Organ chip platform integrated with optical tweezers

Abstract

The utility model relates to the technical field of biological tissue engineering, in particular to an organ chip platform integrated with optical tweezers, which is used for assembling and culturing three-dimensional cell tissues and comprises an organ chip with optical transparency and holographic optical tweezers integrated with the organ chip. The organ chip is horizontally arranged and comprises an upper-layer plate, a middle-layer plate and a lower-layer plate which are sequentially stacked, the middle-layer plate is provided with at least two first culture pools used for inducing and differentiating stem cells into different types of cells and at least one second culture pool used for assembling and culturing the different types of cells, and the lower-layer plate is provided with at least two second culture pools used for assembling and culturing the different types of cells. The channel is connected with the first culture pond and the second culture pond; and an objective lens of the holographic optical tweezers faces the top surface or the bottom surface of the organ chip and is used for capturing, moving and assembling cells in the first culture pool or the second culture pool. According to the utility model, the dependence on a micro-pattern processing technology can be reduced, the cost is reduced, and the regulation and control capability on an organoid tissue structure is improved.

Description

Technical Field

[0001] The utility model relates to the technical field of biological tissue engineering, in particular to an organ chip platform integrated with optical tweezers. Background Art

[0002] Organ-on-a-chip is a new research model that can achieve biomimetic construction of a dynamic physiological microenvironment in vitro, control the spatial positioning and differentiation direction of stem cells, and guide stem cells to self-organize into more orderly and repeatable tissue structures similar to real organs, thereby generating corresponding organ functions. It provides a low-cost model for disease research and drug screening that is closer to real physiological and pathological conditions.

[0003] When existing organ chips are used to construct organoid tissues, they usually do so by engraving or printing fine micron-scale patterns on the organ chip, or by utilizing micro-molding technology, such as creating micropores and microchannels, to spatially confine and guide cells in a culture environment. This allows stem cells to utilize their self-organization and self-patterning capabilities, with the help of physical or chemical induction methods, to construct organ chips that simulate the advanced stages of organ development.

[0004] When constructing organoid tissue, this type of organ chip relies heavily on the intricate patterns or three-dimensional structures engraved on it. However, the processing technology for micropatterns remains challenging, costly, and difficult to implement. Furthermore, existing technologies primarily act indirectly on stem cells by regulating the culture environment. Their effectiveness depends on the stem cells' responsiveness to changes in the culture environment and their ability to self-organize. This involves numerous uncontrollable factors, thus limiting their ability to regulate organoid tissue structure. Utility Model Content

[0005] (1) Technical issues to be resolved

[0006] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides an organ chip platform with integrated optical tweezers, which solves the technical problems of the existing organ chip, such as high production cost, difficulty in realization, and limited ability to regulate the tissue structure of organoids.

[0007] (2) Technical solution

[0008] In order to achieve the above-mentioned purpose, the main technical solutions adopted by this utility model include:

[0009] The present invention provides an organ chip platform with integrated optical tweezers, wherein the organ chip platform is used to assemble and culture three-dimensional cell tissues, and comprises an organ chip with optical transparency and holographic optical tweezers integrated with the organ chip;

[0010] The organ chip is arranged horizontally, including an upper plate, a middle plate and a lower plate stacked in sequence. The middle plate is provided with at least two first culture pools for inducing stem cells to differentiate into different types of cells, at least one second culture pool for assembling and culturing the different types of cells, and a channel connecting the first culture pool and the second culture pool; the objective lens of the holographic optical tweezers faces the top surface or bottom surface of the organ chip and is used to capture, move and assemble cells in the first culture pool or the second culture pool.

[0011] Optionally, the holographic optical tweezers include:

[0012] A laser light source, for generating a laser beam;

[0013] an optical path component, disposed between the laser light source and the organ chip, for transmitting and adjusting the laser beam so that the laser beam is irradiated on the organ chip and forms one or more optical traps for capturing, moving, and assembling cells;

[0014] A spatial light modulator is provided between the laser light source and the optical path component, and is used to adjust the position and movement path of the light trap;

[0015] a detection component, used for acquiring images of cells in the organ chip;

[0016] The controller is in communication with the laser light source, the spatial light modulator, the optical path component and the detection component.

[0017] Optionally, the optical path assembly comprises: a beam reduction lens, a dichroic mirror and an objective lens arranged in sequence according to the propagation path of the laser beam;

[0018] The beam reduction lens is used to receive the coded beam generated by the laser light source after being modulated by the spatial light modulator, and adjust the thickness of the coded beam to obtain a shaped beam;

[0019] The dichroic mirror is used to reflect the shaped light beam to the objective lens;

[0020] The objective lens is used to focus the shaped light beam on the organ chip to form a light trap.

[0021] Optionally, the detection assembly includes: an illumination light source, a collimating lens and a CCD (charge coupled device) camera;

[0022] The illumination light source is disposed directly below the organ chip and generates an illumination beam;

[0023] The collimating lens is disposed between the illumination light source and the organ chip, and is used to converge the illumination light beam into a collimated illumination light beam and irradiate the organ chip;

[0024] The CCD camera is disposed directly above the organ chip and is configured to receive a transmitted light beam formed by the collimated illumination light beam passing through the organ chip, and generate an image of cells in the organ chip.

[0025] Optionally, a control valve for blocking the channel is provided on the channel.

[0026] Optionally, the upper plate is provided with a clearance cavity corresponding to the position of the control valve;

[0027] The control valve includes: an electromagnet and a magnet block for blocking the channel, and the magnet block matches the shape of the give way cavity;

[0028] When the electromagnet is energized, the magnet block moves from the channel to the give way cavity under the action of the magnetic field of the electromagnet, so that the channel is conductive;

[0029] When the electromagnet is powered off, the magnet block moves from the clearance cavity to the channel under the action of gravity to block the channel.

[0030] Optionally, each of the first culture tank and the second culture tank further comprises:

[0031] A liquid inlet pipe, used for inputting new culture medium liquid or medicine into the first culture tank and the second culture tank from the outside;

[0032] The liquid outlet pipe is used for the first culture tank and the second culture tank to discharge old culture medium liquid or medicine to the outside.

[0033] Optionally, the bottom of the second culture tank is an arc surface, a plane surface or an inverted cone surface.

[0034] (3) Beneficial effects

[0035] The organ chip platform with integrated optical tweezers provided by the present invention includes an organ chip with optical transparency and holographic optical tweezers integrated with the organ chip; when used for three-dimensional cell assembly, the first culture tank is used to culture stem cells separately and induce differentiation into at least two types of cells, the holographic optical tweezers are used to capture different cells in different first culture tanks, and move the cells from the first culture tank to the second culture tank, and in the second culture tank, assemble the different types of cells into an initial three-dimensional cell tissue according to the proportion, sequence and pattern structure in the target organ tissue, and culture the initial three-dimensional cell tissue in the second culture tank to obtain a three-dimensional cell tissue with a target pattern structure.

[0036] The organ-on-a-chip platform provided by this utility model uses holographic optical tweezers to assemble cells into three-dimensional cellular tissues. Compared to existing organ-on-a-chip systems, this platform no longer relies on finely patterned structures. Instead, it only requires the relatively simple configuration of a first culture tank, a second culture tank, and a channel. This reduces reliance on micropatterning techniques, lowers costs, and facilitates implementation. Furthermore, using holographic optical tweezers to assemble cells causes less damage and contamination to cells, and allows for more precise control of the structure and morphology of three-dimensional cellular tissues, improving the ability to regulate the resulting organoid tissue structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Schematic diagram of the top view of the organ chip provided in the embodiment;

[0038] Figure 2 Schematic diagram of the structure of the organ chip platform with integrated optical tweezers provided in the embodiment;

[0039] Figure 3 for Figure 1 AA section view in the figure;

[0040] Figure 4 for Figure 1 AA section view in.

[0041] [Description of Reference Numerals]

[0042] 100, organ chip; 101, upper plate; 102, middle plate; 103, lower plate; 104, first culture tank; 105, second culture tank; 106, channel; 107, receptacle;

[0043] 2. Objective lens; 3. Laser light source; 4. Spatial light modulator; 5. Beam reduction lens; 6. Dichroic mirror; 7. Illumination light source; 8. Collimating lens; 9. CCD camera; 10. Third reflector; 11. Electromagnet; 12. Magnet block; 13. Liquid inlet pipe; 14. Liquid outlet pipe. DETAILED DESCRIPTION

[0044] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below through specific implementation methods in conjunction with the accompanying drawings.

[0045] An embodiment of the present invention provides an organ chip platform with integrated optical tweezers, which is used to assemble and culture three-dimensional cell tissues. The platform includes an organ chip 100 with optical transparency and holographic optical tweezers integrated with the organ chip.

[0046] The organ chip 100 is placed horizontally on a stage. Figures 1 to 4As shown, the organ chip 100 is arranged horizontally and includes an upper plate 101, a middle plate 102, and a lower plate 103 stacked in sequence. The middle plate 102 is provided with at least two first culture pools 104 for inducing stem cell differentiation into different cell types, at least one second culture pool 105 for assembling and culturing the different cell types, and a channel 106 connecting the first and second culture pools. The objective lens 2 of the holographic optical tweezers faces the top or bottom surface of the organ chip 100 and is used to capture, move, and assemble cells in the first culture pool 104 or the second culture pool 105. It should be noted that the cells here can be single cells or three-dimensional cell spheres. To ensure that the organ chip 100 has high light transmittance and low cytotoxicity, the materials of the upper plate 101, the middle plate 102, and the lower plate 103 can be highly optically transparent glass or a polymer, specifically one of polystyrene (PS), polycarbonate (PC), and polydimethylsiloxane (PDMS).

[0047] When the organ chip platform with integrated optical tweezers provided by the present invention is used for three-dimensional cell assembly, the first culture pool 104 is used to culture stem cells separately and induce differentiation into at least two types of cells, and the holographic optical tweezers are used to capture different cells in different first culture pools 104, and move the cells from the first culture pool 104 to the second culture pool 105, and assemble different types of cells into initial three-dimensional cell tissue in the second culture pool 105 according to the proportion, sequence and pattern structure in the target organ tissue, and culture the initial three-dimensional cell tissue in the second culture pool 105 to obtain a three-dimensional cell tissue with a target pattern structure.

[0048] The organ-on-a-chip platform provided by this utility model uses holographic optical tweezers to assemble cells into three-dimensional cellular tissues. Compared to existing organ-on-a-chip systems, this platform no longer relies on finely patterned structures. Instead, it only requires the relatively simple configuration of a first culture tank, a second culture tank, and a channel. This reduces reliance on micropatterning techniques, lowers costs, and facilitates implementation. Furthermore, using holographic optical tweezers to assemble cells causes less damage and contamination to cells, and allows for more precise control of the structure and morphology of three-dimensional cellular tissues, improving the ability to regulate the resulting organoid tissue structure.

[0049] In a specific implementation of this embodiment, Figure 2 As shown, the holographic optical tweezers include: a laser light source 3, an optical path component, a spatial light modulator 4, a detection component and a controller.

[0050] The laser light source 3 is used to generate a laser beam. The wavelength and power of the laser beam are adjustable. Preferably, in order to reduce damage to cells or cell spheres, the wavelength range of the laser beam can be 1064nm to 1500nm, and the power range can be 30mW to 3W. More preferably, the wavelength of the laser beam is 1064nm. The diameter of cells or cell spheres is usually 5 to 500 microns. The larger the size, the greater the beam energy required and the greater the power of the laser light source. The wavelength of the laser light source commonly used in existing optical tweezers is 540nm, which will damage the cell spheres under high power. This embodiment selects a 1064nm light source, which neither damages the cell spheres nor increases the power, improves the beam energy, and manipulates micron-sized cell spheres.

[0051] The optical path component is disposed between the laser light source 3 and the organ chip 100 and is used to transmit and adjust the laser beam so that the laser beam is irradiated on the organ chip 100 and forms one or more light traps for capturing, moving and assembling cells.

[0052] The spatial light modulator is disposed between the laser light source 3 and the optical path component, and is used to adjust the position and movement path of the light trap.

[0053] The detection component is used to obtain images of cells in the organ chip 100.

[0054] The controller is in communication connection with the laser light source 3, the spatial light modulator 4, the optical path component and the detection component.

[0055] It should be noted that the method for regulating the laser beam by the spatial light modulator 4 and the method for controlling the laser light source 3, spatial light modulator 4, optical path components, and detection components by the controller are all prior arts. The present invention only provides a connection relationship or positional relationship between the various components of a holographic optical tweezers, as well as a relative positional relationship between the various components of the holographic optical tweezers and the organ chip 100. It does not involve improvements to the spatial light modulator 4 and the controller itself, or the computer program loaded thereon.

[0056] More specifically, in the above-mentioned holographic optical tweezers, the optical path component specifically includes: a beam reduction lens 5 , a dichroic mirror 6 and an objective lens 2 which are arranged in sequence according to the propagation path of the laser beam.

[0057] The beam reduction lens 5 is used to receive the coded beam generated by the laser light source 3 after being modulated by the spatial light modulator 4, and adjust the thickness of the coded beam to obtain a shaped beam.

[0058] The dichroic mirror 6 is used to reflect the shaped light beam to the objective lens 2 .

[0059] The objective lens 2 is used to focus the shaped light beam onto the organ chip 100 to form a light trap.

[0060] In the above optical path components, a first reflector can also be added between two adjacent optical path components to adjust the propagation path of the laser beam and optimize the spatial layout of the holographic optical tweezers on the organ chip platform.

[0061] More specifically, in the holographic optical tweezers, the detection assembly includes an illumination light source 7, a collimating lens 8, and a CCD camera 9. The detection assembly can be configured to match the position of the objective lens 2. More preferably, the objective lens 2 is located directly above the organ chip 100. The configuration of the detection assembly is as follows:

[0062] The illumination light source 7 is disposed directly below the organ chip and generates an illumination beam. Specifically, the illumination light source 7 can be an LED lamp, which can be directed directly toward the organ chip 100. If the LED lamp cannot be directed directly toward the organ chip 100 for space conservation, a second reflector can be used to reflect the illumination beam vertically toward the organ chip.

[0063] The collimating lens 8 is disposed between the illumination light source 7 and the organ chip 100 , and is used to converge the illumination light beam into a collimated illumination light beam and illuminate the organ chip 100 .

[0064] The CCD camera 9 is positioned directly above the organ chip 100 and is configured to receive the transmitted light beam formed by the collimated illumination beam passing through the organ chip 100. The transmitted light beam passes through the dichroic mirror 6 and enters the CCD camera 9, thereby forming an image of the cells within the organ chip 100. Specifically, the CCD camera can be directed directly toward the organ chip 100. If this is not possible due to spatial layout considerations, a third reflector 10 can be used to vertically reflect the transmitted light beam toward the CCD camera 9.

[0065] Based on the aforementioned holographic optical tweezers, when cells need to be manipulated to move, a laser beam is directed at the cell or cell sphere using the holographic optical tweezers. The refraction, scattering, and absorption effects of the beam generate a light field gradient around the cell or cell sphere, forming an optical potential well (light trap), which constrains the cell or cell sphere within the light field. The cell or cell sphere shifts with the movement of the beam or the stage, thereby enabling the capture, movement, or assembly of the cell or cell sphere.

[0066] In a preferred implementation scheme of this embodiment, in order to prevent the first culture tank 104 and the second culture tank 105 from contaminating each other during the culture process, a control valve for sealing the channel is provided on the channel 106 so as to isolate the culture environment of the first culture tank 104 and the second culture tank 105 when there is no need to move the cells in the first culture tank to the second culture tank.

[0067] Specifically, if Figure 3 and Figure 4 As shown, the organ chip includes an upper plate 101, a middle plate 102 and a lower plate 103 stacked in sequence, the middle plate 102 is provided with a first culture pool 104, a second culture pool 105, and a channel 106 connecting the first culture pool 104 and the second culture pool 105, and the upper plate 101 is provided with a clearance cavity 107 corresponding to the position of the control valve.

[0068] The control valve includes an electromagnet 11 and a magnet block 12 for blocking the channel, and the magnet block 12 matches the shape of the clearance cavity 107. The electromagnet 11 can be installed on the top surface of the upper plate 101, directly above the clearance cavity 107, to better attract the magnet block 12 and allow it to move between the clearance cavity 107 and the channel 106 below.

[0069] Preferably, the height of the magnet block 12 in the vertical direction is slightly greater than the height of the channel 106 , so as to improve the blocking effect of the magnet block 12 on the channel 106 .

[0070] like Figure 3 As shown, when the electromagnet 11 is energized, the magnet block 12 moves from the channel 106 to the clearance cavity 107 under the action of the magnetic field of the electromagnet 11, so that the channel 106 is conductive; Figure 4 As shown, when the electromagnet 11 is powered off, the magnet block 12 moves from the clearance cavity 107 to the channel 106 under the action of gravity to block the channel.

[0071] In addition, in order to more conveniently replace the culture solution or medicine in the first culture tank 104 and the second culture tank 105, each of the first culture tank 104 and the second culture tank 105 further includes: Figure 1 The liquid inlet pipe 13 and the liquid outlet pipe 14 shown:

[0072] The liquid inlet pipe 13 is used to input new culture medium liquid or medicine from the outside to the first culture tank 104 and the second culture tank 105; the liquid outlet pipe 14 is used to discharge old culture medium liquid or medicine from the first culture tank 104 and the second culture tank 105 to the outside.

[0073] To facilitate cell assembly and maintain the morphology of the assembled 3D tissue, the bottom of the second culture tank 105 is a circular arc, flat surface, or inverted cone. Users can choose an organ chip with a different bottom shape based on the desired 3D tissue structure.

[0074] In this utility model, unless otherwise specified or limited, the terms "installed," "connected," "connect," "fixed," etc. should be understood in a broad sense. For example, they can refer to fixed connection, detachable connection, or integration; mechanical connection, electrical connection; direct connection, or indirect connection through an intermediate medium; internal communication between two components, or interaction between two components. Those skilled in the art will understand the specific meanings of the above terms in this utility model based on specific circumstances.

[0075] In the present invention, unless otherwise expressly specified or limited, when a first feature is “above” or “below” a second feature, it may mean that the first and second features are in direct contact, or that the first and second features are in indirect contact through an intermediate medium. Moreover, when a first feature is “above,” “above,” or “above” a second feature, it may mean that the first feature is directly above or obliquely above the second feature, or simply means that the first feature is at a higher level than the second feature. When a first feature is “below,” “below,” or “below” a second feature, it may mean that the first feature is directly below or obliquely below the second feature, or simply means that the first feature is at a lower level than the second feature.

[0076] In the description of this specification, the description of the terms "one embodiment", "some embodiments", "embodiment", "example", "specific example" or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present utility model. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples without contradiction.

[0077] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are illustrative and cannot be understood as limitations on the present invention. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. An organ-on-a-chip platform with integrated optical tweezers, characterized in that: The organ chip platform is used for assembling and culturing three-dimensional cell tissues, and comprises an organ chip (100) with optical transparency and holographic optical tweezers integrated with the organ chip; The organ chip (100) is arranged horizontally and includes an upper plate (101), a middle plate (102) and a lower plate (103) stacked in sequence. The middle plate (102) is provided with at least two first culture pools (104) for inducing stem cells to differentiate into different types of cells, at least one second culture pool (105) for assembling and culturing the different types of cells, and a channel (106) connecting the first culture pool (104) and the second culture pool (105). The objective lens (2) of the holographic optical tweezers faces the top surface or the bottom surface of the organ chip (100) and is used to capture, move and assemble cells in the first culture pool (104) or the second culture pool (105).

2. The organ chip platform according to claim 1, characterized in that The holographic optical tweezers include: A laser light source (3) for generating a laser beam; an optical path component, disposed between the laser light source (3) and the organ chip (100), for transmitting and adjusting the laser beam so that the laser beam is irradiated on the organ chip (100) and forms one or more light traps for capturing, moving, and assembling cells; A spatial light modulator (4) is arranged between the laser light source (3) and the optical path component, and is used to adjust the position and movement path of the light trap; a detection component for acquiring images of cells in the organ chip (100); The controller is in communication with the laser light source (3), the spatial light modulator (4), the optical path component and the detection component.

3. The organ chip platform according to claim 2, characterized in that The optical path component comprises: a beam reduction lens (5), a dichroic mirror (6), and an objective lens (2) arranged in sequence according to the propagation path of the laser beam; The beam reduction lens (5) is used to receive the coded beam generated by the laser light source (3) and regulated by the spatial light modulator (4), and to adjust the thickness of the coded beam to obtain a shaped beam; The dichroic mirror (6) is used to reflect the shaped light beam to the objective lens (2); The objective lens (2) is used to focus the shaped light beam onto the organ chip (100) to form a light trap.

4. The organ chip platform according to claim 2, characterized in that The detection assembly comprises: an illumination light source (7), a collimating lens (8) and a CCD camera (9); The illumination light source (7) is arranged directly below the organ chip (100) and generates an illumination light beam; The collimating lens (8) is arranged between the illumination light source (7) and the organ chip (100), and is used to converge the illumination light beam into a collimated illumination light beam and irradiate the organ chip (100); The CCD camera (9) is arranged directly above the organ chip (100) and is used to receive a transmitted light beam formed by the collimated illumination light beam passing through the organ chip (100) to generate an image of the cells in the organ chip (100).

5. The organ chip platform according to claim 1, characterized in that The channel (106) is provided with a control valve for blocking the channel.

6. The organ chip platform according to claim 5, characterized in that The upper plate (101) is provided with a clearance cavity (107) corresponding to the position of the control valve; The control valve comprises: an electromagnet (11) and a magnet block (12) for blocking the channel, and the magnet block (12) matches the shape of the clearance cavity (107); When the electromagnet (11) is energized, the magnet block (12) moves from the channel (106) to the clearance cavity (107) under the action of the magnetic field of the electromagnet (11), so that the channel (106) is conductive; When the electromagnet (11) is powered off, the magnet block (12) moves from the clearance cavity (107) to the channel (106) under the action of gravity to block the channel (106).

7. The organ chip platform according to claim 1, characterized in that Each of the first culture tank (104) and the second culture tank (105) further comprises: A liquid inlet pipe (13) is used to input new culture medium liquid or medicine into the first culture tank (104) and the second culture tank (105) from the outside; The liquid outlet pipe (14) is used for the first culture tank (104) and the second culture tank (105) to discharge old culture medium liquid or medicine to the outside.

8. The organ chip platform according to claim 1, characterized in that The bottom of the second culture tank is an arc surface, a plane surface or an inverted cone surface.

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