Automated laboratory equipment

Abstract

This invention provides an automated laboratory system for analyzing biological samples and detecting pipette head leakage events. [Solution] The automated laboratory apparatus 100 includes a pipette head 110 having a channel 114, the channel 114 being connectable to a pipette tip 120, through which fluid is drawn and distributed; a flow controller 130 configured to control the flow of fluid through the channel 114 of the pipette head 110; a pressure sensor 140 configured to detect the pressure in the channel 114 of the pipette head 110 and collect pressure data of the channel 114; and a controller 150 connected to the pressure sensor 140, wherein the controller 150 is configured to extract values ​​for each of two or more characteristics of the pressure data received from the pressure sensor 140 and to record a leakage event when each of the extracted values ​​exceeds its respective characteristic threshold.

Description

Technical Field

[0001] Title of the Invention The present disclosure relates to automated laboratory equipment, and more particularly, but not exclusively, to automated laboratory equipment for analyzing biological samples and detecting leakage events of pipette heads.

Background Art

[0002] Background Large-scale biological sample analyzers are very important in today's laboratory environment to increase and ensure efficiency. Such devices typically use one or more multi-channel pipette heads to perform tests on multiple samples simultaneously, thereby increasing laboratory throughput and reducing the time waiting for test results. These devices are also typically automated, so biological sample analysis can be performed with minimal monitoring, freeing additional time for laboratory staff.

[0003] However, the inventors have noticed significant leakage in multi-channel pipette heads used in such devices, caused, for example, by deterioration of the connection between the channels of the multi-channel pipette head and the disposable pipette tips connected thereto. Such leakage not only causes contamination of the workstation (e.g., by droplets falling onto part of the workstation as the multi-channel pipette head moves), but also leads to a decrease in test performance and accuracy due to an unexplained loss of liquid from the multi-channel pipette head.

[0004] The inventors also acknowledged that existing leak detection processes have proven insufficient to overcome these leak problems. More specifically, existing leak detection processes often return inaccurate results. For example, multichannel pipette heads reported as leak-free are frequently found to be leaking significantly afterward. Alternatively, leak detection processes may return false positive results, leading to unnecessary replacement of multichannel pipette heads. Furthermore, some existing leak detection processes require the instrument to stop performing biological sample analysis during the test period. This generally reduces the efficiency of the instrument and also means that leaks may go undetected for extended periods during the planned leak test period.

[0005] In this way, the inventors recognized the need to provide a more accurate leak detection method that can be performed in situ by analyzing biological samples.

[0006] This disclosure was devised in light of the above considerations. [Overview of the Initiative]

[0007] Summary of the Invention According to one aspect of the present disclosure, an automated laboratory apparatus for analyzing biological samples is provided, the automated laboratory apparatus comprising: a pipette head having a channel, the channel being connectable to a corresponding pipette tip, through which a fluid is drawn and dispensed; a flow controller configured to control the flow of fluid through the channel of the pipette head; a pressure sensor configured to detect the pressure in the channel of the pipette head and collect pressure data of the channel; and a controller connected to the pressure sensor, the controller being configured to receive pressure data from the pressure sensor, extract values ​​for each of two or more characteristics of the received pressure data, compare the extracted values ​​of the two or more characteristics with their respective characteristic thresholds, and record a leakage event when each of the extracted values ​​exceeds its respective characteristic threshold.

[0008] The accuracy of leak detection can be improved by using at least two characteristics of pressure data to determine a leak event. For example, false positive leak events (events that may cause a leak event to be recorded even though there is no leak in other cases, such as the bursting of a bubble in a pipette tip) are less likely to trigger multiple thresholds that match the detectable pressure characteristics of an actual leak event. In this way, false positive leak events can be excluded, improving the overall accuracy of leak detection.

[0009] In a further embodiment, the automated laboratory apparatus presented in the first embodiment is provided, wherein the value of at least one (or only one) characteristic is extracted instead of two or more, and a leakage event is recorded if the evaluated extracted characteristic value exceeds the respective characteristic threshold. In all other respects, the automated laboratory apparatus of the further embodiment is the same as the automated laboratory apparatus of the first embodiment.

[0010] A pipette head may have multiple channels. A pipette head may be a multi-channel pipette head having multiple channels. A multi-channel pipette head may be connectable to multiple pipette tips. Each of the one or more channels may be connectable to a corresponding pipette tip of multiple pipette tips. A pressure sensor may be configured to detect the pressure in each of the one or more channels of the pipette head and to collect pressure data for each of the one or more channels. A controller may be configured to receive pressure data from the pressure sensor for each of the one or more channels, extract values ​​for each of the two or more characteristics of the received pressure data, compare the extracted values ​​of the two or more characteristics with their respective characteristic thresholds, and record a leak event associated with each channel to which the pressure data is related when each of the extracted values ​​exceeds its respective characteristic threshold.

[0011] The channel of the pipette head and / or the pipette tip connected to the channel of the pipette head may extend along the longitudinal axis.

[0012] The pipette head may be movable along its longitudinal axis. The pipette head may be movable within a container along its longitudinal axis. The container may contain the fluid to be aspirated (e.g., a liquid) or may be intended to dispense a fluid (e.g., a liquid or gas) into it. The pipette head may be movable in a first direction along its longitudinal axis until the pipette tip connected to the channel of the pipette head comes into contact with the fluid in the container to be aspirated. Once the fluid is aspirated, the pipette head may be moved in a second direction along the longitudinal axis opposite to the first direction until the pipette tip moves longitudinally away from the side of the container.

[0013] The pipette head may also be movable in a transverse plane perpendicular or substantially perpendicular to the longitudinal axis. For example, the pipette head may be movable in a transverse plane between a first container and a second container. In other words, the pipette head can move laterally from a first position where the pipette head is longitudinally adjacent to the first container to a second position where the pipette head is longitudinally adjacent to the second container. The first container may be intended to hold the fluid aspirated by the pipette head, and the second container may be intended to hold the fluid dispensed from the pipette head, or vice versa.

[0014] If multiple channels exist (i.e., the pipette head is a multi-channel pipette head), each of the multiple pipette tips can be connected to a separate channel of the multi-channel pipette head.

[0015] A pipette tip may include a first end and a second end opposite the first end. The first and second ends of the pipette tip may be at opposing longitudinal ends of the pipette tip. The first end may be attachable to a channel in a pipette head, and the second end may include an opening through which fluid is aspirated and dispensed. The aspirated fluid may be held in the pipette tip between the first and second ends. Advantageously, this means that the fluid aspirated and dispensed through the pipette tip does not enter the pipette head (more specifically the channel in the pipette head), thereby avoiding contamination of the pipette head.

[0016] The pipette tip may be removable from the pipette head.

[0017] The pipette tip may be a disposable pipette tip. A disposable pipette tip may be defined as a pipette tip intended for use only once (i.e., for one analysis) in an automated laboratory apparatus. For example, a disposable pipette tip may include a connector for connection to a pipette head. The disposable tip may be connected to a channel in the pipette head, used to aspirate a fluid, then to dispense the fluid later, and then removed from the channel in the pipette head and discarded.

[0018] Alternatively, the pipette tip may be a reusable pipette tip. A reusable pipette tip may be defined as a pipette tip intended for use in analyzing two or more biological samples (for example, to aspirate and dispense a fluid multiple times in succession).

[0019] The fluid aspirated / distributed through the pipette tip may contain a liquid. The liquid component may be a cell lysate or other liquid solution.

[0020] The fluid aspirated / distributed through the pipette tip may contain a gas. The gas may be air. The gas may be aspirated following the aspiration of the liquid. The gas can provide a buffer between the end of the pipette tip (e.g., through which the fluid is aspirated / distributed) and the previously aspirated liquid. In this way, leakage can be advantageously reduced. The buffer may be referred to as a trailing air gap (TAG).

[0021] If multiple channels exist (i.e., if the pipette head is a multi-channel pipette head), the flow controller may be connected to all channels of the multi-channel pipette head.

[0022] Controlling the fluid flow through the pipette head channel can refer to controlling the gas (e.g., air) passing through the pipette head. This controlled gas may differ from the fluid being drawn in and distributed through the pipette tip.

[0023] A flow controller can control the flow of fluid through the pipette tip via the pipette head.

[0024] Controlling the fluid flow through the pipette head channel causes a change in pressure at the pipette tip, allowing the fluid to be drawn into or displaced from the pipette tip. More specifically, controlling the fluid flow through the pipette head channel can allow the fluid to be drawn out of or pushed into the pipette tip via the connection between the first end of the pipette tip and the channel in the pipette head. In this way, the pressure within the pipette tip can be decreased / increased, thereby causing the fluid to be drawn into or displaced from the pipette tip at the second end of the pipette tip opposite to the first end connected to the channel in the pipette head.

[0025] The flow controller can be a fluid pump that can be used to blow or extract fluid (e.g., air) into or from the channels of the pipette head. The flow controller can also be a piston that can increase or decrease the volume of the channels of the pipette head for blowing or extracting fluid (e.g., air) into or from the channels of the pipette head. The piston may be in a cylinder. The piston can be used to increase or decrease the pressure in the channels of the pipette head.

[0026] In some examples, the controller can extract two or more values for each of one or more of the two or more characteristics of the received pressure data. The two or more values extracted for each of one or more of the respective characteristics can include the maximum value of the respective characteristic and the minimum value of the respective characteristic. The minimum value of the characteristic can be a negative number.

[0027] There may be two or more threshold values for each characteristic. For example, there may be a maximum threshold value and a minimum threshold value for one or more of the two or more characteristics. The maximum characteristic threshold value of each characteristic can be compared with the maximum value extracted for the respective characteristic. The minimum characteristic threshold value of each characteristic can be compared with the minimum value extracted for the respective characteristic.

[0028] A leakage event can correspond to droplets falling from the pipette tip (e.g., formed from the aspirated fluid) and / or a flow of liquid flowing out of the pipette tip.

[0029] For the execution of a biological sample process, a single leakage event can be detected / recorded. Alternatively, multiple leakage events can be detectable / recordable for the execution of a biological sample process.

[0030] In some examples, the two or more characteristics include one or more of the magnitude of the pressure, the relative pressure, the rate of change of the pressure (gradient), and the standard deviation of the rate of change of the pressure.

[0031] The magnitude of the pressure refers to the numerical value of the pressure measured by the pressure sensor (or the average value of the pressure obtained across measurements from multiple pressure sensors). The value can be negative. If the pressure sensor performs multiple measurements, the magnitude of the pressure used may be the most extreme magnitude of the pressure measured across multiple measurements, or across a subset of multiple measurements obtained in a region of interest. The region of interest may be determined by the controller. The most extreme magnitude of the pressure may be the highest and / or lowest pressure values ​​measured.

[0032] Alternatively, the magnitude pressure value can refer to the difference between the most extreme magnitude pressure value measured (e.g., in the region of interest) and the initial pressure measured (e.g., in the region of interest). In this way, the magnitude pressure measurement can be calibrated against the initial pressure conditions.

[0033] A magnitude pressure measurement can be compared to a maximum pressure threshold and / or a minimum pressure threshold. If the magnitude pressure value is the difference between the initial pressure value and the current pressure value, the minimum pressure threshold can be a negative number. A negative threshold can refer to a negative value whose absolute value exceeds the absolute value of the threshold (i.e., a negative value exceeding a negative threshold has a larger negative number).

[0034] The absolute values ​​of the maximum and minimum pressure thresholds may be anywhere within the range of 10 to 250 Pa, more preferably 10 to 100 Pa, more preferably 10 to 50 Pa, more preferably 20 to 30 Pa, or more preferably 25 Pa.

[0035] Relative pressure is sometimes called pressure delta.

[0036] Relative pressure can be the pressure difference between two points in the pressure data. These two points may be the first and last pressure measurements created in the pressure data. Alternatively, the two points may be the first and last pressure measurements created within a defined period / range in the pressure data. Or, relative pressure may be the pressure difference between the maximum and minimum pressure values ​​in the pressure data, or within a defined period / range in the pressure data.

[0037] Before comparing the relative pressure value to the absolute value of the relative pressure threshold, the absolute value of the relative pressure can be obtained.

[0038] The rate of change can refer to the change in pressure within a unit time or between two consecutive magnitude pressure measurements made by a pressure sensor. If multiple rate of change measurements are made, the rate of change used may be the most extreme rate of change value of the created pressure measurements, or it may span a subset of the rate of change of pressure measurements made within a region of interest. The region of interest may be determined by the controller. The most extreme value of the rate of change may be the maximum rate of change of the measured pressure value, and / or the maximum negative rate of change of the measured pressure.

[0039] The absolute value of a measured pressure rate of change can be compared to a pressure rate of change threshold. Separate pressure thresholds may exist for negative and positive pressure rate of change values. A negative value exceeding the negative threshold is interpreted as meaning the absolute value of the negative value is greater than the absolute value of the threshold (i.e., a negative value exceeding the negative threshold has a larger negative number). Alternatively, the same threshold (the absolute value of the threshold) can be used for both positive and negative pressure rate of change values.

[0040] The absolute values ​​of the maximum and minimum pressure change thresholds may be anywhere in the range of 2 to 200 Pa / s, more preferably 10 to 40 Pa / s, and more preferably 0.1 to 20 Pa / s.

[0041] The use of the standard deviation of the rate of change (slope) of pressure has been shown to reliably identify leakage events.

[0042] The standard deviation of the threshold for the rate of change (gradient) of pressure may be within the range of 1 to 100 Pa / s, more preferably within the range of 5 to 75 Pa / s, or more preferably within the range of 50 Pa / s.

[0043] The controller can be configured to stop or pause the biological sample analysis process being performed by the automated laboratory apparatus when a leak event is recorded, or to put the automated laboratory apparatus into an error state after the ongoing sample analysis process is complete, preventing further sample analysis from being initiated.

[0044] Stopping the analysis of a biological sample may include preventing the pipette head / pipette tip from aspirating or dispensing fluid (e.g., via a pressure controller).

[0045] Additionally or alternatively, the controller may be configured to alert the user of a leak when a leak event is detected. The controller may issue a leak notification alert to the user. The automated laboratory equipment may include a user interface that notifies the user of a leak when controlled by the controller. The notification may be delivered via visual, tactile, or voice-generated elements. The controller may be configured to receive an indication from the user (e.g., via the automated laboratory equipment's GUI) that the leak issue has been resolved, and then to resume the analysis process of the suspended biological sample.

[0046] The controller may be configured to record the number of leak events, for example, in short-term or long-term memory (e.g., RAM, onboard HDD, or network storage). The number of recorded leak events may be accessible to the user via the GUI of the automated laboratory equipment.

[0047] In some examples, the controller is configured to stop or pause the biological sample analysis process being performed by the automated laboratory equipment when a predetermined number of leak events spaced apart in time are recorded, or to put the automated laboratory equipment into an error state after the analysis process of the currently performed sample is complete, preventing further sample analysis from being initiated. In other words, in contrast to the above where only a single leak event needs to be detected, the controller can be configured to stop or pause the biological sample analysis process after the analysis process of the currently performed sample is complete, or to put the automated laboratory equipment into an error state, preventing further sample analysis from being initiated, only when a predetermined number of leak events spaced apart in time are recorded or detected.

[0048] By simply stopping the analysis process of the biological sample when two separate leak events are recorded, the automated laboratory equipment can advantageously prevent it from unnecessarily reacting to a single false-positive reading where a leak event is recorded even though no leak is present.

[0049] The predetermined number of leakage events may be 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10.

[0050] In some examples, the controller uses at least one algorithm to extract values ​​for each characteristic. The controller can then use a different algorithm for each of the extracted values.

[0051] In some examples, the controller extracts values ​​for each characteristic from the received pressure data using an algorithm that takes the average across multiple pressure measurements created by the pressure sensor.

[0052] More specifically, the algorithm used takes the average of a set of pressure measurements that make up the set of received pressure data to obtain a set of averaged pressure measurements that make up a new set of averaged pressure data. The number of averaged measurements in the averaged pressure data may be equal to the number of received pressure measurements in the received pressure data. The controller (e.g., via the algorithm) can then extract the values ​​of each of two or more characteristics of the averaged pressure data.

[0053] By averaging across multiple pressure measurements, the controller favorably filters out noise and one-off outlier measurements, thereby reducing the risk of false positive leak events being recorded.

[0054] The algorithm can use a moving average (also known as a moving average).

[0055] Averaging may include obtaining the (e.g., moving) median result. For example, the median may be obtained over 3, 4, 5, 6, 7, 8, 9, 10, or 10+ measurements of the pressure sensor. In this way, one-off outlier measurements can be excluded or their impact can be mitigated.

[0056] Averaging may involve taking a moving average (e.g.) across several measurements. The average may be obtained with between 10 and 100 results, or with more than 100 results. More specifically, the average may be taken using 20-90 results, 30-90 results, 40-90 results, 50-80 results, 60-70 results, or 64 results. In this way, the risk of inducing false positive leak events that should be recorded is reduced.

[0057] In some examples, the pressure sensor is configured to continuously record the pressure in the channel of the pipette head.

[0058] Advantageously, this allows the pressure sensor to provide the controller with a wide range of pressure measurements, which the controller can then consider and use. As a result, leakage events can be detected more accurately.

[0059] Alternatively, the pressure sensor may be configured to record the pressure in the pipette head channel only for one or more predetermined pressure detection periods. Each of these predetermined detection periods can last at least 1, 1.5, 2, 2.5, 3, 3.5, or 4 seconds.

[0060] The pressure sensor can acquire readings every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10+ ms.

[0061] Alternatively, if the pressure sensor is configured to record the pressure in the pipette head channel only during one or more predetermined pressure sensing periods, the pressure sensor may be configured to acquire a specific number of pressure readings within those predetermined pressure sensing periods.

[0062] In some examples, the controller is configured to define a data analysis period within the received pressure data, during which values ​​for each of two or more characteristics of the pressure data are extracted.

[0063] Advantageously, this allows the controller to identify the data most useful for determining a leak event. For example, pressure data measured while the controller is drawing fluid, which may show spikes in pressure readings unrelated to a leak event, can be removed. Thus, leak events can be detected more accurately.

[0064] The data analysis period can last for at least 1, 1.5, 2, 2.5, 3, 3.5, or 4 seconds.

[0065] Two or more characteristics may include the difference between the maximum pressure value measured during the data analysis period and the minimum pressure value measured during the data analysis period, which is referred to herein as delta pressure. The controller may compare the extracted value for delta pressure to one or more delta pressure thresholds. The controller may compare the extracted value for delta pressure to the maximum pressure delta pressure threshold and / or the minimum pressure delta pressure threshold. The maximum pressure delta threshold and the minimum pressure delta threshold are characteristic thresholds, respectively. The minimum pressure delta threshold may be a negative number.

[0066] The absolute values ​​of the maximum and minimum delta pressure thresholds may be anywhere in the range of 10 to 100 Pa, more preferably 10 to 50 Pa, more preferably 20 to 30 Pa, or more preferably 25 Pa.

[0067] In some examples, the data analysis period corresponds to the time when the outer surface of the pipette tip is not immersed in the liquid.

[0068] Advantageously, this improves leak detection by preventing pressure fluctuations caused by pipette tips entering and exiting the liquid from leading to false positive results.

[0069] The controller can determine when the pipette tip has left or entered the liquid by using characteristic features in the recorded pressure data that are predetermined to be caused by these events. The controller can then better select the data analysis period.

[0070] In some examples, the data analysis period corresponds to the time the pipette head moves along the longitudinal axis through which the channel extends.

[0071] Movement of the pipette head along the longitudinal axis can increase the likelihood of leakage events. Therefore, detecting leakage events while the pipette head is moving in this manner makes it possible to detect leakage events that might otherwise be missed. In other words, the sensitivity of the device to leakage events can be increased.

[0072] The data analysis period may further include the period when the pipette head is stationary and / or when the pipette head is moving in a lateral plane perpendicular to the longitudinal axis.

[0073] Alternatively, the data analysis period may correspond to the period during which the pipette head is stationary in both the lateral and longitudinal planes.

[0074] The data analysis period may correspond to the period during which the pipette head and / or pipette tip hold the aspirated fluid. The data analysis period may also correspond to the period during which the aspirated fluid is held at the second end of the pipette tip. In other words, the data analysis period may correspond to the period during which the TAG is not aspirated into the pipette tip.

[0075] In some cases, the data analysis period corresponds to the period immediately following the aspiration of the fluid by the pipette head.

[0076] Advantageously, this allows for the detection and recording of leak events before the pipette head leaves the container from which the fluid has been drawn. Therefore, if a leak (indicated by the recording of one or more leak events) occurs and the analytical process of the biological sample is stopped, the pipette can be held in a position where any leak / droplet returns straight back into the container. In other words, leaks can be contained to avoid contaminating automated laboratory equipment.

[0077] However, this disclosure is not limited in this way. For example, the data analysis period may correspond to the period substantially immediately preceding the distribution of the fluid drawn from the pipette tip (e.g., into a container). Again, this allows the drops from the pipette head to be contained in the container, thus avoiding contamination of automated laboratory equipment. This data analysis period may be performed after any TAG has been distributed.

[0078] In some examples, the automated laboratory apparatus is further configured to perform multiple runs of the biological sample analysis process, and a pressure sensor is configured to record pressure data over multiple runs of the biological sample analysis process.

[0079] "Execution" can be defined as an automated laboratory apparatus that performs a series of steps in which a biological sample is analyzed, and this may include pipette heads used to aspirate, hold, and dispense fluids (possibly multiple times).

[0080] The additional pressure data obtained by measuring over multiple runs is advantageous in that it allows the controller to more accurately detect leak events, especially in the case of low-leakage pipette heads that may only leak once every two or more runs.

[0081] The analytical process for a biological sample includes the steps of using a pipette head / pipette tip, aspirating a predetermined amount of fluid, holding the fluid for a predetermined retention time, and then dispensing the predetermined amount of fluid.

[0082] During a predetermined holding time, the pipette head may be moved longitudinally (for example, moving out of one container and into another to aspirate and distribute fluids). For example, the pipette head / pipette tip may first aspirate fluid from a first container, move longitudinally upward, remain stationary for a while, and then move longitudinally downward into a second container (where the user or another automated arm has replaced the first container), and distribute the aspirated fluid into it.

[0083] Furthermore, the pipette head may also move in a direction parallel to (i.e., within) a side perpendicular to the longitudinal axis for a predetermined holding time (for example, the pipette head may move laterally). For example, the pipette head / pipette tip may first move upward longitudinally to draw fluid from a first container, move laterally within a side on a second container, and then move downward longitudinally into the second container to distribute the drawn fluid.

[0084] In some examples, the controller is configured to define the data analysis period corresponding to each run in a group of runs.

[0085] In some examples, the controller is configured to stop or pause the biological sample analysis process if a leak event is detected during at least two runs of the biological sample analysis process, or to put the automated laboratory device into an error state after the ongoing sample analysis process is complete, preventing further sample analysis processes from being initiated.

[0086] Advantageously, this prevents false or erroneous leak events from a single run, which could be caused by factors other than actual leakage from the pipette tip, from causing unnecessary interruptions to the current or future biological sample analysis process. In other words, leak detection accuracy is improved.

[0087] In some cases, the controller is configured to halt the biological sample analysis process if a leakage event is detected in two adjacent runs of the biological sample analysis process.

[0088] The controller may be a processor (e.g., a CPU) or other component appropriately configured and located within an automated laboratory apparatus. The controller may be configured to control a flow controller, that is, it may issue commands or instructions to the flow controller. The controller may also be configured to perform a requested biological analysis and may be the main controller of the automated laboratory apparatus.

[0089] A second aspect of the present disclosure provides a leak detection method for an automated laboratory apparatus configured to analyze a biological sample, the leak detection method comprising: receiving pressure data from a pressure sensor configured to detect pressure in a channel of a pipette head; extracting a value for each of two or more characteristics of the received pressure data; comparing each of the extracted values ​​of the two or more characteristics with their respective characteristic thresholds; and recording a leak event when each of the extracted values ​​exceeds its respective characteristic threshold.

[0090] The accuracy of leak detection can be improved by using at least two characteristics of pressure data to determine a leak event. For example, false positive leak events (events that may cause a leak event to be recorded even though there is no leak in other cases, such as the bursting of a bubble in a pipette tip) are less likely to trigger multiple thresholds that match the detectable pressure characteristics of an actual leak event. In this way, false positive leak events can be excluded, improving the overall accuracy of leak detection.

[0091] The method may further include the step of detecting the pressure inside the channel of the pipette head using a pressure sensor.

[0092] A person skilled in the art who has been granted this disclosure will understand that a second aspect of this disclosure may include any of the features detailed in the first aspect of this disclosure, unless otherwise expressly excluded and interchangeable. The leak detection method of the second aspect may be stored in a computer-readable storage medium or may be carried out by a controller of an automated laboratory apparatus.

[0093] In a further embodiment, the leak detection method presented in the second embodiment is provided, wherein the value of at least one (or only one) characteristic is extracted instead of two or more, and a leak event is recorded if the evaluated extracted value exceeds the respective characteristic threshold. In all other respects, the method of the further embodiment is the same as the method of the second embodiment.

[0094] A third aspect of the present disclosure provides a second automated laboratory apparatus for analyzing biological samples, the automated laboratory apparatus comprising: a pipette head having a channel, the channel being connectable to a pipette tip, through which a fluid is drawn and dispensed; a flow controller configured to control the flow of fluid through the channel of the pipette head; a pressure sensor configured to detect the pressure in the channel of the pipette head and collect pressure data of the channel; and a controller connected to the pressure sensor, configured to record leak events detected from the pressure data received from the pressure sensor, the automated laboratory apparatus being configured to determine that a leak is present in the pipette head by detecting and recording leak events for two or more runs of the automated laboratory apparatus.

[0095] By detecting and utilizing leak events across multiple runs of automated laboratory equipment, false positive leak events can be minimized.

[0096] By requiring the recording of leak events across multiple runs of the automated laboratory equipment, false positive leak events (such as the bursting of air bubbles in a pipette tip, which in other cases may result in a leak being recorded even though no leak occurred) are prevented from independently leading to a positive leak determination, thereby improving the overall accuracy of leak detection.

[0097] A person skilled in the art who has been granted this disclosure will understand that a third aspect of this disclosure may include any of the features detailed in the first and second aspects of this disclosure, unless otherwise expressly excluded and interchangeable. In particular, note that the only difference in subject matter between the first and third aspects of this disclosure is that the automated laboratory apparatus of the first aspect improves the accuracy of leak detection through the extraction of two or more characteristics of pressure data, while the automated laboratory apparatus of the third aspect improves the accuracy of leak detection through the detection of leak events over two or more runs of the automated laboratory apparatus. Further note that the automated laboratory apparatus of the first aspect of this disclosure details an example in which a leak event is measured over two runs of the automated laboratory apparatus. This expressly indicates that the features of the automated laboratory apparatus of the third aspect of this disclosure may be used in combination with the features detailed in relation to the automated laboratory apparatus of the first aspect of this disclosure. The following describes an explicit example in which the subject matter first detailed in relation to the automated laboratory apparatus of the first aspect of this disclosure may be used in combination with the automated laboratory apparatus of the third aspect of this disclosure.

[0098] In some examples, the controller of an automated laboratory apparatus may be configured to receive pressure data from a pressure sensor, extract values ​​for each of one or more characteristics of the received pressure data, compare the extracted values ​​for one or more characteristics with their respective characteristic thresholds, and record a leakage event if each of the extracted values ​​exceeds its respective characteristic threshold.

[0099] In some cases, automated laboratory equipment may be configured to stop or pause the biological sample analysis process (e.g., corresponding to an automated laboratory run) when a leak event is recorded in at least two separate runs.

[0100] A fourth aspect of the present disclosure provides a leak detection method for an automated laboratory apparatus configured to analyze a biological sample, the method comprising: receiving pressure data from a pressure sensor configured to detect pressure in a channel of a pipette head; recording a leak event detected from the received pressure data; and determining that a leak is present in the pipette head by detecting and recording leak events in two or more runs of the automated laboratory apparatus.

[0101] By requiring the recording of leak events across multiple runs of the automated laboratory equipment, false positive leak events (such as the bursting of air bubbles in a pipette tip, which in other cases may result in a leak being recorded even though no leak occurred) are prevented from independently leading to a positive leak determination, thereby improving the overall accuracy of leak detection.

[0102] For the same reasons set forth above in relation to the third aspect of the Disclosure, a person skilled in the art who has been granted the Disclosure will immediately recognize that the features detailed in relation to the first, second, and third aspects of the Disclosure can be combined with the subject matter of the fourth aspect of the Disclosure.

[0103] Further aspects of the present invention provide a computer program that, when executed on a computer, causes the computer to perform the method of any of the preceding embodiments; a computer-readable medium for storing a computer program that, when executed on a computer, causes the computer to perform the method of any of the preceding embodiments; and a computer system programmed to perform the method of any of the preceding embodiments.

[0104] This disclosure includes combinations of the described embodiments and preferred features, unless such combinations are clearly unacceptable or expressly avoided. [Brief explanation of the drawing]

[0105] Next, embodiments and experiments illustrating the principles of this disclosure will be described with reference to the attached figures.

[0106] [Figure 1] This is a schematic diagram of an automated laboratory system. [Figure 2] This is a flowchart of the first method of leak detection. [Figure 3] This is a flowchart of the second method of leak detection. [Figure 4] Figures 2 and 3 are graph plots of pressure curves used to determine the optimal data analysis period for use in the leak detection method. [Figure 5] This is a graph plot of several additional pressure curves obtained in a similar manner to the pressure curve in Figure 4. [Figure 6] These are correlation histograms used to determine the optimal characteristic thresholds for use in the leak detection methods 1000 and 2000 shown in Figures 2 and 3. [Figure 7] These are graph plots of 20 pressures representing the samples of pressure curves used in the correlation histograms in Figures 6(a) to 6(f). [Modes for carrying out the invention]

[0107] Detailed explanation Hereinafter, aspects and embodiments of the present disclosure will be described with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art.

[0108] Figure 1 is a schematic diagram of an automated laboratory apparatus 100, which includes a workstation 20 supporting containers 22a and 22b, and an apparatus housing 160 positioned above the workstation 20 (on the page's reference frame).

[0109] The apparatus housing 160 includes a multi-channel pipette head 110 to which multiple pipette tips 120 can be connected for aspirating and dispensing fluids. More specifically, the multi-channel pipette head 110 is formed from a body 112 having multiple channels 114 extending internally, the distal end of each of the multiple channels 114 located on the distal end face of the body 112 and fluid-connectable to the corresponding pipette tip of the multiple pipette tips 120. The disclosure is not limited to a multi-channel pipette head. Automated laboratory apparatus may include pipette heads having one or more channels. When a pipette head has two or more channels, as in this example, the pipette head may be called a multi-channel pipette head.

[0110] In this example, the connection between the multiple pipette tips 120 and the multiple channels 114 is at the distal end face of the body 112. However, the disclosure is not limited to this form. For example, in some examples, the multichannel pipette head 110 may include multiple hollow tubular elements protruding from the body 112, each of which is aligned with the distal end of each of the multiple channels 114 to effectively extend each of the multiple channels 114 beyond the body 112. In such examples, the distal end of each hollow tubular element is connectable to the corresponding pipette tip of the multiple pipette tips 120 to fluidly connect each pipette tip to the corresponding channel of the multiple channels 114.

[0111] Each of the pipette tips 120 includes a fluid contact end that represents the furthest point of each pipette tip when connected to the multichannel pipette head 110. The fluid contact end of each pipette tip includes an opening through which fluid is drawn into and distributed from the corresponding pipette tip when the automated laboratory apparatus 100 is in use, as described below.

[0112] Returning to the multichannel pipette head 110, it further includes junctions within the body 112 where each of the multiple channels 114 merges into a parent channel 116. The parent channel 116 extends to the proximal end face of the body 112 opposite the distal end face of the body 112 to form a fluid connection surface through which other components of the automated laboratory apparatus 100 can fluidly connect to the multiple pipette tips 120 (e.g., the flow controller 130 and pressure sensor 140 described below). However, the disclosure is not limited to this form, and instead, each of the multiple channels 114 may extend to the proximal end face of the body 112, each being individually fluidly connectable to other components of the automated laboratory apparatus 100 (e.g., for one or more flow controllers and one or more pressure sensors; each of these components will be described in more detail below). In such an example, the body 112 may simply function to hold each of the multiple pipette tips 120 at a uniform distance from one another.

[0113] The automated laboratory apparatus 100 further includes a flow controller 130, a pressure sensor 140, and a controller 150, each of which is fluidically or electrically connected to the multichannel pipette head 110 as shown in Figure 1.

[0114] The flow controller 130, pressure sensor 140, and controller 150 are each housed inside the housing 160. Furthermore, the multichannel pipette head 110 is movably engaged with the outer surface of the housing 160, thereby allowing the multichannel pipette head 110 to move relative to the housing 160 along both the longitudinal axis (indicated by the double arrow 191) and the lateral plane perpendicular to the longitudinal axis 191. However, in other examples the housing 160 may be omitted, and / or the multichannel pipette head 110 may be attached to a separate operating mechanism (not shown) configured to allow the multichannel pipette head 110 to move in the lateral axis along the longitudinal axis 191.

[0115] The flow controller 130 is a pump / piston. The flow controller 130 is fluidly connected to the multichannel pipette head 110 via a connecting channel 132 that connects to the parent channel 116 via a fluid connection surface. As a result, the flow controller 130 is also fluidly connected to multiple pipette tips 120 via the multichannel pipette head 110. In another example, the flow controller 130 may be individually connected to each multichannel pipette head channel 114 / pipette tip so that the pressure inside each channel / pipette tip can be controlled individually (as described later).

[0116] The flow controller 130 is configured to control the fluid flow, and therefore the pressure, of the multiple pipette tips 120 so as to cause the aspiration or distribution of fluid through the openings of the fluid contact ends of each of the multiple pipette tips 120. For example, by pumping fluid (e.g., gas) from the multiple pipette tips 120 through the multiple channels 114, the flow controller 130 can decrease the pressure of the multiple pipette tips 120, and in this way, the fluid (e.g., air or liquid) is drawn in through the openings of the fluid contact ends of the multiple pipette tips 120. Conversely, the flow controller 130 can increase the pressure of the multiple pipette tips 120 by pumping fluid into the multiple pipette tips 120 from the multichannel pipette head 110, and in this way, the fluid can be distributed through the openings of the fluid contact ends of the multiple pipette tips 120.

[0117] The pressure sensor 140 is also connected to the multichannel pipette head 110 to measure the pressure in the channels of the multiple channels 114. Since each of the channels of the multiple channels 114 is fluidly connected to the corresponding pipette tip of the multiple pipette tips 120, this also means that the pressure sensor 140 can measure the pressure inside the multiple pipette tips 120. In this way, the pressure sensor 140 can collect pressure data about the pipette tips of the multiple pipette tips 120, which can be used to determine if there is leakage from the multichannel pipette head 110, as described below in relation to Figures 2 and 3. In other examples, the pressure sensor 140 may be connected individually to each multichannel pipette head channel 114 / pipette tip to measure the pressure inside each individual / collect each individual pressure data.

[0118] Finally, the controller 150 is electrically connected to the multichannel pipette head 110 and further electrically connected to both the flow controller 130 and the pressure sensor 140.

[0119] The controller 150 is configured to control the automated laboratory apparatus 100 through the execution of one or more runs of the biological sample analysis process, which may include the following steps: The step of lowering the multichannel pipette head 110 along the longitudinal axis 191 into the first container 22a (within the page's reference frame) until the fluid contact ends of multiple pipette tips 120 come into contact with the fluid held in the first container 22a, Steps include drawing a predetermined amount of liquid from the first container 22a into multiple pipette tips 120, Steps include raising the multichannel pipette head 110 from the first container 22a (within the page's reference frame) along the longitudinal axis 191, A step of aspirating a predetermined amount of gas into multiple pipette tips 120 such that a rear gap (TAG) buffer is provided between the aspirated fluid and the openings of the fluid contact ends of the multiple pipette tips 120, The multichannel pipette head 110 is moved in a lateral plane until it is aligned longitudinally with the second container 22b. The step of lowering the multichannel pipette head 110 into the second container 22b along the longitudinal axis 191, The steps include distributing TAGs held in multiple pipette tips 120, and A step of distributing the liquid held in multiple pipette tips 120 into a second container 22b.

[0120] The controller 150 is further configured to receive pressure data from the pressure sensor 140, as described below in relation to Figures 2 and 3, and to use the pressure data to detect and record leakage events of the multichannel pipette head 110. The leakage event is, for example, a droplet falling from one of the multiple pipette tips 120.

[0121] If a leak is detected in the multichannel pipette head, the controller 150 can control the automated laboratory apparatus 100 to shut down / stop the execution of the biological sample analysis process.

[0122] Figure 2 shows a first leak detection method 1000 that can be used by the controller 150 to determine whether the automated laboratory apparatus 100, more specifically the multichannel pipette head 110, of Figure 1 is leaking.

[0123] In step 1002, the controller 150 receives pressure data from the pressure sensor 140. The pressure data includes multiple measurements taken by the pressure sensor 140 at discrete intervals (e.g., every 5 ms) continuously throughout the entire execution of the analysis process of one or more biological samples performed by the automated laboratory apparatus 100.

[0124] Between steps 1002 and 1004, the controller 110 may define a data analysis period for each run of the biological sample analysis process, each data analysis period including a subset of the entire set of pressure measurements obtained for the run of the biological sample analysis process to which the data analysis period relates. The data analysis period can then be used as pressure data received in steps 1004-1006. In other words, the values ​​of each of two or more characteristics may be extracted from and associated with the data analysis period.

[0125] The determination of the optimal data analysis period will be discussed later in relation to Figure 4, but at this point, it should be noted that the data analysis period can correspond to the period during which the outer surface of each of the multiple pipette tips is not immersed in the liquid. For example, this occurs between the liquid aspiration step and the liquid distribution step described in relation to the given example of the biological sample analysis process described above.

[0126] More specifically, the data analysis period can correspond to the period during which the aspirated liquid is held at the opening of the fluid contact end. In other words, it is before the step of aspirating the TAG as clarified in the given example of the biological sample analysis process, or after the step of dispensing the TAG in the given example of the biological sample analysis process.

[0127] More specifically, the data analysis period may still correspond to the period during which the multichannel pipette head 110 is moving along the longitudinal axis 191. For example, this could be during either the upward or downward step of the multichannel pipette head 110 in the given example above of the analysis process of a biological sample.

[0128] More specifically, the data analysis period can still correspond to the period substantially immediately following the aspiration of the fluid by the multichannel pipette head 110. For example, this is during the upward step of the multichannel pipette head 110 in the given example above of the analysis process of a biological sample.

[0129] In steps 1004 to 1006, the controller 150 (hereinafter referred to as the "algorithm," for example, using a droplet detection algorithm) extracts values ​​for each of two or more characteristics of the received pressure data and compares the extracted values ​​of the two or more characteristics with their respective characteristic thresholds.

[0130] Next, the algorithm may proceed to compare the extracted values ​​of two or more characteristics with the respective characteristic thresholds.

[0131] Two or more properties may include one or more of the following: pressure magnitude, rate of change of pressure (slope), and standard deviation of the rate of change of pressure.

[0132] If one of the characteristics is the magnitude of pressure, the corresponding characteristic value can be extracted by selecting a pressure measurement from among several pressure measurements constituting the pressure data, or by selecting a shortened data analysis period, which best fits a given single or multiple criteria. This given single or multiple criteria may be the selection of the largest pressure measurement obtained, in which case the extracted value is the largest pressure measurement in the pressure data / data analysis period. Alternatively, the given single or multiple criteria may be the selection of the smallest pressure measurement obtained, in which case the extracted value is the smallest pressure measurement in the pressure data / data analysis period. The magnitude of pressure can be measured in Pascals.

[0133] If one of the characteristics is the rate of change of pressure, the corresponding characteristic value can be extracted by measuring the rate of change of pressure between each adjacent pair of multiple pressure measurements of the pressure data and selecting the resulting rate of change that best fits a given single or multiple criterion. The given single or multiple criterion may be the selection of the maximum rate of change or the minimum rate of change. The rate of change of pressure can be measured as the time derivative of Pascal (Pa / s).

[0134] If one of the characteristics is the standard deviation of the rate of change of pressure, the corresponding characteristic value can be extracted by measuring the rate of change of pressure between each adjacent pair of multiple pressure measurements of the pressure data, determining the average rate of change using the determined rate of change values, and then determining the standard deviation of the average rate of change. The standard deviation of the rate of change of pressure can be measured as the derivative of Pascals with respect to time, Pa / s.

[0135] In addition to the above, when defining the data analysis period from pressure data, two or more characteristics may include a pressure delta representing the difference between the maximum pressure measured during the data analysis period and the minimum pressure measured during the data analysis period. The values ​​extracted for the delta pressure characteristics may be equivalent to both the maximum delta pressure threshold and the minimum delta pressure threshold. Alternatively, the modulus of the delta pressure threshold value can be obtained to obtain the absolute value of the delta pressure threshold, and this absolute value can be compared to a single absolute delta pressure threshold.

[0136] In some examples, multiple values ​​are extracted for one or more of the two or more characteristics, and each of these values ​​is compared to a separate characteristic threshold. For example, if the characteristics are the magnitude of pressure or the rate of change of pressure, both the maximum and minimum values ​​for each characteristic can be extracted, and each value for each characteristic can be compared to its respective characteristic threshold.

[0137] In some examples, the controller 150 may extract values ​​for each characteristic from the received pressure data using an algorithm that takes the average across multiple pressure measurements made by the pressure sensor 150. For example, the algorithm may take the moving median of multiple (e.g., 5, 10, 15, 20, or 20+) adjacent pressure measurements of the pressure data, and / or the algorithm may also take a moving average of multiple (e.g., 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, or 80+) pressure measurements of the pressure data to generate a set of averaged pressure data consisting of the averaged pressure measurements. The algorithm can then extract values ​​for each characteristic from the averaged pressure data. However, the disclosure is not limited to this form.

[0138] In step 1008, the controller 150 records a leakage event when each of the extracted values ​​exceeds its respective characteristic threshold.

[0139] Following step 1008, the controller 150 may be configured to stop the biological sample analysis process being performed by the automated laboratory apparatus 100 when a set number of leak events are detected. For example, when one, two, three, or more than three leak events are detected. In some examples, the controller 150 may be configured to stop the biological sample analysis process when a leak event is detected in a specified number of consecutive runs. In some examples, the controller 150 may be configured to stop the biological sample analysis process when a leak event is detected in at least two runs of the biological sample analysis process.

[0140] Figure 3 shows a second leak detection method 2000 that can be performed by the controller 150 to determine whether the automated laboratory apparatus 100, more specifically the multichannel pipette head 110, of Figure 1 is leaking.

[0141] In step 2002, similar to step 1002, the controller 150 receives pressure data from the pressure sensor 130.

[0142] In step 2004, the controller 150 is configured to record leak events detected from the received pressure data. For example, the controller 150 may extract one or more values ​​for each of one or more characteristics of the received pressure data, compare one or more extracted values ​​for one or more characteristics with one or more respective characteristic thresholds, and record a leak event when each of the one or more respective characteristic thresholds is exceeded. Similar to the first leak detection method 1000, the characteristics may include pressure magnitude, rate of change of pressure, standard deviation of the rate of change of pressure, and / or a delta pressure threshold representing the difference between the maximum / minimum pressure values ​​measured during the data analysis period.

[0143] In step 2006, the controller determines that a leak exists in the multichannel pipette head 110 by detecting and recording leak events over multiple runs of the automated laboratory apparatus 100 (where “run” is the execution of an analytical process of a biological sample). More specifically, the controller 150 is configured to maintain a summary of leak events and increment the summary by 1 each time a leak event is detected. In other examples, the controller is configured to maintain separate summaries of leak events for each channel and increment each of the respective leak event summaries each time a leak event is detected in the channel to which the respective leak event summaries per run are related. In some examples, the controller 150 is configured to measure a maximum of one leak event per run, but the disclosure is not limited to this configuration, and the controller may instead be configured to measure any number of leak events in each run.

[0144] Following step 2006, the controller 150 may be configured to stop the biological sample analysis process when a leak event is recorded in at least two separate runs of the automated laboratory apparatus 100.

[0145] In a more specific example, the controller 150 may be configured to stop or pause the biological sample analysis process if a leak event is recorded in at least two adjacent runs of the automated laboratory apparatus 100. More specifically, the controller 150 may maintain two separate leak detection tally, the two tally being used in alternating runs of the automated laboratory apparatus 100 (e.g., the first tally being used in the first run, the second tally in the second run, the first tally in the third run, the second tally in the fourth run, and so on), and each of the respective tally may be reset to zero before subsequent use. The controller may then be configured to stop the biological sample analysis process when both the first and second tally are non-zero.

[0146] Figure 4 is a graph plot of pressure curves used to determine the optimal data analysis period for use in the leak detection methods 1000 and 2000 of Figures 2 and 3. The pressure curves were obtained from an automated laboratory apparatus, such as the automated laboratory apparatus 100 shown in Figure 1, which performed the analysis process of a biological sample. The analysis process of the biological sample included a multichannel pipette head moving to a container containing liquid dissolved waste, aspirating 700 μL of the liquid dissolved waste, moving the pipette head away from the liquid dissolved waste and container, and aspirating the TAG. The time between moving away from the liquid dissolved waste and aspirating the TAG was approximately 2.5 seconds, during which 500 measurements (data points) were created at 5 ms intervals by a pressure sensor fluid-connected to a single channel of the multichannel pipette head.

[0147] Based on the following three reference points, the inventors identify the optimal period in this pressure curve for detecting a leak event (e.g., the optimal data analysis period available by the controller 150 in Figure 1 while performing the methods in Figures 2 and 3) as the time from when the multichannel pipette head leaves the dissolution waste liquid until the TAG is aspirated. Since droplet formation is not instantaneous, the correct steps allow for observation of potential droplet formation over several seconds. Since this delays droplet formation and distorts the shape of the pressure curve, subsequent air gaps (TAGs) should not be aspirated during the observation period for reliable droplet detection. Other anomalies from automated laboratory equipment should not significantly impact the data analysis period. An example is the pressure changes caused when a multichannel pipette head is moved into or removed from the liquid being aspirated, as seen in the pressure curves around data points 500 and 1800.

[0148] In other words, the inventors identified the period between 2000 and 2500 data points as the optimal data analysis period. During a period lasting several seconds (Criterion 1), the TAG was not aspirated (Criterion 2), and no other anomalies from the automated laboratory equipment were expected to significantly affect the pressure curve (Criterion 3).

[0149] Figure 5 is a graphical plot of several additional pressure curves obtained in a similar manner to the pressure curve in Figure 4, using seven different multichannel pipette heads. Visual inspection revealed that only the multichannel pipette heads that produced the pressure curves indicated by the arrows showed visible signs of leakage. In Figure 5, the pressure curves shown exhibit much larger pressure magnitude fluctuations over the 2000–2500 data point range, further supporting the inventors' identification of this period as the optimal time for detecting leakage events.

[0150] Figures 6(a) to 6(f) are correlation histograms used to determine the optimal characteristic thresholds for use in the leak detection methods 1000 and 2000 in Figures 2 and 3.

[0151] The correlation histogram is plotted using data extracted from pressure curves obtained in a similar manner to the pressure curves in Figures 4 and 5. More specifically, this dataset includes 619,728 pressure curves measured using 12 automated laboratory devices similar in nature to automated laboratory device 100, each pressure curve obtained while one of the 12 automated laboratory devices was performing an analytical process of a biological sample in which liquid was aspirated into a multichannel pipette head / multiple pipette tips.

[0152] As clearly shown in Figures 4 and 5, each of the 619,728 pressure curves was analyzed during the optimal data analysis period, and the following characteristics were extracted. Pressure delta: Obtained by measuring the difference between the maximum pressure and the minimum pressure during the data analysis period. Std gradient: Obtained by measuring the standard deviation of the average rate of change of pressure during the data analysis period. Maximum gradient: Obtained by measuring the maximum rate of change in pressure during the data analysis period. Min Gradient: Obtained by measuring the minimum rate of change of pressure (which may be a negative number) during the data analysis period.

[0153] Next, this data is used to obtain the correlation histograms shown in Figures 6(a) to 6(f). Figure 6(a) shows the pressure delta plotted against the std gradient, Figure 6(b) shows the pressure delta plotted against the max gradient, Figure 6(c) shows the pressure delta against the min gradient, Figure 6(d) shows the std gradient plotted against the max gradient, Figure 6(e) shows the std gradient plotted against the min gradient, and Figure 6(f) shows the max gradient plotted against the min gradient.

[0154] For each feature, the detected values ​​indicate areas with high incidence. High incidences are located at the points in the histogram with the highest data point density. In each histogram, this is near the (0,0) coordinate marker. These are all from normal / ideal aspiration curves (e.g., no leaks in the multichannel pipette head). From these main clusters, several clusters with low incidences can be seen. These clusters are shown in the circled areas of the histogram and are formed from three different error patterns. More specifically, Minimum Droplet Volume: As the droplet size exceeds the opening of the pipette tip, the pressure increases somewhat more gradually, then decreases more rapidly. Droplet formation at the pipette tip is clearly visible in the pressure curve. This may occur multiple times within the optimal data analysis period of 2.5 seconds mentioned above. Severe leakage: Liquid leaks out from the tip, and droplets form rapidly and randomly, resulting in a somewhat random pattern in the pressure curve. Insufficient liquid in the container being aspirated by a multichannel pipette head: The pressure curve either remains completely flat or shows a single jump or drop. This is likely due to an air bubble bursting inside the pipette tip.

[0155] Some clusters from the various error patterns shown in Figures 6(a)-(f) do not show a clear separation from the major cluster at the (0,0) coordinate of the histogram. This is because the leakage increases gradually. Channels in a multichannel pipette head may begin to leak slightly. This leads to droplet formation, which is shown as a gradual increase in pressure. Subsequently, single droplets, multiple droplets, and finally large leaks occur. Therefore, there is no clear separation between pipetting channels that have not yet shown droplets and pipetting channels that are already leaking slightly.

[0156] Of the 619,728 pressure curves, 3,352 triggered the droplet / leak detection algorithm. All of these curves were visually reviewed, and only a few could not be clearly identified as leak curves. Further analysis of the pressure curves for the full execution of the suspicious curves was performed, but it remains unclear whether leaks occurred in some cases.

[0157] With this in mind, the inventors have selected algorithmic thresholds to enable the detection of the minimum amount of leakage from a single droplet, based on the fact that otherwise, a major leakage event might go undetected as a result of minimal leakage events not being detected, which would otherwise accumulate to form a single major leakage event.

[0158] In particular, the optimal characteristic thresholds for use in the leak detection methods shown in Figures 2 and 3 are as follows: Maximum delta pressure threshold: 25 Pascals Minimum delta pressure threshold: -25 Pascals Standard deviation of pressure change rate: 0.25 Pa / dt (50 Pa / s) Maximum pressure change rate: 0.1 Pa / dt (20 Pa / s) Minimum pressure change rate: -0.1 Pa / dt (-20 Pa / s)

[0159] In the above, dt refers to "per data point". Using a pressure sensor that measured every 5ms (for example, dt = 0.005 seconds), 619,728 pressure curves were obtained.

[0160] Figure 7 shows a selection of 20 “error” pressure curves plotted in the graph of Figure 7, each forming part of the 619,728 pressure curves used to obtain the correlation histograms in Figures 6(a)–(f). Each curve shows the delta pressure (Δp), the maximum rate of change of pressure (slope). max ), minimum rate of change of pressure (gradient) min ), and the standard deviation of the rate of change of pressure (slope σThis includes the value of ). From this selection, only the curve marked with an arrow at the bottom is suspicious. All others show clear signs of leakage.

[0161] Features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, and represented in their specific forms, or with respect to means for performing the disclosed functions or methods or processes for obtaining the disclosed results, may be used, individually or in any combination thereof, as necessary, to implement the present disclosure in its various forms.

[0162] While this disclosure has been described in relation to the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art in light of this disclosure. Therefore, the exemplary embodiments of this disclosure described above are illustrative and not limiting. Various modifications to the embodiments described may be made without departing from the spirit and scope of this disclosure.

[0163] To avoid any misunderstanding, any theoretical explanations provided herein are provided solely for the purpose of improving the reader's understanding. The inventors do not wish to be bound by any of these theoretical explanations.

[0164] Any headings used herein are for organizational purposes only and should not be construed as limiting the subjects described.

[0165] Throughout this Spec., including the following claims, unless the context requires otherwise, the words “comprise” and “include,” as well as variations such as “comprises,” “comprising,” and “including,” will be understood to mean the inclusion of the integer or step or group of integers or steps described, but not the exclusion of any other integer or step or group of integers or steps.

[0166] It should be noted that the singular forms “a,” “an,” and “the” as used herein and in the appended claims include multiple referents unless the context clearly indicates otherwise. Ranges may be expressed herein as “about” one particular value to and / or “about” another particular value. When such ranges are expressed, another embodiment includes one particular value to and / or other particular values. Similarly, the use of the antecedent “about” will be understood to mean that a particular value forms another embodiment when the value is expressed as an approximation. The term “about” with respect to numbers is arbitrary and means, for example, + / - 10%.

Claims

1. An automated laboratory apparatus for analyzing biological samples, wherein the automated laboratory apparatus is A pipette head having a channel, wherein the channel is connectable to a corresponding pipette tip, and a fluid is drawn in and distributed through the pipette tip, A flow controller configured to control the flow of the fluid through the channel of the pipette head, A pressure sensor configured to detect the pressure in the channel of the pipette head and to collect pressure data of the channel, and The controller is connected to the pressure sensor, and the controller is The pressure data is received from the pressure sensor. Values ​​are extracted for each of the two or more characteristics of the received pressure data. The extracted values ​​of the two or more characteristics are compared with their respective characteristic thresholds. An automated laboratory apparatus configured to record a leakage event when each of the extracted values ​​exceeds its respective characteristic threshold.

2. The automated laboratory apparatus according to claim 1, wherein the two or more characteristics include one or more of the magnitude of the pressure, the relative pressure, the rate of change of the pressure, and the standard deviation of the rate of change of the pressure.

3. If a predetermined number of temporally separated leakage events are recorded, the controller will: To stop or pause the analysis process of biological samples being performed by the automated laboratory apparatus, or The automated laboratory apparatus according to claim 1 or 2, configured to put the automated laboratory apparatus into an error state after the analysis process of the sample being performed is completed, so as not to be able to start any further sample analysis processes.

4. The automated laboratory apparatus according to any one of claims 1 to 3, wherein the controller extracts each of the values ​​of the characteristics from the received pressure data using an algorithm that averages over a plurality of pressure measurements performed by the pressure sensor.

5. The automated laboratory apparatus according to any one of claims 1 to 4, wherein the pressure sensor is configured to continuously record the pressure in the channel of the pipette head.

6. The automated laboratory apparatus according to any one of claims 1 to 5, wherein the controller is configured to determine a data analysis period in the received pressure data during which the values ​​of each of the two or more characteristics of the pressure data are extracted.

7. The automated laboratory apparatus according to claim 6, wherein the data analysis period corresponds to the period during which the outer surface of the pipette tip is not immersed in the liquid.

8. The automated laboratory apparatus according to claim 6 or 7, wherein the data analysis period corresponds to the period during which the pipette head moves along the longitudinal axis through which the channel of the pipette head extends.

9. The automated laboratory apparatus according to any one of claims 6 to 8, wherein the data analysis period corresponds to the period substantially immediately following the aspiration of the fluid by the pipette head.

10. The automated laboratory apparatus according to any one of claims 1 to 9, further configured to perform multiple runs of the analysis process of a biological sample, wherein the pressure sensor is configured to record pressure data over the multiple runs of the analysis process of the biological sample.

11. The automated laboratory apparatus according to claim 10, wherein the controller is configured to determine the data analysis period corresponding to each of the plurality of executions.

12. If a leakage event is detected during at least two executions of the analysis process of the biological sample, the controller shall If a leakage event is detected during at least two executions of the analysis process for the biological sample, the analysis process for the biological sample may be stopped or paused, or The automated laboratory apparatus according to claim 11, configured to put the automated laboratory apparatus into an error state after the analysis process of the sample being performed is completed, so as not to start any further analysis processes of samples.

13. A leak detection method for an automated laboratory apparatus configured to analyze biological samples, wherein the leak detection method is A step of receiving pressure data from a pressure sensor configured to detect the pressure inside the channel of a pipette head, A step of extracting values ​​for each of two or more characteristics of the received pressure data, A step of comparing the extracted values ​​of each of the two or more characteristics with their respective characteristic thresholds, A method comprising the step of recording a leakage event when each of the extracted values ​​exceeds its respective characteristic threshold.

14. An automated laboratory apparatus for analyzing biological samples, wherein the automated laboratory apparatus is A pipette head having a channel, wherein the channel is connectable to a pipette tip, and a fluid is drawn in and distributed through the pipette tip, Means for controlling the flow of the fluid through the channel of the pipette head, A pressure sensor configured to detect the pressure inside the channel of the pipette head and to collect pressure data of the channel, and A controller connected to the pressure sensor, the controller being configured to record leakage events detected from pressure data received from the pressure sensor, The automated laboratory apparatus is configured to determine that a leak exists in the pipette head by detecting and recording leak events during two or more runs of the automated laboratory apparatus.

15. A leak detection method for an automated laboratory apparatus configured to analyze biological samples, wherein the leak detection method is A step of receiving pressure data from a pressure sensor configured to detect the pressure inside the channel of a pipette head, The steps include recording the leakage event detected from the received pressure data, and A method comprising the step of determining that a leak exists in the pipette head by detecting and recording leak events during two or more runs of the automated laboratory apparatus.

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