System and method for controlling microfluid process through platform motion posture

Abstract

The invention discloses a system for controlling a microfluid process through a platform motion posture, and the system comprises a movable platform which is used for bearing a microfluid device; the driving mechanism is coupled with the movable platform and is configured to drive the movable platform to move and control one or more movement posture parameters of the platform; the micro-fluid device is fixed on the movable platform, and at least one micro-channel network and a plurality of cavities are arranged in the micro-fluid device; wherein the driving mechanism is used for globally changing an effective force field suffered by each position in the microfluid device by changing the motion posture parameters of the movable platform, so that a pressure difference required for driving liquid to flow, distribute or stop in the micro-channel network is generated, and programmed control on a microfluid process is realized.

Description

Technical Field

[0001] This invention relates to the fields of microfluidic chips and biological tissue engineering, and in particular to a multifunctional chip system integrating centrifugation drive, droplet logic control and organoid culture, for realizing precise quantification, timing control and automated high-throughput supply of liquid reagents in organoid culture. Background Technology

[0002] Current organoid culture relies on manual medium replacement, which has three major drawbacks: Precision defects: Liquid delivery volume error >10% (>1μL), far exceeding the tolerance threshold of the organoid microenvironment; Time lag: The detection of accumulated metabolic waste (such as lactic acid) relies on endpoint methods and cannot respond in real time to dynamic changes in pH (clinical data: organoid survival rate decreases by 40% when pH < 7.0). Throughput bottleneck: Commercial microfluidic systems only support ≤6 channels of parallel operation, which is insufficient to meet the needs of high-throughput drug screening. Traditional microfluidics rely on solenoid valves / pneumatic pumps, with more than 50 valves integrated on a single chip, a failure rate of >23%, and valve chamber volume ≥10μL, resulting in reagent waste. Independent control of multiple channels requires independent pump sources, which increases the system size exponentially. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a highly integrated, reliable and high-throughput microfluidic manipulation scheme to overcome the problems of system complexity, poor accuracy and low throughput caused by relying on discrete external actuators.

[0004] To achieve the above objectives, the present invention adopts the following technical solution: A system for controlling a microfluidic process via platform motion posture includes: a movable platform for carrying a microfluidic device; a drive mechanism coupled to the movable platform and configured to drive the movable platform to move and control one or more motion posture parameters of the platform; and a microfluidic device fixed on the movable platform, which internally includes at least one microchannel network and multiple chambers. The drive mechanism, by changing the motion posture parameters of the movable platform, globally alters the effective force field at various locations within the microfluidic device, thereby generating the pressure differential required to drive the liquid to flow, distribute, or stagnate in the microchannel network, thus achieving programmed control of the microfluidic process.

[0005] In some embodiments, at least one of the following technical means is also included: The motion attitude parameters include the deflection angle (θ2) of the movable platform relative to a reference direction.

[0006] The drive mechanism includes at least two motors, and the deflection angle (θ2) of the movable platform is adjusted by controlling the phase difference (θ1) between the at least two motors.

[0007] The motion attitude parameters include the rotational angular velocity (ω) of the movable platform.

[0008] The microfluidic device integrates a microchannel network that incorporates one or more fluid logic gate units. Its channel structure is designed to respond to an input signal and output a logic operation result.

[0009] The input signal comes from an environmental sensor integrated on the microfluidic device.

[0010] The microfluidic device includes a cell or organoid culture region.

[0011] The present invention also adopts the following technical solutions: A method for controlling a microfluidic process, the method comprising: providing a movable platform on which a microfluidic device is fixed; controlling the motion of the movable platform and one or more motion attitude parameters by a drive mechanism; and globally altering the effective force field distribution acting on the microfluidic device by changing the motion attitude parameters, thereby programmatically controlling the flow, distribution, mixing, or stagnation of liquid within the device.

[0012] Furthermore, The programmed control includes executing a predetermined sequence of operations, which is defined by a series of different motion posture parameters and their duration.

[0013] This invention also includes the following technical solutions: A computer storage medium having a computer program stored thereon, which, when executed by a processor, implements the method for controlling a microfluidic process as described in any of the preceding claims.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention precisely controls the motion attitude parameters (such as deflection angle and rotational angular velocity) of a movable platform through a drive mechanism, thereby globally altering the effective force field distribution acting on the entire microfluidic device. This global force field modulation can generate controllable pressure differences at different locations in the microfluidic network, which directly drive the directional flow, quantitative distribution, or precise stagnation of the liquid. Since liquid actuation and control are entirely achieved through the overall motion attitude of the platform, the reliance on traditional discrete external pumps and valves is fundamentally eliminated, resulting in higher system integration, simplified structure, improved reliability (no valve wear or blockage failures), and reduced reagent waste (no pump / valve dead volume). Furthermore, this platform-based global control method is particularly suitable for parallel and synchronous manipulation of multiple chambers or channels, laying the technological foundation for high-throughput biological applications such as large-scale organoid culture and drug screening.

[0015] By setting the motion posture parameters, including the deflection angle of the movable platform, the directional components of the force field can be more precisely controlled, making it possible to realize more complex liquid manipulation logic (such as selectively opening channels with different flow directions).

[0016] By employing at least two motors and adjusting the deflection angle by controlling their phase difference, a compact and highly precise method for achieving deflection angle control is provided.

[0017] By setting the motion posture parameters, including rotational angular velocity, the magnitude of centrifugal force can be linearly controlled, thereby providing a direct control dimension for achieving precise quantitative delivery and distribution of liquids.

[0018] By integrating fluid logic gate units into the microfluidic network, the microfluidic device itself possesses certain information processing and autonomous response capabilities, enabling it to automatically execute predetermined fluid operations based on environmental inputs (such as sensor signals), thereby improving the system's automation level and intelligence.

[0019] By using an integrated environmental sensor to generate the input signal, real-time monitoring and closed-loop control of the environment in which the microfluidic process is located are achieved. For example, it can automatically trigger a liquid change operation in response to pH changes in the culture environment, which significantly improves the stability and reliability of the culture process.

[0020] By setting up cell or organoid culture regions, the system and method of this invention can be directly applied to cutting-edge biological fields, solving the urgent need in these fields for automated, high-throughput, and precise culture platforms.

[0021] The programmed control includes executing a sequence of operations defined by motion posture parameters and duration, which automates and repeats complex multi-step fluid operation processes, greatly reducing the burden and error of manual operation.

[0022] By applying the method to automated culture medium replacement, drug delivery, or concentration gradient generation, the high efficiency of this invention in biological experiments such as organoid culture is demonstrated. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the structure of a microfluidic device (organoid culture chip) in one embodiment of the present invention.

[0024] Figures 2(a)-2(g) This is a schematic diagram of the workflow for microfluidic chip solution quantification in one embodiment of the present invention.

[0025] Figure 2(h)-2(k) This is a schematic diagram of the workflow of the flow control chip in one embodiment of the present invention, which can interrupt liquid inlet.

[0026] Figures 3(a)-3(g) This is a schematic diagram of the flow path selection process of a microfluidic chip in one embodiment of the present invention.

[0027] Figure 3(h) is a schematic diagram of the sequential liquid injection working sequence in one embodiment of the present invention.

[0028] Figure 4 A schematic diagram of the structure of a fluid logic gate unit in one embodiment of the present invention.

[0029] Figures 5(a)-5(f) This is a schematic diagram demonstrating the effect of a binary adder in one embodiment of the present invention.

[0030] Figure 6 This is a schematic microscopic image of an organoid model cultured in a microfluidic device according to one embodiment of the present invention.

[0031] Explanation of reference numerals in the attached drawings: First inlet 11, Second inlet 11', Culture chamber 12, First outlet 13, Second outlet 13'. Detailed Implementation

[0032] The embodiments of the present invention will be described in detail below. It should be emphasized that the following description is merely exemplary and not intended to limit the scope and application of the present invention.

[0033] It should be noted that when a component is referred to as "fixed to" or "set on" another component, it can be directly on or indirectly on that other component. When a component is referred to as "connected to" another component, it can be directly connected to or indirectly connected to that other component. Furthermore, a connection can be used for both fixing and circuit / signal connectivity.

[0034] It should be understood that the terms "length", "width", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", and "outer" indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing the embodiments of the present invention and simplifying the description, and do not indicate or imply that the device or element 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 present invention.

[0035] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of embodiments of the present invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0036] The basic concept of this invention is as follows: This invention provides an organoid culture chip system and control method integrating centrifugal drive and droplet logic control. The core of this invention lies in using multi-position centrifugal force to replace traditional pumps and valves across the entire domain, and achieving intelligent control through droplet logic water circuits, ultimately realizing efficient, precise, and high-throughput organoid culture. The core includes: 1. Centrifugal Force Replaces Pumps and Valves Globally: Utilizing deflection angle pulses generated by a multi-position centrifuge platform as a global control signal. By precisely controlling the chip's rotational speed (ω) and deflection angle (θ2), the direction and magnitude of the effective centrifugal force at each point on the chip are dynamically changed, thereby achieving "logic control" of the start-up, stop-up, directional transport, quantitative distribution, and mixing of liquids (culture medium, drugs, cell suspensions) in different channels, without the need for any external pumps or valves.

[0037] 2. The microchannel network integrated into the chip contains basic logic units such as AND gates, OR gates, and XOR gates composed of microchannels. These logic water circuits can respond to signals from integrated sensors (such as pH sensors) and output droplet control commands (such as performing liquid replacement or drug delivery) according to preset logic, realizing a certain degree of autonomous decision-making and automated control.

[0038] 3. The core of the droplet logic control layer is a fluid logic gate unit composed of microchannels, which utilizes the flow characteristics of the liquid, the pressure difference between chambers, and deflection angle control to implement Boolean logic operations. The structure of each logic gate unit is as follows: (1) AND gate waterway: Structure: It includes two input chambers (Input A, Input B), a shared waste chamber, an output chamber, and a specific network of flow channels connecting them. The flow channel design ensures that liquid flows preferentially to the waste chamber.

[0039] Working principle: When only one input chamber contains liquid (Input A=1, B=0 or A=0, B=1), the liquid will preferentially flow into the waste liquid chamber under the action of the deflection pulse, and the output chamber will be empty (Output=0). Only when both input chambers contain liquid simultaneously (Input A=1, B=1), one portion of the liquid will flow into the waste liquid chamber, while the other portion of liquid can enter the output chamber through a specific flow channel (Output=1).

[0040] (2) OR gate (or gate) waterway: Structure: It also includes two input chambers, one waste liquid chamber, and one output chamber. Its flow channel design makes the flow resistance of the output chamber lower than that of the waste liquid chamber.

[0041] Working principle: As long as there is liquid in any one or two input chambers (Input A=1 or B=1 or A=B=1), the liquid will preferentially flow to the output chamber (Output=1) under the action of the deflection pulse. The output is 0 only when there is no input (Input A=0, B=0).

[0042] (3) XOR gate (exclusive OR gate) waterway: Structure: Contains a siphon structure or asymmetric flow channel, the highest point of which is precisely calculated.

[0043] Working principle: When the two input states are the same (A=B=0 or A=B=1), the liquid either cannot start or is introduced into the waste liquid chamber (Output=0) after flowing past the highest point due to the symmetrical force field. When the two input states are different (A=1, B=0 or A=0, B=1), the asymmetrical force field distribution enables the liquid to overcome the siphon effect or flow to the control threshold, and finally enter the output chamber (Output=1).

[0044] 4. Fluid implementation mechanism of logical operations The essence of logical operations is to control the "running action" of the liquid by using the deflection angle pulse (θ2 pulse) as a global clock signal.

[0045] (1) Clock signal: The periodic deflection of the platform provides a synchronized execution cycle for the liquid on the entire chip. Each cycle contains one positive deflection and one negative deflection, corresponding to "execute input operation" and "execute output operation" respectively.

[0046] (2) Operation Mechanism: Within a complete deflection cycle: Input stage (e.g., counterclockwise deflection): The liquid in the input chamber is released and flows into the water channel network of the logic gate under the pressure difference generated by the coupling of centrifugal force and deflection angle, and the path is selected according to the flow channel structure and hydrophilicity / hydrophobicity; Calculation and output stage (e.g., clockwise deflection): After the direction of the flow is changed, the liquid with the determined direction is pushed into the final waste liquid chamber or output chamber according to its position, completes a logic operation, and saves the result (with droplets / without droplets) in the output chamber. This process does not require external pump valve intervention, and complex multi-step logic sequences can be realized only through the programming control of deflection angle and speed.

[0047] 5. The conversion process from sensor signal to droplet control This system achieves closed-loop automatic control from environmental sensing to liquid handling, and its transition process is as follows: (1) Signal sensing: The sensor (pH sensor) integrated on the chip monitors the culture environment parameters (pH value) in real time.

[0048] (2) Signal interpretation: The sensor converts the continuous physical / chemical signal into an electrical signal. The control unit reads the signal and interprets it according to the preset threshold (such as pH<7.0), converting it into a binary logic signal (such as "1" representing that the liquid needs to be changed, and "0" representing that it is normal).

[0049] (3) Logic Trigger: The binary signal is fed into a droplet logic gate (such as an OR gate). The OR gate is characterized by "1 for 1", meaning that as long as the sensor sends an alarm signal (1), the OR gate will output a high-level command (1). Command Execution: After receiving the command output by the OR gate, the control unit immediately calls the preset "liquid replacement operation" control sequence. This sequence is a set of pre-programmed (ω, θ2, t) parameter combinations. For example: a) Step 1 (Waste Discharge): Switch the control platform to (ω=1000 rpm, θ2=+18°, t=20s). Under these parameters, centrifugal force will throw the waste liquid away from the waste liquid chamber.

[0050] b) Step 2 (Liquid Addition): Switch the control platform to (ω=400 rpm, θ2=-15°, t=30s). Under these parameters, the fresh culture medium inlet is in a favorable position, and the culture medium is precisely injected into the culture chamber.

[0051] (4) Closed-loop process: After the liquid is changed, the sensor continues to monitor. If the environmental parameters return to normal, the system remains in standby mode. If the conditions are still not met, the process may be triggered again until the conditions are met.

[0052] An integrated pH sensor monitors culture environment parameters in real time and converts them into electrical signals, which are then transmitted to the main control unit. The main control unit compares the sensor readings with a preset threshold (e.g., pH < 7.0). If the condition is met, the main control unit directly calls a pre-stored sequence of motion posture parameters corresponding to the 'medium change operation' (e.g., Step 1: ω = 1000 rpm, θ2 = +18°, t = 20s; Step 2: ω = 400 rpm, θ2 = -15°, t = 30s) and drives the platform to execute it, thus forming a closed-loop control.

[0053] 6. For example Figure 1 As shown, the chip employs a dual-inlet (first inlet, second inlet), multiple culture chambers, and dual-outlet (waste liquid outlet, collection outlet) topology, but it is fabricated on a circular centrifugal microfluidic chip. The culture chamber array is arranged circumferentially, and the first inlet 11, second inlet 11', first outlet 13, and second outlet 13' are connected to the culture chambers through radial and circumferential flow channels. All key nodes of the flow channels integrate active siphon valves based on deflection angle control, replacing traditional physical valves.

[0054] 7. In this multi-position centrifugal microfluidic system, the siphon valve has a similar structure to the traditional design, but its control method and performance are significantly improved. Its design parameters are as follows: (1) Basic structure: a) Shape: Classic inverted U-shaped microchannel.

[0055] b) Flow channel cross-section: A square cross-section is preferred. Experiments have verified that a flow channel size of 500 μm × 500 μm provides the best operational reliability and control efficiency.

[0056] c) Critical Dimension - Siphon Bridge Height (H) height Experiments show that when the height of the siphon bridge is 0.5 times the depth of the chamber (0.5h), the valve can open stably and reliably at various speeds.

[0057] (2) Opening conditions: By controlling the chip platform to deflect to a specific negative angle (θ2 = -30°) at a constant rotation speed, the centrifugal force generated by the change in geometric position overcomes the capillary force, pushing the liquid instantaneously over the highest point of the siphon valve, thus achieving rapid and active opening. The critical condition for valve opening is the pressure difference P between the chambers. ac >0, P is controlled by the deflection angle θ2 according to the formula in claim 2. ac The point at which the valve opens is when it changes from negative to positive.

[0058] (3)Closing condition: It can be actively closed through the program. When it is necessary to interrupt the flow path, the control platform deflects to a specific positive angle (such as θ2 = +18°). At this time, the direction of the force field is reversed, and the liquid is pulled back into the source chamber or flung towards the waste liquid chamber opposite to the target chamber, and the liquid column in the siphon structure is interrupted, and the valve closes. This is the basis for the system to achieve advanced functions such as "interruptible liquid intake".

[0059] 8. Working principle: The operation of this active siphon valve completely depends on the dynamic regulation of the deflection angle θ2 on the effective centrifugal force direction at each point on the chip. Its working cycle is as follows: (1)Priming (Pre - filling / Ready state): The chip rotates at a speed ω, but the deflection angle θ2 is controlled at an angle that makes P ac <0 (for example, θ2 = 0°). At this time, the liquid surface tension (capillary force) and the negative pressure difference maintain the liquid in the liquid storage chamber and cannot cross the highest point of the siphon valve. A meniscus is formed at the entrance of the siphon tube and remains stable.

[0060] (2)Actuation: When it is necessary to transfer liquid, the control system issues an instruction to drive the platform to quickly deflect to a negative angle (such as θ2 = - 30°). This deflection makes the rotation radius R3 of the target chamber (the outlet side of the siphon valve) significantly larger than the rotation radius R1 of the source chamber (the inlet side), that is, R3(θ2)>R1(θ2). According to the pressure difference formula P ac >0, a positive pressure difference from the source chamber to the target chamber is generated. This pressure difference strongly pushes the liquid, instantly overcoming the capillary force, causing the liquid to rush over the highest point of the siphon valve and quickly fill the entire siphon flow path, and then flow into the target chamber, and the valve opens.

[0061] (3)Closure: When it is necessary to中止流动 (stop the flow) or perform multi - step operations, the control system drives the platform to deflect to a positive angle (such as θ2 = +18°). This deflection makes R3(θ2)<R1(θ2), resulting in P ac <0. The effective component force direction of the centrifugal force becomes from the target chamber back to the source chamber or towards the waste liquid chamber. This reverse force pulls back the liquid in the siphon tube or changes its flow direction, thus interrupting the continuous liquid column and destroying the siphon effect, and the valve closes.

[0062] 9. Mathematical relationship between the phase difference of the two motors and the deflection angle (1)Mechanical structure design The platform employs a spatial four-bar linkage, with two servo motors (Motor A and Motor B) driving two connecting components (A and B) respectively. Connecting component A is hinged to the chip platform, while connecting component B is connected to a slide rail on the chip platform via a pin. By controlling the phase angle difference θ1 between the two motors, the chip platform can be deflected around the hinge, resulting in three states: counterclockwise deflection (θ2<0), no deflection (θ2=0), and clockwise deflection (θ2>0). (2) Formula for calculating deflection angle θ2 θ1: Phase angle difference between motor A and motor B; θ2: Deflection angle of the chip platform; L1, L2: Lengths of connectors A and B, respectively. This formula shows that by precisely controlling the phase difference θ1 between the two motors, the deflection angle θ2 of the chip can be precisely controlled, thereby achieving the positional change of each point on the chip relative to the rotation center.

[0063] 10. The physical mechanism by which the direction of centrifugal force controls liquid flow (1) Pressure difference caused by centrifugal force In centrifugal microfluidic chips, the centrifugal force on a liquid is converted into a pressure difference, propelling the liquid through the flow channels. The formula for the pressure difference is: Where: ρ: liquid density; ω: angular velocity; R1, R2: distances from the droplet's location to the center of rotation.

[0064] (2) The effect of deflection angle on the direction of centrifugal force After the chip is deflected, the distance R from a certain point (x,y) on it to the center of rotation will change. Therefore, by controlling the deflection angle θ2, the magnitude and direction of the centrifugal force on a certain point on the chip can be changed, thereby controlling whether the liquid can overcome the resistance of surface tension, capillary force and other resistances to achieve flow or stop.

[0065] (3) Working principle of active siphon valve In traditional centrifugal microfluidic chips, the opening of the siphon valve depends on a deceleration-acceleration process. In this design, by controlling the deflection angle θ2, the valve can be opened and closed at a constant rotational speed: when θ2 is adjusted to a certain angle, the pressure difference PAC across the siphon pipe is greater than 0, and liquid begins to flow; when θ2 is adjusted back, PAC is less than or equal to 0, and the flow stops. This "deflection angle pulse control" enables control of liquid flow without changing the rotational speed, greatly improving the flexibility and stability of control.

[0066] Example 1: A chip system for high-throughput organoid culture and drug screening. I. Detailed Composition of Chip Structure See Figure 1(Schematic diagram of chip structure) The centrifugal microfluidic chip provided in this embodiment is disc-shaped, with polymethyl methacrylate (PMMA) as the substrate. The disc has a diameter of 120 mm and a thickness of 5 mm. The chip is manufactured by precision CNC (computer numerical control) milling, and the surfaces of the flow channels and chambers are treated with plasma hydrophilic treatment.

[0067] The chip comprises the following functional areas and structures from top to bottom: 1. Sample loading area: Located near the chip rotation center, including: (1) First inlet 11: It is a cylindrical chamber with a diameter of 4 mm and a depth of 2 mm, designed with a volume of 25 μL, for loading organoid cell suspension and culture medium.

[0068] (2) Second inlet 11': The structure is symmetrical to the first inlet, and the designed volume is 25 μL. It is used to load culture medium containing chemokines (such as CXCL12) or the drug to be tested.

[0069] A waste liquid chamber with a volume of 200 μL is used to collect waste liquid.

[0070] 2. Cultivation Region: Located in the central radius area of ​​the chip, including: Culture chamber 12: Contains an 8×8 hydrogel microcavity array, supporting the parallel culture of 64 organoids. The microcavity diameter is preferably 200 μm. An array of micropillars (50 μm in diameter, 0.4 mm in height, and 100 μm spacing) is designed along the bottom of each chamber to assist in organoid colonization.

[0071] Binary tree distribution structure: used to distribute the mother liquor to 8 channels and generate 8 different drug concentration gradients (0-100μM) by controlling the number of droplet merging.

[0072] 3. The collection and detection area, located at the outermost edge of the chip, includes: First outlet 13 and second outlet 13': each is a chamber with a diameter of 3 mm and a depth of 1 mm, with a volume of 7 μL, used to collect cells that have migrated from the culture chamber.

[0073] 4. Microfluidic Network: Connecting the above chambers, all channels have a 100μm × 100μm square cross-section. The first inlet is connected to the inlet of the eight culture chambers via a main inlet channel. The outlet of each culture chamber is connected to the outlet via a migration channel. The second inlet merges with the main inlet channel near the culture chamber via another independent channel. At key nodes at the inlet and outlet of each culture chamber, the channels are designed as inverted U-shaped siphon structures, with their highest point 0.5mm higher than the liquid level in the chamber. The opening and closing of the siphon valves are entirely controlled by the deflection angle of the chip.

[0074] 5. Sealing layer: A 0.2mm thick PET (polyethylene terephthalate) film is used, which is bonded to the chip substrate with pressure-sensitive adhesive to achieve full sealing of the chip.

[0075] The design of the microchannel network and siphon valve structure enables various complex fluid manipulation functions to be achieved by precisely controlling the platform's rotational angular velocity (ω) and deflection angle (θ2). Its basic working principle is as follows: Quantitative analysis of solutions (see Figures 2(a) - 2(c)): Figure 2(a) Initial state: The liquid is stored in the inlet chamber, and the platform rotates with an initial angular velocity ω1 and a deflection angle θ2=0°.

[0076] Figure 2(b) First centrifugation: The control system applies a deflection angle pulse (e.g., rapidly adjusts θ2 to -30° and holds for time t1). In this attitude, as shown in formula P... ac As described above, a pressure differential sufficient to overcome the capillary resistance of the siphon valve is generated, and the liquid is pushed over the highest point of the siphon valve and begins to fill the downstream metering loop.

[0077] Figure 2(c) Second centrifugation: The platform deflection angle is adjusted back (e.g., to +10°), and the rotational speed is appropriately increased to ω2. Under this attitude, the force field direction changes, P ac <0, flow interruption. The liquid that has entered the metering loop is precisely divided, while the remaining liquid is retained in the inlet chamber, thus achieving precise metering at the nanoliter (nL) level.

[0078] Interrupted liquid inlet (see) Figure 2(d)-Figure 2(g) ): Figure 2(d) Initial state: Same as Figure 2(a).

[0079] Figure 2(e) First centrifugation: Same as Figure 2A(b), start liquid flow.

[0080] Figure 2(f) Second centrifugation: Before the target chamber is completely filled with liquid, the controller actively adjusts the deflection angle θ2 to a positive value (e.g., +18°). This operation immediately makes P ac When the force field is less than 0, it reverses and forcibly pulls the flowing liquid column back, interrupting the siphon process and achieving a "pause" or "shutdown" of the flow.

[0081] Figure 2(g) Third centrifugation: Applying a negative deflection pulse again allows the flow to restart from the point of interruption. This function can be used to achieve complex time-sharing injection operations.

[0082] Flow path selection (see Figure 2(h) -2(k)): Figure 2(h) Initial state: One source chamber is connected to two or more outlet channels with different geometries (such as siphon valve height, flow channel length).

[0083] Figures 2(i)-2(k) First, second, and third centrifugation: By programming and controlling different combinations of parameters (ω, θ2, t), the magnitude and direction of the generated centrifugal force can be precisely controlled. Due to the different flow resistances and start-up thresholds of each pathway, specific parameters will only satisfy the opening condition of one pathway (P). ac >0), while other pathways remain closed (P). ac (≤ 0), thus enabling selective diversion of liquid to the target outlet without the need for physical valve switching.

[0084] Sequential liquid introduction (see Figures 3(a)-3(h)): Figure 3(a) Initial state: Multiple oral cavity chambers are filled with different reagents.

[0085] Figures 3(b)-3(f) Results of the first to fifth centrifugations: By programming a timing control sequence (as shown in Figure 3(g)), the motion attitude (ω, θ2) of the platform is changed sequentially according to the preset order and time. This allows the liquid to flow out of different inlet chambers in a specific order and with a quantitative volume, thus realizing a complex and automated multi-step fluid operation process.

[0086] Figure 3(h) is a schematic diagram of the programmed control timing for implementing sequential liquid injection in one embodiment of the present invention. This timing diagram defines a sequence of instructions for the drive mechanism to control the movable platform to execute a series of different motion posture parameters (such as rotational angular velocity ω and deflection angle θ2) and their durations (t). This preset timing program ensures that multiple liquid reagents loaded in different inlet chambers can be triggered and delivered sequentially according to a predetermined order, precise timing, and quantitative volume, ultimately achieving a complex, automated, multi-step fluid operation process.

[0087] To further achieve intelligent fluid control, the microchannel network can integrate fluid logic gate units composed of microchannels (see...). Figure 4 The logic gates, from left to right, consist of an AND gate, an OR gate, and an XOR gate. The 'inputs' (Input A, Input B) of these gates are the presence or absence of liquid in the chambers (representing logic '1' or '0'), and the 'outputs' are whether a droplet enters the output chamber. The platform's periodic deflection (θ2 pulse) serves as a global 'clock signal,' driving all logic gates to operate synchronously. Within one deflection cycle, the liquid in the input chambers is distributed according to the fluid resistance path determined by the flow channel design, and the final result (with or without droplets) is latched into the output chamber.

[0088] Based on these basic logic units, more complex fluid computing circuits can be built, such as binary half-adders and full adders (see...). Figures 5(c)-5(f) ). Figures 5(c)-5(f) This demonstrates how binary addition can be implemented by connecting different logic gates through microchannels: 5(c) represents the initial input state (e.g., A=0, B=1). After the first deflection clock cycle in Figure 5(d), the second in Figure 5(e), and the third in Figure 5(f), the droplet (representing the data bits) moves, interacts, and finally reaches the correct output chamber in the channel, yielding the sum and carry of the addition operation. This shows that the system can perform history-dependent, multi-step sequential logic operations, laying the foundation for fully liquid-driven on-chip automated control.

[0089] II. Composition and Connection of Control Systems Referring to Figure 2 (system composition diagram), the control system includes: 1. Multi-position centrifugal drive unit: Utilizing two integrated servo motors (model: HS100-A, Feimai Technology) (other motors capable of achieving equivalent precision speed and position control can also be used), the chip fixture is driven by a spatial four-bar linkage. The motors have a maximum speed of 3000 rpm and a position control accuracy of 0.036° (10000 pulses / revolution). By controlling the phase difference between the two motors, the deflection angle (θ2) of the chip fixture can be precisely controlled, ranging from -85° to +85°.

[0090] 2. Main Control Unit: The core is an ESP32-WROOM-32D microcontroller (the main control unit can also be other microprocessors or PLC controllers with similar performance). This controller connects to two servo motor drivers via the RS485 communication protocol to send speed and position commands; simultaneously, it connects to a magnetic encoder (AS5600) via an I2C bus to read the motor position in real time, realizing closed-loop control.

[0091] 3. Image Monitoring Unit: A USB 3.0 industrial camera (5-megapixel resolution) is installed 50mm directly above the chip, equipped with a fixed-magnification microscope lens, providing a field of view covering at least four culture chambers. This camera connects to a host computer via a USB interface.

[0092] 4. Host Computer Software: Developed using Python 3.8, integrating a PyQt5 graphical interface. The main functional modules of the software include: Sequence programming module: Allows users to set up complex control sequences graphically or via script.

[0093] Real-time monitoring module: Displays real-time images transmitted from industrial cameras, and can take photos and record videos.

[0094] Communication control module: responsible for sending command packets to the ESP32 controller via serial port.

[0095] Data management module: Stores all experimental parameters and image data.

[0096] III. Specific Operating Steps 1. Chip pretreatment: The chip was sterilized by irradiating it under a UV lamp for 30 minutes. Inside a clean bench, 20 μL of a Matrigel-containing tumor organoid cell suspension (cell density 5 × 10^6 cells / mL) was added to the first inlet. 20 μL of culture medium containing 100 nM CXCL12 chemokine was added to the second inlet.

[0097] 2. Cell loading and culture: The chip is mounted on a multi-position centrifuge platform.

[0098] In the host computer software, the "loading" sequence was set and run: rotation speed 600 rpm, deflection angle -30°, duration 45 seconds. Under these parameters, the first inlet was at its lowest point, and centrifugal force overcame capillary force to push the cell suspension to fill the main inlet channel and break through the highest point of the siphon valve, ultimately distributing it evenly into the 64 culture microcavities. The program automatically reduced the rotation speed to 0 and allowed it to stand for 5 minutes (this standing time needs to be optimized according to the hydrophilicity / hydrophobicity of the channel and the properties of the liquid), using capillary action to allow the siphon valve to complete priming again, re-forming the liquid bridge, preparing for the next trigger. The chip was removed and placed in a standard cell culture incubator (37°C, 5% CO2) for 72 hours to allow organoid formation, and the organoid model structure was maintained for more than 5 days.

[0099] 3. Automated liquid replacement operation (demonstrating droplet logic control): The chip is reinstalled onto the platform. The chip's integrated pH sensor (via a corresponding signal acquisition circuit) feeds environmental information back to the main control unit in real time. The program within the control unit compares the sensor reading with a set threshold (e.g., pH < 7.0). When the condition is met, the program logic (not fluid logic) triggers a preset 'liquid change + chemical dosing' control sequence and drives the platform to perform the corresponding actions, running the 'liquid change + chemical dosing' sequence: Step 1 (Emptying waste liquid): Rotation speed 1000 rpm, deflection angle +18°, duration 20 seconds. At this angle, the liquid in the culture chamber is thrown towards the waste liquid chamber away from the center.

[0100] Step 2 (Dosage Addition): Rotation speed 400 rpm, deflection angle -15°, duration 30 seconds. At this angle, the second inlet is in a favorable position, allowing for precise injection of the drug-containing culture medium into the culture chamber.

[0101] 4. Drug gradient generation and screening (demonstrating high-throughput applications): The test drug stock solution is injected through inlet 2. Using a binary tree distribution structure and droplet logic control, the drug is distributed to eight independent culture zones. The final drug concentration in each zone is determined by the logical path it flows through (binary codes 000 to 111 correspond to eight concentrations).

[0102] 5. Data Collection and Analysis: Throughout the migration process, the host computer software controls an industrial camera to automatically focus on and capture a high-resolution image of the culture chamber and exit area every hour. Microscopic images are acquired periodically using the industrial camera to analyze the survival rate, morphological changes, or fluorescence intensity of organoids at different drug concentrations.

[0103] Figure 4 This is a schematic microscopic image of an organoid model cultured in a microfluidic device according to one embodiment of the present invention. The image shows co-cultured vascular endothelial cells HUVEC (marked in red) and tumor cells HepG2 (marked in green). Yellow dashed lines indicate the initial boundaries of the organoid vascular network module region; white dashed lines indicate the initial boundaries of the organoid tumor cell module region. The image scale bar is 200 μm. This fluid logic processing capability, combined with the pH sensor signal described in the embodiment, can construct a purely fluid closed-loop feedback system without external electrical control. For example, changes in the pH of the sensor chamber cause changes in the properties of the liquid within it (such as viscosity and interfacial tension), thereby directly affecting its response characteristics as an input to the logic gate, ultimately automatically triggering a liquid replacement operation.

[0104] The present invention is not limited to the specific values ​​mentioned above. Those skilled in the art can make adaptive adjustments to parameters such as rotation speed, deflection angle, size, and duration based on the actual application scenario and the inspiration of the above embodiments.

[0105] In this embodiment, the specific values ​​of parameters such as the siphon valve height, rotation speed, and deflection angle need to be pre-calculated using the aforementioned force balance model or determined through experimental calibration, based on the flow channel size, liquid properties (surface tension, viscosity, density), and chip surface characteristics (contact angle). The values ​​given in this embodiment are merely examples for specific systems (e.g., aqueous solutions, PMMA material, 100μm×100μm flow channels).

[0106] Example 2 The basic concept of this embodiment is as follows: This embodiment aims to provide a specific system for controlling microfluidic processes through platform motion posture. Its core lies in using a movable platform with precisely controllable deflection angle and rotation speed to replace traditional pumps and valves. By changing the platform's motion posture, the centrifugal force field is globally regulated, thereby driving and controlling the liquid within the microfluidic device. At the same time, the microfluidic device integrates a fluid logic unit and a culture area, enabling it to respond to environmental signals and perform automated, high-throughput organoid culture operations.

[0107] This embodiment provides a system for controlling microfluidic processes through platform motion posture. The system includes a movable platform, a drive mechanism, and a microfluidic device. The movable platform is used to support the microfluidic device. In this embodiment, the movable platform is specifically a disc-shaped chip holder made of aluminum alloy, used to clamp and fix the microfluidic device. The drive mechanism is coupled to the movable platform and configured to drive the movable platform to move and precisely control one or more motion posture parameters of the platform. In this embodiment, the drive mechanism specifically includes two servo motors (model: HS100-A). These two motors jointly drive the chip holder through a spatial four-bar linkage. By controlling the phase difference between the two servo motors, the deflection angle θ2 of the chip holder relative to the horizontal reference direction can be precisely adjusted, with an adjustment range between -85° and +85°. Simultaneously, by controlling the motor speed, the rotational angular velocity ω of the movable platform can be precisely controlled, with a maximum motor speed of 3000 rpm. The microfluidic device is fixed on the movable platform and contains at least one microchannel network and multiple chambers. In this embodiment, the microfluidic device is specifically a centrifugal microfluidic chip. The chip substrate is polymethyl methacrylate (PMMA), with a disk diameter of 120 mm and a thickness of 5 mm. The chip is precision CNC milled, and the surfaces of the channels and chambers undergo plasma hydrophilic treatment. The microchannel network within the chip connects the following main chambers: two sample loading inlets (first inlet and second inlet, each with a volume of 25 μL), a waste liquid chamber (volume of 200 μL), a collection outlet (volume of 7 μL), and an organoid culture region (i.e., a hydrogel microcavity array) containing 64 microcavities (diameter of 200 μm). All channels have a cross-section of 100 μm × 100 μm square. Inverted U-shaped siphon structures are designed at key nodes of the channels (such as the inlet and outlet ends of the culture chambers), with their highest point 0.5 mm higher than the liquid level in the chamber. The drive mechanism globally alters the effective centrifugal force field at various locations within the microfluidic device by changing the motion attitude parameters of the movable platform (i.e., deflection angle θ2 and rotational angular velocity ω). This generates the pressure differential required to drive the liquid to flow, distribute, or stagnate within the microfluidic network, enabling programmed control of the microfluidic process. For example, precise quantitative release and transfer of the liquid can be achieved by combining different ω values ​​(e.g., 200-600 rpm) with θ2 (e.g., -30° to +18°).

[0108] The specific defects addressed by this embodiment are: It solves the problems of low operational accuracy, lagging timing control, limited throughput, and poor system complexity and reliability caused by the reliance on manual operation and external pump and valve systems in traditional organoid culture.

[0109] Detailed technical solution, component names, connection relationships, or spatial relationships: As mentioned above, the system mainly consists of a chip fixture (movable platform), two servo motors and their driven four-bar linkage (drive mechanism), and a centrifugal microfluidic chip (microfluidic device). The chip is fixed to the center of the platform by the fixture. The motors constitute the core of the drive mechanism and are coupled to the platform through mechanical linkages. The inlet, flow channel, culture chamber, and outlet on the chip are integrated onto the same substrate using microfabrication technology. See [link to relevant documentation] for spatial relationships. Figure 1 .

[0110] Working principle: During system operation, the main controller sends commands to the drive mechanism to control the speed and relative phase of the two servo motors, thereby precisely setting the platform's rotational angular velocity ω and deflection angle θ2. Different combinations of ω and θ2 generate different effective centrifugal force vector distributions on the rotating chip. This global force field change generates controllable pressure differences at different locations in the chip's flow channel network. These pressure differences drive the liquid to overcome surface tension, capillary forces, and other flow characteristics. By programming a series of (ω, θ2, duration) operation sequences, complex fluid manipulation procedures such as loading, dispensing, mixing, and liquid replacement can be implemented. The pH sensor integrated on the chip monitors the environment in real time, and its signal can be used as a trigger condition to input the control logic, automatically invoking the corresponding operation sequence.

[0111] Dimensions: Chip diameter 120mm, thickness 5mm. Culture microcavity diameter 200μm. Flow channel cross-section 100μm×100μm. Siphon valve height 0.5mm above liquid surface. Servo motor (HS100-A, Feimai Technology, Shenzhen, China; the HS100-A servo motor can maintain a stable maximum speed of 3000r / min. Precise control of the deflection angle of the centrifugal microfluidic platform is achieved through the phase angle difference between the two servo motors; 10,000 pulses represent 360° of motor rotation, with a deflection angle accuracy of 0.04°). Position control accuracy 0.036°.

[0112] Implementation steps (in chronological order): Chip pretreatment steps: The operator places the chip under a UV lamp for 30 minutes to sterilize it.

[0113] Sample addition procedure: In a clean bench, using a micropipette (DRUMMOND Microcaps, USA), add 20 μL of tumor organoid cell suspension containing Matrigel (Corning®, 354607 (96-well plate, 5 / incubator)) to the first inlet of the microarray (cell density 5 × 10^6 cells / mL); add 20 μL of culture medium containing 100 nM CXCL12 chemokine to the second inlet. (Cell culture incubator model: Eppendorf CellXpert C170i) Installation steps: The operator installs the sampled chip onto the movable platform (chip fixture).

[0114] Programmed control steps (cell loading): The "loading" control sequence is initiated via the host computer software. The control unit drives the platform to operate at a speed of 600 rpm, a deflection angle of -30°, and a duration of 45 seconds. Under these parameters, centrifugal force propels the cell suspension to fill the channels and inject it into the culture microcavities.

[0115] Static culture procedure: After the program is completed, remove the chip and place it in a 37°C, 5% CO2 cell culture incubator for static culture for 72 hours.

[0116] Programmed control steps (automated medium change): After cultivation, the chip is reinstalled on the platform. The control unit continuously monitors the integrated pH sensor. When the pH value is detected to be <7.0, the "medium change" sequence is automatically triggered: First, the rotation speed is 1000 rpm, the deflection angle is +18°, and the duration is 20 seconds to drain the waste liquid; then, the rotation speed is 400 rpm, the deflection angle is -15°, and the duration is 30 seconds to inject fresh culture medium.

[0117] Experimental verification: To verify the beneficial effects of the system in this embodiment, the following tests were conducted: Liquid Quantitative Accuracy Test: Under different combinations of (ω, θ2) parameters, the actual volume of liquid delivered to the culture chamber is measured. The deviation from the target volume is calculated to evaluate the control accuracy.

[0118] Comparison object: Traditional pneumatic micro-pump system.

[0119] Test results: Parameter combination Target volume (μL) Measured average volume (μL) Standard deviation (μL) Error comparison with traditional methods <![CDATA[(ω=400 rpm, θ2=-15°)]]> 2.0 2.02 0.03 Traditional pump and valve system error >10% <![CDATA[(ω=00 rpm, θ2=-30°)]]> 5.0 4.95 0.08 Traditional pump and valve system error >10% High-throughput culture effect test: The formation rate, survival rate and morphological consistency of organoids in 64 culture chambers were statistically analyzed.

[0120] Comparison object: 6-channel commercial microfluidic culture system.

[0121] Test results: Cultivation System Organoid formation rate (%) Survival rate on day 5 of culture (%) Morphological consistency score (1-5) Embodiments of the present invention 95 90 4.8 Commercial 6-channel system 80 75 3.5 System reliability testing: Continuous operation__ 1000 A sequence of ___ fluid change operations, recording the number of system failures (such as fluid dispensing failures).

[0122] Test results: Failure rate = 0.2 %.

[0123] Example 3 The difference between this embodiment and Embodiment 2 is that the microfluidic network within the microfluidic device integrates one or more fluid logic gate units. In this embodiment, a droplet OR logic gate unit is specifically integrated. This OR gate is configured to respond to an input signal (i.e., a pH < 7.0 signal detected by the pH environment sensor integrated on the microfluidic device) and output a logical operation result (high level / action trigger) by changing the direction of liquid flow (i.e., triggering the platform deflection angle to switch to +18° to execute the drainage action). Its working principle is as follows: when the sensor detects that the ambient pH is lower than the threshold, the signal is read by the main control unit and determined to be a valid input ("1") to the OR gate. Then, a preset sequence of motion attitude parameters corresponding to the drainage action (ω = 1000 rpm, θ2 = +18°) is invoked to complete the logical output of waste liquid drainage.

[0124] Example 4 The difference between this embodiment and Embodiment 2 lies in the use of programmed control. This embodiment details a method for controlling a microfluidic process for automated drug delivery and concentration gradient generation in organoids. This method is based on the system of Embodiment 2. The method includes: providing a movable platform on which a microfluidic device is fixed; controlling the movement of the movable platform and one or more motion attitude parameters (ω, θ2) through a drive mechanism; and globally altering the effective force field distribution acting on the microfluidic device by changing the motion attitude parameters, thereby programmatically controlling the flow, distribution, and mixing of liquid within the device. The programmed control includes executing a predetermined sequence of operations, defined by a series of different motion attitude parameters and their durations. Specifically, in the drug gradient generation of this embodiment, the sequence is programmable as follows: injecting the drug stock solution from inlet 2 into the microfluidic network by controlling (ω=500 rpm, θ2=-10°, t=40s).

[0125] By controlling (ω=300 rpm, θ2=0°, t=60s), the integrated binary tree liquid distribution structure within the chip is utilized (see...). Figures 3(a)-3(f)The method distributes the drug into eight different branch channels. The final drug concentration in each branch is controlled by the number of times the droplets merge as they flow through that branch (binary encoding), generating a concentration gradient from 0 to 100 μM. This method achieves complex liquid distribution and gradient generation entirely through programmed changes in the platform's motion attitude, without requiring any external valve switching.

[0126] The above-described embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A system for controlling a microfluidic process by platform motion posture, characterized in that, The method comprises: providing a movable platform on which a microfluidic device is fixed; controlling the motion and one or more motion attitude parameters of the movable platform by a driving mechanism; globally changing the effective force field distribution acting on the microfluidic device by changing the motion attitude parameters, thereby programmatically controlling the flow, distribution, mixing or stagnation of liquid in the device. The motion attitude parameters include a deflection angle (θ2) of the movable platform relative to a reference direction. The driving mechanism includes at least two motors, and the deflection angle (θ2) of the movable platform is adjusted by controlling the phase difference (θ1) between the at least two motors.

2. The system of claim 1, wherein, The motion attitude parameters include the rotational angular velocity (ω) of the movable platform.

3. The system of claim 2, wherein, The microfluidic device includes one or more fluid logic gate units, and the channel structure of the fluid logic gate units is designed to be able to respond to an input signal and output a logic operation result.

4. The system of claim 1, wherein, The input signal is from an environmental sensor integrated on the microfluidic device.

5. The system of claim 1, wherein, The microfluidic device includes a cell or organoid culture area.

6. The system of claim 5, wherein, The method comprises: providing a movable platform on which a microfluidic device is fixed; controlling the motion and one or more motion attitude parameters of the movable platform by a driving mechanism; globally changing the effective force field distribution acting on the microfluidic device by changing the motion attitude parameters, thereby programmatically controlling the flow, distribution, mixing or stagnation of liquid in the device.

7. The system of claim 1, wherein, The programmable control includes executing a predetermined operation sequence defined by a series of different motion attitude parameters and their durations.

8. A method of controlling a microfluidic process, characterized by, The program is executed by a processor to implement the method of controlling a microfluidic process according to any one of claims 8 to 9.

9. The method of claim 8, wherein, ​ 10. A computer storage medium having stored thereon a computer program, characterized in that ​

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