High-precision organ chip model with temperature control function

Abstract

The utility model discloses a high-precision organ chip model with a temperature control function, the model comprises a top cover, cell culture chambers, a bottom cover, nano wires, a thin-film resistance heater and a temperature control unit, and a plurality of mutually communicated cell culture chambers are arranged between the top cover and the bottom cover. According to the liver-kidney-intestine combined multi-organ chip, the defects that in the prior art, the mode is not suitable for the multi-organ chip or a tumor thermal therapy chip, for example, the intestine reservoir (top) needs to simulate 37 DEG C enteric cavity fluid, the liver reservoir (middle) maintains a 37 DEG C metabolic environment, and the kidney reservoir (bottom) is cooled to 25 DEG C to simulate urine discharge are overcome; the tumor area of the tumor thermal therapy chip needs to be rapidly heated to 43 DEG C, and the surrounding normal tissue area (adjacent reservoir) is maintained at 37 DEG C. Therefore, the high-precision organ chip model with the temperature control function, which can dynamically adjust the temperatures of a plurality of regions of the organ chip, is provided.

Description

Technical Field

[0001] This utility model relates to the field of organ bionics and microfluidic chips for microenvironment reconstruction, specifically to a high-precision organ-on-a-chip model with temperature control function. Background Technology

[0002] Organ-on-a-chip (OIC) is a microfluidic chip biomimetic system fabricated using microfabrication technology to simulate the complex microstructure, microenvironment, and physiological functions of specific human organs. It is also called a microphysiological system. It is a novel experimental method proposed in recent years for biomedical research such as drug evaluation and disease model construction.

[0003] Chinese patent CN201721402861.8 discloses an auxiliary device for real-time temperature and humidity control of microfluidic chips, which directly controls the temperature of the organ-on-a-chip through the inlet and outlet of the circulating gas.

[0004] The applicant discovered the following technical problems when implementing the above-mentioned technical solution:

[0005] This method is not applicable to multi-organ chips or tumor hyperthermia chips. For example, in a multi-organ chip that combines liver, kidney, and intestine, the intestinal reservoir (top) needs to simulate intestinal fluid at 37°C, the liver reservoir (middle) needs to maintain a metabolic environment at 37°C, and the kidney reservoir (bottom) needs to be cooled to 25°C to simulate urine excretion. In contrast, the tumor area of ​​a tumor hyperthermia chip needs to be rapidly heated to 43°C, while the surrounding normal tissue area (adjacent reservoir) is maintained at 37°C.

[0006] Therefore, providing a high-precision organ-on-a-chip model with temperature control function that can dynamically adjust the temperature of multiple regions of the organ-on-a-chip is a problem that this invention urgently needs to solve. Utility Model Content

[0007] To address the aforementioned technical problems, the purpose of this invention is to overcome the limitations of existing methods for multi-organ-on-a-chip or tumor hyperthermia chips. For example, in a multi-organ-on-a-chip combining liver, kidney, and intestine, the intestinal reservoir (top) needs to simulate intestinal fluid at 37°C, the liver reservoir (middle) maintains a 37°C metabolic environment, and the kidney reservoir (bottom) is cooled to 25°C to simulate urine excretion. In contrast, the tumor region of a tumor hyperthermia chip needs to be rapidly heated to 43°C, while the surrounding normal tissue region (adjacent reservoirs) is maintained at 37°C. This provides a high-precision organ-on-a-chip model with temperature control capabilities that can dynamically adjust the temperature of multiple regions within the organ-on-a-chip.

[0008] To achieve the above objectives, this utility model provides a high-precision organ-on-a-chip model with temperature control function. The model includes: a top cover, a cell culture chamber, a bottom cover, nanowires, a thin-film resistance heater, and a temperature control unit. Several interconnected cell culture chambers are arranged between the top cover and the bottom cover. Several temperature control units corresponding to each cell culture chamber are arranged on one side of the top cover. The two ends of the nanowires are respectively connected to the corresponding temperature control unit and the cell culture chamber. A thin-film resistance heater is arranged at the end of the nanowires away from the temperature control unit.

[0009] Preferably, the nanowire is an Ag nanowire, and its outer surface is covered with AgCl nanowires.

[0010] Preferably, the thin-film resistance heater is a thin-film platinum resistance heater.

[0011] Preferably, the top cover is provided with a plurality of top middle reservoirs that are connected to each cell culture chamber in a one-to-one correspondence, and the bottom cover is provided with a plurality of bottom middle reservoirs that are connected to each cell culture chamber in a one-to-one correspondence, as well as a plurality of microchannels that can connect each bottom middle reservoir.

[0012] Preferably, one side of the bottom cover is provided with several negative pressure units that are connected to each bottom reservoir in a corresponding manner through thin tubes.

[0013] Preferably, the negative pressure unit is a miniature peristaltic pump or a syringe.

[0014] Preferably, the top cover and bottom cover are made of transparent material.

[0015] According to the above technical solution, the beneficial effects of this utility model compared with the prior art are as follows: This application cultivates multiple normal tissues and tumor area culture chambers in a cell culture chamber, and heats the tumor area to 43°C through nanowires using an independently set temperature control unit, thereby maintaining the surrounding normal tissues at 37°C. This simulates the difference between tumor cell apoptosis and normal cell survival during hyperthermia, verifying drug targeting. Alternatively, multiple liver-kidney-intestinal cell culture chambers connected in series via microchannels can be set up. The intestinal reservoir (top) needs to simulate 37°C intestinal fluid, the liver reservoir (middle) maintains a 37°C metabolic environment, and the kidney reservoir... (Bottom) The temperature is lowered to 25°C to simulate urine excretion, thereby studying the dynamic effect of temperature changes on the activity of drug-metabolizing enzyme (CYP3A4). Each temperature control unit is independently powered and connected to the main control board via FPC (flexible printed circuit board), and then heated by a thin-film resistance heater. The temperature control unit also includes a main control chip, a communication interface, and a temperature sensor. It is connected to the host computer and other communication units via the communication interface. The temperature sensor monitors the temperature of the target area in real time, and the main control chip processes the sensor data and issues control commands. By independently controlling the temperature of each cell culture chamber, it is possible to simulate multiple organ-on-a-chip.

[0016] Other features and advantages of this utility model will be described in detail in the following detailed description section; and all parts not covered in this utility model are the same as or can be implemented using existing technology. Attached Figure Description

[0017] The accompanying drawings are provided to further illustrate the present invention and form part of the specification. They are used together with the following detailed description to explain the present invention, but do not constitute a limitation thereof. In the drawings:

[0018] Figure 1 This is a three-dimensional high-precision organ-on-a-chip model with temperature control function provided in a preferred embodiment of the present invention. Figure 1 .

[0019] Figure 2 This is a three-dimensional high-precision organ-on-a-chip model with temperature control function provided in a preferred embodiment of the present invention. Figure 2 .

[0020] Figure 3 This is a partial plane of a high-precision organ-on-a-chip model with temperature control function provided in a preferred embodiment of the present invention. Figure 1 .

[0021] Figure 4 This is a partial plane of a high-precision organ-on-a-chip model with temperature control function provided in a preferred embodiment of the present invention. Figure 2 .

[0022] Explanation of reference numerals in the attached diagram: 1-Top cover; 101-Top middle reservoir; 2-Cell culture chamber; 3-Bottom cover; 301-Bottom middle reservoir; 302-Microchannel; 4-Nanowire; 5-Temperature control unit; 6-Negative pressure unit. Detailed Implementation

[0023] The specific embodiments of this utility model will be described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are for illustration and explanation only and are not intended to limit the scope of this utility model.

[0024] In the description of the embodiments of this utility model, it should be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," indicating orientation or positional relationships, are based on the orientation or positional relationships shown in the accompanying drawings, or the orientation or positional relationships commonly used when the utility model product is in use. These are merely for the convenience of describing the utility model and simplifying the description, and do not indicate or imply that the device or component referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the utility model. Furthermore, the terms "first," "second," and "third," etc., are only used for distinguishing descriptions and should not be construed as indicating or implying relative importance. Additionally, the terms "horizontal," "vertical," and "suspended," etc., do not indicate that the component is required to be absolutely horizontal or suspended, but rather that it can be slightly tilted. For example, "horizontal" simply means that its direction is more horizontal than "vertical," and does not mean that the structure must be completely horizontal, but can be slightly tilted.

[0025] In the description of the embodiments of this utility model, it should also be noted that, unless otherwise explicitly specified and limited, the terms "set," "install," "connect," and "link" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this utility model according to the specific circumstances.

[0026] To further understand the features, technical means, and specific objectives and functions achieved by this utility model, the following detailed description of this utility model is provided in conjunction with the accompanying drawings and specific embodiments.

[0027] Reference Figures 1-3A high-precision organ-on-a-chip model with temperature control function, the model includes: a top cover 1, a cell culture chamber 2, a bottom cover 3, nanowires 4, a thin-film resistance heater, and a temperature control unit 5. Several interconnected cell culture chambers 2 are arranged between the top cover 1 and the bottom cover 3. Several temperature control units 5 corresponding to each cell culture chamber 2 are arranged on one side of the top cover 1. The two ends of the nanowires 4 are respectively connected to the corresponding temperature control unit 5 and the cell culture chamber 2. A thin-film resistance heater is arranged at the end of the nanowires 4 away from the temperature control unit 5.

[0028] This application simulates the difference between tumor cell apoptosis and normal cell survival during hyperthermia by culturing multiple normal tissues and tumor regions within a cell culture chamber 2, and heating the tumor region to 43°C via nanowires 4 using an independently set temperature control unit 5. This is achieved by heating the tumor region to 43°C while maintaining the surrounding normal tissue at 37°C. Alternatively, multiple liver-kidney-intestinal cell culture chambers 2 connected in series via microchannels 302 are configured. The intestinal reservoir (top) is designed to simulate 37°C intestinal fluid, the liver reservoir (middle) is maintained at 37°C, and the kidney reservoir (bottom) is cooled to 25°C to simulate... Urine is excreted to study the dynamic effects of temperature changes on the activity of drug-metabolizing enzyme (CYP3A4). Each temperature control unit 5 is independently powered and connected to the main control board via an FPC (flexible printed circuit board). It is then heated by a thin-film resistance heater. Each temperature control unit 5 also includes a main control chip, a communication interface, and a temperature sensor. It is connected to a host computer and other communication units via the communication interface. The temperature sensor monitors the temperature of the target area in real time, and the main control chip processes the sensor data and issues control commands. By independently controlling the temperature of each cell culture chamber 2, it is possible to simulate multiple organ-on-a-chip systems.

[0029] The nanowire 4 is an Ag nanowire, and its outer surface is covered with AgCl nanowires.

[0030] The resistivity of the Ag nanowires in this application is approximately 1.59 × 10⁻⁻⁻⁶. 8 The Ω·m is much lower than that of traditional metals (such as Cu, which has a Ω·m of 1.68 × 10⁻⁻⁻⁶). 8AgCl nanowires exhibit high strength (Ω·m) and their one-dimensional structure reduces electron scattering, enabling efficient current transfer and ensuring rapid heater response (step heating time <30 seconds). They also possess photocatalytic antibacterial activity (generating reactive oxygen species (ROS) under visible light), inhibiting bacterial adhesion (e.g., E. coli) to the surface of the wires and reducing the risk of biofilm formation (antibacterial rate >99%). Furthermore, they demonstrate high stability in physiological saline or cell culture media, resisting oxidation or sulfidation (unlike Ag nanowires, which are easily oxidized to Ag₂O), ensuring long-term stability of electrical performance. Using Ag nanowires with AgCl nanowires on their outer surface allows for both efficient current transfer and suitability for long-term organ-on-a-chip culture (e.g., liver-on-a-chip requiring continuous operation for more than 7 days).

[0031] The thin-film resistance heater is specifically a thin-film platinum resistance heater.

[0032] The thin-film platinum resistance thermometer of this application is commonly used in temperature sensors. Its α value is 0.00385 / °C, which is much higher than that of other metals (such as Cu's 0.0043 / °C). The linear relationship between temperature change and resistance value is better, ensuring temperature measurement and control accuracy of ±0.1°C, meeting the needs of precision experiments such as drug screening and disease models. The heat capacity of the thin-film platinum resistance thermometer is only about 0.1 J / (g·K). With the serpentine microstructure design (heating area ratio >80%), the step heating time (35→40°C) is <30 seconds and the cooling time is <20 seconds, supporting dynamic physiological simulation (such as circadian rhythm and thermotherapy response).

[0033] Reference Figure 4 The top cover 1 is provided with a plurality of top middle reservoirs 101 that are connected to each cell culture chamber 2 in a one-to-one manner. The bottom cover 3 is provided with a plurality of bottom middle reservoirs 301 that are connected to each cell culture chamber 2 in a one-to-one manner, and a plurality of microchannels 302 that can connect each bottom middle reservoir 301.

[0034] Top reservoir: simulates a capillary network (inputting oxygen and nutrients).

[0035] Bottom reservoir: mimics venous sinuses or interstitial fluid (collects metabolic waste).

[0036] This application involves adding culture medium to the top intermediate reservoir 101, allowing cells in the cell culture chamber 2 to absorb the medium and excrete waste into the bottom intermediate reservoir 301. Culture medium is supplied independently to each cell culture chamber 2, avoiding cross-contamination between different areas. Excretion is collected centrally to prevent the accumulation of metabolic waste within the culture chambers (e.g., simulating urine excretion on a kidney-on-a-chip). Each culture chamber has independent inlet / outlet of medium, suitable for multi-organ microarrays (e.g., liver-kidney combination). The flow rate difference between the top and bottom reservoirs simulates the concentration gradient in the physiological environment (e.g., blood concentration after intestinal absorption). Cell-secreted metabolites (e.g., lactic acid, urea) are directly discharged into the bottom reservoir through microchannel 302, avoiding acidification within the culture chamber (pH fluctuation <0.1). In tumor microarrays, excretions (e.g., drug metabolites) are rapidly removed, maintaining stable drug concentrations in the culture medium and improving experimental reproducibility.

[0037] Reference Figure 2 The bottom cover 3 has several negative pressure units 6 connected to each bottom reservoir 301 via thin tubes on one side.

[0038] This application uses a negative pressure unit 6 to periodically discharge metabolites from the bottom middle reservoir 301; the negative pressure range is -5 to -20 kPa, and the discharge rate can reach 1–5 μL / s, avoiding acidification of metabolites in the culture chamber (pH fluctuation <0.1). The inner diameter of the thin tube is 50–100 μm, combined with PDMS hydrophobic surface treatment, to reduce protein or cell debris deposition.

[0039] Reference Figure 3 The negative pressure unit 6 is specifically a miniature peristaltic pump or a syringe.

[0040] The flow rate range of this micro-peristaltic pump is typically 0.1–100 μL / min, supporting flexible adjustment from micro-discharge (e.g., single-cell metabolite collection) to medium flow rates (e.g., batch discharge from organ-on-a-chip). Simulating glomerular filtration rate (GFR) in a kidney-on-a-chip, the flow rate accuracy reaches ±1 μL / min, closely approximating physiological conditions. Smooth flow is achieved through continuous squeezing of the tubing by rollers, avoiding the periodic pulsation of the syringe and reducing mechanical interference with the cell culture environment, making it suitable for long-term experiments. The syringe, using a precision syringe (e.g., Hamilton syringe) with an electric plunger, allows for manual timed discharge or programmable control (e.g., discharge every 2 hours), offering low cost and suitability for small laboratories or disposable experiments.

[0041] The top cover 1 and the bottom cover 3 are made of transparent material.

[0042] This application uses PDMS or a glass substrate with a transmittance of >90% (visible light band), supporting real-time observation of cell morphology, migration and metabolic activities using high-resolution microscopes (such as confocal and phase contrast microscopes).

[0043] The device provided by this invention, in use, cultivates multiple normal tissues and tumor area culture chambers within the cell culture chamber 2. A separately configured temperature control unit 5 heats the tumor area to 43°C via nanowires 4 through a thin-film resistance heater, maintaining the surrounding normal tissue at 37°C. This simulates the difference between tumor cell apoptosis and normal cell survival during hyperthermia, verifying drug targeting. Alternatively, multiple liver-kidney-intestinal cell culture chambers 2 connected in series via microchannels 302 can be configured. The intestinal reservoir (top) needs to simulate 37°C intestinal fluid, the liver reservoir (middle) maintains a 37°C metabolic environment, and the kidney reservoir (bottom) is cooled to... A simulated 25°C urine excretion was used to study the dynamic effects of temperature changes on the activity of a drug-metabolizing enzyme (CYP3A4). Each temperature control unit 5 was independently powered and connected to the main control board via a flexible printed circuit board (FPC) with nanowires 4. Heating was then achieved through a thin-film resistance heater. Each temperature control unit 5 also included a main control chip, a communication interface, and a temperature sensor. The communication interface connected to a host computer and other communication units. The temperature sensor monitored the temperature of the target area in real time, and the main control chip processed the sensor data and issued control commands. By independently controlling the temperature of each cell culture chamber 2, multiple organ-on-a-chip simulations were possible.

[0044] The preferred embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0045] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way without contradiction. In order to avoid unnecessary repetition, this utility model will not describe the various possible combinations separately.

[0046] Furthermore, various different embodiments of this utility model can be combined in any way, as long as they do not violate the spirit of this utility model, they should also be regarded as the content disclosed by this utility model.

Claims

1. A high-precision organ-on-a-chip model with temperature control function, characterized in that, The model includes: a top cover (1), a cell culture chamber (2), a bottom cover (3), a nanowire (4), a thin-film resistance heater, and a temperature control unit (5). Several interconnected cell culture chambers (2) are arranged between the top cover (1) and the bottom cover (3). Several temperature control units (5) corresponding to each cell culture chamber (2) are arranged on one side of the top cover (1). The nanowire (4) is connected to the corresponding temperature control unit (5) and the cell culture chamber (2) at its opposite ends. A thin-film resistance heater is arranged at the end of the nanowire (4) away from the temperature control unit (5).

2. A high-precision organ-on-a-chip model with temperature control function according to claim 1, characterized in that, The nanowire (4) is an Ag nanowire, and its outer surface is covered with AgCl nanowires.

3. A high-precision organ-on-a-chip model with temperature control function according to claim 1, characterized in that, The thin-film resistance heater is specifically a thin-film platinum resistance heater.

4. A high-precision organ-on-a-chip model with temperature control function according to claim 1, characterized in that, The top cover (1) is provided with a number of top middle reservoirs (101) that are connected to each cell culture chamber (2) in a one-to-one correspondence. The bottom cover (3) is provided with a number of bottom middle reservoirs (301) that are connected to each cell culture chamber (2) in a one-to-one correspondence, and a number of microchannels (302) that can connect each bottom middle reservoir (301).

5. A high-precision organ-on-a-chip model with temperature control function according to claim 4, characterized in that, The bottom cover (3) has several negative pressure units (6) connected to each bottom reservoir (301) one by one through thin tubes.

6. A high-precision organ-on-a-chip model with temperature control function according to claim 5, characterized in that, The negative pressure unit (6) is specifically a micro peristaltic pump or a syringe.

7. A high-precision organ-on-a-chip model with temperature control function according to claim 1, characterized in that, The top cover (1) and the bottom cover (3) are made of transparent material.

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