second substrate (130) may be disposed on the upper portion of the plurality of cell culture chips (110).

[0136] At this time, the first electrode (134a) and the first terminal (134b) of the second substrate (130) are disposed in the receiving space (MR) of each of the plurality of cell culture chips (110), and the second electrode (134a') and the second terminal (134b') can be disposed in the medium input space (ER) of each of the plurality of cell culture chips (110).

[0137] Meanwhile, the second substrate (130) can be accommodated in the second housing (142) included in the housing part (140).

[0138] The first housing (141) and the second housing (142) can be joined by a hinge on one side to form an opening and closing structure.

[0139] When the second housing (142) is covered and closed on the first housing (141), as described above, the second substrate (130) is placed on top of the plurality of cell culture chips (110), and each of the plurality of first electrodes (134a) and the plurality of first terminals (134b) of the second substrate (130) is inserted into the receiving space (MR) of each of the plurality of cell culture chips (110), and each of the plurality of second electrodes (134a') and the plurality of second terminals (134b') of the second substrate (130) can be inserted into the medium input space (ER) of each of the plurality of cell culture chips (110).

[0140] At this time, a first electrode (134a) and a first terminal (134b) may be inserted into each of the receiving spaces (MR) of each of the plurality of cell culture chips (110), and a second electrode (134a') and a second terminal (134b') may be inserted into each of the medium input spaces (ER) of each of the plurality of cell culture chips (110).

[0141] Hereinafter, a cell culture chip (110) according to another embodiment of the present invention will be described in detail.

[0142] FIG. 17 is a perspective view of a cell culture chip according to another embodiment of the present invention, FIG. 18 is an exploded perspective view of a cell culture chip according to one embodiment of the present invention, and FIG. 19 is a cross-sectional view along A4-A4' of FIG. 17.

[0143] Referring further to FIGS. 17 to 19, a transepithelial electrical resistance measuring device (100) according to another embodiment of the present invention may include a plurality of cell culture chips (110) according to another embodiment of the present invention. For example, a transepithelial electrical resistance measuring device (100) according to another embodiment of the present invention may include eight cell culture chips (110) according to another embodiment of the present invention.

[0144] A cell culture chip (110) according to another embodiment of the present invention, unlike a cell culture chip (110) according to one embodiment of the present invention, may not have a first electrode (114a), a first terminal (114b), an electrode extension line (115a), and a terminal extension line (115b), and may only have a biomimetic tissue chip (111), a membrane (112), and a wafer (116).

[0145] Accordingly, repetitive explanations will be omitted.

[0146] FIG. 20 is a perspective view of a second substrate included in a transepidermal electrical resistance measuring device according to another embodiment of the present invention, and FIG. 21 is an exploded perspective view of a second substrate included in a transepidermal electrical resistance measuring device according to another embodiment of the present invention.

[0147] Referring further to FIGS. 20 and 21, the second substrate (130) may have a plurality of first electrodes (134a) for applying a resistance measurement current to each of the medium (M) and cells (C) contained in the receiving space (ER) of each of the plurality of cell culture chips (110), a plurality of second electrodes (134a') for applying the resistance measurement current to each of the medium (M) introduced into the medium introduction space (MR) of each of the plurality of cell culture chips (110), a plurality of first terminals (134b) for measuring a first potential from the medium (M) and cells (C) contained in the receiving space (ER) of each of the plurality of cell culture chips (110) and to which a voltage is applied due to the resistance measurement current, and a plurality of second terminals (134b') for measuring a second potential from the medium (M) introduced into the medium introduction space (MR) of each of the plurality of cell culture chips (110) and to which a voltage is applied due to the resistance measurement current.

[0148] To this end, the second substrate (130) may comprise a second base substrate (131), a second input / output terminal (132), a plurality of first current wires (133a), a plurality of first electrodes (134a), a plurality of second current wires (133a'), a plurality of second electrodes (134a'), a plurality of first voltage wires (133b), a plurality of first terminals (134b), a plurality of second voltage wires (133b'), a plurality of second terminals (134b'), a first terminal PCB (PCB), a second terminal PCB (PCB'), and a mask layer (135).

[0149] The second base substrate (131) may be a base substrate of a conventional PCB.

[0150] The second input / output terminal (132) is positioned at the bottom of the second base substrate (131) and receives a resistance measurement current from an external current source and outputs it to a plurality of first current wires (133a), and then receives a resistance measurement current flowing to a plurality of second current wires (133a') and outputs it to the input section (220) of the electrical resistance calculation device (200).

[0151] Conversely, the second input / output terminal (132) can receive a resistance measurement current from an external current source and output it to a plurality of second current wires (133a'), and then receive a resistance measurement current flowing to a plurality of first current wires (133a) and output it to the input section (220) of the electrical resistance calculation device (200).

[0152] At this time, the second input / output terminal (132) can receive a resistance measurement current output from the output section (210) of the electrical resistance calculation device (200).

[0153] Meanwhile, the second input / output terminal (132) can output a first potential input from a plurality of first voltage wires (133b).

[0154] Specifically, the second input / output terminal (132) can output the first potential applied to a plurality of first voltage wires (133b) to the input section (220) of the transverse epithelial electrical resistance calculation device (200).

[0155] Meanwhile, the second input / output terminal (132) can output a second potential input from a plurality of second voltage wires (133b).

[0156] Specifically, the second input / output terminal (132) can output the second potential applied to a plurality of second voltage wires (133b) to the input section (220) of the transverse epithelial electrical resistance calculation device (200).

[0157] The second input / output terminal (132) may be provided with 32 input / output pins, each of which is electrically connected to one end of each of the plurality of first current wires (133a), each of which is electrically connected to one end of each of the plurality of first voltage wires (133b), each of which is electrically connected to one end of each of the plurality of second current wires (133a'), each of which is electrically connected to one end of each of the plurality of second voltage wires (133b'), each of which is electrically connected to one end of each of the plurality of second voltage wires (133b').

[0158] A plurality of first current wires (133a) are disposed on the lower part of the second base substrate (131), one end of which is electrically connected to each of the plurality of input / output pins of the second input / output terminal (132), and the other end of which can be electrically connected to each of the plurality of first electrodes (134a).

[0159] A plurality of first electrodes (134a) are formed in a bar shape and mounted on one side of a first terminal PCB (PCB), one end of which is electrically connected to the other end of each of a plurality of first current wires (133a), and can be inserted into the upper part of a receiving space (ER) from the other end.

[0160] A plurality of first voltage wires (133b) are disposed on the lower part of the second base substrate (131), one end of which is electrically connected to each of the plurality of input / output pins of the second input / output terminal (132), and the other end of which can be electrically connected to each of the plurality of first terminals (134b).

[0161] A plurality of first terminals (134b) are mounted on the other side of the first terminal PCB (PCB) and are formed in a bar shape with the same length as a plurality of first electrodes (134a), one end of which is electrically connected to the other end of each of the plurality of first voltage wires (133b), and can be inserted into the upper part of the receiving space (ER) from the other end.

[0162] A plurality of second current wires (133a') are disposed on the lower part of the second base substrate (131), one end of which is electrically connected to each of the plurality of input / output pins of the second input / output terminal (132), and the other end of which can be electrically connected to each of the plurality of second electrodes (134a').

[0163] A plurality of second electrodes (134a') are mounted on one side of a second terminal PCB (PCB') and are formed in a bar shape with a longer length than a plurality of first electrodes (134a), one end of which is electrically connected to the other end of each of a plurality of second current wires (133a'), and can be inserted into the upper part of a culture medium insertion space (MR) from the other end.

[0164] A plurality of second voltage wires (133b') are disposed on the lower part of the second base substrate (131), one end of which is electrically connected to each of the plurality of input / output pins of the second input / output terminal (132), and the other end of which can be electrically connected to each of the plurality of second terminals (134b').

[0165] A plurality of second terminals (134b') are mounted on the other side of the second terminal PCB (PCB') and are formed in a bar shape with the same length as the plurality of second electrodes (134a), one end of which is electrically connected to the other end of each of the plurality of second voltage wires (133b'), and can be inserted into the upper part of the culture medium insertion space (MR) from the other end.

[0166] Meanwhile, the plurality of input / output pins, plurality of second current wires (133a), plurality of second electrodes (134a), plurality of second voltage wires (133b), and plurality of second terminals (134b) of each of the second input / output terminals (132) may not be particularly limited in the type of material as long as they are made of a conductive material.

[0167] Accordingly, when the resistance measurement current output from the output section (210) of the transepithelial electrical resistance calculation device (200) is input to the second input / output terminal (132) and then input to the plurality of first current wires (133a), it flows through the plurality of first electrodes (134a), then through the medium (M) and cells (C) contained in the receiving space (ER), and then flows to the medium (M) contained in the medium input space (MR), and then flows again in the order of the plurality of second electrodes (134a') and the plurality of second current wires (133a'), and then is output through the second input / output terminal (132) and input to the input section (220) of the transepithelial electrical resistance calculation device (200).

[0168] Conversely, when the resistance measurement current output from the output section (210) of the transepithelial electrical resistance calculation device (200) is input to the second input / output terminal (132) and then input to the plurality of second current wires (133a'), it flows through the plurality of second electrodes (134a'), then through the medium (M) contained in the medium input space (MR), and then through the medium (M) and cell (C) contained in the receiving space (ER), and then flows again in the order of the plurality of first electrodes (134a) and the plurality of first current wires (133a), and then is output through the second input / output terminal (132) and input to the input section (220) of the transepithelial electrical resistance calculation device (200).

[0169] Meanwhile, due to the resistance measurement current, a resistance measurement voltage, which is the potential difference between the first potential and the second potential, can be applied to the medium (M) and cell (C) contained in the receiving space (ER) and the medium (M) contained in the medium input space (MR).

[0170] Meanwhile, the first potential applied to the first terminal (134b) from the medium (M) and cell (C) located above the membrane (112) in the receiving space (ER) is applied in sequence through a plurality of first voltage wires (133b), and finally, the first potential is output through the second input / output terminal (132) and can be input to the input section (220) of the transepithelial electrical resistance calculation device (200).

[0171] Additionally, the second potential applied to the second terminal (134b') from the medium (M) located in the medium input space (MR) is applied to a plurality of second voltage wires (133b'), and then the second potential is finally output through the second input / output terminal (132) and can be input to the input section (220) of the transepidermal electrical resistance calculation device (200).

[0172] The second mask layer (135) is located in the lower part of the second base substrate (131).

[0173] The lower part of the second base substrate (131) can be formed to cover the plurality of first electrodes (134a), plurality of second electrodes (134a'), plurality of first terminals (134b), plurality of second terminals (134b'), first terminal PCB (PCB), second terminal PCB (PCB'), and second input / output terminal (132) so that only these are exposed to the outside.

[0174] The second mask layer (135) may not be limited in the type of material provided that it is made of an insulating material.

[0176] Below, the electrical resistance calculation device (200) will be described.

[0177] FIG. 22 is a block diagram of a device for calculating transepidermal electrical resistance according to one embodiment of the present invention.

[0178] Referring further to FIG. 22, the transepidermal electrical resistance calculation device (200) may include an output unit (210), an input unit (220), a processor (230), and a memory (240).

[0179] The output unit (210) can output a resistance measurement current to the transepidermal electrical resistance measuring device (100).

[0180] More specifically, the output unit (210) can output a resistance measurement current to either the first input / output terminal (122) or the second input / output terminal (132) of the electrical resistance calculation device (100) according to one embodiment.

[0181] Additionally, the output unit (210) can output a resistance measurement current to the second input / output terminal (132) of the electrical resistance calculation device (100) according to another embodiment.

[0182] To this end, the output unit (210) may be equipped with a current output module that is a current source, and the electrical resistance calculation device (200) may be connected to the first input / output terminal (122) and the second input / output terminal (132) by electrical wiring.

[0183] Meanwhile, the input unit (220) can receive the first potential and the second potential from the transepidermal electrical resistance measuring device (100).

[0184] More specifically, the input unit (220) may receive a first potential from the first input / output terminal (122) of the transepidermal electrical resistance calculation device (100) according to one embodiment, and receive a second potential from the second input / output terminal (132) of the transepidermal electrical resistance calculation device (100) according to one embodiment.

[0185] Additionally, the input unit (220) can receive a first potential and a second potential from the second input / output terminal (132) of the electrical resistance calculation device (100) according to another embodiment.

[0186] At this time, the input unit (220) can individually receive a resistance measurement current for each of the plurality of cell culture chips (110).

[0187] The processor (230) can calculate the electrical resistance of the transepidermal layer based on the resistance measurement current, the first potential, and the second potential.

[0188] More specifically, the processor (230) can calculate a resistance measurement voltage, which is the potential difference between the first potential and the second potential, calculate the total resistance of the material (medium, cell, membrane) through which the resistance measurement current has passed using the resistance measurement voltage and the resistance measurement current, and calculate the transepithelial electrical resistance by subtracting the resistance of the medium, the resistance of the membrane, and the ohmic resistance of the electrode medium interface from the total resistance.

[0189] Meanwhile, the processor (230) can calculate the degree of cell culture, which indicates the degree of cell culture based on the rate of change in resistance of the epithelial electrical resistance.

[0190] Specifically, the processor (230) can calculate a cell culture degree indicating that the degree of cell culture is greater as the rate of change of resistance of the epithelial electrical resistance decreases.

[0191] The processor (230) can control the overall operation of the transverse electrical resistance calculation device (200) by controlling the components of the robot inspection device (100) using various programs stored in the memory (240). The processor (230) may be composed of RAM, ROM, a graphics processing unit, a main CPU, first to n interfaces, and a bus. At this time, the RAM, ROM, graphics processing unit, main CPU, first to n interfaces, etc., may be connected to each other through a bus.

[0192] RAM stores the O / S and application programs. Specifically, when the transepidermal electrical resistance calculation device (200) boots up, the O / S is stored in RAM, and various application data selected by the user can be stored in RAM.

[0193] A set of instructions for booting the system is stored in the ROM. When a turn-on command is input and power is supplied, the main CPU copies the O / S stored in the memory (240) to the RAM according to the instructions stored in the ROM, and executes the O / S to boot the system. When booting is complete, the main CPU copies various application programs stored in the memory (240) to the RAM, and executes the application programs copied to the RAM to perform various operations.

[0194] The main CPU accesses memory (240) and performs booting using the OS stored in memory (240). Then, the main CPU performs various operations using various programs, content, data, etc. stored in memory (240).

[0195] The first to n interfaces are connected to the various components described above. One of the first to n interfaces may be a network interface connected to an external device through a network.

[0196] Meanwhile, the processor (230) may include one or more cores (not shown) and a graphics processing unit (not shown) and / or other components, and a connection channel (e.g., a bus, etc.) for transmitting and receiving signals.

[0197] The memory (240) can store various programs and data required for the operation of the electrical resistance calculation device (200). The memory (240) can be implemented as non-volatile memory, volatile memory, flash memory, hard disk drive (HDD), or solid-state drive (SSD).

[0198] The memory (240) can store programs (one or more instructions) for processing and controlling the processor (230). The programs stored in the memory (240) can be divided into multiple modules according to their function.

[0199] The present invention has been described above with reference to preferred embodiments. Those skilled in the art will understand that the present invention can be implemented in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

[0200] As described above, although the present invention has been explained by limited embodiments and drawings, the present invention is not limited thereto, and it is obvious that various modifications and variations are possible within the scope of the technical spirit of the present invention and the equivalent scope of the claims described below by those skilled in the art to which the present invention belongs. Explanation of the symbols

[0202] 10: Multi-electrical resistance measurement system for biological tissues 100: Transepithelial electrical resistance measurement device 110: Cell culture chip 200: Transepithelial electrical resistance calculation device

Claims

Claim 1 A plurality of cell culture chips comprising: a medium input space into which a medium is introduced; a receiving space into which a cell surrounded by the medium is received; a first electrode for applying a resistance measuring current to the medium received in the receiving space; a first terminal for measuring a first potential from the medium to which a voltage is applied due to the resistance measuring current; and a membrane through which the medium passes, which supports the cell within the receiving space so that the cell is spaced apart from the first electrode and the first terminal; and a first substrate having the plurality of cell culture chips disposed on top of each of the plurality of cell culture chips and electrically connected to the first electrode and the first terminal provided on each of the plurality of cell culture chips. and a second substrate having a plurality of second electrodes for applying a resistance measuring current to each of the medium and each of the cells contained in the receiving space of each of the plurality of cell culture chips, and a plurality of second terminals for measuring a second potential from each of the medium and the cells to which a voltage is applied due to the resistance measuring current, wherein a resistance measuring voltage, which is a potential difference between the first potential and the second potential, is applied to the medium and the cells due to the resistance measuring current applied through the first electrode and the second electrode, and the plurality of cell culture chips are a wafer; and a biomimetic tissue chip having a medium input hole formed through in the vertical direction and forming part of a medium input space into which the medium is introduced, and a cell input hole formed through in the vertical direction into which the cell is introduced or into which the cell and the medium are introduced and which forms part of the receiving space, and disposed on the upper part of the wafer and in which the medium is moved between the medium input hole and the cell input hole.A transepithelial electrical resistance measuring device comprising: a biomimetic tissue chip having a bottom surface between the culture medium input hole and the cell input hole that is more recessed than other bottom surfaces, such that when the biomimetic tissue chip is placed in contact with the upper surface of the wafer, the culture medium is moved between the culture medium input hole and the cell input hole through a space formed by the bottom surface between the culture medium input hole and the cell input hole being spaced apart from the upper surface of the wafer. Claim 2 The transepithelial electrical resistance measuring device according to claim 1, wherein the plurality of cell culture chips further comprises: a membrane disposed inside the cell input hole that allows the culture medium to pass in the up-and-down direction within the receiving space and supports the cells without allowing them to pass in the down direction within the receiving space; the first electrode disposed below the culture medium input hole; an electrode extension line formed integrally with the first electrode and electrically connected to the first electrode; the first terminal disposed below the culture medium input hole; and a terminal extension line formed integrally with the first terminal and electrically connected to the first terminal; and wherein the wafer is characterized in that the first electrode, the electrode extension line, the first terminal, and the terminal extension line are formed on the upper surface. Claim 3 In paragraph 2, the first substrate comprises: a first base substrate; a first input / output terminal disposed on the upper portion of the first base substrate, to which the resistance measurement current is input / output and the first potential is output; a plurality of first current wires disposed on the upper portion of the first base substrate, one end of which is electrically connected to the first input / output terminal; a plurality of current connection wires that electrically connect the plurality of first current wires to each of the first electrode or the electrode extension line provided on each of the plurality of cell culture chips; a plurality of first voltage wires disposed on the upper portion of the first base substrate, one end of which is electrically connected to the first input / output terminal; and a plurality of voltage connection wires that electrically connect the plurality of first voltage wires to each of the first terminal or the terminal extension line provided on each of the plurality of cell culture chips. and a first mask layer covering the upper portion of the first base substrate such that only the plurality of current connection wires, the plurality of voltage connection wires, and the first input / output terminal are exposed to the outside among the upper portions of the first base substrate; wherein the second substrate comprises: a second base substrate; a second input / output terminal disposed at the lower portion of the second base substrate, to which the resistance measurement current is input / output and the second potential is output; a plurality of second current wires disposed at the lower portion of the second base substrate, one end of which is electrically connected to the second input / output terminal; a plurality of second electrodes formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of second current wires, and inserted into the upper portion of the receiving space from the other end; a plurality of second voltage wires disposed at the lower portion of the second base substrate, one end of which is electrically connected to the second input / output terminal; a plurality of second terminals formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of second voltage wires, and inserted into the upper portion of the receiving space from the other end;A transepithelial electrical resistance measuring device characterized by comprising: a second mask layer covering the lower portion of the second base substrate such that only a plurality of second electrodes, a plurality of second terminals, and a second input / output terminal are exposed to the outside among the lower portions of the second base substrate. Claim 4 delete Claim 5 A plurality of cell culture chips having a medium input space into which a medium is introduced, a receiving space communicating with the medium input space and receiving the medium and a cell surrounded by the medium, and a membrane that supports the cell within the receiving space and through which the medium passes; and a plurality of first electrodes for applying a resistance measurement current to each of the medium and each of the cells contained in the receiving space of each of the plurality of cell culture chips, a plurality of second electrodes for applying the resistance measurement current to each of the medium introduced in the medium introduction space of each of the plurality of cell culture chips, a plurality of first terminals for measuring a first potential from the medium and cells contained in the receiving space of each of the plurality of cell culture chips to which a voltage is applied due to the resistance measurement current, and a plurality of second terminals for measuring a second potential from the medium introduced in the medium introduction space of each of the plurality of cell culture chips to which a voltage is applied due to the resistance measurement current; wherein a resistance measurement voltage, which is a potential difference between the first potential and the second potential, is applied to the medium and the cells due to the resistance measurement current applied through the first electrode and the second electrode, and the plurality of cell culture chips are wafers; A biomimetic tissue chip having a culture medium input hole formed penetrating in the vertical direction and forming part of a culture medium input space into which the culture medium is introduced, and a cell input hole formed penetrating in the vertical direction into which the cell is introduced or into which the cell and the culture medium are introduced and which forms part of the receiving space, wherein the culture medium is moved between the culture medium input hole and the cell input hole, and disposed on the upper part of the wafer;A transepithelial electrical resistance measuring device comprising: a biomimetic tissue chip having a bottom surface between the culture medium input hole and the cell input hole that is more recessed than other bottom surfaces, such that when the biomimetic tissue chip is placed in contact with the upper surface of the wafer, the culture medium is moved between the culture medium input hole and the cell input hole through a space formed by the bottom surface between the culture medium input hole and the cell input hole being spaced apart from the upper surface of the wafer. Claim 6 A transepithelial electrical resistance measuring device according to claim 5, further comprising: a membrane in which the plurality of cell culture chips are disposed inside the cell input hole, allowing the culture medium to pass in the up-and-down direction within the receiving space, while supporting the cells without allowing them to pass in the down direction within the receiving space. Claim 7 In claim 5, the second substrate comprises: a second base substrate; a second input / output terminal disposed below the second base substrate, to which the resistance measurement current is input / output and to which the first potential and the second potential are output; a plurality of first current wires disposed below the second base substrate, one end of which is electrically connected to the second input / output terminal; and a plurality of first electrodes formed in a bar shape, one end of which is electrically connected to the other end of each of the plurality of first current wires, and inserted from the other end into the upper part of the receiving space. A plurality of first voltage wires disposed on the lower part of the second base substrate, with one end electrically connected to the second input / output terminal; a plurality of first terminals formed in a bar shape, with one end electrically connected to the other end of each of the plurality of first voltage wires, and inserted into the upper part of the receiving space from the other end; a plurality of second current wires disposed on the lower part of the second base substrate, with one end electrically connected to the second input / output terminal; a plurality of second electrodes formed in a bar shape, with one end electrically connected to the other end of each of the plurality of second current wires, and inserted into the upper part of the culture medium input space from the other end; a plurality of second voltage wires disposed on the lower part of the second base substrate, with one end electrically connected to the second input / output terminal; a plurality of second terminals formed in a bar shape, with one end electrically connected to the other end of each of the plurality of second voltage wires, and inserted into the upper part of the culture medium input space from the other end; A transepidermal electrical resistance measuring device characterized by having a second mask layer covering the lower portion of the second base substrate such that only the plurality of first electrodes, the plurality of first terminals, the plurality of second electrodes, the plurality of second terminals, and the second input / output terminal are exposed to the outside among the lower portions of the second base substrate. Claim 8 delete Claim 9 A system for measuring multiple electrical resistances of biological tissues, comprising: a transepithelial electrical resistance measuring device according to any one of claims 1 to 3 and claims 5 to 7; and a transepithelial electrical resistance calculating device; wherein the transepithelial electrical resistance calculating device comprises: an output unit that outputs a resistance measuring current to the transepithelial electrical resistance measuring device; an input unit that receives a first potential and a second potential output from the transepithelial electrical resistance measuring device; and a processor that calculates the transepithelial electrical resistance based on the resistance measuring current, the first potential, and the second potential; wherein the processor calculates a cell culture degree indicating the degree of cell culture based on the resistance change rate of the transepithelial electrical resistance.

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