Gradient ultracentrifugation collection device

Abstract

The present disclosure relates to improved liquid handling systems and associated methods for collecting, separating, dispensing, or transporting liquid containing selected desired portions of a liquid sample to a desired location. Some examples provided in the present disclosure relate to extracting a substance of interest from a layered, graduated, or separated sample.

Description

[Technical field]

[0001] The embodiments described in this disclosure relate generally to improved processes for identifying and extracting a material of interest from a layered, graded, or partitioned sample.

[0002] (Related Applications) This application claims the benefit of U.S. Provisional Application No. 63 / 362,489, entitled "GRADIENT ULTRACENTRIFUGATION AUTOMATED COLLECTOR," filed April 5, 2022, which is incorporated by reference in its entirety into this disclosure. [Background technology]

[0003] Unit operations for processing collected biological samples involve preferential separation of desired and undesired molecular species. In particular, gradient separation allows for the preferential separation of certain molecular species based on their inherent physiochemical properties. Optimizing unit operations at this stage can improve overall purity and yield and reduce processing time. Summary of the Invention

[0004] Existing methods, processes, and machines for extracting substances of interest from samples layered, graded, or separated by ultracentrifugation are very labor intensive. The lack of automation of these methods, processes, and machines increases the potential for inconsistency, operator variability, and product contamination. When performed manually, an operator extracting a substance of interest from a sample layered, graded, or separated by ultracentrifugation must visually inspect the sample to determine the boundary conditions and the specific layer, gradation, or partition in which the substance of interest resides, and finally extract the substance of interest from only the determined layer, gradation, or partition. Repeating this process across many sample sets can result in reproducibility issues, measurement errors, and cross-contamination of samples. Additionally, some regulatory compliance rules when formulating compounds for pharmaceutical use may require lower error rates and cross-contamination than would be possible using manual methods.

[0005] Existing labor-intensive methods, processes, and machines for extracting substances of interest from layered, graded, or separated samples have limited progress toward certain regulatory compliance of manufacturing processes due to reproducibility issues. Thus, the present disclosure is directed to providing progress toward regulatory compliance of highly labor-intensive manufacturing processes while increasing reproducibility, reducing operator variability, and reducing the potential for product contamination.

[0006] Provided herein are methods and systems relating to separating products.

[0007] Accordingly, the present disclosure provides an automated liquid handling system. In some embodiments, the liquid handling system includes an imaging station and a collection device. In some embodiments, the automated liquid handling system includes an imaging station, a collection device, and a control computer. In some embodiments, the imaging station is configured to image the sample and transmit the sample images to the control computer. In some embodiments, the imaging station and the collection device are operably connected to the control computer. In some embodiments, the imaging station, the collection device, and / or the control computer are operably connected via a wired connection. In some embodiments, the imaging station, the collection device, and / or the control computer are operably connected via a wireless connection. In some embodiments, the sample images are transmitted to the control computer via a wired connection. In some embodiments, the sample images are transmitted to the control computer wirelessly. In some embodiments, the control computer is configured to process the sample images. In some embodiments, the control computer is configured to instruct the collection device to transfer a defined extraction volume from the sample to a sample collection container. In some embodiments, the control computer is configured to automatically calculate the defined extraction volume. In some embodiments, an operator defines the extraction volume. In some embodiments, the automated liquid handling system includes an imaging station, a collection device, and a control computer.

[0008] In some embodiments, the imaging station and the collector are separate components. In some embodiments, the imaging station and the collector are integrated into a single system. In some embodiments, one or more of the imaging station, the collector, and the control computer are separate components. In some embodiments, one or more of the imaging station, the collector, and the control computer are integrated into a single system. In some embodiments, the imaging station includes a sample storage device, a light source, and an imaging device. In some embodiments, the sample storage device, the light source, and the imaging device are integrated into a single imaging station. In some embodiments, the automated liquid handling system further includes a Graphical User Interface (GUI) or monitor operably connected to the control computer. In some embodiments, one or more of the imaging station, the collector, the collection container, the control computer, or the graphical user interface or monitor are integrated into a single functional system.

[0009] In some embodiments, the imaging device comprises a camera. In some embodiments, the sample store comprises a tube rack. In some embodiments, the sample store comprises a multi-well plate rack. In some embodiments, the sample store has a particular opacity. In some embodiments, the light source corresponds to a particular opacity of the sample store. In some embodiments, the light source is located above, below, or at an angle to the sample store. In some embodiments, the light source is located above the sample store. In some embodiments, the light source is located below the sample store. In some embodiments, the light source is located at an angle to the sample store. In some embodiments, the light source, light source position, and opacity of the sample store are collectively selected for suitability of their combination for imaging samples contained in the sample store.

[0010] In some embodiments, the collection apparatus includes a collection arm and a collection device. In some embodiments, the collection device is removably attached to the collection arm. In some embodiments, the collection arm is configured to be instructed by the control computer to move in three dimensions, including in the x-, y-, and z-directions. In some embodiments, the control computer instructs the collection device to move laterally, horizontally, and / or vertically along the collection arm. In some embodiments, the control computer instructs the control arm to move vertically on its y-axis. In some embodiments, the control computer instructs the control arm to move laterally on its x-axis. In some embodiments, the light source is integrated into the collection arm. In some embodiments, the control computer instructs the collection arm to position the collection device at a predetermined extraction coordinate.

[0011] In some embodiments, the collection device includes a means for transferring the sample from the sample storage device to the sample collection container. In some embodiments, the collection device includes a pipette. In some embodiments, the collection device includes a needle and a syringe. In some embodiments, the collection device includes a vacuum. In some embodiments, the automated liquid handling system further includes a tip rack. In some embodiments, the automated liquid handling system further includes a tip waste container.

[0012] In some embodiments, a method for automatically extracting a substance from a sample is disclosed. In some embodiments, the disclosed method for automatically extracting a substance from a sample includes the steps of loading the sample into an imaging station, illuminating the sample, imaging the illuminated sample, transmitting the sample image to a control computer, calculating an extraction volume and extraction coordinates based on the sample image, instructing a collection arm to direct a collection device to the calculated extraction coordinates, aspirating the calculated extraction volume from the sample into the collection device, and instructing the collection arm to direct the collection device to a collection container located at a predetermined coordinate and dispensing the extraction volume into the collection container. In some embodiments, the method for automatically extracting a substance from a sample further includes repeating the steps described above for each of n samples, where n is a non-negative integer.

[0013] In some embodiments, a method for automatically extracting a substance from a sample includes loading one or more samples into an imaging station, illuminating one or more samples to capture one or more illuminated sample images, capturing one or more illuminated sample images, transmitting one or more sample images to a control computer, calculating an extraction volume and extraction coordinates based on the sample images, directing a collection arm to direct a collection device to the calculated extraction coordinates, aspirating the calculated extraction volume from one or more samples into the collection device, directing the collection arm to direct the collection device to one or more collection containers, and dispensing the extraction volume into one or more collection containers. In some embodiments, the method for automatically extracting a substance from a sample further includes repeating the steps described above for each of the one or more samples.

[0014] In some embodiments, the method for automatically extracting a substance from a sample further comprises disposing of the used tip after dispensing the extracted sample volume into a collection device.

[0015] In some embodiments, the step of calculating the extraction amount and the extraction coordinates based on the sample image comprises the step of defining an extraction boundary. In some embodiments, the step of defining the extraction boundary is performed by a control computer. In some embodiments, the step of defining the extraction boundary is performed by an operator. In some embodiments, the operator is a computer program. In some embodiments, the operator is a human being.

[0016] In some embodiments, the method for automatically extracting material from a sample further comprises centrifuging the sample prior to the loading step into the imaging station. In some embodiments, the sample comprises a layered sample, a graded sample, or a separated sample. In some embodiments, the material extracted comprises a layer, stage, or portion of a layered sample, a graded sample, or a separated sample. In some embodiments, the method for automatically extracting material from a sample further comprises one or more samples prior to the loading step. In some embodiments, the one or more samples comprise a layered sample, a graded sample, or a separated sample. In some embodiments, the material extracted comprises a layer, stage, or portion of a layered sample, a graded sample, or a separated sample. [Brief description of the drawings]

[0017] [Figure 1] 1 is a schematic diagram of a non-limiting example of an improved liquid treatment machine. [Diagram 2] 1 is a flow chart of a non-limiting example of a process for automatically extracting substances from a layered, graduated, or separated sample. [Diagram 3]FIG. 1 is a schematic diagram of a non-limiting example of a computing system configured to control one or more aspects of the liquid treatment system disclosed in the present disclosure. [Figure 4] Non-limiting illustrations of images showing some examples of setpoints close to the desired extraction band (left) and extraction results with high aspiration speed (right). [Diagram 5] Non-limiting illustrations of images showing some examples of set points below and above the desired extraction band (left side) and extraction results with low aspiration speed (right side). [Figure 6] Table showing some examples of recovery of capsids from tubes with different set heights and different aspiration rates. [Figure 7] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 8] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 9] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 10] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 11] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 12] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 13] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) [Figure 14] Non-limiting illustrations of images showing some examples of set points (left) and recovery (right) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Although certain preferred embodiments and examples are disclosed below, the scope of protection of the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or applications, as well as modifications and equivalents thereof. Thus, the scope of the invention of the present disclosure is not limited by any of the specific embodiments described below. For example, in any method or process disclosed in this disclosure, the acts or operations of the method or process can be performed in any suitable order and are not necessarily limited to any of the specific sequences disclosed. Various operations may be described as multiple discrete operations that are ordered in a manner that may be helpful to understand a particular embodiment. However, the order of description should not be construed to make these operations dependent on the order of description. Furthermore, the structures, systems, and / or devices described in this disclosure may be implemented as integrated or separate parts. For purposes of comparing various embodiments, certain aspects and advantages of these embodiments are described. It is not necessary that all such aspects or advantages are achieved by a particular embodiment. Thus, for example, various embodiments can be implemented in a manner that achieves or optimizes one advantage or group of advantages taught in the present disclosure, without necessarily achieving other aspects or advantages taught or suggested by the present disclosure.

[0019] Specific embodiments in the present disclosure are described to provide a general understanding of the principles of the structure, function, manufacture, and application of the devices and methods disclosed in the present disclosure. One or more examples of these embodiments are shown in the accompanying drawings. Those skilled in the art will understand that the devices and methods specifically described in the present disclosure and shown in the accompanying drawings are non-limiting examples, and that the scope of protection of the present invention is defined only by the claims. Features shown or described in connection with one embodiment can be combined with features of other embodiments. Such modifications and variations are intended to be included within the scope of the present technology.

[0020] Existing methods for identifying and extracting materials of interest from layered, graded, or separated samples by centrifugation, i.e., gradient ultracentrifugation, are limited because they require an operator to visually inspect each sample to determine the location of the desired density gradient separated material, such as DNA-containing viral particles, from empty particles. The material is then manually extracted from the layered, graded, or separated sample using a means such as a needle and syringe, or a pipette. To extract the material of interest, the operator must manually push a needle through the wall of the centrifuge tube into the identified layer, stage, or portion of interest. The material is then extracted into a syringe for further processing. The operator must manually repeat this process for each sample. Other methods, such as the CsCl gradient, can use the refractive index of a density gradient to separate materials of interest by density. This refractive index can be compared to a reference range of refractive indexes in which the materials of interest reside. The gradient may then be separated into portions based on refractive index cutoffs using a blunt end needle connected to a syringe with the needle located at the bottom of the centrifuge tube. The substance of interest may then be extracted into a syringe for further processing.

[0021] Existing methods, processes, and machines for extracting substances of interest from layered, graded, or separated samples require a large amount of manual labor. The lack of automation in these methods, processes, and machines increases the likelihood of inconsistency, operator error, operator variability, and product contamination. Some embodiments of the present disclosure relate to improved computerized liquid handling devices that automate the process of substance extraction. Some embodiments of the present disclosure relate to methods and systems for product separation.

[0022] Some embodiments of the present disclosure relate to an automated (e.g., robotic) method for collecting a desired portion from an ultracentrifuge tube. In some embodiments, one or more tubes are inoculated with the same viral load, and each of the one or more tubes has the same CsCl concentration. The same centrifugation or spin or parameters are then applied to the one or more tubes, resulting in the same or substantially identical band separation in each of the one or more tubes. Thus, a single tube can be used to set the exact collection point and collection volume for extraction of the desired material. This extraction can be repeated for each subsequent tube. The speed and reproducibility allows for an automated collection process, eliminating current industry bottlenecks and improving product quality in the manufacture of gene therapy products.

[0023] Provided in the present disclosure are methods and systems relating to separating desired portions of a product, such as a liquid product, from undesired portions.

[0024] In some embodiments, an automated liquid handling system is disclosed, the liquid handling system including an imaging station and a collection device operably connected to a control computer. Images of samples are captured and transmitted from the imaging station to the operably connected control computer. The control computer processes one or more sample images to direct the collection device to transfer a defined extraction volume from a particular location in one or more of the n samples to a sample collection container.

[0025] In some embodiments, the imaging station includes a sample store, a light source, and an imaging device. In some embodiments, the imaging device includes a camera. In some embodiments, the sample store includes a tube rack. In some embodiments, the sample store includes a multi-well plate rack. In some embodiments, the opacity of the sample store is selected for use in imaging samples illuminated by a particular light source. In some embodiments, the light source is selected for use in imaging samples contained in a sample store having a predetermined opacity. In some embodiments, the light source is located below the sample store.

[0026] In some embodiments, the disclosed system further comprises a graphical user interface or monitor operably connected to the control computer. In some embodiments, the collection apparatus comprises a collection arm and a collection device. In some embodiments, the collection device is removably attached to the collection arm. In some embodiments, the collection arm further comprises mechanical means for moving the collection device laterally along the collection arm.

[0027] In some embodiments, the control computer instructs the collection device to move laterally along the collection arm. In some embodiments, the collection arm is configured to be instructed by the control computer to move in the x, y, and z directions. In some embodiments, the control computer instructs the control arm to position the collection device at a predetermined extraction coordinate. In some embodiments, the collection device includes a pipette. In some embodiments, the collection device includes a needle and a syringe. In some embodiments, one or more of the imaging station, the collection device, the collection container, or the control computer are integrated into a single functional unit. In some embodiments, the disclosed system further includes a tip rack. In some embodiments, the disclosed system further includes a tip waste container.

[0028] In some embodiments, a method for automatically extracting substances from samples is disclosed, the method comprising: a) loading n samples into an imaging station; b) illuminating the samples; c) imaging the illuminated samples; d) sending one or more sample images to a control computer; e) displaying one or more sample images to an operator, who defines an extraction boundary; f) calculating an extraction volume and extraction coordinates based on the defined extraction boundary; g) instructing a collection arm to direct a collection device to the calculated extraction coordinates; h) aspirating the calculated extraction volume from the sample into the collection device; i) instructing the collection arm to direct the collection device to an appropriate depth in a collection container located at a predetermined coordinate; j) dispensing the extraction volume into the collection container; k) repeating steps b to j for each of the n samples; and l) instructing the control arm to direct the collection device to a predetermined home position.

[0029] In some embodiments, the disclosed method further comprises centrifuging the n samples prior to loading the n samples into the imaging station. In some embodiments, one or more of the n samples comprise a layered sample, a graded sample, or a separated sample. In some embodiments, the extracted material comprises a layer, stage, or portion of a layered sample, a graded sample, or a separated sample.

[0030] In some embodiments, a method for automatically extracting material from a sample is disclosed, the method comprising the steps of: a) loading n samples into an imaging station; b) illuminating the samples; c) imaging the illuminated samples; d) sending one or more sample images to a control computer; e) displaying one or more sample images to an operator; f) the operator defining an extraction boundary; g) calculating an extraction amount and extraction coordinates based on the defined extraction boundary, instructing a collection arm to direct a collection device above a tip in a tip rack located at a predetermined coordinate, instructing the collection device to pick up the tip at a first end of the collection device; and h) collecting the sample at the determined extraction coordinates. the step of aspirating a calculated extraction volume from the sample into the collection device; the step of directing the collection arm to direct the collection device to an appropriate depth in a collection container located at predetermined coordinates; the step of dispensing the extraction volume into the collection container; the step of directing the collection arm to direct a first end of the collection device with the tip to a coordinate suitable for tip disposal above or within a tip waste container located at predetermined coordinates; the step of directing the collection arm to direct a first end of the collection device with the tip to a coordinate suitable for tip disposal above or within a tip waste container located at predetermined coordinates; the step of directing the collection device to dispense a used tip into the tip waste container; the step of repeating steps b through o for each of the n samples; and the step of directing the control arm to direct the collection device to a predetermined home position.

[0031] In some embodiments, the method further comprises centrifuging the n samples prior to loading the samples into the imaging station. In some embodiments, the samples comprise layered samples, graded samples, or separated samples. In some embodiments, the extracted material comprises one layer, stage, or portion of a layered sample, graded sample, or separated sample.

[0032] <Automatic liquid treatment device> FIG. 1 is a schematic diagram of a non-limiting embodiment of an improved liquid handler.

[0033] Currently, methods of extracting substances of interest from layered, graded, separated, or otherwise separated or divided samples are labor intensive. An automated liquid handling device 100 is provided. An operator loads samples into a sample storage device, such as a tube rack 101 in an imaging station 102. In some embodiments, centrifuge tubes are collected after ultracentrifugation, such as gradient ultracentrifugation. In some embodiments, the sample storage device is transparent. In some embodiments, the sample storage device is opaque. The sample storage device has an opacity selected for use with a desired light source 103. In some embodiments, the opacity of the sample storage device is selected for suitability for use in imaging layered, graded, or separated samples 104 contained within tubes in the sample storage device. In some embodiments, the imaging station 102 includes a single tube rack. In some embodiments, the imaging station includes multiple tube racks. In some embodiments, the tube rack includes a means for accommodating, i.e., securing, tubes of the same size in the imaging station. In some embodiments, the tube rack includes a means for accommodating or securing tubes of various sizes in the imaging station. In some embodiments, the imaging station includes a multi-well plate rack. In some embodiments, the imaging station includes both a tube rack and a multi-well plate rack. In some embodiments, the multi-well plate has two or more wells. In some embodiments, the multi-well plate is a 6-well plate, a 12-well plate, a 24-well plate, a 48-well plate, a 96-well plate, a 384-well plate, a 1536-well plate. In some embodiments, the multi-well plate is a deep well plate.

[0034] In a preferred embodiment, the tube is an ultracentrifuge tube. In some embodiments, the tube is a microcentrifuge tube, a specialized microcentrifuge tube, a screw-cap microtube, a microtiter tube, an Eppendorf tube, a Falcon tube, a PCR tube, or other suitable tube. Tubes suitable for use in the present disclosure may be of any size. For example, the volume of the tube may be 250 μL, 400 μL, 500 μL, 1 mL, 1.2 mL, 1.5 mL, 2 mL, 5 mL, 10 mL, 14 mL, 15 mL, 25 mL, 50 mL, 250 mL, or any volume up to or exceeding 250 mL. In some embodiments, the volume of the tube is 50 mL. In some embodiments, the tube is transparent. In some embodiments, the tube has an opacity selected for use with a desired light source and tube rack, the selected opacity being such that imaging of layered, graded, or separated samples contained within the ultracentrifuge tube secured within the tube rack is possible. In some embodiments, the ultracentrifuge tube has a cap. In some embodiments, the operator opens the tube by removing, unscrewing, or replacing the cap of the ultracentrifuge. In some embodiments, the tube does not have a cap.

[0035] In some embodiments, the light source is integrated into the sample storage device. In some embodiments, the light source is integrated into the imaging station. In some embodiments, the light source, the sample storage device, and the imaging station are integrated into a single unit. In some embodiments, the light source illuminates the sample from below the sample. In some embodiments, the light source illuminates the sample from the side of the sample, above the sample, or at an angle to the sample. In some embodiments, the light source comprises an LED light source. In some embodiments, the light source comprises a strip or other shaped LED light source (e.g., multiple LED light sources). In some embodiments, the light source illuminates the sample continuously. In some embodiments, the light source illuminates the sample intermittently. In some embodiments, the intensity of the light source is adjustable or may be adjustable. For example, in some embodiments, the luminous intensity of the light source can be adjusted to approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, or 100% of the maximum luminous intensity of the light source, or to a luminous intensity within a range defined by any two of the aforementioned numerical values. For example, in some embodiments, the luminous intensity of the light source is or can be adjustable between about 1%-100%, 1%-75%, 1%-50%, 1%-25%, 1%-10%, 1%-5%, 5%-100%, 5%-75%, 5%-50%, 5%-25%, 5%-10%, 10%-100%, 10%-75%, 10%-50%, 10%-25%, 25%-100%, 25%-75%, 25%-50%, 50%-100%, 50%-75%, or 75%-100% of the maximum luminous intensity of the light source. In some embodiments, the light source illuminates a single sample. In some embodiments, the light source illuminates multiple samples.In some embodiments, the light source illuminates 1, 3, 5, 6, 10, 12, 18, 24, 25, 30, 36, 42, 48, 50, 54, 60, 66, 72, 75, 78, 84, 90, 96, 100, 102, 114, 125, or 126 samples, or a number of samples within a range defined by any two of the aforementioned numbers. For example, in some embodiments, the light source illuminates 1-126, 1-125, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-125, 5-100, 5-75, 5-50, 5-25, 5-10, 10-125, 10-100, 10-75, 10-50, 10-25, 25-125, 25-100, 10-75, 25-50, 50-125, 50-100, 50-75, 75-125, 75-100, or 100-125 samples. In some embodiments, the light source, the tube rack, and the imaging station are modularized components. In some embodiments, the imaging station further includes a means for imaging the layered, staged, or separated samples, for example, using the camera assembly 105. In some embodiments, the camera assembly is integrated into the imaging station. In some embodiments, the camera is integrated into the sample storage device. In some embodiments, the camera assembly is a modularized device. In some embodiments, the data is stored locally on the control computer, in an integrated hard drive or integrated data storage device, in an external hard drive or external data storage device, in the cloud, or any other data storage means.

[0036] In some embodiments, an illuminated tube is located in front of the camera. The camera assembly captures images of the samples in the sample storage device and transmits the images to the control computer 106. In some embodiments, the control computer is integrated into a stand-alone unit that includes the imaging station and the collection device. In some embodiments, the integrated system includes a graphical user interface or monitor. In some embodiments, the integrated device can wirelessly transmit images to an external computer or device. In some embodiments, the image of the sample is displayed to the operator. The operator then defines the boundaries of the sample to be collected by selecting the bottom and top points of the sample that contain any material of interest, or otherwise identifies or defines the boundaries. In some embodiments, the image of the sample is or can be displayed to the operator along with a graded scale on the back or side of the tube. In some embodiments, the scale helps the operator define the extraction boundaries. In some embodiments, the operator defines the extraction boundaries by manually entering the coordinates of the material of interest into the control computer. In some embodiments, the operator defines the extraction boundary by boxing, circling, or otherwise drawing the extraction boundary. In some embodiments, the image is or can be processed. Alternatively, image processing is or can be otherwise applied to the image captured by the system embodiment. Processing the image may include evaluating the intensity of each pixel in the image and assigning a value to each pixel according to the intensity. This process may then include evaluating the intensity of the pixels over a predetermined height anywhere in the sample or sample collection container. The operator and / or a computer, processor, or other suitable means or method may then determine the extraction boundary based on the intensity of the pixels at different heights in the sample image. The control computer then determines the extraction volume and the position of the needle 107 based on the defined extraction boundary.In some embodiments, the sample image is saved. In some embodiments, the sample image with the defined extraction boundary is saved. In some embodiments, a record of the defined extraction boundary, initial needle position, volume aspirated, and other data accumulated or generated during the extraction process is saved. In some embodiments, an estimate of pixel intensity in the sample image is saved or storable.

[0037] The collection device 107 includes a collection arm 108 and a collection device 109. In some embodiments, the collection device includes a means for aspirating and / or dispensing sample material to be extracted. In some embodiments, the means for aspirating and dispensing the material to be extracted includes a needle. In some embodiments, the needle is connected to a syringe or other means for aspirating the material of interest from the sample and dispensing the material of interest into a sample collection container. In some embodiments, the collection device includes a pipette. In some embodiments, the collection device is attached to the collection arm. In some embodiments, the collection device is removably attached to the collection arm. In some embodiments, the collection arm and collection device are integrated into a single collection device. In some embodiments, the collection arm includes a mechanical means for moving the collection device laterally along the length of the collection arm. A control computer 106 directs the movement of the collection arm and the collection device. The control computer directs the movement of the collection device to position the collection device at the appropriate sample extraction or sample dispensing position. The control computer directs the movement of the collector between samples in the sample storage device and between the samples and the sample collection container 110. In some embodiments, the control computer guides the collector to the appropriate position in the sample based on the defined extraction boundary. A calculated amount of sample is aspirated into the collector. The control computer then directs the collector arm to orient the collector into or over the sample collection container located at the predetermined coordinates. The extracted material is dispensed into the sample collection container. The control computer then directs the collector arm to position the collector at the appropriate point in the second sample in the sample storage device using the starting collector depth and the extraction volume, which is calculated to extract the material of interest from the first sample. In some embodiments, the operator may define different extraction boundaries for each sample, each row of samples, or each column of samples in the sample storage device.In some embodiments, the operator may prescribe different extraction volumes for each tube, each row of tubes, or each row of tubes in the sample storage device. In some embodiments, the height and extraction rate are adjusted or adjustable to a particular height and extraction rate suitable for efficient extraction of the sample. In some embodiments, the extraction rate is about 1 μL / s, 2 μL / s, 3 μL / s, 4 μL / s, 5 μL / s, 6 μL / s, 7 μL / s, 8 μL / s, 9 μL / s, 10 μL / s, 20 μL / s, 25 μL / s, 30 μL / s, 40 μL / s, 50 μL / s, 60 μL / s, 70 μL / s, 80 μL / s, 90 μL / s, 100 μL / s, 200 μL / s, 250 ...0 μL / s, 400 μL / s, 500 μL / s, 600 μL / s, 700 μL / s, 800 μL / s, 900 μL / s, 1000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 2000 μL / s, 200 1 μL / s, 150 μL / s, 200 μL / s, 250 μL / s, 300 μL / s, 400 μL / s, 500 μL / s, 600 μL / s, 700 μL / s, 750 μL / s, 800 μL / s, 900 μL / s, or 1000 μL / s, or a rate within a range defined by any two of the aforementioned values. For example, in some embodiments, the extraction rate is about 1 μL / s to 1000 μL / s, 1 μL / s to 750 μL / s, 1 μL / s to 500 μL / s, 1 μL / s to 250 μL / s, 1 μL / s to 100 μL / s, 1 μL / s to 50 μL / s, 1 μL / s to 25 μL / s, 1 μL / s to 10 μL / s, 10 μL / s to 25 μL / s, 1 ... s~1000μL / s, 10μL / s~750μL / s, 10μL / s~500μL / s, 10μL / s~250μL / s, 10μL / s~100μL / s , 10μL / s~50μL / s, 10μL / s~25μL / s, 25μL / s~1000μL / s, 25μL / s~750μL / s, 25μL / s~500 μL / s, 25μL / s~250μL / s, 25μL / s~100μL / s, 25μL / s~50μL / s, 50μL / s~1000μL / s, 50μL / s~750μL / s, 50μL / s~500μL / s, 50μL / s~250μL / s, 50μL / s~100μL / s, 100μL / s~1000μL / s, 100μL / s~750μL / s, 100μL / s~500μL / s, 100μL / s~250μL / s, 250μL / s~1000μL / s, 25 0 μL / s to 750 μL / s, 250 μL / s to 500 μL / s, 500 μL / s to 1000 μL / s, or 750 μL / s to 1000 μL / s.In some embodiments, the extraction rate is about 0.001 mL / s, 0.01 mL / s, 0.1 mL / s, 0.5 mL / s, 1 mL / s, 2 mL / s, 3 mL / s, 4 mL / s, 5 mL / s, 6 mL / s, 7 mL / s, 8 mL / s, 9 mL / s, 10 mL / s, 15 mL / s, 20 mL / s, 25 mL / s, 30 mL / s, 35 mL / s, 40 mL / s, 45 mL / s, 50 mL / s, 60 mL / s, 70 mL / s, 75 mL / s, 80 mL / s, 90 mL / s, or 100 mL / s, or an extraction rate within a range defined by any two of the aforementioned values. For example, in some embodiments, the extraction rate is about 0.001 mL / s to 100 mL / s, 0.001 mL / s to 75 mL / s, 0.001 mL / s to 50 mL / s, 0.001 mL / s to 25 mL / s, 0.001 mL / s to 10 mL / s, 0.001 mL / s to 5 mL / s, 0.001 mL / s to 1 mL / s, 0.001 mL / s to 0.05 mL / s, 0.001 mL / s to 0.01 mL / s, 0.01 mL / s to 100 mL / s, 0.01 mL / s to 75 mL / s, 0.01 mL / s to 50 mL / s, 0.01 mL / s to 25 mL / s, 0.001 mL / s to 1 mL / s, .01mL / s~10mL / s, 0.01mL / s~5mL / s, 0.01mL / s~1mL / s, 1mL / s~100mL / s, 1mL / s~75mL / s, 1mL / s~50mL / s, 1mL / s~25mL / s, 1mL / s~10mL / s, 10mL / s~100mL / s, 10mL / s~75mL / s, 10mL / s~50mL / s, 10mL / s~25mL / s, 25mL / s~100mL / s, 25mL / s~75mL / s, 25mL / s~50mL / s, 50mL / s~100mL / s, or 75mL / s~100mL / s. In some embodiments, the extraction rate is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% of the maximum extraction rate of the extraction device, or an extraction rate within a range defined by any two of the aforementioned values.For example, in some embodiments, the extraction rate is about 1%-100%, 1%-75%, 1%-50%, 1%-25%, 1%-10%, 10%-100%, 10%-75%, 10%-50%, 10%-25%, 25%-100%, 25%-75%, 25%-50%, 50%-100%, 50%-75%, or 75%-100% of the maximum extraction rate of the extractor. In some embodiments, the extraction rate is 3 mL / min to 15 mL / min. In some embodiments, the aspiration rate is 0.05 mL / s to 0.25 mL / s. In some embodiments, the aspiration rate is 1 mL / min, 2 mL / min, 3 mL / min, 4 mL / min, 5 mL / min, 6 mL / min, 7 mL / min, 8 mL / min, 9 mL / min, 10 mL / min, 11 mL / min, 12 mL / min, 13 mL / min, 14 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, 30 mL / min, 35 mL / min, 40 mL / min, 45 mL / min, 50 mL / min, or any value in between. In some embodiments, the extraction rate is 0.01 mL / s, 0.02 mL / s, 0.03 mL / s, 0.04 mL / s, 0.05 mL / s, 0.06 mL / s, 0.07 mL / s, 0.08 mL / s, 0.09 mL / s, 0.10 mL / s, 0.15 mL / s, 0.20 mL / s, 0.25 mL / s, 0.30 mL / s, 0.35 mL / s, 0.40 mL / s, 0.50 mL / s, 0.60 mL / s, 0.70 mL / s, 0.80 mL / s, 0.90 mL / s, 1.0 mL / s, or any value therebetween. In some embodiments, the extraction volume is the volume of the sample. In some embodiments, the extraction volume is between 5 mL and 15 mL. In some embodiments, the volume extracted is about 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 20 mL, 25 mL, 30 mL, 40 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL, 100 mL, or a volume within a range defined by any two of the aforementioned numeric values.In some embodiments, the extraction volume is about 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, 600 mL, 700 mL, 750 mL, 800 mL, 900 mL, or 1000 mL, or a volume within a range defined by any two of the aforementioned numeric values.

[0038] FIG. 4 is a non-limiting illustration of images showing some examples of set points close to the desired extraction band (left side) and extraction results with high aspiration speed (right side).

[0039] FIG. 5 is a non-limiting illustration of images showing some examples of extraction results with set points below and above the desired extraction band (left side) and low aspiration speed (right side).

[0040] In some embodiments, the aspiration rate and needle height are or can be determined based on their suitability for extracting the desired substance. For example, in some embodiments, the needle is or can be placed near the desired extracting substance, and the aspiration rate is or can be decreased or increased to extract the substance from that height.

[0041] FIG. 2 is a flow chart of a non-limiting example of a process 200 for automatically extracting substances from a layered, graduated, or separated sample.

[0042] In block 201, a layered, staged, or separated sample, for example a sample containing a mixture of DNA-containing and empty viral particles, is layered, staged, or separated by gradient ultracentrifugation. After centrifugation, in block 202, the sample is loaded into an imaging station. In some embodiments, the sample is loaded into the imaging station by an operator. In some embodiments, the sample is loaded into the imaging station by an automated device. In some embodiments, the loading of the sample is predefined or predefined by an operator, and the sample is loaded or loadable by an automated device. Once one, some, or all of the samples are loaded, in block 203, the first sample is illuminated. In block 204, an image of the first sample in the sample storage device can be captured. The first sample image is then transmitted to a control computer in block 205. In some embodiments, the sample image is transmitted wirelessly. In some embodiments, the sample image is transmitted to the control computer via physical means. In block 206, the control computer displays one or more sample images to an operator, who in block 207 defines an extraction boundary, for example by selecting the nadir and apex of a layer, stage, or portion to be collected from the sample. In block 208, the control computer calculates the volume of extraction to be extracted according to the information provided to the operator. The volume of extraction can be determined by defining a set of coordinates for the placement of a collection device to extract the identified layer, stage, or portion from a layered, staged, or separated sample. Then, in block 209, the control computer directs a collection arm, including a collection device such as a needle and syringe, so that the needle is located at the predetermined extraction coordinate. Then, in block 210, the calculated volume of extraction is aspirated from the sample, the volume of extraction containing the substance of interest, such as DNA-containing virus particles (as opposed to empty virus particles).After extracting the material of interest from a sample, e.g., a layered, staged, or separated sample, in block 211 the control computer directs the collection arm to position the collection device over or within a sample collection container for dispensing the extracted sample into the sample collection container. Once the sample collection container is properly positioned, in block 212 the control computer directs dispensing of the extracted material into the container. Then, in block 213 the control computer directs movement of the collection arm to position the collection device over a second sample in the sample storage device. In block 214 the sample extraction process is repeated for one or more additional samples, using the position of the collection device for each additional sample and the sample extraction volume originally calculated for the first sample.

[0043] In some embodiments, the light source illuminates the sample intermittently. In some embodiments, the light intensity of the light source is adjustable or can be adjustable. For example, in some embodiments, the light intensity of the light source is adjustable to emit light at an intensity that is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, or 100% of the maximum light intensity of the light source, or within a range defined by any two of the aforementioned values. For example, in some embodiments, the light intensity of the light source is adjustable between about 1%-100%, 1%-75%, 1%-50%, 1%-25%, 1%-10%, 1%-5%, 5%-100%, 5%-75%, 5%-50%, 5%-25%, 5%-10%, 10%-100%, 10%-75%, 10%-50%, 10%-25%, 25%-100%, 25%-75%, 25%-50%, 50%-75%, or 75%-100% of the maximum light intensity of the light source. In some embodiments, the light source illuminates a single sample. In some embodiments, the light source illuminates multiple samples. In some embodiments, the light source illuminates 1, 3, 5, 6, 10, 12, 18, 24, 25, 30, 36, 42, 48, 50, 54, 60, 66, 72, 75, 78, 84, 90, 96, 100, 102, 114, 125, or 126 samples, or a number of samples within a range defined by any two of the aforementioned numeric values. For example, in some embodiments, the light source illuminates 1-126, 1-125, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-125, 5-100, 5-75, 5-50, 5-25, 5-10, 10-125, 10-100, 10-75, 10-50, 10-25, 25-125, 25-100, 25-75, 50-125, 50-100, 50-75, 75-100, or 100-125 samples. In some embodiments, for each sample, new sampling boundaries and sampling amounts are defined.In some embodiments, the extraction boundaries and volumes for extracting a particular sample may be determined and stored as a protocol for use in extracting subsequent volumes from tubes containing the same type of sample. For example, in some embodiments, the extraction boundaries and volumes for extracting capsids from a 40 mL volume in a 50 mL tube may be determined for a control sample. These values ​​may be stored for later use in extracting capsids from other tubes of the same size and volume. In some embodiments, different programs may be pre-determined and stored for each different type to be extracted. In some embodiments, the height and extraction rate are adjustable to a particular height and extraction rate suitable for efficient extraction of the sample. In some embodiments, the extraction rate is about 1 μL / s, 2 μL / s, 3 μL / s, 4 μL / s, 5 μL / s, 6 μL / s, 7 μL / s, 8 μL / s, 9 μL / s, 10 μL / s, 20 μL / s, 25 μL / s, 30 μL / s, 40 μL / s, 50 μL / s, 60 μL / s, 70 μL / s, 80 μL / s, 90 μL / s, 1 The rate is 00 μL / s, 150 μL / s, 200 μL / s, 250 μL / s, 300 μL / s, 400 μL / s, 500 μL / s, 600 μL / s, 700 μL / s, 750 μL / s, 800 μL / s, 900 μL / s, or 1000 μL / s, or a rate within a range defined by any two of the aforementioned numbers.For example, in some embodiments, the extraction rate is about 1 μL / s to 1000 μL / s, 1 μL / s to 750 μL / s, 1 μL / s to 500 μL / s, 1 μL / s to 250 μL / s, 1 μL / s to 100 μL / s, 1 μL / s to 50 μL / s, 1 μL / s to 25 μL / s, 1 μL / s to 10 μL / s, 10 μL / s to 10 00μL / s, 10μL / s~750μL / s, 10μL / s~500μL / s, 10μL / s~250μL / s, 10μL / s~100μL / s, 10μL / s s~50μL / s, 10μL / s~25μL / s, 25μL / s~1000μL / s, 25μL / s~750μL / s, 25μL / s~500μL / s, 25μL / s L / s~250μL / s, 25μL / s~100μL / s, 25μL / s~50μL / s, 50μL / s~1000μL / s, 50μL / s~750μL / s , 50μL / s~500μL / s, 50μL / s~250μL / s, 50μL / s~100μL / s, 100μL / s~1000μL / s, 100μL / s~7 50μL / s, 100μL / s~500μL / s, 100μL / s~250μL / s, 250μL / s~1000μL / s, 250μL / s~750μL / s, 250 μL / s to 500 μL / s, 500 μL / s to 1000 μL / s, 500 μL / s to 750 μL / s, or 750 μL / s to 1000 μL / s. In some embodiments, the extraction rate is about 0.001 mL / s, 0.01 mL / s, 0.1 mL / s, 0.5 mL / s, 1 mL / s, 2 mL / s, 3 mL / s, 4 mL / s, 5 mL / s, 6 mL / s, 7 mL / s, 8 mL / s, 9 mL / s, 10 mL / s, 15 mL / s, 20 mL / s, 25 mL / s, 30 mL / s, 35 mL / s, 40 mL / s, 45 mL / s, 50 mL / s, 60 mL / s, 70 mL / s, 75 mL / s, 80 mL / s, 90 mL / s, or 100 mL / s, or an extraction rate within a range defined by any two of the aforementioned numbers.For example, in some embodiments, the extraction rate is about 0.001 mL / s to 100 mL / s, 0.001 mL / s to 75 mL / s, 0.001 mL / s to 50 mL / s, 0.001 mL / s to 25 mL / s, 0.001 mL / s to 10 mL / s, 0.001 mL / s to 5 mL / s, 0.001 mL / s to 1 mL / s, 0.001 mL / s to 0.05 mL / s, 0.001 mL / s to 0.01 mL / s, 0.01 mL / s to 100 mL / s, 0.01 mL / s to 75 mL / s, 0.01 mL / s to 50 mL / s, 0.01 mL / s to 25 mL / s, 0.01 mL / s ~10mL / s, 0.01mL / s~5mL / s, 0.01mL / s~1mL / s, 1mL / s~100mL / s, 1mL / s~75mL / s, 1mL / s~50mL / s, 1mL / s~25mL / s, 1mL / s~10mL / s, 10mL / s~100mL / s, 10mL / s~7 5mL / s, 10mL / s~50mL / s, 10mL / s~25mL / s, 25mL / s~100mL / s, 25mL / s~75mL / s, 25mL / s~50mL / s, 50mL / s~100mL / s, 50mL / s~75mL / s, or 75mL / s~100mL / s. In some embodiments, the extraction rate is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% of the maximum extraction rate of the extractor, or an extraction rate within a range defined by any two of the aforementioned values. For example, in some embodiments, the extraction rate is about 1%-100%, 1%-75%, 1%-50%, 1%-25%, 1%-10%, 10%-100%, 10%-75%, 10%-50%, 10%-25%, 25%-100%, 25%-75%, 25%-50%, 50%-75%, or 75%-100% of the maximum extraction rate of the extractor.

[0044] <Computer System> In some examples, the systems, processes, and methods described in this disclosure may be performed by a computing system, such as the example shown in Figure 3. Exemplary computer system 302 may communicate with one or more computing systems 320 and / or one or more data sources 322 via one or more networks 318. While Figure 3 illustrates an embodiment of computing system 302, it is recognized that the functionality provided in the components and modules of computer system 302 may be combined into fewer components and modules or further separated into additional components and modules.

[0045] The computer system 302 may include a sample analysis module 314 that performs the functions, methods, operations, and / or processes described in this disclosure. The sample analysis module 314 is executed on the computer system 302 by a central processing unit (CPU) 306, which is described further below.

[0046] In general, the term "module" as used in this disclosure refers to logic implemented in hardware or firmware, or a collection of software instructions with entry and exit points. Modules are written in a programming language such as JAVA, C, C++, etc. Software modules can be compiled or linked into executable programs, installed in dynamic link libraries, or written in interpreted languages ​​such as BASIC, PERL, LAU, PHP, Python, etc. Software modules can be called by other modules or by themselves, and / or in response to detected events or interrupts. Modules implemented in hardware include logic units, such as gates and flip-flops, connected together, and / or may include programmable units, such as programmable gate arrays and processors.

[0047] Generally, a module described in this disclosure refers to a logical module that can be combined with other modules or divided into sub-modules, regardless of its physical configuration or storage. The modules can be executed by one or more computing systems and stored on or within any suitable computer-readable medium, or can be implemented in whole or in part in specially designed hardware or firmware. Any of the methods, calculations, processes, or analyses described above are readily performed through the use of a computer, although not all calculations, analyses, and / or optimizations require the use of a computer system. Also, in some embodiments, process blocks described in this disclosure can be modified, rearranged, combined, and / or omitted.

[0048] <Computational System Components> The computer system 302 includes one or more processing units (CPUs) 306, which may include a microprocessor. The computer system 302 further includes a physical memory 310 and a mass storage device 304. The physical memory 310 may be a random access memory (RAM) for temporary storage of information or a read-only memory (ROM) for permanent storage of information. The mass storage device 304 may be a backing store, a hard drive, a rotating magnetic disk, a solid-state disk (SSD), a flash memory, a phase-change memory (PCM), a 3D XPoint® memory, a diskette, or an optical media storage device. Alternatively, the mass storage device may be implemented in an array of servers. Typically, the components of the computer system 302 are connected to the computer by a standard-based bus system. The bus system may be implemented by a variety of protocols, such as Peripheral Component Interconnect (PCI), Micro Channel, SCSI, Industrial Standard Architecture (ISA), and Extended ISA (EISA) architectures.

[0049] The computer system 302 includes one or more input / output (I / O) devices and interfaces 312, such as a keyboard, a mouse, a touchpad, and a printer. The I / O devices and interfaces 312 may include one or more display devices, such as a monitor. The display devices allow data to be visually presented to a user. More specifically, the display devices provide for the display of GUIs, such as application software data, and for the display of multimedia. The I / O devices and interfaces 312 may also provide communication interfaces to various external devices. The computer system 302 may include one or more multimedia devices 308, such as, for example, speakers, a video card, a graphics accelerator, and a microphone.

[0050] <Computing system equipment / Operating System (OS)> Computer system 302 may be implemented on a variety of computing devices, such as a server, a Windows server, a Structure Query Language (SQL) server, a UNIX server, a personal computer, a laptop computer, etc. In other embodiments, computer system 302 may be implemented on a cluster computer system, a mainframe computer system, and / or other suitable computing systems suitable for controlling and / or communicating with large databases, performing high volume transaction processing, and generating reports from large databases. Computer system 302 is typically controlled and coordinated by operating system software, such as, for example, z / OS, Windows, Linux, UNIX, BSD, PHP, SunOS, Solaris, MacOS, iCloud services, or other compatible operating systems, including proprietary operating systems. The operating system controls and schedules computer processes for execution, performs memory management, provides file system, network, and I / O services, and provides user interfaces, such as a graphical user interface (GUI), among other things.

[0051] <Network> The computer system 302 illustrated in FIG. 3 is connected to a network 318, such as a LAN, WAN, or the Internet, via a communication connection 316 (including wired, wireless, or a combination thereof). The network 318 communicates with a variety of computing devices and / or other electronic devices. The network 318 communicates with one or more computing systems 320, as well as one or more data sources 222. The sample analysis module 314 can access or be accessed by the computing systems 320 and / or data sources 322 via a web-enabled user access point. The connection may be a direct physical connection, a virtual connection, and other types of connections. The web-enabled user access point may include a browser module, which presents data using text, graphics, audio, video, and other media, and allows interaction with the data via the network 318.

[0052] The output module can be implemented as a combination of fully addressable displays, such as cathode ray tubes (CRT), liquid crystal displays (LCD), plasma displays, other types of displays, and / or combinations of displays. The output module can be implemented to communicate with input devices 312, which include software having a suitable interface that allows a user to access data through the use of stylized screen elements, such as menus, windows, dialog boxes, toolbars, and control elements (e.g., radio buttons, checkboxes, sliding scales, etc.). The output module can also communicate with a set of input and output devices to receive signals from a user.

[0053] <Other systems> Computer system 302 may include one or more internal and / or external data sources (e.g., data source 322). In some embodiments, the repository and one or more of the aforementioned data sources may be implemented by relational databases, such as DB2, Sybase®, Oracle®, CodeBase®, and Microsoft® SQL Server, as well as other types of databases, such as flat-file databases, entity-relationship databases, object-oriented databases, and / or record-based databases.

[0054] The computer system 302 may also have access to one or more databases 322. The databases 322 may be stored in a database or data repository. The computer system 302 may access the one or more databases 322 over a network 318 or may directly access the databases or data repository via I / O devices and interfaces 312. A data repository that stores the one or more databases 322 may be provided within the computer system 302.

[0055] <Numbered arrangement> Some embodiments provided in this disclosure are illustrated by the following numbered arrangements and are provided as possible combinations or overlapping embodiments. (Placement 1) 1. An automated liquid handling system comprising: An imaging station; A collection device; Including, the imaging station is configured to image the sample and transmit the sample image to the control computer; the imaging station and the acquisition device are operably connected to a control computer; The control computer is configured to process the sample images; the collection device transfers a predetermined volume from the sample to a sample collection container; Automated Liquid Handling Systems. (Placement 2) The control computer is configured to define one or more extraction points from the sample; 2. The automated liquid handling system according to claim 1. (Placement 3) The luminous intensity of the light source corresponds to a particular opacity of the sample storage device; 2. The automated liquid handling system according to claim 1. (Placement 4) The luminous intensity of the light source is adjustable. 2. The automated liquid handling system according to claim 1. (Placement 5) The light source is located above, below, or at an angle to the sample storage device. 2. The automated liquid handling system according to claim 1. (Placement 6) The predetermined extraction volume is about 0 mL to 50 mL. 2. The automated liquid handling system according to claim 1. (Placement 7) It is configured to extract a predetermined amount of extraction at an extraction rate of about 0.001 mL / s to 25 mL / s. 2. The automated liquid handling system according to claim 1. (Placement 8) Imaging devices include cameras, 2. The automated liquid handling system according to claim 1. (Placement 9) configured to execute an extraction program for extracting a desired portion from the sample; 2. The automated liquid handling system according to claim 1. (Placement 10) The imaging station and the acquisition device are separate components; 2. The automated liquid handling system according to claim 1. (Placement 11) The imaging station and the acquisition device are integrated into a single system. 2. The automated liquid handling system according to claim 1. (Placement 12) One or more of the imaging station, the acquisition device, and the control computer are separate components; 2. The automated liquid handling system according to claim 1. (Placement 13) One or more of the imaging station, the acquisition device, and the control computer are integrated into a single system; 2. The automated liquid handling system according to claim 1. (Placement 14) The imaging station includes a sample storage device, a light source, and an imaging device. 2. The automated liquid handling system according to claim 1. (Placement 15) The sample storage device, light source, and imaging equipment are integrated into a single system. 2. The automated liquid handling system according to claim 1. (Placement 16) The sample storage device includes a tube rack; 2. The automated liquid handling system according to claim 1. (Placement 17) The sample storage device includes a multi-well plate rack; 2. The automated liquid handling system according to claim 1. (Placement 18) The sample storage device has a particular opacity; 2. The automated liquid handling system according to claim 1. (Placement 19) The light source is located above the sample storage device. 2. The automated liquid handling system according to claim 1. (placement 20) The light source is located below the sample storage device. 2. The automated liquid handling system according to claim 1. (Placement 21) The light source is positioned at an angle to the sample storage device. 2. The automated liquid handling system according to claim 1. (Placement 22) the light source, the position of the light source, and the opacity of the sample storage device are collectively selected for their suitability in combination for imaging the sample contained in the sample storage device; 2. The automated liquid handling system according to claim 1. (Placement 23) further comprising a graphical user interface (GUI) operably connected to the control computer; 2. The automated liquid handling system according to claim 1. (Placement 24) The collection device includes a collection arm and a collection device. 2. The automated liquid handling system according to claim 1. (Placement 25) The collection device is removably attached to the collection arm; 2. The automated liquid handling system according to claim 1. (Placement 26) The control computer is configured to direct the collection device to move laterally, horizontally, and / or vertically along the collection arm; 2. The automated liquid handling system according to claim 1. (Placement 27) The collection arm is configured to be directed by a control computer to move in an x-direction, a y-direction, and / or a z-direction. 2. The automated liquid handling system according to claim 1. (Placement 28) The light source is integrated into the collecting arm. 2. The automated liquid handling system according to claim 1. (Placement 29) The control computer is configured to direct the collection arm to position the collection device at predetermined extraction coordinates or extraction coordinates determined by an operator. 2. The automated liquid handling system according to claim 1. (placement 30) the collection device includes means for transferring the sample from the sample storage device to a sample collection container; 2. The automated liquid handling system according to claim 1. (Placement 31) The collection device includes a pipette; 2. The automated liquid handling system according to claim 1. (Placement 32) The collection device includes a needle and a syringe; 2. The automated liquid handling system according to claim 1. (Placement 33) One or more of the imaging station, the collection device, the collection container, or the control computer are integrated into a single system; 2. The automated liquid handling system according to claim 1. (Placement 34) Further comprising a tip rack, 2. The automated liquid handling system according to claim 1. (Placement 35) Further comprising a tip waste container. 2. The automated liquid handling system according to claim 1. (Placement 36) The imaging station and the acquisition device are integrated into a single system. 36. The automated liquid handling system according to any one of configurations 1 to 35. (Placement 37) One or more of the imaging station, the acquisition device, and the control computer are separate components; 37. The automated liquid handling system according to any one of configurations 1 to 36. (Placement 38) One or more of the imaging station, the acquisition device, and the control computer are integrated into a single system; 38. The automated liquid handling system according to any one of configurations 1 to 37. (Placement 39) The imaging station includes a sample storage device, a light source, and an imaging device. 39. The automated liquid handling system according to any one of configurations 1 to 38. (Placement 40) The sample storage device, light source, and imaging equipment are integrated into a single system. 40. The automated liquid handling system according to any one of configurations 1 to 39. (Placement 41) The sample storage device includes a tube rack; 41. The automated liquid handling system according to any one of configurations 1 to 40. (Placement 42) The sample storage device includes a multi-well plate rack; 42. The automated liquid handling system according to any one of configurations 1 to 41. (Placement 43) The sample storage device has a particular opacity; 43. The automated liquid handling system according to any one of configurations 1 to 42. (Placement 44) The light source is located above the sample storage device. 44. The automated liquid handling system according to any one of configurations 1 to 43. (Placement 45) The light source is located below the sample storage device. 45. The automated liquid handling system according to any one of configurations 1 to 44. (Placement 46) The light source is positioned at an angle to the sample storage device. 46. ​​The automated liquid handling system according to any one of configurations 1 to 45. (Placement 47) the light source, the position of the light source, and the opacity of the sample storage device are collectively selected for their suitability in combination for imaging the sample contained in the sample storage device; 47. The automated liquid handling system according to any one of configurations 1 to 46. (Placement 48) further comprising a graphical user interface (GUI) operably connected to the control computer; 48. The automated liquid handling system according to any one of configurations 1 to 47. (Placement 49) The collection device includes a collection arm and a collection device. 49. The automated liquid handling system according to any one of configurations 1 to 48. (Placement 50) The collection device is removably attached to the collection arm; 50. The automated liquid handling system according to any one of configurations 1 to 49. (Placement 51) The control computer directs the collection device to move laterally, horizontally, and / or vertically along the collection arm; 51. The automated liquid handling system according to any one of configurations 1 to 50. (Placement 52) The collection arm is configured to be directed by a control computer to move in an x-direction, a y-direction, and / or a z-direction. 52. The automated liquid handling system according to any one of configurations 1 to 51. (Placement 53) The light source is integrated into the collecting arm. 53. The automated liquid handling system according to any one of configurations 1 to 52. (Placement 54) The control computer directs the collection arm to position the collection device at predetermined extraction coordinates or extraction coordinates determined by the operator; 54. The automated liquid handling system according to any one of configurations 1 to 53. (Placement 55) the collection device includes means for transferring the sample from the sample storage device to a sample collection container; 55. The automated liquid handling system according to any one of configurations 1 to 54. (Placement 56) The collection device includes a pipette; 56. The automated liquid handling system according to any one of configurations 1 to 55. (Placement 57) The collection device includes a needle and a syringe; 57. The automated liquid handling system according to any one of configurations 1 to 56. (Placement 58) One or more of the imaging station, the collection device, the collection container, or the control computer are integrated into a single system; 58. The automated liquid handling system according to any one of configurations 1 to 57. (Placement 59) Further comprising a tip rack, 59. The automated liquid handling system according to any one of configurations 1 to 58. (Placement 60) Further comprising a tip waste container. 59. The automated liquid handling system according to any one of configurations 1 to 59. (Placement 61) 1. A method for automatically extracting a substance from a sample, comprising: Step a) loading the sample into an imaging station; a step b of irradiating the sample; a step c of imaging the illuminated sample; Step d of transmitting the sample image to a control computer; Step e of calculating extraction amounts and extraction coordinates based on the sample image; Step f of directing the collection arm to orient the collection device to the calculated extraction coordinates; a step g of aspirating the calculated volume of the sample into a collection device; h directing the collection arm to direct the collection device to a collection vessel located at a predetermined coordinate and dispensing the sample volume into the collection vessel; Including, method. (Placement 62) repeating steps a through h for each of the n samples; n is a non-negative integer. 62. The method according to claim 61. (Placement 63) 1. A method for automatically extracting a substance from a sample, comprising: a) loading one or more samples into an imaging station; Irradiating the one or more samples to obtain one or more irradiated samples step b; a step c of imaging the illuminated sample or samples; a step d of transmitting one or more sample images to a control computer; a step e of calculating extraction amounts and extraction coordinates based on the sample image; Step f of directing the collection arm to orient the collection device to the calculated extraction coordinates; g. aspirating the extracted material from the sample or samples into a collection device based on the calculated extracted volume; h directing the collection arm to direct the collection device to one or more collection containers; Dispensing the extracted material into one or more collection vessels i; Including, method. (Placement 64) repeating steps b through h for each of the one or more samples; 64. The method according to claim 63. (Placement 65) and further comprising obtaining a pipette tip prior to aspiration of the sample. 64. The method according to claim 63. (Placement 66) and disposing of the used tip after dispensing the extracted sample volume into a collection device. 64. The method according to claim 63. (Placement 67) The step of calculating the extraction amount and the extraction coordinates based on the sample image includes: Defining an extraction boundary Including, 64. The method according to claim 63. (Placement 68) The step of defining the extraction boundary is performed by a control computer. 64. The method according to claim 63. (Placement 69) and further comprising centrifuging the sample prior to loading into the imaging station. 64. The method according to claim 63. (placement 70) The sample may be a layered sample, a graded sample, or a separated sample. 64. The method according to claim 63. (Placement 71) The material to be extracted may comprise a layered sample, a graded sample, or a single layer, stage, or portion of a separated sample; The method according to any one of configurations 63 to 70. (Placement 72) The operator is a computer program, The method according to any one of configurations 63 to 70. (Placement 73) The operator is a human being, The method according to any one of configurations 63 to 70. (Placement 74) and further comprising centrifuging each of the one or more samples prior to loading into the imaging station. The method according to any one of configurations 63 to 70. (placement 75) The one or more samples include a layered sample, a graded sample, or a separated sample; The method according to any one of configurations 63 to 70. (Placement 76) The material to be extracted may comprise a layered sample, a graded sample, or a single layer, stage, or portion of a separated sample; The method according to any one of configurations 63 to 70. (Placement 77) The step of defining the extraction boundary is performed by an operator. The method according to any one of configurations 63 to 70.

[0056] <Example> Example 1 - Capsid Recovery The efficiency of extraction of capsids from tubes with different set points and aspiration rates was evaluated. Tubes containing the same viral load of capsids in either 1.3142 g / mL CsCl (test conditions 1, 3, 4, 6, 7), 1.5227 g / mL CsCl (test conditions 9, 10, "high density"), or 1.1720 g / mL CsCl (test conditions 11, 12, "low density") were prepared under the same spin conditions and loaded into the automated liquid handling device.

[0057] FIG. 6 is a table showing several examples of recovery of capsids from tubes with different set heights and different aspiration rates.

[0058] Test conditions 1, 3, and 4 show that capsids were extracted from tubes with the same CsCl concentration and set point, but with different aspiration rates (1%, 3%, and 5% of the maximum aspiration rate, respectively). Test conditions 6 and 7 show that capsids were recovered from tubes with the same CsCl concentration and aspiration rate (1% of the maximum aspiration rate), but with different set points. Test conditions 9 and 10 show that capsids were recovered from tubes with the same CsCl concentration and aspiration rate (1% of the maximum aspiration rate), but with different set points (low or lower, and close). Test conditions 11 and 12 show that different extraction volumes (6.8 mL and 8.7 mL, respectively) were used.

[0059] As shown in Figure 6, capsids are recovered with efficiencies ranging from 82% to 105% by various combinations of aspiration rate and set point. Furthermore, the results show the recovery of capsids with various CsCl concentrations.

[0060] In the preceding description, the present invention has been described with reference to specific embodiments. However, it will be apparent that various modifications and changes may be made thereto without departing from the broader spirit and scope of the present invention. The specification and drawings should therefore be regarded in an illustrative rather than a restrictive sense.

[0061] Indeed, although the present invention has been disclosed in the context of certain embodiments and examples, those skilled in the art will understand that the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or uses of the invention, as well as obvious variations and equivalents thereof. In addition, while several variations of the embodiments of the present invention have been shown and described in detail, other variations within the scope of the present invention will be apparent to those skilled in the art based on this disclosure. It is also envisioned that various combinations or subcombinations of the specific features and aspects of the embodiments can be made and are within the scope of protection of the present invention. It should be understood that various features and aspects of the disclosed embodiments can be combined with or substituted for each other to form different aspects of the disclosed embodiments of the invention. The methods described in this disclosure do not have to be performed in the order described. Therefore, it is intended that the scope of protection of the invention disclosed in this disclosure should not be limited by the specific embodiments described above.

[0062] It will be understood that the disclosed systems and methods each have several innovative aspects, and that no single aspect is solely responsible or required for the desirable attributes disclosed in this disclosure. The various features and processes described above may be used independently of each other or may be combined in various forms. All possible combinations and subcombinations are intended to fall within the scope of protection of this disclosure.

[0063] Certain features described in this disclosure in the context of separate embodiments may be implemented in combination within a single embodiment. Conversely, various features described in the context of a single embodiment may be implemented separately in multiple embodiments, or in any suitable subcombination in multiple embodiments. Also, features may be described as representing a particular combination, and even if initially claimed, one or more features from a claimed combination may be cut out of the combination in some cases, and the claimed combination may be made into a subcombination or a variation of the subcombination. No single feature or group of features is necessary or essential to each and every embodiment.

[0064] Additionally, conditional terms used in this disclosure, such as "can," "can be," "may," "could," "for example," and the like, are generally intended to indicate that a particular embodiment includes a particular feature, element, and / or step, while other embodiments do not include that feature, element, and / or step, unless otherwise stated or understood in the language used. Thus, such conditional terms are generally not intended to require that the feature, element, and / or step be in any way in one or more embodiments, nor do they imply that one or more embodiments necessarily include logic for determining whether those features, elements, and / or steps are included or performed in a particular embodiment, regardless of whether the author has input or expressed it. Terms such as "comprises," "includes," "has," and the like are synonymous and are used inclusively in an open format and do not exclude additional elements, features, acts, operations, etc. Additionally, the term "or" is used in its inclusive (not exclusive) sense, so that, for example, when used to connect a list of elements, the term "or" means one, some, or all of the elements in the list. Additionally, the terms "a," "the," and "said" as used in this disclosure and claims should be construed to mean "one or more," or "at least one," unless otherwise specified. Similarly, while operations may be depicted in the figures in a particular order, it should be recognized that such operations need not be performed in the particular order depicted or in the sequential order, and that all of the illustrated operations are performed to achieve a desired result. The figures may also depict one or more exemplary processes generally in the form of a flow chart. However, other operations not depicted may be incorporated into the exemplary methods and processes depicted generally. For example, one or more additional operations may be performed before, after, simultaneously with, or between any of the illustrated operations. Also, operations may be rearranged or reordered in other embodiments. In certain circumstances, multitasking and parallel processing may be advantageous.Also, the separation of various system parts in the above-described embodiments should not be understood as requiring such separation in all embodiments, and it should be understood that the described program components and systems may generally be integrated together in a single software product or packaged in multiple software products. Also, other embodiments are within the scope of the following claims. In some cases, the actions recited in the claims may be performed in a different order and still achieve desirable results.

[0065] In addition, the methods and apparatuses disclosed herein may be subject to various modifications and alternative forms, examples of which have already been shown in the drawings and will be described in detail in this disclosure. However, the present invention should not be limited to the specific forms or methods disclosed, but rather, it should be understood that the present invention covers all modifications, equivalents, and alternatives falling within the spirit and scope of the various described embodiments and the appended claims. In addition, the disclosure of any particular features, aspects, methods, properties, characteristics, attributes, elements, etc., associated with an embodiment or embodiment is applicable to all other embodiments or embodiments described in this disclosure. The methods disclosed herein do not have to be performed in the order described. Although the methods disclosed herein may include certain actions taken by a practitioner, the methods may also include, explicitly or implicitly, any third-party instructions for those actions. The ranges disclosed in this disclosure include all overlaps, subranges, and combinations thereof. Terms such as "up to," "at least," "greater than," "less than," "between," and the like, include the numerical values ​​referenced. Numeric values ​​preceded by terms such as "about" or "approximately" are inclusive of the stated numerical value and should be interpreted case by case (e.g. interpreted as precisely as reasonably possible under the circumstances, e.g. interpreted as ±5%, ±10%, ±15%, etc.). For example, "about 3.5 mm" includes "3.5 mm". Words preceded by terms such as "substantially" are inclusive of the stated numerical value and should be interpreted case by case (e.g. interpreted as closely as reasonably possible under the circumstances). For example, "substantially constant" includes "constant". Unless otherwise stated, all measurements are taken at standard conditions of temperature, pressure, etc.

[0066] As used in this disclosure, a phrase referring to "at least one" of a list of items refers to any combination of those items and includes a single item. For example, the phrase "at least one of A, B, or C" includes A, B, C, A and B, A and C, B and C, and A, B and C. A conjunction such as "at least one of X, Y, and Z" is generally intended to indicate that an item, term, etc. may be at least one X, Y, or Z, unless otherwise indicated. Thus, such conjunctions are generally not intended to imply that a particular embodiment requires that at least one X, at least one Y, and at least one Z, respectively, are present. The headings provided in this disclosure, if any, are for convenience only and do not necessarily affect the scope or meaning of the apparatus and methods disclosed in this disclosure.

[0067] Therefore, the claims are not intended to be limited to the embodiments shown in this disclosure, but should be limited by the widest scope consistent with the disclosure, principles, and novel features disclosed in this disclosure. Overall, the claim language should be interpreted broadly based on the language employed in the claims. The claims should not be limited to the non-exclusive embodiments and examples illustrated and described in this disclosure or discussed during prosecution of the application.

[0068] Those skilled in the art will appreciate that in some embodiments, the functionality provided by the described components, structures, methods, and processes may be provided in alternative ways, such as being divided into more components or methods, or integrated into fewer components or methods. Additionally, while various methods may be illustrated as being performed in a particular order, those skilled in the art will appreciate that in other embodiments the methods may be performed in other orders and in other ways.

[0069] Also, although there may be some embodiments within the scope of this disclosure that are not explicitly described above or elsewhere in this disclosure, this disclosure is contemplated to include all embodiments within the scope of what is shown and described in this disclosure. Also, this disclosure is contemplated to include the following embodiments, i.e., embodiments that include any combination of any structure, material, step, or other feature disclosed anywhere in this disclosure with any other structure, material, step, or other feature disclosed anywhere in this disclosure.

[0070] Also, certain features described in the present disclosure in the context of separate embodiments may be implemented in combination in a single embodiment. Conversely, various functions described in the context of a single embodiment may be implemented separately in multiple embodiments, and in any suitable subcombination. Also, although features may be described as acting in a particular combination, one or more features from a combination described in a claim may, in some cases, be cut out of the combination, and the combination may be interpreted as a subcombination or a variation of the subcombination.

[0071] Also, although components and operations may be depicted in the drawings or described in the specification in a particular arrangement or order, such components and operations need not be arranged and performed in the particular arrangement and order shown, nor in sequential order, nor including all components and operations, to achieve desirable results. Other components and operations not depicted or described may be incorporated into the embodiments and examples. For example, one or more additional operations may be performed before, after, simultaneously with, or between any of the described operations. Also, operations may be rearranged or reordered in other examples. Also, it should be understood that the separation of various system components in the above examples should not be understood as requiring such separation in all examples, and that the described components and systems may generally be integrated together in a single product or packaged in multiple products.

[0072] In summary, various exemplary embodiments and examples are disclosed for machines, devices, processes, and methods for automatically extracting substances from layered, staged, or separated samples. Although systems, techniques, and methods are disclosed in the context of these embodiments and examples, the disclosure extends beyond the specifically disclosed embodiments to other alternative embodiments and / or other uses of the embodiments, as well as specific variations and equivalents thereof. The disclosure expressly contemplates that various features and aspects of the disclosed embodiments can be combined with or substituted for one another. Thus, the scope of the disclosure should not be limited by the specific disclosed embodiments described above, but should be determined only by a fair interpretation of the following claims and all of their equivalents.

Claims

1. An automated liquid processing system, An imaging station including a light source, a sample storage device, and an imaging device, Collection device, Includes, The imaging station is configured to capture images of a sample and transmit the sample images to a control computer. The imaging station and acquisition device are operablely connected to the control computer. The control computer is configured to process the sample image. The collection device transfers a predetermined amount of sample to a sample collection container. Automatic liquid processing system.

2. The control computer is configured to specify one or more extraction points from the sample. The automated liquid processing system according to claim 1.

3. The luminous intensity of the light source corresponds to a specific opacity of the sample storage device. The automated liquid processing system according to claim 1.

4. The light source is positioned above, below, or at an angle to the sample storage device. The automated liquid processing system according to claim 1.

5. Imaging equipment includes cameras, The automated liquid processing system according to claim 1.

6. It is configured to run an extraction program to extract a desired portion from a sample. The automated liquid processing system according to claim 1.

7. One or more of the imaging station, acquisition device, and control computer are independent components. or One or more of the imaging station, acquisition device, and control computer are integrated into a single system. The automated liquid processing system according to claim 1.

8. The sample storage device, light source, and imaging equipment are integrated into a single system. The automated liquid processing system according to claim 1.

9. The light source, the position of the light source, and the opacity of the sample storage device are selected collectively based on the suitability of the combination of these factors for imaging the samples contained in the sample storage device. The automated liquid processing system according to claim 1.

10. Further including a graphical user interface (GUI) operablely connected to a control computer, The automated liquid processing system according to claim 1.

11. The collection device includes a collection arm and a collection mechanism. The automated liquid processing system according to claim 1.

12. The control computer is configured to instruct the collection equipment to move laterally, horizontally, and / or vertically along the collection arm. The automatic liquid processing system according to claim 11.

13. The control computer is configured to instruct the collection arm to position the collection device at predetermined extraction coordinates, or extraction coordinates determined by the operator. The automatic liquid processing system according to claim 11.

14. One or more of the imaging station, collection device, collection container, or control computer are integrated into a single system. The automated liquid processing system according to claim 1.

15. One or more of the imaging station, acquisition device, and control computer are independent components. The automated liquid processing system according to claim 1.

16. A method for automatically extracting substances from a sample, Step a involves loading the sample into the imaging station, Step b involves irradiating the sample, Step c involves imaging the irradiated sample, Step d involves sending a sample image to the control computer, Step e involves calculating the extraction amount and extraction coordinates based on the sample image, Step f involves instructing the collection arm to move towards the calculated extraction coordinates, Step g involves drawing the calculated extraction amount from the sample into the collection device, Step h involves instructing the collection arm to move towards a collection container located at a predetermined coordinate, and dispensing the desired amount into the collection container. including, method.

17. The process further includes repeating steps a through h for each of the n samples, n is a non-negative integer. The method according to claim 16.

18. A method for automatically extracting substances from a sample, Step a involves loading one or more samples into the imaging station, Irradiate one or more samples, and one or more irradiated samples step b, Step c involves imaging one or more irradiated samples, Step d involves transmitting one or more sample images to a control computer, Step e involves calculating the extraction amount and extraction coordinates based on the sample image, Step f involves instructing the collection arm to move towards the calculated extraction coordinates, Step g involves aspirating the extracted substance from one or more samples into a collection device based on the calculated extraction volume, Step h involves instructing the collection arm to move the collection device toward one or more collection containers, Step i involves dispensing the extracted substance into one or more collection containers, including, method.

19. The process further includes repeating steps b through h for each of one or more samples. The method according to claim 18.

20. The step of obtaining a pipette tip before aspirating the sample further includes: The method according to claim 16 or 18.

21. The step of calculating the extraction amount and extraction coordinates based on the sample image is: Steps to define the extraction boundary including, The method according to claim 16 or 18.

22. The step of defining the extraction boundary is performed by the control computer. The method according to claim 21.

23. The step of centrifugating the sample before loading it into the imaging station further includes the step of loading the sample into the imaging station. The method according to claim 16 or 18.

24. The sample includes layered samples, stepwise samples, or separated samples. The method according to claim 16 or 18.

25. The calculated extraction rate from the sample is 3 mL / min to 15 mL / min. The method according to claim 16 or 18.

Images