Substance dispensing system for a biological sample analysis instrument

Abstract

The present invention provides a substance dispensing system for a biological sample analysis instrument. The substance dispensing system can be used to prepare a fluid substance, such as a sample, using dispensing tips in different operating modes based on a volume of the fluid substance to be prepared. Thus, the substance dispensing system improves accuracy and / or precision of pipetting with the dispensing tips.

Description

[0001] This application was filed as a PCT international patent application on August 24, 2018, and claims priority to U.S. Provisional Patent Application Serial No. 62 / 550,440, filed on August 25, 2017, the entire disclosure of which is incorporated herein by reference. Background Technology

[0002] Some bioanalytical instruments utilize substance preparation systems for preparing fluid substances such as blood samples and reagents. Improperly prepared fluid substances can lead to false results that are difficult to detect. In some cases, such substance preparation systems are used to aliquot, aspirate, and dispense fluid substances through various containers, such as pipette tips, sample reservoirs, dilution reservoirs, and reaction reservoirs. Fluctuations in the aliquots, aspirates, and dispenses of fluid substances within these containers relative to the required amounts can affect analytical results and reduce the reliability of the analysis. Therefore, it is essential to accurately prepare the required amounts of substance to ensure reliable results. Summary of the Invention

[0003] Generally, this disclosure relates to a substance dispensing system for biological sample analysis instruments. In one feasible configuration and as a non-limiting example, the substance dispensing system includes a pipetting system and precise dispensing controls for operating the pipetting system. Various aspects described in this disclosure include, but are not limited to, the following.

[0004] One aspect is a method for preparing a fluid substance for evaluation. The method may include aspirating a first volume of fluid substance from a first reservoir to a dispensing tip; dispensing a second volume of fluid substance from the dispensing tip to a second reservoir by dispensing the second volume of fluid substance from the dispensing tip to the second reservoir; and rinsing the dispensing tip with at least a portion of the fluid substance from the second reservoir.

[0005] In some examples, the step of rinsing the dispensing tip may include drawing a third volume of fluid material from the second reservoir into the dispensing tip; and dispensing a fourth volume of fluid material from the dispensing tip into the second reservoir.

[0006] In some examples, the method may also include dispensing a third volume of fluid material; and re-aspirating the third volume of fluid material.

[0007] In some examples, the method may also include the steps of repeatedly dispensing and aspirating a third volume.

[0008] In some examples, the third volume and the fourth volume are equal.

[0009] In some examples, the dispensing tip may include a one-time dispensing tip.

[0010] In some examples, the second reservoir includes a dilution reservoir. In some examples, the second reservoir includes a reaction reservoir. In some examples, the first reservoir includes a sample reservoir.

[0011] In some examples, the step of aspirating a first volume of fluid material may include aspirating a fifth volume of fluid material from a first reservoir to a dispensing tip; and dispensing a sixth volume of fluid material from the dispensing tip to the first reservoir to contain the first volume of fluid material in the dispensing tip.

[0012] In some examples, the first volume is less than 25 μL. In some examples, the first volume is less than 20 μL. In some examples, the first volume is less than 30 μL.

[0013] In some examples, the sixth volume is larger than the fifth volume.

[0014] In some examples, the first volume is equal to the second volume.

[0015] In some examples, the first reservoir includes a sample reservoir containing equal volumes of fluid material, and the second reservoir includes a reaction reservoir.

[0016] In some examples, the first reservoir includes a sample tube. In some examples, the second reservoir includes a sample container.

[0017] In some examples, the method may also include determining the surface level of the fluid material contained in the first reservoir before aspirating the first volume of fluid material.

[0018] In some examples, the steps of determining the surface level of a fluid substance may include lowering a dispensing tip into a first reservoir; detecting a pressure increase at the distal end of the dispensing tip; and calculating the surface level of the fluid substance based on the pressure increase.

[0019] In some examples, the steps of calculating the surface level of a fluid substance include: determining the travel distance of the dispensing nozzle until an increase in pressure is detected; and calculating the surface level of the fluid substance based on the travel distance.

[0020] In some examples, the step of determining the surface level of the fluid substance further includes: venting air from the dispensing nozzle before a pressure increase is detected; and balancing the pressure inside the dispensing nozzle with the atmospheric environment after a pressure increase is detected and before the first volume is aspirated.

[0021] In some examples, the step of equalizing the pressure inside the dispensing tip with the atmospheric environment includes opening a valve disposed between the dispensing tip and the syringe assembly.

[0022] In some examples, the step of determining the surface level of a fluid substance also includes determining that the pressure increase is greater than a threshold.

[0023] Another aspect is an apparatus for dispensing fluid substances. This apparatus may include a pipetting system and a dispensing control system. The pipetting system may include a sample pipetting module configured to engage a dispensing tip. The dispensing control system is used to control the pipetting system to aspirate a first volume of fluid substance from a first reservoir to a dispensing tip; and to dispense a second volume of fluid substance from the dispensing tip to a second reservoir by dispensing the second volume of fluid substance from the dispensing tip to the second reservoir; and to rinse the dispensing tip using at least a portion of the fluid substance from the second reservoir.

[0024] In some examples, the dispensing control system may further control the pipetting system to aspirate a third volume of fluid material from the second reservoir to the dispensing tip; and to dispense a fourth volume of fluid material from the dispensing tip to the second reservoir.

[0025] In some examples, the dispensing control system can further control the pipetting system to dispense a third volume of fluid; and to aspirate a third volume of fluid again.

[0026] In some examples, the dispensing control system can further control the pipetting system to repeat the steps of dispensing and aspirating a third volume.

[0027] In some examples, the third and fourth volumes are equal. In some examples, the dispensing tip includes a disposable dispensing tip. In some examples, the second reservoir includes a dilution reservoir. In some examples, the second reservoir includes a reaction reservoir. In some examples, the first reservoir includes a sample reservoir.

[0028] In some examples, the dispensing control system may further control the pipetting system to aspirate a first volume of fluid material by: aspirating a fifth volume of fluid material from the first reservoir to the dispensing tip; and dispensing a sixth volume of fluid material from the dispensing tip to the first reservoir, thereby containing the first volume of fluid material in the dispensing tip.

[0029] In some examples, the first volume is less than 25 μL. In some examples, the first volume is less than 20 μL. In some examples, the first volume is less than 30 μL.

[0030] In some examples, the sixth volume is greater than the fifth volume. In some examples, the first volume is equal to the second volume.

[0031] In some examples, the first reservoir includes a sample reservoir containing equal volumes of fluid material, and the second reservoir includes a reaction reservoir. In some examples, the first reservoir includes a sample tube. In some examples, the second reservoir includes a sample reservoir.

[0032] In some examples, the dispensing control system may further control the pipetting system to determine the surface level of the fluid material contained in the first reservoir before aspirating the first volume of fluid material.

[0033] In some examples, the dispensing control system may further control the pipetting system to lower the dispensing tip into the first reservoir; detect an increase in pressure at the distal end of the dispensing tip; and calculate the surface level of the fluid material based on the pressure increase.

[0034] In some examples, the dispensing control system may further control the pipetting system to: determine the travel distance of the dispensing tip until an increase in pressure is detected; and calculate the surface level of the fluid material based on the travel distance.

[0035] In some examples, the dispensing control system may further control the pipetting system to expel air from the dispensing tip before a pressure increase is detected; and to equalize the pressure inside the dispensing tip with the atmospheric environment after a pressure increase is detected and before the first volume is aspirated.

[0036] In some examples, the dispensing control system can further control the pipetting system to equalize the pressure inside the dispensing tip with the atmospheric environment by opening a valve located between the dispensing tip and the syringe assembly.

[0037] In some examples, the dispensing control system can further control the pipetting system to determine if the pressure increase exceeds a threshold.

[0038] Another aspect is a method for preparing a sample for evaluation. This method may include aspirating a volume of sample from a first reservoir to a dispensing tip; diluting the sample by dispensing that volume of sample from the dispensing tip into a dilution reservoir containing a diluent; and rinsing the dispensing tip with at least a portion of a fluid substance from the dilution reservoir, the fluid substance containing the sample and the diluent.

[0039] In some examples, the step of rinsing the dispensing tip may include aspirating a first volume of fluid material from the dilution reservoir into the dispensing tip; and dispensing the first volume of fluid material from the dispensing tip into the dilution reservoir.

[0040] In some examples, the method may also include the steps of repeatedly aspirating a first volume of fluid material and dispensing the first volume of fluid material.

[0041] In some examples, the method may also include, after diluting the sample, aspirating only a portion of the fluid substance from the dilution reservoir to the dispensing tip; moving the dispensing tip to a second reservoir; and dispensing at least a portion of the aspirated fluid substance from the dispensing tip to the second reservoir.

[0042] Another aspect is an apparatus for preparing substances for evaluation. This apparatus may include: a pipetting system comprising a sample pipetting module configured to engage a dispensing tip; and a dispensing control system controlling the pipetting system to perform the following operations: aspirating a volume of sample from a first reservoir to the dispensing tip; diluting the sample by dispensing that volume of sample from the dispensing tip to a dilution reservoir containing a diluent; and rinsing the dispensing tip with at least a portion of a fluid substance from the dilution reservoir, the fluid substance containing the sample and the diluent.

[0043] In some examples, the dispensing control system may further control the pipetting system to aspirate a first volume of fluid material from the dilution reservoir to the dispensing tip; and to dispense the first volume of fluid material from the dispensing tip to the dilution reservoir.

[0044] In some examples, the dispensing control system may further control the pipetting system to repeat the steps of aspirating a first volume of fluid and dispensing a first volume of fluid.

[0045] In some examples, the dispensing control system may further control the pipetting system to aspirate only a portion of the fluid material from the dilution reservoir to the dispensing tip after the sample has been diluted; to move the dispensing tip to a second reservoir; and to dispense at least a portion of the aspirated fluid material from the dispensing tip to the second reservoir.

[0046] Another aspect is a method for preparing a fluid substance for evaluation. This method may include aspirating a first volume of fluid substance from a first reservoir to a dispensing tip; and dispensing a second volume of fluid substance from the dispensing tip to a second reservoir by: lowering the dispensing tip to a first height in the second reservoir, the first height being configured such that the distal end of the dispensing tip remains above the surface level in the second reservoir after dispensing; dispensing the fluid substance from the dispensing tip to the second reservoir; and lowering the dispensing tip to a second height, the second height being configured such that the distal end of the dispensing tip contacts the surface level in the second reservoir after dispensing.

[0047] In some examples, the step of dispensing a second volume of fluid may also include using a sensor to detect whether the fluid in the second reservoir is in contact with the distal end of the dispensing tip; and transmitting a signal from the sensor to a control device, which may be used by the control device to stop moving the dispensing tip.

[0048] In some examples, the first volume is larger than the second volume. In some examples, the second volume is greater than 25 μL.

[0049] Another aspect is an apparatus for preparing fluid substances for evaluation. This apparatus may include: a pipetting system comprising a sample pipetting module configured to engage a dispensing tip; and a dispensing control system controlling the pipetting system to aspirate a first volume of fluid substance from a first reservoir to the dispensing tip; and to dispense a second volume of fluid substance from the dispensing tip to a second reservoir by: lowering the dispensing tip to a first height in the second reservoir, the first height being configured such that the distal end of the dispensing tip remains above the surface liquid level in the second reservoir after dispensing; dispensing fluid substance from the dispensing tip to the second reservoir; and lowering the dispensing tip to a second height, the second height being configured such that the distal end of the dispensing tip contacts the surface liquid level in the second reservoir after dispensing.

[0050] In some examples, the dispensing control system may further control the pipetting system to: use sensors to detect whether fluid material in the second reservoir is in contact with the distal end of the dispensing tip; and transmit signals from the sensors to a control unit, which may be used by the control unit to stop moving the dispensing tip.

[0051] In some examples, the first volume is larger than the second volume. In some examples, the second volume is greater than 25 μL.

[0052] Another aspect is a method for preparing a fluid substance for evaluation. This method may include determining the volume of the fluid substance to be dispensed into a reservoir; dispensing the fluid substance into the reservoir in a first operating mode when the volume is determined to be less than a reference value; and dispensing the fluid substance into the reservoir in a second operating mode when the volume is determined to be not less than the reference value.

[0053] Another aspect is an apparatus for preparing fluid substances for evaluation. This apparatus may include: a pipetting system comprising a sample pipetting module configured to engage a dispensing tip; and a dispensing control system controlling the pipetting system to: determine the volume of fluid substance to be dispensed into a reservoir; dispensing the fluid substance into the reservoir in a first operating mode when the determined volume is less than a reference value; and dispensing the fluid substance into the reservoir in a second operating mode when the determined volume is not less than a reference value. Attached Figure Description

[0054] Figure 1 An exemplary instrument for analyzing biological samples is shown schematically.

[0055] Figure 2 This is a schematic diagram of an exemplary pipetting system.

[0056] Figure 3 An exemplary sample pipetting module is shown.

[0057] Figure 4 An exemplary operation of the sample pipetting system is illustrated schematically.

[0058] Figure 5 This is a flowchart illustrating an exemplary method for operating a material distribution system.

[0059] Figure 6 This is a flowchart of an exemplary method for drawing a sample from a sample reservoir and dispensing the sample into a reaction reservoir.

[0060] Figure 7 This is a flowchart illustrating an exemplary method that performs the extraction and pushback processes.

[0061] Figure 8 This is a schematic diagram of the dispensing tip relative to the sample reservoir.

[0062] Figure 9 This is an example table for assigning suction head heights.

[0063] Figure 10 This is an example table for over-extraction and back-extraction of the target sample volume.

[0064] Figure 11 The execution is illustrated schematically. Figure 7 An exemplary order of methods.

[0065] Figure 12 This is a timing diagram showing the execution... Figure 7 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0066] Figure 13 This is a flowchart of an exemplary method for performing a rinsing action.

[0067] Figure 14 This is an example table for the assigned suction head height.

[0068] Figure 15 The execution is illustrated schematically. Figure 13 An exemplary order of methods.

[0069] Figure 16 This is a timing diagram showing the execution... Figure 13 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0070] Figure 17 This is a flowchart of an exemplary method that has performed the extraction process.

[0071] Figure 18 The execution is illustrated schematically. Figure 17 An exemplary order of methods.

[0072] Figure 19 This is a timing diagram showing the execution... Figure 17 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0073] Figure 20 This is a flowchart of an exemplary method for performing a two-step assignment action.

[0074] Figure 21 It shows the execution Figure 20 A timing diagram of an exemplary sequence of methods.

[0075] Figure 22 This schematically illustrates the execution Figure 20 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0076] Figure 23 This is a flowchart illustrating an exemplary method of drawing a sample from a sample tube and dispensing the sample into a sample reservoir.

[0077] Figure 24 This is a flowchart illustrating an exemplary method for detecting the surface liquid level of a sample and performing the extraction and pushback process.

[0078] Figure 25 The execution is illustrated schematically. Figure 24 An exemplary order of methods.

[0079] Figure 26 This is a timing diagram showing the execution... Figure 24 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0080] Figure 27 This is a flowchart illustrating an exemplary method for detecting the surface liquid level of a sample and performing the extraction and pushback process.

[0081] Figure 28 The execution is illustrated schematically. Figure 27 An exemplary order of methods.

[0082] Figure 29 This is a timing diagram showing the execution... Figure 27 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0083] Figure 30 This is a flowchart illustrating an exemplary method for performing a dilution process.

[0084] Figure 31 This is an example table for the extraction and pushback volumes for dilution.

[0085] Figure 32 The execution is illustrated schematically. Figure 30 An exemplary order of methods.

[0086] Figure 33 This is a timing diagram showing the execution... Figure 30 The method involves adjusting the position of the suction tip and the movement of the syringe over time.

[0087] Figure 34 An exemplary architecture of a computing device that implements aspects of this disclosure is illustrated schematically.

[0088] Figure 35 This is a timing diagram illustrating exemplary pump motor stepping and vertical drive motor stepping over cycle time when performing small-volume sample pipetting without dilution.

[0089] Figure 36 This is a timing diagram illustrating exemplary pump motor stepping and vertical drive motor stepping over cycle time when performing pipetting of a medium volume sample without dilution.

[0090] Figure 37 This is a timing diagram illustrating exemplary pump motor stepping and vertical drive motor stepping over cycle time when performing large-volume sample pipetting without dilution.

[0091] Figure 38 This is a timing diagram showing the exemplary pump motor stepping and vertical drive motor stepping over cycle time when performing a 100-fold dilution.

[0092] Figure 39 This is a timing diagram showing exemplary pump motor stepping and vertical drive motor stepping over cycle time during a 10-fold dilution.

[0093] Figure 40 This is a schematic diagram of an exemplary dilution process and a table of exemplary dilution rates for different volumes.

[0094] Figure 41 This is a graph illustrating a set of exemplary experiments performed using the system of this disclosure. Detailed Implementation

[0095] Various embodiments will now be described in detail with reference to the accompanying drawings, in which similar reference numerals denote similar parts and components. The mention of various embodiments is not intended to limit the scope of the appended claims. Furthermore, any examples listed in this specification are not intended to be limiting, but merely to set forth a number of possible embodiments with respect to the appended claims.

[0096] Generally, the material distribution systems of this disclosure improve the accuracy and / or precision of pipetting. For example, the systems of this disclosure enable accurate and / or precise pipetting using disposable tips (i.e., disposable tip pipetting). The pipetting methods described in this disclosure can be improved in terms of accuracy and / or precision based on statistical experiments. In some examples, higher precision configurations and / or methods can be achieved by characterizing various parameters. The systems of this disclosure allow for shorter instrument cycle times while maintaining sufficient accuracy. References herein Figure 41 Exemplary results of such experiments are described.

[0097] The system disclosed herein also improves the dilution and volume range of pipetting. In an exemplary embodiment, the system can handle samples as small as 2 μL and as large as 100 μL. Additionally, in an exemplary embodiment, the system can operate in multiple modes for different pipetting volumes. For example, a first mode can be used for a range of 0 to 25 μL (e.g., ...). Figure 35 The second mode can be used in the range of 25 to 50 μL (as shown in the "small" volume). Figure 36 The "medium" volume shown), and the third mode can be used in the range of 50 to 100 μL (as indicated). Figure 37 (The "large" volume is indicated). In some implementations, if the sample volume is less than 25 μL, multiple mixing strokes (e.g., three) can be performed. If the sample volume is equal to or greater than 25 μL, no mixing stroke is performed, which saves overall processing time.

[0098] Figure 1 An exemplary instrument 100 for analyzing biological samples is schematically illustrated. In some embodiments, instrument 100 includes a substance dispensing system 102 and a precision dispensing control system 106, the substance dispensing system including a pipetting system 104. In other embodiments, instrument 100 also includes a substance evaluation system 108. One or more containers 110 are used to contain, move, and receive fluid substances 112 and are used by at least one of systems 102 and 108 of instrument 100. In some embodiments, instrument 100 is automated or semi-automated, wherein containers 110 are used by instrument 100 without being controlled by a human operator or subject to minimal operator intervention.

[0099] The biological sample analyzer 100 is used to analyze biological samples for various purposes. In some embodiments, the biological sample analyzer 100 includes a blood sample analyzer or device. For example, in some embodiments, the biological sample analyzer 100 is used to collect, test, process, store, and / or transfuse blood and its components. Blood collection may be performed at a blood donation center. The collected blood and its components are then typically processed, tested, and dispensed at or through a blood bank or clinical laboratory.

[0100] The substance dispensing system 102 utilizes container 110 and is used to aliquot, aspirate, and dispense fluid substance 112 using container 110. Container 110 is used to prepare one or more substances to be analyzed by substance evaluation system 108. Container 110 can be of various types, such as sample tubes (also referred to herein as sample tubes), pipette tips, and reservoirs. In some embodiments, container 110 may include one or more dispensing tips 120, one or more tubes 122, and one or more reservoirs 124. In other embodiments, other types of containers may be used in instrument 100.

[0101] Dispensing tips 120 are provided to the material dispensing system 102 to aliquot or aspirate material 112 from other containers such as tubes 122 or reservoirs 124. For example, dispensing tips 120 are used to aliquot samples from sample tubes or aspirate samples or reagents from sample or reagent reservoirs. An example of a dispensing tip is part number MIS_PRT-000024938, purchased from Beckman Coulter, Inc., Brea, California. As described herein, some embodiments of pipette tips are disposable after single or multiple uses.

[0102] Tube 122 is a sterile glass or plastic tube with a closure to contain substance 112. In some examples, tube 122 includes a sample tube or specimen tube containing a blood sample. In some embodiments, tube 122 is configured to be evacuated to create a vacuum inside the tube, thereby facilitating the extraction of a predetermined volume of substance therein.

[0103] The reservoir 124 is provided to the material dispensing system 102 to contain the substance 112 for preparation and analysis. In some embodiments, the material dispensing system 102 aspirates the substance 112 from the reservoir 124 and / or dispenses the substance 112 into the reservoir 124. Examples of reservoirs 124 include sample reservoirs 130, dilution reservoirs 132, and reaction reservoirs 134.

[0104] In some embodiments, the dispensing tip 120, tube 122, and reservoir 124 are configured to be hydrophobic. For example, the dispensing tip 120, tube 122, and reservoir 124 may be made of a hydrophobic material such that their surfaces are not wetted but rather droplets.

[0105] In illustrative examples of blood sample analysis, fluid substance 112 can be any one or any mixture of blood sample, diluent, and reagent. In some embodiments, fluid substance 112 is a fluid of a single substance. In other embodiments, fluid substance 112 is a mixture of multiple substances. In various embodiments, fluid substance 112 can be the sample to be analyzed, sample preparation components, diluent, buffer, reagent, or any combination thereof. Where fluid substance 112 involves blood or its components, examples of fluid substance 112 include whole blood, plasma, serum, red blood cells, white blood cells, platelets, diluent, reagent, or any combination thereof. In other embodiments, fluid substance 112 can be any type suitable for dispensing onto a container or tray for further analysis. Furthermore, fluid substance can be other types of bodily fluid substances, such as saliva, cerebrospinal fluid, urine, amniotic fluid, feces, mucus, cell or tissue extracts, nucleic acids, or any other type of bodily fluid, tissue, or material suspected of containing the target analyte.

[0106] The pipetting system 104 is used to deliver fluid substances 112 using container 110. For example, the pipetting system 104 may be fluidly connected to one or more containers to deliver, for example, reagents, diluents, and buffers. See examples of pipetting devices. Figure 2 A more detailed description and illustration are provided.

[0107] The precision dispensing control system 106 is used to control the dispensing of fluid substance 112 using container 110. For example, the precision dispensing control system 106 controls other means of the pipetting system 104 and the substance dispensing system 102 to precisely dispense fluid substance 112 into container 110 (e.g., reservoir 124) for subsequent analysis, such as by substance evaluation system 108. Improper fluid substance dispensing can lead to false results, which may be indistinguishable from true results, or may otherwise impair the operation of the biological sample analysis instrument 100.

[0108] The substance evaluation system 108 is used to evaluate fluid substances 112 provided using container 110. For example, the substance evaluation system 108 performs blood donor screening, transfusion testing, and / or clinical diagnosis. The substance evaluation system 108 can perform other types of analysis or evaluation for various purposes. For example, the substance evaluation system 108 can use any known analytical method and detection system to analyze a variety of fluid substances 112. Common examples include spectrophotometric detection and analysis for clinical chemistry testing, immunoassays, microbial identification, and antibiotic susceptibility testing, as well as nucleic acid testing using fluorescently labeled primers and probes. Other analytical methods compatible with semi-automatic or automated sample handling on a tray are also known and compatible with the principles of this disclosure. Some biosample analysis instruments 100 can be configured by the user to select the substance evaluation system 108 suitable for various research or diagnostic analyses.

[0109] Continue to refer to Figure 1 In some implementations, instrument 100 is used to communicate with management system 114 via data communication network 116. For example, instrument 100 includes communication devices (such as...) Figure 34 The instrument 100 communicates with the management system 114 through the communication device 846.

[0110] In some implementations, the management system 114 is located remotely from instrument 100 and is configured to perform diagnostics based on data from instrument 100. Additionally, instrument 100 can evaluate instrument performance and generate reports. An example of the management system 114 includes one or more computing devices executing a ProSevice remote service application, purchased from Beckman Coulter, Inc., Brea, CA.

[0111] The Beckman Coulter ProService remote service application uses a Remote Application Processor (RAP) box to provide a secure and continuous connection between a bioanalytical instrument 100 and a remote diagnostic command center (e.g., management system 114) via a network (e.g., network 116). The RAP box can connect the bioanalytical instrument 100 to the remote diagnostic command center via an Ethernet port, Wi-Fi, or cellular network over the Internet. The bioanalytical instrument 100 can send instrument data (such as instances of tagged trays) to the RAP box. The RAP box then secures this data and forwards it to the remote diagnostic command center. All communication between the bioanalytical instrument 100 and the remote diagnostic command center can be coordinated through the RAP box. The RAP box can connect to the network using a static or Dynamic Host Configuration Protocol (DHCP) IP address. The RAP box can be hardware with a computer processing board and connection ports capable of securely transmitting instrument data from the bioanalytical instrument 100 to the remote diagnostic command center. For example, the RAP box may have one or more Ethernet connection ports, one or more computer processing boards for Wi-Fi or cellular network connectivity, a power outlet connection port, or any combination thereof.

[0112] The RAP box may have an internal firewall to securely and continuously transmit instrument data from the biosample analyzer 100 and the remote diagnostic command center. This internal firewall creates a dedicated instrument network that isolates the biosample analyzer 100 from other network traffic existing on that network. Furthermore, the RAP box ensures data transmission from one or more analyzers to the biosample analyzer 100 through one or more mechanisms. First, outbound startup data messages are protected by encryption and sent through the firewall via HTTPS on port 443 (a standard port for secure internet use). Data is transmitted during Secure Sockets Layer (SSL), a protocol used for securely transmitting information over the internet. SSL establishes a secure connection between the client and server through which data can be securely sent. Two-factor authentication helps prevent unauthorized access to transmitted data. An example of an SSL connection is a 128-bit AES, FIPS-compliant encryption algorithm. Another mechanism by which the RAP box protects data is the use of Remote Desktop Sharing (RDS) sessions. The RDS session is maintained through a secure Virtual Private Network (VPN) tunnel that encapsulates the session between the biosample analysis instrument 100 and the remote diagnostic command center to ensure that no third party intercepts the data being shared.

[0113] Still refer to Figure 1 Data communication network 116 transmits digital data between one or more computing devices, such as between instrument 100 and management system 114. Examples of network 116 include local area networks (LANs) and wide area networks (WANs), such as the Internet. In some embodiments, network 116 includes a wireless communication system, a wired communication system, or a combination of wireless and wired communication systems. In various possible embodiments, wired communication systems may use electrical or optical signals to transmit data. Wireless communication systems typically transmit signals via electromagnetic waves, such as in the form of optical or radio frequency (RF) signals. Wireless communication systems typically include an optical transmitter or RF transmitter for transmitting optical or RF signals and an optical receiver or RF receiver for receiving optical or RF signals. Examples of wireless communication systems include Wi-Fi communication devices (such as those utilizing wireless routers or wireless access points), cellular communication devices (such as those utilizing one or more cellular base stations), and other wireless communication devices.

[0114] Figure 2 This is a schematic diagram of an exemplary pipetting system 104. The pipetting system 104 includes a sample pipetting module 150, a vertical transfer device 152, and a horizontal transfer device 154.

[0115] In the illustrated example, pipetting system 104 is a sample pipetting system. Throughout this document, pipetting system 104 is also referred to as sample pipetting system 104. Sample pipetting system 104 performs various pipetting operations.

[0116] The sample pipetting module 150 is used to supply liquid from the dispensing tip supply unit 180 ( Figure 4 The system receives a dispensing tip (also referred to herein as a pipette tip) 120 and engages the dispensing tip with the sample pipetting module 150. An example of the sample pipetting module 150 is shown below. Figure 3 A more detailed description and illustration are provided.

[0117] The vertical conveying device 152 is used to move the sample pipetting module 150 vertically along it. As described herein, the vertical conveying device 152 moves the sample pipetting module 150 to adjust the position of the dispensing tip 120 relative to the tube 122 or reservoir 124 for aspiration or dispensing.

[0118] A horizontal transfer device 154 is used to guide the sample pipetting module 150 along it. As described herein, the sample pipetting module 150 is movable between different positions along the sample transfer guide 514. For example, the sample pipetting module 150 can be moved to the tip supply position 170, the sample aspiration position 172, the sample dilution position 174, the sample dispensing position 176, and the tip waste position 178, as in combination. Figure 4 As discussed further.

[0119] The vertical transfer device 152 and the horizontal transfer device 154 can operate together and / or individually to transfer the sample pipetting module 150 between the two positions along any desired path. For example, the vertical transfer device 152 and the horizontal transfer device 154 can operate selectively and / or simultaneously to move the sample pipetting module 150 from the starting position to the ending position by bypassing any obstacles arranged between the starting and ending positions.

[0120] Figure 3 An example of a sample pipetting module 150 is schematically shown. The sample pipetting module 150 includes a base 160 and a mandrel 162 (also referred to herein as a tube) supported at the base 160. The base 160 can be vertically guided by a vertical delivery device 152. The mandrel 162 is configured to mount a dispensing tip 120, which is also referred to herein as a pipetting tip or probe, aspiration tip or probe, or disposable tip or probe. For example, the sample pipetting module 150 engages the pipetting tip by pressing the mandrel 162 into it and lifting the mandrel 162 that mates with the pipetting tip. The mandrel 162 can be removed from the base 160. In some embodiments, the mandrel 162 has a tapered tip 165 that engages a corresponding tapered seat portion 167 of the dispensing tip 120 (similar to a machine taper, Morse taper, etc.). When the dispensing tip 120 is engaged, friction holds the dispensing tip 120 on the mandrel 162 and forms an airtight joint. The dispensing tip 120 can be removed by driving it outward from the mandrel 162.

[0121] A vertical drive motor may be used to engage the tapered seat portion 167 of the dispensing tip 120 with the tapered tip 165 of the spindle 162. A spring assembly 169 with fixed or near-fixed stiffness may be provided to ensure consistent engagement of the dispensing tip 120 with the spindle 162 and to ensure that the dispensing tip 120 has a consistent overall length and / or position (i.e., the distal end 320 of the dispensing tip 120). In some embodiments, the vertical drive motor may be used to drive the tapered seat portion 167 of the dispensing tip 120 from the tapered tip 165 of the spindle 162.

[0122] In some embodiments, the sample pipetting module 150 includes a sample aliquoting unit and a sample precision pipetting unit. The sample aliquoting unit is used to aspirate aliquots of the sample from sample tubes 122 located in a sample display unit (SPU) and dispense the aliquots into sample reservoirs. For example, to enable sampling of small volumes (e.g., for pediatric samples), sampling can be performed directly from the SPU (i.e., pipetting). The sample aliquoting unit discards used pipette tips upon completion of pipetting each sample. The sample precision pipetting unit aspirates the sample from the sample reservoir and dispenses the sample into a reaction reservoir. In some embodiments, the sample may first be dispensed into a dilution reservoir for sample dilution, and then into the reaction reservoir. The sample precision pipetting unit discards used pipette tips upon completion of the predetermined test.

[0123] The sample pipetting module 150 also includes a syringe assembly 164. The syringe assembly 164 may include a plunger that can be pulled or pushed along the interior of the barrel, thereby allowing the syringe assembly 164 to receive or expel liquid or gaseous substances through the open end of the dispensing tip 120. A motor 166 (e.g., a stepper motor) is used to actuate the syringe assembly 164. The syringe assembly is in fluid communication with the dispensing tip 120 via a fluid line 161.

[0124] In some examples, the sample pipetting module 150 includes a valve 168 configured to selectively connect the dispensing tip 120 to either the syringe assembly 164 or the environment, such that the dispensing tip 120 is in fluid communication with either the syringe assembly 164 or the environment. Examples of valve 168 include a three-way valve disposed between the syringe assembly 164 and the dispensing tip 120. Exemplary operation of valve 168 is described below. Figure 25 describe.

[0125] Figure 4 Exemplary operation of the sample pipetting system 104 is illustrated. In some examples, the sample pipetting system 104 may move the sample pipetting module 150 to the tip supply position 170, the sample aspiration position 172, the sample dilution position 174, the sample dispensing position 176, and the tip waste position 178.

[0126] For example, the sample is aspirated using a dispensing tip to avoid the risk of contamination. The sample pipetting module 150 is movable to the tip supply position 170. In this position, the sample pipetting module 150 is vertically lowered to insert a mandrel 162 into a dispensing tip 120 supplied by the dispensing tip supply unit 180, thereby attaching the dispensing tip 120 to the mandrel 162. The sample pipetting module 150 then moves to the sample aspiration position 172, where it is used to aspirate a predetermined volume of sample from the sample container. As described herein, in some embodiments, the sample container may be a sample tube 122 or a sample reservoir 130.

[0127] In some examples, the sample pipetting module 150 is optionally moved to the sample dilution position 174. At the sample dilution position 174, the sample pipetting module 150 is lowered such that the dispensing tip 120 is positioned within the dilution reservoir 132 containing the diluent.

[0128] Subsequently, the sample pipetting module 150 moves to the sample dispensing position 176 to dispense the aspirated volume of sample (or diluted sample) into the reservoir 124. As described herein, in some embodiments, the reservoir 124 may be a sample reservoir 130 or a reaction reservoir 134. After dispensing, the sample pipetting module 150 moves to the tip waste position 178 to discard the dispensing tip into the dispensing tip waste unit 182.

[0129] Figure 5 This is a flowchart illustrating an exemplary method 200 for operating a material dispensing system 102, including a sample pipetting system 104 and a precision dispensing control system 106. Method 200 also refers to... Figure 4 Description. Although method 200 is described herein primarily as being performed by sample pipetting system 104, it should be noted that method 200 may be performed at least in part by one or more other systems or devices, such as precision dispensing control system 106 in material dispensing system 102 or other systems, with or without cooperation with sample pipetting system 104.

[0130] Generally, two different sample sources can be used in instrument 100. In one embodiment, a sample can be aspirated from sample tube 122 displayed in the sample holder. For example, sample pipetting system 104 is used to aspirate aliquots of the sample from sample tube 122 located in the sample holder and dispense the aliquots of the sample into sample reservoir 130. Alternatively, sample pipetting system 104 is used to aspirate the sample from sample reservoir 130 and dispense the sample into reaction reservoir 134. In some embodiments, the sample can be diluted using dilution reservoir 132 before being dispensed into reaction reservoir 134.

[0131] Method 200 may begin with operation 202, in which the dispensing tip 120 is engaged with the sample pipetting module 150. For example... Figure 4 As shown, the sample pipetting module 150 lowers the base 160 and mandrel 162 from the starting position 190. In some embodiments, the mandrel 162 may be lowered at an increased speed 230 (i.e., acceleration) before approaching the dispensing tip 120. After arranging the mandrel 162 adjacent to the dispensing tip 120, the mandrel 162 may be further lowered at a constant speed 232 until the mandrel engages the dispensing tip, then decelerated to a standstill and establishing the relative position of the end 163 and / or distal end 320 of the dispensing tip 120 with respect to the mandrel 162. After the dispensing tip 120 is in place, the sample pipetting module 150 raises the mandrel 162 and returns to the starting position 190 or another position.

[0132] At operation 204, if a sample is to be drawn from sample reservoir 130, method 200 proceeds to operation 206. Alternatively, if a sample is to be drawn from sample tube 122, method 200 continues to operation 210.

[0133] At operation 206, the sample pipetting system 104 moves the sample pipetting module 150 to the sample reservoir 130 containing aliquots of the sample. For example... Figure 4 As shown, the sample pipetting system 104 can move the sample pipetting module 150 to the sample aspiration position 172 of the sample reservoir 130.

[0134] At operation 208, sample pipetting system 104 is used to aspirate a sample from sample reservoir 130. An exemplary aspiration method from sample tube 122 is described below. Figure 6 describe.

[0135] At operation 210, the sample pipetting system 104 moves the sample pipetting module 150 to the sample tube 122 containing the sample. For example... Figure 4 As shown, the sample pipetting system 104 can move the sample pipetting module 150 to the sample aspiration position 172 of the sample tube 122.

[0136] At operation 212, the sample pipetting module 150 is used to detect the surface liquid level of the sample in sample tube 122. When the volume of sample contained in sample tube 122 is unknown, it is necessary to measure or estimate the liquid level of the sample in sample tube 122 to ensure that the dispensing tip 120 is lowered sufficiently to reach the distal end 320 of the dispensing tip 120. Figure 8The dispensing tip 120 is held below the surface liquid level while aspirating a volume of sample from the sample tube 122. As described herein, in some embodiments, the dispensing tip 120 is lowered while air is purged from the dispensing tip and the surface liquid level of the sample is sensed. After a surface liquid level is detected at a location, the dispensing tip 120 can aspirate the sample at that location without rising and returning to the starting position. Therefore, the dispensing tip does not need to rise and fall to aspirate the sample. Instead, the dispensing tip can be lowered only once to simultaneously measure the surface liquid level and aspirate the sample, which is referred to herein as single-dive mode. In contrast, in dual-dive mode, the dispensing tip 120 is lowered while purging air to sense the liquid level, and then raised above the surface liquid level to balance the internal pressure. The dispensing tip then lowers again to aspirate the sample. Therefore, single-dive mode simplifies the process compared to dual-dive mode. An example of single-dive action is shown in the reference. Figures 24 to 26 Further description.

[0137] At operation 214, the sample pipetting module 150 is used to aspirate a sample from the sample tube 122. An exemplary method for detecting the surface liquid level of the sample and aspirating the sample from the sample tube 122 is described below. Figure 24 and Figure 27 describe.

[0138] At operation 216, if dilution is required before allocation, method 200 proceeds to operation 218. If dilution is not required, method 200 jumps to operation 222.

[0139] At operation 218, the sample pipetting module 150 moves to the dilution reservoir 132 containing the diluent. For example... Figure 4 As shown, the sample pipetting module 150 can be moved to the sample dilution position 174 where the dilution reservoir 132 is provided.

[0140] At operation 220, sample pipetting module 150 is used to dilute the sample in dilution reservoir 132. An exemplary dilution method from sample tube 122 is described below. Figure 30 describe.

[0141] At operation 222, the sample pipetting module 150 moves the dispensing tip 120 to the reservoir 124. For example... Figure 4 As shown, the sample pipetting module 150 is movable to the sample dispensing position 176 of the reservoir 124. As described herein, the reservoir 124 may be a sample reservoir 130 or a reaction reservoir 134. For example, when a sample is aspirated from the sample tube 122 (as in operation 214), the reservoir 124 may be a sample reservoir 130, such that the sample pipetting module 150 dispenses the sample into the sample reservoir 130. Alternatively, when a sample is aspirated from the sample reservoir 130 (as in operation 208), the reservoir 124 may be a reaction reservoir 134, such that the sample pipetting module 150 dispenses the sample into the reaction reservoir 134.

[0142] At operation 224, the sample pipetting module 150 is used to dispense the aspirated sample (or diluted sample) into the sample reservoir 130 or the reaction reservoir 134. An exemplary dispensing method is described below. Figure 6 (Regarding the distribution method for sample reservoirs) and Figure 23 (Description of the method for dispensing sample tubes)

[0143] At operation 226, the sample pipetting module 150 moves to the tip waste position 178, as follows: Figure 4 As shown. At operation 228, the sample pipetting module 150 removes the dispensing tip 120. In some embodiments, the sample pipetting module 150 lowers the mandrel 162 and the dispensing tip 120 at an increased speed 236 (i.e., acceleration) until they reach the dispensing tip waste unit 182. After the dispensing tip 120 is removed and falls into the dispensing tip waste unit 182, the sample pipetting module 150 can be raised at a constant speed 238.

[0144] Figure 6 This is a flowchart of an exemplary method 250 for drawing a sample from sample reservoir 130 and dispensing the sample into reaction reservoir 134. In some examples, method 250 is designed to implement... Figure 5 Operations 206, 208, 222, and 224. Method 250 is primarily described herein as being performed by the sample pipetting system 104 controlled by the precision dispensing control system 106; however, it should be noted that method 250 may be performed, at least in part, by one or more other systems or devices in the material dispensing system 102, with or without cooperation with the sample pipetting system 104 and the precision dispensing control system 106. Although method 250 is described as including Figure 6 The operations shown herein, but in other embodiments, method 250 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0145] At operation 252, the sample pipetting system 104 moves the sample pipetting module 150 to the sample reservoir 130 containing the sample aliquots, similar to... Figure 5 Operation 206. In some examples, sample reservoir 130 contains equal volumes of sample. Therefore, the volume of sample in sample reservoir 130 is generally known, at least. Therefore, it is generally not necessary to measure or estimate the surface level of the sample in sample reservoir 130 in order to determine how deep the dispensing tip 120 needs to descend to aspirate the sample within sample reservoir 130. In contrast, as described herein, when aspirating samples from other containers such as sample tube 122, the volume of sample contained in such containers is not necessarily known, and it may be necessary to measure or estimate the surface level of the sample in the container.

[0146] At operation 254, if the target sample volume is less than a threshold ("Yes" in this operation), method 250 proceeds to operation 256. Otherwise ("No" in this operation), method 250 continues to operation 266. Therefore, in method 250, the sample pipetting system 104, which can be controlled by the precision dispensing control system 106, operates different processes for aspiration and dispensing based on the target sample volume to be prepared. The threshold can be determined based on various factors. Exemplary factors include the configuration and properties of the dispensing tip (e.g., size, capacity, material, etc.), the arrangement of the dispensing tip relative to the container used for aspiration or dispensing, and the type of sample or other substance. In one example, the threshold is approximately 25 μL. Other thresholds are possible in other examples.

[0147] In some embodiments, the determination of operation 254 can be performed automatically within instrument 100 as part of the sample preparation process. For example, instrument 100 is configured to receive user input of the target sample volume and to determine the operation to be performed at operation 254. In other embodiments, instrument 100 is configured such that a user can manually select the operation to be performed via a user interface associated with instrument 100.

[0148] At operation 256, when the target sample volume is less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs an over-pumping and pushback process to aspirate the sample from the sample reservoir 130. For small sample volumes, the system also aspirates the excess volume beyond the desired sample volume and then pushes back the excess volume. The remaining volume in the dispensing tip is delivered to the dispensing location. An exemplary method for performing the over-pumping and pushback process is described below. Figure 7 describe.

[0149] At operation 258, if dilution is required before distribution, method 250 proceeds to operation 260. If dilution is not required, method 250 jumps to operation 262.

[0150] At operation 260, the sample pipetting system 104 moves the sample pipetting module 150 to the dilution reservoir 132 containing the diluent and dilutes the sample within the dilution reservoir 132. An exemplary dilution method from the sample tube 122 is described below. Figure 30 describe.

[0151] At operation 262, the sample pipetting system 104 moves the sample pipetting module 150 to the reaction reservoir 134, similar to... Figure 5 Operation 222.

[0152] At operation 264, when the target sample volume is less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs a flushing action to dispense the sample into the reaction reservoir 134. An exemplary method for performing the flushing action for dispensing is described below. Figure 13 describe.

[0153] At operation 266, when the target sample volume is not less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs over-extraction of the sample from the sample reservoir 130. For example, the sample pipetting system 104 aspirates a sample volume from the sample reservoir 130 that is greater than the target sample volume. In some embodiments, this over-extraction volume of the sample is predetermined regardless of the target sample volume. In other embodiments, the over-extraction volume of the sample varies according to the target sample volume.

[0154] At operation 268, if dilution is required before distribution, method 250 proceeds to operation 270. If dilution is not required, method 250 jumps to operation 272.

[0155] At operation 270, the sample pipetting system 104 moves the sample pipetting module 150 to the dilution reservoir 132 containing the diluent and dilutes the sample within the dilution reservoir 132. An exemplary dilution method from sample tube 122 is described below. Figure 30 describe.

[0156] At operation 272, the sample pipetting system 104 moves the sample pipetting module 150 to the reaction reservoir 134, similar to... Figure 5 Operation 222.

[0157] At operation 274, when the target sample volume is not less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs a two-step dispensing action to dispense the sample into the reaction reservoir 134. The two-step dispensing action is used to reduce the risk associated with misalignment or other causes. In the first step, the dispensing tip is lowered to a predetermined height (e.g., 2 mm) above the surface liquid level and dispenses the sample at the sample location without liquid pressure from the contained sample. The predetermined height is determined such that the dispensing tip does not contact the surface liquid level after dispensing. In the second step, the dispensing tip is further lowered to a predetermined position, set based on the total volume, to barely contact the surface liquid level (“touch”) in order to collect the sample retained in the tip. An exemplary method for performing the two-step dispensing action is described below. Figure 20 describe.

[0158] See now Figures 7 to 12 This is an exemplary method for performing an over-extraction and pushback process of aspirating a sample from sample reservoir 130 when the target sample volume is less than a threshold. In the illustrated example, the threshold is approximately 25 μL. However, other thresholds are possible in other embodiments.

[0159] Figure 7This is a flowchart illustrating an exemplary method 300 that performs the extraction and pushback processes. In some examples, method 300 is designed to implement... Figure 6 Operation 256. Method 300 is also referred to. Figures 8 to 12 describe. Figure 8 This is a schematic diagram of the dispensing tip 120 relative to the sample reservoir 130. Figure 9 This is an example table for assigning suction head heights. Figure 10 This is an example table for over-extraction and back-extraction of the target sample volume. Figure 11 The execution was shown Figure 7 An exemplary sequence of method 300. Figure 12 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 300.

[0160] Although method 300 is primarily described herein as being performed by sample pipetting system 104 controlled by precision dispensing control system 106, it should be noted that method 300 may be performed, at least in part, by one or more other systems or devices in material dispensing system 102, with or without cooperation with sample pipetting system 104 and precision dispensing control system 106. Although method 300 is described as including Figure 7 The operations shown herein, but in other embodiments, method 300 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0161] See Figure 7 Method 300 may begin with operation 302, in which sample pipetting system 104 is used based on pipette tip aspiration height gauge 310 ( Figure 9 This lowers the dispensing tip 120 to the suction height (H1) within the sample reservoir 130. (As...) Figure 8 As shown, the dispensing tip 120 is lowered toward the bottom of the sample reservoir 130, which is supported by the reagent holder 312. For example, the sample pipetting module 150 lowers the mandrel 162 from the starting position 190 to the aspiration position 192. The aspiration height (H1) is defined by the distance between the bottom 194 of the sample reservoir 130 and the aspiration position 192.

[0162] like Figure 11 As shown, at operation 302, the distal end 320 of the dispensing tip 120 moves from the starting position 190 to the aspiration position 192. At the aspiration position 192, the dispensing tip 120 is immersed at a depth (D1) from the sample meniscus or surface liquid level 322. The depth (D1) can vary based on various factors. In some examples, the depth (D1) is approximately 2 mm.

[0163] Still refer to Figure 7At operation 304, the sample pipetting system 104 is used based on the aspiration volume table 330 ( Figure 10 A first volume (V1) of sample is aspirated from sample reservoir 130. Sample pipetting system 104 is used at this operation to over-absorb the sample, such that the first volume (V1) of the sample is greater than the target sample volume. Also... Figure 11 As shown, the syringe assembly 164 moves the plunger backward to draw a first volume of sample into the dispensing tip 120.

[0164] At operation 306, the sample pipetting system 104 is used to push a second volume (V2) of sample from the dispensing tip 120 back into the sample reservoir 130 based on the aspiration volume table 330. After dispensing the second volume (V2), the dispensing tip 120 will hold the target sample volume. Also as... Figure 11 As shown, syringe assembly 164 pushes the plunger to dispense a second volume of sample into sample reservoir 130.

[0165] At operation 308, the sample pipetting system 104 is used to lift the dispensing tip 120 away from the sample reservoir 130 and end the over-extraction and retraction operation. For example... Figure 11 As shown, for example, the dispensing nozzle 120 moves back to the starting position 190.

[0166] like Figure 9 As shown, in some embodiments, a suction height table 310 is provided to determine the suction height (H1). Table 310 determines the suction height (H1) 316 for each volume 314 of sample to be aspirated from sample reservoir 130. In some embodiments, table 310 is pre-generated and stored in instrument 100. In this example, the sample volume contained in sample reservoir 130 is approximately 165 μL, and the height of the sample from the bottom 194 of sample reservoir 130 (i.e., Figure 11 The height of the surface liquid level 322 is approximately 6.4 mm.

[0167] The aspiration height (H1) 316 may alternatively be represented by a downward pulse (X) 318. The downward pulse (X) is the number of pulses used to operate the sample pipetting module 150 to reduce the dispensing tip 120. The downward pulse (X) defines the distance traveled by the distal end 320 of the dispensing tip 120 between the starting position 190 and the aspiration position 192.

[0168] although Figure 9 Table 310 shown illustrates four items for different suction volumes 314, but the number of items is unlimited, and Table 310 may be limited to... Figure 9 Any number of items other than the four items shown.

[0169] See Figure 10The aspiration volume table 330 determines, based on each target sample volume 332, a first volume (V1) 334 (operation 304) to be aspirated first from the sample reservoir 130 and a second volume V2 (336) to be pushed from the dispensing tip 120 into the sample reservoir 130 (operation 306). For example, to aspirate 10.0 μL into the dispensing tip 120, the dispensing tip 120 first needs to aspirate 15.0 μL of sample from the sample reservoir 130, and then push 5.0 μL of sample back from the dispensing tip 120 into the sample reservoir 130. Conversely, to aspirate 1.0 μL, the dispensing tip 120 first aspirates 3.0 μL from the sample reservoir, and then pushes 3.5 μL back into the sample reservoir 130. Although Figure 10 Table 330 shown illustrates five items for different target sample volumes 332, but the number of items is unlimited, and Table 330 may be limited except for... Figure 10 Any number of items other than the five items shown.

[0170] like Figure 12 Further illustrated are curves 342 showing the change in the dispensing tip position over time and 344 showing the change in syringe movement over time during the execution of method 300. From 0.1 seconds to 0.2 seconds, the dispensing tip 120 is lowered (operation 302), and from 0.2 seconds to 0.4 seconds, a first volume (V1) is drawn into the dispensing tip 120 (operation 304). From 0.6 seconds to 0.7 seconds, a second volume (V2) is pushed back into the sample reservoir 130 (operation 306), and from 0.8 seconds to 0.9 seconds, the dispensing tip 120 is raised back to the starting position (operation 308). As shown, interruption or waiting periods, such as a first interruption period 346 and a second interruption period 348, can be arranged between at least one of adjacent operations 302, 304, 306, and 308. For example, after aspirating a sample at operation 304, the system pauses for a sufficient period of time (first interruption cycle 346) to complete the actual liquid action (operation 306) before pushing back the additional volume.

[0171] Accuracy can be controlled by a combination of aspiration and retraction volumes, which can be selected to achieve the desired performance. In some embodiments, the dispensing tip 120 can be lowered as the liquid surface position changes to reduce contact between the dispensing tip 120 and the sample exterior.

[0172] See Figures 13 to 16 This describes an exemplary method for dispensing a sample by performing a rinsing action when the target sample volume is less than a threshold. In the illustrated example, the threshold is approximately 25 μL. However, other thresholds are possible in other embodiments.

[0173] Figure 13 Is it to execute as Figure 6The flowchart illustrates an exemplary method 350 of the rinsing action shown in operation 264. Method 350 is also referred to... Figures 14 to 16 describe. Figure 14 This is an example table for the assigned suction head height. Figure 15 The execution was shown Figure 13 The exemplary sequence of method 350. Figure 16 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 350.

[0174] Method 350 is primarily described herein as being performed by the sample pipetting system 104 controlled by the precision dispensing control system 106; however, it should be noted that method 350 may be performed, at least in part, by one or more other systems or devices in the material dispensing system 102, with or without cooperation with the sample pipetting system 104 and the precision dispensing control system 106. Although method 350 is described as including Figure 13 The operations shown herein, but in other embodiments, method 300 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0175] See Figure 13 Method 350 may begin with operation 352, in which the sample pipetting system 104 is used based on, for example Figure 14 The pipette tip dispensing height table 380 shown indicates that the dispensing pipette tip 120 is lowered to the dispensing height (H2) within the reaction reservoir 134. For example... Figure 15 As shown, the dispensing nozzle 120 is lowered toward the bottom 198 of the reaction reservoir 134. The reaction reservoir 134 is supported by a bracket, similar to... Figure 8 The sample reservoir 130 is used. For example, the sample pipetting module 150 lowers the mandrel 162 from the starting position 190 to the dispensing position 196. The dispensing height (H2) is defined by the distance between the bottom 198 of the reaction reservoir 134 and the dispensing position 196. In some embodiments, the dispensing height (H2) is determined in a tip dispensing height table 380. An example of Table 380 is shown below. Figure 14 describe.

[0176] At operation 354, the sample pipetting system 104 is used to dispense the sample into the reaction reservoir 134. For example, the sample is dispensed by the syringe assembly 164 (e.g., a pneumatic syringe pump) at a predetermined syringe speed according to the dispensing volume. In some examples, the sample contained in the dispensing tip 120 may be completely dispensed into the reaction reservoir 134 at this operation. In other examples, a portion of the sample contained in the dispensing tip 120 may be dispensed into the reaction reservoir 134 at this operation.

[0177] At operation 356, the sample pipetting system 104 is used to aspirate a predetermined volume of sample from the reaction reservoir 134.

[0178] At operation 358, the sample pipetting system 104 is optionally used to wait for a predetermined time period (e.g., a first time period). During this operation, the dispensing tip 120 remains stationary and no aspiration or dispensing is performed.

[0179] At operation 360, the sample pipetting system 104 pushes a predetermined volume of sample from the dispensing tip 120 back into the reaction reservoir 134. In some embodiments, the entire volume of sample drawn into the dispensing tip at operation 356 is pushed back into the reaction reservoir 134 at this operation. In other embodiments, a portion of the sample drawn into the dispensing tip 120 at operation 356 is pushed back into the reaction reservoir 134.

[0180] At operation 362, the sample pipetting system 104 is optionally used to wait for a predetermined time period (e.g., a second time period). During this operation, the dispensing tip 120 remains stationary and no aspiration or dispensing is performed.

[0181] In some implementations, operations 356, 358, 360, and 362 are repeated a predetermined number of times. At operation 364, if these operations are repeated a predetermined number of times ("Yes" at this operation), method 350 proceeds to operation 366. Otherwise ("No" at this operation), method 350 returns to operation 356 and repeats operation 356 and subsequent operations.

[0182] At operation 366, the sample pipetting system 104 is used to elevate the dispensing tip 120 away from the reaction reservoir 134 and terminate the dispensing action (which may include a rinsing action). Figure 15 As shown, for example, the dispensing nozzle 120 moves back to the starting position 190.

[0183] Therefore, flushing actions (e.g., operations 356, 358, 360, and 362) are performed to accurately dispense small amounts of sample. Flushing actions can be performed with various parameters. In the illustrated example, aspiration and dispensing are repeated three times with aspiration and dispensing volumes of 50 μL, respectively. The waiting time between aspiration and dispensing is approximately 100 milliseconds. While flushing, the dispensing tip 120 can be adjusted to change its height (its vertical position) as the surface liquid level changes.

[0184] In some implementations, after operation 362, the sample pipetting system 104 may draw air into the dispensing tip 120 to reduce splashing caused, for example, by vibration of the dispensing tip 120 as it moves to different positions.

[0185] See Figure 14The pipette tip dispensing height table 380 determines the dispensing height (H2) 384 for each amount 382 of sample to be dispensed into the reaction reservoir 134. In some embodiments, the table 380 is pre-generated and stored in the instrument 100. In this example, the volume of liquid material (such as reagents and / or buffer solutions) already filled in the reaction reservoir 134 is approximately 65 μL, and the height of the liquid material from the bottom 198 of the reaction reservoir 134 (i.e., the height of the liquid meniscus) is approximately 2.8 mm.

[0186] Similar to the tip aspiration height gauge 310, the dispensing height (H2) 384 may alternatively be represented by a downward pulse (X) 386. The downward pulse (X) 386 is the number of pulses used to operate the sample pipetting module 150 to reduce the dispensing tip 120. The downward pulse (X) 386 defines the distance traveled by the distal end 320 of the dispensing tip 120 between the starting position 190 and the dispensing position 196.

[0187] although Figure 14 Table 380 shown illustrates four items for different allocation amounts 382, ​​but the number of items is unlimited, and Table 380 may be limited except for... Figure 14 Any number of items other than the four items shown.

[0188] like Figure 15 As shown, at operation 352, the distal end 320 of the dispensing tip 120 moves from the starting position 190 to the dispensing position 196. At the dispensing position 196, the dispensing tip 120 is immersed at a depth (D2) from the sample meniscus 392. The depth (D2) can vary based on various factors. The depth (D2) is determined such that the rinsing action described in method 350 can be performed at operations 352 and 360 without evacuating or pushing back air. In some examples, the depth (D2) is approximately 2 mm. In some embodiments, the depth (D2) (and the dispensing height (H2)) is determined such that the distal end 320 of the dispensing tip 120 barely contacts (e.g., touches) the surface liquid level 392 in the reaction reservoir 134.

[0189] like Figure 16Further illustrated are curves 396 showing the change in dispensing tip position over time and 398 showing the change in syringe movement over time during execution of method 350. From 1.2 seconds to 1.3 seconds, the dispensing tip 120 is lowered (operation 352), and from 1.3 seconds to 1.5 seconds, the sample is dispensed into the reaction reservoir (operation 354). Then, from 1.6 seconds to 1.7 seconds, a rinsing action 363, including operations 356, 358, 360, and 362, is performed. Each of operations 356, 358, 360, and 362 lasts for 0.05 seconds. In this example, the rinsing action 363 is repeated three times up to 2.2 seconds. Then, from 2.2 seconds to 2.3 seconds, the dispensing tip is raised back to the starting position. As shown, one or more interruption or waiting periods can be provided between at least one of the adjacent operations, such as an interruption period 368 between operation 354 and the first rinsing action 363.

[0190] See Figures 17 to 19 An exemplary method is described for performing an over-extraction process of aspirating a sample from sample reservoir 130 when the target sample volume is not less than a threshold. In the illustrated example, the threshold is approximately 25 μL. However, other thresholds are possible in other embodiments.

[0191] Figure 17 This is a flowchart of an exemplary method 400 that performs the extraction process. In some examples, method 400 is designed to implement... Figure 6 Operation 266. Method 400 also refers to this. Figures 18-19 describe. Figure 18 An exemplary sequence of execution method 400 is shown. Figure 19 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 400.

[0192] Method 400 is primarily described herein as being performed by sample pipetting system 104 controlled by precision dispensing control system 106; however, it should be noted that method 400 may be performed, at least in part, by one or more other systems or devices in material dispensing system 102, with or without cooperation with sample pipetting system 104 and precision dispensing control system 106. Although method 400 is described as including Figure 17 The operations shown herein, but in other embodiments, method 400 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0193] In some implementations, the execution of method 400 is similar to Figure 7 Method 300 differs from it in that the pushback operation 306 is used. For example, operations 402, 404, and 406 in method 400 are similar to those described above and are performed in accordance with the method described above. Figure 7Operations 302, 304, and 308 in method 300 are shown. Specifically, at operation 402, the sample pipetting system 104 is used for... Figure 9 The suction height gauge 310 causes the dispensing pipette tip 120 to descend to the suction height (H1) within the sample reservoir 130. Since operation 402 is similar to... Figure 7 For the sake of brevity, the detailed description of operation 402 is omitted from operation 302.

[0194] At operation 404, the sample pipetting system 104 is used to aspirate a first volume (V1) of sample from the sample reservoir 130. The sample pipetting system 104 is used at this operation to over-absorb the sample, such that the first volume (V1) of the sample is greater than the target sample volume. Also... Figure 18 As shown, the syringe assembly 164 moves the plunger backward to draw a first volume of sample into the dispensing tip 120.

[0195] In some implementations, the dispensing tip 120 is lowered as the surface liquid level decreases during aspiration, thereby reducing the contact of the dispensing tip 120 with the outside of the sample.

[0196] At operation 406, the sample pipetting system 104 is used to elevate the dispensing tip 120 away from the sample reservoir 130 and terminate the over-absorption operation. In some examples, the dispensing tip 120 is moved back to the starting position (e.g., as...). Figure 15 The starting position is shown as 190.

[0197] like Figure 19 Further illustrated are curves 412 showing the change in the dispensing tip position over time and 414 showing the change in syringe movement over time during execution of method 400. From 0.1 seconds to 0.2 seconds, the dispensing tip 120 is lowered (operation 402), and from 0.2 seconds to 0.6 seconds, a first volume (V1) is drawn into the dispensing tip (operation 404). Then, from 0.8 seconds to 0.9 seconds, the dispensing tip 120 is raised back to the starting position (operation 406). As shown, an interruption or wait period 408 can be arranged between operations 404 and 406.

[0198] See Figures 20 to 22 This is an exemplary method for performing a two-step dispensing action to dispense a sample into reaction reservoir 134 when the target sample volume is not less than a threshold. In the illustrated example, the threshold is approximately 25 μL. However, other thresholds are possible in other embodiments.

[0199] Figure 20 This is a flowchart of an exemplary method 430 for performing a two-step allocation action. In some examples, method 430 is designed to implement... Figure 6 Operation 274. Method 430 is also referred to. Figures 21 to 22 describe. Figure 21 An exemplary sequence of execution method 430 is shown. Figure 22 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 430.

[0200] Method 430 is primarily described herein as being performed by the sample pipetting system 104 controlled by the precision dispensing control system 106; however, it should be noted that method 430 may be performed, at least in part, by one or more other systems or devices in the material dispensing system 102, with or without cooperation with the sample pipetting system 104 and the precision dispensing control system 106. Although method 430 is described as including Figure 20 The operations shown herein, but in other embodiments, method 430 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0201] Method 430 may begin with operation 432, in which the sample pipetting system 104 is used to lower the dispensing tip 120 to a first height (H3) within the reaction reservoir 134. Figure 22 As shown, a first height (H3) is determined such that the distal end 320 of the dispensing tip 120 is above the surface liquid level 448 of the substance in the reaction reservoir 134. The first height (H3) is defined by the distance between the bottom 446 of the reaction reservoir 134 and the distal end 320 of the dispensing tip 120. In some embodiments, the first height (H3) is selected such that the distal end 320 of the dispensing tip 120 remains above the increased surface liquid level 448 until the liquid substance is completely dispensed from the dispensing tip 120 into the reaction reservoir 134.

[0202] At operation 434, at the first height (H3), the sample pipetting system 104 begins to dispense the sample into the reaction reservoir 134. In some examples, the sample contained in the dispensing tip 120 may be completely dispensed into the reaction reservoir 134 at this operation. In other examples, a portion of the sample contained in the dispensing tip 120 may be dispensed into the reaction reservoir 134 at this operation.

[0203] At operation 436, the sample pipetting system 104 is used to further lower the dispensing tip 120 to a second height (H4), defined as the distance between the bottom 446 of the reaction reservoir 134 and the distal end 320 of the dispensing tip 120. In some embodiments, the second height (H4) is determined such that the distal end 320 of the dispensing tip 120 barely contacts (e.g., touches) the surface liquid level 448 in the reaction reservoir 134. In other embodiments, the second height (H4) is determined such that the distal end 320 of the dispensing tip 120 is submerged at a predetermined depth (D4) below the surface liquid level 448. This can be based on, for example... Figure 14The suction head assignment height table 380 shown determines the second height (H4). In other embodiments, the second height (H4) may be determined in a different manner.

[0204] In the illustrated embodiment, the sample pipetting system 104 completes dispensing at the first height (H3) (operation 434) before moving to the second height (H4). In other embodiments, the sample may be partially dispensed at the first height (H3), and the remainder of the sample may be dispensed at the second height (H4). In other embodiments, the sample may be at least partially dispensed as the dispensing tip 120 moves from the first height (H3) to the second height (H4).

[0205] Operation 436 was also designated as Figure 21 Step or segment d in (also in Figure 37 (As shown in the diagram). In this step, in some embodiments, droplets may be present on the dispensing tip 120. However, the surface tension in the reaction reservoir 134 can remove the droplets from the dispensing tip 120.

[0206] At operation 438, the sample pipetting system 104 is used to lift the dispensing tip 120 away from the reaction reservoir 134 and end the dispensing. For example... Figure 22 As shown, for example, the dispensing nozzle 120 moves back to the starting position 190.

[0207] At operation 440, the sample pipetting system 104 is used to draw air into the dispensing tip 120, which is in the initial position 190. This operation reduces splashing caused by, for example, vibration of the dispensing tip 120 as it moves to different positions, such as tip waste position 178.

[0208] like Figure 21 Further illustrated are curves 452 showing the change in the dispensing tip position over time and 454 showing the change in syringe movement over time during execution of method 430. From 1.2 seconds to 1.3 seconds, the dispensing tip 120 is lowered to a first height (H3) (operation 432), and from 1.3 seconds to 1.7 seconds, the sample is dispensed into the reaction reservoir (operation 434), while the dispensing tip 120 remains at the first height (H3). Then, from 1.7 seconds to 1.8 seconds, the dispensing tip 120 further descends to a second height (H4) (operation 436). Afterward, from 2.2 seconds to 2.3 seconds, the dispensing tip 120 rises back to the starting position. As shown, the dispensing tip 120 may remain at the second height (H4) for approximately 0.4 seconds (between 1.8 seconds and 2.2 seconds) between operations 436 and 438 (e.g., interruption cycle 456). Figure 21 As shown, curve 452 can be segmented into steps a to g, which correspond to Figure 37 Steps a to g in the above.

[0209] See now Figure 23 An exemplary method 500 is described, in which a sample is drawn from a sample tube 122 and dispensed into a sample reservoir 130. In some examples, method 500 is designed to implement... Figure 5 Operations 210, 212, 214, 222, and 224. While method 500 is primarily described herein as being performed by sample pipetting system 104 controlled by precision dispensing control system 106, it should be noted that method 500 may be performed, at least in part, by one or more other systems or devices in material dispensing system 102, with or without cooperation with sample pipetting system 104 and precision dispensing control system 106. Although method 500 is described as including... Figure 23 The operations shown herein, but in other embodiments, method 500 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0210] Generally speaking, the method of drawing samples from a sample tube and dispensing them into a sample reservoir is similar to 500. Figure 6 The method 250 shown, which involves drawing a sample from a sample reservoir and dispensing it into a reaction reservoir, differs in that the operation for detecting the surface liquid level of the sample contained in the sample tube 122 (such as...) Figure 23 (referring to operations 506 or 518 in method 250). Therefore, the description of the operations in method 250 is hereby incorporated by reference into the operations in method 500 that are similar to those in method 250. The following description of method 500 will be limited primarily to the differences from method 250.

[0211] For example, at operation 502, the sample pipetting system 104 moves the sample pipetting module 150 to the sample tube 122 containing the sample, similar to... Figure 5 Operation 210 in the middle. See reference... Figure 6 As described in operation 252, when a sample is drawn from sample tube 122, the volume of the sample contained in sample tube 122 is not necessarily known, and it may be necessary to measure or estimate the surface liquid level of the sample in sample tube 122.

[0212] At operation 504, if the target sample volume is less than a threshold ("Yes" in this operation), method 500 proceeds to operation 506. Otherwise ("No" in this operation), method 500 continues to operation 518. Therefore, in method 500, the sample pipetting system 104, which can be controlled by the precision dispensing control system 106, operates different processes for aspiration and dispensing based on the target sample volume to be prepared. The threshold can be determined based on various factors. Exemplary factors include the configuration and properties of the dispensing tip 120 (e.g., size, capacity, material, etc.), the arrangement of the dispensing tip 120 relative to the container used for aspiration or dispensing, and the type of sample or other substance. In one example, the threshold is approximately 25 μL. Other thresholds are possible in other examples.

[0213] In some embodiments, determining operation 504 can be performed automatically within instrument 100 as part of the sample preparation process. For example, instrument 100 is configured to receive user input of the target sample volume and determine the operation to be performed at operation 504. In other embodiments, instrument 100 is configured to allow a user to manually select the operation to be performed via a user interface associated with instrument 100.

[0214] At operation 506, the sample pipetting system 104 is used to detect the surface liquid level of the sample in sample tube 122. In some examples, the volume of sample contained in sample tube 122 is unknown when aspirating from it. Therefore, the surface liquid level of the sample in sample tube 122 must be measured or estimated to determine how deep the dispensing tip 120 needs to descend to aspirate the sample from sample tube 122. An example of this operation is shown in [reference]. Figure 24 To describe in more detail.

[0215] At operation 508, when the target sample volume is less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs an over-pumping and back-pulling process to aspirate the sample from the sample tube 122. Operation 508 is similar to... Figure 6 The operation 256 described in [the document] is performed. An exemplary method for performing the extraction and pushback process is described in [reference]. Figure 24 describe.

[0216] At operation 510, if dilution is required before allocation, method 500 proceeds to operation 512. If dilution is not required, method 500 jumps to operation 514. Operation 510 is similar to... Figure 6 The operation 258 described herein shall be performed.

[0217] At operation 512, the sample pipetting system 104 moves the sample pipetting module 150 to the dilution reservoir 132 containing the diluent and dilutes the sample within the dilution reservoir 132. Operation 512 is similar to... Figure 6The operation 260 described herein shall be performed. An exemplary dilution method from sample tube 122 is described in reference [reference needed]. Figure 30 describe.

[0218] At operation 514, the sample pipetting system 104 moves the sample pipetting module 150 to the reaction reservoir 134, similar to... Figure 5 Operation 222. Operation 514 is similar. Figure 6 The operation 262 described herein shall be performed.

[0219] At operation 516, when the target sample volume is less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs a flushing action to dispense the sample into the reaction reservoir 134. Operation 516 is similar to... Figure 6 The operation 264 described above is performed. An exemplary method for performing the assigned flushing action is described above. Figure 13 describe.

[0220] At operation 518, when the target sample volume is not less than a threshold (e.g., 25 μL), the sample pipetting system 104 is used to detect the surface liquid level of the sample in sample tube 122, similar to operation 506. An example of this operation is shown below. Figure 27 To describe in more detail.

[0221] At operation 520, when the target sample volume is not less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs over-extraction of the sample from the sample tube 122. Operation 520 is similar to... Figure 6 The operation 266 described herein is performed. For example, the sample pipetting system 104 aspirates a sample volume greater than the target sample volume from the sample tube 122. In some embodiments, this over-extraction volume of the sample is predetermined regardless of the target sample volume. In other embodiments, the over-extraction volume of the sample varies according to the target sample volume.

[0222] At operation 522, if dilution is required before allocation, method 500 proceeds to operation 524. If dilution is not required, method 500 jumps to operation 526. Operation 522 is similar to... Figure 6 The operation 268 described herein shall be performed.

[0223] At operation 524, the sample pipetting system 104 moves the sample pipetting module 150 to the dilution reservoir 132 containing the diluent and dilutes the sample within the dilution reservoir 132. Operation 524 is similar to that described above. Figure 6 The operation 270 shown is performed. An exemplary dilution method from sample tube 122 is described below. Figure 30 describe.

[0224] At operation 526, the sample pipetting system 104 moves the sample pipetting module 150 to the reaction reservoir 134, similar to... Figure 5 Operation 222. Operation 526 is similar. Figure 6 The operation 272 described herein shall be performed.

[0225] At operation 528, when the target sample volume is not less than a threshold (e.g., 25 μL), the sample pipetting system 104 performs a two-step dispensing action to dispense the sample into the reaction reservoir 134. Operation 528 is similar to that described above. Figure 6 Operation 274, as shown, is performed. An exemplary method for performing the two-step allocation action is described above. Figure 20 describe.

[0226] See now Figures 24 to 26 An exemplary method is described, which detects the surface liquid level of a sample in sample tube 122 and performs an over-extraction and pushback process of aspirating the sample from sample tube 122 when the target sample volume is less than a threshold. In the illustrated example, the threshold is approximately 25 μL. However, other thresholds are possible in other embodiments.

[0227] Figure 24 This is a flowchart illustrating an exemplary method 550 for detecting the surface level of a sample using a single submersible motion and performing a pump-and-pull-back process. In some examples, method 550 is designed to implement... Figure 23 Operations 506 and 508. Method 550 is also referred to. Figure 25 and 26 describe. Figure 25 The execution was shown Figure 24 The exemplary sequence of method 550. Figure 26 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 550.

[0228] Method 550 is primarily described herein as being performed by the sample pipetting system 104 controlled by the precision dispensing control system 106; however, it should be noted that method 550 may be performed, at least in part, by one or more other systems or devices in the material dispensing system 102, with or without cooperation with the sample pipetting system 104 and the precision dispensing control system 106. Although method 550 is described as including Figure 24 The operations shown herein, but in other embodiments, method 300 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0229] Method 550 may begin with operation 552, in which the sample pipetting system 104 is used to lower the dispensing tip 120 into the sample tube 122. Then, at operation 554, the sample pipetting system 104 is used to expel air from the dispensing tip 120. In some examples, air is expelled from the dispensing tip 120 as the dispensing tip 120 lowers into the sample tube 122. Figure 25 As shown, the dispensing tip 120 is lowered when it is above the surface liquid level 580 of the sample in the sample tube 122, and air can be blown out from the dispensing tip 120 as it descends.

[0230] At operation 556, the sample pipetting system 104 is used to monitor pressure changes at the dispensing tip 120. In some examples, the pressure change at the dispensing tip 120 is monitored as the dispensing tip 120 is lowered relative to the sample tube 122. For example, the sample pipetting system 104 includes a sensing device 581 configured to monitor pressure changes at the distal end 320 of the dispensing tip 120. Pressure changes at the distal end 320 of the dispensing tip 120 can indicate that the dispensing tip 120 is in contact with the liquid level 580 at the distal end 320. Therefore, the sensing device 581 is used to detect whether the sample in the sample tube 122 is in contact with the distal end of the dispensing tip 120. In addition, the sensing device 581 can transmit a signal to a control device (e.g., a precision dispensing control system 106) so that the control device uses the signal to stop lowering the dispensing tip 120. For example, the dispensing tip 120 moves downward into the sample tube 122 while air is blown out from the dispensing tip 120, and the sample pipetting system 104 stops moving the dispensing tip 120 downward when it contacts the surface liquid level 580 of the sample in the sample tube 122 and detects the pressure change caused by the contact surface liquid level.

[0231] At operation 558, the sample pipetting system 104 determines whether the pressure change is greater than a threshold. If the pressure change is greater than the threshold ("Yes" at this operation), method 550 moves to operation 560. Otherwise ("No" at this operation), method 550 returns to operation 552 and performs operation 552 and subsequent operations.

[0232] In other embodiments, the sample pipetting system 104 may simply determine whether any pressure change is detected at operation 558. If any pressure change is detected, method 550 continues at operation 560. Otherwise, method 550 returns to operation 552.

[0233] At operation 560, the sample pipetting system 104 obtains the travel distance (D5) of the dispensing tip 120. At operation 562, the sample pipetting system 104 then calculates the height (H5) of the surface liquid level 580 based on the travel distance (D5).

[0234] At operation 564, the sample pipetting system 104 is used to further lower the dispensing tip 120 to the aspiration height (H6) within the sample tube 122. In some embodiments, based on, for example... Figure 9 The suction height (H6) is determined using the suction head suction height table 310 described herein. In other embodiments, the suction height (H6) is determined in a different manner. For example... Figure 25 As shown, the distal end 320 of the dispensing tip 120 moves from the starting position 190 to the suction position 582. At the suction position 582, the dispensing tip 120 is immersed at a depth (D6) from the surface liquid level 580. The depth (D6) can vary based on various factors. In some examples, the depth (D6) is approximately 2 mm.

[0235] At operation 566, the sample pipetting system 104 is used to equalize the pressure within the dispensing tip 120 with the atmospheric environment before sample aspiration. In some embodiments, the sample pipetting system 104 opens valve 168 (e.g., a three-way valve) to establish fluid communication between the dispensing tip 120 and the atmospheric environment, while simultaneously closing the fluid communication between the dispensing tip 120 and the syringe assembly 164. By venting the dispensing tip 120 to the atmospheric environment, the positive pressure within the dispensing tip 120 is released to eliminate bias pressure. When the pressure is equalized, valve 168 closes. As described herein, operation 566 can be omitted when aspiration volumes are large, and the sample pipetting system 104 can accurately aspirate samples without this operation.

[0236] At operation 568, the sample pipetting system 104 is used to aspirate a first volume (V1) of sample from the sample tube 122. In some embodiments, based on, for example... Figure 10 The aspiration volume table 330 described herein determines the first volume (V1). The sample pipetting system 104 is used to over-absorb the sample at this operation point such that the first volume (V1) of the sample is greater than the target sample volume. Also as... Figure 25 As shown, the syringe assembly 164 moves the plunger backward to draw a first volume of sample into the dispensing tip 120.

[0237] At operation 570, the sample pipetting system 104 is used to push a second volume (V2) of sample from the dispensing tip 120 back into the sample tube 122. In some embodiments, the second volume (V2) is determined based on the aspiration volume table 330. After dispensing the second volume (V2), the dispensing tip 120 will hold the target sample volume. Also as... Figure 25 As shown, syringe assembly 164 pushes the plunger to dispense a second volume of sample into the sample reservoir.

[0238] In some implementations, as the surface liquid level 580 changes due to aspiration and pushback operations, the sample pipetting system 104 can move the dispensing tip 120 up or down to reduce contact between the dispensing tip 120 (e.g., its distal end 320) and the outside of the sample.

[0239] In some implementations, after waiting for a predetermined period of time to complete the actual liquid action, an additional sample is pushed back into sample tube 122 to eliminate the negative pressure generated in operation 568 and / or operation 570.

[0240] At operation 572, the sample pipetting system 104 is used to lift the dispensing tip 120 away from the sample tube 122 and end the over-extraction and retraction operation. For example... Figure 25 As shown, for example, the dispensing nozzle 120 moves above the surface liquid level 580.

[0241] At operation 574, the sample pipetting system 104 is used to draw air into the dispensing tip 120 above the surface liquid level. This operation reduces splashing caused by, for example, vibration of the dispensing tip 120 as it moves to different locations, such as sample dispensing position 176.

[0242] like Figure 26 Further illustrated are curves 592 showing the change in the position of the dispensing pipette tip over time and 594 showing the change in syringe movement over time during execution of method 550. From 0.1 seconds to 0.7 seconds, the dispensing pipette tip 120 is lowered (operations 552 and 564), and air is expelled from the dispensing pipette tip 120 (operation 554). As described above, operations 552 and 565 are performed continuously, such that as air is expelled from the dispensing pipette tip 120, the dispensing pipette tip 120 is lowered to a first height (H6). From 0.75 seconds to 0.95 seconds, a first volume (V1) is drawn into the dispensing pipette tip (operation 568). From 1.0 seconds to 1.05 seconds, a second volume (V2) is pushed back into the sample tube 122 (operation 570), and from 1.1 seconds to 1.2 seconds, the dispensing pipette tip 120 is raised again (operation 572). As shown in the figure, interrupt or wait cycles, such as a first interrupt cycle 596, a second interrupt cycle 597, and a third interrupt cycle 598, can be arranged between at least one of adjacent operations 552, 554, 556, 568, 570, and 572.

[0243] As referred above Figure 25 As described above, the process of opening valve 168 to the atmospheric environment is related to level detection. This level detection is particularly useful when aspirating from sample tube 122, as the content of fluid substance 112 may be unknown. This content can be calculated in sample reservoir 130, so a level detection process may not usually be necessary.

[0244] exist Figure 25At step A, valve 168 fluidly connects the interior of the dispensing tip 120 to the syringe assembly 164. The syringe assembly 164 pumps air through valve 168 and into the interior of the dispensing tip 120. Vertical movement of the dispensing tip 120 toward the fluid substance 112 begins at step A and continues into step B while valve 168 is in the same position. At step C, the surface level 580 of the fluid substance 112 is detected (e.g., by monitoring the air pressure inside the dispensing tip 120 and the syringe assembly 164). In some embodiments, the maximum time taken for steps ABC is 1.0 second.

[0245] Between steps C and D, valve 168 connects the internal fluid of dispensing tip 120 to the atmospheric environment. Between steps C and D, the distal end 320 of dispensing tip 120 moves below the surface level 580 of the fluid substance 112. However, as the opening at the distal end 320 of dispensing tip 120 is sufficiently small and the surface tension of fluid substance 112 is sufficiently high, fluid substance 112 does not enter the interior of dispensing tip 120. In some embodiments, the time taken between steps C and D is 50 milliseconds.

[0246] In some implementations, the time between the start of step D and the start of step E is 0.6 seconds. Before step E begins, valve 168 fluidly connects the interior of the dispensing tip 120 to the syringe assembly 164 and closes the connection to the atmospheric environment.

[0247] In step E, syringe assembly 164 aspirates a portion of fluid substance 112 into the interior of dispensing tip 120. In some embodiments, the time between the start and end of step E is 0.6 seconds. Valve 168 continues to fluidly connect the interior of dispensing tip 120 to syringe assembly 164.

[0248] In some implementations, the time between the end of step E and the start of step F is 350 milliseconds. Valve 168 continues to fluidly connect the interior of the dispensing tip 120 to the syringe assembly 164.

[0249] In step F, syringe assembly 164 pushes a portion of fluid substance 112 back from the interior of dispensing tip 120 into sample tube 122. In some embodiments, the time between the start and end of step F is 50 milliseconds. Valve 168 continues to fluidly connect the interior of dispensing tip 120 to syringe assembly 164.

[0250] The vertical movement of the dispensing tip 120 away from the fluid substance 112 occurs between steps F and G. In some embodiments, the time between the end of step F and step G is 0.6 seconds. Valve 168 continues to fluidly connect the interior of the dispensing tip 120 to the syringe assembly 164.

[0251] See now Figures 27 to 29 This is an exemplary method for detecting the surface liquid level of the sample in sample tube 122 and performing an over-extraction process of aspirating the sample from sample tube 122 when the target sample volume is not less than a threshold. In the illustrated example, the threshold is approximately 25 μL. However, other thresholds are possible in other embodiments.

[0252] Figure 27 This is a flowchart illustrating an exemplary method 600 for detecting the surface liquid level of a sample and performing a pump-and-pull-back process. In some examples, method 550 is designed to implement... Figure 23 Operations 518 and 520. Method 600 is also referred to. Figure 28 and 29 describe. Figure 28 The execution was shown Figure 27 An exemplary sequence of method 600. Figure 29 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 600.

[0253] Method 600 is primarily described herein as being performed by a sample pipetting system 104 controlled by a precision dispensing control system 106. However, it should be noted that method 600 may be performed, at least in part, by one or more other systems or devices within the material dispensing system 102, with or without cooperation with the sample pipetting system 104 and the precision dispensing control system 106. Although method 600 is described as including… Figure 27 The operations shown herein, but in other embodiments, method 600 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0254] In the illustrated example, method 600 includes operations 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, and 622. These operations are performed in a manner similar to operations 552, 554, 556, 558, 560, 562, 564, 566, 568, 572, and 574, respectively. Therefore, for the sake of brevity, descriptions of operations 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, and 622 are omitted. Therefore, method 600 does not include a push-back action after aspirating a first volume of sample from sample tube 122, but the remaining operations are the same as or similar to those in method 550.

[0255] like Figure 29Further illustrated are curves 624 showing the change in the position of the dispensing tip over time and 626 showing the change in the syringe movement over time during the execution of method 600. From 0.1 seconds to 0.7 seconds, the dispensing tip 120 is lowered (operations 602 and 614), and air is expelled from the dispensing tip 120 (operation 604). As described above, operations 602 and 614 are executed consecutively, such that as air is expelled from the dispensing tip 120, the dispensing tip 120 is lowered to a first height (H6). From 0.75 seconds to 1.05 seconds, a first volume (V1) is drawn into the dispensing tip (operation 618). Then, from 1.1 seconds to 1.2 seconds, the dispensing tip 120 is raised again (operation 620). As shown, interruption or waiting cycles, such as a first interruption cycle 628 and a second interruption cycle 630, can be arranged between at least one of adjacent operations 602, 604, 614, 618, and 620.

[0256] See now Figures 30 to 33 This describes an exemplary method for diluting a sample. Specifically, Figure 30 This is a flowchart illustrating an exemplary method 650 for performing the dilution process. In some examples, method 650 is designed to implement... Figure 5 Operation 220 Figure 6 Operations 260 and 270, and Figure 23 Operations 512 and 514 are referenced in the text. Method 650 is also referenced. Figures 31 to 33 describe. Figure 31 This is an example table for the extraction and pushback volumes for dilution. Figure 32 The execution was shown Figure 30 The exemplary sequence of method 650. Figure 33 The changes in the position of the dispensing tip and the alteration of the syringe motion over time are shown during the execution of method 650.

[0257] Method 650 is primarily described herein as being performed by sample pipetting system 104 controlled by precision dispensing control system 106; however, it should be noted that method 650 may be performed, at least in part, by one or more other systems or devices in material dispensing system 102, with or without cooperation with sample pipetting system 104 and precision dispensing control system 106. Although method 650 is described as including Figure 30 The operations shown herein, but in other embodiments, method 300 may also include only some of these operations and / or additional operations associated with the operations described herein.

[0258] See Figure 30 Method 650 may begin with operation 652, in which the sample pipetting system 104 is used to lower the dispensing tip 120 to a predetermined height (H7). Figure 32The height (H7) is defined by the distance between the bottom 682 of the dilution reservoir 132 and the distal end 320 of the dispensing tip 120. In some embodiments, the height (H7) is determined such that the distal end 320 of the dispensing tip 120 barely contacts (e.g., touches) the surface liquid level 686 in the dilution reservoir 132. In other embodiments, the height (H7) is determined such that the distal end 320 of the dispensing tip 120 is submerged at a predetermined depth (D7) below the surface liquid level 686.

[0259] like Figure 32 and 33 As shown, at operation 652, the distal end 320 of the dispensing tip 120 moves from the starting position 190 to the aspiration position 684. At the aspiration position 684, the dispensing tip 120 is immersed at a predetermined depth (D7) from the sample meniscus or surface liquid level 686. The depth (D7) can vary based on various factors. In some examples, the depth (D7) is approximately 2 mm.

[0260] At operation 654, the sample pipetting system 104 is used to dispense the sample into the dilution reservoir 132. In some embodiments, the entire sample contained in the dispensing tip 120 is dispensed into the dilution reservoir 132. In other embodiments, only a portion of the sample contained in the dispensing tip 120 is dispensed into the dilution reservoir 132. The sample can be dispensed by operating the syringe assembly 164 based on a predetermined syringe velocity distribution. Such a predetermined syringe velocity distribution can be determined based on the sample and / or diluent volume.

[0261] At operation 656, the sample pipetting system 104 is used to draw a predetermined volume of substance (e.g., a mixture of sample and diluent) from the dilution reservoir 132. In some embodiments, based on Figure 31 The dilution table 672 shown is used to determine the predetermined volume of the substance to be extracted. In other embodiments, the predetermined volume may be determined in different ways.

[0262] At operation 658, the sample pipetting system 104 may be paused for a predetermined period of time (e.g., a first interruption time). In other embodiments, operation 658 may be omitted.

[0263] At operation 660, the sample pipetting system 104 is used to push a predetermined volume of substance from the dispensing tip 120 back into the dilution reservoir 132. In some embodiments, the predetermined volume of substance to be dispensed is determined based on dilution table 672. In other embodiments, the predetermined volume may be determined in a different manner.

[0264] At operation 662, the sample pipetting system 104 may be paused for a predetermined period of time (e.g., a second interruption time). In other embodiments, operation 662 may be omitted.

[0265] At operation 664, if the suction (operation 656) and dispensing (operation 658) are repeated a predetermined number of times ("Yes" at this operation), then method 650 continues to execute operation 666. Otherwise ("No" at this operation), method 650 returns to operation 656 and executes that operation and subsequent operations.

[0266] At operation 666, the sample pipetting system 104 is used to aspirate the diluted sample from the dilution reservoir 132. In some embodiments, the sample pipetting system 104 aspirates a target volume of diluted sample to be dispensed into the reaction reservoir 134. In another embodiment, the sample pipetting system 104 aspirates a volume of diluted sample larger than the target volume to be dispensed into the reaction reservoir 134.

[0267] In some embodiments, as the surface liquid level 686 decreases due to this aspiration operation, the sample pipetting system 104 can move the dispensing tip 120 downward to reduce contact between the dispensing tip 120 (e.g., its distal end 320) and the outside of the sample in the dilution reservoir 132.

[0268] At operation 668, the sample pipetting system 104 is used to lift the dispensing tip 120 away from the dilution reservoir 132. For example... Figure 32 As shown, for example, the dispensing nozzle 120 moves above the surface liquid level 686.

[0269] At operation 670, the sample pipetting system 104 is used to draw air into the dispensing tip 120 above the surface liquid level 686. This operation reduces splashing caused by, for example, vibration of the dispensing tip 120 as it moves to different locations, such as sample dispensing position 176.

[0270] See Figure 31 This is an exemplary table 672 for the extraction and pushback volumes of dilution, which determines the distribution volume 676 and the suction volumes 678 and 680 for the total volume of the substance in the dilution reservoir 132. In some embodiments, table 672 is pre-generated and stored in instrument 100.

[0271] In some embodiments, the aspiration volumes 678 and 680 at operation 656 may differ across different cycles. Additionally or alternatively, the dispensing volume 676 at operation 660 may differ across different cycles. In some embodiments, as shown in Table 672, the aspiration volume 678 in the second cycle differs from the aspiration volume 680 in other cycles. In the illustrated example, the aspiration volume 678 in the second cycle is 7 μL larger than the aspiration volume 680 in other cycles. For example, with a total volume 674 of approximately 50 μL in dilution reservoir 132, the aspiration volume 678 at the second time point is 27 μL, which is 7 μL larger than the 20 μL aspiration volume 680 at other time points, and the dispensing volume at operation 656 is approximately 20 μL. In other embodiments, the aspiration volumes 678, 680, and / or the dispensing volume 676 are designed differently.

[0272] like Figure 33 Further illustrated are curves 692 showing the change in dispensing tip position over time and 694 showing the change in syringe movement over time during method 650. From 1.2 seconds to 1.4 seconds, the dispensing tip 120 is lowered (operation 652), and from 1.45 seconds to 1.65 seconds, the sample is dispensed (operation 654). Then, from 1.75 seconds to 2.1 seconds, a first cycle is performed, aspirating the diluted sample from dilution reservoir 132 and dispensing it into dilution reservoir 132 (operations 656, 658, 660, and 662). The same cycle is repeated up to 4.1 seconds. After completing the dispensing and aspiration cycle, from 4.1 seconds to 4.3 seconds, the diluted sample is finally aspirated into the dispensing tip (operation 666), and from 4.3 seconds to 4.4 seconds, the dispensing tip is raised again (operation 668). As shown in the figure, interrupt or wait cycles, such as a first interrupt cycle 695 and a second interrupt cycle 696, can be arranged between at least one of adjacent operations 652, 654, 656, 658, 660, 662, 666 and 668.

[0273] The aspiration and dispensing operations can be designed with appropriate parameters to ensure uniform sample dilution. For example, in the illustrated example, the aspiration and dispensing operations can be repeated eight times. The mixing dispensing volume 676 and the mixing aspiration volumes 678, 680 can vary depending on the total volume 674 in the dilution reservoir. For example, the second mixing aspiration volume 678 is larger than the other mixing aspiration volume 680 (e.g., 7 μL larger) to maintain the steady-state liquid in the dispensing tip 120 and avoid the inclusion of air bubbles during dilution. Regarding the first aspiration, mixing efficiency is considered from the perspective of the high concentration of sample still retained in the dispensing tip 120. In some embodiments, the waiting time between aspiration and dispensing (operations 656 and 660) (operations 658 and 662) is approximately 100 milliseconds, such as... Figure 33As shown. The syringes used for aspiration and dispensing (operations 656 and 660) are operated at a relatively high speed. In some embodiments, the syringe used for aspiration is slower than the syringe used for dispensing to maintain a balance between the actual aspirated volume and the actual dispensed volume.

[0274] In some embodiments, the sample pipetting system 104 is used to open valve 168 to eliminate bias pressure prior to at least one of the aspiration operations 656. This operation may be performed similarly to operation 566 as described above.

[0275] Figure 34 Exemplary architectures of computing devices that can be used to implement aspects of this disclosure are shown, including a biological sample analysis instrument 100 or various systems of instrument 100 (such as a substance dispensing system 102 and a substance evaluation system 108) and a management system 114. Additionally, one or more devices or units included in the system of instrument 100 can also be used as... Figure 34 The computing device shown is implemented using at least some components. Such a computing device is designated herein by reference numeral 800. The computing device 800 is used to execute the operating system, application programs, and software modules (including software engines) described herein.

[0276] In some implementations, computing device 800 includes at least one processing device 802, such as a central processing unit (CPU). Various processing devices are available from multiple manufacturers, such as Intel Corporation or Advanced Micro Devices. In this example, computing device 800 also includes system memory 804 and a system bus 806, which couples multiple system components, including system memory 804, to processing device 802. System bus 806 is one of many different types of bus architectures, including a memory bus or memory controller; a peripheral bus; and a local bus using any of a variety of bus architectures.

[0277] Examples of computing devices suitable for computing device 800 include desktop computers, laptop computers, tablet computers, and mobile devices (such as smartphones, etc.). A mobile digital device or other mobile device, or other device configured to process digital instructions.

[0278] System memory 804 includes read-only memory 808 and random access memory 810. A basic input / output system 812 containing basic routines is typically stored in read-only memory 808. These basic routines are used for things like transferring information within computing device 800 during startup.

[0279] In some embodiments, computing device 800 also includes an auxiliary storage device 814, such as a hard disk drive, for storing digital data. The auxiliary storage device 814 is connected to system bus 806 via an auxiliary storage interface 816. The auxiliary storage device and its associated computer-readable medium provide non-volatile storage for computer-readable instructions (including application programs and program modules), data structures, and other data to computing device 800.

[0280] While the exemplary environment described herein uses a hard disk drive as a secondary storage device, other types of computer-readable storage media are used in other embodiments. Examples of these other types of computer-readable storage media include magnetic tape cassettes, flash memory cards, digital video disks, Bernoulli cassettes, optical disc read-only memory, digital universal disk read-only memory, random access memory, or read-only memory. Some embodiments include non-transitory media.

[0281] Several program modules may be stored in auxiliary storage device 814 or memory 804, including operating system 818, one or more application programs 820, other program modules 822 and program data 824.

[0282] In some embodiments, computing device 800 includes input devices to enable a user to provide input to computing device 800. Examples of input devices 826 include keyboard 828, pointer input device 830, microphone 832, and touch-sensitive display 840. Other embodiments include other input devices 826. Input devices are typically connected to processing device 802 via input / output interface 838 coupled to system bus 806. These input devices 826 can be connected via many different input / output interfaces, such as parallel ports, serial ports, game ports, or universal serial buses. Wireless communication between the input devices and interface 838 is also possible, and in some possible embodiments, it includes infrared, Wireless technology, WiFi technology (802.11a / b / g / n, etc.), cellular or other radio frequency communication systems.

[0283] In this exemplary embodiment, the touch-sensitive display device 840 is also connected to the system bus 806 via an interface such as a video adapter 842. The touch-sensitive display device 840 includes touch sensors for receiving input from the user when the user touches the display. These sensors may be capacitive sensors, pressure sensors, or other touch sensors. The sensors detect not only contact with the display but also the location of the contact and its movement over time. For example, a user may move a finger or stylus on the screen to provide write input. The write input is evaluated, and in some embodiments, it is converted into text input.

[0284] In addition to the display device 840, the computing device 800 may include various other peripheral devices (not shown), such as speakers or printers.

[0285] The computing device 800 also includes a communication device 846 configured to establish communication across a network. In some embodiments, when used in a local area network (LAN) or wide area network (WAN) environment (such as the Internet), the computing device 800 is typically connected to a network via a network interface (such as a wireless network interface 848). Other possible embodiments use other wired and / or wireless communication devices. For example, some embodiments of the computing device 800 include an Ethernet network interface or a modem for communication across the network. In other embodiments, the communication device 846 is capable of short-range wireless communication. Short-range wireless communication is unidirectional or bidirectional short- to medium-range wireless communication. Short-range wireless communication can be established according to various technologies and protocols. Examples of short-range wireless communication include radio frequency identification (RFID), near field communication (NFC), etc. Technology and Wi-Fi technology.

[0286] Computing device 800 typically includes at least some form of computer-readable medium. Computer-readable medium includes any available medium that can be accessed by computing device 800. For example, computer-readable medium includes computer-readable storage media and computer-readable communication media.

[0287] Computer-readable storage media include volatile and non-volatile, removable and non-removable media implemented in any means for storing information such as computer-readable instructions, data structures, program modules or other data. Computer-readable storage media include, but are not limited to, random access memory, read-only memory, electrically erasable programmable read-only memory, flash memory or other storage technologies, optical disc read-only memory, digital versatile optical disc or other optical storage, magnetic tape cassettes, magnetic tape, disk storage or other magnetic storage devices, or any other medium that can be used to store desired information and is accessible by the computing device 800.

[0288] Computer-readable communication media are generally specifically expressed as computer-readable instructions, data structures, program modules, or other data in modulated data signals (such as carrier waves or other transmission mechanisms), and include any information transmission medium. The term "modulated data signal" refers to a signal having one or more of its characteristics set or altered in a certain way to encode information in the signal. For example, computer-readable communication media include wired media, such as wired networks or direct wired connections; and wireless media, such as voice, radio frequency, infrared, and other wireless media. Any combination of the above is also included within the scope of computer-readable media.

[0289] See you again Figure 34 The computing device 800 may include a location identification device 850. The location identification device 850 is configured to identify the location or geographic location of the computing device 800. The location identification device 850 may use various types of geolocation or positioning systems, such as network-based systems, transceiver-based systems, SIM-based systems, Wi-Fi positioning systems, and hybrid positioning systems. Network-based systems utilize the network infrastructure of service providers, such as cellular tower triangulation. Transceiver-based systems typically use the Global Positioning System (GPS). Wi-Fi positioning systems may be used when GPS is unsuitable due to various reasons, including multipath propagation and indoor signal congestion. Hybrid positioning systems combine network-based and transceiver-based technologies to determine location, such as assisted GPS.

[0290] See Figures 35 to 37 Detailed timing diagrams illustrate exemplary pump motor stepping and vertical drive motor stepping of different sample volumes over cycle time without dilution. Specifically, Figure 35 Exemplary pump motor stepping and vertical drive motor stepping are shown as they progress over cycle time when performing small volume sample pipetting (e.g., in the range of 0 to 25 μL) without dilution. As described above, push-back and flushing processes can be performed for small quantities. Figure 36 Exemplary pump motor stepping and vertical drive motor stepping are shown as they progress over cycle time when performing pipetting of medium-volume samples (e.g., in the range of 25 to 50 μL) without dilution. As described above, push-back and flushing processes can be performed for medium volumes. Figure 37 Exemplary pump motor stepping and vertical drive motor stepping are shown as they progress over cycle time when performing large-volume sample pipetting (e.g., in the range of 50 to 100 μL) without dilution. As described above, over-extraction processes can be performed in large quantities.

[0291] See Figure 38 and 39 The detailed timing diagram illustrates exemplary pump motor stepping and vertical drive motor stepping over cycle time in the case of dilution. Specifically, Figure 38 Exemplary pump motor stepping and vertical drive motor stepping are shown as the cycle time progresses during a 100-fold dilution, and Figure 39 Exemplary pump motor stepping and vertical drive motor stepping are shown as the cycle time progresses during a 10-fold dilution.

[0292] exist Figures 35 to 39 In this process, the motor stepping is proportional to the pumping volume output of the pump or the linear displacement driven by the Z-axis.

[0293] Figure 40This is a schematic diagram of an exemplary dilution process and a table of exemplary dilution rates for different volumes.

[0294] Figure 41 A set of exemplary experiments performed using the system of this disclosure are shown, demonstrating improved accuracy and / or precision. As shown, the number of strokes and the amount drawn into the dispensing tip 120 are varied independently, and the resulting precision is measured. As curve A shows, increasing the number of pump strokes tends to improve accuracy. Curve A also shows that increasing the amount drawn into the dispensing tip 120 tends to improve accuracy. Curve B shows the standard deviation (σ) of the experimental test results. For a given instrument cycle time, a smaller sample size (e.g., mixing volume) may be rapidly over-pumped and discharged to improve accuracy. For a given instrument cycle time, a larger sample size (e.g., mixing volume) may have high accuracy due to its larger size. The mixing volume can be defined as the maximum amount in the dispensing tip 120.

[0295] As described herein, the material distribution system of this disclosure improves the accuracy and / or precision of pipetting with disposable pipette tips 120 (i.e., disposable pipette tip pipetting). The pipetting methods described in this disclosure can be further improved in terms of accuracy and / or precision based on statistical experiments.

[0296] Regulatory agencies may focus on both the accuracy and precision of pipetting. For example, the Food and Drug Administration (FDA) focuses on the precision of the instrument certification process. Generally, precision involves the mathematical concept of the coefficient of variation (CoV) of a multivariate dataset (e.g., a dataset of paired x, y values, a pair of independent and dependent variables, etc.). Accuracy is expressed in ±μL / μL (i.e., dimensionless). In some examples, an accuracy with a 20% window (i.e., ±10%) may be required. This precision corresponds to a statistical confidence interval (e.g., 2CoV, 2σ, 2 standard deviations based on a normal error distribution, etc.). For example, for a 2μL sample, ±10% corresponds to ±0.2μL. For a 100μL sample, ±10% corresponds to ±10μL. In some examples, calibration can address accuracy requirements if precision is satisfied.

[0297] The various examples and teachings provided above are provided by way of illustration only and should not be construed as limiting the scope of this disclosure. Those skilled in the art will readily understand that various modifications and variations can be made without departing from the true spirit and scope of this disclosure, and without following the examples and applications illustrated and described herein.

Claims

1. A method for preparing a fluid substance (112) for evaluation, the method comprising: The first volume of the fluid substance (112) is drawn from the first reservoir to the dispensing nozzle (120); as well as The second volume of the fluid substance (112) is dispensed from the dispensing nozzle (120) into the second reservoir in the following manner: The dispensing tip (120) is lowered to a first height (H3) in the second reservoir, the first height (H3) being configured such that the distal end (320) of the dispensing tip (120) is held above the surface liquid level in the second reservoir; The fluid substance (112) is partially dispensed from the dispensing nozzle (120) into the second reservoir at a first height (H3), such that the dispensing nozzle retains the remainder of the fluid substance in the second volume therein; The dispensing tip (120) is lowered to a second height (H4), the second height being configured such that the distal end (320) of the dispensing tip (120) contacts the surface liquid level in the second reservoir; as well as The remaining portion of the fluid substance in the second volume is dispensed from the dispensing nozzle (120) to the second height (H4) of the second reservoir, such that the surface tension of the surface liquid level removes the droplets from the dispensing nozzle.

2. The method according to claim 1, wherein the first volume is larger than the second volume.

3. The method according to claim 1, wherein the second volume is greater than 25 μL.

4. The method according to claim 1, comprising: The dispensing nozzle (120) is rinsed with at least a portion of the fluid substance (112) from the second reservoir; The rinsing of the dispensing nozzle (120) includes: The third volume of the fluid substance (112) is drawn from the second reservoir into the dispensing nozzle (120); as well as The fourth volume of the fluid substance (112) is dispensed from the dispensing nozzle (120) into the second reservoir.

5. The method according to claim 4, comprising: Repeat the steps of dispensing and aspirating the third volume.

6. The method of claim 1, wherein distributing the second volume of the fluid substance comprises: A sensor is used to detect whether the fluid substance (112) in the second reservoir is in contact with the distal end (320) of the dispensing nozzle (120); as well as The signal is transmitted from the sensor to the control device, which can be used by the control device to stop the movement of the dispensing tip (120).

7. The method of claim 1, wherein aspirating the first volume of the fluid substance (112) comprises: The fifth volume of the fluid substance (112) is drawn from the first reservoir into the dispensing nozzle (120); as well as The sixth volume of the fluid substance (112) is dispensed from the dispensing nozzle (120) into the first reservoir to contain the first volume of the fluid substance (112) in the dispensing nozzle (120).

8. The method of claim 1, wherein the first volume is equal to the second volume.

9. The method according to claim 1, wherein the first reservoir comprises a sample reservoir (130) containing equal volumes of the fluid substance (112), and the second reservoir comprises a reaction reservoir (134).

10. The method of claim 1, wherein the first reservoir comprises a sample tube (122).

11. The method according to claim 1, comprising: Before aspirating the first volume of the fluid substance (112), determine the surface level of the fluid substance (112) contained in the first reservoir; Determining the surface liquid level of the fluid substance (112) includes: The dispensing nozzle (120) is lowered into the first reservoir; The pressure increase at the distal end (320) of the dispensing tip (120) is detected; and The surface liquid level of the fluid substance (112) is calculated based on the increase in pressure; The calculation of the surface liquid level of the fluid substance (112) includes: The travel distance of the dispensing nozzle (120) is determined until the increase in pressure is detected; and The surface liquid level of the fluid substance (112) is calculated based on the travel distance; Determining the surface liquid level of the fluid substance (112) includes: Air is expelled from the dispensing nozzle (120) before an increase in pressure is detected; and After the pressure increase is detected and before the first volume is aspirated, the pressure inside the dispensing nozzle (120) is brought into equilibrium with the atmospheric environment. The process of balancing the pressure inside the dispensing nozzle (120) with the atmospheric environment includes: Open the valve (168) located between the dispensing tip (120) and the syringe assembly (164).

12. An apparatus for preparing a fluid substance (112) for evaluation, comprising: A pipetting system (104) comprising a sample pipetting module (150) configured to engage a dispensing tip (120); and A dispensing control system controls the pipetting system (104) to perform the following operations: The first volume of the fluid substance (112) is drawn from the first reservoir to the dispensing nozzle (120); and The second volume of the fluid substance (112) is dispensed from the dispensing nozzle (120) into the second reservoir in the following manner: The dispensing tip (120) is lowered to a first height (H3) in the second reservoir, the first height (H3) being configured such that the distal end (320) of the dispensing tip (120) is held above the surface liquid level in the second reservoir; The fluid substance (112) is partially dispensed from the dispensing nozzle (120) to the first height (H3) of the second reservoir, such that the dispensing nozzle retains the remainder of the fluid substance in the second volume therein; The dispensing tip (120) is lowered to a second height (H4), the second height (H4) being configured such that the distal end (320) of the dispensing tip (120) contacts the surface liquid level in the second reservoir; and The remaining portion of the fluid substance in the second volume is dispensed from the dispensing nozzle (120) to the second height (H4) of the second reservoir, such that the surface tension of the surface liquid level removes the droplets from the dispensing nozzle.

13. The device according to claim 12, comprising: The dispensing nozzle (120) is flushed with at least a portion of the fluid substance (112) from the second reservoir; The dispensing control system controls the pipetting system (104) to perform the following operations: The third volume of the fluid substance (112) is drawn from the second reservoir into the dispensing nozzle (120); The fourth volume of the fluid substance (112) is dispensed from the dispensing nozzle (120) into the second reservoir; The dispensing control system controls the pipetting system (104) to perform the following operations: Distribute the fluid substance (112) in the third volume; The fluid substance (112) in the third volume is aspirated again; The dispensing control system controls the pipetting system (104) to perform the following operations: Repeat the steps of dispensing and aspirating the third volume; The dispensing control system controls the pipetting system (104) to aspirate a first volume of the fluid substance (112) in such a way that: The fifth volume of the fluid substance (112) is drawn from the first reservoir into the dispensing nozzle (120); and The sixth volume of the fluid substance (112) is dispensed from the dispensing nozzle (120) into the first reservoir to contain the first volume of the fluid substance (112) in the dispensing nozzle (120).

14. The apparatus of claim 12, wherein the first reservoir comprises a sample tube (122).

15. The apparatus of claim 12, wherein the dispensing control system controls the pipetting system (104) to determine the surface level of the fluid substance (112) contained in the first reservoir before aspirating a first volume of the fluid substance (112) and to balance the pressure inside the dispensing tip (120) with the atmospheric environment by: Open the valve (168) located between the dispensing tip (120) and the syringe assembly (164).

16. The device of claim 12, wherein the first volume is larger than the second volume.

17. The device of claim 12, wherein the second volume is greater than 25 μL.

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