CN114904469B - Synthesizer, synthesizer and synthesizing method - Google Patents
Synthesizer, synthesizer and synthesizing method Download PDFInfo
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- CN114904469B CN114904469B CN202110177590.5A CN202110177590A CN114904469B CN 114904469 B CN114904469 B CN 114904469B CN 202110177590 A CN202110177590 A CN 202110177590A CN 114904469 B CN114904469 B CN 114904469B
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- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title abstract description 17
- 238000000018 DNA microarray Methods 0.000 claims abstract description 202
- 238000006243 chemical reaction Methods 0.000 claims abstract description 105
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 85
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 34
- 239000000463 material Substances 0.000 claims description 30
- 229920002521 macromolecule Polymers 0.000 claims description 7
- 238000001308 synthesis method Methods 0.000 claims description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 230000000903 blocking effect Effects 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 239000000470 constituent Substances 0.000 description 4
- 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
- 239000013615 primer Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 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
- 238000007599 discharging Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 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
- 102000053602 DNA Human genes 0.000 description 1
- 239000003155 DNA primer Substances 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
- 229940104302 cytosine Drugs 0.000 description 1
- 238000006073 displacement reaction 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
- 238000005406 washing Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- 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
The synthesis device comprises a feeding device, an identification device, a plurality of accommodating parts, a mechanical arm, a reaction device and a transfer device, wherein the feeding device is used for providing biochips to preset positions, the identification device is used for identifying the identification of the biochips at the preset positions and feeding back generated identification information to a control device, the mechanical arm is used for sorting the biochips at the preset positions to the corresponding accommodating parts under the control of the control device, the reaction device comprises a plurality of reaction containers, the plurality of accommodating parts comprise a plurality of first accommodating parts, the plurality of first accommodating parts respectively correspond to the plurality of reactors, the transfer device is used for transferring the biochips in the plurality of first accommodating parts to the plurality of reaction containers, the reaction containers can be switched between a reaction state position and a blanking state position, the reaction containers are used for carrying out synthesis reaction on the biochips in the reaction state position, and the reaction containers are used for transferring the biochips to the feeding device in the blanking state position. The invention also provides a synthesizer and a synthesizing method.
Description
Technical Field
The invention relates to biological macromolecule synthesis, in particular to a synthesis device, a synthesizer and a synthesis method for synthesizing biological macromolecules.
Background
Common biological macromolecules include proteins, nucleic acids (DNA, RNA, etc.), carbohydrates. Biological macromolecules are mostly polymerized from simple constituent structures, the constituent units of proteins are amino acids, and the constituent units of nucleic acids are nucleotides. The biomacromolecule can be synthesized in vivo by a simple structure. If the biomacromolecule is needed to be synthesized artificially, a special instrument, namely a synthesizer, is needed to synthesize the biomacromolecule.
Taking DNA synthesis as an example, DNA synthesis refers to a method of artificially ligating deoxynucleotides one by one in order of predetermined nucleotides to synthesize a DNA strand. For example, DNA single-stranded sequence CGTGCA … … is synthesized manually from left to right.
The existing synthesizer is to fix the single-stranded oligonucleotide on a glass synthesis column, then soak the synthesis column in a container, and then add various corresponding nucleotide reagents into the container to make the single-stranded oligonucleotide continuously extend according to the required sequence. However, the principle of synthesis by the synthesizer has complex process, low synthesis flux and large 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 foregoing, it is desirable to provide a synthesizer, synthesizer and synthesizing method that solve at least one of the above problems.
The utility model provides a synthesizer for synthesize biomacromolecule, includes feedway, recognition device, a plurality of holding piece, manipulator, reaction unit and transfer device, feedway is used for providing biochip to preset position, recognition device is used for discernment preset position's sign of biochip and feeds back to a controlling means with the sign information that generates, the manipulator is used for with the biochip that is located preset position is selected to corresponding holding piece under controlling means's control, reaction unit includes a plurality of reaction vessels, including a plurality of first holding piece in the plurality of holding pieces, a plurality of first holding piece corresponds with a plurality of reactors respectively, transfer device is used for transferring the biochip that is located in a plurality of first holding pieces to a plurality of reaction vessels, the reaction vessel can be between reaction state position and unloading state position, the reaction vessel is used for carrying out synthetic reaction to the biochip in the reaction state position, the reaction vessel is used for transferring the biochip in the reaction vessel to in the reaction vessel in unloading state position to the feedway.
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 is further used for transferring a biochip with all synthesis reactions completed from a preset position to one accommodating area under the control of the control device.
Further, the plurality of containers further comprises a third container, and the manipulator transfers the unidentifiable biochip from a 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 piece forms a through hole, and the opening and closing assembly 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 container.
Further, the opening and closing assembly comprises a shielding piece arranged at the bottoms of the first accommodating pieces and a first driving piece connected with the shielding piece, the shielding piece comprises a plurality of shielding parts, a plurality of shielding parts are respectively provided with a through hole at the same side in the arrangement direction, the first driving piece is used for driving the shielding piece to move in a first direction under the control of the control device so as to enable the shielding part to be staggered with the through holes to transfer the biological chips in the first accommodating pieces, and driving the shielding piece to move in the direction opposite to the first direction so as to enable the shielding part to shield the through holes again.
Further, the first accommodating part is fixed on the opening and closing component, the transferring device further comprises a conveying device fixedly connected with the opening and closing component, and the conveying device is used for driving the opening and closing component to move to the material rotation and displacement under the control of the control device so as to transfer the biochip in the first accommodating part to the reaction container, and driving the opening and closing component to move to the material receiving and delivering position so as to receive the biochip 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.
The synthesizer comprises the synthesizer, a control device for controlling the synthesizer, an input part and an output part which are connected with the control device, wherein the control device runs corresponding programs according to the content input from the input part to control the synthesizer, and relevant information is displayed on the output part.
A method of synthesis for synthesizing a biological macromolecule, comprising:
Identifying the identification of the biochip located 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 the biochip with all the synthesis reactions completed, controlling the manipulator to transfer the biochip from the predetermined position to a first container corresponding to the current synthesis reaction among a plurality of first containers corresponding to a plurality of reaction vessels for carrying out the synthesis reaction;
controlling the transfer device to transfer the biochips in the first containers to the reaction containers;
Controlling a reaction container to carry out synthesis 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 vessel to be switched to a blanking state position so as to transfer the biochip after the synthesis reaction to the preset position.
Further, when the biochip is a biochip in which all the synthesis reactions are completed, the control robot transfers the biochip from the predetermined position into a receiving area of the second receiving member including a plurality of receiving areas.
In the synthesizer and the synthesis method, the plurality of first accommodating parts and the plurality of reaction containers are mutually independent, and the reaction containers can carry out synthesis reaction while the biochip positioned at the preset position is transferred to the first accommodating parts through the manipulator, so that the cycle period of synthesis is reduced.
Drawings
FIG. 1 is a schematic diagram of the synthesis of DNA using a biochip with a tag according to the present invention.
FIG. 2 is a schematic view of the appearance of the synthesizer of the present invention.
Fig. 3 is a schematic diagram of the constituent elements 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 synthesizing apparatus in fig. 4.
Fig. 6 is a perspective view of the synthesizing device of fig. 5 at another angle.
Fig. 7 is a perspective view of the identification device and guide of fig. 5 removed.
Fig. 8 is an enlarged view of the feeding means in fig. 7.
Fig. 9 is a perspective view of an adsorption device of the robot of fig. 7.
FIG. 10 is a schematic view of the reaction vessel of FIG. 5 in a blanking state.
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 method of synthesizing an embodiment of the present invention.
Description of the main reference signs
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It will be understood that when an element is referred to as being "mounted" to another element, it can be directly on the other element or intervening elements may also be present. When an element is referred to as being "disposed on" another element, it can be directly on the other element or intervening elements 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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "or/and" as used herein includes any and all combinations of one or more of the associated listed items.
The synthesizer of the present invention can be used to synthesize biological macromolecules including, but not limited to, proteins, nucleic acids (DNA, RNA, etc.), carbohydrates, and the like. The carrier synthesized by the biomacromolecules is a biochip, and the biomacromolecules are fixed on the surface of the biochip and are continuously prolonged in a synthesizer according to the required sequence, so that the final required macromolecular structure is synthesized.
Referring to FIG. 1, for example, using a synthetic oligonucleotide primer, an oligonucleotide single strand 10 is immobilized on the surface of a biochip 20. A plurality of oligonucleotide single strands (two oligonucleotide single strands are shown) may be immobilized on the surface of the biochip 20. The oligonucleotide single strands are extended by the synthesizer according to the present invention according to a desired sequence. Before synthesis by the synthesizer of the present invention, a short oligonucleotide strand may be immobilized on the surface of the biochip 20, or a specific biological linker may be provided on the surface of the biochip 20, and the immobilized short oligonucleotide strand or the specific biological linker may be extended to obtain the desired oligonucleotide primer structure. The biochip 20 is further provided with a label 21, where the label 21 is shown in a hatched portion in the figure, and the label 21 is an identity mark 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, bar code, RFID tag or other existing means. In other embodiments, the identifier 21 may be disposed at other specific locations or at several other specific locations of the biochip 20.
Referring to FIGS. 2 to 4, the synthesizer 30 is used for synthesizing biomacromolecules, and in this embodiment, the synthesis of oligonucleotide primers is still described as an example. The synthesizer 30 includes a housing 31, a display 32 and an input member 33. In one embodiment, the display 32 and the input member 33 are integrated on a touch screen display. It will be appreciated that the input member 33 may also be provided separately from the display 32, including input devices such as a keyboard, mouse, etc. The synthesizer 30 further comprises reagent providing means 34, synthesizing means 35 placed inside said housing 31 and control means 36. The reagent supplying apparatus 34 is used for supplying a synthesis reagent to the synthesizing apparatus 35 for the biochip 20 to perform a synthesis reaction. The control device 36 is communicatively connected to the display 32, the input unit 33, the reagent supplying apparatus 34, and the synthesizing apparatus 35, and may be as large as one server, one host, or as small as one chip. The control device 36 is used for running corresponding programs according to the content input by the input part 33, controlling the synthesizing device 35 and the reagent providing device 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, and may be a local control device or a remote control device. The input unit 33 may set the synthesis reaction required for each biochip 20, define the abnormal characteristics (such as the unrecognizable mark) of the abnormal biochip 20, and the like. The housing 31 is also provided with at least one channel 37 communicating with the interior of the synthesizer 30, and the internal structure of the synthesizer 30 can be contacted through the channel 37, and the biochip 20 to be synthesized with the oligonucleotide primer can be placed in the same.
Referring to fig. 5 to 7, the synthesizing apparatus 35 includes a feeding device 351 for feeding a biochip, an identification device 352 for identifying the biochip, a plurality of receiving members 353 for receiving the biochip, a robot 354 for transferring the biochip to the receiving members 353, a reaction device 355 including a plurality of reaction vessels 3551, and a transfer device 356 for transferring the biochip from the receiving members 353 to the reaction vessels 3551.
Referring to fig. 7 and 8, the feeding device 351 is configured to receive a biochip and transfer the biochip to a predetermined location. The feeding device 351 further includes a vibration plate 3511 having a feed chute 35111 and a discharge opening (not shown) and a guide 3512. The guide 3512 is located outside the vibration plate 3511 and is communicated with the discharge port of the vibration plate 3511. A vibrating rail 35112 is disposed in the vibrating tray 3511, and the vibrating rail 35112 is used for orderly arranging the biochips entering the feeding trough 35111 and outputting the biochips to the guide 3512. The guide 3512 is formed with a downward inclined slide 35121, and the predetermined position is disposed at the end of the slide 35121, and the biochip output to the guide 3512 through the outlet slides along the slide 35121 to the predetermined position.
Referring to fig. 5 and 8, the identification device 352 is configured to identify the identification of the biochip at the predetermined location and feed back the generated identification information to the control device 36. The recognition device 352 includes an image capturing element 3521 and an image recognition element (not shown). The image capturing part 3521 is for capturing an image of a biochip at a predetermined position. The image recognition part is used for analyzing the image of the biochip and transmitting the identification information on the obtained biochip to the control device 36. It is understood that the image recognition unit may also be provided in the control device 36, and the image capturing unit 3521 transmits the captured image of the biochip to the control device 36, and the control device 36 recognizes the identifier on the biochip according to the image of the biochip to acquire the identifier information.
The recognition means 352 further includes a position recognition part 3522, and the position recognition part 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 device 36 controls the image capturing part 3521 to capture an image of the biochip according to the recognition result that the biochip has been moved to the predetermined position. Specifically, the slideway 35121 forms a plurality of detection holes 35122 at the predetermined positions, and the position identifying member 3522 includes a signal emitting member 35221 and a signal receiving member 35222 at both sides of the detection hole 35122. The signal emitting part 35221 is used for emitting a laser signal, and the laser signal is used for being emitted to the signal receiving part 35222 through the detection hole 35122. Since the detection hole 35122 will be shielded when the biochip moves to the detection hole 35122, the signal receiver 35222 will not receive the laser signal, and thus the signal receiver 35222 determines that the biochip moves to a predetermined position when the laser signal is not received. In contrast, the signal receiving part 35222 determines that the biochip is not moved to a predetermined position when the laser signal is received.
In another embodiment, the recognition device 352 does not include the position recognition part 3522, and when the recognition device 352 does not include the position recognition part 3522, the image capturing part 3521 continuously captures an image at a predetermined position, and the image recognition part judges whether the predetermined position includes a biochip and recognizes a mark on the biochip based on the continuously captured image.
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 plurality of first receiving parts 3531 are fixed to each other and disposed side by side, and are respectively matched with the plurality of reaction vessels 3551, for receiving 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 first containers 3531 correspond to the four reaction containers 3551, respectively. The four first receiving parts 3531 correspond to the four reaction vessels 3551, respectively. The second receiving part 3532 includes a plurality of receiving areas 35321 and the receiving area 35321 is used for receiving all biochips in which the synthesis reaction is completed. The third receiving part 3533 serves to receive a non-identifiable biochip.
The control device 36 determines whether the biochip is a biochip in which all synthesis reactions are completed or a biochip which cannot be recognized or a biochip in which synthesis sequence binding is not performed, based on the identification information of the current biochip and the synthesis sequence of each biochip. The control device 36 also determines the position information of the synthesis reaction currently being performed and the first housing part 3531 to which the current biochip is transferred when the current biochip is not a biochip in which all the synthesis reactions are completed, and transmits the transfer instruction including the position information to the robot 354 to control the robot 354 to transfer the biochip. The control device 36 also determines positional information of a receiving area 35321 in the second receptacle 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 positional information to the robot 354. The control device 36 also binds a synthesis sequence to the current biochip when the current biochip is a biochip for which synthesis sequence binding is not performed, so that the current biochip is a biochip for which all synthesis reactions are not completed, and correspondingly, transmits a corresponding transfer instruction to the robot 354 in the case where the biochip is a biochip for which all synthesis reactions are not completed as described above.
The manipulator 354 is configured to transfer the biochip located at the predetermined position to the corresponding first receiving member 3531 or second receiving member 3532 or third receiving member 3533 according to a transfer instruction sent by the control device 36.
Specifically, referring to fig. 7 and 9, the manipulator 354 includes a manipulator 3541 and an adsorption device 3542 fixed at the end of the manipulator 3541. The mechanical arm 3541 may be a multi-axis mechanical arm such as a four-axis mechanical arm or a six-axis mechanical arm. The mechanical arm 3541 is configured to drive the adsorbing device 3542 to move to the predetermined position to enable the adsorbing device 3542 to adsorb the biochip, and drive the adsorbing device 3542 to move above the first accommodating part 3531 to which the biochip is to be transferred to enable the adsorbing device 3542 to release the biochip from the corresponding first accommodating part 3531. The robot arm 3541 is also reset after the adsorption device 3542 releases the biochip to be transferred to the next biochip.
In one embodiment, the suction device 3542 includes a negative pressure suction nozzle 35421 and a negative pressure air supply 35422 connected to the negative pressure suction nozzle 35421. The control device 36 controls the negative pressure air supply device 35422 to be turned on to make the negative pressure suction nozzle 35421 suck the biochip at the predetermined position when the suction device 3542 moves to the predetermined position, and controls the negative pressure air supply device 35422 to be turned off to make the negative pressure suction nozzle 35421 release the biochip in the corresponding first container 3531 when the suction device 3542 moves to above the first container 3531 to which the sucked biochip should be transferred.
Referring to fig. 5 and 10, the reaction containers 3551 of the reaction device 355 correspond to the first containers 3531, and are used for performing a synthesis reaction or washing of the biochip from the first containers 3531, respectively. The synthesis reaction performed in each reaction vessel 3551 is different, and if the number of the reaction vessels 3551 is four, the synthesis reaction vessels are used for adenine (a), thymine (T), cytosine (C) and guanine (G) respectively.
Specifically, each reaction vessel 3551 includes a synthesis reaction column 35511 and a sealing cover 35512 that is openably and closably connected to the synthesis reaction column 35511. The sealing cap 35512 is used to seal the synthesis reaction column 35511 so that the biochip can complete the synthesis reaction. The sealing cap 35512 is used to insert a biochip into the synthesis reaction column 35511 when the synthesis reaction column 35511 is not covered. The reaction device 355 further comprises an opening and closing driving member 3552, wherein the opening and closing driving member 3552 is connected to the sealing cover 35512, and is used for driving the sealing cover 35512 to rise and fall so as to enable the sealing cover 35512 to leave or seal the synthetic reaction column 35511.
The plurality of reaction vessels 3551 may be switched between a material receiving position, a material reaction state position, and a blanking state position. The reaction vessel 3551 is positioned at the material receiving position for receiving the biochip in the first receptacle 3531 transferred by the transfer device 356. The reaction vessel 3551 is positioned at the reaction state position for receiving a synthesis reagent and performing a synthesis reaction. The reaction vessel 3551 is arranged at the discharging 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 the positioning body 3553 in parallel. The rotation driving assembly 3554 is configured to drive the positioning body 3553 to rotate around a first rotation direction by a preset angle according to a rotation command sent by the control device 36, and rotate around a direction opposite to the first rotation direction for resetting a preset time after the positioning body 3553 rotates around the preset angle. The control device 36 sends the rotation command to the rotation driving unit 3554 when the reaction device 355 completes the synthesis reaction. The position of the positioning body 3553 when rotating around the first rotating direction by a preset angle is the blanking state position, and the position of the positioning body 3553 when rotating around the direction opposite to the first rotating direction and resetting is the material reaction state position. The synthesis apparatus 35 further comprises a guide 357. One end of the guide 357 is opposite to the feeding device 351, and the other end is opposite to the reaction vessel 3551 when the reaction vessel 3551 rotates a preset angle about a first rotation direction, so as to guide the biochip poured out of the reaction vessel 3551 to the feeding device 351.
The vertical driving component 3556 is configured to drive the positioning body 3553, the reaction vessel 3551, and the horizontal driving component 3555 to move downward 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 vessel 3551 to move forward a predetermined horizontal distance when the reaction vessel 3551 moves to the second predetermined height according to the material receiving command sent by the control device 36, so that the reaction vessel 3551 is located at the material receiving position. In the material receiving position, the reaction vessel 3551 is located directly below the first receptacle 3531. Wherein the control device 36 sends the material receiving instruction when the first accommodating part 3531 is located at the material transferring 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 predetermined horizontal distance to withdraw the reaction vessel 3551 from below the first receiving member 3531 when the biochip is transferred from the first receiving member 3531 to the reaction vessel 3551, 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 from the second predetermined height to the first predetermined height to return the reaction vessel 3551 to the material reaction state position when the positioning body 3553 and the reaction vessel 3551 move backward by the predetermined horizontal distance.
Referring to fig. 7, 11, 12 and 13, the transferring device 356 is configured to transfer the biochips in the first receiving members 3531 to the reaction containers 3551 at the material receiving position under the control of the control device 36. In the process of transferring the biochip by the transfer device 356, the control device 36 controls the feeding device and the manipulator 354 to stop moving, and after the biochip is transferred, the feeding device and the manipulator 354 are started to move.
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 part 3531 forms a through hole 35311. The opening and closing assembly 3561 is used for shielding the bottom of the through hole 35311 to receive the biochip transferred by the robot 354, and opening 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 plate 35611 disposed at the bottom of the first receiving members 3531 and a first driving member 35612 connected to the shielding plate 35611. The shielding plate 35611 includes a plurality of shielding portions 356111, and a plurality of through holes 356112 are formed on the same side of the shielding portions 356111 in the arrangement direction. The shielding part 356111 serves to shield the through hole 35311 so that the biochip in the first receptacle 3531 can stay in the first receptacle 3531. The perforation 356112 is used to align with the through hole 35311 such that the biochip in the first receptacle 3531 is transferred through the through hole 35311 and the perforation 356112 to the reaction vessel 3551 at the material receiving location. The first driving member 35612 is used for driving the shielding plate 35611 to move in a first direction under the control of the control device 36 so that the shielding portion 356111 is staggered from the through hole 35311 and the through hole 356112 is aligned with the through hole 35311, so as to transfer the biochip in the first receiving member 3531. The first driving member 35612 is further configured to drive the shielding plate 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 include four first receiving members 3531, the shielding plate 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 aligned with the through holes 35311 of the three first receiving members 3531, and the shielding plate 35611 has a side edge serving as a fourth through hole 356112 for alignment with the through hole 35311 of the fourth first receiving member 3531.
The opening and closing assembly 3561 further comprises a first detecting member 35613, a second detecting member 35614, a first connecting member 35615, and a second connecting member 35616. The first detecting member 35613 and the second detecting member 35614 are fixed on the first connecting member 35615 and are arranged at intervals. The second connector 35616 is connected to the shielding 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 356151 and the second connector 35616 includes a slider (not shown) that mates with the slide 356151 and is slidably coupled to the slide 356151. The second connector 35616 includes a hanging blocking piece 356161, and the first driving member 35612 is used for driving the second connector 35616 to slide on the first connector 35615, so as to move the shielding piece 35611 and the blocking piece 356161. The first detecting element 35613 is configured to detect whether the blocking piece 356161 moves to a first preset position and transmit a detection result to the control device 36. The blocking piece 356161 is located at a first preset position in an initial state, and the shielding portion shields the through hole 35311 in the first preset position. When the control device 36 controls the transfer device 356 to transfer the biochip, the first driving member 35612 is controlled to drive the second connecting member 35616 to move towards the first direction, and the first driving member 35612 is controlled to stop driving the second connecting member 35616 to move towards the first direction according to the detection result sent by the second detecting member 35614 and detected that the baffle 356161 moves to the second preset position, at this time, the through hole 356112 is aligned with the through hole 35311, so that the biochip falls. 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 the detection result sent by the first detecting member 35613 and detected 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 receptacle 3531 to fall down.
In one embodiment, the first connecting member 35615 is also fixedly connected to the first receiving member 3531. Specifically, the second connector 35616 is connected above the shielding plate 356161 and forms a via 356162. The first connection member 35615 includes a first connection portion 356152 and a second connection portion 356153. The first detecting element 35613 and the second detecting element 35614 are fixed on the first connecting portion 356152, and the second connecting element 35616 is slidably connected to the first connecting portion 356152. The second connection part 356153 is disposed on the shielding plate 356161 through the via hole 356162. The second connection part 356153 includes a plurality of connection blocks 356154 arranged at intervals, a connection groove 35312 is formed between two adjacent first receiving parts 3531, the connection block 356154 is fixedly disposed in the connection groove 35312, and the through hole 35311 communicates with a space adjacent to the connection block 356154, so that the first receiving parts 3531 are opposite to the shielding plate 35611. In this embodiment, the second connecting portion 356153 includes three connecting pieces 356154, and the plurality of receiving pieces 353 includes four first receiving pieces 3531, wherein the through holes 35311 of two first receiving pieces 3531 are communicated with two gaps between the three connecting pieces 356154 such that the through holes 35311 are opposite to the shielding pieces 35611, and the other two first receiving pieces 3531 are located at opposite ends of the second connecting portion 356153 such that the through holes 35311 of the other two first receiving pieces 3531 are directly opposite to the shielding pieces 35611.
In one embodiment, as described above, the first receiving member 3531 is fixed to the opening/closing assembly 3561. The transfer device 356 further comprises a delivery device 3562 fixedly coupled to the opening and closing assembly 3561. The conveying device 3562 is configured to drive the opening and closing assembly 3561 to move according to a transfer instruction of the control device 36, so that the first accommodating part 3531 moves from the material receiving position to the material transferring position and from the material transferring position to the material receiving position. The first receiving member 3531 is configured to receive the biochip transferred by the robot 354 when the first receiving member is positioned at the material receiving position. The first receiving part 3531 is used for transferring the biochip in the first receiving part 3531 to the reaction vessel 3551 when the material is transferred. The control device 36 sends the transfer command when the number of the biochips in the first container 3531 reaches a preset number, and the transfer command includes driving the opening and closing component 3561 to move so that the first container 3531 is located at the material transfer position, and driving the opening and closing component 3561 to reversely move to the material receiving position when the material transfer position transfers the biochips in the first container 3531 to the reaction container 3551. In one embodiment, the preset number refers to the sum of all the biochips in the first container 3531, and in another embodiment, the preset number refers to the maximum number of biochips contained in the plurality of first containers 3531.
Specifically, the conveying device 3562 includes a track 35621 and a second driving member 35622. The opening and closing assembly 3561 is slidably coupled to the track 35621, and in particular, the first connector 35615 of the opening and closing assembly 3561 is slidably coupled to the track 35621 as described above. The material receiving and delivering position and the material transferring position are arranged at two different positions on the track 35621. The second driving member 35622 is connected to the opening and closing assembly 3561, specifically, the first connecting member 35615 of the opening and closing assembly 3561 as described above. The second driving member 35622 is configured to drive the opening and closing assembly 3561 to move back and forth along the track 35621 to move the first receiving member 3531 to a material receiving position or a material transferring position. The second driving member 35622 may be a linear cylinder.
Referring to fig. 14, fig. 14 is a flowchart of a method for synthesizing a biomacromolecule, wherein the method comprises the following steps.
Step S110: the identification of the biochip located at a predetermined position is recognized and corresponding identification information is generated.
Step S120: whether the biochip is a biochip in which all synthesis reactions are completed or a biochip which cannot be identified or a biochip in which synthesis sequence binding is not performed is determined according to the identification information of the current biochip and the synthesis sequence of each biochip.
When the biochip is not a biochip in which all the synthesis reactions are completed, proceeding 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 an unidentifiable biochip, the process proceeds to step S150; when the biochip is a biochip in which synthesis sequence binding is not performed, the process proceeds to step S160.
Step S130: the control robot 354 transfers 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 advances to step S170.
Step S140: the control robot 354 transfers the biochip from a predetermined position to a receiving area 35521 of the second receiving member 3532.
Step S150: the control robot 354 transfers the biochip from the predetermined position to the third receptacle 3533.
Step S160: bind a synthetic sequence to the biochip and proceed to step S130.
Step S170: the control transfer device 356 transfers the biochips in the plurality of first containers 3531 to the plurality of reaction vessels 3551.
Step S180: the reaction vessel 3551 is controlled to perform a synthesis reaction.
Step S190: the reaction vessel 3551 is controlled to be shifted to a discharging state position to transfer the biochip after the synthesis reaction is performed to the predetermined position, and returns to step S110 again, and the foregoing steps are repeated until all the synthesis reactions are completed by the biochip.
The plurality of first receiving parts 3531 and the plurality of reaction containers 3551 in the synthesizer 30 and the synthesizing method are independent of each other, and the reaction containers 3551 can perform a synthesizing reaction while the biochip located at a predetermined position is transferred to the first receiving parts 3531 by the manipulator 354, so that a synthesizing cycle period is reduced.
It will be appreciated by persons skilled in the art that the above embodiments have been provided for the purpose of illustrating the invention and are not to be construed as limiting the invention, and that suitable modifications and variations of the above embodiments are within the scope of the invention as claimed.
Claims (8)
1. The synthesis device is used for synthesizing biological macromolecules and is characterized by comprising a feeding device, an identification device, a plurality of accommodating parts, a manipulator, a reaction device and a transfer device, wherein the feeding device is used for providing a biochip to a preset position, the identification device is used for identifying the identification of the biochip at the preset position and feeding back the generated identification information to a control device, the manipulator is used for sorting the biochip at the preset position to the corresponding accommodating parts under the control of the control device, the reaction device comprises a plurality of reaction containers, and the plurality of accommodating parts comprise a plurality of first accommodating parts and second accommodating parts; the control device determines whether the biochip is a biochip with all synthesis reactions completed or a biochip without synthesis sequence binding according to the identification information of the current biochip and the synthesis sequence of each biochip; the manipulator transfers biochips, in which not all the synthesis reactions of the current biochips are completed, to the plurality of first accommodating pieces under the control of the control device; the transfer device is used for transferring the biochips in the first accommodating parts to a plurality of reaction vessels, the reaction vessels can be switched between a reaction state position and a blanking state position, the reaction vessels are used for carrying out synthesis reaction on the biochips in the reaction vessels in the reaction state position, and the reaction vessels are used for transferring the biochips in the reaction vessels to the feeding device in the blanking state position; the second accommodating part comprises a plurality of accommodating areas, and the manipulator transfers a biochip with all synthesis reactions completed from the preset position to one accommodating area under the control of the control device; and when the current biochip is a biochip which is not subjected to synthesis sequence binding, the control device binds a synthesis sequence to the current biochip, so that the current biochip becomes a biochip with all synthesis reactions not completed, and sends a corresponding transfer instruction to the manipulator.
2. The synthesizer of claim 1, further comprising a third receptacle, wherein the manipulator further transfers unidentifiable biochips from a predetermined location to the third receptacle under control of the controller.
3. The synthesizer of claim 1, wherein the transfer device comprises a shutter assembly, the first housing member defining a through-hole, the shutter assembly being adapted to conceal a bottom of the through-hole to receive the biochip transferred by the robot and to open the bottom of the through-hole to transfer the biochip to the reaction vessel.
4. The synthesizer of claim 3, wherein said opening and closing assembly comprises a shielding plate disposed at the bottoms of said first receiving parts and a first driving part connected to said shielding plate, said shielding plate comprises a plurality of shielding parts, each of which forms a perforation on the same side in the arrangement direction, said first driving part is used for driving said shielding plate to move in a first direction under the control of said control device so as to shift said shielding part from said perforation to transfer the biochip in the first receiving part, and driving said shielding plate to move in a direction opposite to said first direction so as to shield said perforation again.
5. The synthesizer of claim 3, wherein said first container is fixed to said opening and closing assembly, said transfer means further comprises a conveyor fixedly connected to said opening and closing assembly, said conveyor being adapted to drive said opening and closing assembly to a material transfer position under the control of said control means to transfer the biochips in the first container to said reaction vessel, and to drive said opening and closing assembly to a material pick-up position to receive the biochips transferred by the robot.
6. The synthesizing apparatus according to claim 1, wherein the identifying means includes a position identifying means for identifying whether the biochip is moved to the predetermined position, an image capturing means for capturing an image of the predetermined position when the biochip is moved to the predetermined position, and an image identifying means for analyzing the image of the biochip and acquiring identification information on the biochip.
7. A synthesizer according to any one of claims 1 to 6, comprising synthesizing means, control means for controlling said synthesizing means, input means for connecting said control means with output means, said control means running corresponding programs to control said synthesizing means in accordance with the content input from said input means, and displaying related information on said output means.
8. A synthesis method according to any one of claims 1 to 6, comprising:
Identifying the identification of the biochip located at a predetermined position and generating corresponding identification information;
determining whether the biochip is a biochip with all synthesis reactions completed 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 the biochip with all the synthesis reactions completed, controlling the manipulator to transfer the biochip from the predetermined position to a first container corresponding to the current synthesis reaction among a plurality of first containers corresponding to a plurality of reaction vessels for carrying out the synthesis reaction;
controlling the transfer device to transfer the biochips in the first containers to the reaction containers;
Controlling a reaction container to carry out synthesis reaction at a reaction state position, wherein the reaction container can be switched between the reaction state position and a blanking state position;
Controlling the reaction vessel to be switched to a blanking state position so as to transfer the biochip after the synthesis reaction to the preset position;
when the biochip is a biochip in which all the synthesis reactions are completed, controlling the robot to transfer the biochip from the predetermined position into a receiving area of a second receiving member including a plurality of receiving areas;
when the biochip is not bound with the synthesis sequence, binding a synthesis sequence to the biochip, and controlling the manipulator to transfer the biochip from the preset position to the corresponding first accommodating part.
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