CN114904469A - Synthesizer, synthesizer and synthesizing method - Google Patents
Synthesizer, synthesizer and synthesizing method Download PDFInfo
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- CN114904469A CN114904469A CN202110177590.5A CN202110177590A CN114904469A CN 114904469 A CN114904469 A CN 114904469A CN 202110177590 A CN202110177590 A CN 202110177590A CN 114904469 A CN114904469 A CN 114904469A
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- 230000002194 synthesizing effect Effects 0.000 title claims description 23
- 238000000034 method Methods 0.000 title claims description 17
- 238000000018 DNA microarray Methods 0.000 claims abstract description 182
- 238000006243 chemical reaction Methods 0.000 claims abstract description 99
- 238000003786 synthesis reaction Methods 0.000 claims description 80
- 230000015572 biosynthetic process Effects 0.000 claims description 35
- 239000000463 material Substances 0.000 claims description 33
- 229920002521 macromolecule Polymers 0.000 claims description 9
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000000903 blocking effect Effects 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 230000006820 DNA synthesis Effects 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000003155 DNA primer Substances 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000013615 primer Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0053—Details of the reactor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
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- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
Abstract
A synthesizer is composed of a feeder for providing biochips to predefined positions, a recognizer for recognizing the identity of biochips at predefined positions and feeding back the generated information to a controller, a manipulator for sorting the biochips at predefined positions to relative containers under the control of controller, and a transfer unit for transferring the biochips to multiple reaction containers, the reaction vessel is used to transfer the biochip to the feeding device when in the feeding position. The invention also provides a synthesizer and a synthesis method.
Description
Technical Field
The invention relates to biomacromolecule synthesis, in particular to a synthetic device, a synthetic instrument and a synthetic method for synthesizing biomacromolecules.
Background
Common biological macromolecules include proteins, nucleic acids (DNA, RNA, etc.), carbohydrates. The biomacromolecules are mostly polymerized from simple constitutive structures, the constitutive units of proteins are amino acids, and the constitutive units of nucleic acids are nucleotides. Biological macromolecules can be synthesized in vivo from simple structures. If biomacromolecules need to be artificially synthesized, the biomacromolecules need to be synthesized by a special instrument, namely a synthesizer.
In the case of DNA synthesis, DNA synthesis refers to a method of synthesizing DNA strands by artificially ligating deoxynucleotides one by one in a predetermined nucleotide order. For example, the DNA single-stranded sequence CGTGCA … … was synthesized manually from left to right.
The existing synthesizer fixes the single-chain oligonucleotide on a glass synthesis column, then soaks the synthesis column in a container, and then adds various corresponding nucleotide reagents into the container to continuously extend the single-chain oligonucleotide according to the required sequence. However, the synthesis principle of the synthesizer is complex in process, low in synthesis flux and large in reagent consumption. In addition, in the process of synthesizing the biomacromolecule, the synthesis cycle period is long, and the target synthesis task cannot be changed.
Disclosure of Invention
In view of the above, it is desirable to provide a synthesizer, a synthesizer and a synthesizing method, which solve at least one of the above problems.
A synthesis device for synthesizing biomacromolecules comprises a feeding device, an identification device, a plurality of containing pieces, a manipulator, a reaction device and a transfer device, wherein the feeding device is used for providing biochips to a preset position, the identification device is used for identifying the identifications of the biochips at the preset position and feeding generated identification information back to a control device, the manipulator is used for sorting the biochips at the preset position to the corresponding containing pieces under the control of the control device, the reaction device comprises a plurality of reaction containers, the containing pieces comprise a plurality of first containing pieces, the first containing pieces respectively correspond to a plurality of reactors, the transfer device is used for transferring the biochips in the first containing pieces to a plurality of reaction containers, and the reaction containers can be converted between a reaction state position and a blanking state position, the reaction container is used for carrying out synthesis reaction on the biochip when in the reaction state position, and the reaction container is used for transferring the biochip in the reaction container to the feeding device when in the discharging state position.
Further, the plurality of accommodating parts further comprise a second accommodating part, the second accommodating part comprises a plurality of accommodating areas, and the manipulator further transfers all biochips of which the synthesis reactions are finished from a preset position to one accommodating area under the control of the control device.
Further, the plurality of containers further include a third container, and the manipulator further transfers the unrecognized biochip from the predetermined position to the third container under the control of the control device.
Further, the transfer device comprises an opening and closing assembly, the first accommodating part forms a through hole, the opening and closing assembly is used for shielding the bottom of the through hole to receive the biological chip transferred by the manipulator and opening the bottom of the through hole to transfer the biological chip to the reaction container.
Furthermore, the opening and closing assembly comprises a shielding sheet arranged at the bottom of the first accommodating parts and a first driving part connected with the shielding sheet, the shielding sheet comprises a plurality of shielding parts, the shielding parts are respectively provided with a through hole at the same side in the arrangement direction, and the first driving part is used for driving the shielding sheet to move in a first direction under the control of the control device so that the shielding parts and the through holes are staggered to transfer the biological chips in the first accommodating parts, and driving the shielding sheet to move in a direction opposite to the first direction so that the shielding parts shield the through holes again.
Furthermore, the first accommodating part is fixed on the opening and closing assembly, the transfer device further comprises a conveying device fixedly connected with the opening and closing assembly, and the conveying device is used for driving the opening and closing assembly to move to the material transfer position under the control of the control device so as to transfer the biological chips in the first accommodating part to the reaction container and driving the opening and closing assembly to move to the material receiving position so as to receive the biological chips transferred by the manipulator.
Further, the recognition device includes a position recognition part for recognizing whether the biochip is moved to the predetermined position, an image capturing part for capturing an image of the predetermined position when the biochip is moved to the predetermined position, and an image recognition part for analyzing the image of the biochip and acquiring identification information on the biochip.
A synthesizer comprises the synthesizer, a control device for controlling the synthesizer, and an input part and an output part which are connected with the controller, wherein the controller runs a corresponding program according to the content input from the input part to control the synthesizer, and displays the related information on the output part.
A synthetic method for synthesizing a biological macromolecule, comprising:
identifying the identification of the biochip at a predetermined position and generating corresponding identification information;
determining whether the biochip is a biochip with all synthesis reactions completed according to the identification information of the current biochip and the synthesis sequence of each biochip;
when the biochip is not a biochip with all synthesis reactions completed, controlling the manipulator to transfer the biochip from the preset position to a first accommodating part corresponding to the current synthesis reaction in a plurality of first accommodating parts corresponding to a plurality of reaction containers for carrying out the synthesis reaction;
controlling the transfer device to transfer the biochips in the first accommodating parts to the reaction containers;
controlling a reaction container to carry out synthetic reaction at a reaction state position, wherein the reaction container can be switched between the reaction state position and a blanking state position;
and controlling the reaction container to be switched to a blanking state position so as to transfer the biochip subjected to the synthesis reaction to the preset position.
Further, when the biochip is a biochip in which all synthesis reactions are completed, the robot is controlled to transfer the biochip from the predetermined position to a housing section of a second housing member including a plurality of housing sections.
In addition, because a plurality of reaction vessels and a plurality of first sorting components are correspondingly arranged, the biochips can be sorted to the corresponding reaction vessels according to the identification information of the biochips, and even if the synthesis sequence of the biochips is modified or added in the synthesis process, the modified or newly added synthesis sequence can be adapted through the change of the sorting sequence, thereby realizing the synthesis work with higher degree of freedom.
Drawings
FIG. 1 is a schematic diagram of DNA synthesis using a biochip having a label according to the present invention.
FIG. 2 is a schematic external view of the synthesizer of the present invention.
Fig. 3 is a schematic diagram of the constituent parts of the synthesizer shown in fig. 2.
Fig. 4 is a perspective view of the synthesizer of fig. 2 with a portion of the housing removed.
Fig. 5 is a perspective view of the combining apparatus of fig. 4.
Fig. 6 is a perspective view of the combining device of fig. 5 from another angle.
Fig. 7 is a perspective view of fig. 5 with the identification device and the material guide removed.
Fig. 8 is an enlarged view of the feeding device of fig. 7.
Fig. 9 is a perspective view of the suction device of the robot hand in fig. 7.
FIG. 10 is a schematic view of the reaction vessel of FIG. 5 in a blanking position.
Fig. 11 is a perspective view of the transfer device of fig. 7.
Fig. 12 is a partially exploded view of the transfer device of fig. 11 with the housing removed.
Fig. 13 is a further exploded view of the transfer device of fig. 12.
FIG. 14 is a flow chart of a synthesis method according to an embodiment of the present invention.
Description of the main elements
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It will be understood that when an element is referred to as being "mounted on" another element, it can be directly on the other element or intervening elements may also be present. When a component is referred to as being "disposed on" another component, it can be directly on the other component or intervening components may also be present.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "or/and" includes any and all combinations of one or more of the associated listed items.
The synthesizer of the present invention can be used for synthesizing biological macromolecules, including but not limited to proteins, nucleic acids (DNA, RNA, etc.), saccharides, etc. The carrier for synthesizing the biological macromolecules is a biochip, the biological macromolecules are fixed on the surface of the biochip and are continuously prolonged in a synthesizer according to a required sequence, and therefore a finally required macromolecular structure is synthesized.
Referring to FIG. 1, taking the synthesis of oligonucleotide primers as an example, a single oligonucleotide 10 is immobilized on the surface of a biochip 20, and multiple single oligonucleotide strands (two single oligonucleotide strands are shown) can be immobilized on the surface of the biochip 20, and the single oligonucleotide strands are extended by the synthesizer of the present invention according to the desired sequence. Before the synthesis by the synthesizer of the present invention, a short oligonucleotide chain segment may be fixed on the surface of the biochip 20 in advance, or a specific biological linker may be arranged on the surface of the biochip 20, and the oligonucleotide chain segment or specific biological linker fixed in advance may be extended continuously to obtain the desired oligonucleotide primer structure. The biochip 20 is further provided with an identifier 21, the identifier 21 is shown by a shaded portion in the figure, and the identifier 21 is an identity label corresponding to the biochip 20 and is used for distinguishing the biochip 20 from other biochips 20. The identification 21 may be represented by a two-dimensional code, a bar code, an RFID tag, or other known means. In other embodiments, the mark 21 may be disposed at other specific positions or at several other specific positions of the biochip 20.
Referring to FIGS. 2 to 4, the synthesizer 30 is used for synthesizing biological macromolecules, and in the present embodiment, the synthesis of oligonucleotide primers is still exemplified. The synthesizer 30 includes a housing 31, and a display 32 and an input unit 33 fixed to the housing. In one embodiment, the display 32 and input device 33 are integrated on a touch screen display. It will be appreciated that the input component 33 may also be provided separately from the display 32, including a keyboard, mouse, or other input device. The synthesizer 30 further comprises a reagent supplying means 34, a synthesizing means 35 disposed inside the housing 31, and a control means 36. The reagent supplying device 34 is used for supplying the synthesizing reagent to the synthesizing device 35 for the biochip 20 to perform the synthesizing reaction. The control device 36 is communicatively connected to the display 32, the input unit 33, the reagent supplying device 34, and the synthesizing device 35, and may be a server, a host, or a chip. The control unit 36 is used for executing a corresponding program according to the content input by the input unit 33, controlling the synthesis unit 35 and the reagent supply unit 34, and displaying related information (such as abnormality information, completion information, etc.) on the display 32. The control device 36 may be disposed inside the housing 31, or outside the housing 31, which may be a local control device or a remote control device. The input unit 33 may input the content by setting the synthesis reaction to be performed for each biochip 20, defining the abnormal features (e.g., unrecognizable identification) of the abnormal biochip 20, and so on. The housing 31 is also provided with at least one channel 37 communicating with the inside of the synthesizer 30, and the channel 37 can be used for contacting the internal structure of the synthesizer 30 and also placing a biochip 20 and the like to be subjected to oligonucleotide primer synthesis.
Referring to FIGS. 5 to 7, the synthesizing apparatus 35 includes a supply unit 351 for supplying the biochips, an identification unit 352 for identifying the biochips, a plurality of containers 353 for accommodating the biochips, a robot 354 for transferring the biochips to the containers 353, a reaction unit 355 including a plurality of reaction vessels 3551, and a transfer unit 356 for transferring the biochips from the containers 353 to the reaction vessels 3551.
Referring to FIGS. 7 and 8, the feeding device 351 is used for receiving and transporting the biochip to a predetermined position. The feeding device 351 further includes a vibration plate 3511 and a guide 3512 having a feeding chute 35111 and a discharge port (not shown). The guide 3512 is located outside the vibration disk 3511 and communicates with a discharge port of the vibration disk 3511. A vibration rail 35112 is arranged in the vibration disc 3511, and the vibration rail 35112 is used for outputting the biochips entering the feed chute 35111 to the guide 3512 after being orderly arranged. The guide 3512 is formed with a downwardly inclined slide 35121, and the predetermined position is provided at the end of the slide 35121, and the biochip discharged to the guide 3512 through the discharge port slides along the slide 35121 to the predetermined position.
Referring to fig. 5 and 8, the identification means 352 is used for identifying the identity of the biochip located at the predetermined position and feeding the generated identity information back to the control means 36. The recognition device 352 includes an image capturing unit 3521 and an image recognition unit (not shown). The image capturing unit 3521 is used for capturing an image of the biochip at a predetermined position. The image recognition component is used to analyze the image of the biochip and to send the identification information on the obtained biochip to the control device 36. It is understood that the image recognizing unit may be disposed in the control unit 36, the image capturing unit 3521 transmits the captured image of the biochip to the control unit 36, and the control unit 36 recognizes the identifier on the biochip according to the image of the biochip to obtain the identifier information.
The recognition means 352 further includes a position recognizer 3522, the position recognizer 3522 is configured to recognize whether the biochip is moved to the predetermined position and transmit the generated corresponding recognition result to the control means 36. The control unit 36 controls the image-capturing part 3521 to capture an image of the biochip according to the recognition result that the biochip has moved to the predetermined position. Specifically, the slide 35121 forms a plurality of inspection holes 35122 at the predetermined positions, and the position identifier 3522 includes a signal emitter 35221 and a signal receiver 35222 at both sides of the inspection hole 35122. The signal emitter 35221 is used to emit a laser signal for emission through the detection hole 35122 to the signal receiver 35222. Since the biochip moves to the sensing hole 35122 to shield the sensing hole 35122, the signal receiving part 35222 does not receive the laser signal, and thus, the signal receiving part 35222 determines that the biochip moves to a predetermined position when the laser signal is not received. On the contrary, the signal receiving part 35222 judges that the biochip has not moved to the predetermined position when the laser signal is received.
In another embodiment, the recognition device 352 does not include the position recognizer 3522, and when the recognition device 352 does not include the position recognizer 3522, the image capturing unit 3521 continuously captures images at a predetermined position, and the image recognizer judges whether the predetermined position includes a biochip and recognizes a mark on the biochip based on the continuously captured images.
Referring to fig. 6 and 7 again, the plurality of receiving members 353 includes a plurality of first receiving members 3531, second receiving members 3532 and third receiving members 3533. The first receiving parts 3531 are fixed to each other and arranged side by side, and respectively match with the reaction vessels 3551, so as to receive biochips corresponding to synthesis reactions performed in the reaction vessels 3551. In this embodiment, the number of the first containers 3531 is four, and the four containers correspond to four reaction vessels 3551. The four first containers 3531 correspond to the four reaction vessels 3551, respectively. The second container 3532 includes a plurality of container regions 35321, and the container regions 35321 are used for containing biochips in which all synthesis reactions are completed. The third container 3533 is used for containing the biochip which cannot be identified.
The control device 36 determines whether the biochip is a biochip with all synthesis reactions completed or a biochip which cannot be identified or a biochip without synthesis sequence binding according to the identification information of the current biochip and the synthesis sequence of each biochip. The control unit 36 further determines a synthesis reaction to be currently performed and position information of one of the first receiving members 3531 to which the current biochip should be transferred when the current biochip is not a biochip in which all the synthesis reactions are completed, and transmits the transfer command including the position information to the robot 354 to control the robot 354 to transfer the biochip. The control unit 36 also determines position information of a receiving area 35321 in the second receiving member 3532 to which the current biochip should be transferred when the current biochip is a biochip in which all synthesis reactions are completed, and transmits the transfer instruction including the position information to the robot 354. The control device 36 further binds a synthesis sequence to the current biochip to make the current biochip a biochip with less than all synthesis reactions when the current biochip is a biochip without binding synthesis sequences, and correspondingly, sends a corresponding transfer instruction to the manipulator 354 when the biochip is a biochip with less than all synthesis reactions.
The robot 354 is used for transferring the biochip positioned at the predetermined position to the corresponding first container 3531, second container 3532 or third container 3533 according to a transfer instruction sent by the control device 36.
Specifically, referring to fig. 7 and 9, the robot 354 includes a robot arm 3541 and a suction device 3542 fixed to a distal end of the robot arm 3541. The robot arm 3541 may be a four-axis robot arm or a six-axis robot arm, or other multi-axis robot arm. The robot arm 3541 is configured to drive the adsorption device 3542 to move to the predetermined position so that the adsorption device 3542 adsorbs the biochip, and to drive the adsorption device 3542 to move to a position above the first container 3531 to which the biochip should be transferred so that the adsorption device 3542 releases the biochip into the corresponding first container 3531. The robot arm 3541 is also reset after the adsorption apparatus 3542 releases the biochip to wait for the next transfer operation of the biochip.
In one embodiment, the suction device 3542 includes a negative pressure suction nozzle 35421 and a negative pressure air supply device 35422 connected to the negative pressure suction nozzle 35421. The control unit 36 controls the negative pressure air supply unit 35422 to be turned on when the suction unit 3542 moves to the predetermined position so that the negative pressure suction nozzle 35421 sucks up the biochip at the predetermined position, and controls the negative pressure air supply unit 35422 to be turned off when the suction unit 3542 moves to above the first container 3531 to which the sucked biochip should be transferred so that the negative pressure suction nozzle 35421 releases the biochip in the corresponding first container 3531.
Referring to fig. 5 and 10, a plurality of reaction containers 3551 of the reaction device 355 correspond to a plurality of first containers 3531, and are respectively used for performing a synthesis reaction or cleaning on biochips from the plurality of first containers 3531. The synthesis reaction performed in each reaction vessel 3551 is different, and for example, four reaction vessels 3551 are used for adenine (a), thymine (T), cytosine (C) and guanine (G) synthesis.
Specifically, each of the reaction vessels 3551 includes a synthesis reaction column 35511 and a sealing cover 35512 openably and closably connected to the synthesis reaction column 35511. The sealing cap 35512 is used to seal the synthesis reaction column 35511 to make the biochip complete the synthesis reaction. When the sealing cap 35512 is not covering the synthesis reaction column 35511, it is used to place a biochip into the synthesis reaction column 35511. The reaction device 355 further includes an opening and closing driving member 3552, and the opening and closing driving member 3552 is connected to the sealing cover 35512 for driving the sealing cover 35512 to ascend and descend so that the sealing cover 35512 is separated from or seals the synthesis reaction column 35511.
The plurality of reaction vessels 3551 may be switched among a material receiving station, a material reaction station, and a material discharge station. The reaction vessel 3551 is used for receiving the biochip in the first container 3531 transferred by the transfer device 356 when the reaction vessel 3551 is located at the material receiving position. The reaction vessel 3551 is configured to receive a synthesis reagent and perform a synthesis reaction when the reaction vessel is in the reaction state position. The reaction vessel 3551 is located at the feeding position for transferring the biochip in the reaction vessel 3551 to the feeding device 351.
Specifically, the reaction device 355 further includes a positioning body 3553, a rotation driving assembly 3554 connected to the positioning body 3553, a horizontal driving assembly 3555 connected to the positioning body 3553, and a vertical driving assembly 3556 connected to the positioning body 3553.
The plurality of reaction vessels 3551 are fixed to a positioning member 3553 in parallel. The rotation driving assembly 3554 is configured to drive the positioning body 3553 to rotate in a first rotation direction by a preset angle according to a rotation command sent by the control device 36, and rotate in a direction opposite to the first rotation direction for a preset time after the positioning body 3553 rotates by the preset angle, so as to reset. The control device 36 sends the rotation command to the rotation driving assembly 3554 when the reaction device 355 completes the synthesis reaction. The position of the positioning body 3553 rotating a preset angle around the first rotating direction is the blanking state position, and the position of the positioning body 3553 rotating around the direction opposite to the first rotating direction and resetting is the material reaction state position. The synthesizing device 35 further includes a material guide 357. One end of the guide member 357 is opposite to the feeder 351 and the other end is opposite to the reaction vessel 3551 when the reaction vessel 3551 rotates a predetermined angle around the first rotation direction, so as to guide the biochip poured out of the reaction vessel 3551 to the feeder 351.
The vertical driving assembly 3556 is used for driving the positioning body 3553, the reaction vessel 3551 and the horizontal driving assembly 3555 to move downwards from a first preset height to a second preset height according to a material receiving instruction sent by the control device 36. The horizontal driving assembly 3555 is configured to drive the positioning body 3553 and the reaction container 3551 to move forward a preset horizontal distance when the reaction container 3551 moves to the second preset height according to the material receiving instruction sent by the control device 36, so that the reaction container 3551 is located at the material receiving position. In the material receiving position, the reaction vessel 3551 is located right below the first container 3531. Wherein the control device 36 sends the material receiving instruction when the first container 3531 is located at the material transfer position. The horizontal driving assembly 3555 is further configured to drive the positioning body 3553 and the reaction vessel 3551 to move backward by the preset horizontal distance when the biochip is transferred from the first container 3531 to the reaction vessel 3551, so that the reaction vessel 3551 is extracted from below the first container 3531, and the vertical driving assembly 3556 is further configured to drive the positioning body 3553, the reaction vessel 3551 and the horizontal driving assembly 3555 to move upward by the preset horizontal distance from the second preset height to the first preset height, so that the reaction vessel 3551 is reset to the material reaction state position.
Referring to fig. 7, 11, 12 and 13, the transferring device 356 is used for transferring the biochips in the first containers 3531 to the reaction vessels 3551 at the material receiving position under the control of the control device 36. In the process of transferring the biochip by the transferring device 356, the control device 36 controls the feeding device and the manipulator 354 to stop, and after the transfer of the biochip is completed, the feeding device and the manipulator 354 are started to operate.
The transfer device 356 includes an opening and closing assembly 3561 and a housing 3563 for shielding the opening and closing assembly 3561. The first receiving member 3531 forms a through hole 35311. The opening and closing member 3561 is used to cover the bottom of the through hole 35311 to receive the biochip transferred by the robot 354, and to open the bottom of the through hole 35311 to transfer the biochip to the reaction vessel 3551.
The opening and closing assembly 3561 includes a shielding piece 35611 disposed at the bottom of the first accommodating pieces 3531 and a first driving piece 35612 connected to the shielding piece 35611. The shielding sheet 35611 includes a plurality of shielding portions 356111, and a plurality of shielding portions 356111 respectively form a through hole 356112 at the same side in the arrangement direction. The shielding part 356111 is used to shield the through hole 35311 so that the biochip in the first container 3531 can stay in the first container 3531. The through hole 356112 is used to align with the through hole 35311 so that the biochip in the first container 3531 can be transferred to the reaction vessel 3551 at the material receiving position through the through hole 35311 and the through hole 356112. The first driving unit 35612 is used to drive the shielding plate 35611 to move in a first direction under the control of the control device 36 to make the shielding portion 356111 misaligned with the through hole 35311 so as to align the through hole 356112 with the through hole 35311, so as to transfer the biochip in the first accommodating member 3531. The first driver 35612 is further used to drive the shielding piece 35611 to move in a direction opposite to the first direction, so that the shielding portion 356111 shields the through hole 35311 again. In this embodiment, the plurality of receiving members 353 includes four first receiving members 3531, the shielding sheet 35611 includes four shielding portions 356111 and three through holes 356112 disposed between the four shielding portions 356111, the three through holes 356112 are respectively configured to align with the through holes 35311 of the three first receiving members 3531, and one side of the shielding sheet 35611 is used as a fourth through hole 356112 configured to align with the through hole 35311 of the fourth first receiving member 3531.
The opening and closing assembly 3561 further includes a first detecting member 35613, a second detecting member 35614, a first connecting member 35615 and a second connecting member 35616. The first detecting element 35613 and the second detecting element 35614 are fixed on the first connecting element 35615 and are spaced apart from each other. The second connector 35616 is connected to the shield plate 35611 and the first driver 35612, and is slidably disposed on the first connector 35615. In one embodiment, the first connector 35615 includes a slide rail 356151, and the second connector 35616 includes a slide (not shown) that mates with the slide rail 356151, and the slide is slidably connected to the slide rail 356151. The second connecting member 35616 includes a suspended blocking piece 356161, and the first driving member 35612 is used for driving the second connecting member 35616 to slide on the first connecting member 35615, so as to move the shielding piece 35611 and the blocking piece 356161. The first detecting member 35613 is used for detecting whether the flap 356161 moves to a first predetermined position and transmitting the detection result to the control device 36. The blocking piece 356161 is located at a first preset position in the initial state, and the shielding portion shields the through hole 35311 in the first preset position. When the control device 36 controls the transferring device 356 to transfer the biochip, the first driving device 35612 is first controlled to drive the second connecting member 35616 to move toward the first direction, and the first driving device 35612 is controlled to stop driving the second connecting member 35616 to continue moving toward the first direction according to the detection result sent by the second detecting device 35614 and detected that the blocking piece 356161 moves to the second preset position, at this time, the through hole 356112 is aligned with the through hole 35311 to drop the biochip. The control device 36 controls the first driving member 35612 to drive the second connecting member 35616 to move in a direction opposite to the first direction after the blocking piece 356161 is located at the second preset position for a preset time, and controls the first driving member 35612 to stop driving the second connecting member 35616 to move continuously according to a detection result sent by the first detecting member 35613 and used for detecting that the blocking piece 356161 moves to the first preset position, so as to reset the shielding piece 35611. The preset time is for the biochip in the first container 3531 to fall.
In one embodiment, the first connecting member 35615 is further fixedly connected to the first receiving member 3531. Specifically, the second connector 35616 is connected above the shield 356161 and forms a through hole 356162. The first connector 35615 includes a first connector 356152 and a second connector 356153. The first detecting element 35613 and the second detecting element 35614 are fixed to the first connecting portion 356152, and the second connecting element 35616 is slidably connected to the first connecting portion 356152. The second connecting portion 356153 is disposed on the shielding piece 356161 through the through hole 356162. The second connecting portion 356153 includes a plurality of connecting blocks 356154 arranged at intervals, a connecting groove 35312 is formed between two adjacent first receiving members 3531, the connecting block 356154 is fixedly disposed on the connecting groove 35312, so that the through hole 35311 is communicated with a gap adjacent to the connecting block 356154, and the first receiving members 3531 are opposite to the shielding plate 35611. In this embodiment, the second connecting portion 356153 includes three connecting blocks 356154, and the plurality of receiving members 353 includes four first receiving members 3531, wherein the through holes 35311 of two first receiving members 3531 communicate with two gaps between the three connecting blocks 356154 so that the through holes 35311 are opposite to the shielding plates 35611, and the other two first receiving members 3531 are located at opposite ends of the second connecting portion 356153 so that the through holes 35311 of the other two first receiving members 3531 are directly opposite to the shielding plates 35611.
In one embodiment, as described above, the first receiving member 3531 is fixed to the opening and closing assembly 3561. The transfer device 356 further includes a delivery device 3562 fixedly connected to the opening and closing assembly 3561. The conveying device 3562 is used for driving the opening and closing assembly 3561 to move according to a transfer instruction of the control device 36, so that the first accommodating piece 3531 moves from the material receiving position to the material transfer position and from the material transfer position to the material receiving position. The first container 3531 is used for receiving the biochip transferred by the robot 354 when the first container is located at the material receiving position. The first container 3531 is used for transferring the biochip in the first container 3531 to the reaction vessel 3551 when the first container 3531 is located at the material transfer position. The control device 36 sends the transfer instruction when the number of the biochips in the first container 3531 reaches a preset number, wherein the transfer instruction includes driving the open-close assembly 3561 to move so that the first container 3531 is located at the material transfer position, and driving the open-close assembly 3561 to move reversely to the material receiving position when the material transfer position transfers the biochips in the first container 3531 to the reaction vessel 3551. In one embodiment, the predetermined number refers to the sum of all biochips in the first container 3531, and in another embodiment, the predetermined number refers to the maximum number of biochips in the plurality of first containers 3531.
Specifically, the conveying device 3562 includes a track 35621 and a second driving member 35622. The switch assembly 3561 is slidably coupled to the rail 35621, and in particular, the first connecting member 35615 of the switch assembly 3561 is slidably coupled to the rail 35621 as described above. The material receiving position and the material transferring position are disposed at two different positions on the rail 35621. The second actuator 35622 is coupled to the opening and closing assembly 3561, and in particular, to the first linkage 35615 of the opening and closing assembly 3561, as described above. The second driving member 35622 is used for driving the opening and closing assembly 3561 to move back and forth along the rail 35621 so as to move the first accommodating member 3531 to the material receiving position or the material transferring position. The second driver 35622 may be a linear cylinder.
Referring to FIG. 14, FIG. 14 is a flow chart of a method for synthesizing a biological macromolecule, which includes the following steps.
Step S110: the identification of the biochip located at the predetermined position is recognized and corresponding identification information is generated.
Step S120: and determining whether the biochip is a biochip with all synthesis reactions completed or an unidentifiable biochip or a biochip without synthesis sequence binding according to the identification information of the current biochip and the synthesis sequence of each biochip.
When the biochip is not one in which all the synthesis reactions are completed, the process proceeds to step S130; when the biochip is a biochip in which all the synthesis reactions are completed, the process proceeds to step S140; when the biochip is unidentifiable, the process proceeds to step S150; if the biochip is a biochip without binding of synthetic sequences, the process proceeds to step S160.
Step S130: the robot 354 is controlled to transfer the biochip from the predetermined position to one of the plurality of first containers 3531 corresponding to the current synthesis reaction, the plurality of first containers 3531 corresponding to the plurality of reaction vessels 3551 for performing the synthesis reaction. After step S130, the process proceeds to step S170.
Step S140: the robot 354 is controlled to transfer the biochip from the predetermined position to a receiving area 35521 of the second receiving member 3532.
Step S150: the robot 354 is controlled to transfer the biochip from the predetermined position to the third housing area 35521.
Step S160: binding a synthetic sequence to the biochip, and proceeding to step S130.
Step S170: the transfer control unit 356 transfers the biochips in the plurality of first containers 3531 to the plurality of reaction vessels 3551.
Step S180: the reaction vessel 3551 was controlled to conduct the synthesis reaction.
Step S190: the reaction vessel 3551 is controlled to be switched to the feeding state position to transfer the biochip after the synthesis reaction to the predetermined position, and the step S110 is returned again, and the above steps are repeated until the biochip completes all the synthesis reactions.
In the synthesizer 30 and the synthesizing method, the plurality of first containers 3531 and the plurality of reaction vessels 3551 are independent of each other, and when the biochip at a predetermined position is transferred to the first container 3531 by the manipulator 354, the reaction vessels 3551 can perform a synthesis reaction, so that a synthesis cycle is reduced, and in addition, since the plurality of reaction vessels 3551 are correspondingly arranged with the plurality of first sorting components, the biochip can be sorted to the corresponding reaction vessels 3551 according to identification information of the biochip, and even if a synthesis sequence of the biochip is modified or added during synthesis, the modified or added synthesis sequence can be adapted by changing the sorting sequence, thereby realizing synthesis work with higher degree of freedom.
It should be understood by those skilled in the art that the above embodiments are only for illustrating the present invention and are not to be used as a limitation of the present invention, and that suitable changes and modifications of the above embodiments are within the scope of the claimed invention as long as they are within the spirit and scope of the present invention.
Claims (10)
1. A synthesis device for synthesizing biomacromolecules is characterized by comprising a feeding device, an identification device, a plurality of containing pieces, a manipulator, a reaction device and a transfer device, wherein the feeding device is used for providing biochips to a preset position, the identification device is used for identifying the identifications of the biochips at the preset position and feeding generated identification information back to a control device, the manipulator is used for sorting the biochips at the preset position to the corresponding containing pieces under the control of the control device, the reaction device comprises a plurality of reaction containers, the containing pieces comprise a plurality of first containing pieces, the first containing pieces respectively correspond to a plurality of reactors, the transfer device is used for transferring the biochips in the first containing pieces to the reaction containers, and the reaction containers can be converted between a reaction state position and a blanking state position, the reaction container is used for carrying out synthesis reaction on the biochip when in the reaction state position, and the reaction container is used for transferring the biochip in the reaction container to the feeding device when in the feeding state position.
2. The synthesis device according to claim 1, wherein the plurality of receiving members further comprises a second receiving member comprising a plurality of receiving areas, and the manipulator further transfers a biochip having all synthesis reactions completed from a predetermined position to a receiving area under the control of the control device.
3. The synthesizer according to claim 1, further comprising a third container in said plurality of containers, wherein said robot further transfers an unidentifiable biochip from a predetermined position to said third container under the control of said controller.
4. The synthesizer according to claim 1, wherein the transfer device comprises an opening and closing member, the first container forms a through hole, the opening and closing member is used for shielding the bottom of the through hole to receive the biochip transferred by the manipulator and opening the bottom of the through hole to transfer the biochip to the reaction vessel.
5. The combining device of claim 4, wherein the opening/closing assembly comprises a shielding plate disposed at the bottom of the first receiving members and a first driving member connected to the shielding plate, the shielding plate comprises a plurality of shielding portions, the shielding portions respectively form a through hole at the same side in the arrangement direction, and the first driving member is used for driving the shielding plate to move in a first direction under the control of the control device so that the shielding portions are staggered from the through holes to transfer the biochips in the first receiving members, and driving the shielding plate to move in a direction opposite to the first direction so that the shielding portions shield the through holes again.
6. The synthesizer according to claim 4, wherein the first container is fixed to the opening and closing assembly, and the transferring device further comprises a conveying device fixedly connected to the opening and closing assembly, the conveying device is configured to drive the opening and closing assembly to move to the material transferring position under the control of the control device so as to transfer the biochip in the first container to the reaction vessel, and drive the opening and closing assembly to move to the material receiving position so as to receive the biochip transferred by the manipulator.
7. The synthesizer according to claim 1, wherein the identifier comprises a position identifier for identifying whether the biochip is moved to the predetermined position, an image capturing member for capturing an image of the predetermined position when the biochip is moved to the predetermined position, and an image identifier for analyzing the image of the biochip and acquiring the identification information on the biochip.
8. A synthesizer comprising the synthesizer according to any one of claims 1 to 7, a control device for controlling the synthesizer, and an input unit and an output unit connected to the control device, wherein the control device executes a corresponding program according to a content input from the input unit to control the synthesizer and displays related information on the output unit.
9. A method of synthesis for synthesizing a biological macromolecule, comprising:
identifying the identification of the biochip at a predetermined position and generating corresponding identification information;
determining whether the biochip is a biochip with all synthesis reactions completed according to the identification information of the current biochip and the synthesis sequence of each biochip;
when the biochip is not a biochip with all synthesis reactions completed, controlling the manipulator to transfer the biochip from the preset position to a first accommodating part corresponding to the current synthesis reaction in a plurality of first accommodating parts corresponding to a plurality of reaction containers for carrying out the synthesis reaction;
controlling the transfer device to transfer the biochips in the first accommodating parts to the reaction containers;
controlling a reaction container to carry out synthetic reaction at a reaction state position, wherein the reaction container can be switched between the reaction state position and a blanking state position;
and controlling the reaction container to be switched to a feeding state position so as to transfer the biochips subjected to the synthesis reaction to the preset position.
10. The method of synthesizing as set forth in claim 9, wherein when the biochip is a biochip in which all synthesis reactions are completed, the robot is controlled to transfer the biochip from the predetermined position to a housing section of a second housing member including a plurality of housing sections.
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