KR20200051481A - Biomemetic chip device - Google Patents

Abstract

The present invention provides a biomimetic chip device. The present invention provides a biomimetic chip device which comprises a body; a main channel disposed in the body, and extending in one direction; a plurality of culture chambers disposed to be spaced apart from each other on the main channel; a first storage tank disposed at one end of the main channel, and storing a first fluid; and a second storage tank disposed at the other end of the main channel, and storing the first fluid. The body is tilted based on a first shaft vertical to the one direction such that the first fluid flows between the first storage tank and the second storage tank. According to the present invention, a size and a weight of the device can be reduced.

Description

Bio-simulation chip device {BIOMEMETIC CHIP DEVICE}

The present invention relates to a bio-simulated chip device.

When developing food or new drugs, a preclinical test is a step to evaluate the efficacy and toxicity of the ingredients. In these preclinical testing steps, side effects and efficacy can be predicted using human or animal cells. However, since the accuracy of the cell culture model is not high in the related art, development cost and time are required.

Accordingly, on-chip cell culture technology is being applied to preclinical tests performed when developing food or new drugs. On-chip cell culture technology is a technology that can increase the physiological similarity of cells by culturing cells in a microchip that creates an environment similar to the internal environment of a living body including a human body. For example, intestinal cells and liver cells may be cultured in a completed chip to simulate intestinal absorption and liver metabolic reactions similar to those in the human body.

Recently, it has been reported that when cells are cultured on a microfluidic chip that mimics blood flow and intestinal fluid flow in a human body without culturing the cells in a plastic dish, cell activity and function are improved. Accordingly, there is a growing need for cell culture chips, which are cell culture systems that include fluid flow.

Currently, research on 3D cell culture and organ-on-a-chip is underway, but it is difficult to form a multi-organ network on a single chip because it mainly simulates the limited functions of a single organ model. The interactions between organs cannot be simulated. For this reason, it is essential to optimize the conditions for culturing various organs together after forming a multi-organ network in vitro. However, since there is no device capable of simulating a living environment similar to the real living condition, it is difficult to conduct research on this. In particular, in the case of brain research, in vitro experiments in which various brain regions are formed in vitro and selective external stimulation of a specific brain region can be investigated to investigate effects on other brain regions connected thereto.

In addition, since the structure of the chip is different and complex for each type of organ to be simulated of some chips capable of cultivating two or more organs, it is connected with an external system such as an external pump, tubing, or electric wire. It is difficult to implement a high-speed and large-capacity processing system due to incompatibility. In addition, the conventional cell culture device includes only a non-exposed model as a culture model, and the flow of the culture fluid in the device is made in both directions, and thus is different from the flow of blood or body fluid in the living body.

Lastly, in the case of the conventional organ-simulating chip, cells are attached to the inside surface of the chip and cultured, so that it cannot be recovered outside the chip to proceed with further analysis.

An object of the present invention is to provide a biomimetic chip device that simulates a bioenvironment including a human body.

One side of the present invention, the body, disposed in the body, the main channel extending in one direction, a plurality of culture chambers spaced apart from each other on the main channel, disposed at one end of the main channel, the first fluid It includes a first reservoir for storing, the second reservoir is disposed at the other end of the main channel, and the second reservoir for storing the first fluid, the body is tilted around the first axis perpendicular to the one direction, the first Provided is a biomimetic chip device that flows fluid between the first reservoir and the second reservoir.

In addition, in the bio-simulation chip device, a plurality of culture models are cultured in the culture channel, and the plurality of culture models may be arranged in the one direction according to the order in which blood is supplied in vivo.

In addition, the culture model includes a non-exposure model inside the living body and an exposure model outside the living body, and the first fluid cultures the culture chamber and the exposure model for culturing the non-exposure model from the first reservoir. Through the culture chamber, it can flow to the second reservoir.

In addition, the bypass channel is disposed in parallel with the main channel to return the first fluid moved from the first reservoir to the second reservoir to the first reservoir.

In addition, when the body is tilted in the first direction, the first fluid moves along the main channel, and when the body is tilted in the second direction opposite to the first direction, the first fluid is applied to the bi You can move along the pass channel.

In addition, a first valve unit disposed at both ends of the main channel and a second valve unit disposed at both ends of the bypass channel may be further included.

Further, the first valve unit and the second valve unit may be ball valves that move the first fluid in a predetermined flow direction.

In addition, the second fluid is moved, and further comprising a sub-channel in which some sections are arranged side by side with the bypass channel, the first fluid moving the bypass channel and the second fluid moving the sub-channel The material can be exchanged.

In addition, a membrane may be provided between the bypass channel and the sub-channel.

In addition, the bypass channel and the sub-channel may exchange material between the first fluid and the second fluid when the body rotates in a predetermined direction.

The biomimetic chip device according to the present invention does not have a pump or a microtube, and can simply form a fluid flow by tilting the device based on gravity, thereby reducing the size and weight of the device.

In addition, the bio-simulation chip device according to the present invention includes a culture model for non-exposed organs and exposed organs in a living body, controls the flow of fluid to be the same as the flow of blood in the living body, and also provides a membrane formed in the bypass channel. Through the movement of the target material, it is possible to implement the same culture environment as the real biological environment by simulating the discharge of substances in the body.

1 is a view showing a bio-simulation chip device according to an embodiment of the present invention.
FIG. 2 is a view showing a cross-section of a biomimetic chip device cut along line II-II in FIG. 1.
3 is an enlarged view of A of FIG. 2.
4 is a view showing that the bio-simulation chip device is tilted about the axis AX ₁ .
5 is a view showing a bio-simulation chip device having a bypass channel and a valve unit as another embodiment.
6 is a view showing a bio-simulation chip device having a sub-channel and a membrane as another embodiment.
7 is an enlarged view of B in FIG. 6.
8 is a view showing a bio-simulation chip device according to another embodiment of the present invention.
FIG. 9 is a view showing a cross-section of a biomimetic chip device cut along line VIII-VIII in FIG. 8.
10 is an enlarged view of C of FIG. 9.
11 is a view showing that the bio-simulation chip device of FIG. 8 is tilted about the axis AX ₁ .
12 is a view showing that the bio-simulation chip device of FIG. 8 is tilted about the axis AX ₂ .
13 is a perspective view showing a culture device according to another embodiment of the present invention.
14 is a cross-sectional view showing a culture chamber system in which the culture device of FIG. 13 is installed.
15 is a plan view showing the support plate of FIG. 13.
16 is a view showing a coupling relationship between the connection frame and the support plate.
17A and 17B are views showing the operation of the culture apparatus.
18 is a view showing a method of culturing a culture model using a culture device according to another embodiment of the present invention.

The present invention can be applied to various transformations and can have various embodiments, and specific embodiments will be illustrated in the drawings and described in detail in the description of the invention. However, this is not intended to limit the present invention to a specific embodiment, it should be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the present invention, even though it is illustrated in other embodiments, the same reference numerals are used for the same components.

Terms such as first and second may be used to describe various components, but the components should not be limited by the terms. The terms are only used to distinguish one component from other components.

The terms used in the present application are only used to describe specific embodiments, and are not intended to limit the present invention. In this application, terms such as “include” or “have” are intended to indicate that a feature, number, step, operation, component, part, or combination thereof described in the specification exists, one or more other features. It should be understood that the existence or addition possibilities of fields or numbers, steps, operations, components, parts or combinations thereof are not excluded in advance.

Hereinafter, the present invention will be described in detail with reference to embodiments related to the present invention shown in the accompanying drawings.

1 is a view showing a bio-simulation chip device 200 according to an embodiment of the present invention, and FIG. 2 is a view showing a cross-section of the bio-simulation chip device 200 cut along line II-II of FIG. 1. to be.

1 and 2, the biomimetic chip device 200 according to an embodiment of the present invention includes a body 210 and a main channel 220 disposed in the body 210 and extending in one direction. , A plurality of culture chambers 230 spaced apart from each other on the main channel 220, a first reservoir 241 disposed at one end of the main channel 220 and storing a first fluid, and a main channel ( It is disposed at the other end of 220, includes a second reservoir 242 for storing the first fluid, the body 210 is tilted around a first axis perpendicular to one direction, the first fluid to the first reservoir ( 241) and the second reservoir 242.

The body 210 forms a basic shape of the bio-mimicking chip device 200, and other members may be disposed. The shape of the body 210 is not particularly limited, and may be a rectangular parallelepiped shape extending in one direction in one embodiment of the present invention. In one embodiment, the body 210 may be made of a transparent material so that the inside of the body 210 can be easily observed from the outside. A member for tilting the bio-mimicking chip device 200 may be coupled to one side of the body 210.

Referring to FIG. 2, the main channel 220 is disposed on the body 210 and extends in one direction. The main channel 220 is disposed inside the body 210 to provide an internal flow path through which the first fluid moves. As described later, one end of the main channel 220 is connected to the first storage tank 241, and the other end is connected to the second storage tank 242. In one embodiment of the present invention, the main channel 220 may be arranged in the X-axis direction (longitudinal direction of the bio-mimicking chip device 200) to be parallel to the bottom surface of the body 210.

The first fluid is a fluid required to cultivate and grow the culture model (M), and in one embodiment of the present invention may be a culture solution that supplies oxygen and nutrients to the culture model (M).

The culture model M according to an embodiment of the present invention is a model corresponding to a specific part of a living body, and may include a non-exposure model (M _A ) inside the living body and an exposure model (M _B ) outside the living body. The non-exposure model (M _A ) may include a model for non-exposed organs such as liver, tumor, heart, and the like. The exposure model M _B may include a model for exposed organs such as skin, nasal cells, and the like.

A plurality of culture chambers 230 are disposed on the main channel 220. A culture model is disposed in each culture chamber 230 and cultured. The number of the culture chamber 230 and the culture model M is not particularly limited, and an appropriate number may be arranged in consideration of the characteristics of the culture model M and the purpose of the experiment.

As another embodiment, the culture model M may be arranged in one direction according to the order in which blood is supplied in vivo. Specifically, blood flows from the body in the order of the brain, heart, liver, tumor, skin, and nasal passages, and flows from the internal center of the body toward the periphery. In consideration of this, the culture model M may be disposed in the culture chamber 230 in the order of the non-exposure model M _A and the exposure model M _B from the first reservoir 241 toward the second reservoir 242. . In addition, the non-exposed model (M _A) are arranged in the model brain, heart model, liver model, tumor model order, exposure model (M _B) may be arranged in the skin model, nasal model order. Therefore, the first fluid is supplied from the first storage tank 241 and flows through the main channel 220 according to the order in which blood is supplied in vivo, and then passes through the non-exposure model (M _A ) and the exposure model (M _B ). 2 Move to the storage tank (242). Through this configuration, it is possible to implement a culture environment in consideration of the flow of blood in an actual living body.

The non-exposed model M _A may be disposed in the culture chamber 230 in the form of a spheroid as a three-dimensional organoid. Accordingly, the non-exposure model (M _A ) maintains a three-dimensional shape without adsorbing on the surface inside the culture chamber 230 and is cultured while staying in the space within the culture chamber 230. Therefore, after the incubation model (M _A ) is cultured, it can be recovered to the outside of the device for further analysis. The exposure model M _B may be disposed in the culture chamber 230 through the culture unit 250. This will be described in more detail with reference to FIG. 3.

3 is an enlarged view of A of FIG. 2.

2 and 3, the exposure model M _B is disposed in the culture unit 250 and can be inserted into the culture chamber 230 through grooves formed on the upper surface of the body 210. The culture unit 250 is detachable from the bio-mimicking chip device 200, and includes a guide unit 251 and a bottom membrane 252.

The guide portion 251 is a member having a V-shape whose top is bent outward when viewed from the front. The bent portion of the guide portion 251 is supported on the upper surface of the body 210, and the side wall of the guide portion 251 is supported on the side wall of a groove (not shown) formed on the upper surface of the body 210. The lower end of the guide portion 251 may be formed of a flat bottom layer 252. The bottom membrane 252 is a membrane capable of material exchange with the outside, and in the exposure model M _B , exposed cells may be disposed on the bottom membrane 252 and vascular endothelial cells below the bottom membrane 252.

As described above, the exposure model M _B may be disposed in the culture unit 250 outside the bio-mimicking chip device 200, and then inserted into the culture chamber 230. The culture unit 250 may be a transwell.

That is, the biometric simulation chip device 200, the unexposed model placed in the culture chamber 230, a (M _A) to the spheroid shape, and exposure model (M _B) in accordance with one embodiment of the invention the culture unit (250 ), The culture model can be modularized. Accordingly, the culture model can be easily taken out from the biomimetic chip device 200 during or during the cultivation process, and further analysis can be performed outside the biomimetic chip device 200.

In another embodiment, the bio-simulation chip device 200 may further include a loading channel (not shown) and a loading chamber (not shown) to set the non-exposed model M _A into the culture chamber 230. . Specifically, a loading chamber in which a non-exposure model M _A is seated on one side of the body 210, such as a loading channel 370 and a loading chamber 380 of the bio-simulation chip device 300 shown in FIGS. 8 and 9. And a loading channel extending from the loading chamber and connected to the culture chamber 230. Accordingly, as the body 210 is tilted about a second axis parallel to one direction in which the main channel 220 extends (eg, axis AX _{2 in} FIG. 1), a non-exposed model M in the loading chamber (M _A ) may be loaded into the culture chamber 230 through a loading channel.

In another embodiment, an inlet for seating the non-exposed model M _A in the culture chamber 230 may be formed directly above the culture chamber 230. For example, the culture chamber 230 has an open top surface, such as the storage tank 240, so that the non-exposed model M _A can be directly seated into the culture chamber 230. In this case, the bio-simulation chip device 200 does not have a loading channel and a loading chamber, so it can be made of a simpler structure. In addition, the bio-simulation chip device 200 may further include a cover (not shown) for opening and closing the open top surface of the culture chamber 230.

1 and 2, the storage tank 240 may include a first storage tank 241 and a second storage tank 242 as members for storing and supplying the first fluid. The first storage tank 241 is disposed on one side of the upper surface of the body 210, and the second storage tank 242 is disposed on the other side of the upper surface of the body 210. In one embodiment of the present invention, the first reservoir 241 and the second reservoir 242 may be inserted into the body 210 through grooves (not shown) formed on the upper surface of the body 210.

The first reservoir 241 is connected to one end of the main channel 220, and the second reservoir 242 is connected to the other end of the main channel 220. The first storage tank 241 and the second storage tank 242 have an internal space for storing the first fluid therein. The first storage tank 241 and the second storage tank 242 may have various shapes, and may have a cylindrical shape or a tapered shape. In an embodiment of the present invention, the first storage tank 241 and the second storage tank 242 may have a cylindrical shape having an internal space. In addition, in order to supply the first fluid from the outside, the first reservoir 241 and the second reservoir 242 may have an open top surface.

As another embodiment, the bio-simulation chip device 200 may selectively include a cover (not shown) that can open and close the upper surface of the storage tank 240. Accordingly, even if the biological simulation chip device 200 is tilted, it is possible to prevent the first fluid from being released from the storage tank 240.

4 is a view showing that the bio-simulation chip device 200 is tilted around the axis AX ₁ .

1, 2, and 4, the axis AX ₁ may be positioned at the center of the X-axis direction of the bio-simulation chip device 200 so as to be parallel to the Y axis. As shown in FIG. 4, when the biomimetic chip device 200 is tilted clockwise around the axis AX ₁ , the first fluid is transferred from the first reservoir 241 through the main channel 220 to each culture chamber ( 230). The first fluid that has passed through the culture chamber 230 moves to the second storage tank 242. Conversely, when the bio-simulation chip device 200 is tilted counterclockwise about the axis AX ₁ , the first fluid moves from the second reservoir 242 to the first reservoir 241.

In addition, as described above, the bio-simulation chip device 200 may further include a loading channel and a loading chamber for seating the non-exposed model M _A in the culture chamber 230. In this case, the body 210 may be tilted around the axis AX ₂ to move the unexposed model M _A injected into the loading chamber to the culture chamber 230. Referring to FIG. 1, in one embodiment of the present invention, the axis AX ₂ may be located under the culture model M on the bottom surface of the body 210.

As described above, the biomimetic chip device 200 according to the present invention does not include a pump, a micro tube, or a tubing, and can simply form a flow of fluid by tilting the device based on gravity, so that the size of the device And weight can be reduced.

Meanwhile, the size of the exposure model M _A and the non-exposure model M _B may be larger than the size of the internal channel of the main channel 220. Accordingly, even if the bio-simulation chip device 200 is tilted, the exposure model M _A and the non-exposure model M _B itself do not move to another culture chamber 230 while being disposed in each culture chamber 230. . That is, each of the exposure model (M _A) and the non-exposed model (M _B) can be incubated with the different exposure model (M _A) and the non-exposed model (M _B) and a spatially separated state.

5 is a view showing a bio-simulation chip device 200 having a bypass channel 260 and a valve unit 270 as another embodiment, and FIG. 5 (a) shows that the first fluid is the main channel 220. In FIG. 5 (b), the first fluid flows in the bypass channel 260.

Referring to FIG. 5, the biomimetic chip device 200 of the present invention may further include a bypass channel 260. The bypass channel 260 is disposed on the body 210 in parallel with the main channel 220, one end is connected to the first storage tank 241, and the other end is connected to the second storage tank 242. The bypass channel 260 returns the first fluid moved from the first reservoir 241 to the second reservoir 242 back to the first reservoir 241.

In addition, referring to FIG. 5, the biomimetic chip device 200 of the present invention may further include a valve unit 270. The valve unit 270 is a member that allows the fluid to flow only in a predetermined direction, and controls the first fluid flowing through the main channel 220 and the bypass channel 260. The valve unit 270 may be disposed in the main channel 220 and the bypass channel 260, respectively.

The valve unit 270 may include a first valve unit 271 and a second valve unit 272. The first valve unit 271 is disposed at one end and the other end of the main channel 220 to control the flow of the first fluid moving from the first reservoir 241 to the second reservoir 242. The second valve unit 272 is disposed at one end and the other end of the bypass channel 260 to control the flow of the first fluid moving from the second reservoir 242 to the first reservoir 241.

Specifically, as shown in Figure 5 (a), when the bio-simulation chip device 200 is tilted in the clockwise direction around the axis AX ₁ , the first storage tank 241 to the second storage tank 242, the first Fluid flow occurs. The flow of the first fluid generated at this time is for supplying oxygen and nutrients to the culture chamber 230 disposed on the main channel 220 and must pass through the main channel 220. Accordingly, the first valve unit 271 is opened and the second valve unit 272 is closed. Accordingly, the first fluid flows inside the main channel 220 from the first storage tank 241 to the second storage tank 242, and does not flow inside the bypass channel 260.

Conversely, as shown in Figure 5 (b), when the bio-simulation chip device 200 is tilted in the counterclockwise direction around the axis AX ₁ , the first storage tank 241 from the second storage tank 242 Fluid flow occurs. The flow of the first fluid generated at this time is for recovering the first fluid supplied to the culture chamber 230 and must pass through the bypass channel 260. Thus, the first valve unit 271 is closed and the second valve unit 272 is opened. Accordingly, the first fluid flows inside the bypass channel 260 from the second storage tank 242 to the first storage tank 241, and does not flow inside the main channel 220.

As described above, the valve unit 270 is sufficient as long as it is a configuration capable of selectively controlling the flow of the first fluid, and is not particularly limited. In one embodiment of the present invention, the valve unit 270 may be a ball valve composed of a ball and a ball support. Accordingly, when the bio-simulation chip device 200 is tilted around the axis AX ₁ , as shown in FIG. 5 (a), the ball deviates from the ball support and the main channel 220 or the bypass channel 260 As this is closed, the flow of the first fluid may be blocked. Conversely, as shown in FIG. 5 (b), the flow of the first fluid may be permitted as the ball is seated on the ball support and the main channel 220 or the bypass channel 260 is opened.

As described above, the biomimetic chip device 200 of the present invention allows the first fluid to flow only in one of the main channel 220 or the bypass channel 260, that is, the first fluid flows only in a single direction. Can be configured. Through this, it is possible to implement a culture environment similar to an actual biological environment in which blood is supplied only in one direction.

6 is a view showing a bio-simulation chip device 200 having a sub-channel 280 and a membrane 290 as another embodiment, and FIG. 7 is an enlarged view of FIG. 6B.

6 and 7, the bio-simulation chip device 200 may further include a sub-channel 280. Both ends of the sub-channel 280 are respectively connected to the additional reservoir R, and some sections may be arranged in parallel with the bypass channel 260. In addition, material exchange may occur in a section in which the bypass channel 260 and the sub-channel 280 are arranged side by side.

In detail, the bio-simulation chip device 200 may further include a membrane 290 between the bypass channel 260 and the sub-channel 280. The membrane 290 is disposed at the interface between the bypass channel 260 and the sub-channel 280 to induce material exchange between the bypass channel 260 and the sub-channel 280.

For example, the first fluid supplied from the first reservoir 241 and moved to the second reservoir 242 through the culture chamber 230 supplies oxygen and nutrients to each culture model M and wastes therefrom. Receive. Therefore, the first fluid moved to the second storage tank 242 cannot be used again. In this case, the second fluid supplied from the additional reservoir R flows through the sub-channel 280, and the bypass channel 260 according to the concentration difference through the membrane 290, the size of the material, and the pore size inside the membrane And selective material exchange.

Specifically, as the body 210 is tilted, the first fluid moves from the second reservoir 242 to the first reservoir 241, and the second fluid also flows between the additional reservoirs R in the same direction as the first fluid. Move. At this time, waste products contained in the first fluid may move to the second fluid through the membrane 290 (EM ₁ ), and oxygen and nutrients contained in the second fluid may move to the first fluid (EM ₂ ). The second fluid that supplies oxygen and nutrients and receives waste products is recovered in an additional storage tank (R). Then, by analyzing the recovered waste, it is possible to monitor the culture state of the culture model (M).

In another embodiment, the membrane 290 may be composed of a plurality of layers. Specifically, the membrane 290 may include a first membrane disposed on the bypass channel 260 side and a second membrane disposed on the sub channel 280 side.

In another embodiment, the material exchange between the bypass channel 260 and the sub-channel 280 may be set to occur only when the body 210 is tilted in a specific direction. Specifically, the body 210 is tilted counterclockwise around the axis AX ₁ so that the first fluid flows through the bypass channel 260, and the second fluid also subchannels 280 in the same direction as the first fluid. It can be set that the material exchange between the bypass channel 260 and the sub-channel 280 occurs only in the case of flowing. In this case, the valve unit 270 may also be disposed at both ends of the sub-channel 280.

In this way, the bio-simulation chip device 200 may be provided with a membrane 290 to implement a simple kidney function capable of selectively separating a specific substance between fluid flows.

In another embodiment, the main channel 220, the culture chamber 230, and the storage tank 240 may be arranged in a plurality of rows. Specifically, the biomimetic chip device 200 of the present invention may be configured to correspond to a standard 96-well microplate format. Accordingly, it is possible to increase the compatibility with the existing cell culture automation equipment, and to promote the practical use of high-speed and large-capacity screening.

8 is a view showing a bio-simulation chip device 300 according to another embodiment of the present invention, and FIG. 9 is a view showing a cross-section of the bio-simulation chip device 300 cut along line VII-VIII in FIG. 8. to be.

8 and 9, the bio-simulation chip device 300 according to another embodiment of the present invention includes a body 310 and a main channel 320 disposed in the body 310 and extending in one direction. , A plurality of culture chambers 330 are spaced apart from each other on the main channel 320, a first storage tank 341 is disposed at one end of the main channel 320 to store the first fluid, and the main channel ( 320, a second storage tank 342 for storing the first fluid, and a sub-channel 350 connected to at least one of the plurality of culture chambers 330 and extending in one direction and the other. , It is disposed at the end of the sub-channel 350, and includes an injection chamber 360 for supplying a second fluid to the culture chamber 330 through the sub-channel 350.

The body 310 forms a basic shape of the bio-mimicking chip device 300, and other members may be disposed. The body 310 may be the same as the body 210 of the bio-simulation chip device 200 according to an embodiment of the present invention described above, and detailed description thereof will be omitted.

Referring to FIG. 9, the main channel 320 is disposed on the body 310 and extends in one direction. The main channel 320 is disposed inside the body 310 to provide an internal passage through which the first fluid moves. One end of the main channel 320 is connected to the first storage tank 341, and the other end is connected to the second storage tank 342. In one embodiment of the present invention, the main channel 320 may be disposed inside the body 310, and in the X-axis direction (longitudinal direction of the bio-simulation chip device 300) to be parallel to the bottom surface of the body 310. Can be deployed. For example, the main channel 320 may be configured as a microscopic channel array having a width and height of 3 μm to 5 μm in order to guide and promote the direction in which the neurites of the brain models grow as the culture model M.

The first fluid is a fluid required to cultivate and grow the culture model (M), and in one embodiment of the present invention may be a culture solution that supplies oxygen and nutrients to the culture model (M).

The culture model M is not particularly limited, and may be a model corresponding to a specific part of the living body. In one embodiment of the present invention, the culture model (M) may be a 3D brain organoid model composed of nerve cells in different brain regions.

The culture chamber 330 is a member having an interior space in which the culture model M is cultured. A plurality of culture chambers 330 are disposed on the main channel 320, and a culture model M may be disposed in each culture chamber 330 to be cultured. The number of the culture chamber 330 and the culture model M is not particularly limited, and an appropriate number may be arranged in consideration of the characteristics of the culture model M and the purpose of the experiment.

The storage tank 340 may include a first storage tank 341 and a second storage tank 342 as members for storing and supplying the first fluid. The first storage tank 341 and the second storage tank 342 may be the same as the first storage tank 241 and the second storage tank 242 of the bio-simulation chip device 200 according to the embodiment of the present invention described above, , Detailed description thereof will be omitted.

The flow of the first fluid may be generated by tilting the body 310. For example, as the body 310 is tilted around a first axis perpendicular to one direction in which the main channel 320 extends (eg, axis AX _{1 in} FIG. 8), the first reservoir 341 And a flow of the first fluid in the second storage tank 342 and the main channel 320 connecting the same.

The sub-channel 350 is connected to the culture chamber 330 and is disposed inside the body 310 to provide an internal flow path through which the second fluid moves. The sub-channel 350 may include a first injection tube 351 and a second injection tube 352. Each of the first injection tube 351 and the second injection tube 352 extends from the culture chamber 330 and may be disposed to be symmetrical with each other. In an embodiment of the present invention, the first injection tube 351 and the second injection tube 352 may be arranged in a V shape around the culture chamber 330.

The sub-channel 350 may be disposed on the same plane as the main channel 320. The sub-channel 350 may be disposed for all the culture chambers 330, or may be selectively disposed for some culture chambers 330 that need to supply a second fluid.

In another embodiment, the sub-channels 350 may extend in opposite directions with respect to the culture chamber 330. That is, the first injection tube 351 and the second injection tube 352 are extended in opposite directions with respect to the culture chamber 330, so that the sub-channel 350 and the main channel 320 intersect each other. Can be.

The second fluid can be the same or different fluid than the first fluid. In one embodiment of the present invention, the second fluid may be a culture medium or a drug that imparts chemical stimulation to the culture model (M).

The injection chamber 360 is connected to an end of the sub-channel 350 and supplies a second fluid to the culture chamber 330 through the sub-channel 350. The injection chamber 360 may include a first injection portion 361 and a second injection portion 362. In one embodiment of the present invention, the first injection portion 361 and the second injection portion 362 may be inserted into the body 310 through a groove (not shown) formed on the upper surface of the body 310. The first injection part 361 is connected to the other end of the first injection tube 351, the second injection part 362 is connected to the other end of the second injection tube 352, and the first injection part 361 The second injection parts 362 are spaced apart from each other. That is, the first injection pipe 351 and the first injection portion 361 and the second injection pipe 352 and the second injection portion 362 may be disposed to be symmetrical to each other around the culture chamber 330. .

The first injection unit 361 and the second injection unit 362 each have an internal space for storing a second fluid therein. The first injection portion 361 and the second injection portion 362 may have various shapes, and in one embodiment of the present invention, may have a tapered shape or the like. In addition, in order to supply the second fluid from the outside, the first injection unit 361 and the second injection unit 362 may have an open top surface.

In another embodiment, the injection chamber 360 may be selectively activated when the flow of the first fluid is interrupted by the culture model M in the culture chamber 330. For example, when the culture model (M) is a neuron model, as the culture model (M) is cultured, the neural projections extending from each culture model (M) are connected to each other and the main channel (320) The flow path narrows. Accordingly, the flow resistance of the fluid in the main channel 320 increases, and the first fluid may not be smoothly supplied to the culture model M through the main channel 320. In this case, the second fluid may be supplied from the injection chamber 360 to the culture chamber 330 by tilting the body 310 to supply the culture solution to the culture model M. The body 310 may be tilted about a first axis (eg, axis AX _{1 in} FIG. 8) perpendicular to one direction in which the main channel 320 extends. In addition, the second fluid may be a culture medium.

In another embodiment, the second fluid stored in each injection chamber 360 may be different drugs. Accordingly, chemical stimulation may be imparted using different drugs to the culture model M disposed in each injection chamber 360.

The loading channel 370 has one end connected to the culture chamber 330 and is disposed inside the body 310 to provide an internal passage through which the culture model M can move. The loading channel 370 may extend in a direction different from one direction in which the main channel 320 extends. Accordingly, even if the body 310 is tilted to supply the first fluid, the first fluid does not leak from the main channel 320 to the loading chamber 380. In one embodiment of the present invention, the loading channel 370 may be arranged to be perpendicular to one direction in which the main channel 320 extends. Also, the loading channel 370 may be disposed on the same plane as the main channel 320.

The loading chamber 380 is connected to the other end of the loading channel 370 and is a member to which the culture model M is injected and seated from the outside. In one embodiment of the present invention, the loading chamber 380 may be inserted into the body 310 through a groove (not shown) formed on the upper surface of the body 310. The loading chamber 380 has an internal space in which the culture model M is seated. The loading chamber 380 may have various shapes, and in one embodiment of the present invention, may have an inner space and a tapered shape. In addition, the loading chamber 380 may have an open top surface so that the culture model M is injected from the outside.

The culture model M of the loading chamber 380 may be loaded into the culture chamber 330 through the loading channel 370 as the body 310 is tilted. Specifically, as the body 310 is tilted about a second axis parallel to one direction in which the main channel 320 extends (eg, axis AX _{2 in} FIG. 1), the culture in the loading chamber 380 The model M can be loaded into the culture chamber 330 by moving through the loading channel 370.

As another embodiment, the bio-simulation chip device 300 may selectively include a cover (not shown) that can open and close the upper surfaces of the storage tank 340, the injection chamber 360, and the loading chamber 380. Accordingly, the storage tank 340, the injection chamber 360 and the loading chamber 380 are covered by the cover even if the bio-simulation chip device 300 is tilted, so that the storage tank 340, the injection chamber 360 and the loading chamber It is possible to prevent the first fluid, the second fluid, or the culture model M from escaping from 380.

In another embodiment, the culture model M may be directly introduced into the culture chamber 330 without going through the loading channel 370 and the loading chamber 380. For example, the culture chamber 330 has an open top surface, such as a storage tank 340, so that the culture model M can be directly seated into the culture chamber 330. In this case, the bio-simulation chip device 300 does not have a loading channel 370 and a loading chamber 380, so it can be made of a simpler structure. In addition, the bio-simulation chip device 300 may further include a cover (not shown) for opening and closing the open top surface of the culture chamber 330.

As another embodiment, the body 310 may be formed by combining a plurality of members. For example, the body 310 may be divided into a lower body and an upper body, and after another member is disposed on the lower body, the upper body may be covered thereon. Accordingly, the culture model M can be observed by separating only the upper body from the lower body, or the culture model M can be taken out from the bio-simulation chip device 300.

As another embodiment, the main channel 320, the sub channel 350 and the loading channel 370 may be arranged to have a slope with respect to the bottom surface of the body 310. For example, the loading channel 370 can be arranged to slope downward toward the culture chamber 330. Accordingly, when the culture model M is injected into the loading chamber 380, the culture model M may be naturally moved to the culture chamber 330 along the loading channel 370 to be seated.

10 is an enlarged view of C of FIG. 9.

As described above, the main channel 320 is disposed to extend in one direction on the body 310, and the culture chamber 330 is disposed on the main channel 320. The culture model M is disposed inside the culture chamber 330 and cultured. The sub-channel 350 is connected to the culture chamber 330 and is arranged in a V shape around the culture chamber 330. The loading channel 370 extends from the main channel 320 in a direction different from one direction in which the main channel 320 is disposed.

In another embodiment, the diameter of the main channel (320) d ₁ and the diameter of the sub-channels (350) d ₂ may satisfy the relationship d ₁ <d _2. Accordingly, the hydraulic pressure of the first fluid flowing through the main channel 320 may be greater than the hydraulic pressure of the second fluid flowing through the sub-channel 350.

Hereinafter, with reference to FIGS. 8 to 12, the operation of the bio-simulation chip device 300 according to an embodiment of the present invention will be described.

11 is a view showing that the bio-simulation chip device 300 is tilted about the axis AX ₁ , and FIG. 12 is a view showing that the bio-simulation chip device 300 is tilted about the axis AX ₂ .

8 to 11, the axis AX ₁ may be positioned at the center of the X-axis direction of the bio-simulation chip device 300 so as to be parallel to the Y axis. As shown in FIG. 8, when the bio-simulation chip device 300 is tilted clockwise around the axis AX ₁ , the first fluid is supplied from the first reservoir 341 to incubate each through the main channel 320. It is supplied to the chamber 330. The first fluid is moved to the second storage tank 342 through the culture chamber 330. Conversely, when the bio-simulation chip device 300 is tilted counterclockwise around the axis AX ₁ , the first fluid is supplied from the second reservoir 342 and moves to the first reservoir 341.

In addition, when the bio-simulation chip device 300 is tilted clockwise around the axis AX ₁ , the second fluid stored in the first injection unit 361 is transferred to the culture chamber 330 through the first injection tube 351. After being supplied, it moves to the second injection part 362 through the second injection tube 352. Conversely, when the bio-simulation chip device 300 is tilted counterclockwise around the axis AX ₁ , the second fluid is cultured through the second injection tube 352, the second fluid stored in the second injection unit 362. After being supplied to the chamber 330, it is moved to the first injection unit 361 through the first injection tube 351.

8 to 10 and 12, the axis AX ₂ may be located on the bottom surface of the bio-simulation chip device 300 so as to be parallel to the X axis. In one embodiment of the present invention axis AX ₂ may be located below the culture model (M). As shown in Figure 12, when the bio-simulation chip device 300 is tilted clockwise around the axis AX ₂ , the culture model M injected into the loading chamber 380 is cultured through the loading channel 370 Go to (330).

As described above, the bio-simulation chip device 300 according to the present invention does not include a pump, a micro tube, or a tubing, and can easily form a flow of fluid by tilting the device based on gravity, so that the size of the device And weight can be reduced.

Meanwhile, the size of the culture model M may be larger than the size of the internal channel of the main channel 320. Accordingly, even if the biological simulation chip device 300 is tilted, the culture model M does not move from the culture chamber 330 to another culture chamber 330. That is, each culture model (M) can be cultured in a spatially separated state from other culture models (M).

In addition, the bio-simulation chip device 300 may further include a multi-electrode array (MEA). The multi-electrode array is disposed under the culture model (M) to measure electrical signals of the culture model (M). For example, a multi-electrode array may be arranged under the artificial neural network formed by the culture model M, and chemical stimulation may be applied to the culture model M to measure electrical signals generated from the artificial neural network.

In another embodiment, the main channel 320, the culture chamber 330, and the storage tank 340 may be arranged in a plurality of rows. Specifically, the biomimetic chip device 300 of the present invention may be configured to correspond to a standard 96-well microplate format. Accordingly, it is possible to increase the compatibility with the existing cell culture automation equipment, and to promote the practical use of high-speed and large-capacity screening.

13 is a perspective view showing the culture apparatus 100 according to another embodiment of the present invention, and FIG. 14 is a cross-sectional view showing the culture chamber system 1 in which the culture apparatus 100 of FIG. 13 is installed.

13 and 14, the culture device 100 is installed in the culture chamber system 1 and can culture cells in the biomimetic chip device 200. Various types of bio-simulation chip devices may be installed in the culture device 100, and an embodiment of the present invention will be described with reference to the culture device 100 on which the bio-mime chip device 200 is installed for convenience.

The culture chamber system 1 may include a housing 10, a circulation fan 20, and a controller 30. The culture device 100 of the bio-mimicking chip device 200 may be installed inside the housing 10. The inner plate 11 is disposed at the top and bottom of the housing 10, respectively. The inner plate 11 is provided with a plurality of through-holes (H), the air inside the housing 10 can maintain a uniform temperature in the entire area while flowing inside the chamber.

The circulation fan 20 is installed on one side of the housing 10, and allows air to flow to maintain a constant temperature inside the housing 10.

The controller 30 can control the culture chamber system 1 and the culture device 100. The controller 30 may control the operation of the circulation fan 20 or control the internal temperature of the culture chamber system 1 by driving a heating unit (not shown) or a cooling unit (not shown). In addition, the controller 30 may drive the driving unit 120 of the culture device 100 to generate the flow of the first fluid and the second fluid (hereinafter, also referred to as 'fluid') in the bio-simulation chip device 200. have.

The culture apparatus 100 may include a base 110, a driving unit 120, a support plate 130, and a connection frame 140. The culture device 100 may form a flow of fluid in the inner channel of the bio-simulation chip device 200 by tilting the support plate 130 in the left-right direction. That is, the culture apparatus 100 may generate a fluid flow based on gravity.

The base 110 has a flat plate shape and is supported on the bottom of the culture chamber system 1. A plurality of support plates 130 are spaced apart from the upper portion of the base 110.

The driving unit 120 is disposed between the base 110 and the support plate 130. The driving unit 120 may generate a driving force so that the support plate 130 rotates, and transmit the driving force to the support plate 130. The driving unit 120 is connected to a support plate disposed at the bottom of the plurality of support plates 130. That is, the driving unit 120 tilts only the support plate 130 disposed at the bottom, but other remaining support plates may also be tilted by the connection frame 140.

A connector 125 may be disposed between the driving unit 120 and the support plate 130. The connector 125 is mounted on the lower portion of the support plate 130 and is connected to the driving unit 120 to rotate. The tilting display unit 126 is mounted on one side of the connector 125 to check the tilting angle of the support plate 130.

15 is a plan view showing the support plate 130 of FIG. 13.

13 and 15, a plurality of support plates 130 may be provided and may be disposed to be spaced apart from each other in the height direction from the top of the base 110. A bio-mimicking chip device 200 may be mounted on the support plate 130.

When the driving plate 120 is driven, the support plate 130 is tilted around the first rotational axis P, and the fluid moves to the internal channel of the biomimicking chip device 200 by the inclination of the support plate 130. . The first rotation axis P may correspond to the axis AX ₁ of the bio-simulation chip device 200 according to the embodiment of the present invention described above.

As another embodiment, the support plate 130 may be configured to tilt around a second rotation axis (not shown) perpendicular to the first rotation axis P. That is, when the driving unit 120 is driven, the support plate 130 is tilted about the second rotation axis, and a flow is formed in the fluid inside the bio-simulation chip device 200 by the inclination of the support plate 130 do. At this time, the second rotation axis may correspond to the axis AX ₂ of the bio-simulation chip device 200. In this case, a tilting display unit (not shown) capable of checking the tilting angle along the axis AX ₂ may be additionally provided.

The support plate 130 may include a plurality of guide slits extending in at least two directions. The guide slit extends along the movement direction of the clamp 135 and can guide the movement of the clamp 135. The guide slit may include a first guide slit 131 extending in the front-rear direction and a second guide slit 132 extending in the width direction.

Clamps 135 are disposed on the first guide slit 131 and the second guide slit 132, respectively. The clamp 135 may support the side surface of the bio-mimicking chip device 200 in at least two directions. That is, the clamp 135 may move along the first guide slit 131 or the second guide slit 132 according to the size of the bio-simulation chip device 200, and hold a side surface of the bio-simulation chip device 200. Position can be fixed.

The support plate 130 is provided with a guide slit and a clamp 135, and the bio-mimicking chip device 200 having various sizes can be applied.

16 is a view showing a coupling relationship between the connection frame 140 and the support plate 130.

13 and 16, the connection frame 140 may extend in a height direction to connect a plurality of support plates 130. In addition, since the connection frame 140 is rotatably connected to the support plate 130, the support plate 130 may be tilted.

The connecting frame 140 is mounted to stack a plurality of support plates 130 and has at least three supporters for balance. The connection frame 140 is a first supporter 141 disposed on one side of the front side of the support plate 130 and a first supporter 141 disposed on the other side of the front side of the support plate 130 and disposed to face the first supporter 141. A second supporter 142 and a third supporter 143 disposed at the center of the back side of the support plate 130 may be provided.

The first supporter 141 and the second supporter 142 are disposed on both sides of the front surface of the support plate 130. Since no other structures are disposed on the front surface between the first supporter 141 and the second supporter 142, the bio-mimicking chip device 200 can be easily installed and removed. In detail, in order to install or remove the bio-mimicking chip device 200 from the support plate 130 disposed on the middle layer in FIG. 13, the first supporter 141 and the first supporter 141 are not disassembled. The bio-simulation chip device 200 may be installed or removed as a space between the second supporters 142. In addition, since no other structures are disposed in the space between the first supporter 141 and the second supporter 142, the bio-simulation chip device is automatically generated using a transfer device (not shown) outside the culture chamber system 1 200 can be installed or removed.

17A and 17B, when the support plate 130 is tilted, the first supporter 141 and the second supporter 142 move in opposite directions. That is, when the first supporter 141 rises, the second supporter 142 descends, and when the first supporter 141 descends, the second supporter 142 rises. Thus, the support plate 130 can be tilted in one direction. However, at this time, the first supporter 141 and the second supporter 142 do not move in the width direction of the support plate 130.

The third supporter 143 is disposed at the center of the rear surface of the support plate 130 to form a balance on the support plate 130. Since the third supporter 143 is disposed on the rear surface of the culture chamber system 1, even when the third supporter 143 is disposed at the center of the rear surface of the support plate 130, when installing or removing the biomimetic chip device 200 Does not interfere.

Since the third supporter 143 is disposed at the center, balance can be maintained. Unlike the first supporter 141 and the second supporter 142, the third supporter 143 does not move in the height direction even if the support plate 130 is tilted. Since the position of the third supporter 143 is fixed when the support plate 130 is rotated, the support plate 130 can be stably installed.

The support plate 130 rotates around the first rotation axis P. The first rotation shaft P is disposed to penetrate the center of the support plate 130. The first rotation shaft P extends from the center between the first supporter 141 and the second supporter 142 toward the third supporter 143.

The connecting frame 140 may extend in a height direction by connecting a plurality. The first supporter 141 may connect the 1a supporter 141a and the 1b supporter 141b, and the second supporter 142 may connect the 2a supporter 142a and the 2b supporter 142b.

16, the 1a supporter 141a and the 1b supporter 141b are connected by inserting a projection 146 into the insertion hole 147. That is, the protrusion 146 of the 1b supporter 141b is inserted into the insertion hole 147 of the 1a supporter 141a and extends in the height direction. At this time, a magnetic material is disposed in the protrusion 146 or the insertion hole 147 to improve the bonding force.

The connection frame 140 is connected so that the support plate 130 can rotate. The connection frame 140 is provided with a pivot pin 145, and the pivot pin 145 is inserted into the opening of the connection end 136 disposed under the support plate 130. Since the pivot pin 145 can rotate at the connection end, the support plate 130 can be tilted.

17A and 17B are diagrams showing the operation of the culture apparatus 100.

17A and 17B, the culture apparatus 100 may tilt the support plate 130 to form a flow of fluid. When the driving unit 120 rotates in one direction, one side of the support plate 130 and the first supporter 141 descend, and the other side of the support plate 130 and the second supporter 142 rise. Thereby, the fluid moves from the other side of the bio-simulation chip device 200 to one side.

In addition, when the driving unit 120 rotates in the other direction, one side of the support plate 130 and the first supporter 141 rise, and the other side of the support plate 130 and the second supporter 142 descend. Thereby, the fluid moves from one side of the bio-simulation chip device 200 to the other side.

The tilting angle of the support plate 130 can be controlled by the controller 30. The tilt angle of the support plate 130 determines the flow rate of the fluid. If the tilting angle of the support plate 130 is large, the velocity of the fluid flowing through the channel of the biomimetic chip device 200 is fast, whereas, if the tilting angle is small, the microchannel of the biomimetic chip device 200 flows The velocity of the fluid is slow. Therefore, the controller 30 can control the flow rate of the fluid by adjusting the tilting angle of the support plate 130, thereby controlling the culture speed of the culture model.

In addition, the tilting period of the support plate 130 can be controlled by the controller 30. The injection timing of the tilting cycle of the support plate 130 is determined. Therefore, the controller 30 can change the tilting cycle to adjust the timing of the fluid injection according to each culture model.

When the support plate 130 is tilted, the first supporter 141 and the second supporter 142 move in the height direction, but do not move in the width direction of the support plate 130. Since the first supporter 141 and the second supporter 142 are connected to rotate with the support plate 130, when the support plate 130 is tilted, the first supporter 141 and the second supporter 142 are high. Move only in the direction.

If the first supporter and the second supporter move in the width direction, that is, if the connecting frame performs a pendulum motion, the rotation distance of the biomimetic chip device disposed at the lower side and the rotation distance of the biomimetic chip device disposed at the upper part are different. . Therefore, since the flow amount of fluid in the bio-simulated chip device disposed on the top and the flow amount of fluid on the microfluidic device disposed on the bottom are different from each other, each layer cannot be uniformly cultured.

In addition, if the first supporter and the second supporter move in the width direction, the support plate disposed at the top is shaken in the left-right direction, and the device becomes unstable.

However, the culture device 100 of the biomimetic chip device 200 according to the present invention is the first supporter 141 and the second supporter 142 is disposed to be rotatable with the support plate 130, the first supporter 141 ) And the second supporter 142 moves only in the height direction. Thus, the culture device 100 only changes the height of both ends of the bio-simulation chip device 200, and does not move the position. Thus, the culture device 100 can form a constant flow of fluid in the bio-simulation chip device 200 and improve the stability of the device.

In another embodiment, the culture device 100 may allow the controller 30 to adjust the tilt angle and the tilting cycle of the bio-mimicking chip device 200 to flow fluid to suit each culture model. For example, the speed of the fluid may be adjusted by adjusting the tilting angle of the support plate 130. In addition, by adjusting the tilting cycle of the support plate 130, it is possible to adjust the timing of the fluid injection.

In addition, the tilting angle of the support plate 130 can be continuously adjusted according to the culture model. For example, if the fluid should be supplied under different conditions according to the culture model M of the biomimetic chip device 200, the controller 30 adjusts the tilting angle each time the fluid passes through each culture chamber 230. Can be.

Through such a configuration, the culture apparatus 100 according to the present invention can culture the culture model M by reflecting the body environment and perform experiments by controlling the flow rate and injection timing of the fluid.

In the present invention, the culture apparatus 100 may flow in a fluid by forming an inclination in the biomimetic chip apparatus 200 without installing an additional driving source in the biomimetic chip apparatus 200. Since the fluid flows on a gravitational basis, it is possible to simply move the fluid and supply a certain amount of fluid.

The culture device 100 according to the present invention may apply a biological simulation chip device 200 of various sizes. Since the clamp 135 of the support plate 130 can move along the guide slit, the biomimicking chip device 200 of various sizes can be fixed to the support plate 130.

The culture apparatus 100 according to the present invention can maintain a constant flow rate of a fluid and secure structural stability. Since the first supporter 141 and the second supporter 142 are disposed to be rotatable with the support plate 130, the first supporter 141 and the second supporter 142 move only in the height direction and in the width direction Since it does not move, since the tilting angle and tilting distance of the support plate 130 are constant for each layer, the biomimetic chip device 200 installed in each layer can move a certain amount of fluid and ensure structural stability of the device. .

18 is a view showing a culture method using the culture device 100 according to another embodiment of the present invention.

Referring to FIG. 18, a culture method using the culture apparatus 100 according to another embodiment of the present invention comprises the steps of: seating the biomimetic chip device 200 on the culture apparatus 100 (S100), and the mounted biomimetics The step of fixing the chip device 200 (S200) and the step of tilting the biological simulation chip device 200 (S300) are included.

First, the bottom surface of the body 210 of the bio-simulation chip device 200 is seated on the top surface of the support plate 130 of the culture device 100. At this time, the first fluid is injected into the storage tank 240 of the bio-simulation chip device 200. In addition, a non-exposed model (M _A ) of the culture model (M) is mounted in the loading chamber, and an exposure model (M _B ) of the culture model (M) is seated in the culture unit 250. Corresponding to the number of support plates 130, a plurality of bio-simulation chip devices 200 may be seated.

Next, the seated bio-simulation chip device 200 is fixed with a clamp 135. Referring to FIG. 15, in a state where the bio-simulation chip device 200 is seated on the upper surface of the support plate 130, the bio-simulation chip device 200 is moved by moving the clamp 135 along the guide slits 131 and 132. Can support.

Next, by tilting the support plate 130 by operating the driving unit 120, the bio-simulation chip device 200 is tilted. As described above, the plurality of support plates 130 are connected by the connection frame 140. Therefore, even if only the support plate 130 disposed at the bottom is tilted according to the operation of the driving unit 120, the remaining support plates 130 may be tilted together.

Tilting the support plate 130 (S300) comprises: tilting the support plate 130 to seat the culture model M in the culture chamber 230, and tilting the support plate 130 to first fluid It may include the step of supplying to the culture model (M).

Specifically, the driving plate 120 is operated through the controller 30 to tilt the support plate 130 around the second rotation axis (not shown). As described above, the second rotation axis is an axis perpendicular to the first rotation axis P, and may correspond to the axis AX ₂ . Accordingly, the unexposed model M loaded in the loading chamber moves from the loading chamber to the culture chamber 230 along the loading channel. In addition, a non-exposure model M _A is placed in each culture chamber 230, and an exposure model M _B is set in the culture unit 250. After the non-exposure model M _A is seated in the culture chamber 230, the drive unit 120 is operated again to tilt the support plate 130 around the second rotation axis, thereby maintaining the horizontality of the support plate 130 Can be. The tilting angle can be properly adjusted through the controller 30.

Next, the driving plate 120 is operated to tilt the support plate 130 around the first rotational axis P. Specifically, the use of the controller 30 by operating the driving system 120, support plate 130, the first pivot axis (P _-) when rotated in the clockwise direction around the, the first reservoir 241, second It is positioned higher than the reservoir 242. Accordingly, the first fluid stored in the first reservoir 241 is supplied to the culture model M while passing through the main channel 220, and then supplied to the second reservoir 242. In contrast, the support plate 130, the first pivot axis (P _-) goes through the case to the center rotating in a counterclockwise direction, the second reservoir 242, the first fluid of the main channel 220, stored in the culture After being supplied to the model M, it is supplied to the second storage tank 242. That is, by tilting the support plate 130, it is possible to form a flow of the first fluid in the bio-simulation chip device 200.

Depending on the type and culture timing of the culture model M, an appropriate tilting angle and tilting cycle may be set using the controller 30 to match the optimum culture conditions or experimental conditions. Specifically, the tilting angle of the support plate 130 may be increased to increase the flow rate of the first fluid, or the tilting angle of the support plate 130 may be decreased to decrease the flow rate of the first fluid. Alternatively, the timing at which the first fluid is supplied to the culture model M may be controlled by adjusting the tilting cycle. In addition, the tilting angle of the support plate 130 can be continuously adjusted according to the culture model M. For example, when the first fluid is to be supplied under different conditions for the non-exposed model M _A and the exposed model M _B , the first fluid is used to generate the non-exposed model M _A using the controller 30. The tilting angle when passing and the tilting angle when passing through the exposure model M _B may be adjusted differently.

In another embodiment, material exchange between the first fluid and the second fluid may be performed by tilting the support plate 130. For example, the first fluid is supplied to the culture model (M) by tilting the support plate 130 by rotating the first pivot (P) clockwise, and then the first pivot (P) is counterclockwise. Rotate to tilt the support plate 130 again. Accordingly, a flow of the first fluid is formed in the bypass channel 260, and a flow of the second fluid is formed in the sub channel 280. In addition, mass exchange between the first fluid and the second fluid occurs through the membrane 290 disposed at the interface between the bypass channel 260 and the sub-channel 280. That is, waste products or the like may move from the first fluid to the second fluid, and nutrients or the like may move from the second fluid to the first fluid.

In another embodiment, when the culture model (M) is cultured using the culture device 100 equipped with the biomimicking chip device 300 according to the present invention, the second fluid stored in the injection chamber 360 is cultured. The support plate 130 can be tilted to supply it to the chamber 330. For example, as the culture model M in the biomimetic chip device 300 is cultured, the flow cross-sectional area of the main channel 320 may be narrowed due to neural projections extending from the culture model M. Accordingly, the fluid flow resistance in the main channel 320 is increased, and the first fluid may not flow smoothly. In this case, after injecting a second fluid into the injection chamber 360 of the bio-simulation chip device 300, tilting the support plate 130 around the first rotational axis P, from the injection chamber 360 The second fluid is supplied to the culture model (M). At this time, the second fluid may be the same fluid as the first fluid.

In another embodiment, in the case of using the biomimetic chip device 300 according to the present invention, different chemical stimuli may be imparted to each culture model M by tilting the support plate 130. For example, a second fluid is injected into the injection chamber 360 of the bio-simulation chip device 300. In this case, different types of second fluid may be injected into each injection chamber 360, and the second fluid may be a drug for imparting chemical stimulation to the culture model M. Next, when the support plate 130 is tilted around the first rotation axis P, the second fluid is supplied from the injection chamber 360 to the culture model M. As described above, the culture model M given the chemical stimulation by the second fluid may display different electrical signals.

In yet another embodiment, the method may further include measuring an electrical signal of the culture model M of the biomimicking chip device 300 according to the present invention. For example, in the culture device 100 equipped with a bio-simulation chip device 300 having a multi-electrode arrangement, as described above, by tilting the support plate 130 around the first rotational axis P , Chemical stimulation can be imparted to the culture model (M). Accordingly, an electrical signal generated from the culture model M can be measured. In this case, the culture apparatus 100 may be further provided with a display means capable of visually displaying an electrical signal generated in the culture model M in connection with a multi-electrode arrangement.

In the case of a conventional cell culture device, it is common to culture a two-dimensional cell model in a static environment to form up to two neural networks. However, such a conventional cell culture device is focused on the convenience of the experiment, and actual biocompatibility is poor. Specifically, in the case of a two-dimensional cell model, the shape of the cell model is flat and stretched on the surface, all cells are uniformly exposed to the culture solution and the drug, and the connection between cells is only connected in one direction, so that Different. In addition, since the cell model is statically cultured, it is impossible to implement cell culture conditions that reflect the actual biological environment.

On the other hand, the culture model (M) according to an embodiment of the present invention is a three-dimensional organoid model, the shape of the cell model has a shape in an actual living body (ellipsoid, etc.), and the culture solution in the cell model as in a real living environment And drug concentration gradients exist, and intercellular connections are made on all sides of the cell, resembling the real biological environment. In addition, the biomimetic chip device according to an embodiment of the present invention can implement a cell culture condition reflecting an actual bioenvironment by culturing a 3D organoid model in a dynamic culture environment.

In particular, the biomimetic chip device according to the present invention does not have a pump or a micro tube, and can simply form a fluid flow by tilting the device based on gravity, thereby reducing the size and weight of the device. .

In addition, the biomimetic chip device according to the present invention includes a culture model for non-exposed organs and exposed organs in a living body, and controls the flow of fluid to be the same as the flow of blood inside the living body, thereby realizing the same culture environment as the real biological environment You can.

In addition, the biomimetic chip device according to the present invention can be placed in a culture chamber so that the culture models are spatially separated from each other, and selectively stimulate a specific culture model by supplying different drugs for each culture model.

In addition, the bio-simulation chip device according to the present invention can realize a real bio-network by connecting the culture models cultured in the culture chamber to each other. In particular, by culturing different neural cell models that mimic specific parts of a living body as a culture model to form an artificial neural network, it is possible to effectively observe the reaction in the artificial neural network when stimulating a specific culture model.

In the present specification, the present invention has been mainly described with limited embodiments, but various embodiments are possible within the scope of the present invention. Also, although not described, it will be said that equivalent means are also incorporated into the present invention. Therefore, the true protection scope of the present invention should be defined by the claims below.

1: Culture system
100: culture device
200: bio-simulation chip device
200: bio-simulation chip device
M: culture model
M _A : Non-exposure model
M _B : Exposure model

Claims (10)

body;
A main channel disposed in the body and extending in one direction;
A plurality of culture chambers spaced apart from each other on the main channel;
A first storage tank disposed at one end of the main channel and storing a first fluid; And
It is disposed on the other end of the main channel, a second reservoir for storing the first fluid; includes,
The body is tilted around a first axis perpendicular to the one direction to flow the first fluid between the first reservoir and the second reservoir, a bio-simulation chip device. According to claim 1,
The bio-simulation chip device
A plurality of culture models are cultured in the culture chamber, wherein the plurality of culture models are arranged along the one direction in the order in which blood is supplied in vivo. According to claim 2,
The culture model includes a non-exposure model inside the living body and an exposure model outside the living body,
The first fluid flows from the first reservoir through the culture chamber for culturing the non-exposure model and the culture chamber for culturing the exposure model, and flows to the second reservoir. According to claim 1,
And a bypass channel disposed in parallel with the main channel to return the first fluid moved from the first reservoir to the second reservoir to the first reservoir. According to claim 4,
When the body is tilted in the first direction, the first fluid moves along the main channel,
When the body is tilted in a second direction opposite to the first direction, the first fluid moves along the bypass channel. According to claim 4,
A first valve unit disposed at both ends of the main channel; And
And a second valve unit disposed at both ends of the bypass channel. The method of claim 6,
The first valve unit and the second valve unit are ball valves that move the first fluid in a predetermined flow direction, and a bio-simulation chip device. According to claim 4,
The second fluid is moved, a portion of the sub-channel is arranged in parallel with the bypass channel; further comprises,
And the first fluid moving the bypass channel exchanges material with the second fluid moving the sub-channel. The method of claim 8,
And a membrane between the bypass channel and the sub-channel. The method of claim 8,
The bypass channel and the sub-channel
A biomimetic chip device in which the first fluid and the second fluid exchange substances when the body rotates in a predetermined direction.

Images