Automatic pretreatment method and system for urine sample

Abstract

The invention provides an automatic urine sample preprocessing method and system for pharmacokinetic parameter calculation. The method is realized through an integrated automatic process as follows: identifying a urine cup with an identity label, transferring a urine sample to a measuring cylinder, accurately measuring the volume of urine by using a sensor, adding a stabilizing solution according to a preset proportion, then performing standardized mixing to form a mixed solution, and finally sub-packaging the mixed solution into a cryopreservation tube in a high-flux manner. The technical problem that in the prior art, due to manual operation, urine volume measurement is not accurate, medicine components are degraded after being in vitro, data tracing is difficult and the like is solved, and finally the technical pain point that key pharmacokinetic parameter calculation results are seriously inaccurate is caused. By providing a high-precision and high-reproducibility qualified sample, the quality of subsequent analysis data is guaranteed from the source, and the accuracy, research efficiency and data compliance of PK parameter calculation are remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological liquid sample standardization pretreatment, in particular to a urine sample automatic pretreatment method and system. BACKGROUND

[0002] The technical field to which the present application belongs is the pharmacokinetics (PK) research using biological samples, which is a core link of new drug research and development and generic drug evaluation. Among them, the analysis of urine samples to obtain drug excretion information plays an irreplaceable role in calculating key PK parameters such as renal clearance, final cumulative excretion, and original drug excretion fraction. The accuracy of these parameters directly determines the judgment of the main excretion pathway of the drug and provides key scientific basis for dose adjustment for special groups such as patients with renal dysfunction.

[0003] However, the bottleneck and main error source of obtaining high-quality urine data that can be used for accurate calculation of the above PK parameters is in the pretreatment stage before sample analysis. In the current industry practice, this pretreatment process, especially when dealing with a large number of urine samples generated by large-scale clinical trials such as bioequivalence (BE) studies, generally relies on tedious manual operations. This traditional mode has the following serious technical defects, which directly damage the reliability of the final PK parameters:

[0004] Measurement error of key raw data: the excretion amount of a drug in a certain time period is obtained by multiplying the urine concentration in that time period by the urine volume. In manual operation, it is easy to introduce parallax and estimation error by measuring the volume with a graduated cylinder; at the same time, it is also easy to make mistakes in manually recording the urine volume and collection time. These seemingly small volume measurement or recording deviations will directly lead to significant distortion of the calculated excretion amount, and this error will be cumulatively accumulated, eventually causing a huge deviation between the calculated total excretion and renal clearance and the true value.

[0005] Uncontrollable pre-analysis variation of analyte concentration: many drugs or their key metabolites such as glucuronide or sulfate conjugates formed in vivo are unstable in ex vivo urine and are easily affected by urine pH, temperature or endogenous enzymes to cause degradation, or "reverse conversion" of metabolites to original drugs. In the manual operation process, there is an uncontrollable time delay and inconsistency in operation between sample collection and the addition of stabilizers, which will cause different degrees of degradation between different samples, making the measured drug concentration unable to truly reflect its excretion status in vivo, and seriously affecting the accuracy of PK model analysis.

[0006] Data integrity and traceability risks: When handling hundreds of urine samples, manual sample identification check, information entry and aliquot labeling are prone to sample mix-up or information recording errors. In a clinical study strictly following GLP / GCP regulations, such errors are disastrous, which not only invalidates individual data points, but also may render the entire subject's dataset untrustworthy, causing huge R&D loss.

[0007] Processing throughput and lack of standardization: Manual processing procedures are inefficient and cannot match the high-throughput sample analysis requirements in modern drug development, becoming a bottleneck in the entire study cycle. More importantly, the operation methods of different operators, or even the same operator at different time points (such as the intensity and time of mixing samples, the accuracy of pipetting) are difficult to completely unify, introducing a large inter-operator and intra-operator variation. This non-standardized processing procedure leads to increased data dispersion, reducing the statistical power of the study results.

[0008] Therefore, there is an urgent need in the art for an automated, high-throughput solution that seamlessly integrates key steps from sample reception identification, accurate volume measurement, immediate stabilization processing to standardized aliquoting, to improve the quality of urine samples from the source, ensuring the accuracy, precision and reliability of subsequent pharmacokinetic parameter calculations.

[0009] It should be noted that the information disclosed in the above background section is only used to strengthen the understanding of the background of the present application, and therefore can include information that does not constitute prior art known to those of ordinary skill in the art. SUMMARY

[0010] Therefore, the present application provides an automated urine sample preprocessing method and system, aiming to provide a method that can realize the automation of the entire process from sample reception to preprocessing completion, improve the efficiency, accuracy, standardization and biosafety of urine sample preprocessing.

[0011] The present application provides an automated urine sample preprocessing method, comprising the following steps:

[0012] Transferring a urine cup containing a urine sample and carrying an identity label to a predetermined urine cup processing station;

[0013] Identifying the identity label of the urine cup to obtain urine sample information;

[0014] Transferring the urine sample in the urine cup to a measuring cylinder by a first mechanical arm;

[0015] Detecting the liquid level of the urine sample in the measuring cylinder by a liquid level sensor, and calculating the volume of the urine sample according to the liquid level and the known geometric dimensions of the measuring cylinder;

[0016] According to the volume of the urine sample and a preset volume ratio, the first pipettor adds the stabilizing liquid into the cuvette;

[0017] The driving mixing mechanism mixes the urine sample in the cuvette with the stabilizing liquid to form a mixed liquid;

[0018] The second pipettor sucks a predetermined amount of the mixed liquid from the cuvette and injects the mixed liquid into at least one cryogenic tube;

[0019] The cryogenic tube containing the mixed liquid is transferred to the collection station.

[0020] In some optional embodiments, the urine sample automated pretreatment method further comprises:

[0021] The photoelectric sensor array detects whether the urine cup is tipped over or broken on the transfer path, and sends out a first alarm signal when tipping over or breaking is detected.

[0022] In some optional embodiments, the identity is a barcode, and the barcode is scanned by a barcode reader to obtain the urine sample information.

[0023] In some optional embodiments, the first mechanical arm transfers the urine sample into the cuvette by turning over the urine cup, and places the urine cup in the waste collection area after the transfer is completed.

[0024] In some optional embodiments, the liquid level sensor is a non-contact ultrasonic liquid level sensor.

[0025] In some optional embodiments, the liquid level sensor is a laser ranging sensor, which determines the liquid level by emitting a laser beam and receiving a reflected signal.

[0026] In some optional embodiments, the urine sample automated pretreatment method further comprises:

[0027] The total weight of the cuvette and the urine sample therein is weighed by the precision balance, and the tare weight of the cuvette is subtracted to obtain the weight of the urine sample;

[0028] The volume of the urine sample is calculated according to the weight of the urine sample and a preset urine density value.

[0029] In some optional embodiments, the urine sample automated pretreatment method further comprises:

[0030] The liquid surface image of the urine sample in the cuvette is obtained by the optical imaging device;

[0031] The liquid surface image is processed to identify and exclude the interference of bubbles on the liquid surface judgment, and the liquid surface height information is extracted from the image;

[0032] The volume calculated based on weight and the volume calculated based on optical liquid level are checked. If the difference between the two exceeds a preset threshold, a second alarm signal is sent out.

[0033] In some alternative embodiments, the preset range of the volume ratio of the stabilizing liquid to the urine sample is 0.5:100 to 2:100.

[0034] In some alternative embodiments, the mixing mechanism is a shaking platform, and the mixing is achieved by making the shaking platform perform reciprocating motion at a preset frequency and amplitude.

[0035] In some alternative embodiments, the urine sample automated pretreatment method further comprises:

[0036] The urine sample in the measuring cylinder and the stabilizing liquid are pumped into a closed mixing channel with internal microstructure, and the liquid generates turbulent flow when flowing through the microstructure, thereby achieving mixing and forming a mixed liquid.

[0037] In some alternative embodiments, the urine sample automated pretreatment method further comprises:

[0038] Ultrasonic energy is applied externally or internally to the measuring cylinder, and the cavitation effect and acoustic streaming effect generated by the ultrasonic waves in the liquid are used to promote rapid and uniform mixing of the urine sample and the stabilizing liquid, thereby forming a mixed liquid.

[0039] In some alternative embodiments, the urine sample automated pretreatment method further comprises that the second pipette is a multi-channel pipette with at least eight independent pipetting channels, and the mixed liquid is simultaneously sucked from the measuring cylinder and injected into at least eight cryogenic tubes through each channel.

[0040] In some alternative embodiments, the urine sample automated pretreatment method further comprises:

[0041] The used pipette tips on the second pipette are automatically detached into a designated waste tip collection container.

[0042] In some alternative embodiments, the urine sample automated pretreatment method further comprises:

[0043] The mixed liquid is introduced into a disposable distribution chip with a liquid storage cavity and a plurality of parallel microfluidic distribution channels;

[0044] By applying a precisely controlled air pressure to the liquid storage cavity, the mixed liquid is driven through the plurality of parallel microfluidic distribution channels and simultaneously injected into the corresponding at least one cryogenic tube at the end of each channel.

[0045] In some alternative embodiments, the urine sample automated pretreatment method further comprises:

[0046] The at least one cryogenic tube is automatically screwed or crimped with a tube cap by an automatic cap opening / closing device.

[0047] In some optional embodiments, the urine sample automated pretreatment method further comprises:

[0048] After installing the tube cap on the cryogenic tube, a pre-prepared label containing urine sample information is automatically pasted on the tube wall of each cryogenic tube by a label printing and pasting device.

[0049] In some optional embodiments, the urine sample automated pretreatment method further comprises:

[0050] The operating state parameters of the first mechanical arm, the first pipettor, the mixing mechanism, and the second pipettor are monitored in real time, and the urine sample information, the calculated urine sample volume, the added stabilizing liquid volume, and the operating state parameters are recorded and stored in the database.

[0051] In some optional embodiments, the urine sample automated pretreatment method is performed in a closed workstation with an air purification system.

[0052] In some optional embodiments, the urine sample automated pretreatment method further comprises the following steps:

[0053] The concentration of the mixed solution in the cryogenic tube is detected, and the target parameter is calculated accordingly. The target parameter is obtained by calculating the percentage of the amount of drug excreted in each time period to the total dose, and the calculation formula is:

[0054] m(t) = p V

[0055]

[0056] In the formula, m(t) is the amount of drug excreted in t time period, p is the drug concentration, V is the urine sample volume, R(t) is the percentage in t time period, and M is the total dose of the drug.

[0057] The embodiments of the present application also provide a urine sample automated pretreatment system, comprising:

[0058] A urine cup conveying unit is configured to convey a urine cup containing a urine sample and carrying an identity label.

[0059] An identity label recognition unit is arranged on or adjacent to the urine cup conveying path and is configured to recognize the identity label of the urine cup.

[0060] A first mechanical arm is configured to transfer the urine sample in the urine cup to a measuring cylinder.

[0061] A liquid level sensor is configured to detect the liquid level of the urine sample in the measuring cylinder and output a liquid level signal.

[0062] A first pipettor is configured to add a stabilizing liquid to the measuring cylinder.

[0063] a mixing mechanism, the graduated cylinder being placed on or in the mixing mechanism, the mixing mechanism being configured to mix the urine sample in the graduated cylinder with the stabilizing liquid to form a mixed liquid;

[0064] a second pipettor configured to aspirate a predetermined amount of the mixed liquid from the graduated cylinder and inject the mixed liquid into at least one cryogenic tube;

[0065] a cryogenic tube conveying unit for conveying the cryogenic tube containing the mixed liquid to a collection station;

[0066] a control unit electrically connected with the identity recognition unit, the first mechanical arm, the liquid level sensor, the first pipettor, the mixing mechanism, the second pipettor, and the conveying unit, and configured to implement the automatic urine sample pretreatment method described above.

[0067] In some optional embodiments, the control unit is configured with a storage module for storing the known geometric dimensions of the graduated cylinder, and the control unit is configured to:

[0068] obtain the urine sample information based on the identity recognized by the identity recognition unit;

[0069] calculate the volume of the urine sample based on the liquid level signal output by the liquid level sensor and the known geometric dimensions of the graduated cylinder stored in the storage module;

[0070] control the first pipettor to add the stabilizing liquid to the graduated cylinder according to the calculated volume of the urine sample and the preset volume ratio;

[0071] control the mixing mechanism, the second pipettor, and the conveying unit to perform predetermined operations.

[0072] In some optional embodiments, the liquid level sensor is a non-contact ultrasonic liquid level sensor or a laser ranging sensor; and / or, the mixing mechanism is an oscillation platform or a closed mixing channel with internal microstructure or an ultrasonic mixing device.

[0073] In some optional embodiments, the second pipettor includes a multi-channel pipette tip capable of simultaneously injecting the mixed liquid into multiple cryogenic tubes; or, the system further includes a disposable dispensing chip configured with a liquid storage cavity and multiple parallel microfluidic dispensing channels, and a gas pressure control device for driving the mixed liquid to pass through the dispensing chip, the mixed liquid being introduced into the liquid storage cavity and driven by the gas pressure control device to pass through the multiple parallel microfluidic dispensing channels and simultaneously injected into corresponding cryogenic tubes.

[0074] In some optional embodiments, the automatic urine sample pretreatment system further includes:

[0075] an automatic cap opening / closing device configured to automatically open the tube cap before the mixed liquid is injected into the cryogenic tube, and automatically tighten or press the tube cap after the injection, the automatic cap opening / closing device being electrically connected with and controlled by the control unit; and

[0076] The label printing and pasting device is configured to automatically paste a prefabricated label containing information corresponding to the urine sample on the tube wall of the cryopreservation tube after the tube cover is installed on the cryopreservation tube. The label printing and pasting device is electrically connected to the control unit and controlled by the control unit.

[0077] It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory, and are not limiting to the present application.

[0078] The urine sample automatic pretreatment method and system has the following beneficial effects:

[0079] Compared with the prior art, the urine sample automatic pretreatment method and system provided by the present application integrates the key steps of identity recognition, urine sample transfer, accurate volume measurement based on sensors or weight, stable liquid addition according to a preset ratio, standardized mixing, and automatic packaging into a seamless automatic process, which brings significant organic beneficial effects. The automatic process fundamentally eliminates subjective errors and operation inconsistencies introduced by manual operation, ensures the accuracy of each sample volume data and the stability of the drug after being separated from the body, and thus provides highly accurate and reliable raw data for calculating key pharmacokinetic parameters. At the same time, the automatic identity recognition and data recording function builds a complete audit tracking chain, effectively avoiding the risk of sample confusion and information loss, ensuring the integrity and traceability of the data, and meeting the requirements of GLP / GCP and other regulations. By realizing the high standardization and high throughput of the process, the present application not only greatly reduces the data variability and improves the statistical power of the research results, but also significantly improves the overall research efficiency, and finally systematically solves the technical pain points of inaccurate pharmacokinetic parameter calculation caused by data quality problems in traditional methods. BRIEF DESCRIPTION OF DRAWINGS

[0080] Other features, objects, and advantages of the present application will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings.

[0081] Figure 1 is a flowchart of a urine sample automatic pretreatment method according to an embodiment of the present application;

[0082] Figure 2 is a structural schematic diagram of a urine sample automatic pretreatment system according to an embodiment of the present application;

[0083] Figure 3 is a flowchart of a urine sample automatic pretreatment method according to another embodiment of the present application;

[0084] Figure 4 is a structural schematic diagram of a urine sample automatic pretreatment system according to another embodiment of the present application.

[0085] Wherein, 1-closed chamber, 2-collection line, 21-workbench, 211-urine cup placement position, 212-measuring cylinder placement position, 213-shaking shaker, 2131-shaking placement position, 214-suction nozzle set position, 215-frozen tube placement position, 216-waste conveying position, 217-stabilizing liquid tank, 221-urine cup moving and overturning mechanism, 222-measuring cylinder moving mechanism, 223-urine measuring mechanism, 224-stabilizing liquid adding mechanism, 225-mixed liquid pipetting mechanism, 31-urine cup feeding mechanism, 311-urine cup conveying belt, 312-bar code label scanner, 32-measuring cylinder feeding mechanism, 321-measuring cylinder feeding machine, 322-measuring cylinder conveying belt, 33-suction nozzle feeding mechanism, 331-suction nozzle conveying belt, 332-suction nozzle placement tray, 34-frozen tube feeding and cap removing mechanism, 341-frozen tube conveying belt, 342-cap removing assembly, 343-tube cap conveying line, 344-cap screwing assembly, 4-waste conveying device, 41-waste conveying belt, 42-waste box, 5-refrigeration chamber, 6-label marking and labeling machine, 7-trolley, 8-infrared sensor, 9-urine cup, 10-measuring cylinder, 11-suction nozzle, 12-frozen tube. DETAILED DESCRIPTION

[0086] Example implementations will now be described more fully with reference to the accompanying drawings. Example implementations may, however, be implemented in many different forms and should not be construed as limited to the examples set forth herein; rather, these implementations are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the example implementations to those skilled in the art. The described features, structures, or characteristics can be combined in one or more implementations.

[0087] In addition, the accompanying drawings are included to provide a further understanding of the present application, and are incorporated in and constitute a part of this specification. The drawings illustrate embodiments of the present application and, together with the description, serve to explain the principles of the present application. In the drawings:

[0088] The flow diagrams in the various figures presented herein can be viewed as being composed of a plurality of blocks that represent computer instructions or steps. Flow diagrams can also be viewed as computers, or processors, that receive a sequence of instructions that execute the steps shown in the figures, either in the order shown in the figures or in a different order. The illustrated flow diagrams are examples of machine implementations. Given the same instructions, a variety of machines and / or processors can carry out the instructions in the same or a different order to achieve the same results.

[0089] The urine sample automatic pretreatment method and system disclosed by the present application integrates multiple discrete, error-prone and labor-dependent urine sample pretreatment steps in traditional pharmacokinetic research into a data-driven, process-controlled closed-loop automated process through a set of precisely coordinated mechanical and electrical and sensing systems. The starting point of the process is to identify the identity of the urine cup to give each physical sample a unique, fully traceable digital identity, providing a physical guarantee for data integrity for all subsequent operations. Then, the urine sample is completely transferred to a graduated cylinder by a first mechanical arm in a standardized manner, and objective physical quantity measurement means such as a liquid level sensor are used to replace subjective error-prone manual visual inspection, thereby obtaining high-precision urine volume data. Based on this accurate volume, the system can accurately add a stabilizing liquid in a pre-set, optimized proportion through a first pipette, which ensures the chemical kinetic stability of the drug or its metabolites after being separated from the body. Subsequently, a mixing mechanism is driven to standardize and homogenize the liquid, ensuring the uniformity of the sample at the microscopic level, so that any aliquot taken by a second pipette can truly represent the average concentration of the entire original urine sample. Therefore, the present application converts the steps in the traditional pretreatment process that are full of human uncertainty into a data-driven, process-controlled continuous operation process through a series of automated and programmed operations. This transformation fundamentally solves the core technical problems in this field, such as inaccurate urine volume measurement, degradation of drug components after being separated from the body, confusion of sample information, and inconsistent operation methods, which ultimately lead to inaccurate pharmacokinetic parameter calculation results. The present application provides high-quality and highly reproducible qualified samples for subsequent drug concentration analysis, making the key pharmacokinetic parameters such as renal clearance and cumulative excretion calculated based on these sample data achieve unprecedented accuracy and reliability, thereby providing a solid technical support for scientific and rigorous drug evaluation.

[0090] As shown in Figure 1 The present application provides a urine sample automatic pretreatment method, which aims to realize the full-process automation of urine samples from receiving to completing pretreatment, including the following steps:

[0091] S100, a urine cup containing a urine sample and carrying an identity is transferred to a predetermined urine cup processing station. The urine cup is a container for containing a urine sample, which can be made of polypropylene, polyethylene or polystyrene, etc., and can be in the shape of a cylinder, a square or a cone, etc. The identity is used to uniquely identify the urine sample in the urine cup, and the identity can be a bar code, a two-dimensional code, an RFID tag, etc. The urine cup can be transferred by a conveyor belt, a mechanical arm or other automated transfer device, and the predetermined urine cup processing station is a specific position for subsequent processing.

[0092] S200, identify the identity of the urine cup to obtain the urine sample information. The identity recognition unit can be a barcode scanner, a two-dimensional code scanner or an RFID reader, etc. The urine sample information includes patient ID, sample number, collection time, etc. These information are one-to-one corresponding to the urine sample, which provides the basis for subsequent sample management and traceability.

[0093] S300, transfer the urine sample in the urine cup to a measuring cylinder by the first mechanical arm. The first mechanical arm can be selected from joint robot, SCARA robot or Delta robot, etc. The measuring cylinder is a container with precise scale, which is used to receive and measure the volume of the urine sample. Its material can be glass, plastic or other corrosion-resistant materials.

[0094] S400, detect the liquid level of the urine sample in the measuring cylinder by the liquid level sensor, and calculate the volume of the urine sample according to the liquid level and the known geometric size of the measuring cylinder. The liquid level sensor can be selected from ultrasonic liquid level sensor, laser liquid level sensor or capacitive liquid level sensor, etc. The geometric size information of the measuring cylinder is pre-stored in the system, which is used to accurately calculate the volume of the urine sample according to the liquid level.

[0095] S500, according to the volume of the urine sample and the preset volume ratio, add stabilizing liquid to the measuring cylinder by the first pipette. The stabilizing liquid is used to inhibit the degradation or change of the components in the urine sample. The type and addition ratio of the stabilizing liquid are determined according to the specific analysis requirement. The first pipette can be selected from syringe pump, peristaltic pump or automatic pipette, etc.

[0096] S600, drive the mixing mechanism to mix the urine sample and the stabilizing liquid in the measuring cylinder to form a mixed liquid. The mixing mechanism can be selected from shaking platform, rotary mixer or ultrasonic mixer, etc. The purpose of mixing is to make the stabilizing liquid fully contact with the urine sample to ensure the stabilization effect.

[0097] S700, draw a predetermined amount of mixed liquid from the measuring cylinder by the second pipette, and inject the mixed liquid into at least one cryogenic tube. The second pipette can be selected from single-channel pipette, multi-channel pipette or microfluidic dispensing chip, etc. The predetermined amount of mixed liquid is determined according to the subsequent analysis requirement. The cryogenic tube is used for long-term storage of the processed urine sample, and its material can be polypropylene or other low-temperature resistant materials.

[0098] S800, transfer the cryogenic tube containing the mixed liquid to the collection station. The transfer can be carried out by conveyor belt, mechanical arm or other automatic transfer device. The collection station is a specific position set in the system for collecting the processed urine sample.

[0099] Through the above steps, the whole process automation of the urine sample from receiving to completing the pretreatment is realized, so as to overcome the shortcomings of manual operation. The urine sample automatic pretreatment method provided by the embodiment of the application can reduce human operation errors, improve the accuracy and standardization degree of sample processing, and effectively improve the sample processing efficiency.

[0100] In some embodiments, between step S100 and step S200, further comprising: detecting whether the urine cup is tilted or damaged on the conveying path through the photoelectric sensor array, and issuing a first alarm signal when the tilting or damage is detected. This step aims to ensure the safety of the urine cup during conveying, avoiding sample loss or contamination due to tilting or damage. The photoelectric sensor array is composed of a plurality of photoelectric sensors, which can be selected from a pair of photoelectric sensors, a reflective photoelectric sensor or a diffuse reflective photoelectric sensor, etc. The photoelectric sensor array is arranged along the urine cup conveying path for real-time monitoring of the state of the urine cup. When the urine cup is tilted or damaged, the light signal detected by the photoelectric sensor array changes, the system judges that the state of the urine cup is abnormal, and a first alarm signal is issued. The first alarm signal can be an audible and visual alarm, an SMS alarm or an email alarm, etc. to prompt the operator to handle it in time. This step can effectively prevent sample loss or contamination caused by abnormal state of the urine cup, and ensure the smooth progress of the pretreatment process.

[0101] In some embodiments, in step S200, the identity is a barcode, and the barcode is scanned by a barcode reader to obtain the urine sample information. This step uses barcode technology to realize automatic identification and input of urine sample information. The barcode is a pattern composed of a series of black and white stripes, which contains specific coded information. The barcode reader is an optoelectronic scanning device that can emit a light beam and receive the light signal reflected by the barcode, then convert the light signal into an electrical signal, and decode it into the corresponding character information. The barcode reader can be a handheld barcode scanner or a fixed barcode scanning platform. By scanning the barcode on the urine cup with the barcode reader, the patient ID, sample number, collection time, etc. related to the urine sample can be quickly and accurately obtained, avoiding errors that may be caused by manual input, and improving the efficiency and accuracy of information input.

[0102] In some embodiments, in step S300, the first robotic arm transfers the urine sample into the measuring cylinder by inverting the urine cup and places the urine cup in the waste collection area after the transfer is completed. This step provides a specific implementation of urine sample transfer by controlling the movement of the robotic arm to invert the urine cup and use gravity to pour the urine sample into the measuring cylinder. The angle and speed of inversion can be adjusted according to the shape of the urine cup and the volume of the urine sample to ensure that the urine sample is transferred as completely as possible into the measuring cylinder, for example, programmable tilt angle, rotation speed and dwell time. After the transfer is completed, the first robotic arm transports and places the empty urine cup in the designated waste collection area, which is used to collect used urine cups to facilitate subsequent unified processing and disposal, avoiding environmental pollution and biological safety risks. This step replaces the manual pouring of urine samples by an automated robotic arm, improving transfer efficiency and safety, and reducing sample residue to ensure the accuracy of subsequent volume measurements.

[0103] In some embodiments, in step S400, the liquid level sensor is a non-contact ultrasonic liquid level sensor. This step provides a specific type of liquid level sensor for liquid level detection using a non-contact ultrasonic liquid level sensor. The ultrasonic liquid level sensor emits ultrasonic pulses and receives echoes reflected from the liquid surface to calculate the liquid level based on the propagation time of the ultrasonic waves. The non-contact measurement method avoids direct contact between the sensor and the urine sample, reducing the risk of cross-contamination and minimizing interference with the sample. Ultrasonic liquid level sensors generally have high measurement accuracy and fast response speed, meeting the requirements of automated preprocessing for volume measurement. In addition, non-contact ultrasonic liquid level sensors are not sensitive to sample physical properties such as color and transparency, making them highly adaptable.

[0104] In some embodiments, in step S400, the liquid level sensor is a laser ranging sensor that determines the liquid level by emitting a laser beam and receiving the reflected signal. This step provides another specific type of liquid level sensor for liquid level detection using a laser ranging sensor. The laser ranging sensor emits a laser beam and measures the time or phase difference of the reflected signal to calculate the distance between the sensor and the liquid surface, thereby determining the liquid level. Laser ranging sensors have high measurement accuracy, fast response speed, and are less affected by environmental light interference, enabling accurate measurement of the liquid level of the urine sample. Laser ranging sensors can use time-of-flight laser ranging sensors or phase laser ranging sensors to meet different measurement requirements. This step uses laser ranging sensors to achieve accurate measurement of the liquid level of the urine sample, providing accurate data for subsequent volume calculation.

[0105] In some embodiments, after step S300 and before step S400, further comprising:

[0106] The total weight of the measuring cylinder and the urine sample therein is weighed by the precision balance, and the tare weight of the measuring cylinder is subtracted to obtain the weight of the urine sample;

[0107] In step S400, the volume of the urine sample is calculated according to the weight of the urine sample and the preset urine density value.

[0108] This embodiment provides a scheme for measuring the volume of a urine sample based on the weighing method. A precision balance is used to accurately weigh the total weight of the measuring cylinder and the urine sample therein, and its accuracy can reach 0.01 g or higher. The tare weight of the measuring cylinder is the weight of the measuring cylinder itself, which can be a fixed value measured in advance and stored in the system, or it can be measured in real time by the balance. The weight of the urine sample is obtained by subtracting the tare weight of the measuring cylinder from the total weight. The urine density value can be a preset average density value, for example, 1.015 g / mL, or it can be set and adjusted in the system according to the sample source population or known sample type. Then, the volume of the urine sample is calculated by the formula: volume = weight / density. This scheme uses the weight method to measure the volume, which can avoid the measurement error that may exist in the liquid level sensor, improve the accuracy and reliability of the volume measurement, and is not affected by the physical properties such as color and transparency of the urine sample.

[0109] In some embodiments, the urine sample automatic pretreatment method further comprises:

[0110] The liquid surface image of the urine sample in the measuring cylinder is acquired by the optical imaging device; the liquid surface image is processed to identify and exclude the interference of bubbles on the judgment of the liquid surface, and the liquid surface height information is extracted from the image; the volume calculated based on the weight and the volume calculated based on the optical liquid surface height are combined for verification, and if the difference between the two exceeds a preset threshold, a second alarm signal is sent. Based on the volume measurement based on the weight method, the optical imaging device is introduced for auxiliary verification to improve the accuracy and reliability of volume measurement. The optical imaging device can be a CCD camera or a CMOS camera, cooperating with a suitable light source such as an LED backlight or a lateral structured light, for acquiring the liquid surface image of the urine sample in the measuring cylinder. Image processing algorithms are used to identify and exclude the interference of bubbles, meniscus, etc. on the judgment of the liquid surface, and to accurately extract the liquid surface height information, for example, using edge detection, Hough transform, template matching, etc. The system control unit compares the volume calculated based on the weight method with the volume measured based on the optical method, and if the relative difference or absolute difference between the two exceeds the preset allowable error threshold, for example, ±2% or ±0.5mL, it is considered that the measurement result is abnormal, a second alarm signal is triggered, indicating that there may be problems such as too large deviation of urine density from the preset value, serious pollution or obstruction of optical measurement, improper placement of the container, etc. so that the operator can check and handle it in time. The joint verification of the weight method and the optical method can effectively improve the accuracy, reliability and identification ability of abnormal conditions of volume measurement.

[0111] In some embodiments, in step S500, the preset range of the volume ratio of the stabilizing liquid to the urine sample is 0.5:100 to 2:100. This step limits the volume ratio range between the stabilizing liquid and the urine sample. The addition ratio of the stabilizing liquid needs to be selected according to the specific analysis requirements and the properties of the stabilizing liquid. If the addition ratio is too low, the expected stabilization effect may not be achieved; if the addition ratio is too high, it may interfere with subsequent analysis. Therefore, the present embodiment limits the preset range of the volume ratio of the stabilizing liquid to the urine sample to 0.8:100 to 1.2:100, which can ensure the stabilization effect and minimize the interference with subsequent analysis. This ratio can be adjusted according to specific experimental requirements, for example, for some urine samples with high stability requirements, a ratio close to 2:100 can be selected; for analysis with high interference requirements, a ratio close to 0.5:100 can be selected.

[0112] In some embodiments, the mixing mechanism in step S600 is a shaking platform, and the mixing is achieved by making the shaking platform perform reciprocating motion with a preset frequency and amplitude. This step provides a specific type of mixing mechanism and a mixing method, and the urine sample and the stabilizing liquid are mixed by the shaking platform through reciprocating motion. The shaking platform is a platform that can perform reciprocating motion, and the measuring cylinder can be stably placed on the platform. The frequency and amplitude of the reciprocating motion can be adjusted according to the properties and volume of the urine sample, for example, the frequency ranges from 50 to 300 rpm, and the amplitude ranges from 10 to 50 mm. By controlling the motion parameters of the shaking platform, the urine sample and the stabilizing liquid in the measuring cylinder generate inertial force and shear force, thereby achieving sufficient mixing. The reciprocating motion can be linear reciprocating, circular reciprocating, or elliptical reciprocating, etc. This step realizes uniform mixing of the urine sample and the stabilizing liquid by a simple and reliable shaking method, and provides a guarantee for subsequent analysis and detection.

[0113] In some embodiments, step S600 includes pumping the urine sample and the stabilizing liquid in the measuring cylinder into a closed mixing channel with internal microstructures, such as staggered static mixing elements, and the liquid generates turbulent flow when flowing through the microstructures to achieve mixing and form a mixed liquid. This embodiment provides another specific implementation of online mixing, and the urine sample and the stabilizing liquid are pumped into a closed mixing channel with internal microstructures to achieve mixing by inducing turbulent flow using the microstructures. The internal microstructures of the mixing channel can be staggered static mixing elements such as miniaturized versions of Kenics, Sulzer or SMX mixing elements, periodic obstacle arrays, curved or serpentine channels, or specific structures that utilize fluid inertial effects such as Tesla valve structures, Dean vortex induction structures, etc. Precise fluid pumps such as micro gear pumps, syringe pumps or peristaltic pumps are used to pump the urine and the stabilizing liquid into the mixing channel in proportion. When the liquid flows through these microstructures, it is forced to repeatedly split, converge, rotate, stretch and fold, thereby spontaneously generating strong microscale vortexes and chaotic convection on the flow path, achieving efficient passive mixing. The closed mixing channel can avoid sample evaporation, external environmental pollution and generation of aerosols during operation, and is more secure and accurate.

[0114] In some embodiments, step S600 comprises applying ultrasonic energy outside or inside the measuring cylinder, utilizing the cavitation effect and acoustic streaming effect generated by ultrasonic waves in liquids to facilitate rapid and uniform mixing of the urine sample and the stabilizing liquid, forming a mixed liquid. This embodiment provides another specific implementation of online mixing, by applying ultrasonic energy outside or inside the measuring cylinder, utilizing the cavitation effect and acoustic streaming effect generated by ultrasonic waves in liquids to facilitate rapid and uniform mixing of the urine sample and the stabilizing liquid. The ultrasonic transducer can be placed outside the measuring cylinder, delivering ultrasonic energy to the urine sample through the measuring cylinder wall, or the ultrasonic transducer can be directly immersed in the urine sample inside the measuring cylinder. The ultrasonic frequency and power can be adjusted according to the properties and volume of the urine sample to achieve the best mixing effect. The cavitation effect refers to the formation, vibration, and collapse process of microbubbles generated by ultrasonic waves in liquids, and the collapse of these bubbles can release local energy, thereby facilitating the mixing of liquids. The acoustic streaming effect refers to the directional flow generated by ultrasonic waves in liquids, which can accelerate the convection and mixing of liquids. By utilizing the cavitation effect and acoustic streaming effect of ultrasonic waves, rapid and uniform mixing of the urine sample and the stabilizing liquid can be achieved.

[0115] In some embodiments, in step S700, the second pipettor is a multi-channel pipettor with at least eight independent pipetting channels, simultaneously aspirating the mixed liquid from the measuring cylinder and injecting into at least eight cryogenic tubes through each channel. This embodiment provides a specific implementation of mixed liquid dispensing, using a multi-channel pipettor with at least eight independent pipetting channels to achieve parallel dispensing of the mixed liquid. The multi-channel pipettor has multiple, for example, 8, 12, 16 or more, independently controlled pipetting channels, each channel can be equipped with a disposable sterile pipette tip, and the channels can be independently controlled for aspiration and dispensing actions. Through the multi-channel pipettor, the mixed liquid can be aspirated from the measuring cylinder simultaneously, and injected into multiple cryogenic tubes through each channel, thereby significantly improving the dispensing efficiency and throughput. Each channel can independently control the aspiration speed and tip immersion depth to reduce bubble aspiration and cross contamination, further ensuring the quality of dispensing. Compared with single-channel pipettors, this embodiment can significantly improve the dispensing efficiency and is more suitable for large-scale sample processing requirements.

[0116] In some embodiments, after step S700, further comprising: automatically dismounting the used pipetting tip on the second pipettor into a designated waste tip collection container. This step describes a waste disposal measure for the second pipettor using disposable pipetting tips, i.e., after completing the aliquoting of the mixed solution, automatically dismounting the used pipetting tip into a designated waste tip collection container. The dismounting mechanism can be a pneumatic ejection mechanism, a mechanical claw grabbing mechanism, or an electromagnet adsorption mechanism, etc., and the waste tip collection container is a sealed container with a biohazard label to ensure the safety of the operator. This step can effectively avoid manual contact with the used pipetting tip, reduce the biological safety risk and cross contamination risk, and facilitate subsequent unified disposal of waste, reducing environmental pollution.

[0117] In some embodiments, step S700 comprises:

[0118] introducing the mixed solution into a disposable aliquoting chip having a reservoir and a plurality of parallel microfluidic aliquoting channels;

[0119] driving the mixed solution through the plurality of parallel microfluidic aliquoting channels by applying a precisely controlled air pressure to the reservoir, and simultaneously injecting the corresponding at least one cryogenic tube from the end of each channel.

[0120] wherein the disposable microfluidic aliquoting chip refers to a chip that integrates microchannels, microcavities, and other microstructures for precise control and dispensing of microscale liquids. The reservoir is an area on the chip for temporarily storing the mixed solution to be aliquoted, and its volume is designed to meet the total volume requirement for a single aliquot. The plurality of parallel microfluidic aliquoting channels are microchannels branching from the reservoir, with the same or different geometric dimensions such as channel width, depth, and length. These channels are arranged in parallel and each is connected to one or more outlets. The precisely controlled air pressure refers to the pressure applied to the reservoir of the chip, which is precisely adjusted by a precise air pressure control system in terms of magnitude, duration, and pulse mode to drive the liquid to flow and aliquot within the microfluidic chip. In a specific implementation, the material of the disposable microfluidic aliquoting chip can be selected from medical grade polymer materials such as polymethyl methacrylate (PMMA), cyclic olefin copolymer (COC), or cyclic olefin polymer (COP), which have good biocompatibility, chemical stability, and processability. The shape and size of the reservoir can be designed according to actual needs, such as circular, rectangular, or elliptical. The geometric dimensions of the microfluidic aliquoting channels, such as width and depth, can be designed to be between a few microns and a few hundred microns, and the number of channels can be determined according to the number of cryogenic tubes to be aliquoted, such as 2, 4, 8, or more.

[0121] The embodiment of the present application can realize precise control of the liquid separation volume, significantly improve the precision and repeatability of liquid separation, avoid the use of traditional pipette tips, eliminate the risk of cross contamination, and ensure the sterility of the dispensing process. Through the design of parallel microfluidic channels, multi-channel parallel liquid separation is realized, and the liquid separation efficiency is improved. The use of disposable chips simplifies cleaning and maintenance work and reduces operating costs.

[0122] In some embodiments, further comprising automatically screwing or pressing the cap of the at least one cryogenic tube by an automatic cap opening / closing device. The cryogenic tube after the completion of the mixed liquid dispensing is automatically capped in the urine sample automatic pretreatment process, which is specifically realized by the automatic cap opening / closing device. This step is performed after the completion of the mixed liquid injection in step S700 and before the transfer of the cryogenic tube to the collection station in step S800. In the prior art, manual capping has the problems of low efficiency, easy to make mistakes, and low standardization, and the present embodiment aims to overcome these defects through automation. The automatic cap opening / closing device automatically completes the screwing or pressing operation of the cryogenic tube through precise mechanical movement, avoiding the randomness and uncertainty of manual operation, improving the efficiency and consistency of capping, and ensuring the sealing of the cryogenic tube, thereby avoiding sample contamination or evaporation and ensuring the quality and integrity of the sample. The automatic cap opening / closing device can have various implementations. For example, for screw cap cryogenic tubes, the device can include one or more rotating cap screwing heads driven by servo motors or stepper motors. The screwing head is equipped with a torque sensor and a control system, which can accurately control the tightening force to ensure that the cap is tightly closed, but not too tight to damage or difficult to open again. The screwing head can use replaceable clamps or clamps to accommodate different sizes of screw cap cryogenic tubes. For example, for press cap cryogenic tubes, the device can include one or more linear pressing mechanisms driven by air cylinders or linear motors. The pressing mechanism can apply uniform pressure to firmly press the cap onto the cryogenic tube. The linear pressing mechanism can also use replaceable pressure heads to accommodate different sizes of press cap cryogenic tubes. In addition, the automatic cap opening / closing device can also integrate a visual positioning system to accurately identify the position and attitude of the cryogenic tube through a camera and image processing algorithm, ensuring that the screwing head or pressing mechanism can accurately align the cap, thereby improving the success rate and reliability of the operation. The above-mentioned automatic cap opening / closing device can be fixed near the dispensing station, or integrated with the cryogenic tube conveying unit to move synchronously with the cryogenic tube to realize continuous automatic operation.

[0123] By using the automatic cap opening / closing device, not only the efficiency and standardization of capping are improved, but also the manual operation is significantly reduced, reducing the risk of direct contact between the operator and the sample, thereby reducing the bio-safety risk. At the same time, precise torque control or pressure control ensures the sealing of the cryogenic tube, avoids sample evaporation or contamination, and ensures the quality of the sample and the reliability of long-term storage.

[0124] In some embodiments, after installing the tube cap for the cryogenic tube, a label printing and sticking device is used to automatically stick a pre-made label containing the urine sample information on the tube wall of each cryogenic tube. The purpose is to achieve the final physical solidification of sample information, ensure the establishment of a clear and lasting association between each cryogenic tube and its corresponding urine sample information, and achieve complete traceability of sample source, processing process and experimental data. The pre-made label contains the urine sample information obtained by the identity identification unit, such as patient ID, sample number, collection time, processing date, etc., and can also include research project code, stabilizer type, volume, etc. Experimental parameters to meet different information needs. The label content can be one-dimensional bar code, two-dimensional bar code such as QR code or DataMatrix code, text, numbers, graphics or their combination.

[0125] The label printing and sticking device generally includes three main components: a label printer, a label peeler and a label sticking mechanism. The label printer can be a thermal printer or a thermal transfer printer. The thermal printer uses a thermal print head to heat special thermal paper, causing it to develop and form an image. The thermal transfer printer uses a heated print head to transfer ink on the carbon ribbon to the label material. Compared with thermal printing, thermal transfer printing labels have higher durability and chemical corrosion resistance, and are more suitable for long-term storage environment labels. The printer can print labels corresponding to each urine sample in real time or in batches according to the instructions sent by the control unit. The label peeler is responsible for automatically peeling the printed label from the backing paper. Common peeling methods include mechanical peeling through blades or scrapers and pneumatic peeling using air flow. The label sticking mechanism is responsible for accurately sticking the peeled label to the predetermined position on the tube wall of the cryogenic tube. The sticking method can be a mechanical arm cooperating with a suction cup or an air blowing device. The mechanical arm controls the suction cup or air blowing device to move above the cryogenic tube, sucks or blows the label, and then accurately attaches it to the tube wall. It can also be a rotary rolling sticking mechanism that rolls the label flat onto the rotating cryogenic tube. To ensure the firmness and consistency of the label sticking, the sticking mechanism can be equipped with a pressure sensor to control the sticking pressure. The predetermined position on the tube wall is usually located on the cylindrical side wall of the cryogenic tube, which is convenient for scanning and manual reading. The label material should be special label paper or synthetic material that is resistant to low temperature, corrosion, strong adhesion and not easy to fall off, to ensure that the label information is clear and identifiable under long-term storage conditions. The size, shape and color of the label can be customized according to the specifications of the cryogenic tube and user needs.

[0126] Through the automatic label printing and pasting process, errors that may occur in manual labeling, such as label information entry errors, inaccurate pasting positions, label skewing or wrinkling, etc., can be avoided, the labeling efficiency and accuracy can be improved, and the label information on each cryopreservation tube can be ensured to be completely consistent with the actual sample information, thereby realizing the full traceability of sample information. Moreover, the printed label has uniqueness, avoiding the possibility of human modification and increasing the safety of sample management.

[0127] In some embodiments, the running state parameters of the first mechanical arm, the first pipettor, the mixing mechanism, and the second pipettor are also monitored in real time, and the urine sample information, the calculated urine sample volume, the added stabilizing liquid volume, and the running state parameters are recorded and stored in association in the database. The purpose is to realize comprehensive monitoring and data recording of the entire urine sample pretreatment process and ensure the traceability and quality control of the process. By monitoring the running state parameters of the key equipment in real time, such as the movement speed and position accuracy of the first mechanical arm, the injection flow and pressure of the first pipettor, the oscillation frequency and amplitude of the mixing mechanism, and the liquid suction and dispensing speed of the second pipettor, potential abnormal conditions or faults can be discovered in time, and appropriate corrective measures can be taken to avoid errors or deviations in the sample processing process. At the same time, these running state parameters are stored in association with the key data such as urine sample information, volume measurement results, and stabilizing liquid addition amount in the database, establishing a complete electronic record chain and providing a reliable data basis for subsequent quality traceability, data analysis, and process optimization.

[0128] Further, the running state parameters include: motor current, position encoder reading, movement trajectory deviation of each axis of the first mechanical arm; step motor speed, syringe piston position, pressure sensor reading of the first pipettor; motor current, oscillation frequency, oscillation amplitude, temperature sensor reading of the mixing mechanism; liquid suction speed, liquid dispensing speed, probe liquid level tracking sensor reading of the second pipettor. The database can be a relational database or a non-relational database such as Hadoop, or a file storage system. The stored data format can be structured data, unstructured data, or a hybrid mode. In order to ensure the security of the data, data encryption, access permission control, data backup, etc. can be adopted. At the same time, the system should also provide data query, statistics and export functions to facilitate users to analyze and utilize the data.

[0129] Through real-time monitoring and data recording of the running state parameters, the stability and reliability of the urine sample pretreatment process can be effectively improved, potential abnormal conditions or faults can be discovered in time, appropriate corrective measures can be taken to avoid errors or deviations in the sample processing process, the integrity and traceability of the data can be ensured, a reliable data basis can be provided for subsequent quality traceability, data analysis, and process optimization, and the accuracy and reliability of the experimental results are guaranteed.

[0130] In some embodiments, the method is performed in a closed workstation with an air purification system. The entire urine sample pretreatment process of the embodiments of the present application is not performed in an open environment, but is completed in a physically isolated, air-purified closed space. The main purpose of the closed workstation is to provide a clean operating environment, avoid or reduce the pollution of particulate matter, microorganisms and other pollutants in the air to the urine sample, ensure the purity of the pretreated sample, especially for subsequent high-sensitivity analysis and detection; protect the operating personnel from exposure to potential biological hazardous substances (such as pathogenic microorganisms, viruses) in the urine sample, reduce the occupational health and safety risk; prevent the diffusion of volatile components in the urine sample into the laboratory environment, reduce the interference to other experiments or equipment; maintain a stable temperature and humidity environment, reduce the influence of environmental factors on the sample processing results.

[0131] In some embodiments, the urine sample automated pretreatment method further comprises the following steps:

[0132] The concentration of the mixed solution in the cryotube with a set volume is detected, and the target parameter is calculated therefrom. The target parameter is obtained by calculating the percentage of the amount of drug excreted in each time period to the total dose, and the calculation formula is:

[0133] m(t) = p V

[0134]

[0135] In the formula, m(t) is the amount of drug excreted in the t time period, p is the drug concentration, V is the volume of the urine sample, R(t) is the percentage in the t time period, and M is the total dose of the drug.

[0136] As shown in Figure 2 The embodiments of the present application provide a urine sample automated pretreatment system, which comprises a urine cup conveying unit M100, an identity recognition unit M200, a first mechanical arm M300, a liquid level sensor M400, a first pipettor M500, a mixing mechanism M600, a second pipettor M700, a cryotube conveying unit M800, and a control unit M900.

[0137] The urine cup conveying unit M100 is used to convey the urine cup containing the urine sample and the identity label. In the embodiment of the present application, the urine cup conveying unit M100 refers to a device capable of automatically or semi-automatically moving the urine cup containing the urine sample from the feeding area to the subsequent processing station. The urine cup conveying unit M100 can be realized in various forms, for example, a synchronous belt conveying belt, in which the material of the conveying belt can be selected from polypropylene (PP) or polytetrafluoroethylene (PTFE) with corrosion resistance and easy cleaning; a chain conveying belt, in which the material of the chain can be selected from stainless steel or engineering plastic; a circulating conveying line with independent urine cup tray, in which the material of the tray is selected to be consistent with the conveying belt, and a conductive material can also be considered to prevent static adsorption; or even a simple pneumatic or hydraulic pushing device. The urine cup conveying unit M100 can also be integrated with sensors for detecting whether the urine cup reaches the designated position and whether there is an abnormal situation such as blockage or dumping. The urine cup conveying unit M100 is not limited to the specific forms described above, and any device capable of realizing the automatic conveying function of the urine cup can be applied to the present application.

[0138] The identity label recognition unit M200 is arranged on or adjacent to the urine cup conveying path, and is used to recognize the identity label of the urine cup. The identity label recognition unit M200 automatically obtains various information related to the urine sample by scanning or reading the identity label attached to the urine cup. The "identity label" in the embodiment of the present application can be a bar code, a two-dimensional code, an RFID tag or any other machine-readable mark. The identity label recognition unit M200 needs to accurately and quickly read these labels and transmit the obtained information to the control unit M900 to realize the automatic input and management of sample information. The "urine sample information" recognized by the identity label recognition unit M200 includes but is not limited to patient ID, sample number, collection time, experimental type, etc., which is crucial for subsequent sample processing, data analysis and result tracing. The implementation of the identity label recognition unit M200 includes a bar code scanner, which selects a laser or LED light source and decodes the algorithm according to the common bar code standard; a two-dimensional code scanner, which uses a CCD or CMOS image sensor and supports multiple two-dimensional code formats; an RFID reader / writer, which has a working frequency of high frequency (HF) or ultra-high frequency (UHF) and a label that meets the ISO 18000 series standard. The unit can be integrated with an illumination device and an image processing algorithm to improve the accuracy and reliability of recognition, especially in the case of label contamination or insufficient light. The identity label recognition unit M200 is not limited to the specific forms described above, and any device capable of realizing the automatic recognition function of the identity label of the urine cup can be applied to the present application. By automatically recognizing the identity label on the urine cup, the errors that may occur in manual input are avoided, and the efficiency and accuracy of information management are improved.

[0139] The first mechanical arm M300 is configured to transfer the urine sample in the urine cup to a measuring cylinder. The first mechanical arm M300 is used to accurately and reliably transfer the urine sample in the urine cup to the measuring cylinder or other designated container. The motion trajectory and posture of the first mechanical arm M300 need to be precisely programmed to ensure a smooth and spill-free transfer process and minimize sample loss. The end of the mechanical arm is usually equipped with a specially designed clamp or suction cup for grabbing and fixing the urine cup. The mechanical arm needs to have sufficient flexibility and motion range to adapt to urine cups of different sizes and shapes and be able to reach the designated transfer location. The first mechanical arm M300 can adopt various types of robots, such as six-axis articulated robots, providing maximum flexibility and motion range; SCARA robots, suitable for planar positioning and vertical motion; Delta robots, suitable for high-speed grabbing and placing. The driving mode of the mechanical arm can be servo motor, stepper motor or pneumatic / hydraulic drive. The material of the clamp can be selected from materials resistant to chemical corrosion and low adsorption, such as polypropylene (PP) or polytetrafluoroethylene (PTFE). During the transfer process, the mechanical arm can control the inclination angle, rotation speed and dwell time of the urine cup to ensure that the sample is completely transferred to the measuring cylinder as much as possible. The first mechanical arm M300 is not limited to the specific form described above, and any mechanical device that can achieve the function of automatic transfer of urine samples can be applied to the present invention.

[0140] The liquid level sensor M400 is configured to detect the liquid level of the urine sample in the measuring cylinder and output a liquid level signal. The liquid level sensor M400 is used to accurately measure the liquid level of the urine sample in the measuring cylinder and convert the height information into an electrical signal output to the control unit M900. The liquid level sensor M400 can adopt various measurement principles, such as ultrasonic liquid level sensor M400, which measures the liquid level using the reflection principle of ultrasonic waves, with the advantages of non-contact and wide measurement range; laser liquid level sensor M400, which measures the liquid level using the laser ranging principle, with the advantages of high precision and fast response speed; capacitive liquid level sensor M400, which determines the liquid level by measuring the change in capacitance, suitable for small and high-precision measurements; pressure type liquid level sensor M400, which calculates the liquid level by measuring the pressure at the bottom of the liquid column, suitable for large range liquid level measurement, etc. The selection of the liquid level sensor M400 needs to consider the size of the measuring cylinder, the properties of the urine, the measurement accuracy requirements and the cost, etc. The liquid level sensor M400 can be fixedly installed above the measuring cylinder, or can be driven by a driving mechanism to move up and down to realize scanning measurement of the liquid level. The liquid level signal output by the liquid level sensor M400 is usually an analog voltage or current signal, which needs to be amplified, filtered and converted by a signal conditioning circuit before being recognized and processed by the control unit M900. The liquid level sensor M400 is not limited to the specific form described above, and any sensor that can achieve the function of accurate measurement of liquid level can be applied to the present invention.

[0141] A first pipette M500 is configured to add the stabilization liquid into the cuvette. The first pipette M500 refers to a device used to accurately add the stabilization liquid into the cuvette containing the urine sample. The first pipette M500 needs to be able to accurately control the volume of stabilization liquid added and ensure that the addition process is free of contamination. The first pipette M500 can take various forms of implementation, such as a syringe pump, which delivers liquid by precisely controlling the displacement of the piston of a syringe, with the advantages of high precision and good controllability; a peristaltic pump, which delivers liquid by squeezing an elastic pipeline, with the advantages of no contamination and easy cleaning; an automatic pipette, which has the functions of automatic liquid suction, liquid discharge and replacement of the suction head, suitable for high-throughput and multi-sample processing. The first pipette M500 is usually controlled by a control unit M900 and can automatically perform the addition operation according to the preset program and parameters. The first pipette M500 can be equipped with a liquid level sensor M400 for monitoring the remaining amount of stabilization liquid and sending an alarm signal when the remaining amount is insufficient. The material of the pipette needs to be resistant to chemical corrosion and will not contaminate the urine sample. The way to add the stabilization liquid can be to inject it directly into the cuvette through a nozzle, or to insert a slender probe below the liquid surface to reduce the generation of air bubbles. The first pipette M500 is not limited to the specific forms described above, and any device that can achieve the function of accurate addition of stabilization liquid can be applied to the present application. The volume ratio of stabilization liquid to urine sample can be adjusted according to experimental requirements, and the typical ratio range is 0.5:100 to 2:100.

[0142] The mixing mechanism M600, on which or in which the measuring cylinder can be placed, is configured to mix the urine sample in the measuring cylinder with the stabilizing liquid to form a mixed liquid. The mixing mechanism M600 refers to a device that can fully mix the urine sample in the measuring cylinder with the stabilizing liquid. The purpose of mixing is to ensure that the stabilizing liquid can be uniformly dispersed in the urine sample, so as to fully exert its stabilizing effect. The mixing mechanism M600 needs to be able to provide sufficient mixing intensity while avoiding excessive stirring or generating air bubbles. The mixing mechanism M600 can be implemented in various forms, such as a shaking platform that realizes mixing through horizontal or vertical shaking, the frequency and amplitude of which can be adjusted; a rotary mixer that realizes mixing by rotating the measuring cylinder, the speed of which can be adjusted; a magnetic stirrer that realizes mixing by rotating a magnetic stir bar, the rotation speed of which can be adjusted; and an ultrasonic mixer that utilizes the cavitation effect and acoustic streaming effect generated by ultrasonic waves in the liquid to promote mixing, the frequency and intensity of which can be adjusted. The measuring cylinder can be placed on the mixing mechanism M600 or inside the mixing mechanism M600. The mixing mechanism M600 can be equipped with a temperature control device to maintain a constant temperature during mixing. The time and intensity of mixing can be adjusted according to the properties of the urine sample and the type of stabilizing liquid. The mixing mechanism M600 is not limited to the specific forms described above, and any device that can achieve the function of fully mixing the urine sample with the stabilizing liquid can be applied to the present application.

[0143] The second pipette M700 is configured to aspirate a predetermined amount of mixed liquid from the measuring cylinder and inject the mixed liquid into at least one cryogenic tube. The second pipette M700 refers to a device for accurately aspirating the mixed urine sample from the measuring cylinder and dispensing a certain volume of the sample into multiple cryogenic tubes. The purpose of dispensing is to facilitate subsequent analysis and storage. The second pipette M700 needs to be able to accurately control the volume of aspiration and dispensing, and ensure that the dispensing process is free of contamination. The second pipette M700 can be implemented in various forms, such as a single-channel pipette that dispenses one cryogenic tube at a time; a multi-channel pipette that can dispense multiple cryogenic tubes at the same time, improving dispensing efficiency; a microdispenser suitable for small-volume dispensing; and a non-contact dispenser that can avoid direct contact between the pipette and the sample, reducing the risk of contamination. The pipette can be equipped with disposable tips to avoid cross-contamination. The volume of dispensing can be adjusted according to experimental requirements, with a volume range of 0.1 mL to 2 mL. The pipette can be equipped with a liquid level sensor M400 for monitoring the liquid level in the measuring cylinder and issuing an alarm signal when the liquid level is too low. The pipette can be equipped with a barcode scanner for scanning the barcode on the cryogenic tube to realize traceability of the sample information. The second pipette M700 is not limited to the specific forms described above, and any device that can achieve the function of accurately dispensing the mixed liquid can be applied to the present application.

[0144] The cryotube conveying unit M800 is used to convey the cryotube containing the mixed solution to the collection station. The cryotube conveying unit M800 refers to a device used to move the divided cryotube from the division station to the collection station. The purpose of conveying is to facilitate the subsequent processing and storage of samples. The cryotube conveying unit M800 needs to be able to stably and reliably convey the cryotube, and avoid the tipping or damage of the cryotube. The cryotube conveying unit M800 can be implemented in various forms, such as a conveyor belt that can continuously convey multiple cryotubes, a mechanical arm that can grasp a single or multiple cryotubes for conveying, a pneumatic conveying system that uses air flow to send the cryotube to the designated position, and a rotary disc that places the cryotube on the rotary disc and takes it out after rotating to the designated position. The cryotube conveying unit M800 can be equipped with sensors for detecting whether the cryotube has reached the designated position, and whether there are abnormal conditions such as blockage or tipping. The cryotube conveying unit M800 can be connected with an automatic labeling machine and an automatic capping machine to realize automatic labeling and capping of the cryotube. The material of the cryotube conveying unit M800 needs to be resistant to low temperature to adapt to the storage environment of the cryotube. The cryotube conveying unit M800 is not limited to the specific forms described above, and any device that can realize the automatic conveying function of the cryotube can be applied to the present application.

[0145] A control unit M900 is electrically connected with the identity recognition unit M200, the first mechanical arm M300, the liquid level sensor M400, the first pipettor M500, the mixing mechanism M600, the second pipettor M700, and the cryotube conveying unit M800. The control unit M900 is configured with a storage module for storing the known geometric dimensions of the measuring cylinder. The control unit M900 is configured to: (i) obtain urine sample information based on the identity recognized by the identity recognition unit M200; (ii) calculate the volume of the urine sample based on the liquid level signal output by the liquid level sensor M400 and the known geometric dimensions of the measuring cylinder stored in the storage module; (iii) control the first pipettor M500 to add the stabilizing liquid into the measuring cylinder according to the calculated volume of the urine sample and the preset volume ratio; and (iv) control the mixing mechanism M600, the second pipettor M700, and the conveying unit M800 to perform predetermined operations. The control unit M900 is responsible for coordinating and controlling the operation of each component, realizing the automatic operation of the entire automated preprocessing process. The control unit M900 can be one or more computers, PLCs, or other types of programmable controllers. The control unit M900 has sufficient data processing capacity, storage capacity, and communication interfaces to meet the operational requirements of the system. The control unit M900 implements various control algorithms through programming, such as PID control, motion control, image processing, etc. The control unit M900 can be equipped with a human-machine interface for parameter setting, state monitoring, and fault diagnosis. The control unit M900 is connected with the laboratory information management system (LIMS) to realize automatic uploading and downloading of data. The control unit M900 can realize remote monitoring and control through the network. The control unit M900 has safety protection functions such as overload protection, short circuit protection, emergency stop, etc. The storage module is used to store the known geometric dimensions of the measuring cylinder, which are used to calculate the volume of the urine sample. The storage module can be a hard disk, solid state disk, flash memory, or other types of storage media. The control unit M900 obtains urine sample information by reading the identity recognized by the identity recognition unit M200, and associates these information with subsequent processing data. The control unit M900 calculates the volume of the urine sample based on the liquid level signal output by the liquid level sensor M400 and the known geometric dimensions of the measuring cylinder stored in the storage module. The calculation method can use lookup table method, formula method, or other types of calculation methods. The control unit M900 controls the first pipettor M500 to add the stabilizing liquid into the measuring cylinder according to the calculated volume of the urine sample and the preset volume ratio. The control unit M900 controls the mixing mechanism M600, the second pipettor M700, and the conveying unit to perform predetermined operations according to the preset program, realizing the automatic operation of the automated preprocessing process. The control unit M900 can record the operation data of each step, such as urine volume, stabilizing liquid volume, mixing time, dispensing volume, etc., for quality traceability and data analysis.The control unit M900 is not limited to the specific form described above, and any device capable of realizing the functions of system coordination control and data processing can be applied to the present application.

[0146] In some embodiments, the control unit M900 is configured with a storage module for storing the known geometric dimensions of the measuring cylinder, and the control unit M900 is configured to:

[0147] Obtain urine sample information based on the identity recognized by the identity recognition unit M200;

[0148] Based on the liquid level signal output by the liquid level sensor M400 and the known geometric dimensions of the measuring cylinder stored in the storage module, the volume of the urine sample is calculated;

[0149] According to the calculated volume of the urine sample and the preset volume ratio, the first pipettor M500 is controlled to add a stabilizing liquid to the measuring cylinder;

[0150] The mixing mechanism M600, the second pipettor M700, and the cryotube conveying unit M800 are controlled to perform predetermined operations.

[0151] In some embodiments, the second pipettor M700 includes a multi-channel pipetting head that can simultaneously inject mixed liquid into multiple cryotubes; alternatively, the system further includes a disposable dispensing chip configured with a liquid storage cavity and multiple parallel microfluidic dispensing channels, and a gas pressure control device for driving the mixed liquid through the dispensing chip, the mixed liquid being introduced into the liquid storage cavity and driven through the multiple parallel microfluidic dispensing channels by the gas pressure control device to be simultaneously injected into the corresponding cryotubes.

[0152] In some embodiments, the urine sample automated pretreatment system further comprises:

[0153] An automatic cap opening / closing device configured to automatically open the cap of the cryotube before the mixed liquid is injected into the cryotube, and to automatically tighten or press the cap after the injection, the automatic cap opening / closing device being electrically connected to and controlled by the control unit M900;

[0154] A label printing and sticking device configured to automatically stick a pre-made label containing urine sample information on the wall of the cryotube after the cap is installed, the label printing and sticking device being electrically connected to and controlled by the control unit M900.

[0155] Through the cooperative work of the above technical features, the urine sample automatic pretreatment system provided by the embodiment of the present application can realize the automation of the whole process of the urine sample from receiving to completing the pretreatment, including volume measurement, stabilizer addition, mixing, sub-packaging and information management, and solves the problems of low efficiency, easy error, high biological safety risk and low standardization degree in the prior art. The system can significantly improve the efficiency, accuracy, standardization degree and biological safety of the urine sample pretreatment, provide high-quality and traceable pretreated samples for subsequent clinical tests, pharmacokinetic studies or other biological analysis, and liberate manpower and reduce labor intensity.

[0156] As shown in Figure 3 The embodiment of the present application also provides a urine sample automatic collection method, which is used to obtain the percentage of the amount of drug excreted with urine in each time period to the total dose of drug administration. The urine sample in a specified time period is collected, 1-2 mL of urine is extracted from the urine sample for drug concentration determination, and the volume of the urine sample in the specified time period is measured. The amount of drug excreted in each time period is calculated by the product of the concentration and the volume, and the percentage of the amount of drug excreted in each time period to the total dose is calculated by dividing the amount of drug excreted in each time period by the total dose of drug administration.

[0157] Specifically includes the following steps:

[0158] P1, preparation process, specifically includes:

[0159] (1) Paste the bar code indicating the patient information and the time period information in the fixed position of the urine cup carrying the urine sample, which is convenient for scanning. In this example, the urine cup is a medical standard urine cup;

[0160] (2) Collect the urine cup with the bar code pasted, and transport it to the urine cup loading position by the trolley;

[0161] (3) Place the whole set of suction nozzles to be used in the suction nozzle loading position by the trolley;

[0162] (4) After unpacking the cryogenic tube, place it in the cryogenic tube loading position. In this example, the capacity of the cryogenic tube is 10 mL;

[0163] (5) Place the disposable measuring cylinder to be used in the measuring cylinder loading position by the trolley. In this example, the capacity of the measuring cylinder is 200 mL, which is greater than the total volume of the urine to ensure that the urine is not spilled when it is shaken evenly.

[0164] The materials of the above containers in contact with urine can be plastic, glass or 304 stainless steel.

[0165] P2, automatic loading, including:

[0166] 2.1 Place the urine cups carrying urine samples on the urine cup conveying belt with cup guards in turn, 8 urine cups are placed on each batch, and the bar code directions of all urine cups are uniformly directed to the scanner, during the process of the urine cup conveying belt driving the urine cups into the urine cup placement positions in the closed room, the scanner scans the bar codes on the urine cups in turn to obtain the urine sample information.

[0167] Further, it is also necessary to ensure that there is no empty space between the two adjacent urine cups. The infrared sensor detects whether there is a vacancy within the equidistant range. If there is, the urine cup conveying belt is paused and an alarm is given to prompt manual feeding or feeding.

[0168] 2.2 After 8 urine cups are placed in the urine cup placement positions in the closed room, the corresponding number of measuring cylinders are placed on the measuring cylinder conveying belt, and the measuring cylinder conveying belt is used to send the measuring cylinders into the corresponding measuring cylinder placement positions in the closed room, so that each measuring cylinder corresponds to the corresponding number and position of urine cups.

[0169] P3, total volume measurement of urine sample.

[0170] The mechanical gripper picks up the 8 urine cups in the urine pouring position and moves them to the urine pouring position, i.e. directly above the measuring cylinder placement position. By turning the gripper, the urine in the urine cups is completely introduced into the corresponding 8 measuring cylinders. At the same time, the urine cups with the poured urine samples are placed on the waste conveying belt by the mechanical gripper, and then conveyed to the waste box by the waste conveying belt. Then, the 8 liquid level sensors are attached to the corresponding measuring cylinders by the mechanical arm. The 8 liquid level sensors are moved from top to bottom by the lead screw until the 8 liquid level sensors simultaneously have signals. The corresponding liquid level height when each liquid level sensor has a signal is recorded online, and the total volume of the urine sample of each urine cup is calculated and output to the corresponding personal information.

[0171] P4, urine mixing.

[0172] The 4 batches of 32 disposable measuring cylinders containing urine samples after urine volume detection are transferred from the measuring cylinder placement position to the shaking placement position of the shaking shaker in turn. After the liquid displacement gun is moved to the stable liquid tank to suck 10 mL of stable liquid, it is moved to above the measuring cylinder. The stable liquid with a set proportion is injected into the corresponding disposable measuring cylinder. In this embodiment, the volume ratio of stable liquid to urine sample is 1:100. Different sample addition ratios can also be set according to actual test requirements, and the present application does not make specific limitations. The stable liquid addition amount is accurate to 0.01 mL. After the stable liquid displacement gun returns to the stable liquid tank after injecting stable liquid into the measuring cylinder, it is emptied and cleaned before sucking 10 mL of stable liquid for the next time.

[0173] When all the disposable cylinders are injected with the corresponding proportion of stable liquid, start the shaking shaker to mix the stable liquid with the urine sample, and stop. In this embodiment, the shaking shaker uses a penicillin shaker, and the mixing time is set to 60 seconds. To shorten the mixing time, the number of shaking and placing positions of the shaking shaker can be increased.

[0174] P5, mixed liquid collection, including:

[0175] 5.1 After the cryogenic tube is uncapped, it is transported to the cryogenic tube placement position (in this example, 16 cryogenic tubes are placed at a time, arranged in a 2*8 manner) by the cryogenic tube conveying belt, and the cryogenic tube cap is moved to the capping position.

[0176] 5.2 After the suction nozzle is transported to the suction nozzle fitting position in the closed chamber by the suction nozzle conveying machine, it is fitted on the mixed liquid pipette. The mixed liquid pipette is the same as the stable liquid pipette, and there are 8 in a row. After the 8 mixed liquid pipettes with suction nozzles are translated to the top of the shaking and placing position of the shaking shaker, they are inserted downward below the liquid level of the cylinder, 5mL of mixed liquid is sucked, and then translated to the top of the first row of cryogenic tubes, 1mL of mixed liquid is injected into the first row of cryogenic tubes, and then the pipette is translated to the top of the second row of cryogenic tubes, 1mL of mixed liquid is injected into the second row of cryogenic tubes. After the mixed liquid injection is completed, the 8 mixed liquid pipettes with suction nozzles are moved to the top of the corresponding 8 cylinders, the remaining mixed liquid is injected back into the cylinder, and then the 8 suction nozzles are removed at the waste conveying position for cleaning before being translated to the suction nozzle fitting position to fit the suction nozzle for the next time. The cylinder containing the mixed liquid is placed on the waste conveying position by the mechanical gripper and conveyed to the waste box outside the closed chamber together with the suction nozzle, and the step is repeated to complete the mixed liquid transfer to the cryogenic tube.

[0177] 5.3 The two rows of cryogenic tubes with injected mixed liquid are transported by the cryogenic tube conveying belt to the capping position, where the cryogenic tube cap is screwed on, and then sent out of the closed chamber. The scanned barcode information is reprinted on the self-adhesive thermal sensitive barcode by the barcode printer outside the closed chamber according to the sequence. When the assembled cryogenic tube is transferred to the label position, the barcode is pasted and automatically transported to the manual pickup position. The staff transports it to the refrigeration chamber by trolley or places it in the collection basket for manual processing.

[0178] 6, drug amount calculation.

[0179] The cryogenic tube in the refrigeration chamber or the collection basket is taken out for drug concentration determination. After obtaining the drug concentration, the volume of the corresponding urine sample is multiplied to obtain the drug amount of the urine sample collected in the current time period. Finally, the percentage of the drug amount discharged in each time period to the total dose (i.e. the target parameter) is obtained by dividing the total dose. The calculation formula is as follows:

[0180] m(t) = p * V

[0181]

[0182] In the formula, m(t) is the amount of drug excreted during time period t, ρ is the drug concentration, V is the urine sample volume, R(t) is the percentage during time period t, and M is the total dose administered.

[0183] To achieve the above automated urine sample collection methods, such as Figure 4 As shown, the present invention also proposes an automatic urine sample collection system, which includes a urine sample collection line 2 located in a sterile, temperature- and humidity-controlled closed chamber 1, and a feeding device, a waste conveying device 4, a cold storage chamber 5, a labeling and applicating machine 6, and a central control machine located outside the closed chamber 1. A workbench 21 is provided in the closed chamber 1 along the X-axis direction. On the workbench 21, there are in sequence a urine cup placement position 211, a measuring cylinder placement position 212 (i.e., a urine pouring position), a urine measurement position, a shaking insulator 213 with a shaking placement position 2131, a suction nozzle set position 214, a cryopreservation tube placement position 215, a waste conveying position 216, and a stabilizing liquid tank 217. On the frame above the workbench 21, there are a urine cup moving and flipping mechanism 221, a measuring cylinder moving mechanism 222, a urine measurement mechanism 223, a stabilizing liquid adding mechanism 224, and a mixed liquid transfer mechanism 225.

[0184] The feeding device includes a urine cup feeding mechanism 31, a measuring cylinder feeding mechanism 32, a suction nozzle feeding mechanism 33, and a cryopreservation tube feeding and cap removal mechanism 34, which are installed on the feeding side of the urine sample collection line 2.

[0185] The urine cup feeding mechanism 31 includes a urine cup conveyor belt 311, a cup protector disposed on the urine cup placement position on the urine cup conveyor belt 311, and a barcode label scanner 312 disposed on one side of the urine cup conveyor belt 311. A trolley 7 containing urine cups 9 to be tested is pushed onto the feeding side of the urine cup conveyor belt 311, and urine cups 9 with barcode labels are placed sequentially and tightly on their respective urine cup positions. Figure 1 The illustration shows a method implemented manually, but other automated methods can also be used; this embodiment does not impose a specific limitation. The central control unit controls the stepper drive motor of the urine cup conveyor belt 311 to transport multiple urine cups 9 containing urine samples to the urine cup placement position 211 in batches.

[0186] In addition, during the delivery process, the barcode label scanner 312 scans the barcode label on each urine cup 9 to obtain the patient's personal information and time information, and then sends it to the central control unit for storage; an infrared sensor 8 is also provided at the urine cup placement position 211 to detect whether there are any gaps within the equidistant range, ensuring that there are no gaps between two adjacent urine cups 9.

[0187] The measuring cylinder feeding mechanism 32 comprises a measuring cylinder feeding machine 321 and a measuring cylinder conveying belt 322, and a plurality of measuring cylinder placing positions 212 are arranged on the measuring cylinder conveying belt 322. The trolley 7 loaded with the disposable measuring cylinder 10 is pushed to the measuring cylinder feeding machine 321 of the measuring cylinder conveying belt 322, and the disposable measuring cylinder 10 is sequentially placed in the measuring cylinder feeding machine 321. For example, Figure 1 The above process is shown as being completed by manual operation, but in actual use, other automatic methods can also be used, and the present embodiment is not limited in this regard. The disposable measuring cylinder 10 is placed in the measuring cylinder placing position 212 on the measuring cylinder conveying belt 322 by the measuring cylinder feeding machine 321. The central control machine controls the step drive motor of the measuring cylinder feeding machine 321 and the measuring cylinder conveying belt 322 to convey a plurality of disposable measuring cylinders 10 to the measuring cylinder placing position 212 in batches to wait for liquid pouring and volume measurement.

[0188] The urine cup moving and overturning mechanism 221 comprises a first mechanical gripper, a first X-axis movement module and a first Z-axis movement module. The first X-axis movement module comprises a first X-axis step motor, a first X-axis screw and a first X-axis sliding block. The first X-axis step motor drives the first X-axis screw to rotate under the control of the central control machine, and then the first X-axis sliding block slides on the first X-axis screw. The first Z-axis movement module is installed on the first X-axis sliding block and comprises a first Z-axis step motor, a first Z-axis screw and a first Z-axis sliding block. The first Z-axis step motor drives the first Z-axis screw to rotate under the control of the central control machine, and then the first Z-axis sliding block slides on the first Z-axis screw. The first mechanical gripper is arranged on the first Z-axis sliding block and has the functions of grabbing and pouring.

[0189] When the urine cup 9 of the current batch is conveyed to the urine cup placing position 211, the central control machine controls the first X-axis step motor to move to the position directly above the urine cup placing position 211, and then controls the first Z-axis step motor to move the first mechanical gripper downward to the urine cup 9. After the first mechanical gripper grabs the urine cup 9, it is lifted up. Then the first X-axis step motor is controlled to start moving to the position directly above the measuring cylinder placing position 212, so that each urine cup 9 is aligned with the corresponding measuring cylinder 10. The first mechanical gripper is controlled to pour the urine sample into the measuring cylinder 10. Finally, the first X-axis step motor is controlled to move the first mechanical gripper with the urine cup 9 to the waste conveying position 216, which is conveyed to the waste box 42 by the waste conveying belt 41.

[0190] The urine measurement mechanism 223 comprises a second Z-axis movement module and a liquid level sensor. The second Z-axis movement module has the same structure as the first Z-axis movement module. The liquid level sensor is installed on the second Z-axis sliding block. The central control machine controls the second Z-axis step motor to move from top to bottom. During the movement, the liquid level sensor detects the height of the liquid level in the corresponding measuring cylinder 10 and sends the height information to the central control machine to convert it into the volume of the corresponding urine sample and record it in the corresponding personal information.

[0191] The cylinder moving mechanism 222 comprises a second mechanical gripper, a second X-axis movement module, and a third Z-axis movement module. The second X-axis movement module is composed of a second X-axis stepper motor, a second X-axis screw, and a second X-axis sliding block. The second X-axis stepper motor drives the second X-axis screw to rotate under the control of the central control machine, thereby making the second X-axis sliding block slide on the second X-axis screw. The third Z-axis movement module is installed on the second X-axis sliding block and is composed of a third Z-axis stepper motor, a third Z-axis screw, and a third Z-axis sliding block. The third Z-axis stepper motor drives the third Z-axis screw to rotate under the control of the central control machine, thereby making the third Z-axis sliding block slide on the third Z-axis screw. The second mechanical gripper is arranged on the third Z-axis sliding block and only has a grabbing function.

[0192] When the urine sample in the current measuring cup 10 is measured in volume, the central control machine drives the cylinder moving mechanism 222 to grab the corresponding disposable measuring cup 10 by the second mechanical gripper and moves the batch of disposable measuring cups 10 to the shaking placement position 2131 of the shaking table 213.

[0193] The shaking table 213 is provided with multiple sets of shaking placement positions 2131, which can shake multiple batches of measuring cups 10. When the multiple sets of shaking placement positions 2131 are all filled with measuring cups 10, a stable liquid injection step is performed. The stable liquid injection process needs the cooperation of the stable liquid adding mechanism 224, the suction nozzle feeding mechanism 33, and the stable liquid tank 217.

[0194] The suction nozzle feeding mechanism 33 comprises a suction nozzle conveying belt 331 and a suction nozzle 11 placement tray 332 arranged on the nozzle conveying belt. Each suction nozzle placement tray 332 is provided with multiple suction nozzle placement positions, and each suction nozzle placement position is placed with a suction nozzle 11 for a pipette. When the suction nozzle placement tray 332 is placed on the suction nozzle conveying belt 331, the central control machine controls the stepper motor of the suction nozzle conveying belt 331 to drive the suction nozzle conveying belt 331 to move, thereby conveying the suction nozzle placement tray 332 to the suction nozzle assembly position 214.

[0195] The stable liquid tank 217 is arranged on the table top of the workbench 21 and contains sufficient prepared stable liquid. In this example, the stable liquid is 10% Triton X-100 stable liquid.

[0196] The stable liquid adding mechanism 224 comprises a first pipette, a third X-axis movement module and a fourth Z-axis movement module. The third X-axis movement module is composed of a third X-axis stepper motor, a third X-axis screw and a third X-axis slider. The third X-axis stepper motor is controlled by the central control machine to drive the third X-axis screw to rotate, so that the third X-axis slider slides on the third X-axis screw. The fourth Z-axis movement module is installed on the third X-axis slider and is composed of a fourth Z-axis stepper motor, a fourth Z-axis screw and a fourth Z-axis slider. The fourth Z-axis stepper motor is controlled by the central control machine to drive the fourth Z-axis screw to rotate, so that the fourth Z-axis slider slides on the fourth Z-axis screw. The first pipette is arranged on the fourth Z-axis slider.

[0197] After the multiple sets of oscillation placement positions 2131 are all filled with the graduated cylinders 10, the stable liquid injection process is started. The central control machine controls the stable liquid adding mechanism 224 to move to the position directly above the suction nozzle assembly position 214, controls the first pipette to move downward to the position of the suction nozzle 11 and to assemble the suction nozzle 11 on the head of the first pipette. The first pipette is lifted and translated to the stable liquid tank 217 to suck a certain amount of stable liquid, and then is translated to the position directly above the oscillation placement position 2131. According to the volume of the urine sample measured in advance, the central control machine controls the first pipette to inject the stable liquid into the corresponding graduated cylinder 10 according to the set proportion, and then is translated to the stable liquid tank 217 to release the remaining stable liquid. At the same time, the oscillation shaker 213 is started to make the stable liquid and the urine sample fully oscillate and mix to form a mixed liquid, and then the mixed liquid pipetting process is performed.

[0198] The mixed liquid pipetting process needs the cooperation of the mixed liquid pipetting mechanism 225, the cryogenic tube loading and cap assembling and disassembling mechanism 34, the waste conveying device 4, the refrigeration chamber 5 and the label marking and labeling machine 6.

[0199] The cryogenic tube loading and cap assembling and disassembling mechanism 34 comprises a cryogenic tube conveying belt 341, a cap disassembling assembly 342, a cap conveying line 343 and a cap assembling assembly 344. The cryogenic tube conveying belt 341 is provided with a cryogenic tube loading position, a cap disassembling position, a cryogenic tube placement position 215, a cap assembling position and a picking position in sequence. Figure 1 As shown in FIG. 8, the manual method is adopted, but in the specific implementation process, other automatic methods can also be adopted, which is not limited in the embodiment. After the cryogenic tube 12 is placed on the loading rack and placed on the cryogenic tube loading position (automatically inserted into the conveying belt storage rack), the cap disassembling assembly 342 removes the cap of the cryogenic tube 12 at the cap disassembling position by a mechanical hand, and conveys the removed cap to the cap assembling assembly 344 through the cap conveying line 343. The cap assembling assembly 344 reassembles the cap on the cryogenic tube 12 at the cap assembling position by a mechanical hand. Then, the cryogenic tube conveying belt 341 moves to the manual picking position, and is transported to the refrigeration chamber 5 or placed in a collection basket for manual processing.

[0200] In addition, during the movement of the cryogenic tube conveying belt 341 to the manual picking position, a label marking and pasting machine 6 is arranged on both sides of the cryogenic tube conveying belt 341, and a barcode label corresponding to the patient's urine sample is printed and pasted on the corresponding cryogenic tube 12. In addition, an infrared sensor 8 is arranged at the manual picking position to detect whether there is a vacancy within the equidistant range, so as to ensure that there is no vacancy between the adjacent two cryogenic tubes.

[0201] The mixed solution pipetting mechanism 225 comprises a second pipetting gun, a fourth X-axis movement module and a fifth Z-axis movement module. The fourth X-axis movement module is composed of a fourth X-axis stepper motor, a fourth X-axis screw and a fourth X-axis sliding block. The fourth X-axis stepper motor drives the fourth X-axis screw to rotate under the control of the central control machine, so that the fourth X-axis sliding block slides on the fourth X-axis screw. The fifth Z-axis movement module is installed on the fourth X-axis sliding block and is composed of a fifth Z-axis stepper motor, a fifth Z-axis screw and a fifth Z-axis sliding block. The fifth Z-axis stepper motor drives the fifth Z-axis screw to rotate under the control of the central control machine, so that the fifth Z-axis sliding block slides on the fifth Z-axis screw. The second pipetting gun is arranged on the fifth Z-axis sliding block.

[0202] After the stable liquid and the urine sample are fully shaken and mixed in the shaking incubator 213 to form a mixed solution, the central control machine controls the mixed solution pipetting mechanism 225 to move to the position directly above the suction nozzle set position 214, controls the second pipetting gun to move downward to the suction nozzle 11 and sets the suction nozzle 11 on the head of the second pipetting gun, lifts the second pipetting gun and moves it to the position directly above the shaking placement position 2131, and then the second pipetting gun moves downward to suck a certain amount of mixed solution under the liquid surface of the graduated cylinder 10. The amount of the mixed solution is 5mL in the embodiment of the present application. Then the second pipetting gun is lifted and moved to the position directly above the first row of cryogenic tubes 12, and a certain amount of mixed solution is injected into the first row of cryogenic tubes 12. The amount of the mixed solution is 1mL in the embodiment of the present application. Then the second pipetting gun is moved to the position directly above the second row of cryogenic tubes 12, and a certain amount of mixed solution is injected into the second row of cryogenic tubes 12. The amount of the mixed solution is 1mL in the embodiment of the present application. After the above steps are completed, the second pipetting gun moves to the position above the graduated cylinder 10 of the shaking placement position 2131 to discharge the remaining mixed solution into the graduated cylinder 10, and then moves to the waste conveying position 216. The suction nozzle 11 on the head is removed for internal cleaning, and then returns to the position directly above the suction nozzle set position 214 to prepare for the next pipetting of the mixed solution. The second mechanical gripper of the graduated cylinder moving mechanism 222 grabs the discarded disposable graduated cylinder 10 that has been pipetted in the shaking placement position 2131 to the waste conveying position 216, and is conveyed to the waste tank 42 by the waste conveying device 4.

[0203] The waste conveying device 4 comprises a waste conveying belt 41 and a waste tank 42. The waste conveying belt 41 is provided with a waste conveying position 216 at one end of the closed room 1, and the other end of the waste conveying belt 41 leads to the waste tank 42. The waste tank 42 is arranged outside the closed room 1, and is used to treat waste and waste liquid, such as Figure 1The process shown is completed manually, but other automated methods can also be used in the actual implementation. This embodiment does not impose any specific limitations. During the automatic urine sample collection process, the waste conveyor belt 41 is used to receive and uniformly process the used waste urine cups 9, waste disposable measuring cylinders 10, and waste suction nozzles 11.

[0204] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of this application, and all such modifications or substitutions should be considered within the scope of protection of this application.

Claims

1. An automated urine sample pretreatment method, characterized in that, Includes the following steps: The urine cup containing the urine sample and with the identification tag attached is delivered to the designated urine cup processing station; Identify the urine cup to obtain urine sample information; The urine sample in the urine cup is transferred into the measuring cylinder by the first robotic arm; The liquid level of the urine sample in the graduated cylinder is detected by a liquid level sensor, and the volume of the urine sample is calculated based on the liquid level and the known geometric dimensions of the graduated cylinder. According to the volume of the urine sample and the preset volume ratio, a stabilizing solution is added to the graduated cylinder using a first pipette; The driving mixing mechanism mixes the urine sample in the measuring cylinder with the stabilizing liquid to form a mixture; A predetermined amount of the mixture is drawn from the graduated cylinder using a second pipette, and the mixture is injected into at least one cryopreservation tube; The cryopreservation tube containing the mixture is transferred to the collection station.

2. The automated urine sample pretreatment method according to claim 1, characterized in that, The method further includes: The photoelectric sensor array detects whether the urine cup is tipped over or damaged on the conveying path, and issues a first alarm signal when tipping over or damage is detected.

3. The automated urine sample pretreatment method according to any one of claims 1, characterized in that, The first robotic arm transfers the urine sample into the measuring cylinder by flipping the urine cup, and then places the urine cup in the waste collection area after the transfer is completed.

4. The automated urine sample pretreatment method according to any one of claims 1, characterized in that, The method further includes: The total weight of the graduated cylinder and the urine sample inside it is measured using a precision balance, and the tare weight of the graduated cylinder is subtracted to obtain the weight of the urine sample. The volume of the urine sample is calculated based on the weight of the urine sample and a preset urine density value.

5. The automated urine sample pretreatment method according to claim 4, characterized in that, Also includes: The liquid level image of the urine sample inside the graduated cylinder is obtained using an optical imaging device. The liquid surface image is processed to identify and eliminate the interference of air bubbles in the liquid surface judgment, and the liquid surface height information is extracted from the image; The volume is verified by combining the volume calculated based on weight and the volume calculated based on optical liquid level. If the difference between the two exceeds a preset threshold, a second alarm signal is issued.

6. The automated urine sample pretreatment method according to claim 1, characterized in that, The preset range for the volume ratio of the stabilizing solution to the urine sample is 0.5:100 to 2:

100.

7. The automated urine sample pretreatment method according to claim 1, characterized in that, The method includes: Ultrasonic energy is applied to the outside or inside of the graduated cylinder, and the cavitation effect and acoustic flow effect generated by the ultrasound in the liquid are used to promote the rapid and uniform mixing of the urine sample and the stabilizing liquid to form the mixture.

8. The automated urine sample pretreatment method according to claim 1, characterized in that, The second pipette is configured to have at least eight independent pipetting channels, which simultaneously draw the mixture from the graduated cylinder and inject it into at least eight corresponding cryovials through each channel.

9. The automated urine sample pretreatment method according to claim 1, characterized in that, The method further includes the following steps: The concentration of the mixture in a predetermined volume within the cryovial is detected, and a target parameter is calculated accordingly. This target parameter is obtained by calculating the percentage of drug excreted in each time period relative to the total dose, using the following formula: m(t)=ρ·V In the formula, m(t) is the amount of drug excreted during time period t, ρ is the drug concentration, V is the urine sample volume, R(t) is the percentage during time period t, and M is the total dose administered.

10. An automated urine sample pretreatment system, characterized in that, include: Urine cup delivery unit, used to deliver urine cups containing urine samples and attached with identification tags; An identification unit is disposed on or adjacent to the urine cup conveying path and is used to identify the identification of the urine cup. The first robotic arm is configured to transfer a urine sample from the urine cup into a measuring cylinder; A liquid level sensor is configured to detect the liquid level height of the urine sample in the graduated cylinder and output a liquid level height signal; A first pipette is configured to add a stabilizing liquid to the graduated cylinder; A mixing mechanism connected to the graduated cylinder, the mixing mechanism being configured to mix a urine sample in the graduated cylinder with a stabilizing solution to form a mixture; A second pipette is configured to draw a predetermined amount of the mixture from the graduated cylinder and inject the mixture into at least one cryopreservation tube; A cryopreservation tube transfer unit is used to transfer the cryopreservation tube containing the mixture to the collection station; The control unit is electrically connected to the identification unit, the first robotic arm, the liquid level sensor, the first pipette, the mixing mechanism, the second pipette, and the transfer unit, and is used to implement the automated urine sample pretreatment method as described in any one of claims 1 to 9.

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