Well plate device implementing high-speed drug screening based on three-dimensional biological model

Abstract

Embodiments of the present invention relate to a device for implementing high-speed drug screening based on a three-dimensional biological model, and the device according to one aspect is an analysis device for a three-dimensional biological model, the device comprising: a well plate; a probe provided in the well plate; and a plunger located to be spaced apart from the well plate, wherein: the well plate includes a well configured to accommodate the three-dimensional biological model, the well being a region in which at least a portion of the upper surface of the well plate is recessed along a first direction; at least a portion of the probe is located in the well; and the plunger is movable in the well along the first direction.

Description

Well plate device enabling high-speed drug screening based on a 3D biological model

[0001] Embodiments of the present invention relate to a device for implementing high-speed drug screening based on a three-dimensional biological model.

[0002] Organoids are representative biological models of microphysiological systems (MPS) that mimic the intercellular interactions and biological microenvironments of tissues or organs in vitro. They are being widely studied as tools for efficient and accurate drug development, as well as for diagnostic research and regulatory reform. However, while decades of advancement in biomimicry have been achieved across various organs, standardization and the assurance of reproducibility remain insufficient.

[0003] Meanwhile, conventional 2D multiple electrode arrays (MEAs) are designed to analyze biological models, such as single-layer (2D) cultured neural networks, and have limitations in analyzing multi-layer (3D) cultured models due to structural limitations that result in an extremely limited contact area. Consequently, despite exhibiting high numerical specifications, there is a problem with low utility for analyzing 3D biological models. For instance, there are limitations in observing signals occurring deep within the body, and it is impossible to evaluate electrical characteristics, such as potential difference and impedance measurements inside and outside the biological model. These problems are not significantly improved even when electrodes are arranged on a curved surface to match the shape of the 3D biological model.

[0004] Three-dimensional biological models are high-cost research materials that require delicate management during long culture periods of approximately several months. Since they are small in size—ranging from several centimeters to typically less than 1 mm—and are prone to damage, performing sensitive analyses of the biological model's microenvironment requires more precise sample manipulation and appropriate control methods compared to general experimental environments. However, existing analytical devices or methods rely excessively on manual user operation, making it difficult to ensure the precision of the inspection process and resulting in low throughput due to reduced inspection efficiency.

[0005] According to one aspect of the present invention, an analysis device for a three-dimensional biological model, such as an organoid, can be provided to perform analysis of the three-dimensional biological model simply and accurately.

[0006] According to another aspect of the present invention, an analysis device for a three-dimensional biological model capable of multiple simultaneous analyses of a plurality of three-dimensional biological models can be provided.

[0007] An apparatus according to one embodiment of the present invention is an analysis apparatus for a three-dimensional biological model, comprising: a well plate; a probe provided in the well plate; and a plunger positioned spaced apart from the well plate; wherein the well plate comprises a well that accommodates the three-dimensional biological model, wherein at least a portion of the upper surface of the well plate is recessed along a first direction, and at least a portion of the probe is located within the well, and the plunger may be movable along the first direction within the well.

[0008] In an apparatus according to one embodiment, the three-dimensional biological model may include at least one selected from the group consisting of a heart organoid, a blood vessel organoid, a retinal organoid, a brain organoid, a spinal cord organoid, a tumor organoid, a neural organoid, an organoid containing cells subjected to optogenetic manipulation, a lung organoid, a stomach organoid, a small intestine organoid, a liver organoid, a pancreas organoid, a kidney organoid, a bladder organoid, a testis organoid, an ovary organoid, a bone marrow organoid, a thymus organoid, a skin organoid, a hair follicle organoid, an inner ear organoid, and an olfactory epithelial organoid.

[0009] In an apparatus according to one embodiment, the well comprises a first well extending to a first depth and a second well extending from the first depth to a second depth, wherein the second depth is a depth further spaced from the upper surface of the well plate than the first depth, and at least a portion of the probe may be located within the second well.

[0010] In an apparatus according to one embodiment, the first well includes a first opening and a first inner wall, and the second well includes a second opening and a second inner wall, and the first well and the second well may be connected through the second opening.

[0011] In a device according to one embodiment, the area of ​​the first opening may be larger than the area of ​​the second opening.

[0012] In a device according to one embodiment, the area of ​​the second opening is 2,000 μm 2 up to 50mm 2 It could be.

[0013] In a device according to one embodiment, the probe may be extended along the first direction.

[0014] In a device according to one embodiment, the probe may include a plurality of electrodes arranged along the first direction.

[0015] In a device according to one embodiment, the probe may be spaced apart from the second opening.

[0016] In a device according to one embodiment, the distance between the probe and the second opening may be within 5 mm.

[0017] In a device according to one embodiment, the plunger may include a rod and a pad located at one end of the rod.

[0018] In a device according to one embodiment, the area of ​​the pad may be larger than the area of ​​the second opening.

[0019] In a device according to one embodiment, the device further comprises a cover for opening and closing the well plate; and the plunger can be coupled with the cover at the other end of the rod.

[0020] In a device according to one embodiment, the plunger can guide the three-dimensional biological model to enter the second well.

[0021] In an apparatus according to one embodiment, the wells are provided in a plurality of numbers, and each of the plunger and the probe may be provided in a plurality of numbers corresponding to each of the plurality of wells.

[0022] According to one aspect of the present invention, an analysis device for a three-dimensional biological model, such as an organoid, can be provided to perform analysis of the three-dimensional biological model simply and accurately.

[0023] According to another aspect of the present invention, an analysis device for a three-dimensional biological model capable of multiple simultaneous analyses of a plurality of three-dimensional biological models can be provided.

[0024] FIG. 1 is a drawing showing an example of a device according to one embodiment of the present invention.

[0025] Figure 2 is a diagram showing an example of a state in which a three-dimensional biological model is accommodated in the device illustrated in Figure 1.

[0026] FIG. 3 is a drawing showing an example of a probe according to one embodiment of the present invention.

[0027] Figure 4 is a diagram showing an example of performing an analysis on a three-dimensional biological model by manipulating a plunger.

[0028] Since the embodiments described in this specification may be modified in various different forms, the technology according to one embodiment is not limited to the embodiments described below. Furthermore, throughout the specification, the terms "comprising," "having," "containing," or "having" any component do not exclude other components but may include additional components unless specifically stated otherwise, and do not exclude elements, materials, or processes not additionally listed.

[0029] In this specification, "identical or uniform" may mean that they are identical or uniform to one another within an acceptable margin of error, unless otherwise specified. For example, the statement that certain components or physical property measurements are identical may include not only that the two objects being compared are completely identical, but also that they are identical within a margin of error. Meanwhile, the statement that certain physical property measurements are identical may mean that the difference between the measurements between the objects is approximately less than 5%, specifically less than 3%, and more specifically less than 1%.

[0030] In this specification, the angle formed by two objects being perpendicular, or parallel or parallel to each other, may include not only geometrically perpendicular or parallel but also within a slight margin of error.

[0031] The numerical ranges used in this specification include lower and upper limits and all values ​​within the range, increments logically derived from the form and width of the defined range, all of which are limited values, and all possible combinations of upper and lower limits of numerical ranges limited in different forms.

[0032] Unless otherwise specifically defined in this specification, “about” may be considered to be a value within 30%, 25%, 20%, 15%, 10%, or 5% of the specified value.

[0033] In this specification, the use of terms such as "first," "second," or "third" preceding any component is intended solely to avoid confusion regarding the components being referred to, and is unrelated to the order, importance, or hierarchical relationship between the components. For example, an invention comprising only the second component without the first component is also possible.

[0034] In this specification, the term "electrically connected" may mean any method of connection in which a plurality of objects can be connected so as to be electrically connected to one another without limitation, and the plurality of objects to be interconnected may be directly connected or connected through a third object, etc., and may be implemented in various ways.

[0035] In this specification, a configuration defined as “…part” or “…unit” may, without limitation, mean a single component or a set of two or more identical or similar components that have commonalities in terms of function, and said set of components may be composed of a combination of hardware and / or software without limitation.

[0036] The present invention will be described in detail below. However, the following description is merely illustrative and does not imply that the present invention is limited to the exemplary embodiments described below.

[0037] FIG. 1 is a drawing showing an example of a device according to one embodiment of the present invention.

[0038] Figure 2 is a diagram showing an example of a state in which a three-dimensional biological model is accommodated in the device illustrated in Figure 1.

[0039] Referring to FIGS. 1 and 2, an apparatus (10) according to one aspect of the present invention is an analysis apparatus (10) for a three-dimensional biological model (50), comprising: a well plate (100); a probe (400) provided in the well plate (100); and a plunger (200) positioned spaced apart from the well plate (100), wherein the well plate (100) includes a well (110) that accommodates the three-dimensional biological model (50), wherein at least a portion of the upper surface (100A) of the well plate (100) is recessed along a first direction (DR1), and at least a portion of the probe (400) is located within the well (110), and the plunger (200) may be movable along the first direction (DR1) within the well (110).

[0040] In one embodiment, the device (10) may be a device (10) for analyzing a three-dimensional biological model (50). In an exemplary embodiment, the device (10) may be a device (10) for electrically or electrochemically analyzing the three-dimensional biological model (50). Meanwhile, the device (10) may be a device (10) capable of performing electrical or electrochemical analysis of the three-dimensional biological model (50) simply and accurately.

[0041] In one embodiment, the three-dimensional biological model (50) may be a plurality of units. As will be described later, the device (10) according to one aspect of the present disclosure may be a device (10) capable of simultaneously performing electrical or electrochemical analysis on a plurality of three-dimensional biological models (50) with a simple operation.

[0042] FIG. 2 shows an example of the three-dimensional biological model (50) being accommodated in the device (10). In an exemplary embodiment, the three-dimensional biological model (50) may float in the well (110) while immersed in the culture medium (20), or a portion of it may come into contact with the inner wall of the well (e.g., the first inner wall (1112) described later).

[0043] In an exemplary embodiment, the three-dimensional biological model (50) may be a tissue removed from a living organism or a cultured cell culture. For example, the cell culture may be a spheroid or an organoid.

[0044] In one embodiment, the three-dimensional biomodel (50) may include a biomodel capable of generating an electrical signal or a biomodel capable of generating a signal linked thereto in response to light stimulation.

[0045] In one embodiment, the three-dimensional biomodel (50) may include an organoid model that mimics human organs and tumors.

[0046] In one embodiment, the three-dimensional biological model (50) may include at least one selected from the group consisting of a heart organoid, a blood vessel organoid, a retinal organoid, a brain organoid, a spinal cord organoid, a tumor organoid, a neural organoid, an organoid containing cells subjected to optogenetic manipulation, a lung organoid, a stomach organoid, a small intestine organoid, a liver organoid, a pancreas organoid, a kidney organoid, a bladder organoid, a testicular organoid, an ovarian organoid, a bone marrow organoid, a thymus organoid, a skin organoid, a hair follicle organoid, an inner ear organoid, and an olfactory epithelial organoid.

[0047] In one embodiment, the three-dimensional biological model (50) may be a cardiac organoid (CO) or a retinal organoid (RO).

[0048] In one embodiment, the diameter of the three-dimensional biological model (50) may be 50 μm to 5 mm. In an exemplary embodiment, the diameter of the three-dimensional biological model (50) may be a diameter measured by a known image analysis method.

[0049] In one embodiment, the culture medium (20) may be an electrolyte solution based on a basic ionic buffer solution similar to PBS (phosphate-buffered saline), with various nutrients, growth factors, and signaling substances added to it so that the cells constituting the organoid form a three-dimensional structure and function similar to an internal organ.

[0050] Referring again to FIGS. 1 and FIGS. 2, a device (10) according to one aspect of the present invention may include a well plate (100).

[0051] In one embodiment, the well plate (100) may include a well (110).

[0052] In one embodiment, the well (110) may be an area in which at least a portion of the upper surface (100A) of the well plate (100) is recessed along the first direction (DR1).

[0053] In such an embodiment, the well plate (100) is a plate-shaped structure having an upper surface (100A) and a lower surface (100B) in general, provided that, in detail, at least a portion of the upper surface (100A) may be in a recessed shape. Furthermore, as will be described later, the well plate (100) may be a structure in which the upper surface (100A) is in a recessed shape in a plurality of areas spaced apart from each other.

[0054] Meanwhile, at least a portion of the upper surface (100A) of the well plate (100) may be sunken along the first direction (DR1). Referring to FIGS. 1 and 2, the first direction (DR1) may mean a direction parallel to the direction connecting the upper surface (100A) and the lower surface (100B) of the well plate (100) by the shortest distance, and may mean both directions among the parallel directions. If the upper surface (100A) of the well plate (100) undergoes a deformation of shape along the first direction (DR1), it may be assumed that it protrudes or is sunken along the first direction (DR1). Among these, the well (110) may be an area where at least a portion of the upper surface (100A) of the well plate (100) is sunken along the first direction (DR1).

[0055] Accordingly, in the above embodiment, with reference to FIGS. 1 and FIGS. 2, the well (110) may refer to an area in which at least a portion of the upper surface (100A) of the well plate (100) is recessed. Meanwhile, it is sufficient that the well (110) is formed as described above, and its detailed shape may not be particularly limited. For example, with reference to FIGS. 1 and FIGS. 2, the well (110) is depicted as approximately a hemispherical area and a cylindrical area including a hemisphere on one side, but it is not necessarily limited thereto, and it is understood that it may have various shapes as long as it does not impair the scope defined in the present invention.

[0056] Meanwhile, in one embodiment, a separate member corresponding to the shape of the well (110) may be provided in the well (110). In this case, the member may be a detachable member within the well (110). In this case, the inner wall of the well (110) (the first inner wall (1112) and the second inner wall (1122) to be described later) may come into contact with the member, and the three-dimensional biological model (50) and the culture medium (20) to be described later may be contained within the member. In this case, the details regarding the first opening (1111) and the second opening (1121) described below may be understood as a description regarding the upper opening and the lower opening of the member, and the details regarding the first inner wall (1112) and the second inner wall (1122) may be understood as a description regarding the upper inner wall and the lower inner wall of the member. However, this is an example provided as necessary, and it goes without saying that the present invention is not necessarily limited thereto.

[0057] In one embodiment, the well (110) can accommodate the three-dimensional biomodel (50).

[0058] As described above, since the well (110) is a recessed area of ​​at least a portion of the upper surface (100A) of the well plate (100), the well (110) formed in the well plate (100) can accommodate the three-dimensional biological model (50) to be analyzed.

[0059] For example, one of the above three-dimensional biological models (50) may be accommodated, but it is not necessarily limited thereto, and it is of course possible to accommodate multiple of the above three-dimensional biological models (50) in one well (110) as needed.

[0060] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the well (110) includes a first well (111) which is an area up to a first depth (D1) and a second well (112) which is an area from the first depth (D1) to a second depth (D2), wherein the second depth (D2) is a depth further separated from the upper surface (100A) than the first depth (D1), and at least a portion of the probe (400) may be located within the second well (112).

[0061] Referring to FIGS. 1 and FIGS. 2, the well (110) may include a first well (111) and a second well (112).

[0062] In one embodiment, the well (110) may include the first well (111). Meanwhile, in the well (110), the first well (111) may be a region up to the first depth (D1).

[0063] In such an embodiment, the first well (111) can be directly connected to an external space.

[0064] In one embodiment, the well (110) may include the second well (112). Meanwhile, in the well (110), the second well (112) may be an area from the first depth (D1) to the second depth (D2).

[0065] Meanwhile, referring to FIGS. 1 and 2, in one embodiment, the second depth (D2) may be a depth further separated from the upper surface (100A) compared to the first depth (D1).

[0066] Accordingly, the well (110) can be divided into a first well (111) and a second well (112) according to its depth. In other words, the well (110) can be divided into a second well (112), which is located deeper, and a first well (111), which is located higher and adjacent to the upper surface (100A).

[0067] Meanwhile, in the definition above, the total depth of the well (110) may be the second depth (D2). Meanwhile, the first depth (D1) may not be particularly limited as long as it is deeper than the size of the three-dimensional biological model (50). The first depth (D1) may be a depth located closer to the upper surface (100A) than the second depth (D2) when referring to the definition above.

[0068] Meanwhile, in one embodiment, at least a portion of the probe (400) may be located within the second well (112). Details regarding this will be described later.

[0069] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the first well (111) includes a first opening (1111) and a first inner wall (1112), and the second well (112) includes a second opening (1121) and a second inner wall (1122), and the first well (111) and the second well (112) may be connected through the second opening (1121).

[0070] Referring to FIGS. 1 and FIGS. 2, in one embodiment, the first well (111) may include a first opening (1111) and a first inner wall (1112).

[0071] In one embodiment, the first well (111) may include a first opening (1111).

[0072] The first opening (1111) may represent an area that serves as a boundary between the first well (111) and the external space. Accordingly, the first well (111) and the external space may be connected through the first opening (1111), and furthermore, the well (110) and the external space may be connected through the first opening (1111).

[0073] In one embodiment, the first well (111) may include a first inner wall (1112).

[0074] The first inner wall (1112) may form the inner boundary of the first well (111). Meanwhile, the first inner wall (1112) may be connected to the upper surface of the well plate (100).

[0075] Although this is a non-limiting example, in terms of process, the first well (111) (or the well (110) itself) may be formed by recessing at least a portion of the upper surface (100A) of the well plate (100). In this case, the first inner wall (1112) can be understood as a portion that originally constituted the upper surface (100A) of the well plate, but whose shape and position have been altered as a result of recessing at least a portion of the upper surface (100A) as described above. However, this is merely an example for convenience of explanation, and the present invention is not limited thereto.

[0076] In one embodiment, the first well (111) may have a shape in which the cross-sectional area becomes narrower as it approaches the first depth (D1). Meanwhile, the cross-sectional area here may refer to the cross-section that can be observed when the first well (111) is cut by a virtual plane perpendicular to the first direction (DR1). This can be applied in the same way to the description of the remaining cross-sectional areas.

[0077] As described below, as the plunger (200) moves in the first direction (DR1), the three-dimensional biological model (50) can be guided to enter the second well (112). In this case, if the first well (111) has a shape in which the cross-sectional area becomes narrower as it approaches the first depth (D1), the three-dimensional biological model (50), which moves together with the plunger (200) moving in the first direction (DR1), can easily approach the second opening (1121) formed near the first depth (D1). Therefore, as the first well (111) has such a shape, the three-dimensional biological model (50) can be easily entered into the second well (112) simply by operating the plunger (200).

[0078] In an exemplary embodiment, the first well (111) may have a hemispherical shape. However, it is not necessarily limited thereto, and may not be particularly limited as long as it corresponds to a shape in which the cross-sectional area becomes narrower as it approaches the first depth (D1).

[0079] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the second well (112) may include a second opening (1121) and a second inner wall (1122).

[0080] In one embodiment, the second well (112) may include a second opening (1121).

[0081] The second opening (1121) may refer to an area that forms the boundary between the second well (112) and the first well (111). Accordingly, the first well (111) and the second well (112) can be connected through the second opening (1121).

[0082] In one embodiment, the second well (112) may include a second inner wall (1122).

[0083] The second inner wall (1122) may form the inner boundary of the second well (112). Meanwhile, the second inner wall (1122) may be connected to the first inner wall (1112).

[0084] Meanwhile, referring to the definition of the second well (112) described above, at least a portion of the second inner wall (1122) may consequently be located in the deepest part of the well (110).

[0085] In one embodiment, the shape of the second well (112) may not be particularly limited, but it is preferable to have a shape in which the change in cross-sectional area is not large at least in the part where the second opening (1121) is located.

[0086] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the area of ​​the first opening (1111) may be larger than the area of ​​the second opening (1121).

[0087] Meanwhile, based on the above description, the second opening (1121) may be located approximately at the first depth (D1). Therefore, the second opening (1121) is located deeper than the first opening (1111), and the area of ​​the second opening (1121) may be smaller than the area of ​​the first opening (1111).

[0088] In one embodiment, the cross-sectional area of ​​the second well (112) may be smaller than the cross-sectional area of ​​the first well (111). Accordingly, the area of ​​the second well (112) itself may be narrower than the area of ​​the first well (111).

[0089] Referring again to FIGS. 1 and 2, in one embodiment, the area of ​​the second opening (1121) is 2,000 μm 2 up to 50mm 2 It could be.

[0090] Within the numerical range described above, the three-dimensional biological model (50) can be easily guided into the second well (112) by the plunger (200) described later.

[0091] If the value is less than the above-described numerical range, it may be difficult for the three-dimensional biological model (50) to be analyzed to enter the second well (112), and conversely, if the value exceeds the above-described numerical range, the area of ​​the second opening (1121) becomes too large compared to the three-dimensional biological model (50) to be analyzed, so it may be difficult for the three-dimensional biological model (50) to be guided into the second well (112) even by the plunger (200) to be described later.

[0092] As described above, the well (110) includes a first well (111) and a second well (112) located according to depth, and the area of ​​each opening (first opening (1111), second opening (1121)) is different, and consequently, the cross-sectional area or the size of the area may be different.

[0093] Accordingly, as described in FIG. 1, FIG. 2 and the drawings to be described later, the three-dimensional biological model (50) will be located mainly in the first well (111) while floating in the culture medium (20) contained together in the well (110) or in contact with the first inner wall (1112). However, when analysis is required, it can enter the second well (112) by user intent and operation, and analysis can be performed through the probe (400) located in the second well (112). Accordingly, it is convenient to contain the three-dimensional biological model (50) until the user needs it, and when the user needs it, the contained three-dimensional biological model (50) can be analyzed quickly, simply, and accurately.

[0094] FIG. 3 is a drawing showing an example of a probe according to one embodiment of the present invention.

[0095] Referring to FIG. 3, in one embodiment, the device (10) may include a probe (400).

[0096] In one embodiment, the probe (400) has a shape that extends in one direction (DRE) and may include a plurality of electrodes (410) arranged along said direction (DRE).

[0097] In one embodiment, the probe (400) may come into contact with the three-dimensional biological model (50) during the analysis process of the three-dimensional biological model (50). In an exemplary embodiment, the probe (400) may be invasively inserted into the three-dimensional biological model (50). Accordingly, at least a portion of the probe (400) may enter the interior of the three-dimensional biological model (50) during the analysis process and may measure electrical signals, etc. occurring inside the three-dimensional biological model (50), or / or apply electrical stimulation into the three-dimensional biological model (50).

[0098] Referring to FIG. 3, in one embodiment, the probe (400) may be extended in one direction (DRE). Meanwhile, in this specification, the direction (DRE) refers only to the direction (DRE) in which the probe (400) is extended, and does not refer to an absolute direction within the device (10). Meanwhile, for example, as shown in FIG. 1 and FIG. 2, the probe (400) may be configured to extend along the first direction (DR1), where the direction (DRE) and the first direction (DR1) may be the same.

[0099] Meanwhile, referring to FIG. 3, in one embodiment, the probe (400) may have a smaller width at its end compared to the width of the rest of its portion in order to be inserted more smoothly into the three-dimensional biological model (50), and at least a portion of the end may have a pointed shape. However, it is not necessarily limited thereto, and if necessary, at least a portion of the end may have a blunt shape, or the width of the end and the width of the rest of its portion may be substantially the same. Meanwhile, the end may refer to a portion of the probe (400) intended to be the part that first contacts the three-dimensional biological model (50).

[0100] In one embodiment, the probe (400) may include a chemically stable material that does not electrochemically affect the three-dimensional biological model (50). For example, the material may be silicon. In such an embodiment, the probe (400) may be a silicon material probe.

[0101] Referring again to FIG. 3, in one embodiment, the probe (400) may include a plurality of electrodes (410) arranged along the direction (DRE).

[0102] In such an embodiment, the probe (400) comprises a plurality of electrodes (410), and each of the plurality of electrodes (410) may be arranged along the direction (DRE). Additionally, the plurality of electrodes (410) may be placed on both sides, and the plurality of electrodes (410) placed on each cross-section may be arranged in multiple rows. Thus, as will be described later, electrical signals according to depth within the three-dimensional biological model (50) can be measured based on the electrical signals obtained from each of the plurality of electrodes (410). The electrode may be, for example, an electrode containing platinum, but is not necessarily limited thereto.

[0103] Meanwhile, the configuration illustrated in FIG. 3 is illustrated to explain the configuration of the device (10) of the present invention, and it goes without saying that the present invention is not limited to what is illustrated in FIG. 3. For example, the number, location, size, ratio, shape, shading, etc. of each configuration illustrated in 3 are arbitrary and can be freely configured within the scope that does not impair the matters defined in the present invention. This can be applied in the same way to all the remaining drawings.

[0104] Meanwhile, according to an exemplary embodiment, the probe (400) described above may utilize a commercial probe. For example, Cambridge NeuroTech’s H2 may be used, but is not necessarily limited thereto.

[0105] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the probe (400) may be provided in the well plate (100).

[0106] In one embodiment, the probe (400) may be extended along the first direction (DR1).

[0107] As previously explained, the probe (400) has a shape that extends along one direction (DRE), and when the probe (400) having such a shape is provided on the well plate (100), it can be provided to extend along the first direction (DR1).

[0108] In such an embodiment, the probe (400) may include a plurality of electrodes (410) arranged along the first direction (DR1).

[0109] Referring to FIGS. 1 and 2, in one embodiment, the probe (400) may be provided to extend along the first direction (DR1) from the lower surface (100B) of the well plate (100).

[0110] As in the above-described embodiment, at least a portion of the probe (400) may be located within the well (110), and specifically, may be located within the second well (112), as described above.

[0111] In such an embodiment, the probe (400) extends along the first direction (DR1) from the lower surface of the well plate (100), and some part may be located within the plate portion of the well plate (100) other than the well (110), and the remaining part may extend out from the plate portion and be located within the second well (112).

[0112] Meanwhile, as in the embodiment described above, the probe (400) may include a terminal end intended to be the part that first contacts the three-dimensional biological model (50). In such an embodiment, the terminal end may be located within the second well (112).

[0113] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the probe (400) may be spaced apart from the second opening (1121).

[0114] The probe (400) extending along the first direction (DR1) from the lower surface (100B) of the well plate (100) may be spaced apart from the second opening (1121). That is, the probe (400) may be spaced apart from the second opening (1121) in a direction toward the lower surface (100B) of the well plate (100).

[0115] Referring to the embodiments described above, this can be expressed differently as follows: the probe (400) may mean that at least a part thereof is located only within the second well (112) and not within the first well (111).

[0116] As explained above, the three-dimensional biological model (50) can be analyzed by entering the second well (112) through user intent and operation when analysis is required. At this time, if at least a part of the probe (400) is also located in the first well (111), the three-dimensional biological model (50) and the probe (400) can easily come into contact without user intent and operation, making it difficult to perform the above operation.

[0117] Referring again to FIG. 1, in one embodiment, the distance (d) between the probe (400) and the second opening (1121) may be within 5 mm.

[0118] In an exemplary embodiment, the distance (d) between the probe (400) and the second opening (1121) may be 0.00001 mm to 5 mm, 0.0001 mm to 5 mm, 0.001 mm to 5 mm, or 0.01 mm to 5 mm.

[0119] Within the numerical range described above, the three-dimensional biological model (50), guided into the second well (112) by the plunger (200) described later, can be easily positioned so as to be analyzed by the probe (400). For example, when guiding the three-dimensional biological model (50) into the second well (112), it can be invaded by the probe (400) with high accuracy.

[0120] If the value is less than the aforementioned numerical range, the three-dimensional biological model (50) may come into contact with the probe (400) even with unintended manipulation, and if the value exceeds the aforementioned numerical range, it may become difficult to position the three-dimensional biological model (50), which has been guided into the second well (112), so that it can be analyzed by the probe (400).

[0121] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the device (10) may include a plunger (200).

[0122] In one embodiment, the plunger (200) may be positioned spaced apart from the well plate (100). This can be compared to the probe (400) being provided on the well plate (100).

[0123] In one embodiment, the plunger (200) may be movable along the first direction (DR1) within the well (110).

[0124] As the plunger (200) is positioned apart from the well plate (100) within the device (10), at least the plunger (200) may be able to move independently of the well plate (100). In such an embodiment, the plunger (200) may be provided in the device (10) so as to be able to move along the first direction (DR1) within the well (110). Such an embodiment may be illustrated in FIG. 4, which will be described later.

[0125] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the plunger (200) may include a rod (210) and a pad (220) located at one end of the rod (210).

[0126] In one embodiment, the plunger (200) may include a rod (210).

[0127] In one embodiment, the rod (210) may also be extended in one direction, just like the probe (400). Meanwhile, in one embodiment, when the plunger (200) moves along the first direction (DR1) within the well (110), the extension direction of the rod (210) may also be the same as the first direction (DR1).

[0128] In one embodiment, the rod (210) may include a material that is relatively rigid and chemically stable. Accordingly, the rod (210) may consequently be a part that supports the external force to be applied through the plunger (200) and may not cause a significant chemical reaction even when in contact with the culture medium (20) contained within the well (110).

[0129] Meanwhile, the shape of the rod (210) may not be particularly limited. For example, it may not be particularly limited as long as it is a shape that can be extended in one direction, such as a cylindrical shape or a rectangular prism shape. Meanwhile, its cross-sectional area may also not be particularly limited, and as long as it is smaller than the cross-sectional area of ​​the first opening (1111), it may have a cross-sectional area within the range required to achieve its functional significance.

[0130] Meanwhile, the above rod (210) may have a structure with a hollow formed inside, or may have a form that does not contain a hollow inside but is filled with at least a portion, and various other forms may be exemplified.

[0131] In one embodiment, the plunger (200) may include a pad (220).

[0132] In one embodiment, the pad (220) may be located at one end of the rod (210).

[0133] Meanwhile, the upper end of the rod (210) may be the upper end intended to be closest to the three-dimensional biological model (50) when the plunger (200) is operated. Accordingly, the pad (220) located at the upper end of the rod (210) may be located at a position intended to come into contact with the three-dimensional biological model (50) when the plunger (200) is operated.

[0134] In one embodiment, the pad (220) may include a material that is relatively soft and chemically stable. In such an embodiment, the pad (220) may be soft overall and may not cause a significant chemical reaction even when in contact with the culture medium (20) and / or the three-dimensional biological model (50) contained within the well (110).

[0135] Meanwhile, by positioning the pad (220) at a location intended to contact the three-dimensional biological model (50), the pad (220) can come into contact with the three-dimensional biological model (50) when the plunger (200) is operated. At this time, as described above, since the plunger (200) can have flexibility, the impact that may be applied to the three-dimensional biological model (50) when it comes into contact with the three-dimensional biological model (50) can be minimized.

[0136] In one embodiment, the pad (220) may include at least one of an elastic synthetic polymer (Polydimethylsiloxane, Polyethylene-co-vinyl acetate, Polyurethane, Hydrogel, etc.) and a natural polymer (Collagen, Gelatin, Silk fibroin, Chitosan, etc.) based porous structure as its material, which is harmless to cell survival, has mechanical support and appropriate permeability, and has chemical stability and biocompatibility.

[0137] Referring again to FIG. 1, in one embodiment, the area of ​​the pad (220) may be larger than the area of ​​the second opening (1121).

[0138] In an exemplary embodiment, the area of ​​the pad (220) may refer to the area of ​​the cross-section observed when the pad (220) is cut along a virtual plane perpendicular to the first direction (DR1) when the pad (220) has a predetermined thickness.

[0139] As previously explained, the three-dimensional biological model (50), which is floating or submerged in the culture medium (20) contained in the well (110) and in contact with the first inner wall (1112), can guide the plunger (200) to move along the first direction (DR1) within the well (110) to enter the second well (112).

[0140] In such an embodiment, if the area of ​​the pad (220) of the plunger (200) is smaller than the second opening (1121), there is a risk that the plunger (200) may also enter the second well (112) during operation. In this case, damage may occur to the pad (220) or the plunger (200) itself, or the three-dimensional biological model (50) or probe (400) may be destroyed or damaged. To control this, careful operation by the user may be required, and consequently, the analysis process by the device (10) may become difficult.

[0141] In one embodiment, the area of ​​the pad (220) may be smaller than the area of ​​the first opening (1111).

[0142] Referring again to FIGS. 1 and FIGS. 2, in one embodiment, the device (10) further includes a cover (300) for opening and closing the well plate (100); and the plunger (200) can be coupled to the cover (300) at the other end of the rod (220).

[0143] In one embodiment, the device (10) may further include a cover (300). The cover (300) can open and close the well plate (100).

[0144] The cover (300) may seal the well plate (100) if necessary. In a specific embodiment, the cover (300) may seal the well (110) of the well plate (100) from the outside. In such an embodiment, the upper surface (100A) of the well plate (100) may be adjacent to the cover (300). Although not necessarily limited thereto, the lower surface (100B) of the well plate (100) may not be covered by the cover (300).

[0145] In one embodiment, the cover (300) may be configured to be separate from the well plate (100). In another embodiment, the cover (300) may be configured to be connected to the well plate (100) via a hinge connection or the like, and various other embodiments may be envisioned.

[0146] In one embodiment, the plunger (200) can be coupled with the cover (300) at the other end of the rod (210).

[0147] As described above, the pad (220) is positioned at one end of the rod (210). In this embodiment, the other end can be combined with the cover (300).

[0148] In this embodiment, the guiding operation of the three-dimensional biological model (50) can be performed simply and accurately by the plunger (200) fixed to the cover (300) by only the simple operation of sealing the well plate (100) with the cover (300). In this case, the wells (110) can also be sealed by the cover (300), thereby providing an environment for analyzing the three-dimensional biological model (50), which makes it possible to perform a more accurate and convenient analysis.

[0149] Figure 4 is a diagram showing an example of performing an analysis on a three-dimensional biological model by manipulating a plunger.

[0150] As previously explained, the plunger (200) can be moved along the first direction (DR1) within the well (110) to guide the three-dimensional biomodel (50) into the second well (112).

[0151] In one embodiment, the plunger (200) can guide the three-dimensional biomodel (50) to enter the second well (112).

[0152] Before the user attempts to perform an analysis of the three-dimensional biological model (50), the three-dimensional biological model (50) may be contained within the well (110). In an exemplary embodiment, the three-dimensional biological model (50) may be floating within the culture medium (20) contained within the well (110), or a portion of it may be in contact with the first inner wall (1112).

[0153] When the user begins to perform an analysis of the three-dimensional biological model (50), the user can operate the plunger (200). Specifically, the plunger (200) can be operated to move along the first direction (DR1) within the well (110). In an exemplary embodiment, such operation may be possible simply by closing the cover (300).

[0154] When the plunger (200) moves along the first direction (DR1) within the well (110) (specifically, the first well (111)), the pad (220) located at one end of the plunger (200) can provide an external force to the three-dimensional bio-model (50).

[0155] Accordingly, the three-dimensional biological model (50) may move toward the second opening (1121). This can be achieved more easily by the structural characteristics of the first well (111), which has a shape in which the cross-sectional area becomes narrower as it approaches the second opening (1121).

[0156] When the above three-dimensional bio-model (50) enters the above second well (112), at least the plunger can apply an external force to the three-dimensional bio-model (50) until the three-dimensional bio-model (50) is fully positioned within the above second well (112).

[0157] At this time, the three-dimensional biological model (50) may come into contact with the probe (400) which is spaced apart from the second opening (1121) in the manner described above. When the three-dimensional biological model (50) is guided as described above with reference to the area of ​​the second opening (1121), it may be easily invaded by the probe (400). Such a manner is illustrated in FIG. 4.

[0158] In one embodiment, the wells (110) are provided in a plurality, and each of the plungers (200) and the probes (400) may be provided in a plurality so as to correspond to each of the plurality of wells (110).

[0159] In one embodiment, the well (110) in the well plate (100) may be provided in multiple numbers. Since the details regarding each individual well (110) can be applied in the same way as the details described above with reference to FIG. 1 and FIG. 2, etc., redundant descriptions will be omitted below.

[0160] The number of wells (110) provided in the well plate (100) may not be particularly limited. For example, it may be a 12-well plate with 12 wells, but it is not necessarily limited to this, and may be configured in various ways as needed, such as a 6-well plate, a 24-well plate, a 48-well plate, a 72-well plate, a 96-well plate, a 384-well plate, etc.

[0161] In one embodiment, the probe (400) in the well plate (100) may be provided in multiple numbers.

[0162] In such an embodiment, the number of probes (400) may be the same as the number of wells (110).

[0163] Meanwhile, in the above embodiment, the probe (400) may be provided to be positioned in each of the wells (110). Since the manner in which the probe (400) is positioned in the well (110) can be applied in the same way as described with reference to FIG. 1 and FIG. 2, redundant descriptions will be omitted below.

[0164] In another embodiment, the number of probes (400) may be greater than the number of wells (110).

[0165] Meanwhile, in the above embodiment, a plurality of probes (400) may be provided to be located in at least some of each of the wells (110). That is, in some wells (110), a plurality of probes (400) may be located in one well (110).

[0166] In one embodiment, the plunger (200) in the cover (300) may be provided in multiple numbers.

[0167] In such an embodiment, the number of plungers (200) may be the same as the number of wells (110).

[0168] Meanwhile, in the above embodiment, the plunger (200) may be provided to be coupled to each position corresponding to each well (110) in the cover (300). Since the aspects such as the positional relationship between the well (110) and the plunger (200) can be applied in the same way as described with reference to FIG. 1 and FIG. 2, redundant descriptions will be omitted below.

[0169] In such an embodiment, the above analysis can be performed simultaneously in a plurality of wells (110). Meanwhile, a different three-dimensional biological model (50) may be contained in each of the plurality of wells (110), or the analysis conditions may be set differently for each. In such an embodiment, the device (10) can accurately perform electrochemical analysis on various types of three-dimensional biological models (50) under various analysis conditions with just a single simple operation.

[0170] In such an embodiment, the risk of loss may be reduced when the culture medium is replaced according to experimental conditions or when the biological model (50) fixed to the probe (400) is continuously cultured.

[0171] Although the present invention has been described above by way of embodiments, this is provided only to aid in a more comprehensive understanding of the invention, and the invention is not limited to the above examples. Those skilled in the art can make various modifications and variations from this description.

[0172] Accordingly, the scope of the concept of the present invention shall be considered to include not only the claims set forth below but also all things equivalent to or having equivalent variations thereof.

Claims

1. As an analysis device for a three-dimensional biological model, Well plate; A probe provided in the well plate above; and A plunger positioned spaced apart from the well plate; comprising, The above well plate is, At least a portion of the upper surface of the well plate is a region recessed along a first direction, comprising a well that accommodates the three-dimensional biological model, and A device in which at least a portion of the probe is located within the well, and the plunger is movable along the first direction within the well.

2. In Paragraph 1, The above 3D biological model is, A device comprising at least one selected from the group consisting of cardiac organoids, vascular organoids, retinal organoids, brain organoids, spinal cord organoids, tumor organoids, neural organoids, organoids containing cells subjected to optogenetic manipulation, lung organoids, gastric organoids, small intestine organoids, liver organoids, pancreatic organoids, kidney organoids, bladder organoids, testicular organoids, ovarian organoids, bone marrow organoids, thymus organoids, skin organoids, hair follicle organoids, inner ear organoids, and olfactory epithelial organoids.

3. In Paragraph 1, The above well is, It includes a first well, which is an area up to a first depth, and a second well, which is an area from the first depth to a second depth, and The second depth is a depth further spaced from the upper surface of the well plate compared to the first depth, and A device in which at least a portion of the probe is located within the second well.

4. In Paragraph 3, The above first well is, It includes a first opening and a first inner wall, The above second well is, It includes a second opening and a second inner wall, A device in which the first well and the second well are connected through the second opening.

5. In Paragraph 4, A device in which the area of ​​the first opening is larger than the area of ​​the second opening.

6. In Paragraph 5, The area of ​​the second opening is 2,000 μm 2 up to 50mm 2 Person, device.

7. In Paragraph 4, The above probe is a device extending along the first direction.

8. In Paragraph 7, The above probe is, A device comprising a plurality of electrodes arranged along the first direction.

9. In Paragraph 7, The above probe is a device spaced apart from the above second opening.

10. In Paragraph 9, A device in which the distance between the probe and the second opening is within 5 mm.

11. In Paragraph 4, The above plunger is, A device comprising a rod and a pad located at one end of the rod.

12. In Paragraph 11, A device in which the area of ​​the pad is larger than the area of ​​the second opening.

13. In Paragraph 11, The above device is, It further includes a cover for opening and closing the well plate; The above plunger is a device that is coupled to the cover at the other end of the rod.

14. In Paragraph 11, The above plunger is, A device that guides the above-described three-dimensional biological model to enter the above-described second well.

15. In Paragraph 1, The above well is provided in multiple numbers, A device in which each of the above plunger and the above probe is provided in multiple numbers to correspond to each of the multiple wells.

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