TW201944051A - System for extracting biomolecules from a sample and related methods - Google Patents

Abstract

An automated system for isolating biomolecules from a biological sample is described herein. Further described are methods for operating such systems. Also described are components of the automated system, such as a liquid handling system, a robotic arm, sample tube racks, an analytical instrument, a barcode reader, and sample processing modules, which can include a shaker, a magnetic bead biomolecule isolation system, an endotoxin control system, a heated incubator, or a chilled incubator.

Description

   System and related method for extracting biomolecules from a sample   

The invention relates to an automated sample processing system and its components, including a liquid processing system, a sample tube holder suitable for a liquid processing system, a magnetic bead separation system, and a method of using the same.

Automated systems have previously been used to isolate nucleic acids from biological samples. Compared to manual bench-top separation technology, such systems allow increased efficiency and quality control. The automated system sold from QIAGEN under the trade name QIAsymphony® SP System is an exemplary system that automatically processes biological samples for nucleic acid isolation. Automated systems typically use liquid handling systems and bead separation techniques to mix reagents with biological samples, remove non-target components from the samples, and separate target biomolecules.

Despite the benefits of known automated systems for separating biomolecules from biological samples, such systems are often affected by incomplete biomolecule recovery and cross-contamination, have limited sample throughput, and are usually limited to relatively small processes Its sample volume. These defects can lead to inaccurate diagnostic analysis or poor research results. In this technology, there is still a need to develop automated systems for separating biomolecules from samples. These systems have increased quantity and quality of biomolecule recovery, increased sample processing throughput, processing of larger sample volumes, and limited Cross contamination.

The disclosures of all publications, patents, and patent applications mentioned herein are incorporated by reference in their entirety. In the event of any reference incorporated by reference in conflict with the present disclosure, the present disclosure shall control.

This article describes an automated system for separating biomolecules from biological samples. Components of the automated system, such as a liquid handling system and / or a biomolecule separation system, are also described, which may employ one or more magnets. The method for operating such a system is further described.

In some embodiments, the liquid handling system includes: at least one pipette system including: a multi-channel pipette, the multi-channel pipette including an upper region attached to a support structure, and a lower distribution region, the lower The distribution region includes at least a first liquid port on the side of the distribution region fluidly connected to the first channel and a second liquid port at the tip of the distribution region fluidly connected to the second channel; a control valve that controls liquid flow through the pipetting The first or second channel of the tube; and a pump fluidly connected to the control valve. A multi-channel pipette may have two or more (e.g., three, four, five or more) channels. In some embodiments, the multi-channel pipette is a dual-channel pipette.

In some embodiments, the second channel of the multi-channel pipette passes through and is parallel to the first channel of the multi-channel pipette. In some embodiments, the second channel of the multi-channel pipette is adjacent to the first channel of the multi-channel pipette.

In some embodiments, the second liquid port includes a concave cutout.

In some embodiments, the first liquid port is configured to spray liquid onto an inner wall of the container.

In some embodiments, at least a portion of the pipette is coated with a hydrophobic layer.

In some embodiments, the second channel is fluidly connected to a liquid storage circuit between the multi-channel pipette and the control valve. In some embodiments, the liquid storage circuit has a liquid storage capacity of about 2 mL or more.

In some embodiments, the liquid treatment system includes a liquid waste management system connected to a second channel of the multi-channel pipette. In some embodiments, the liquid processing system includes a valve between the second channel of the multi-channel pipette and the liquid waste management system.

In some embodiments, the pump includes a first liquid port fluidly connected to the control valve, and a second liquid pump fluidly connected to the washing liquid container.

In some embodiments, the liquid processing system includes a plurality of reagent tanks fluidly connected to a reagent valve configured to select a reagent from the plurality of reagent tanks, wherein the reagent valve is fluidly connected to the control valve.

In some embodiments, the support structure is attached to a robot arm. In some embodiments, the robot arm is configured to move at least in a direction of a vertical axis.

In some embodiments, the multi-channel pipette is attached to a support block, and wherein the support block is attached to the support structure via an elastic mechanism configured to at least partially absorb an upward force applied on the pipette. . In some embodiments, the liquid handling system includes a plurality of pipette systems, wherein each pipette system includes a multi-channel pipette attached to a support block. In some embodiments, the elastic mechanism includes two or more springs and two or more guide mechanisms.

In some embodiments, the liquid handling system further includes a pipette cleaning system including a container having an open top and at least one cleaning tube positioned vertically within the container. In some embodiments, the cleaning tube is sized and shaped to receive a multi-channel pipette. In some embodiments, the container includes a bottom including a drainage port.

Also provided herein is a method of operating the above-mentioned liquid handling system, comprising aspirating liquid into a pipette via a second liquid port. In some embodiments, the method includes lowering a pipette into a sample tube containing a liquid. In some embodiments, the method includes contacting a pipette with the bottom of the sample tube. In some embodiments, the liquid contains magnetic beads. In some embodiments, the liquid contains a target biomolecule. In some embodiments, the liquid is stored in a liquid storage circuit. In some embodiments, the method includes dispensing liquid via a second liquid port.

This document further provides a method of operating the above-mentioned liquid processing system, further comprising spraying liquid from the first liquid port onto the inner wall of the container. In some embodiments, the method includes using a spray to wash the beads off the inner wall of the container. In some embodiments, the beads are magnetic beads.

This article also provides an automated system for separating biomolecules from a sample, including the above-mentioned liquid processing system, further including a magnetic bead regeneration system, a second liquid processing system, a shaker, a sample tube holder, a biomolecule separation system, and magnetic beads One or more of a regeneration system, a cold storage unit, a barcode reader, or an analytical instrument.

Further provided herein is an automated system for separating biomolecules from a biological sample, comprising (a) a liquid handling system including a pipette operable to move at least on a vertical axis; (b) a sample tube Racks; and (c) one or more lids configured to fit on one or more sample tubes contained in a sample tube rack, the one or more lids included in each of the one or more sample tubes The sealable port on the person thereby allows the pipette to enter the sample tube through the sealable port, wherein the sealable port is sealed when the pipette is withdrawn from the sample tube.

In some embodiments of the automated system, the sealable port includes two or more communicating slots. In some embodiments, the sealable port includes an elastomer or rubber.

In some embodiments of the automated system, the sample tube rack includes a base that fits into a sample tube rack fixture attached to a surface. In some embodiments, the base includes a groove or protrusion, and the receiving block includes a complementary groove or protrusion. In some embodiments, the surface is part of a biomolecule separation system that includes a magnet that can be configured into a valid configuration and an invalid configuration, wherein when the magnet is in a valid configuration, the magnet applies a magnetic field to one or more sample tubes So that the magnetic beads in the sample tube are bonded to the inner surface of the one or more sample tubes, and wherein when the magnet is in an inactive configuration, the magnetic field is removed to release most of the magnetism from the inner surface of the one or more sample tubes Beads.

In some embodiments of the automated system, the system further includes one or more of a magnetic bead regeneration system, a vibrator, a magnetic bead separation system, a pipette cleaning system, a cold storage unit, a barcode reader, or an analytical instrument.

This document also provides an automated system for separating biomolecules from a biological sample, including: (a) a first liquid processing system including at least one pipette system, the pipette system including (i) a multi-channel pipette A tube (e.g., a dual-channel pipette) including an upper region attached to a support structure, and a lower distribution region including at least a first liquid on a side of the distribution region fluidly connected to the first channel A port and a second liquid port fluidly connected to the second channel at the tip of the dispensing area; (ii) a control valve that controls the flow of liquid through the first or second channel of the pipette; and (iii) a fluid connection A pump to a control valve; (b) a second liquid processing system including at least one pipette, wherein the second liquid processing system is configured to process a liquid volume smaller than the first liquid processing system; (c) a sample tube rack; (d) one or more lids configured to fit on one or more sample tubes contained within a sample tube rack, the one or more lids including a cover on each of the one or more sample tubes Sealable port, which Allow the pipette from the first liquid processing system or the second liquid processing system to enter the sample tube through the sealable port, where the sealable port is sealed when the pipette is withdrawn from the sample tube; and (e) biomolecule separation A system configured to bind magnetic beads to the side of a sample tube with a magnetic field in an effective configuration.

In some embodiments of the automated system, the biomolecule separation system is operable to configure the magnet into a valid configuration and an invalid configuration, wherein when the magnet is in a valid configuration, the magnet applies a magnetic field to one or more sample tubes to The magnetic beads in the sample tube are bonded to the inner surface of the one or more sample tubes, and wherein when the magnet is in an invalid configuration, the magnetic field is removed to release most of the magnetic beads from the inner surface of the one or more sample tubes.

In some embodiments, the automated system also includes one or more of a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a barcode reader, or an optical detector.

In some embodiments of the automation system, the system is housed within a housing. In some embodiments, the housing is sealed. In some embodiments, the housing includes a sterilization system. In some embodiments, the sterilization system includes an air filter or an ultraviolet lamp.

In some embodiments of the automation system, a computer system is used to operate the automation system.

1‧‧‧ base unit

2‧‧‧Working Platform

3‧‧‧ gate

4‧‧‧ top

5‧‧‧air filtration system

6‧‧‧ reagent tank

7‧‧‧ robot arm

8‧‧‧ Magnetic Bead Regeneration System

9‧‧‧Biomolecule separation system

10‧‧‧Liquid Handling System

12‧‧‧Second liquid treatment system

13‧‧‧Sample input / output module

14‧‧‧ consumable delivery system

17‧‧‧Barcode Reader

18‧‧‧Storage cabinet

18A‧‧‧Horizontal Orbit

19‧‧‧ depth orbit

20‧‧‧ depth orbit

21‧‧‧ the first vertical track

22‧‧‧ Second vertical track

23‧‧‧Consumable delivery system

24‧‧‧ Subject

25‧‧‧ Operating System

26‧‧‧finger

27‧‧‧bearing

28‧‧‧rotation control mechanism

29‧‧‧ base

30‧‧‧Temperature control unit

31‧‧‧ sidewall

32‧‧‧ window

33‧‧‧casters

34‧‧‧base

35‧‧‧ sample tube holder fixings

36‧‧‧Vibration Platform

37‧‧‧ cushion

38‧‧‧sample tube rack

39‧‧‧Guide

40‧‧‧Guide

41‧‧‧space or groove

42‧‧‧space or groove

43‧‧‧ magnetic placement board

44‧‧‧ Magnet

45‧‧‧ support element

46‧‧‧Guide

47‧‧‧ sample tube

48‧‧‧ Cover

49‧‧‧Sealing port

50‧‧‧ base

51‧‧‧ hinge

52‧‧‧side support

53‧‧‧ with buckle

54‧‧‧Receiving slot

55‧‧‧Clean Room

56‧‧‧Vibrator

57‧‧‧ opening

58‧‧‧Magnet

59‧‧‧First liquid port

59a‧‧‧first channel

59b‧‧‧First liquid port

59c‧‧‧First liquid port

60‧‧‧Second liquid port

60a‧‧‧Second channel

60b‧‧‧Second liquid port

61‧‧‧Dual-channel pipette

62‧‧‧Control Valve

63‧‧‧First channel catheter

64‧‧‧Second channel catheter

65‧‧‧Liquid storage circuit

66‧‧‧ Tee connector

67‧‧‧Waste Management Conduit

68‧‧‧Waste management system

69‧‧‧Two-way solenoid valve

70‧‧‧ reagent tank

71‧‧‧ reagent valve

72‧‧‧ compressed air

73‧‧‧ reagent supply catheter

74‧‧‧pump

75‧‧‧first pump port

76‧‧‧Sink

77‧‧‧Second pump port

78‧‧‧ Washing liquid duct

79a‧‧‧Dual channel pipette

79b‧‧‧Dual channel pipette

79c‧‧‧Dual-channel pipette

79e‧‧‧ dual channel pipette

79f‧‧‧ Dual Channel Pipette

80a‧‧‧Control Valve

80b‧‧‧Control Valve

80c‧‧‧Control Valve

80d‧‧‧Control Valve

80e‧‧‧Control Valve

80f‧‧‧Control Valve

81a‧‧‧First channel catheter

81b‧‧‧First channel catheter

81c‧‧‧First channel catheter

81d‧‧‧First channel catheter

81e‧‧‧First channel catheter

81f‧‧‧First channel catheter

82a‧‧‧Second channel catheter

82b‧‧‧Second channel catheter

82c‧‧‧Second channel catheter

82d‧‧‧Second Channel Catheter

82e‧‧‧Second Channel Catheter

82f‧‧‧Second Channel Catheter

83a‧‧‧Liquid storage circuit

83b‧‧‧Liquid storage circuit

83c‧‧‧Liquid storage circuit

83d‧‧‧Liquid storage circuit

83e‧‧‧Liquid storage circuit

83f‧‧‧Liquid storage circuit

84a‧‧‧ Waste Management Conduit

84b‧‧‧Waste management duct

84c‧‧‧Waste Management Conduit

84d‧‧‧ Waste Management Conduit

84e‧‧‧ Waste Management Conduit

84f‧‧‧ Waste Management Conduit

85a‧‧‧pump

85b‧‧‧ pump

85c‧‧‧ pump

85d‧‧‧ pump

85e‧‧‧ pump

85f‧‧‧ pump

86‧‧‧ reagent tank

87‧‧‧ reagent valve

88‧‧‧ reagent supply line

89a‧‧‧Tee connector

89b‧‧‧ Tee connector

89c‧‧‧ Tee connector

89d‧‧‧ Tee Connector

89e‧‧‧Tee connector

90‧‧‧washing liquid tank

91‧‧‧washing liquid duct

92a‧‧‧ Tee Connector

92b‧‧‧ Tee connector

92c‧‧‧ Tee Connector

92d‧‧‧ Tee Connector

92e‧‧‧ Tee connector

94‧‧‧ support structure

95‧‧‧ vertical arm

96‧‧‧ Attachment area

97a‧‧‧pipette

97b‧‧‧ pipette

97c‧‧‧pipette

97d‧‧‧ Pipette

97e‧‧‧ Pipette

97f‧‧‧ Pipette

98‧‧‧ limit agency

99‧‧‧ support block

100‧‧‧first spring

101‧‧‧second spring

102‧‧‧First rail

103‧‧‧Second rail

104‧‧‧ support structure

105‧‧‧ vertical arm

106‧‧‧Limiting agency

107a‧‧‧ pipette

107b‧‧‧ pipette

107c‧‧‧ pipette

108‧‧‧ Adjustable spacer

109a‧‧‧Flexible mechanism

109b‧‧‧Flexible mechanism

109c‧‧‧Flexible mechanism

110‧‧‧Guide

111‧‧‧Drive System

112a‧‧‧ pipette

112b‧‧‧ pipette

112c‧‧‧ pipette

113a‧‧‧First port

113b‧‧‧First port

113c‧‧‧First port

114a‧‧‧Pump

114b‧‧‧Pump

114c‧‧‧ pump

115a‧‧‧ pipette catheter

115b‧‧‧pipette catheter

115c‧‧‧pipette catheter

116‧‧‧washing liquid tank

117‧‧‧washing liquid duct

118a‧‧‧Second Port

118b‧‧‧Second Port

118c‧‧‧Second Port

119a‧‧‧ Tee connector

119b‧‧‧ Tee connector

120‧‧‧ Slim Container

121‧‧‧ Open top

122a‧‧‧clean tube

122b‧‧‧clean tube

122c‧‧‧clean tube

122d‧‧‧clean tube

122e‧‧‧clean tube

122f‧‧‧clean tube

123‧‧‧Inner surface

124a‧‧‧Scaffold

124b‧‧‧ bracket

124c‧‧‧Scaffold

124d‧‧‧Scaffold

124e‧‧‧Scaffold

124f‧‧‧ bracket

125a‧‧‧ Drain

125b‧‧‧ Drain

125c‧‧‧ Drain

125d‧‧‧ Drain

125e‧‧‧ Drain

125f‧‧‧ Drain

126‧‧‧ Drain

127‧‧‧ sample tube

128‧‧‧ cooler

129‧‧‧lifting system

129a‧‧‧drive system

129b‧‧‧Guide

130‧‧‧Transverse Transportation System

130a‧‧‧Drive System

130b‧‧‧rail

131‧‧‧first channel

132‧‧‧Second Channel

133‧‧‧First liquid port

133a‧‧‧Liquid port opening

133b‧‧‧Liquid port opening

134‧‧‧ Tip

135‧‧‧Second liquid port

1610‧‧‧Memory section

1600‧‧‧Computer system

1602‧‧‧Main System

1604‧‧‧Motherboard

1606‧‧‧Input / Output (`` I / O '') section

1608‧‧‧Central Processing Unit (`` CPU '')

1612‧‧‧Flash Memory Card

1614‧‧‧Keyboard

1616‧‧‧Disk storage unit

1618‧‧‧Media Drive Unit

1620‧‧‧Computer-readable media

1622‧‧‧Program

1624‧‧‧Display

Figure 1 illustrates an exemplary automated system for separating biomolecules. FIG. 1A shows an enlarged view of a robot arm of the system shown in FIG. 1.

FIG. 2 illustrates an exemplary consumable delivery system that can be used with an automation system.

Figure 3 shows an exemplary incubator that can be heated or cooled, which can be used with an automated system.

FIG. 4 illustrates an exemplary automation system packaged in an exemplary housing.

FIG. 5 illustrates an exemplary biomolecule separation system that can be used with an automated system.

FIG. 6 illustrates an exemplary sample tube rack that can be used with a biomolecule separation system.

FIG. 7 illustrates an exemplary magnetic bead regeneration system that can be used with an automated system.

8A and 8B illustrate an embodiment of a distribution area of a dual-channel pipette, wherein FIG. 8A shows a perspective image and FIG. 8B shows a contour image. FIG. 8C shows a cross-sectional view of a two-channel pipette showing the second channel through the first channel. Figure 8D shows a cross-sectional view of a dual channel pipette from the line labeled "A-A" in Figure 8C.

Figure 9A shows a schematic diagram of an exemplary liquid handling system that can be used with an automated system equipped with a single dual channel pipette. FIG. 9B shows a schematic diagram of a liquid processing system having a similar configuration applied to a liquid processing system including a plurality of dual-channel pipettes.

FIG. 10A illustrates an exemplary liquid handling system attached to a robot arm, and FIG. 10B illustrates a support structure connected to a plurality of pipettes in detail.

11A and 11B illustrate an exemplary small volume liquid processing system.

Figure 12 shows a schematic view of an exemplary setup of a small volume liquid processing system.

Figure 13 shows a schematic diagram of an exemplary large volume liquid processing system integrated with a small volume liquid processing system.

FIG. 14A shows an exemplary pipette cleaning system, and FIG. 14B shows a cross-sectional view of the pipette cleaning system shown in FIG. 14A.

FIG. 15 illustrates an exemplary bracket that can be used for a sample input module and / or a sample output module.

FIG. 16 depicts an exemplary computer system configured to operate an automated system described herein or perform any of the processes described herein.

FIG. 17A shows an alignment view showing one embodiment of an exemplary dual channel pipette. FIG. 17B shows a perspective image of a dispensing area of an exemplary two-channel pipette of a liquid processing system. Figure 17C shows a cross-section of an exemplary dual channel pipette viewed upwards.

    Cross-references to related applications    

This application claims the priority and rights of the international patent application PCT / CN2018 / 083155 filed on April 16, 2018, the disclosure of which is incorporated herein by reference in its entirety.

This article describes an automated system for separating biomolecules from a biological sample, and a method for operating such a system. The automated system may include a liquid processing system, a robotic arm, one or more sample tube holders, and / or a sample processing module (e.g., a shaker, a magnetic bead biomolecule separation system, an endotoxin control system, a heated incubator, and / Or cooling the incubator). Optionally, the automated system may include a barcode reader that may be used to track samples in the system; or an analytical instrument such as an optical detector for analyzing the sample.

Further described is a liquid handling system that can be a component of an automated system. The liquid handling system may include at least one multi-channel pipette attached to a liquid handling system support structure. A multichannel pipette can have two or more (e.g., three, four, five, or more) channels. In some embodiments, the multi-channel pipette is a dual-channel pipette. The multi-channel pipette includes a distribution region having a first liquid port on a side of the distribution region and a second liquid port at a tip of the distribution region. In some embodiments, the multi-channel pipette further includes additional channels (eg, a third channel and / or a fourth channel), which can also be used to disperse and / or pump liquids. For example, in a multi-channel pipette, there may be two or more channels for dispersing liquid and / or two or more channels for extracting liquid. The liquid handling system includes a valve that controls the flow of liquid through the first passage or the second passage. The liquid flowing through the first channel is dispensed through a first liquid port on the side of the dispensing area of the pipette, which causes the liquid to be ejected to the side. The lateral spraying of the liquid allows the inner wall of the container to be washed, for example, to allow beads that may adhere to the side of the sample tube to escape. The second liquid port can be larger than the first liquid port and can be used to draw or dispense a larger liquid volume. In some embodiments, the second liquid port includes a concave cutout. The valve can be controlled by a computer system to control the flow of liquid through the first channel of the pipette or the second channel of the pipette.

Instead of or in addition to multi-channel pipettes (e.g., dual-channel pipettes or pipettes with three or more channels), some embodiments of liquid handling systems also include one or more single-channel pipettes tube. In a single-channel pipette, the same channel can be used to dispense and / or draw liquid.

The automated system may include a sample tube rack and one or more lids configured to fit on one or more sample tubes contained within the sample tube rack. The one or more lids allow the liquid handling system to access the inside of the sample tube without substantially exposing the contents of the sample tube to the external environment, thereby limiting cross-contamination of the contents of the sample tube. The one or more covers include a sealable port on each sample tube contained in the holder, which allows a pipette from the liquid handling system to enter the sample tube through the sealable port. When the pipette is withdrawn from the sample tube, the sealable port is sealed. In some embodiments, the lid is configured to cover the plurality of sample tubes and is optionally attached to the sample tube holder, such as by a hinge.

definition

As used herein, unless the context clearly indicates otherwise, the singular forms "a / an" and "the" include plural referents.

References to "about" a value or parameter herein include (and describe) a change in that value or parameter itself. For example, references to "about X" include descriptions of "X".

It should be understood that the aspects and variations of the present invention described herein include "consisting of aspects and variations" and / or "consisting essentially of aspects and variations".

Where a range of values is provided, it should be understood that every intermediate value between the upper and lower limits of that range, and any other stated or intervening value in that stated range are encompassed within the scope of this disclosure. In scope. When the ranges include an upper limit or a lower limit, ranges excluding any of the limits included in them are also included in the disclosure.

It should be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the invention. Some headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

automated system

Figure 1 illustrates an exemplary automated system for separating biomolecules. The system components may be mounted on the work platform 2 or in a storage cabinet 18 positioned behind the work platform 2. The storage cabinet 18 may store components that are not frequently involved in sample processing, such as reagent tanks 6, additional sample tubes or multiwell plates; or structural supports for one or more robotic arms 7. The automation system includes a liquid processing system 10 and optionally a second liquid processing system 12, each of which can be connected to a robot arm 7. The automated system may also include a biomolecule separation system 9 that can be used, for example, to isolate a target biomolecule from a source sample by using magnetic bead affinity purification; and a magnetic bead regeneration system 8. The sample input / output module 13 may be disposed on the work platform 2 and may receive samples obtained from the subject, or may receive biomolecules separated by an automated system for users to retrieve. In some embodiments of an automated system, the system includes an additional robotic arm that can transfer system consumables, such as multiwell plates or sample tubes, which can be individually or in the form of groups contained within a sample tube rack To send. The barcode reader 17 may optionally be included in the automated system, which can scan the barcode or other identifier on the sample tube to track the location of the sample or consumables within the system. In some embodiments, the automated system includes an analysis instrument 16 that can analyze biomolecules separated by the system.

The robotic arm can manipulate system components attached to the arm in two or three dimensions, depending on the arrangement of other components in the system. In the automation system shown in FIG. 1, the robot arm 7 operates the first liquid processing system 10, the second liquid processing system 12, and the consumable conveying system 14 in three dimensions. FIG. 1A shows an enlarged view of a robot arm of the system shown in FIG. 1. The robot arm may include a lateral track that allows movement of components at the end of the robot arm to move along the length of the system; and a depth track attached to the lateral track that allows components to move along the depth of the system. The assembly can be directly attached to a vertical track, which is connected to a depth track. The robot arm may have a common track or a separate track. In some embodiments, the robotic arm allows rotational movement, such as where the robotic arm is connected to system components. As shown in FIG. 1A, the lateral rail 18A is positioned in a storage cabinet behind the work platform and is elevated above the work platform. In the example shown, the two depth rails 19 and 20 share the same lateral rail 18A. To move along the length of the system, the depth orbits 19 and 20 can independently travel along the lateral orbit 18A. In some embodiments, each depth track is connected to a separate lateral track. The depth rail 19 is connected to each of a first vertical rail 21 connected to the first liquid processing system 10 and a second vertical rail 22 connected to the second liquid processing system 12. The vertical track 21 and the vertical track 22 can independently travel along the depth track 19 so as to move in the depth dimension of the system. The liquid processing system 10 can be vertically moved by adjusting the vertical rail 21, and the liquid processing system can be independently moved vertically by adjusting the vertical rail 22. The depth track 20 is connected to a consumable delivery system 23. The consumable delivery system 23 may travel along the depth track 20 to move in the depth dimension, and the depth track 20 may travel along the lateral track 18A to move along the length of the system. The consumable delivery system 23 may also have one or two rotation axes, which allows greater maneuverability of the consumable delivery system 23. The consumable delivery system 23 is configured to transport consumables in the system, such as plates or sample tubes, and may include removable fingers that are operable to handle and transport consumables, such as from a consumables reservoir into the system Desired location. The robotic arms shown in the system of FIG. 1A are exemplary and other robotic arms that can be used with automated systems are known in the art.

FIG. 2 illustrates an exemplary consumable delivery system. The consumable delivery system includes a main body 24 that houses an operating system 25 that controls the fingers 26. The operating system 25 can operate the fingers 26 between a closed configuration and an open configuration in which the fingers are spaced apart to hold consumables such as multiwell plates or sample tubes, while in the open configuration the fingers Space apart to release consumables. The operating system 25 may include a power system, such as a hydraulic cylinder, a cylinder, or an electric motor, which may provide power for the movement of the fingers 26. The operating system 25 may also include a guide assembly, such as a linear guide, a guide shaft, or a guide sleeve, which may align the directional movement of the fingers 26. The consumable conveying system further includes a bearing 27 and a rotation control mechanism 28 that can rotate the main body 24. In some embodiments, the body is rotatable between about 0 ° and about 270 °.

The automated system may optionally include a sample tracking device, which may be, for example, a barcode scanner or a radio frequency identification (RFID) scanner. In some embodiments, the sample tracking device is connected to a consumable delivery system, such as in FIG. 2, the sample tracking device 17 is connected to the main body 24 of the consumable delivery system. The sample tube can be marked with a barcode or RFID tag, and the sample tracking device can scan the tag to track the position of the sample within the system. The tracked position can be transmitted to the computer system operating the automation system.

The system may include a sample input module and a sample output module. In some embodiments, the sample input module and the sample output module are the same module. The sample input module and the sample output module are configured to hold a sample tube. An input biological sample (such as a saliva, urine, stool, or blood sample) contained in a sample tube is placed in the sample input module. Such biological samples can be used by the system to isolate biological molecules such as nucleic acids, proteins and / or antibodies. In some embodiments, the sample tube is contained within a sample tube rack. A cap with one or more sealable ports can cover the sample tube, which allows the sample to be taken by the liquid processing module while the liquid processing module is kept sealed when it is not receiving the contents of the sample tube. The lid may be a separate cap for the sample tube, or it may be an engagement lid that includes a sealable port for each sample tube in the sample tube holder. During sample processing, the robotic arm can position the liquid handling system on the sample tube containing the biological sample, and can lower the pipette to access the biological sample in the sample tube. Reagents can be added to the sample and / or the sample can be aspirated into a pipette for transport to another location in the system, such as a sample processing tube. Once the target biomolecule is separated by an automated system, the composition containing the target biomolecule can be dispensed into a sample tube in a sample output module. Once the sample is in the sample tube in the sample output module, the sample can be retrieved by the user for further processing, or it can be analyzed using an analytical instrument. For example, the liquid processing system can draw a sample from a sample processing tube in a sample output module and dispense the sample into a multiwell plate. Multiwell plates can be transported to analytical instruments, such as using a consumable delivery system attached to a robotic arm.

Exemplary analytical instruments that can be used with automated systems include, but are not limited to, fluorometers, optical detectors, mass spectrometers, calorimeters, or nucleic acid sequencers. Other analytical instruments that can be used with automated systems are known. For example, analytical instruments can be used to determine the concentration of a biological molecule (e.g., a protein or a nucleic acid), an antibody titer, a nucleic acid sequence, or the presence or amount of one or more analytes.

The sample input and / or output module is configured to hold a plurality of sample tubes, such as about 6 or more, about 12 or more, about 24 or more, about 48 or more, About 96 or more, or about 192 or more sample tubes. In some embodiments, the input module and / or output module includes a cooler and can cool the sample tube to about 0 ° C to about 20 ° C, such as about 0 ° C to about 4 ° C, about 4 ° C to about 10 ° C , About 10 ° C to about 15 ° C, or about 15 ° C to about 20 ° C. In some embodiments, the input module and / or the output module include an insulating block, which is resistant to the heating of the sample tube. The input module and / or output module may be configured to lift and / or move a sample tube or a row of sample tubes laterally as appropriate. For example, the sample tube can be lifted or moved so that the tracking device can read the sample tube tag (eg, RFID or barcode). In some embodiments, the input module and / or output module includes a lifting system, which may include a drive system (such as a motor, hydraulic cylinder, or air cylinder) and a guide (such as a guide rail, guide shaft, or guide sleeve) . The lifting system can be operated to lift the sample tube or the row of sample tubes. In some embodiments, the input module and / or output module includes a horizontal transporter that can transport the sample tubes or a row of sample tubes laterally. A lateral transporter may include a drive system (such as a motor, hydraulic cylinder, or air cylinder) and a guide (such as a rail, guide shaft, or guide sleeve).

FIG. 15 illustrates an exemplary bracket that can be used for a sample input module and / or a sample output module. The holder is configured to hold one or more sample tubes 127, which may be arranged in columns and / or rows. The holder includes a cooler 128, which cools the sample tubes in the module. The module further includes a lifting system 129, which includes a driving system 129a and a guide 129b. The lifting system 129 allows the sample tube to move in a vertical direction. The module also includes a horizontal transport system 130 for horizontal movement of the sample tube, which includes a drive system 130a and a guide rail 130b.

In some embodiments, the automated system includes a heated incubator and / or a cooled incubator. The sample tube can be placed in a heated or cooled incubator before, during, or after processing. For example, in some embodiments, the sample input module and / or the sample output module are cooled. In some embodiments, a heated incubator can be used to pre-treat a biological sample. In some embodiments, the heated incubator is heated to a temperature of about 25 ° C to about 100 ° C, such as about 25 ° C to about 30 ° C, about 30 ° C to about 37 ° C, about 37 ° C to about 42 ° C, about 42 ° C To about 60 ° C, about 60 ° C to about 80 ° C, or about 80 ° C to about 100 ° C. In some embodiments, the cooling incubator is cooled to a temperature of about -20 ° C to about 20 ° C, such as about -20 ° C to about -10 ° C, about -10 ° C to about 0 ° C, about 0 ° C to about 10 ° C , Or about 10 ° C to about 20 ° C. Figure 3 shows an exemplary incubator that can be heated or cooled. The incubator includes a base 29 and a temperature control unit 30. The base 29 can be fixed to a working platform of the system, and the temperature control unit 30 can be heated or cooled. The temperature control unit 30 includes a plurality of containers that can receive a sample tube or a micro tube.

In some embodiments, the automated system includes a vibrator, shaker, or other mixing device. During sample processing, the sample tube can be placed on a shaker, shaker, or other mixing device using a consumable delivery system. In some embodiments, a shaker, shaker, or other mixing device is configured to hold one or more individual sample tubes, or a sample tube holder that can hold one or more sample tubes.

Contamination of sample processing by the system can be limited by including a housing that encloses the system. The system may further include one or more additional anti-fouling features, such as UV lamps and / or air filtration systems for sterilization. The automation system may be packaged in a housing, as shown for example in FIG. 4. The housing protects samples and system components from external sources of contamination. The housing may include a door 3 that can be opened by a user to place a sample in the sample input module, remove a sample from the sample output module, add or replace consumables, or otherwise maintain the system. The door 3 may include a window that allows a user to observe the operation of the system. The casing further includes a casing top 4 and a side wall 31, and the side wall 31 optionally includes a window 32. In some embodiments, an air filtration system 5 may be included, which may be disposed on the top 4 of the housing, the side wall 31 of the housing, or any other suitable location. Optionally, the air filtration system 5 maintains a positive pressure in the housing. In some embodiments, the automated system includes a UV lamp that can be used to sterilize surfaces on the system to avoid cross-contamination. In some embodiments, the UV lamp is positioned on the inner surface of the housing, such as the inner surface of the housing top 4 or the inner surface of the side wall 31. In some embodiments, the system is positioned on a base unit 1, which optionally includes casters 33. Other methods for limiting cross-contamination or removing endotoxins are described herein, such as caps for sample tubes that include sealable ports.

In some embodiments, the automated system for separating biomolecules from a biological sample includes a liquid processing system including (a) at least one pipette system including a multi-channel pipette, the multi-channel pipette The liquid tube includes an upper region attached to the support structure, and a lower distribution region, the lower distribution region including at least a first liquid port fluidly connected to the side of the first channel on the side of the distribution region, and a second fluid channel connected to the second channel. A second liquid port at the tip of the distribution area; (b) a control valve that controls the flow of liquid through the first or second channel of the pipette; and (c) a pump fluidly connected to the control valve. In some embodiments, the multi-channel pipette is a dual-channel pipette. In some embodiments, a multichannel pipette has three or more (e.g., three, four, five, or more) channels. It is also contemplated in this application that, in certain embodiments, the pipette system described herein includes a single channel pipette. Liquid handling systems including such pipette systems can accommodate relatively large or small sample volumes.

In some embodiments, the automated system for separating biomolecules from a biological sample includes a liquid processing system including at least one pipette system, the pipette system including a single-channel pipette, the single-channel The pipette includes an upper region attached to the support structure, and a lower distribution region. In some embodiments, a single channel pipette may be configured to dispense liquid and draw liquid.

In some embodiments, the automated system further includes one or more of a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a barcode reader, or an optical detector. In some embodiments, the automation system is housed within a housing, which optionally includes a sterilization system (such as a UV lamp and / or air filter). In some embodiments, a computer system is used to operate the automation system.

In some embodiments, an automated system for separating biomolecules from a biological sample includes: (a) a liquid handling system including (i) at least one pipette system, the pipette system comprising: a multi-channel pipette A tube (e.g., a dual channel pipette) comprising an upper region attached to a support structure, and a lower distribution region, the lower distribution region including at least: a first fluidly connected first channel on a side of the distribution region A liquid port and a second liquid port fluidly connected to the second channel at the tip of the distribution area; (ii) a control valve that controls the flow of liquid through the first or second channel of the pipette; and (iii) fluid A pump connected to the control valve; (b) a sample tube holder; and (c) one or more covers configured to fit on one or more sample tubes contained in the sample tube holder, the cover included in the one Sealable port on each of the plurality of sample tubes, which allows a pipette from a liquid handling system to enter the sample tube through the sealable port, wherein the sealable port is sealed when the pipette is withdrawn from the sample tube . In some embodiments, the automated system also includes one or more of a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a barcode reader, or an optical detector. In some embodiments, the automation system is housed within a housing, which optionally includes a sterilization system (such as a UV lamp and / or air filter). In some embodiments, a computer system is used to operate the automation system.

In some embodiments, an automated system for separating biomolecules from a biological sample includes: (a) a liquid handling system comprising (i) at least one pipette system, the pipette system comprising: a multi-channel pipette A tube (e.g., a dual channel pipette) comprising an upper region attached to a support structure, and a lower distribution region, the lower distribution region including at least: a first fluidly connected first channel on a side of the distribution region A liquid port and a second liquid port fluidly connected to the second channel at the tip of the distribution area; (ii) a control valve that controls the flow of liquid through the first or second channel of the pipette; and (iii) fluid A pump connected to the control valve; (b) one or more covers configured to fit on one or more sample tubes contained in a sample tube rack, the cover included in each of the one or more sample tubes The sealable port on the device allows the pipette from the liquid processing system to enter the sample tube through the sealable port, wherein the sealable port is sealed when the pipette is withdrawn from the sample tube; and (c) biomolecule separation system, Configured to form a magnetic field by the effective configuration of the magnetic beads are bound to the side of the sample tube. In some embodiments, the biomolecule separation system is operable to configure the magnet into a valid configuration and an invalid configuration, wherein when the magnet is in a valid configuration, the magnet applies a magnetic field to one or more sample tubes to cause the sample tubes The magnetic beads in are bonded to the inner surface of one or more sample tubes, and wherein when the magnet is in an invalid configuration, the magnetic field is removed to release most of the magnetic beads from the inner surface of the one or more sample tubes. Optionally, the automated system further includes one or more of a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a barcode reader, or an optical detector. In some embodiments, the automation system is housed within a housing, which optionally includes a sterilization system (such as a UV lamp and / or air filter). In some embodiments, a computer system is used to operate the automation system.

In some embodiments, an automated system for separating biomolecules from a biological sample includes: (a) a first liquid processing system including at least one pipette system, the pipette system including (i) a multi-channel pipette A liquid pipe (e.g., a dual-channel pipette) comprising an upper region attached to a support structure, and a lower distribution region, the lower distribution region including at least: a first fluidly connected first channel on a side of the distribution region; A liquid port and a second liquid port fluidly connected to the second channel at the tip of the distribution area; (ii) a control valve that controls the flow of liquid through the first or second channel of the pipette; and (iii) A pump fluidly connected to the control valve; (b) a second liquid processing system including at least one pipette, wherein the second liquid processing system is configured to process a liquid volume smaller than the first liquid processing system; (c) a sample tube (D) one or more lids configured to fit on one or more sample tubes contained within a sample tube rack, the lids comprising a sealable seal on each of the one or more sample tubes Port, which allows from A pipette of a liquid handling system or a second liquid handling system enters a sample tube through a sealable port, wherein the sealable port is sealed when the pipette is withdrawn from the sample tube; and (e) a biomolecule separation system, which It is configured to bind the magnetic beads to the side of the sample tube with a magnetic field in an effective configuration. In some embodiments, the biomolecule separation system is operable to configure the magnet into a valid configuration and an invalid configuration, wherein when the magnet is in a valid configuration, the magnet applies a magnetic field to one or more sample tubes to cause the sample tubes The magnetic beads in are bonded to the inner surface of one or more sample tubes, and wherein when the magnet is in an invalid configuration, the magnetic field is removed to release most of the magnetic beads from the inner surface of the one or more sample tubes. Optionally, the automated system further includes one or more of a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a barcode reader, or an optical detector. In some embodiments, the automation system is housed within a housing, which optionally includes a sterilization system (such as a UV lamp and / or air filter). In some embodiments, a computer system is used to operate the automation system.

Biomolecule separation system and magnetic bead regeneration

Automated systems can isolate target biomolecules, such as proteins, antibodies, or nucleic acids (such as DNA or RNA), depending on the reagents used in the system. Bead separation technology can be used to bind the target biomolecules to the beads, and separate the target biomolecules bound to the beads from other biological sample components to isolate the target biomolecules. In some embodiments, the automated system includes a bead regeneration system that allows continuous reuse of beads in an automated system. Beads that can be coated or charged with an affinity molecule, such as an oligonucleotide, an antigen, or an antibody to provide electrostatic affinity, are mixed with the sample, and the target biomolecule is bound to the beads.

In some embodiments, the beads are magnetic. Once bound to the target biomolecule, a biomolecule separation system can be used to separate the magnetic beads from the remaining sample component liquid in the sample. The biomolecule separation system is configured to selectively apply a magnetic field to a sample tube, which pulls magnetic beads bound to a target biomolecule to the inner wall of the sample tube. Use a liquid handling system to withdraw liquid from the sample tube, leaving magnetic beads attached to the wall of the sample tube. Magnetic beads can be washed using a liquid handling system, and the magnetic field can be removed from the sample tube to release the magnetic beads. In some embodiments, the liquid processing system wash the beads adhered to the wall of the sample tube, thereby suspending them in the liquid.

The biomolecule separation system may include one or more magnets that may be configured to apply a magnetic field to one or more sample tubes in an effective configuration and to an ineffective position that does not apply a magnetic field to one or more sample tubes. In some embodiments, the magnet is a permanent magnet. The permanent magnet can be configured into an effective configuration by positioning the permanent magnet near one or more sample tubes, and can be configured into an invalid configuration by moving the permanent magnet away from one or more sample tubes. In some embodiments, the magnet is a transient magnet, such as by applying a current to the transient to generate a magnetic field in a valid configuration, and stopping the current to turn off the magnetic field in an invalid configuration. The magnet should be positioned close to the sample tube, for example within about 5 mm of the sample tube. In some embodiments, the magnet is positioned within about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm of the sample tube. In some embodiments, the magnet is positioned from about 0.5 mm to about 5 mm from the sample tube.

The biomolecule separation system can accommodate relatively large sample tubes and sample volumes in sample tubes. In some embodiments, the volume of the sample tube used with the biomolecule separation system is about 1 mL to about 500 mL, such as about 1 mL to about 5 mL, about 5 mL to about 15 mL, about 15 mL to about 40 mL, about 40 mL to about 60 mL, About 60 mL to about 80 mL, about 80 mL to about 100 mL, about 100 mL to about 250 mL, or about 250 mL to about 500 mL. In some embodiments, the volume of the sample tube used with the biomolecule separation system is about 78 mL. The volume of liquid in the sample tube is preferably small enough to avoid spillage during sample processing. However, depending on the size of the sample tube, the volume of liquid in the sample tube may be large. For example, in some embodiments, the liquid volume is up to about 80 mL, such as about 1 mL to about 5 mL, about 5 mL to about 15 mL, about 15 mL to about 40 mL, about 40 mL to about 60 mL, or about 60 mL to about 80 mL. In some embodiments, the liquid volume is about 50 mL. In some embodiments, the volume of the sample tube is about 78 mL, and the liquid volume in the sample tube is up to about 50 mL. In some embodiments, the volume of the input biological sample processed by the automated system is up to about 80 mL, such as about 1 mL to about 5 mL, about 5 mL to about 15 mL, about 15 mL to about 40 mL, about 40 mL to about 60 mL, or about 60 mL to about 80mL. In some embodiments, the volume of the input biological sample processed by the automated system is about 50 mL.

Figure 5 illustrates an exemplary biomolecule separation system. The biomolecule separation system includes a base 34 and a sample tube holder fixture 35 attached to the base 34. In some embodiments, the base 34 is a vibrator, and may include a vibration platform 36. The sample tube holder holder 35 may be attached to the vibration platform 36 so that the liquid in the sample tube held by the holder fixed to the sample tube holder holder 35 can be mixed by shaking or shaking the sample tube. Optionally, one or more pads 37 may be attached to the underside of the base, thereby stabilizing the base during vibration or shaking. One or more sample tube holders 38 may be fixed to the sample tube holder holder 35. The sample tube holder holder 35 may include one or more guides 39 and 40 (for example, grooves or protrusions), which may interact with one or more guides (for example, complementary recesses) on the bottom of the sample tube holder 38 Grooves or protrusions) to hold the test tube holder 38 in place when vibrating.

In some embodiments, the sample tube holder holder 35 is configured to hold one or more sample tube holders, such as about 1 to about 20, about 2 to about 18, about 4 to about 16, and about 6 to about 12 or about 8 to about 10. The sample tube racks 38 may be arranged in one or more rows and one or more columns. Between each column, there are spaces or grooves 41. In some embodiments, there is a space or groove 42 on the outer edge of the sample tube holder holder 35 parallel to the space or groove 41 separating the columns.

In some embodiments, the biomolecule separation system further includes one or more magnetic placement plates 43 configured to slide within a space or groove under the control of a drive system. A plurality of magnetic placement plates 43 may be connected to the support element 45 at the distal end. The plurality of magnetic placement plates 43 are not connected at the proximal end, which allows the magnetic placement plates 43 to slide in space or grooves without directly contacting the sample tube. The magnetic placement plates 43 each include a plurality of magnets 44, which may be permanent magnets. When the magnet 44 is configured in an effective position, the magnet is placed near the sample tube, for example, by sliding the magnetic placement plate 43 in a space or a groove. In order to switch the magnet 44 to an invalid configuration, the magnetic placement plate 43 slides in the groove so that the magnet 44 is no longer adjacent to the sample tube. The support element 45 can be fitted to the guide 46, thereby preventing the support element 45 and the magnetic placement plate 43 from being displaced. When the vibrator is stopped, the magnetic placement plate 43 can be moved away from or positioned near the sample tube holder 38. When the vibrator is working, the magnetic placement plate 43 can be kept away, so that the liquid contents of the sample tube holder 38 are mixed, or the magnetic placement plate 43 in an effective configuration can be positioned near the sample tube holder 38, thereby adhering to the sample tube. The magnetic beads on the inner wall of the rack 38 are washed.

In an alternative embodiment, the biomolecule separation system includes a magnetic placement plate at a fixed location on either side of each column of the test tube rack, such as by permanently attaching a magnet to a vibrator. The magnetic placement plate may include a plurality of transient magnets, wherein the magnets are activated by passing a current through the magnets.

The sample tube holders that can be used with the biomolecule separation system are configured to hold a plurality of sample tubes, which can be arranged in one or more columns or one or more rows. In some embodiments, the sample tube holder is configured to arrange the sample tubes in two rows, which allows a magnet to be positioned near each sample tube. In some embodiments, the sample tube holder is configured to arrange the sample tubes in a single tube, which allows two magnets to be positioned adjacent to each sample tube, with the magnets positioned on opposite sides of the sample tube. The sample tube holder can hold about 4 to about 12 sample tubes, such as about 6, 8 or 10 sample tubes.

FIG. 6 illustrates an exemplary sample tube rack that can be used with a biomolecule separation system. Although this sample tube holder is described in the context of a biomolecular separation system, it should be understood that the sample tube holder can be used with any other system or can be used without a corresponding system. In the illustrated embodiment, the sample tube rack is configured to hold six sample tubes 47 in two rows and three rows, but it should be understood that the sample tube rack may be configured to hold an alternative number of sample tubes in an alternative arrangement. The sample tube holder includes a lid 48 that fits on the sample tube 47 contained in the sample tube holder. The lid includes a sealable port 49 above each sample tube 47. The sealable port 49 is made of a flexible material such as rubber or an elastomer such as silicon or elastic plastic, which is preferably resistant to chemicals used in the system. The sealable port 49 allows a pipette from the liquid handling system to enter the sample tube and is sealed when the pipette is withdrawn from the sample tube. The sealable port 49 includes two or more communicating slits. When the pipette is lowered, the pipette separates the flaps formed by the communicating slits, allowing the pipette to enter the sample tube. The pipette can then be raised, which allows the flaps to be connected together, thereby sealing the sample tube.

The base 50 of the sample tube holder may include one or more guides that fit into the guides of the sample tube holder holder of the biomolecule separation system. In some embodiments, the guide of the sample tube holder and the sample tube holder are arranged to require the sample tube holder to be mounted to the sample tube holder holder in a predetermined orientation. In some embodiments, the lid 48 includes a hinge 51 that connects the lid 48 to a side support 52 of the sample tube holder. The sample tube can be removed or added to the sample tube rack by lifting the lid. Hinged connections, if present, allow easy access to add or remove sample tubes. Optionally, a closing mechanism such as the mating buckle 53 and the receiving groove 54 may be positioned on a side of the sample tube holder opposite to the hinge 51. The mating catch 53 can be positioned on the lid, and the receiving groove 54 can be positioned on the side support, and the lid can be locked in place after the lid 48 is closed.

In some embodiments, there is an automated system for separating biomolecules from a biological sample, including a liquid handling system including: a pipette operable to move on at least a vertical axis; and including a lid A sample tube holder, the lid configured to fit on one or more sample tubes contained in the sample tube holder, the cover including a sealable port on each of the one or more sample tubes, the sealable The port allows the pipette to enter the sample tube through a sealable port, where the sealable port is sealed when the pipette is withdrawn from the sample tube. In some embodiments, the sample tube holder includes a base that fits into a sample tube holder attached to a surface, which may be part of a biomolecule separation system. The biomolecule separation system may include a magnet that can be configured into a valid configuration and an invalid configuration, wherein when the magnet is in a valid configuration, the magnet applies a magnetic field to one or more sample tubes to bind the magnetic beads in the sample tube to The inner surface of one or more sample tubes, and wherein when the magnet is in an invalid configuration, the magnetic field is removed to release most of the magnetic beads from the inner surface of the one or more sample tubes. In some embodiments, the automated system further includes one or more of a magnetic bead regeneration system, a vibrator, a magnetic bead separation system, a pipette cleaning system, a cold storage unit, a bar code reader, or an analytical instrument.

In some embodiments of the automated system, the magnetic beads used to isolate the target biomolecule are regenerated. The automated system may include a magnetic bead regeneration system accessible by the liquid processing system. The magnetic bead regeneration system includes a clean room, a magnet, and a mixer. The clean room includes an opening at the top of the room. One or more pipettes from the liquid handling system can be lowered into the clean room through the opening to dispense liquid and / or used magnetic beads, or to draw used liquid or regenerated magnetic beads. The opening may include a seal, which may be a flexible material, such as rubber, silicon, or a resilient plastic. Dropping one or more pipettes into the clean room displaces the seal to allow access to the chamber. When the pipette is lifted from the clean room, the seal closes the opening, thereby restricting liquid from overflowing from the clean room during mixing. The magnet can be selectively operated with an effective configuration that applies a magnetic field to the clean room and an invalid configuration that does not apply a magnetic field to the clean room. The magnet may be a transient magnet, which is configured as a valid configuration by passing a current through the transient magnet, and is configured as a deactivated configuration by cutting off the current. In some embodiments, the magnet is a permanent magnet that is positioned adjacent to the clean room in the active configuration and moves away from the clean room in the invalid configuration.

The liquid processing system can transfer the used magnetic beads from the biomolecule separation system to the clean room of the magnetic bead regeneration system. Once the magnetic beads are distributed in the clean room, the magnetic beads can adhere to the inner wall of the clean room when the magnet is in a valid configuration. In some embodiments, the interior walls of the clean room are coated with a hydrophobic material, such as polytetrafluoroethylene. When the magnetic beads are adhered to the inner wall of the clean room, the liquid processing system can extract liquid from the clean room without substantial loss of the magnetic beads. The liquid handling system can then dispense the cleaning solution in the clean room, and the magnet can be operated in an ineffective configuration to release the magnetic beads into the solution. The mixer mixes the beads with the cleaning solution. Any combination of the required liquid reagents can be used and the cycle repeated as needed. For example, the magnet can be operated in an effective configuration so that the magnetic beads adhere to the side of the clean room, the liquid processing system can draw the used cleaning solution from the clean room, the liquid processing system can distribute the washing solution to the clean room, and The magnet can be operated in an invalid configuration to allow the beads to be suspended in the washing solution. In some embodiments, the magnetic beads are washed one, two, three or more times. After the required number of cleaning cycles, the liquid handling system can withdraw the regenerated magnetic beads from the clean room when the magnet is in an invalid configuration. The regenerated magnetic beads can then be used in a biomolecule separation system.

In some embodiments, the mixer of the magnetic bead regeneration system is a vibrator. For example, the clean room may be attached to a vibrator, and the contents of the clean room are mixed by vibrating the clean room. In some embodiments, the mixer is an agitator, which includes an agitator motor and an impeller disposed in a clean room. In this embodiment, the impeller can be operated to mix the liquid contents of the clean room.

FIG. 7 illustrates an exemplary magnetic bead regeneration system that can be used with an automated system. The magnetic bead regeneration system includes a cleaning chamber 55 attached to a vibrator 56. When activated, the vibrator 56 may mix the liquid contents of the clean room 55. The clean room includes an opening 57 on top of the clean room 55. As shown, the clean room 55 is elongated and has elongated openings 57 but it should be understood that there may be more than one opening, for example, 2, 3, 4, 5, 6, or more than 6 openings. The size and shape of the opening 57 may be designed to allow a minimum clearance of the pipette in the liquid handling system. The opening 57 may further include a seal that is displaced as the pipette is pressed down on the seal when entering the cleaning chamber 55 through the opening 57. The selectively operable magnet 58 is positioned along the elongated outer wall of the cleaning chamber 55. In an alternative configuration, a magnet 58 is attached to the vibrator 56. During the magnetic bead regeneration process, the magnet 58 may be selectively operated in a valid configuration or an invalid configuration. For example, when the vibrator 56 is stopped, the magnet 58 may be moved away from or positioned near the clean room 55. When the vibrator 56 is in operation, the magnet 58 can be kept away so that the liquid contents of the cleaning chamber 55 can be mixed, or the magnet 58 in an effective configuration can be positioned near the cleaning chamber 55 so as to adhere to the cleaning chamber 55 The magnetic beads on the inner wall are washed.

Liquid handling system

Automated systems include liquid handling systems that are used to transfer liquids throughout the system. The liquid processing system may include a large volume liquid processing system, a small volume liquid processing system, or both a large volume liquid processing system and a small volume liquid processing system. In some embodiments, a small volume liquid processing system is integrated with a large volume liquid processing system. In some embodiments, the small volume liquid processing system and the large volume liquid processing system are systems that operate independently.

Large volume liquid processing systems can be used to deliver relatively large volumes of liquid, such as about 10 microliters (μL) to about 100 mL, such as about 10 μL to about 100 μL, about 100 μL to about 1 mL, about 1 mL to about 10 mL, about 10 mL to about 50 mL, or about 50 mL to about 100 mL. Small volume liquid processing systems can be used to deliver relatively small volumes of liquid, such as about 1 μL to about 10 mL, such as 1 μL to about 10 μL, about 10 μL to about 100 μL, about 100 μL to about 500 μL, about 500 μL to about 1 mL, about 1 mL to about 1 mL 5 mL, or about 5 mL to about 10 mL. Other transfer volumes for large volume liquid handling systems and / or small volume liquid handling systems may be considered.

Large volume liquid handling systems include one or more multi-channel pipettes (eg, one or more dual-channel pipettes). In some embodiments, the large volume liquid processing system includes 2, 3, 4, 5, 6, 7, 8, or 8 or more multichannel pipettes. Multichannel pipettes each have an upper region attached to a support structure, and a distribution region. The distribution area includes multiple (e.g., two or more) liquid ports. In some embodiments, the distribution region includes at least a first liquid port on a side of the distribution region fluidly connected to the first channel in the plurality of pipettes, and Second liquid port. A control valve for each multi-channel pipette controls the flow of liquid through the first or second channel of the pipette. In some embodiments, the second liquid port includes a concave cutout. The concave cutout ensures that substantially all of the liquid in the sample tube is removed when the tip of the pipette is lowered to the bottom of the sample tube. In some embodiments, one or more multi-channel pipettes are non-magnetic. In some embodiments, at least a portion of the multi-channel pipette is coated with a hydrophobic layer, such as a polytetrafluoroethylene layer. In some embodiments, the first channel or the second channel is coated with a hydrophobic layer. In some embodiments, the outer surface of the multi-channel pipette is coated with a hydrophobic layer. In some embodiments, the entire multi-channel pipette is coated with a hydrophobic layer. In some embodiments, the outer surface of the multi-channel pipette is coated with a hydrophobic layer and is non-magnetic.

The diameter of the first liquid port may be smaller than the diameter of the second liquid port, thereby controlling the speed of the liquid dispensed from the first liquid port or the second liquid port. This allows, for example, the liquid dispensed via the first liquid port on the side of the dispensing area to be sprayed at a sufficient speed to wash the beads attached to the inner surface of the container within the automated system. The second channel can pass through the first channel so that the first channel can access the liquid port on the side of the pipette, and the second channel can access the liquid port at the tip of the pipette. As an example, the diameter of the second channel may be about 0.6 mm to about 1 mm (such as about 0.8 mm in diameter), which may pass through the first channel having a diameter of about 1.4 mm to about 2.5 mm. In another example, the first channel and the second channel are adjacent to each other and optionally parallel to each other.

8A and 8B illustrate an embodiment of a distribution area of a dual-channel pipette, wherein FIG. 8A shows a perspective image and FIG. 8B shows a contour image. The pipette includes a first channel that spans the length of the pipette and is fluidly connected to the control valve. At the distribution area of the dual-channel pipette, the first channel terminates at a first liquid port 59 provided on the side of the distribution area of the pipette. In some embodiments, the first channel terminates in two or more liquid ports disposed on a side of the dispensing area. The port can partially or completely surround the diameter of the pipette. The first liquid port 59 is disposed at an angle (preferably, an angle of 90 °) with respect to the first liquid channel. In this orientation, the liquid flowing from the first liquid port 59 is ejected outward. When the pipette is positioned in the clean room of the sample tube or magnetic bead regeneration system, the liquid flowing from the first liquid port 59 can wash the inner wall of the sample tube or the inner wall of the clean room. The second channel also spans the length of the pipette and is fluidly connected to the control valve, and may extend parallel to the first channel. The second channel ends in a second liquid port 60, which is positioned at the tip of the pipette. In some embodiments, the tip of the pipette is tapered. The second liquid port 60 may include a concave cutout that prevents the second liquid port 60 from forming a seal with the bottom of the container, and allows efficient liquid flow when liquid is dispensed or withdrawn from the pipette.

Figure 8C shows a cross-sectional view of a dual channel pipette of a liquid handling system and shows how two channels are connected to a liquid port. In the embodiment shown in FIG. 8C, the first channel 59a is connected to two openings of the first liquid ports 59b and 59c. The first channel 59a of the dual channel pipette includes connections at 59d to other components of the liquid handling system (e.g., control valves) in the upper area. The second passage 60a passes through the first passage 59a and is fluidly connected to the second liquid port 60b. The second channel 60a is connected to other components of the liquid processing system in the upper area at 60c. Fig. 8D shows a cross-section of a dual channel pipette viewed upward along line A-A of Fig. 8C. As shown in FIG. 8D, the openings of the first liquid ports 59b and 59c are fan-shaped to increase the ejection of the liquid flowing from the first liquid port. As shown, the openings 59b and 59c each have an opening arc angle of about 80 °, but in some embodiments, the angle is about 60 ° to about 120 °. Although the pipette shown in FIGS. 8A-8D is shown as having two openings with a first liquid port, it is contemplated that the first liquid port may have 1, 2, 3, 4, 5, or 5 or more openings. The height of the opening may be, for example, about 0.1 mm to about 0.5 mm, such as about 0.2 mm to about 0.4 mm, or about 0.3 mm.

17A-17C illustrate another exemplary embodiment of a dual channel pipette. FIG. 17A shows an aligned view of a dual-channel pipette, and FIG. 17B shows a perspective image of a dispensing area of a dual-channel pipette of a liquid processing system. The dual-channel pipette includes a first channel 131 for dispensing liquid and a second channel 132 for withdrawing liquid from the pipette. At the distribution area of the dual-channel pipette, the first channel terminates at a first liquid port 133 provided on the side of the distribution area of the pipette. The first channel may terminate in one or more liquid port openings, such as two liquid port openings 133a and 133b, as shown in FIG. 17C. In some embodiments, the first liquid port may have 1, 2, 3, 4, 5, or 5 or more openings. The height of the opening may be, for example, about 0.1 mm to about 0.5 mm, such as about 0.2 mm to about 0.4 mm, or about 0.3 mm. The tip 134 of the first channel 131 is generally sealed so that the dispensed liquid flows out of one or more ports 133 on the side of the first channel 131. When the pipette is positioned in the clean room of the sample tube or magnetic bead regeneration system, the liquid flowing from the first liquid port 133 can wash the inner wall of the sample tube or the inner wall of the clean room. The second channel 132 also spans the length of the pipette and is fluidly connected to the control valve, and may extend parallel to the first channel 131. The second channel terminates at a second liquid port 135, which is located at the tip of the pipette. In some embodiments, the tip of the pipette is tapered. The second liquid port 135 may include a concave cutout that prevents the second liquid port from forming a seal with the bottom of the container and allows efficient liquid flow when liquid is dispensed or withdrawn from the pipette.

Fig. 17C shows a cross-section of the dual channel pipette viewed at cross-section A-A of Fig. 17A. The first channel 131 of the illustrated embodiment includes two first liquid port openings 133a and 133b on opposite sides of the first channel 131 in the distribution area of a dual channel pipette. The second channel 132 does not include an opening on the side of the channel.

In some embodiments, the second channel is fluidly connected to a liquid storage circuit, which may be disposed between the second channel of the dual-channel pipette and the control valve. Liquid drawn into the multi-channel pipette (which may be, for example, a two-channel pipette) via the second channel may be stored in the liquid storage circuit during transfer. For example, the separated biomolecules can be pumped from a sample tube in the biomolecule separation system to a liquid storage circuit and transferred to a second sample tube in a sample output module. In another example, magnetic beads can be drawn from a sample tube in a biomolecule separation system into a liquid storage circuit and distributed in a magnetic bead regeneration system. In some embodiments, the liquid storage circuit has a capacity of about 100 μL to about 100 mL, such as between about 100 μL to about 1 mL, about 1 mL to about 10 mL, about 10 mL to about 50 mL, or about 50 mL to about 100 mL. In some embodiments, the liquid storage circuit has a capacity of about 2 mL or more, 5 mL or more, or 10 mL or more.

In some embodiments, the liquid treatment system includes a liquid waste management system fluidly connected to the second channel. The liquid waste management system receives liquid waste, and the liquid waste can be sucked into the second channel of the multi-channel pipette. The connector for the waste management system may be provided along a conduit between the control valve and the second channel of the multi-channel pipette. The connector fluidly connects the second channel of the pipette to a waste management conduit which is fluidly connected to a waste management system. Valves are placed along the waste management conduit to control liquid waste flowing into the waste management system. The valve may be, for example, a two-way valve. In some embodiments, the valve is a solenoid valve. The waste management system may include a pump or vacuum, and by opening the valve for the waste management system, liquid waste in the second channel of the dual channel pipette or in the liquid storage circuit may flow into the liquid waste management system. The pump used in the waste management system may be, for example, a syringe pump or a plunger pump. In some embodiments, the liquid waste management system includes a waste container for receiving waste liquid.

Each multi-channel pipette is connected to a liquid pump, which powers the liquid flowing through the system. The pump may be, for example, a syringe pump or a plunger pump. The pump is fluidly connected to a control valve for a pipette, and the control valve is fluidly connected to a reagent valve which is fluidly connected to a plurality of reagent tanks. The reagent valve can be operated to select a desired reagent from the reagent tank, and the control valve can be operated to fluidly connect the pump to the selected reagent. The pump can then be operated to draw selected reagents into the pump via the pump port. The control valve is operable to fluidly connect the pump to the first or second channel of the multi-channel pipette, and the pump is operable to dispense reagents via the selected channel.

In another mode of operation, the control valve is operable to connect the pump to the second channel, and the pump is operable to draw liquid into the liquid storage circuit. The liquid handling system can be transported within the sample using a robotic arm, and the pump is operable to dispense liquid in the liquid storage circuit via the second channel.

In some embodiments, the pump is fluidly connected to the washing liquid. Optionally, the wash liquid can bypass the reagent and control valves. In some embodiments, the wash fluid is connected to the pump via a second pump port. To wash the pump, the washing fluid can be drawn into the pump via a second pump port and pumped out of the pump via a first pump port. By opening the waste management valve that connects the pipette to the waste management system, the wash fluid can flow through the pump and into the waste management system. In another embodiment, the wash fluid is dispensed from a pipette into a pipette cleaning system or a waste container, which can be connected to a waste management system.

Figure 9A shows a schematic diagram of a liquid handling system that can be used with an automated system equipped with a single dual channel pipette. The diagram shown represents an exemplary configuration, but it should be understood that changes can be made to effective liquid handling within the system. A similar configuration can be applied to a liquid processing system including a plurality of pipettes, for example, as shown in FIG. 9B. As mentioned previously, the liquid paths shown are exemplary and changes can be made to effective liquid handling. The liquid processing system includes a two-channel pipette 61, wherein a first channel is fluidly connected to the control valve 62 via a first channel conduit 63, and a second channel is fluidly connected to the control valve 62 via a second channel conduit 64. The dual channel pipette can be configured as shown in Figures 8A-8D or 9A, but other variations of dual channel pipettes can be used, such as the dual channel pipette shown in Figures 17A-17C. The control valve 62 in the illustrated liquid processing system is a four-way valve, but it should be understood that in other embodiments, the control valve may be several two-way solenoid valves. The liquid storage circuit 65 is provided along the second channel conduit 64 between the control valve 62 and the dual-channel pipette 61. A three-way connector 66 is also provided along the second passage duct 64, which fluidly connects the second passage duct 64 to the waste management duct 67. The waste management conduit 67 leads to a waste management system 68, which may include a pump or vacuum, and a waste tank. A two-way solenoid valve 69 is provided along the waste management conduit 67, which controls the flow into the waste management system 68. A plurality of reagent tanks 70 are fluidly connected to the reagent valve 71, which is configured to select a desired reagent. The reagent valve 71 in the illustrated liquid processing system is an eight-way valve, but it should be understood that in other embodiments, it may be a multi-channel internal communication splitter. Optionally, the compressed air 72 is also fluidly connected to the reagent valve 71, and the reagent valve 71 may be configured to allow air to flow through the liquid processing system. The reagent valve 71 is fluidly connected to the control valve 62 via a reagent supply conduit 73. The control valve 62 is fluidly connected to the pump 74 via a first pump port 75. Optionally, the washing tank 76 containing the washing liquid is fluidly connected to the pump via the washing liquid conduit 78 at the second pump port 77. For washing the system, the pump 74 may suck the washing liquid through the second pump port 77 and discharge into the waste management system 68 through the first pump port 75. The pump 74 is not limited to a syringe pump, but may also be a plunger pump or other liquid delivery device.

FIG. 9B shows the liquid processing system shown in FIG. 9A, which is expanded to include a plurality of dual-channel pipettes. In the example shown, the liquid handling system includes six pipettes, but it should be understood that the system includes additional or fewer pipettes. Each two-channel pipette 79a, 79b, 79c, 79e, and 79f is fluidly connected to a separate control valve 80a, 80b, 80c, 80d, 80e, and 80f. For each pipette, the first channel is fluidly connected to the control valve via separate first channel conduits 81a, 81b, 81c, 81d, 81e, and 81f, and the second channel is via separate second channel conduits 82a, 82b , 82c, 82d, 82e, and 82f are fluidly connected to the control valve, respectively. Separate liquid storage circuits 83a, 83b, 83c, 83d, 83e, and 83f are fluidly connected to each second channel conduit. That is, the liquid storage circuit 83a is fluidly connected to the second channel conduit 82a, the liquid storage circuit 83b is fluidly connected to the second channel conduit 83b, and so on. In addition, each pipette is independently connected to the waste management system via independent waste management conduits 84a, 84b, 84c, 84d, 84e, and 84f and a valve provided on each independent waste management conduit. The waste management system can be shared between separate pipettes or can be separate. For each pipette, each control valve is further fluidly connected to separate pumps 85a, 85b, 85c, 85d, 85e, and 85f. A plurality of reagent tanks 86 fluidly connected to the reagent valve 87 may provide reagents or air to the liquid processing system. The reagent tank can be shared between the pump and the pipette in the system. The reagent supply line 88 fluidly connects a reagent valve 87 to each individual control valve. The reagent supply line 88 may branch at three-way connectors 89a, 89b, 89c, 89d, and 89e to supply reagents to each control valve. The reagent supply line 88 can be terminated at the last control valve 80f in the series because no additional branch is required at this position. The washing liquid in the washing liquid tank 90 may be fluidly connected to the pump via the washing liquid pipe 91. The washing liquid conduit 91 may be branched at the three-way connectors 92a, 92b, 92c, 92d, and 92e to supply washing liquid to the pump. The washer fluid conduit 91 may terminate at the pump 85f because no additional branch is required at this location.

The upper region of the pipette of the liquid handling system is attached to a support block which is connected to the support structure from below the support structure. The support structure may be connected to the robot arm via an attachment area of the support structure. In some embodiments, the pipette passes through a hole in the support block, and in some embodiments, the pipette is attached to the side of the support block. Therefore, the upper part of each pipette is positioned above the support block, and the lower part of each pipette (including the distribution area) is positioned below the support block. The support block can help limit lateral or rotational movement of the pipette during operation. The conduit of each of the first and second channels of each pipette enters the support structure and is connectable to a control valve. In some embodiments, one or both of the control valve and the liquid storage circuit are contained within a support structure. In some embodiments, one or both of the control valve and the liquid storage circuit are housed outside the support structure.

The support block is connected to the support structure via an elastic mechanism. The support structure of the liquid handling system can be lowered by the robot arm so that the tip of the pipette is positioned at the bottom of the sample tube. When the pipette is in contact with the bottom of the sample tube, the elastic mechanism allows the force pushing the pipette upward to be buffered. If the robotic arm continues to push the support structure downward, the upper area of the pipette is pushed towards the support structure. The elastic mechanism may include two or more springs that connect the support block to the support structure. When the support structure is lifted (ie, the pipette tip is not forced down against the surface), the spring is fully extended. When the pipette is forced towards the support structure, the spring is compressed. The elastic mechanism may further include two or more guide members (such as two or more guide rails, guide shafts, or guide sleeves), which limit the lateral movement of the support block. The guide rails may include vertical guide rails directed downward from the bottom of the self-supporting structure. The guide rail fits into the opening of the support block. When the pipette (which is attached to the support block) is pushed towards the support structure, the guide rail can slide vertically within the opening of the support block.

FIG. 10A shows a liquid handling system attached to a robot arm, and FIG. 10B shows a support structure connected to six pipettes. Although the liquid handling system is shown in FIGS. 10A and 10B as having six pipettes, it should be understood that in some embodiments, the liquid handling system includes more or fewer pipettes. The support structure 94 is connected to the vertical arm 95 of the robot arm via an attachment area 96. The attachment region 96 may be an upper portion of the support structure 94, or may be along a side of the support structure 94. The vertical arm 95 of the robot arm can vertically position the support structure 94, including attached pipettes 97a, 97b, 97c, 97d, 97e, and 97f. The vertical arm may include a limit mechanism 98, and the limit mechanism 98 may include a limit switch and a limit block. The limit switch operates the vertical arm 95 to move the support structure 94 vertically, and the limit block sets a hard limit on the movement range of the vertical arm 95.

FIG. 10B provides further details of the support structure, the support block and the elastic mechanism. The illustrated liquid processing system includes a support block 99, which is connected to the support structure 94 via an elastic mechanism. The elastic mechanism includes a first spring 100 and a second spring 101. The first guide rail 102 and the second guide rail 103 extend vertically downward from the support structure 94 into the opening of the support block 99. The pipettes 97a, 97b, 97c, 97d, 97e, and 97f pass through the support block 99, which holds the pipette in place.

Automated systems can also include small volume liquid handling systems that can be used to transfer smaller volumes of liquid throughout the system. For example, small volume liquid processing systems can be used to adjust the pH of a sample or transfer a sample from a sample tube to a multiwell plate, for example for analysis by an analytical instrument. Small volume liquid handling systems include one or more (such as two, three, four, or more) pipettes. Compared with pipettes in large-volume liquid handling systems, pipettes in small-volume liquid handling systems can be single-channel pipettes. The pipette is attached to a support structure, which is attached to a robotic arm, such as a vertical arm of a robotic arm. Similar to a large-volume liquid processing system, a robot arm connected to a small-volume liquid processing system may include a limit mechanism, which may include a limit switch and a limit block to control the movement and range of the robot arm. In some embodiments, the small volume liquid processing system is configured to adjust the distance between two or more pipettes connected to the support structure. This may be useful, for example, when transferring liquid from a plurality of sample tubes to a plurality of wells of a microtiter plate, as the spacing between the sample tube and the wells may be different. In order to adjust the spacing between the pipettes, the small-volume liquid processing system may include an adjustable spacer and a drive system that controls the adjustable spacer. The drive system may include hydraulic cylinders, air cylinders, or electric motors to provide power to control the adjustable spacers. In some embodiments, the adjustable spacer includes a limit switch and a limit block. The limit open relationship is operated by the drive system to adjust the distance between the pipettes, and the limit block limits the range of motion of the adjustable spacer. In some embodiments, the upper region of each pipette is connected to a resilient mechanism. In some embodiments, the elastic mechanism includes a spring and / or a guide (such as a guide rail, a guide shaft, or a guide sleeve).

11A and 11B illustrate an exemplary small volume liquid processing system. The illustrated embodiment shows three pipettes, but it is understood that more or fewer pipettes can be used in the system. The liquid handling system includes a support structure 104 connected to a robotic arm via an attachment area. The robotic arm may include a vertical arm 105 configured to move the support structure 104 in a vertical direction. The vertical arm may include a limit mechanism 106, and the limit mechanism 106 may include a limit switch and a limit block. The limit switch operates the vertical arm 105 to move the support structure 104 vertically, and the limit block sets a hard limit on the movement range of the vertical arm 105. 11B, the support structure 104 is connected to the pipettes 107a, 107b, and 107c. The pipette is connected to the adjustable spacer 108 via elastic mechanisms 109a, 109b, and 109c. The adjustable spacer 108 can slide along the guide 110 under the control of the drive system 111 to reposition the pipette. The elastic mechanism includes a spring and a guide such as a guide rail, a guide shaft, or a guide sleeve. The robotic arm can lower the pipette into a sample tube, a well of a multiwell plate, or other container to draw or dispense liquid. When the pipette reaches the bottom of the container, an upward force can be exerted on the pipette, which is absorbed by the elastic mechanism.

The small volume liquid handling system includes a pump with fluid attached to each pipette. In some embodiments, the pump has a capacity of about 1 mL to about 10 mL, such as about 1 mL to about 2 mL, about 2 mL to about 5 mL, or about 5 mL to about 10 mL. The pump has at least two pump ports. The first pump port is fluidly connected to the pipette, and the pump can be activated to draw liquid into the pipette from the tip of the pipette and dispense liquid from the tip of the pipette. The second pump port is fluidly connected to the washing liquid conduit, and the washing liquid conduit is fluidly connected to a washing liquid tank containing the washing liquid. The washing liquid can be sucked into the pump through the washing liquid conduit through the second pump port, and then dispensed through the pipette through the first pump port. The pipette can be washed by circulating the washing solution through the pipette. In some embodiments, the pipette is washed using a pipette cleaning system, as described herein.

Figure 12 shows a schematic view of an exemplary setup of a small volume liquid processing system. The system shown includes three pipettes, but it is understood that additional or fewer pipettes may be included in the system. The pipettes 112a, 112b, and 112c are each connected to the first ports 113a, 113b, and 113c of the pumps 114a, 114b, and 114c via the pipette tubes 115a, 115b, and 115c. The washing liquid tank 116 is fluidly connected to a washing liquid pipe 117, which supplies the washing liquid to a pump. The second ports 118a and 118b are fluidly connected to the washing liquid conduit 117 at the three-way connectors 119a and 119b. The washer fluid conduit 117 is fluidly connected to the second port 118c of the pump 114c, but a three-way connector is not required in the final pump.

In some embodiments, the automated system includes a large volume liquid processing system and a small volume liquid processing system, wherein the system shares a washing liquid tank and a washing liquid conduit. This embodiment of a liquid processing system is shown in FIG.

In some embodiments, the automated system includes a pipette cleaning system configured to clean a pipette of a large volume liquid handling system and / or a small volume liquid handling system. A pipette cleaning system includes a container with an open top and one or more vertically positioned cleaning tubes. Each pipette can be paired with a cleaning tube in a pipette cleaning system. The container of the pipette cleaning system may have an elongated shape configured to receive a linearly arranged pipette in a liquid processing system. The cleaning tube is open at the top and is sized and shaped to receive at least a portion of a pair of pipettes. The bottom end of the cleaning tube is fluidly connected to a drainage port, which is fluidly connected to a waste management system. In some embodiments, there is a drainage port on the bottom of the container outside the cleaning tube, which can receive liquid that overflows from the cleaning tube. The drain at the bottom of the container is also fluidly connected to the waste management system.

To clean a pipette, insert at least a portion of the pipette (eg, at least a dispensing area of the pipette) into a cleaning tube of a pipette cleaning system. Therefore, the inner diameter of the cleaning tube is wider than the outer diameter of the pipette. The washing liquid is pumped into the cleaning tube through a pipette, and the washing liquid is discharged through a drainage port at the bottom of the cleaning tube. The washing liquid can be pumped into the cleaning tube faster than the drainage liquid at the bottom of the cleaning tube, so that the washing liquid overflows from the top of the cleaning tube into the container, thereby washing the outer surface of the pipette. The overflowed washing liquid can then be discharged from the container through a drainage port at the bottom of the container.

FIG. 14A illustrates an exemplary pipette cleaning system. The pipette cleaning system includes an elongated container 120 having an open top 121. The inside of the container includes vertically positioned cleaning tubes 122a, 122b, 122c, 122d, 122e, and 122f. Optionally, the cleaning tube is stabilized by attaching the cleaning tube to the inner surface 123 of the container 120 via the brackets 124a, 124b, 124c, 124d, 124e, and 124f. Fig. 14B shows a cross-sectional view of the pipette cleaning system shown in Fig. 14A. The bottom of the cleaning tube is joined to the bottom of the container 120. Drains 125a, 125b, 125c, 125d, 125e, and 125f at the base of each cleaning tube are fluidly connected to a waste management system. The bottom of the container 120 further includes a drainage port 126 fluidly connected to the waste management system.

In an exemplary embodiment, the liquid handling system includes at least one pipette system including a multi-channel pipette (eg, a dual-channel pipette) including an upper region attached to a support structure, and a lower distribution region The lower distribution region includes at least a first liquid port fluidly connected to the first channel on a side of the distribution region, and a second liquid port fluidly connected to the second channel at a tip of the distribution region; a control valve, which Control the flow of liquid through the first or second channel of the pipette; and a pump fluidly connected to the control valve. The second liquid port may include a concave cutout, and the liquid port may be configured to spray liquid onto an inner wall of the container. In some embodiments, the pump includes a first liquid port fluidly connected to the control valve, and a second liquid port fluidly connected to the washing liquid container. In some embodiments, the support structure is attached to a robot arm, and the robot arm may be configured to move at least in a direction of a vertical axis. In some embodiments, the multi-channel pipette is attached to a support block, and the support block is attached to the support structure via an elastic mechanism configured to at least partially absorb an upward force applied to the pipette.

In some embodiments, the liquid handling system includes at least one pipette system including a multi-channel pipette (e.g., a dual-channel pipette) including an upper region attached to a support structure, and a lower distribution region, The lower distribution area includes at least: a first liquid port fluidly connected to the first channel on a side of the distribution area, and a second liquid port fluidly connected to the second channel at a tip of the distribution area; a control valve, which Control liquid flowing through the first or second channel of the pipette; a pump fluidly connected to the control valve; and a liquid storage circuit positioned between the multi-channel pipette and the control valve, which is fluidly connected to the pipette The second channel. The second liquid port may include a concave cutout, and the liquid port may be configured to spray liquid onto an inner wall of the container. In some embodiments, the pump includes a first liquid port fluidly connected to the control valve, and a second liquid port fluidly connected to the washing liquid container. In some embodiments, the support structure is attached to a robot arm, and the robot arm may be configured to move at least in a direction of a vertical axis. In some embodiments, the multi-channel pipette is attached to a support block, and the support block is attached to the support structure via an elastic mechanism configured to at least partially absorb an upward force applied to the pipette.

In some embodiments, the liquid handling system includes at least one pipette system including a multi-channel pipette (e.g., a dual-channel pipette) including an upper region attached to a support structure, and a lower distribution region, The lower distribution area includes at least: a first liquid port fluidly connected to the first channel on a side of the distribution area, and a second liquid port fluidly connected to the second channel at a tip of the distribution area; a control valve, which Control liquid flowing through the first or second channel of the pipette; pump fluidly connected to the control valve; liquid storage circuit positioned between the multi-channel pipette and the control valve, which is fluidly connected to the first Two channels; and a plurality of reagent tanks fluidly connected to a reagent valve configured to select a reagent from the plurality of reagent tanks, wherein the reagent valve is fluidly connected to the control valve. The second liquid port may include a concave cutout, and the liquid port may be configured to spray liquid onto an inner wall of the container. In some embodiments, the pump includes a first liquid port fluidly connected to the control valve, and a second liquid port fluidly connected to the washing liquid container. In some embodiments, the support structure is attached to a robot arm, and the robot arm may be configured to move at least in a direction of a vertical axis. In some embodiments, the multi-channel pipette is attached to a support block, and the support block is attached to the support structure via an elastic mechanism configured to at least partially absorb an upward force applied to the pipette.

In some embodiments, the liquid handling system includes at least one pipette system including a multi-channel pipette (e.g., a dual-channel pipette) including an upper region attached to a support structure, and a lower distribution region, The lower distribution area includes at least: a first liquid port fluidly connected to the first channel on a side of the distribution area, and a second liquid port fluidly connected to the second channel at a tip of the distribution area; a control valve, Control liquid flowing through the first or second channel of the pipette; pump fluidly connected to the control valve; liquid storage circuit positioned between the multi-channel pipette and the control valve, which is fluidly connected to the first Two channels; a plurality of reagent tanks fluidly connected to a reagent valve configured to select a reagent from the plurality of reagent tanks, wherein the reagent valve is fluidly connected to the control valve; and a second channel of the multi-channel pipette is connected Waste management system. Optionally, there is a valve between the second channel of the dual channel pipette and the liquid waste management system. The second liquid port may include a concave cutout, and the liquid port may be configured to spray liquid onto an inner wall of the container. In some embodiments, the pump includes a first liquid port fluidly connected to the control valve, and a second liquid port fluidly connected to the washing liquid container. In some embodiments, the support structure is attached to a robot arm, and the robot arm may be configured to move at least in a direction of a vertical axis. In some embodiments, the multi-channel pipette is attached to a support block, and the support block is attached to the support structure via an elastic mechanism configured to at least partially absorb an upward force applied to the pipette.

Instructions

The automated systems described herein can be used to isolate biological molecules (such as proteins, antibodies, or nucleic acids) from biological samples. Methods can include methods of adding biological samples to the system, controlling contaminants such as endotoxins, isolating target biomolecules, regenerating magnetic beads, or operating liquid processing systems. The methods described herein allow high-throughput processing of large volumes of biological samples while minimizing contamination.

Operate automated systems for high-throughput processing of biological samples for target biomolecule separation. Generally, the system operates to process incoming biological samples within about 3 to 4 hours, and the number of incoming biological samples that can be processed during this time depends on the number of incoming samples and the capacity of the system. For example, in some embodiments, the system can process up to about 128 samples in about 3 to about 4 hours. The system can also be operated in continuous operation mode, adding new input samples while processing the input samples. In some embodiments, the system is configured to operate continuously for about 1 day or more, 1 week or more, 1 month or more, or up to about 1 year.

In one embodiment, a method of separating a target biomolecule from a biological sample includes loading a biological sample contained in a sample tube into an automated system such as the automated system described herein; using a liquid processing system such as the one described herein Liquid processing system) transfer magnetic beads to biological samples; composite target biomolecules with magnetic beads; use a magnetic field applied to the magnetic beads (e.g., using the biomolecule separation system described herein) to composite the target biomolecules The magnetic beads are attached to the inner surface of the sample tube; the magnetic beads are washed using a liquid processing system (for example, by dispensing reagents in the sample tube); the target biomolecules are dissociated from the washed magnetic beads; After dissolution from the beads, attach the magnetic beads to the inner surface of the sample tube; and transfer the target biomolecules to the container. In some embodiments, the method includes regenerating the magnetic beads, for example, using a magnetic bead regeneration system described herein. In some embodiments, the method further comprises analyzing the target biomolecule using an automated analysis instrument, for example to determine a biomolecule concentration or an antibody titer.

To load a biological sample in an automated system, a biological sample (e.g., saliva, blood, stool, or urine samples from a subject) is dispensed into an open sample tube. The sample tube is then placed in a sample tube rack and capped, the cap configured to allow the liquid handling system to access the inside of the sample tube. The sample may include, for example, a sealable port on a sample tube, which allows a pipette from a liquid handling system to access a biological sample. In some embodiments, a plurality of sample tubes containing a biological sample are placed in a sample tube rack. The lid may cover each of the plurality of sample tubes. A holder comprising a covered sample tube is then mounted on a surface within an automated system, such as a surface on a biomolecule separation system.

Contaminants such as endotoxins can be minimized by activating an air filtration system or UV lamp. In some embodiments, the air filtration system generates positive air pressure within an automated system surrounded by a housing. This prevents contaminants from entering the housing. UV lamps can destroy contaminating biomolecules, bacteria or viruses that may enter the system. In addition, the enclosure seals the automation system, thereby preventing contaminants from entering the system. For example, after loading a sample in an automated system, the case can be sealed by closing the door of the case. Therefore, a method for minimizing contamination in an automation system may include sealing the automation system in a housing; activating a UV lamp, and / or activating an air filtration system

Contaminants can also be minimized by cleaning the liquid handling system, which includes the use of a pipette cleaning system to wash the pipette, as appropriate. Cleaning the liquid handling system includes pumping the washing liquid into a pump and pumping the washing liquid through a pipette. In some embodiments, the washing liquid is pumped via a liquid storage circuit. In some embodiments, the washing liquid is pumped through the first channel and the second channel of the pipette. Additionally or alternatively, the washing liquid may be pumped through another channel (eg, a third channel) of the pipette. When using a pipette cleaning system, the pipette of the liquid handling system can be inserted at least partially into the cleaning tube. The washing liquid pumped from the pipette enters the cleaning tube. In some embodiments, the washing liquid is drained from the bottom of the cleaning tube and / or overflows from the top of the cleaning tube. When the washing liquid overflows from the top of the cleaning tube, the outer surface of the pipette is cleaned.

In some embodiments, there is a method for removing endotoxin from an automated biomolecule separation system, such as the automated system described herein, which method includes multi-channel transfer via a liquid processing system (e.g., as described herein) Liquid tubes (eg, dual-channel pipettes) pump alkaline disinfection solutions, and wash buffers (eg, using a pipette cleaning system described herein) to wash multi-channel pipettes. In some embodiments, the method further includes activating an air filter. In some embodiments, the method further comprises activating a UV lamp.

In some embodiments, a pipette in a liquid handling system is filled with a selected reagent. To fill the pipette, the reagent valve is configured to select the required reagents, and the control valve is configured to fluidly connect the pump to the reagent valve. In some embodiments, the required reagents are pumped into the pump, and the control valve is configured to select the first channel or the second channel of the pipette. Additionally or alternatively, the required reagents can be pumped into the pump and the control valve can be configured to select an additional channel (e.g., a third channel) of the pipette. The required reagents are then pumped through a pipette. If the control valve is configured to select the first channel, the reagent is sprayed from the side of the dispensing area. If the control valve is configured to select the second channel, the reagent flows from the tip of the pipette. Use the pipette cleaning module when filling the pipette. For example, the pipette can be inserted at least partially into the cleaning tube, and the required reagents can be pumped into the cleaning tube. The use of the cleaning module provides a convenient method for collecting and disposing of reagents for filling the pipette.

By distributing the magnetic beads suspended in the solution in a clean room of a magnetic bead regeneration system, magnetic beads can be prepared for use. The magnets are configured in an effective configuration such that the magnetic bead regeneration system is incorporated into the inner surface of the clean room. The liquid handling system draws liquid from the clean room and fills the pipette of the liquid handling system with the required reagents. The magnet is then configured to an invalid configuration and the liquid handling system dispenses the required reagents into the clean room. In some embodiments, the required reagents are dispensed from the side of the dispensing area of the pipette to wash the inner surface of the clean room to remove any magnetic particles adhering to the inner surface. The magnetic beads are then mixed with the required reagents in the clean room. In some embodiments, the liquid handling system draws magnetic beads from the clean room and transports the magnetic beads to a desired location, such as a magnetic bead storage container or a sample tube. In some embodiments, the magnetic beads are washed. For example, the magnets can be configured to be effectively configured to bind the magnetic beads to the inner surface of the clean room, and the liquid handling system can dispense additional required reagents into the clean room. The additional required reagent may be the same as or different from the first required reagent. The magnet can be configured into an invalid configuration, and additional required reagents can be mixed with the magnetic beads and then transferred by the liquid handling system to a desired location within the system (such as a magnetic bead storage container or sample tube).

In order to regenerate the used magnetic beads, a liquid processing system is used to transfer the magnetic beads to a clean room of the magnetic bead regeneration system. Magnetic beads from one or more sample tubes can be transferred to a clean room. For example, a large volume liquid handling system can be used by aspirating magnetic beads into a liquid storage circuit via a liquid port at the tip of a pipette. In some embodiments, before transferring the magnetic beads to the clean room, the desired reagents can be dispensed to the sample through the first channel and the liquid port on the side of the dispensing area of the pipette after removing the isolated target biomolecule Tube, thereby washing the magnetic beads off the inner surface of the sample tube. The biomolecule separation system can be used to mix the magnetic beads in the sample tube with the required reagents to ensure that the magnetic beads are suspended. The magnets of the magnetic bead regeneration system can be configured for effective configuration, so that the magnetic beads are bonded to the inner surface of the clean room. Subsequently, the liquid handling system withdraws the reagent from the clean room, and the magnet is configured into an invalid configuration to release the magnetic beads from the inner surface of the clean room. The liquid handling system dispenses additional required reagents into the clean room, which may be the same as or different from the previously required reagents. In some embodiments, the liquid handling system dispenses additional reagents from the side of the dispensing area of the pipette to wash the magnetic beads off the inner surface of the clean room. Additional required reagents can be mixed with the magnetic beads, for example by shaking the clean room. The same method can be used to replace the reagents once, twice, three times, or four times or more with the same or different reagents to regenerate the magnetic beads. Once the beads are regenerated, the liquid handling system can transfer the beads to a bead storage container or a new biological sample.

To separate the target biomolecules, the magnetic beads are transferred to a sample tube containing a biological sample. Magnetic beads can be transferred, for example, from a magnetic bead storage container or a clean room of a magnetic bead regeneration system. Preferably, the magnetic beads are mixed in a reagent before transfer to ensure uniform suspension of the magnetic beads. The magnetic beads can be transferred using a liquid handling system that draws the magnetic beads into a liquid storage circuit through a liquid port at the tip of a pipette, and then distributes the magnetic beads into a sample tube through the liquid port. A biomolecule separation system is used to mix the biological sample with the magnetic beads to bind the target biomolecules to the magnetic beads. In some embodiments, the magnetic beads are incubated with the biological sample for a period of time. A magnetic field is applied to the sample tube so that the magnetic beads are bonded to the inner wall of the sample tube. For example, a liquid handling system is used to remove liquid from the sample tube and remove the magnetic field from the sample tube. The pipette of the liquid handling system can be cleaned, for example, using a pipette cleaning system, and the required reagents can be added to the sample tube. In some embodiments, the reagent is dispensed from a liquid port on the side of the dispensing area of the pipette to wash the magnetic beads off the side of the sample tube. The contents of the sample tube can be mixed, and a magnetic field can be reapplied to the sample tube to bind the magnetic beads to the inner surface of the sample tube. The liquid can be removed from the sample tube, and the magnetic field can be removed from the sample tube. The magnetic beads were washed twice, three times, or more, as appropriate, using similar methods. To remove the isolated target biomolecules, a dissolution reagent is added to the magnetic beads and mixed. A magnetic field is applied to the sample tube to bind the magnetic beads to the inner surface of the sample tube, and the liquid containing the dissolved target biomolecules is removed and transferred to a separate sample tube, which can be located in the sample output module.

The isolated target molecule can be analyzed by an analytical instrument, for example, to determine protein concentration, antibody titer, or other analytical measurements. The biological sample can be transferred to a multiwell plate, for example using a small volume liquid processing system, and the multiwell plate can be transported to an analytical instrument to analyze the isolated target biomolecules.

In some embodiments, the liquid handling system includes at least one pipette system including a multi-channel pipette (eg, a dual-channel pipette) including a pipette attached to an upper portion of a support structure Area, and a lower distribution area, the lower distribution area including at least a first liquid port on the side of the distribution area fluidly connected to the first channel, and a second liquid at the tip of the distribution area fluidly connected to the second channel Port; a control valve that controls the flow of liquid through the first or second channel of the pipette; and a pump fluidly connected to the control valve; To operate in the second liquid port. In some embodiments, the method includes lowering a multi-channel pipette into a sample tube containing a liquid. In some embodiments, the tip of the multi-channel pipette contacts the bottom of the sample tube. In some embodiments, the method further comprises dispensing a liquid via a second liquid port.

In some embodiments, the liquid handling system includes at least one pipette system including a multi-channel pipette (eg, a dual-channel pipette) including a pipette attached to an upper portion of a support structure Area, and a lower distribution area, the lower distribution area including at least a first liquid port on the side of the distribution area fluidly connected to the first channel, and a second liquid at the tip of the distribution area fluidly connected to the second channel Port; a control valve that controls liquid flow through the first or second channel of the pipette; and a pump fluidly connected to the control valve; operated by spraying liquid from the first liquid port onto the inner wall of the container. In some embodiments, the method includes washing the beads (which may be magnetic beads) from the inner wall of the container using a sprayed liquid.

Computer systems for operating automation systems

An automated system for separating a target biomolecule from a biological sample may include a computer system configured with components of an operating system. For example, a computer system can be used to operate an automated system to perform the methods described herein. For example, a computer system may include instructions for operating a liquid handling system, a robotic arm, a biomolecule separation system, a magnetic bead regeneration system, an analytical instrument, a pipette cleaning system, or any other system component described herein.

In some embodiments, the computer system tracks the location of one or more samples within the automated system. The sample source tube entering the system may include a sample identifier associated with the sample contained therein. The sample identifier scanner can scan the sample identifier at a known location (eg, in a sample source tube holder), and the sample location can be transmitted to the computer system by the sample identifier scanner. The computer system can then operate the liquid handling system or robotic arm to transfer the sample to a sample tube or microplate at a known location.

The computer system operates the liquid handling system to extract and dispense liquid according to a predetermined workflow. Liquid can be withdrawn through the pipette at the first system component and dispensed at different system components. In addition, the computer system can operate one or more valves in the liquid handling system, such as selecting channels or conduits for liquid flow, or selecting reagents.

The computer system may include a user interface (which may be a graphical user interface (GUI)), which may be displayed by a display. The user interface can be used to operate and / or monitor automated systems, such as by managing or checking sample inputs or data output, checking warnings or alarms, pausing or starting automated systems, or controlling temperature or incubation time. FIG. 16 depicts an exemplary computer system 1600 configured to perform any of the processes described herein, including various exemplary processes for operating an automation system. In this context, the computing system 1600 may include, for example, a processor, non-transitory computer-readable media (e.g., memory), storage, and input / output devices (e.g., monitor, keyboard, disk drive, Internet) Connection, etc.). However, the computing system 1600 may include circuitry or other specialized hardware for performing some or all aspects of the process. In some operational settings, the computing system 1600 may be configured as a system including one or more units, each unit configured to perform certain aspects of the process in software, hardware, or some combination thereof. FIG. 16 depicts a computing system 1600 having a number of components that can be used to perform the processes described above. The main system 1602 includes a motherboard 1604, which has an input / output ("I / O") section 1606, one or more central processing units ("CPU") 1608, and a memory that may have a flash memory card 1612 associated therewith. Section 1610. The I / O section 1606 is connected to a display 1624, a keyboard 1614, a magnetic disk storage unit 1616, and a media drive unit 1618. The media drive unit 1618 can read / write computer-readable media 1620, which can include programs 1622 and / or data. At least some values based on the results of the above process can be saved for subsequent use. In addition, a non-transitory computer-readable medium may be used to store (e.g., tangibly embody) one or more computer programs for performing any of the processes described above by a computer. Computer programs can be written, for example, in a general programming language (eg, Pascal, C, C ++, Java, Python, JSON, etc.) or some special application-specific languages.

    Exemplary embodiment    

Embodiment 1. A liquid processing system comprising: at least one pipette system including: a dual-channel pipette including an upper region attached to a support structure, and a lower distribution region including a fluid A first liquid port connected to the first channel on the side of the dispensing area, and a second liquid port fluidly connected to the second channel at the tip of the dispensing area; a control valve that controls the flow of liquid through the pipette The first or second channel; and a pump fluidly connected to the control valve.

Embodiment 2. The liquid processing system of Embodiment 1, wherein the second channel of the dual-channel pipette passes through and is parallel to the first channel of the dual-channel pipette.

Embodiment 3. The liquid processing system of Embodiment 1, wherein the second channel of the dual-channel pipette is adjacent to the first channel of the dual-channel pipette.

Embodiment 4. The liquid processing system of any one of Embodiments 1-3, wherein the second liquid port includes a concave cutout.

Embodiment 5. The liquid processing system of any one of Embodiments 1-4, wherein the first liquid port is configured to spray liquid onto an inner wall of the container.

Embodiment 6. The liquid processing system of any of Embodiments 1-5, wherein at least a portion of the pipette is coated with a hydrophobic layer.

Embodiment 7. The liquid processing system of any of Embodiments 1-6, wherein the second channel is fluidly connected to a liquid storage circuit positioned between the dual-channel pipette and the control valve.

Embodiment 8. The liquid processing system of Embodiment 7, wherein the liquid storage circuit has a liquid storage capacity of about 2 mL or more.

Embodiment 9. The liquid treatment system of any one of Embodiments 1-8, wherein the liquid treatment system includes a liquid waste management system connected to a second channel of a dual channel pipette.

Embodiment 10. The liquid processing system of Embodiment 9, wherein the liquid processing system includes a valve between the second channel of the dual-channel pipette and the liquid waste management system.

Embodiment 11. The liquid processing system of any one of Embodiments 1-9, wherein the pump includes a first liquid port fluidly connected to the control valve, and a second liquid pump fluidly connected to the washing liquid container.

Embodiment 12. The liquid processing system of any one of Embodiments 1-11, comprising a plurality of reagent tanks fluidly connected to a reagent valve, the reagent valve being configured to select a reagent from the plurality of reagent tanks, wherein the reagent valve fluid Connected to the control valve.

Embodiment 13. The liquid processing system of any one of Embodiments 1-12, wherein the support structure is attached to a robot arm.

Embodiment 14. The liquid processing system of Embodiment 13, wherein the robot arm is configured to move at least in a direction of a vertical axis.

Embodiment 15. The liquid processing system of any one of Embodiments 1-14, wherein the dual-channel pipette is attached to a support block, and wherein the support block is attached to the support structure via an elastic mechanism configured to at least Partial absorption of upward force applied to the pipette.

Embodiment 16. The liquid processing system of Embodiment 15, wherein the liquid processing system includes a plurality of pipette systems, wherein each pipette system includes a dual-channel pipette attached to a support block.

Embodiment 17. The liquid processing system of Embodiment 15 or 16, wherein the elastic mechanism includes two or more springs and two or more guide mechanisms.

Embodiment 18. The liquid processing system of any one of Embodiments 1-17, further comprising a pipette cleaning system, the pipette cleaning system including a container having an open top and at least one cleaning tube positioned vertically within the container .

Embodiment 19. The liquid processing system of Embodiment 18, wherein the size and shape of the cleaning tube are designed to receive a dual-channel pipette.

Embodiment 20. The liquid processing system of Embodiment 18 or 19, wherein the container includes a bottom portion and the bottom portion includes a drainage port.

Embodiment 21. A method of operating a liquid processing system according to any one of embodiments 1-20, comprising aspirating liquid into a pipette through a second liquid port.

Example 22. The method of Example 21 includes lowering the pipette into a sample tube containing a liquid.

Example 23. The method of Example 21 includes contacting a pipette with the bottom of a sample tube.

Embodiment 24. The method of any one of Embodiments 21-23, wherein the liquid comprises magnetic beads.

Embodiment 25. The method of any one of Embodiments 21-23, wherein the liquid comprises a target biomolecule.

Embodiment 26. The method of any one of Embodiments 21-25, wherein the liquid is stored in a liquid storage circuit.

Example 27. The method of any one of Examples 21-26, comprising dispensing a liquid through a second liquid port.

Embodiment 28. A method of operating a liquid processing system of any of Embodiments 1-20, comprising spraying liquid from a first liquid port onto an inner wall of a container.

Example 29. The method of Example 28 includes washing the beads from the inner wall of the container using a sprayed liquid.

Embodiment 30. The method of Embodiment 29, wherein the beads are magnetic beads.

Embodiment 31. An automated system for separating biomolecules from a sample, comprising the liquid processing system of any one of embodiments 1-20, further comprising a magnetic bead regeneration system, a second liquid processing system, a vibrator, and a sample One or more of a tube rack, a biomolecule separation system, a magnetic bead regeneration system, a cold storage unit, a barcode reader, or an analytical instrument.

Embodiment 32. An automated system for separating biomolecules from a biological sample, comprising: a liquid handling system including a pipette operable to move at least on a vertical axis; and a sample tube holder; one or more lids, It is configured to fit on one or more sample tubes contained in a sample tube rack, the one or more covers include a sealable port on each of the one or more sample tubes, which allows the pipette to pass through The sealable port enters the sample tube, where the sealable port is sealed when the pipette is withdrawn from the sample tube.

Embodiment 33. The automated system of Embodiment 32, wherein the sealable port includes two or more communicating slits.

Embodiment 34. The automated system of Embodiment 32 or 33, wherein the sealable port comprises an elastomer or rubber.

Embodiment 35. The automated system of any one of Embodiments 32-34, wherein the sample tube holder includes a base that fits into a sample tube holder fixture that is attached to a surface.

Embodiment 36. The automated system of Embodiment 35, wherein the base includes a groove or protrusion, and the receiving block includes a complementary groove or protrusion.

Embodiment 37. The automated system of Embodiment 35 or 36, wherein the surface is a part of a biomolecule separation system, and the biomolecule separation system includes a magnet that can be configured into a valid configuration and an invalid configuration. The magnet applies a magnetic field to the one or more sample tubes so that the magnetic beads in the sample tubes are bonded to the inner surface of the one or more sample tubes, and wherein when the magnet is in an invalid configuration, the magnetic field is removed to remove The inner surface of the sample tube releases most of the magnetic beads.

Embodiment 38. The automated system of any one of Embodiments 31-37, further comprising a magnetic bead regeneration system, a vibrator, a magnetic bead separation system, a pipette cleaning system, a cold storage unit, a bar code reader, or analysis One or more of the instruments.

Embodiment 39. An automated system for separating biomolecules from a biological sample, comprising: (a) a first liquid processing system including: at least one pipette system, including: a dual-channel pipette, including attachment to a support An upper region of the structure, and a lower distribution region including a first liquid port fluidly connected to the first channel on a side of the distribution region and a second fluid port fluidly connected to a second channel at a tip of the distribution region A liquid port; a control valve that controls the flow of liquid through the first or second channel of the pipette; and a pump fluidly connected to the control valve; (b) a second liquid processing system including at least one pipette, wherein the first The two liquid processing system is configured to process a volume of liquid smaller than the first liquid processing system; (c) a sample tube holder; (d) one or more lids configured to fit one or more of the contents contained in the sample tube holder On the sample tube, the one or more covers include a sealable port on each of the one or more sample tubes, which allows a pipette from the first liquid processing system or the second liquid processing system Into the sample tube through the sealable port, where the sealable port is sealed when the pipette is withdrawn from the sample tube; and (e) a biomolecule separation system configured to make the magnetic field The beads bind to the sides of the sample tube.

Embodiment 40. The automated system of Embodiment 39, wherein the biomolecule separation system is operable to configure the magnet into a valid configuration and an invalid configuration, wherein when the magnet is in a valid configuration, the magnet is applied to one or more sample tubes A magnetic field to bind the magnetic beads in the sample tube to the inner surface of the one or more sample tubes, and wherein when the magnet is in an invalid configuration, the magnetic field is removed to release most of the inner surface of the one or more sample tubes Magnetic beads.

Embodiment 41. The automated system of Embodiment 39 or 40, further comprising one or more of a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a barcode reader, or an optical detector .

Embodiment 42. The automated system of any one of Embodiments 39-41, wherein the system is contained within a housing.

Embodiment 43. The automated system of Embodiment 42, wherein the housing is hermetically sealed.

Embodiment 44. The automated system of Embodiment 42 or 43 wherein the housing comprises a sterilization system.

Embodiment 45. The automated system of Embodiment 44, wherein the sterilization system includes an air filter or ultraviolet light.

Embodiment 46. The automated system of any one of Embodiments 39-45, wherein the automation system is operated using a computer system.

    Examples     Example 1-Automation System Preparation

Place 48 50 mL sample tubes (eg, 48 centrifuge tubes or 8 6-well plates) (each containing a biological sample) in 8 sample tube racks. The lid is placed on the sample tube, and each sample tube holder has its own lid. The lid includes six sealable ports that align with the sample tubes in the sample tube holder. The sample tube holder is then fixed on a sample tube holder in the biomolecule separation system.

In addition, place 48 clean 15mL sample tubes or 96-well plates in the sample output module.

Example 2-Endotoxin Control

Sterilize the sample tube. Use a large-volume liquid handler to add the sterilized fluid (Reagent D) to the sample tube in the biomolecule separation system and let it soak for a while.

In order to sterilize the system components and the area inside the system housing, start the UV lamp and air filtration system.

In order to clean the liquid processing system (one or both of the large volume liquid processing system and the small volume liquid processing system), the pipette of the liquid processing system is inserted into the pipette cleaning system. Reagent D is pumped into the cleaning tube via a pipette and allowed to drain through the drain of the pipette cleaning system. The alkaline (alkaline-containing) disinfection solution (Reagent B) is then pumped into the cleaning tube via a pipette and allowed to drain through the drain of the pipette cleaning system.

Example 3-Preparation of Magnetic Beads

The magnetic beads suspended in the liquid are manually placed in the clean room of the magnetic bead regeneration system. The magnet of the magnetic bead regeneration system is activated to induce a magnetic field in the clean room, which magnetic field binds the magnetic beads to the inner surface of the clean room. Remove the supernatant using a large volume liquid handling system and deactivate the magnet.

Use a pipette cleaning system to clean the pipette from a large-volume liquid handling system. Insert the pipette from the liquid handling system into the cleaning tube of the pipette cleaning system, and pump the magnetic bead buffer reagent A through the pipette. Next, the large-volume liquid processing system distributes the reagent A into the clean room of the magnetic bead regeneration system via a port on the side of the distribution area of the pipette. Reagent A was sprayed onto the inner surface of the clean room, and the magnetic beads stuck on the inner surface were removed. The magnetic beads are mixed with the reagent A in the clean room, and the magnet is reconfigured to be effectively configured to induce a magnetic field in the clean room, which magnetic field binds the magnetic beads to the inner surface of the clean room. The supernatant was then removed using a bulk liquid handling system using a liquid port at the tip of a pipette, and the supernatant was disposed of using a liquid waste management system. Once the reagent is withdrawn from the clean room, the magnet is configured to an invalid configuration.

Clean the pipette from the liquid handling system by inserting the pipette into the cleaning tube of the pipette cleaning system, and pump fresh reagent A through the pipette. Subsequently, the large-volume liquid processing system distributes the reagent A to the cleaning chamber of the magnetic bead regeneration system through the liquid port on the side of the pipette distribution area by spraying the inner surface of the cleaning chamber, thereby removing the sticking on the inner surface. Magnetic beads.

Example 4-pH adjustment of isolated target biomolecules

The small volume liquid processing system is used to adjust the pH of the separated target biomolecules in a 15 mL centrifuge tube held in the sample output module. A pipette from a small volume liquid handling system is inserted into a cleaning tube of a pipette cleaning system, and reagent E (which may be an acid or an alkali for adjusting pH) is pumped through the pipette until the cleaning tube overflows. The small volume liquid processing system then dispenses the required amount of reagent E into a sample tube containing the isolated target biomolecules.

Example 5-Isolate a Target Biomolecule

The magnetic beads in the clean room of the magnetic bead regeneration system are mixed in a liquid to ensure uniformity. Using a large volume liquid handling system, transfer a fixed amount of magnetic bead suspension from the clean room to 48 sample tubes (e.g., 48 centrifuge or 86-well plate wells) held in a biomolecule separation system, each sample The tube contains a biological sample. The biological sample is mixed with the magnetic beads and incubated for a period of time to bind the target biomolecules to the magnetic beads.

Several magnets are positioned adjacent to the sample tube, thereby binding the magnetic beads bound to the target molecule to the inner surface of the sample tube. The liquid is transferred to the liquid waste management system by aspirating the liquid through the liquid port from the tip of the pipette of the bulk liquid processing system, removing the supernatant from the sample tube. The magnet is then removed from a location adjacent to the sample tube to destroy the magnetic field in the sample tube, thereby releasing the magnetic beads.

Insert the pipette from the large-volume liquid processor into the cleaning tube of the pipette cleaning system, and pump reagent A through the pipette until the cleaning tube overflows. Reagent A is then sprayed into the sample tube through the liquid port on the side of the pipette dispensing area, thereby washing the magnetic beads from the inner surface of the sample tube. The magnetic beads are mixed with the reagent A in the sample tube, and the magnet is repositioned in an effective configuration, thereby binding the magnetic beads to the inner surface of the sample tube. The liquid is transferred to the liquid waste management system by aspirating the liquid through the liquid port from the tip of the pipette of the bulk liquid processing system, removing the supernatant from the sample tube. The magnet is then removed from a location adjacent to the sample tube to destroy the magnetic field in the sample tube, thereby releasing the magnetic beads.

Insert the pipette from the large-volume liquid processor into the cleaning tube of the pipette cleaning system, and pump the dissolution buffer reagent C through the pipette until the cleaning tube overflows. Reagent C is then sprayed into the sample tube via the liquid port on the side of the pipette dispensing area, thereby washing the magnetic beads from the inner surface of the sample tube. The magnetic beads are mixed with the reagent C in the sample tube, and the magnet is repositioned in an effective configuration, so that the magnetic beads are bound to the inner surface of the sample tube. Reagent C was used to dissolve the target biomolecules from the magnetic beads. When the magnetic beads were bound to the inner surface of the sample tube, the separated biomolecules remained in the solution.

The large volume liquid processing system sucks the solution containing the reagent C and the target biomolecule into the liquid storage circuit, and distributes the separated target biomolecule to a 15mL sample tube (such as a 15mL centrifuge tube or a well in a multiwell plate) in the sample output module. in. Because there are more sample tubes than pipettes, you can use Reagent C to clean the pipette using a pipette cleaning module between transfers of different samples.

The magnet is then removed from a position adjacent to the sample tube to destroy the magnetic field in the sample tube, thereby releasing the magnetic beads. Reagent C is then sprayed into the sample tube via the liquid port on the side of the pipette dispensing area, thereby washing the magnetic beads from the inner surface of the sample tube. The magnetic beads are mixed with the reagent C in the sample tube, and the magnet is repositioned in an effective configuration, so that the magnetic beads are bound to the inner surface of the sample tube. The additional solution is then transferred to the corresponding sample tube in the sample output module.

When transferring the solution containing the separated biomolecules to the sample tube in the output module, raise the sample tube and scan the barcode on the sample tube to track the sample.

Example 6-Optical Detection of Isolated Target Biomolecules

Use a pipette cleaning system to clean the pipette from a small volume liquid handling system. Insert the pipette into the cleaning tube and pump reagent C through the pipette until the cleaning tube overflows and the reagent is discharged from the pipette cleaning system.

100 μL of the separated target biomolecules from 36 sample tubes in the sample output module were transferred to 36 wells of a 96-well plate. The small-volume liquid handling system includes three pipettes, which are cleaned using a pipette cleaning system and reagent B before transferring a new sample.

The 96-well plate is then transferred to an optical detection system using a consumable delivery system configured to transport the 96-well plate to detect the concentration of the target biomolecules separated in the sample.

Example 7-Magnetic Bead Regeneration

Once the separated target biomolecule is transferred from the sample tube in the biomolecule separation system, the magnet in the biomolecule separation system is placed in an invalid configuration to remove the magnetic field in the sample tube, thereby releasing most of the inner surface of the sample tube Magnetic particles. Reagent A is sprayed from the liquid port on the side of the dispensing area of the pipette of the bulk liquid handling system to wash any magnetic beads remaining on the inner surface of the sample tube. A biomolecule separation system is used to mix the magnetic beads and reagent A, and the large-volume liquid processing system sucks the suspended magnetic beads into the liquid storage circuit through the liquid port at the tip of the pipette.

The magnetic beads are transferred to a clean room of a magnetic bead regeneration system by dispensing the magnetic bead suspension through a liquid port at the tip of a pipette. The magnets of the magnetic bead regeneration system are configured to be effectively configured to induce a magnetic field in the clean room and bind the magnetic beads to the inner surface of the clean room. The large volume liquid handling system then removes the supernatant through the liquid port of the pipette tip and transfers the liquid to the liquid waste management system. The magnet is then placed in an inactive position, releasing most of the magnetic beads from the inner surface of the clean room.

Use a pipette cleaning system to clean the pipette of a large-volume liquid handling system. Insert the pipette into the cleaning tube of the pipette cleaning system, and pump reagent A through the pipette until the cleaning tube overflows. Reagent A is sprayed from the liquid port on the side of the dispensing area of the pipette of the bulk liquid handling system to wash any magnetic beads remaining on the inner surface of the sample tube. A magnetic bead regeneration system is used to mix the magnetic beads with the reagent A, and the magnets of the magnetic bead regeneration system are configured to effectively configure a magnetic field in the clean room and bind the magnetic beads to the inner surface of the clean room. The large volume liquid handling system then removes the supernatant through the liquid port of the pipette tip and transfers the liquid to the liquid waste management system. The magnet is then placed in an inactive position to release most of the magnetic beads from the inner surface of the clean room.

Insert the pipette into the cleaning tube of the pipette cleaning system again, and pump the reagent D through the pipette until the cleaning tube overflows. Reagent D is sprayed from a liquid port on the side of the dispensing area of the pipette of the bulk liquid handling system to wash any magnetic beads remaining on the inner surface of the sample tube. A magnetic bead regeneration system is used to mix the magnetic beads and reagent D, and the magnets of the magnetic bead regeneration system are configured to effectively configure a magnetic field in the clean room and bind the magnetic beads to the inner surface of the clean room. The large volume liquid handling system then removes the supernatant via the liquid port of the pipette tip and transfers the liquid to the liquid waste management system. The magnet is then placed in an inactive position, releasing most of the magnetic beads from the inner surface of the clean room.

Insert the pipette into the cleaning tube of the pipette cleaning system again, and pump reagent A through the pipette until the cleaning tube overflows. Reagent A is sprayed from the liquid port on the side of the dispensing area of the pipette of the bulk liquid handling system to wash any magnetic beads remaining on the inner surface of the sample tube. The magnetic bead regeneration system is used to mix the magnetic beads with the reagent A, and the magnets of the magnetic bead regeneration system are configured to effectively configure a magnetic field in the clean room and bind the magnetic beads to the inner surface of the clean room. The large volume liquid handling system then removes the supernatant via the liquid port of the pipette tip and transfers the liquid to the liquid waste management system. The magnet is then placed in an inactive position to release most of the magnetic beads from the inner surface of the clean room.

Insert the pipette into the cleaning tube of the pipette cleaning system again, and pump the magnetic bead storage buffer reagent F through the pipette until the cleaning tube overflows. Reagent F is sprayed from a liquid port on the side of the dispensing area of the pipette of the bulk liquid handling system to wash any magnetic beads remaining on the inner surface of the sample tube. A magnetic bead regeneration system was used to mix magnetic beads and reagent F to complete the magnetic bead regeneration. Magnetic beads can then be reused to separate target biomolecules from fresh biological samples.

Various exemplary embodiments are described herein. Although the examples of the present invention have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are to be understood as being included within the scope of examples of the invention as defined by the scope of the appended patent applications. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, one or more method operations or steps to the objectives, spirit, or scope of the various embodiments. As will be apparent to those skilled in the art, each of the individual variations described and illustrated herein has discrete components and features that are easily separated or combined with the features of any of the other embodiments. Without departing from the scope and spirit of the various embodiments. All such modifications are intended to be within the scope of the patentable applications enclosed herewith.

Claims (48)

    A liquid processing system includes: at least one pipette system, the pipette system includes: a multi-channel pipette, the pipette includes an upper region attached to a support structure, and a lower distribution region The lower distribution area includes at least a first liquid port fluidly connected to a first channel on a side of the distribution area, and a first fluid port fluidly connected to a second channel at a tip of the distribution area. Two liquid ports; a control valve that controls liquid flow through at least the first channel or the second channel of the pipette; and a pump that is fluidly connected to the control valve.         For example, the liquid processing system of claim 1 in which the second channel of the multi-channel pipette passes through and is parallel to the first channel of the channel pipette.         For example, the liquid processing system of claim 1 in which the second channel of the multi-channel pipette is adjacent to the first channel of the multi-channel pipette.         The liquid processing system according to any one of claims 1 to 3, wherein the second liquid port includes a concave cutout.         The liquid processing system according to any one of claims 1 to 4, wherein the first liquid port is configured to spray liquid onto an inner wall of a container.         For example, the liquid handling system according to any one of claims 1 to 5, wherein at least a part of the pipette is coated with a hydrophobic layer.         The liquid processing system according to any one of claims 1 to 6, wherein the second channel is fluidly connected to a liquid storage circuit positioned between the multi-channel pipette and the control valve.         For example, the liquid processing system according to item 7 of the application, wherein the liquid storage circuit has a liquid storage capacity of about 2 mL or more.         The liquid processing system according to any one of claims 1 to 8, wherein the liquid processing system includes a liquid waste management system connected to the second channel of the multi-channel pipette.         For example, the liquid processing system according to item 9 of the application, wherein the liquid processing system includes a valve between the second channel of the multi-channel pipette and the liquid waste management system.         The liquid processing system according to any one of claims 1 to 9, wherein the pump includes a first liquid port fluidly connected to one of the control valves and a second liquid fluidly connected to a washing liquid container Pump.         For example, the liquid processing system of any one of the scope of claims 1 to 11 includes a plurality of reagent tanks which are fluidly connected to a reagent valve which is configured from the plurality of reagents. A reagent is selected in the tank, wherein the reagent valve is fluidly connected to the control valve.         The liquid handling system according to any one of claims 1 to 12, wherein the support structure is attached to a robot arm.         For example, the liquid processing system according to the scope of application of claim 13, wherein the robot arm is configured to move at least in a direction of a vertical axis.         For example, the liquid processing system according to any one of claims 1 to 14, wherein the multi-channel pipette is attached to a support block, and wherein the support block is attached to the support structure via an elastic mechanism, The elastic mechanism is configured to at least partially absorb an upward force applied to the pipette.         For example, the liquid handling system of claim 15 of the patent application scope, wherein the liquid handling system comprises a plurality of pipette systems, wherein each pipette system comprises a multi-channel pipette attached to the support block.         For example, the liquid treatment system of the 15th or 16th in the scope of patent application, wherein the elastic mechanism includes two or more springs and two or more guide mechanisms.         If the liquid handling system of any one of claims 1 to 17 of the patent application scope further comprises a pipette cleaning system, the pipette cleaning system includes a container with an open top and at least one vertically positioned on the Clean tube in container.         For example, the liquid handling system of claim 18, wherein the size and shape of the cleaning tube are designed to receive the multi-channel pipette.         For example, the liquid treatment system of claim 18 or 19, wherein the container includes a bottom, and the bottom includes a drainage port.         For example, the liquid processing system according to any one of claims 1 to 20, wherein the lower distribution area further includes a third port fluidly connected to one of the third channels.         For example, the liquid handling system according to any one of claims 1 to 20, wherein the multi-channel pipette is a dual-channel pipette.         A method of operating a liquid processing system as set forth in any one of claims 1 to 22 of the scope of patent application, which comprises aspirating liquid to the pipette through the second liquid port.         The method of claim 23, which includes lowering the pipette into a sample tube containing the liquid.         The method of claim 23 includes applying the pipette to the bottom of the sample tube.         The method according to any one of claims 23 to 25, wherein the liquid contains magnetic beads.         The method according to any one of claims 23 to 25, wherein the liquid contains a target biomolecule.         The method according to any one of claims 23 to 27, wherein the liquid is stored in a liquid storage circuit.         A method according to any one of claims 23 to 28, which includes dispensing the liquid through the second liquid port.         A method of operating a liquid processing system as set forth in any one of claims 1 to 22 of the patent application scope, comprising spraying liquid from the first liquid port onto an inner wall of a container.         The method of claim 30 includes applying the sprayed liquid to wash off the beads from the inner wall of the container.         If the method of applying for the scope of the patent No. 31, wherein the beads are magnetic beads.         An automated system for separating biomolecules from a sample, comprising a liquid processing system such as any one of claims 1 to 22 of the scope of patent application, further comprising a magnetic bead regeneration system and a second liquid processing system , A vibrator, a sample tube holder, a biomolecule separation system, a magnetic bead regeneration system, a cold storage unit, a bar code reader, or one or more of an analytical instrument.         An automated system for separating biomolecules from a biological sample includes: a liquid handling system including a pipette operable to move at least on a vertical axis; and a sample tube holder; one or more A lid configured to fit on one or more sample tubes contained in the sample tube holder, the one or more covers including a sealable port on each of the one or more sample tubes, which The pipette is allowed to enter the sample tube through the sealable port, wherein the sealable port is sealed when the pipette is withdrawn from the sample tube.         For example, the automated system of claim 34, wherein the sealable port includes two or more communicating slits.         For example, the automated system of claim 34 or 35, wherein the sealable port includes an elastomer or rubber.         For example, the automated system according to any one of claims 34 to 36, wherein the sample tube holder includes a base, the base is fitted into a sample tube holder fixture, and the sample tube holder fixture is attached to a surface.         For example, the automated system of claim 37, wherein the base includes a groove or a protrusion, and the receiving block includes a complementary groove or protrusion.         For example, if the automated system of the 37th or 38th patent scope is applied, the surface is a part of a biomolecule separation system, and the biomolecule separation system includes a magnet that can be configured as a valid configuration and an invalid configuration. When the magnet is in the effective configuration, the magnet applies a magnetic field to the one or more sample tubes so that the magnetic beads in the sample tubes are bonded to the inner surface of the one or more sample tubes, and wherein when the magnet is in the In the invalid configuration, the magnetic field is removed to release most of the magnetic beads from the inner surface of the one or more sample tubes.         For example, the automated system of any one of the 33rd to the 39th patent applications, which further includes a magnetic bead regeneration system, a vibrator, a magnetic bead separation system, a pipette cleaning system, a cold storage unit, One or more of a barcode reader or an analytical instrument.         An automated system for separating biomolecules from a biological sample includes: (a) a first liquid processing system, the liquid processing system includes: at least one pipette system, the pipette system includes: A channel pipette comprising an upper region attached to a support structure and a lower distribution region, the lower distribution region at least including a fluid connection to a first channel on a side of the distribution region A first liquid port, and a second liquid port fluidly connected to a second channel at a tip of the distribution area; a control valve that controls liquid flow through at least the first channel of the pipette or The second channel; and a pump fluidly connected to the control valve; (b) a second liquid processing system including at least one pipette, wherein the second liquid processing system is configured to process less than The liquid volume of the first liquid processing system; (c) a sample tube holder; (d) one or more lids configured to fit on one or more sample tubes contained in the sample tube holder, the one Or more The lid includes a sealable port on each of the one or more sample tubes that allows a pipette from the first liquid processing system or the second liquid processing system to enter the sample through the sealable port In a tube, wherein the sealable port is sealed when the pipette is withdrawn from the sample tube; and (e) a biomolecule separation system configured to cause the magnetic beads to pass through a magnetic field in a valid configuration Bonded to the side of a sample tube.         For example, the automated system of claim 41, wherein the biomolecule separation system is operable to configure a magnet into a valid configuration and an invalid configuration, and when the magnet is in the valid configuration, the magnet is directed to the one A magnetic field is applied to the one or more sample tubes so that the magnetic beads in the sample tube are bonded to the inner surface of the one or more sample tubes, and wherein when the magnet is in the invalid configuration, the magnetic field is removed to automatically The inner surface of the one or more sample tubes releases most of the magnetic beads.         For example, the automated system of item 41 or 42 of the patent application scope further includes a magnetic bead regeneration system, a vibrator, a pipette cleaning system, a cold storage unit, a code reader, or an optical detection system. One or more of the testers.         For example, the automated system according to any one of claims 41 to 43, wherein the system is contained in a housing.         For example, the automatic system under the scope of patent application No. 44 wherein the housing is sealed.         For example, the patent application scope of item 44 or item 45 of the automated system, wherein the housing includes a sterilization system.         For example, the automatic system of claim 46, wherein the sterilization system includes an air filter or an ultraviolet lamp.         For example, the automation system according to any one of claims 41 to 47, wherein a computer system is used to operate the automation system.