Automatic Sample Preparation System

Abstract

To provide an automatic sample preparation system where sample pretreatment, extraction, quantitation and solution preparation are integrated into one system.SOLUTION: An automatic sample preparation system 10 comprises: a sample preparation device 100 configured to pretreat a sample for extraction from the sample; an extraction device 200 configured to utilize an extraction strip to extract a genetic material from the sample; a sample holder 300 configured to hold a container for the sample, a container for the extracted genetic material, and a pipet tip for extraction; a pre-amplification quantification device 400 configured to quantify the genetic material; an amplification sample preparation device 500 configured to prepare a solution available for amplification reaction; a non-extraction pipet tip holder 600; and a pipetting device 700 configured to mix or transfer liquid. The extraction device 200 and the sample holder 300 are provided at opposite sides of the sample preparation device 100 to face each other. The pre-amplification quantification device 400, the amplification sample preparation device 500 and the non-extraction pipet tip holder 600 are provided at a side of the sample holder away from the sample preparation device 100.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to an automatic sample preparation system.

Background Art

[0002] Currently, in fields such as disease diagnosis, drug discovery, environmental monitoring, food inspection, forensic science, and academic research, bioactive substances such as cells, proteins, genetic materials, etc. are often used. Among them, genetic material is one of the basic substances of life, including ribonucleic acid (abbreviation: RNA) and deoxyribonucleic acid (abbreviation: DNA), and is widely present in all animals, plants, microorganisms, and viruses. With the development of biotechnology, it is possible to extract genetic material from biological specimens and perform subsequent analysis and applications. Devices capable of automatically extracting genetic material from specimens have been developed. However, the forms of biological specimens are diverse, and depending on the sampling method, biological specimens include body fluids such as blood, saliva, urine, solid paraffin such as formalin-fixed paraffin-embedding (FFPE) samples, cultured cells, bacterial colonies, nasal swabs, etc. Before extracting these various biological specimens, it is necessary to perform pretreatment so that they become samples suitable for the automatic extraction device and then extract them. The extracted genetic material usually needs to undergo an amplification reaction such as polymerase chain reaction (PCR). Also, depending on subsequent analysis and applications, the genetic material may be quantified before performing the amplification reaction.

[0003] However, currently commercially available automatic extraction devices do not include functions for sample pretreatment, as well as subsequent quantification and solution preparation. In the processes of sample pretreatment, pre-amplification quantification, and solution preparation, technicians and additional equipment are required for operation. Manual operation not only consumes time and labor but also causes human errors. More importantly, manual operation significantly increases the risk of contamination.

Summary of the Invention

Problems to be Solved by the Invention

[0004] An automatic sample preparation system according to an embodiment of the present invention integrates sample pretreatment, extraction, quantification, and solution preparation in one system. Instead of manual operations, the automatic system can reduce the time and labor costs, reduce the errors caused by manual operations, and further reduce the risk of contamination.

Means for Solving the Problems

[0005] An embodiment of the present invention includes a sample preparation device for pretreating a sample to make it in a form used for extraction, an extraction for strip tube is provided, and an extraction device for extracting genetic material from the sample with the extraction for strip tube a sample holder for holding a sample container, a container for the extracted genetic material, and an extraction pipette tip, a pre-amplification quantification device for quantifying the extracted genetic material, an amplification sample preparation device for preparing the extracted genetic material into a solution to be applied to an amplification reaction, a non-extraction pipette tip holder for holding a non-extraction pipette tip, a pipette device that is moved to the sample holder and is provided with an extraction pipette tip to mix or transfer a liquid with the sample preparation device, the extraction device, and the sample holder, or is moved to the non-extraction pipette tip holder and is provided with a non-extraction pipette tip to mix or transfer a liquid with the sample holder, the pre-amplification quantification device, and the amplification sample preparation device, and provides an automatic sample preparation system, wherein the extraction device and the sample holder are provided opposite to each other on both sides of the sample preparation device, and the pre-amplification quantification device, the amplification sample preparation device, and the non-extraction pipette tip holder are provided on one side where the sample holder is away from the sample preparation device.

[0006] According to the automatic sample preparation system which is an embodiment of the present invention, sample pretreatment, extraction, pre-amplification quantification, and amplification solution preparation are integrated in one system. The automatic sample preparation device can perform pretreatment on solid samples such as paraffin in addition to liquid samples. The pipetting device in the automatic sample preparation system can thoroughly mix liquids in a way of repeating pipetting. Compared with stirring and mixing, it can mix liquids more uniformly and avoid damage caused by collisions during stirring. The arrangement method of each device in automatic sample preparation reduces the risk of contamination or damage due to collisions during movement by shortening the movement distance of the pipetting device between each device. By automating each procedure instead of manual operation, the operation is simplified, the costs of time and labor are reduced, and the efficiency is improved. With a standardized process, human errors are reduced and the reliability is improved. More importantly, the risk of being contaminated is significantly reduced.

Brief Description of the Drawings

[0007]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Modes for Carrying Out the Invention

[0008] The following will describe in detail the specific features and advantages of the present invention in embodiments. The content is sufficient for any person skilled in the art to understand the technical content of the present invention and implement it based thereon. According to the content disclosed in this specification, the scope of claims, and the drawings, any person skilled in the art can easily understand the objectives and advantages of the present invention. The following examples will further elaborate on the perspectives of the present invention, but in no way limit the scope of the present invention from any perspective.

[0009] Referring to FIG. 1, FIG. 1 is a plan view schematically showing an automatic sample preparation system according to an embodiment of the present invention. According to an embodiment of the present invention, the automatic sample preparation system 10 includes a sample preparation device 100, an extraction device 200, a sample holder 300, a pre-amplification quantification device 400, an amplified sample preparation device 500, a non-extraction pipette tip holder 600, and a pipette device 700. The extraction device 200 and the sample holder 300 are provided opposite to each other on both sides of the sample preparation device 100, and the pre-amplification quantification device 400, the amplified sample preparation device 500, and the non-extraction pipette tip holder 600 are provided on the side where the sample holder 300 is away from the sample preparation device 100. This arrangement method reduces the risk of contamination or damage due to collision during movement by shortening the movement distance of the pipette device 700 between each device.

[0010] The sample preparation device 100 is used to perform pretreatment on the sample so that the sample is in a form suitable for extraction. The form suitable for extraction refers to a liquid form that can be pipetted with a pipette and mixed with an extraction reagent. The sample can be either liquid or solid. The sample can include paraffin, blood, plasma, serum, saliva, virus, pathogen, bacteria, or cells. For example, when the sample needs to be diluted, the sample is diluted in the sample preparation device 100 so that it is in a form suitable for extraction. For example, the sample preparation device may include a dilution buffer supply device. The sample used for extraction is transferred from the sample preparation device 100 to the extraction device 200 via the pipette device 700 described below for extraction.

[0011] The sample preparation device 100 may include a heating region for heating the placed sample. For example, the heating region may have several heaters. The range of the heating region may cover the entire sample preparation device 100, or may cover a part of the sample preparation device 100. For example, when the sample is paraffin such as FFPE, the paraffin is placed in the heating region of the sample preparation device 100 and melted into a liquid by heating so as to be in a form used for extraction.

[0012] The extraction device 200 performs extraction for strip tube 210 is provided, and extraction for strip tube is used to extract genetic material from the sample with the strip 210. For example, the extraction device 200 may include an extraction for strip tube holder. FIG. 2 shows an example of the extraction for strip tube provided in the extraction device. The extraction for strip tube 210 may have a structure with a plurality of tubes. Some of the tubes may contain reagents for the extraction reaction, such as a magnetic bead-containing buffer, a lysis solution, a washing solution, and an elution solution, and some other tubes may be empty tubes. The reagents in the extraction connected side by side strip for 210 vary depending on the type of sample. A part of the extraction tube strip for 210 may be located in the sample preparation device 100. For example, as shown in FIG. 2, the extraction tube strip for 210 may have two empty tubes at the outermost for placing the sample to be pretreated located in the sample preparation device 100. The extraction device 200 may have a foolproof structure. For example, the extraction device 200 has a structure corresponding to the extraction tube strip for 210 to position the extraction tube strip for 210, preventing misinstallation and ensuring the correct progress of the extraction process. tube

[0013] ​In the extraction device 200, liquid mixing or transfer may be performed by a pipetting device 700 described later. Extraction for Strip tube In the extraction device 200 provided with for , the genetic material in the sample is adsorbed by the magnetic beads of the magnetic bead-containing buffer solution, the solution in the tube is sucked up by the pipetting device 700, moved to the next tube, and the sample is sequentially extracted for Strip tube It is transferred to each tube in for for extraction. In the extraction process, liquid mixing is performed by repeatedly pipetting with the pipetting device 700. The extracted genetic material is transferred to the sample holder 300 via the pipetting device 700.

[0014] The sample holder 300 is used to hold the sample container, the container for the extracted genetic material, and the pipette tip for extraction. The sample container can hold the undiluted sample that is not extracted. The pipette tip for extraction is provided in the pipetting device 700 described later and is used for extraction. The sample holder 300 can arrange the sample container, the pipette tip for extraction, and the container for the extracted genetic material in this order along the direction facing the extraction device 200. In other words, the container for the extracted genetic material is closest to the extraction device 200, and by transferring the extracted genetic material to the container at the shortest distance, the risk of contamination during the transfer process is reduced. The sample holder 300 may have different structures depending on the type of sample. For example, FIGS. 3A to 3D are sample holders 300 applicable to different samples. FIG. 3A is a sample holder 300A applicable to 10 milliliters of serum or plasma, FIG. 3B is a sample holder 300B applicable to paraffin (e.g., FFPE), FIG. 3C is a sample holder 300C applicable to virus or blood, and FIG. 3D is a sample holder 300D applicable to 5 milliliters of serum or plasma. The sample holder 300 may have a foolproof structure. For example, the sample holder 300 has a structure corresponding to the pins and containers to position the sample holder 300 and the containers, thereby preventing misinstallation of the sample holder 300 or misplacement of the containers.

[0015] The pre-amplification quantification device 400 is used to quantify the extracted genetic material. In certain biochemical analyses or applications, it may be necessary to quantify the genetic material in a sample prior to the amplification reaction. The pre-amplification quantification device 400 may be an optical quantification instrument, such as a spectrometer. The extracted genetic material placed in the sample holder 300 by the pipetting device 700 described later can be transferred to the pre-amplification quantification device 400 and optically quantified. The pre-amplification quantification device 400 is provided with, but not limited to, an LED light source, a filter, and a light-emitting diode. For example, the pre-amplification quantification device 400 includes an excitation filter of 475 nm and a scattering filter of 525 nm, measures the genetic material at a specific wavelength, and quantifies the genetic material by creating a calibration curve using the built-in software.

[0016] The amplification sample preparation device 500 is used to prepare the extracted genetic material into a solution suitable for the amplification reaction. The amplification sample preparation device 500 can include an amplification reagent holder 510 and an amplification sample holder 520. The amplification reagent holder 510 is used to hold reagents for the amplification reaction, such as polymerase, dNTP, primers, and buffer solution. The amplification sample holder 520 is used to hold the solution to be applied to the prepared amplification reaction. After transferring the extracted genetic material placed in the sample holder 300 by the pipetting device 700 described later to the amplification sample holder 520, the pipetting device 700 extracts the reagent placed in the amplification reagent holder 510 and adds it to the extracted genetic material to prepare a solution to be applied to the amplification reaction. The prepared solution may be taken out from the automatic sample preparation system 10 and subjected to the next amplification reaction, or it may be stored.

[0017] The non-extraction pipette tip holder 600 is used to hold non-extraction pipette tips. Non-extraction pipette tips are used for mixing or transferring liquids not related to extraction. In other words, the extraction pipette tips placed in the sample holder 300 are used for mixing or transferring liquids in the sample preparation device 100, the extraction device 200, and the sample holder 300, while the non-extraction pipette tips placed in the non-extraction pipette tip holder 600 are used for mixing or transferring liquids in the sample holder 300, the pre-amplification quantification device 400, and the amplified sample preparation device 500. Distinguishing and using extraction pipette tips from non-extraction pipette tips shortens the distance the pipetting device 700 moves in a single procedure and reduces the risk of contamination during the process of attaching or moving the extraction pipette tip.

[0018] The pipetting device 700 is moved to the sample holder 300, where an extraction pipette tip is provided to mix or transfer liquids in the sample preparation device 100, the extraction device 200, and the sample holder 300, or it is moved to the non-extraction pipette tip holder 600, where a non-extraction pipette tip is provided to mix or transfer liquids in the sample holder 300, the pre-amplification quantification device 400, and the amplified sample preparation device 500. For example, the pipetting device 700 may be a robotic arm equipped with a pipette. The pipetting device 700 mixes liquids by repeating pipetting. The pipetting device 700 can automatically detect or manually set the volume of the liquid, and by repeating pipetting according to the volume of the liquid, the liquid is thoroughly mixed. Compared with stirring and mixing, the mixing method of repeating pipetting according to the volume of the liquid mixes the liquid more uniformly and can avoid damage caused by collisions during stirring.

[0019] The pipetting device 700 can include a first pipetting device 710 and a second pipetting device 720. The movement range A of the first pipetting device 710 can include the sample preparation device 100, the extraction device 200, and the sample holder 300. The first pipetting device 710 is moved to the sample holder 300, and an extraction pipette tip is provided to mix or transfer a liquid at the sample preparation device 100, the extraction device 200, and the sample holder 300. The movement range B of the second pipetting device 720 can include the sample holder 300, the pre-amplification quantification device 400, the amplified sample preparation device 500, and the non-extraction pipette tip holder 600. The second pipetting device 720 is moved to the non-extraction pipette tip holder 600, and a non-extraction pipette tip is provided to mix or transfer a liquid at the sample holder 300, the pre-amplification quantification device 400, and the amplified sample preparation device 500. The first pipetting device 710 and the second pipetting device 720 can move in separate areas respectively, and by shortening the movement distance of a single pipetting device, the risk of contamination during the process of attaching or moving the extraction tip is reduced.

[0020] The extraction device 200, the sample preparation device 100, and the sample holder 300 are arranged in this order along a first direction, and the pre-amplification quantification device 400, the amplified sample holder 520, the amplified reagent holder 510, and the non-extraction pipette tip holder 600 are arranged in this order along a second direction, and the first direction is perpendicular to the second direction. With this arrangement method, when the pipetting device 700 provides a non-extraction pipette tip from the non-extraction pipette tip holder 600, moves to the amplified reagent holder 510 to aspirate the reagent, and then adds it to the genetic material held in the amplified sample holder 520, by shortening the movement distance, the risk of the pipetting device 700 being contaminated during the process of attaching or moving the extraction tip is reduced.

[0021] The automatic sample preparation system 10 further includes a waste collector 800. The waste collector 800 is used to collect used pipette tips and waste liquid. For example, the waste collector 800 can be a container or a box, is provided on the outermost side of the device and the holder, and is detachably provided on the automatic sample preparation system 10.

[0022] The automatic sample preparation system 10 further includes a housing 900, and the housing 900 can include an opening 910. The sample preparation device 100, the extraction device 200, the sample holder 300, the pre-amplification quantification device 400, the amplified sample preparation device 500, the non-extraction pipette tip holder 600, and the pipetting device 700 are provided within the housing 900, and the pre-amplification quantification device 400, the amplified sample preparation device 500, and the non-extraction pipette tip holder 600 are located between the sample holder 300 and the opening 910. The housing 900 can further include a door portion to cover the opening 910. This arrangement can facilitate the removal of the solution applied to the amplification reaction prepared from the opening 910 and avoid contact with the sample preparation device 100, the extraction device 200, or the sample holder 300, thereby reducing the risk of contamination and damage due to contact.

[0023] The automatic sample preparation system 10 further includes an image recognition device 920. The image recognition device 920 is provided within the housing 900. The image recognition device 920 can recognize labels or notations on the sample container or the genetic material container. For example, the image recognition device 920 can be a camera. The labels or notations can be letters, numbers, or barcodes. For example, when the sample container is a blood collection tube, the image recognition device 920 recognizes the label on the blood collection tube and transmits the information to a computer so that data collation and analysis can be performed. The image recognition device 920 can also recognize the position and arrangement of consumables. For example, the image recognition device 920 recognizes the number, position, and arrangement of non-extraction pipette tips in the non-extraction pipette tip holder 600, moves the pipetting device 700 to an accurate position to provide a pipette tip, or issues a warning signal when there is a shortage of pipette tips.

[0024] The automatic sample preparation system 10 further includes an ultraviolet sterilizer 930. The ultraviolet sterilizer 930 is provided within a housing 900. The ultraviolet sterilizer 930 is used to sterilize the sample preparation device 100, the extraction device 200, the sample holder 300, the pre-amplification quantification device 400, the amplified sample preparation device 500, the non-extraction pipette tip holder 600, and the pipetting device 700. The ultraviolet sterilizer 930 includes an ultraviolet fluorescent lamp and is provided at an upper portion within the housing 900 or at any position where ultraviolet rays can irradiate each device. The ultraviolet sterilizer 930 can ensure that the interior of the housing 900 is in a sterile state when a sample is inserted.

[0025] Hereinafter, an example from when a sample is inserted into the automatic sample preparation system 10 until it is taken out will be described. First, when the sample is liquid, the container containing the sample is placed in the sample holder 300, and the sample is transferred to the sample preparation device 100 by the first pipetting device 710 and diluted or heat-treated to be in a form suitable for extraction. When the sample is solid, the sample is extracted for strip tube directly into the tube located in the sample preparation device 100 at 210 and diluted or heat-treated to be in a form suitable for extraction. Subsequently, the extracted sample placed in the sample preparation device 100 is transferred to the extraction device 200 by the first pipetting device 710 and sequentially extracted for strip tube with each reaction reagent at 210 to perform an extraction reaction. The extracted sample is transferred into the container placed in the sample holder 300 by the first pipetting device 710. In the above process, the mixing or transfer of the liquid is performed by the first pipetting device 710 provided with the extraction pipette tip held by the sample holder 300.

[0026] Subsequently, when it is necessary to perform quantification before amplification, the extracted sample placed in the sample holder 300 is transferred to the pre-amplification quantification device 400 by the second pipetting device 720 for quantification. Subsequently, according to the quantification result, or when pre-amplification quantification is not required, the extracted sample placed in the sample holder 300 is transferred by the second pipetting device 720 to the amplified sample holder 520 of the amplified sample preparation device 500. The second pipetting device 720 extracts the reagent held in the amplified reagent holder 510 of the amplified sample preparation device 500 and adds it to the extracted sample to prepare a solution for applying to the amplification reaction. The prepared solution may be taken out from the opening 910 and the next amplification reaction may be performed, or it may be stored. In the above process, the mixing or transfer of the liquid is performed by the second pipetting device 720 provided with the non-extraction pipette tip held in the non-extraction pipette tip holder 600.

[0027] According to the automatic sample preparation system which is an embodiment of the present invention, sample pretreatment, extraction, pre-amplification quantification, and amplification solution preparation are integrated in one system. The automatic sample preparation device can perform pretreatment on solid samples such as paraffin in addition to liquid samples. The pipetting device in the automatic sample preparation system can thoroughly mix the liquid by repeating pipetting. Compared with stirring and mixing, the liquid can be mixed more uniformly, and damage due to collision by stirring can be avoided. The arrangement method of each device in the automatic sample preparation reduces the risk of contamination or damage due to collision during movement by shortening the movement distance of the pipetting device between each device. By automating each procedure instead of manual operation, the operation is simplified, the cost of time and labor is reduced, and the efficiency is improved. By a standardized process, human error is reduced and reliability is improved. More importantly, the risk of being contaminated is significantly reduced.

[0028] Although the present invention has been disclosed in the above embodiments as described above, they do not limit the present invention. Changes and modifications made without departing from the spirit and scope of the present invention belong to the scope of patent protection of the present invention. Regarding the protection scope defined by the present invention, reference can be made to the appended claims.

Explanation of reference numerals

[0029] 10: Automatic sample preparation system 100: Sample preparation device 200: Extraction device 210: Extraction for Strip tube 300, 300A, 300B, 300C, 300D: Sample holder 400: Quantification device before amplification 500: Amplified sample preparation device 510: Amplification reagent holder 520: Amplified sample holder 600: Non-extraction pipette tip holder 700: Pipetting device 710: First pipetting device 720: Second pipetting device 800: Waste collector 900: Housing 910: Opening 920: Image recognition device 930: Ultraviolet sterilizer A: Movement range of the first pipetting device B: Movement range of the second pipetting device

Claims

1. A sample preparation device for preprocessing a sample to make it in a form suitable for extraction, an extraction device provided with an extraction strip tube for extracting genetic material from the sample with the extraction strip tube, a sample holder for holding a sample container, a container for the extracted genetic material, and an extraction pipette tip, a pre-amplification quantification device for quantifying the extracted genetic material, an amplification sample preparation device for preparing the extracted genetic material into a solution to be applied to an amplification reaction, a non-extraction pipette tip holder for holding a non-extraction pipette tip, a pipette device that is moved to the sample holder and provided with the extraction pipette tip to mix or transfer liquids in the sample preparation device, the extraction device, and the sample holder, or is moved to the non-extraction pipette tip holder and provided with the non-extraction pipette tip to mix or transfer liquids in the sample holder, the pre-amplification quantification device, and the amplification sample preparation device, wherein the extraction device and the sample holder are provided opposite to each other on both sides of the sample preparation device, and the pre-amplification quantification device, the amplification sample preparation device, and the non-extraction pipette tip holder are provided on one side where the sample holder is away from the sample preparation device, an automatic sample preparation system.

2. Further including a housing, the housing includes an opening, the sample preparation device, the extraction device, the sample holder, the pre-amplification quantification device, the amplification sample preparation device, the non-extraction pipette tip holder, and the pipette device are provided in the housing, and the pre-amplification quantification device, the amplification sample preparation device, and the non-extraction pipette tip holder are located between the sample holder and the opening. The automatic sample preparation system according to Claim 1.

3. The amplification sample preparation device includes an amplification reagent holder and an amplification sample holder. The amplification reagent holder is used to hold reagents used in the amplification reaction, and the amplification sample holder is used to hold a solution to be applied to the prepared amplification reaction. The automatic sample preparation system according to Claim 1.

4. The extraction device, the sample preparation device, and the sample holder are arranged in this order along a first direction, and the pre-amplification quantification device, the amplified sample holder, the amplification reagent holder, and the non-extraction pipette tip holder are arranged in this order along a second direction, and the first direction is perpendicular to the second direction. The automatic sample preparation system according to claim 3.

5. The sample according to claim 1 of the automatic sample preparation system includes paraffin, blood, plasma, serum, saliva, virus, pathogen, bacteria, or cells.

6. The sample preparation device includes a heating region, and the heating region is used to heat the sample. The automatic sample preparation system according to claim 1.

7. The pipetting device mixes the liquid by a method of repeating pipetting. The automatic sample preparation system according to claim 1.

8. The pipetting device includes a first pipetting device and a second pipetting device. The moving range of the first pipetting device includes the sample preparation device, the extraction device, and the sample holder. The moving range of the second pipetting device includes the sample holder, the pre-amplification quantification device, the amplified sample preparation device, and the non-extraction pipette tip holder. The automatic sample preparation system according to claim 1.

9. Further including an image recognition device, the image recognition device is used to recognize labels or notations on the sample container or the genetic material container. The automatic sample preparation system according to claim 1.

10. Further including an ultraviolet sterilizer, the ultraviolet sterilizer is used to sterilize the sample preparation device, the extraction device, the sample holder, the pre-amplification quantification device, the amplified sample preparation device, the non-extraction pipette tip holder, and the pipetting device. The automatic sample preparation system according to claim 1.

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