Automated liquid handling apparatus and control method

Abstract

The application relates to the technical field of automatic experiment equipment control, and discloses an automatic liquid processing device and a control method, which comprise a liquid adding needle, an injection pump, a pressure sensor arranged in a pipeline of the liquid adding needle, a cleaning system, a photoelectric liquid level sensor for monitoring liquid volume in real time and arranged on a waste liquid pipeline, and a controller configured to dynamically correct operation parameters of the injection pump according to monitored pressure of the pressure sensor to compensate for volume deviation caused by abnormal pressure change during liquid suction or discharge by the injection pump, and configured to control the peristaltic pump to pump liquid and judge whether the cleaning system is abnormal according to a monitoring result of the photoelectric liquid level sensor during an initialization process of the device. The application can actively detect and compensate for volume deviation caused by abnormal states such as bubbles or blockage in the pipeline, thereby significantly improving the precision and reliability of liquid adding, and reducing the risk of cross contamination caused by bubble residues.

Description

Technical Field

[0001] This invention relates to the field of automated experimental equipment control technology, specifically to an automated liquid handling device and control method. Background Technology

[0002] Automated liquid handling equipment is widely used in fields such as biomedicine and chemical analysis to perform repetitive operations such as automatic cap opening, barcode scanning, liquid addition, and cleaning. Existing automated liquid handling equipment typically uses preset programs to control robotic arms and pump valves, executing preset action sequences in an open-loop manner.

[0003] However, in the process of filling the pipeline before adding liquid and adding liquid quantitatively, the existing technology usually relies on the preset number of liquid suction and discharge times and volume for open-loop control. It cannot detect whether there are abnormal conditions such as air bubbles or blockages in the pipeline. It lacks a precise compensation mechanism, which leads to a deviation between the actual liquid volume and the theoretical value. The liquid addition accuracy is difficult to guarantee, and cross-contamination is easily caused by residual air bubbles.

[0004] Furthermore, the initialization process of existing equipment typically only includes mechanical zeroing and gripper reset, without covering the status detection of subsequent functional modules such as liquid addition and cleaning. Users cannot immediately know whether the cleaning fluid in the cleaning tank is sufficient or whether the tubing is unobstructed when the equipment is started. This will lead to the discovery of cleaning system abnormalities only when performing the liquid addition needle cleaning step in the experimental procedure, at which point the process is forced to stop. This not only seriously affects the overall work efficiency, but also may cause subsequent samples to be contaminated due to ineffective cleaning of the liquid addition needle, resulting in losses.

[0005] Therefore, there is an urgent need for an automated liquid handling equipment and control method that can improve the accuracy of liquid addition and complete pipeline testing during the initialization phase. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides an automated liquid handling device and control method that can detect air bubbles and blockages in pipelines and compensate for the amount of liquid being sucked or discharged, ensuring the actual amount of liquid added and optimizing the accuracy of liquid addition. At the same time, it avoids problems such as insufficient cleaning fluid or pipeline blockage during the liquid injection needle cleaning step, thereby improving overall work efficiency.

[0007] To achieve the above objectives, as a first aspect, the present invention provides an automated liquid handling device, including a dispensing needle and a syringe pump for driving liquid suction and discharge, the device further comprising: A pressure sensor is installed in the tubing of the injection needle to monitor the pressure in the tubing in real time; The cleaning system includes a cleaning box, waste liquid piping, and a peristaltic pump; A photoelectric liquid level sensor is used to monitor the liquid volume in real time and is installed on the waste liquid pipeline; The controller is configured to dynamically correct the operating parameters of the injection pump when an abnormal pressure change is detected based on the pressure monitored by the pressure sensor during the process of liquid aspiration or drainage by the injection pump, so as to compensate for the volume deviation caused by the abnormal pressure change; it is also configured to control the peristaltic pump to pump liquid during the initialization process of the device, and determine whether there is an abnormality in the cleaning system based on the monitoring results of the photoelectric liquid level sensor.

[0008] According to the present invention, the pressure sensor is further described as a MEMS piezoresistive miniature pressure sensor.

[0009] As a second aspect, the present invention also provides a control method for an automated liquid handling device, applicable to a device including a dosing needle, a syringe pump for driving liquid suction and discharge, and a controller. During the process of performing liquid suction or discharge by the syringe pump to fill a pipeline or add liquid in a quantitative manner, a pressure sensor installed on the pipeline of the dosing needle acquires the pressure information in the pipeline in real time. When the controller detects an abnormal pressure change based on the pressure information, it dynamically corrects the operating parameters of the syringe pump to compensate for the volume deviation caused by the abnormal pressure change.

[0010] Furthermore, the method is also applied to a cleaning system comprising a cleaning box, a waste liquid pipeline, and a peristaltic pump, a photoelectric liquid level sensor installed on the waste liquid pipeline, and a controller. The method includes: during the initialization process of the device, controlling the peristaltic pump to pump liquid; monitoring whether liquid flows through the waste liquid pipeline through the photoelectric liquid level sensor; if no liquid flow is detected within a preset time, determining that the cleaning system is abnormal and triggering an alarm.

[0011] Furthermore, the abnormal pressure change includes the pressure rise rate in the pipeline being lower than a preset threshold; the dynamic correction of the operating parameters of the syringe pump includes: automatically adding at least one supplementary suction action, or adjusting the single stroke volume of subsequent suction and discharge.

[0012] Furthermore, the method also includes: a host computer, which controls the execution of the method in a cascading trigger manner by transmitting status flag bits between the host computer and the controller, wherein the triggering of subsequent operations depends on the completion flag of the preceding operation being set.

[0013] The beneficial effects of this invention are as follows: This invention utilizes a MEMS piezoresistive miniature pressure sensor for real-time monitoring of pipeline pressure. During liquid aspiration or dispensing, the sensor acquires real-time pressure information within the pipeline and dynamically adjusts the syringe pump's operating parameters when abnormal pressure changes are detected, achieving closed-loop control of the liquid dispensing process. This approach proactively detects and compensates for volume deviations caused by abnormal conditions such as air bubbles or blockages within the pipeline, significantly improving the accuracy and reliability of liquid dispensing while reducing the risk of cross-contamination due to residual air bubbles.

[0014] This invention adds a cleaning box status detection process to the equipment initialization process. By using a peristaltic pump and a photoelectric liquid level sensor for real-time monitoring of liquid volume, the user can perform a pre-test of the cleaning system before starting any experimental operation, ensuring that the cleaning system is problem-free. This effectively solves the problem in the prior art where insufficient cleaning fluid or pipeline blockage leads to contamination of the subsequent liquid injection needle after the equipment is started.

[0015] This invention employs a cascading triggering method, where status flags are passed between the host computer and the programmable logic controller (PLC) execution unit, ensuring that the triggering of subsequent operations depends on the completion of preceding operations. This mechanism effectively prevents error accumulation and safely terminates the process in the event of any sub-process anomaly, thereby enhancing the overall system reliability. Attached Figure Description

[0016] Figure 1 This is a schematic flowchart of the automated liquid handling equipment control method of the present invention; Figure 2 This is a schematic diagram of the signaling interaction of the state cascading triggering mechanism of the automated liquid handling equipment control method of the present invention; Figure 3 This is a hardware connection block diagram of the automated liquid handling device of the present invention.

[0017] Among them, 1-host computer, 2-PLC execution unit, 3-X-axis servo motor, 4-Z-axis servo motor, 5-injection pump, 6-peristaltic pump, 7-liquid injection needle, 8-cleaning box, 9-MEMS piezoresistive miniature pressure sensor, 10-photoelectric liquid level sensor. Detailed Implementation

[0018] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0019] like Figure 3As shown, this application provides a control method for an automated liquid handling equipment. The method operates on the automated liquid handling equipment, which includes four main parts: a control system, a motion system, a liquid dispensing system, and a cleaning system. The control system includes a host computer 1 for human-machine interaction and task management, and a PLC execution unit 2 responsible for real-time control and I / O processing. The motion system includes an X-axis servo motor 3 and a Z-axis servo motor 4 for horizontal and vertical movement. The liquid dispensing system includes a syringe pump 5 for precise liquid suction and discharge, a dispensing needle 7, and a MEMS piezoresistive miniature pressure sensor 9 integrated into the dispensing needle 7. The cleaning system includes a peristaltic pump 6 for supplying cleaning fluid, a cleaning box 8 for soaking and cleaning the dispensing needle, and a photoelectric liquid level sensor 10 installed on the waste liquid pipeline. MEMS technology makes the sensor very small, facilitating the integration of the MEMS piezoresistive miniature pressure sensor 9 into a small space near the tip of the dispensing needle 7, thereby enabling the fastest and most sensitive capture of pressure fluctuations within the pipeline, improving the real-time performance and accuracy of anomaly detection. The advantage of using the photoelectric liquid level sensor 10 is that it usually works in a non-contact manner, does not come into direct contact with the cleaning fluid, avoids corrosion and pollution problems, has high reliability and long life, its principle is simple, and its output signal is clear, making it very suitable for the binary judgment of whether there is backflow in this invention.

[0020] The firmware or software logic within the PLC execution unit 2 is designed to continuously receive and process pressure data from the MEMS piezoresistive miniature pressure sensor 9 during the liquid aspiration or dispensing process performed by the syringe pump 5. More importantly, the PLC execution unit 2 is configured to autonomously and dynamically correct the operating parameters of the syringe pump 5 when abnormal pressure changes are detected. The ultimate goal of this correction is to compensate for liquid volume deviations caused by abnormal pressure changes, such as air bubbles, thereby ensuring high-precision liquid handling under all operating conditions. By combining the MEMS piezoresistive miniature pressure sensor 9 with the PLC execution unit 2 equipped with specific logic, this application constructs a complete, self-calibrating liquid dispensing system.

[0021] Specifically, the aforementioned abnormal pressure change can be defined as follows: during liquid aspiration, the rate of pressure rise within the tubing is lower than a preset threshold. This phenomenon is a typical characteristic of air bubble aspiration or ineffective liquid aspiration, because the compressibility of gas is much greater than that of liquid, resulting in slow negative pressure build-up. By setting a clear and quantifiable judgment criterion, abnormality detection becomes more accurate and reliable.

[0022] Accordingly, the specific methods for dynamically correcting the operating parameters of the syringe pump 5 may include: automatically adding at least one supplementary suction action, or adjusting the single stroke volume of subsequent suction and discharge to address the volume deviation problem. Automatic supplementary suction involves immediately executing an additional suction cycle to make up the missing volume when insufficient suction is detected. Adjusting the single stroke volume of subsequent suction and discharge is a more precise adjustment method; the PLC execution unit 2 can estimate the volume loss based on the degree of pressure anomaly and accurately increase this loss in the next suction and discharge stroke.

[0023] Specifically, the PLC execution unit 2 is also configured to perform a self-test of the cleaning box 8 during the equipment initialization process. That is, the PLC execution unit 2 controls the peristaltic pump 6 to pump liquid and determines whether there is any abnormality in the cleaning box 8 based on the monitoring results of the photoelectric liquid level sensor 10. By integrating the MEMS piezoresistive miniature pressure sensor 9 and the photoelectric liquid level sensor 10 into the same device, both the accuracy of liquid addition and the normal state of the equipment during startup are ensured.

[0024] The control method of this application includes the following specific steps: like Figure 1 and Figure 2 As shown, the control method of the equipment follows a cascading triggering mechanism based on status flags. When the user starts an experimental process involving liquid addition on the host computer 1, the host computer 1 does not directly send instructions to each motor and syringe pump 5, but first writes a "request initialization" status flag to the shared memory of the PLC execution unit 2.

[0025] The PLC execution unit 2 periodically scans the memory area. When it detects that the "request initialization" flag is set, it begins to execute the preset initialization action sequence.

[0026] The initialization sequence includes controlling the X-axis servo motor 3 and the Z-axis servo motor 4 to return to the mechanical origin, and resetting other actuators, such as the electric gripper.

[0027] After the routine initialization process is completed, PLC execution unit 2 enters the self-test phase of the cleaning system.

[0028] In the self-test phase of the cleaning system, PLC execution unit 2 first controls the Z-axis servo motor 4 to precisely lower the liquid injection needle 7 and insert it into the preset position inside the cleaning box 8. Then, PLC execution unit 2 starts the peristaltic pump 6, causing it to rotate forward at a low speed, for example, 5 rpm, for a short period, such as 3 seconds, to pump a small amount of cleaning fluid from the storage bottle into the cleaning box 8. Since the liquid level in the cleaning box 8 is dynamically balanced, the pumping in of new liquid forces an equal amount of liquid to flow out from the waste liquid pipe at the bottom. During this period, PLC execution unit 2 continuously monitors the signal of the photoelectric liquid level sensor 10 coupled to the waste liquid pipe. If the signal of the photoelectric liquid level sensor 10 never changes to the "liquid present" state within the 3 seconds of the peristaltic pump 6's operation, PLC execution unit 2 determines that there is an abnormality in the cleaning system, i.e., the cleaning box is short of liquid or the pipe is blocked, and immediately triggers an alarm, sets a "system abnormality" flag, and terminates all subsequent processes. Conversely, if liquid flow is successfully detected, the cleaning system is considered normal.

[0029] Only after the cleaning system passes its self-test will PLC execution unit 2 set the "initialization complete" status flag in shared memory. The host computer 1 continuously polls this flag, and only after detecting that it is set will it confirm that the equipment is ready, and continue to set the next task request flag, such as "request pipeline filling", according to the user's settings.

[0030] When PLC execution unit 2 detects the "Request tubing filling" flag, it begins the pre-filling operation before liquid addition. This pre-filling process completely fills the entire tubing from syringe pump 5 to the tip of the dispensing needle 7 with the liquid to be processed, eliminating all air and ensuring accurate metering. PLC execution unit 2 controls syringe pump 5 to perform a standard aspiration action, for example, drawing 25 mL of liquid. Throughout the aspiration process, PLC execution unit 2 acquires pressure data from MEMS piezoresistive miniature pressure sensor 9 at a high frequency, such as 100 Hz.

[0031] PLC execution unit 2 internally runs a pressure analysis algorithm that compares the rising slope of the real-time pressure curve with a preset threshold, such as 0.5 kPa / s. During normal liquid aspiration, because the liquid is incompressible, the negative pressure in the pipeline builds up rapidly, and the pressure rise rate remains consistently above this threshold. However, if air bubbles are accidentally aspirated during the aspiration process, because gas is compressible, the negative pressure build-up process in the pipeline becomes slower, resulting in a pressure rise rate below 0.5 kPa / s. Once PLC execution unit 2 detects this "abnormal pressure change," it immediately determines that there is a volume deviation in the liquid aspiration and automatically triggers compensation logic.

[0032] In this embodiment, the compensation logic is "automatic supplementary aspiration action". That is, after the current aspiration cycle ends, PLC execution unit 2 will immediately perform an additional, complete 25mL supplementary aspiration action to ensure that air bubbles are expelled and the missing liquid volume is replenished. This process may be repeated until the pressure curves of the continuous aspiration processes conform to the normal model, at which point PLC execution unit 2 will determine that the pipeline is completely and air-free. After completing this step, PLC execution unit 2 sets the "pipeline filling complete" flag.

[0033] Only after confirming the "pipeline filling complete" flag will the host computer initiate the final "request quantitative liquid addition" command. The subsequent quantitative liquid addition process is also monitored in real time by the aforementioned pressure closed-loop calibration mechanism, ensuring highly accurate liquid volume transferred from the sample bottle to the target well plate each time. Through this series of interconnected self-checking, feedback, and compensation mechanisms, the equipment and method provided by this invention achieve extremely high operational reliability and liquid addition accuracy.

[0034] This application embodiment first performs a mandatory self-check on the cleaning system before the experiment begins, thereby eliminating the risk of process interruption and cross-contamination caused by insufficient cleaning fluid or pipeline blockage. Compared with traditional equipment, this significantly reduces the failure rate caused by cleaning problems.

[0035] Secondly, by introducing closed-loop feedback based on MEMS piezoresistive micro pressure sensors during the liquid addition process, volume errors caused by random factors such as bubbles can be captured and compensated in real time, improving the accuracy of quantitative liquid addition from ±5% of traditional open-loop control to within ±0.5%.

[0036] Finally, the state-cascaded triggering control architecture ensures that every step of the entire complex process is executed according to the predetermined logic, avoiding the accumulation of errors.

[0037] The automated liquid handling equipment and control method provided in this application have broad application prospects, especially suitable for scenarios with extremely high requirements for precision, throughput, and reliability. For example, in high-throughput screening (HTS) processes in drug development, researchers need to perform activity tests on tens of thousands of compounds. The equipment of this invention can be deployed in this process to automatically complete the entire process of sampling from microplates of compound libraries, scanning and verifying codes, opening the cap, accurately adding liquid to the reaction plate, and finally thoroughly cleaning the dispensing needle.

[0038] In a specific application, the equipment first performs an initialization process, ensuring sufficient cleaning fluid and unobstructed pipelines through a self-check function, thus guaranteeing continuous operation. Next, the equipment processes different compounds sequentially according to a preset program. Before processing each new compound, the equipment executes a pressure feedback-based pipeline filling procedure, completely replacing any residual liquid in the pipeline with the new compound liquid, and confirming through pressure curves that the pipeline is free of air bubbles and fully filled. This step is crucial to preventing cross-contamination between compounds.

[0039] Subsequently, during the dispensing of microliters of compound solutions into the reaction plate, each aspiration and dispensing action was monitored in real time by pressure sensors. Even when handling certain volatile or highly viscous solvents, the system dynamically adjusts the pump stroke to ensure a highly consistent volume dispensed into each reaction well. This high precision is crucial for obtaining reliable dose-response profiles. After dispensing one compound, the dispensing needle moves to the cleaning chamber for multi-step cleaning in preparation for the next compound. Since the cleaning system was confirmed to be functioning correctly during initialization, this cleaning step can be performed efficiently and reliably. The entire process requires no manual intervention, significantly improving screening efficiency and ensuring the quality of experimental data.

[0040] This application addresses the technical problems in the prior art, such as low liquid addition accuracy due to open-loop control, and process interruption and sample contamination caused by the inability to predict the state of the cleaning system. This method, by introducing closed-loop feedback control and a pre-test process, significantly improves the accuracy, reliability, and automation level of the equipment.

[0041] The following is a description of some of the nouns and terms used in the embodiments of this application: Anomaly in pressure variation refers to a significant deviation of the fluid pressure change curve within the pipeline from the standard pressure change model expected under normal, bubble-free, and blockage-free conditions during the liquid suction or discharge process of automated liquid handling equipment. This deviation is a key indicator for determining whether abnormal fluid conditions exist within the pipeline, such as air bubble intake, cavitation, or minor blockage. In the specific implementation of this application, this anomaly can be specifically manifested as a pressure rise rate lower than a preset normal threshold during the liquid suction phase, or a failure of the pressure to reach the expected peak value during the liquid discharge phase. Detecting this anomaly is a prerequisite for initiating subsequent compensation mechanisms.

[0042] Status flags are specific data signals used in hierarchical control systems, such as systems composed of a host computer and a programmable logic controller (PLC), to synchronize task status and transfer control authority between different control units. These flags are typically stored in a shared memory area. One control unit, such as the host computer, initiates a task request, such as "request initialization," by setting a flag to 1. Another control unit, such as the PLC, sets a corresponding completion flag after completing the task, such as "initialization completed." By querying the status of these flags, a logical execution chain can be constructed.

[0043] Cascading triggering refers to a program control logic based on the aforementioned "status flags". Under this logic, a complex process is decomposed into multiple ordered subtasks. The activation of each subsequent subtask requires the successful setting of the "completion flag" of one or more preceding subtasks as a prerequisite. That is, the successful completion of the previous stage is the only key to triggering the next stage, thereby ensuring the orderliness, reliability, and security of the entire automated process and avoiding the accumulation of errors caused by program disorder or unresolved exceptions.

[0044] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. An automated liquid handling device, comprising a dispensing needle and a syringe pump for driving liquid suction and discharge, characterized in that, The device also includes: A pressure sensor is installed in the tubing of the injection needle to monitor the pressure in the tubing in real time; The cleaning system includes a cleaning box, waste liquid piping, and a peristaltic pump; A photoelectric liquid level sensor is used to monitor the liquid volume in real time and is installed on the waste liquid pipeline; The controller is configured to dynamically correct the operating parameters of the injection pump when an abnormal pressure change is detected based on the pressure monitored by the pressure sensor during the process of liquid aspiration or drainage by the injection pump, so as to compensate for the volume deviation caused by the abnormal pressure change; it is also configured to control the peristaltic pump to pump liquid during the initialization process of the device, and determine whether there is an abnormality in the cleaning system based on the monitoring results of the photoelectric liquid level sensor.

2. The automated liquid handling equipment as described in claim 1, characterized in that, The pressure sensor is a MEMS piezoresistive miniature pressure sensor.

3. A control method for automated liquid handling equipment, applied to equipment including a dispensing needle, a syringe pump for driving liquid suction and discharge, and a controller, characterized in that, During the process of filling or metering the tubing by performing liquid aspiration or dispensing through the injection pump, the pressure information in the tubing is acquired in real time by a pressure sensor installed on the injection needle. When the controller detects an abnormal pressure change based on the pressure information, it dynamically corrects the operating parameters of the injection pump to compensate for the volume deviation caused by the abnormal pressure change.

4. The control method for the automated liquid handling equipment as described in claim 3 is further applied to a device comprising a cleaning system consisting of a cleaning box, a waste liquid pipeline, and a peristaltic pump, a photoelectric liquid level sensor installed on the waste liquid pipeline, and a controller, characterized in that... The method includes: during the initialization process of the device, controlling the peristaltic pump to pump liquid; monitoring whether liquid flows through the waste liquid pipeline through the photoelectric liquid level sensor; if no liquid flow is detected within a preset time, determining that the cleaning system is abnormal and triggering an alarm.

5. The control method for the automated liquid handling equipment as described in claim 3, characterized in that, The abnormal pressure change includes the rate of pressure rise in the pipeline being lower than a preset threshold. The dynamic correction of the operating parameters of the syringe pump includes: automatically adding at least one supplementary suction action, or adjusting the single stroke volume of subsequent suction and discharge.

6. The control method for the automated liquid handling equipment as described in claim 3 or 4, characterized in that, The method also includes a host computer, which controls the execution of the method by transmitting status flag bits between the host computer and the controller in a cascading trigger manner, wherein the triggering of subsequent operations depends on the completion flag of the preceding operation being set.

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