CN111359555A

CN111359555A - Synthesizer, synthesizer and synthesizing method

Info

Publication number: CN111359555A
Application number: CN201811594008.XA
Authority: CN
Inventors: 张焕贵; 汪军; 胡书环; 黄小罗; 倪鸣; 沈玥; 徐讯; 汪建
Original assignee: BGI Shenzhen Co Ltd
Current assignee: BGI Shenzhen Co Ltd; Shenzhen BGI Life Science Research Institute
Priority date: 2018-12-25
Filing date: 2018-12-25
Publication date: 2020-07-03

Abstract

The invention provides a synthetic device for synthesizing biomacromolecules, which comprises a feeding device, an identification device, a reaction container group, a discharging device and a transfer device, wherein the identification device is used for identifying the identification of biochips and feeding back the identification to a control device, the feeding device is used for putting each biochip into a reaction container matched with the biochip in the reaction container group to carry out synthetic reaction under the control of the control device, the discharging device is used for transferring the biochips which are subjected to the synthetic reaction to the transfer device, and the transfer device is used for returning the biochips to the feeding device again. The invention also provides a synthesizer and a synthesis method. The invention has high synthesis flux and high flexibility and can save the dosage of reagents.

Description

Synthesizer, synthesizer and synthesizing method

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 biological macromolecules need to be artificially synthesized, the synthesis needs to be carried out 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 DNA single strand on glass synthesis column, then soaks the column in container, then adds various corresponding nucleotide reagents into the container, makes DNA single strand continuously extend according to the required sequence. However, such synthesizers have limited types of DNA that can be synthesized, low synthesis throughput, and large reagent consumption.

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.

In one aspect, the present invention provides a synthesis apparatus for synthesizing bio-macromolecules, the synthesis apparatus includes a feeding device, a recognition device, a reaction container group, a discharging device and a transfer device, the recognition device is configured to recognize an identifier of a biochip and feed the identifier back to a control device, the feeding device is configured to feed each biochip into a reaction container in the reaction container group matching the biochip to perform a synthesis reaction under the control of the control device, the discharging device is configured to transfer the biochips completing the synthesis reaction to the transfer device, and the transfer device is configured to return the biochips to the feeding device again.

Further, the feeding device is also used for putting the abnormal biological chips into the abnormal chip collecting points for collecting the abnormal biological chips and putting the biological chips which finish all the synthetic reaction processes into the finishing chip collecting points for collecting the biological chips which finish all the synthetic reaction processes under the control of the control device.

Furthermore, each reaction vessel in the reaction vessel group contains a plurality of biochips at the same time for carrying out the synthesis reaction, and the feeding device puts a plurality of biochips which need to carry out the same synthesis reaction into the same reaction vessel of the reaction vessel group under the control of the control device.

Furthermore, the feeding device comprises a sorting device and a feeding assembly, wherein a feeding position is arranged on the sorting device, and the sorting device moves or rotates under the control of the control device, so that the feeding position is used for loading the biochips to the pushing assembly and unloading the biochips to reaction containers matched with the biochips in the reaction container group.

Further, the feeding device comprises a plurality of feeding assemblies, wherein at least some of the feeding assemblies correspond to synthesis component positions, each synthesis component position corresponds to one of the reaction containers in the reaction container group, at least one of the feeding assemblies corresponds to the abnormal chip collection point, and at least another one of the feeding assemblies corresponds to the completed chip collection point.

In another aspect, the present invention further provides a synthesizer including the synthesizer described above, a controller for controlling the synthesizer, and an input unit and an output unit connected to the controller, wherein the controller runs a corresponding program according to a content input from the input unit to control the synthesizer, and displays related information on the output unit.

Further, the input means is used to set the synthesis reaction to be performed for each biochip.

In yet another aspect, the present invention also provides a synthetic method for synthesizing a biological macromolecule, the synthetic method comprising:

s1: identifying the identity of each biochip;

s2: and identifying the biochip which needs to be subjected to the synthetic reaction process according to the identification of each biochip, and putting the biochip which needs to be subjected to the synthetic reaction process into the corresponding reaction container for synthetic reaction.

Further, the synthesis method further comprises: s3: identifying the biochips which have completed all synthesis reaction processes according to the identification of each biochip, and putting the biochips which have completed all synthesis reaction processes into the completed chip collection points; s4: and identifying abnormal biochips according to the identification of each biochip and putting the abnormal biochips into abnormal chip collection points.

Further, the synthesis method further comprises: s5: the biochip on which the synthesis reaction has been completed is unloaded from the reaction vessel, and the aforementioned steps are repeatedly performed.

The synthesis device, the synthesis instrument and the synthesis method provided by the invention utilize the biological chips with the identity marks to carry out biological macromolecular synthesis, the marks of the biological chips can be recognized by the recognition device and are controlled by the control device to carry out a series of synthesis reactions, and each biological chip has the mark different from other biological chips, so each biological chip can synthesize a macromolecular sequence different from other biological chips, and when each component forming the macromolecular sequence is synthesized, each biological chip can share the same reaction container with other biological chips needing to synthesize the same component, and the synthesis reactions are respectively carried out in the reaction container, therefore, the synthesis instrument, the synthesis device and the synthesis method provided by the embodiment of the invention can realize various required synthesis processes, and have high flexibility; the biomacromolecule with different structures can be synthesized in batches, the synthesis flux is high, and in addition, the reagent dosage is greatly saved by the synthetic reaction in a batch soaking mode.

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 schematic perspective view of the synthesis apparatus of the present invention.

Fig. 5 is a perspective view of the combining device shown in fig. 4 from another angle.

Fig. 6 is a perspective view of a feeding device of the synthesizing device shown in fig. 3.

FIG. 7 is a schematic view of the loading device shown in FIG. 6, wherein the loading position and the pushing assembly are in butt joint for loading the biochip.

FIG. 8 is a schematic view of the loading position of the loading device shown in FIG. 6 and the loading assembly docking to unload the biochips.

FIG. 9 is a schematic perspective view of the synthesizer of FIG. 5 with the loading device removed.

FIG. 10 is a schematic diagram of the mechanism of the pouring-returning reaction vessel on the synthesis apparatus shown in FIG. 4.

FIG. 11 is a schematic view showing the operation direction of the transfer device of the synthesizing device shown in FIG. 4.

FIG. 12 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 macromolecule structure is synthesized.

Referring to FIG. 1, for the synthesis of DNA macromolecules, a single DNA strand 10 is fixed on the surface of a biochip 20, a plurality of single DNA strands (two single DNA strands are shown) can be fixed on the surface of the biochip 20, and the single DNA strands are extended by a synthesizer according to a desired sequence. Before the synthesis by the synthesizer of the present invention, a short segment of DNA short chain can be fixed on the surface of the biochip 20 in advance, or a specific linker can be arranged on the surface of the biochip 20, and the DNA short chain or the specific linker fixed in advance is continuously extended to finally obtain the required DNA macromolecular 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 fig. 2 and 3, the synthesizer 30 is used for synthesizing biological macromolecules, and in the present embodiment, the synthesis of DNA macromolecules is still exemplified. The synthesizer 30 includes a housing 31 and a display 32 secured to the housing. In addition, the housing 31 is also provided with corresponding structures or components for placing or accommodating the keyboard 331 and the mouse 332. The synthesizer 30 may be internally provided with a control device 34 communicating with the display 32, the keyboard 331 and the mouse 332, wherein the display 32 is used as an output component of the control device, and the keyboard 331 and the mouse 332 are used as input components of the control device 34. The control device 34 may be as large as one server, one host, or as small as one chip. The control device 34 runs a corresponding program according to the content input by the input unit, controls the synthesizer 35 provided in the synthesizer 30, and displays related information (such as abnormality information and completion information) on the output unit. The input unit may set the synthesis reaction to be performed for each biochip 20, define 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 36 communicating with the interior of the synthesizer 30, and the channel 36 can contact the internal structure of the synthesizer 30 and can be used for placing a biochip 20 and the like to be subjected to DNA macromolecule synthesis. In other embodiments, the control device 34 may be disposed outside the synthesizer 30, and may be a local control device or a remote control device.

Fig. 4-5 are schematic perspective views of a synthesizing device 35 according to an embodiment. The synthesizing device 35 includes a feeding device 351, a recognition device 352, a reaction vessel group 353, a discharging device 354 and a transfer device 355. Wherein the identification means 352 is used for identifying the identifier 21 of each biochip 20 and feeding back the identified identifier 21 to the control device 34, and the loading means 351 is used for loading each biochip 20 into the reaction vessel 3531 matched with the biochip 20 in the reaction vessel group 353 under the control of the control device 34. The reaction vessel bank 353 includes one or more reaction vessels 3531. Each biochip 20 is subjected to a corresponding reaction or washing in a corresponding reaction vessel 3531. The discharging device 354 serves to transfer the reacted/washed biochips 20 to the transferring device 355, and the transferring device 355 serves to return the biochips 20 to the feeding device 351 again.

Further, the loading device 351 is also used for feeding the abnormal biochips 20 and the biochips 20 having completed all the reaction processes to the abnormal chip collecting point for collecting the abnormal biochips 20 and the completed chip collecting point for collecting the biochips 20 having completed all the reaction processes, respectively, under the control of the control device 34.

In this embodiment, the synthesis device 35 further comprises a support frame 356, wherein the support frame 356 comprises a plurality of layers of support structures 3561, wherein the support structure 3561 of the previous layer is stacked on the support structure 3561 of the next layer, so that the synthesis device 35 has a longitudinal structure from top to bottom. The loading device 351 is disposed on the upper supporting structure 3561, the recognition device 352 is disposed at one side of the loading device 351, the reaction container group 353 is disposed on the lower supporting structure 3561, the unloading device 354 is disposed below the reaction container group 353, and the transfer device 355 is disposed at one side of the multi-layer supporting structure 3561 and includes a receiving portion 3551, a clamping portion 3552, and a transferring portion 3553. The container 3551 contains the biochip 20 transferred from the feeding device 354, the holder 3552 movably holds the container 3551 on the conveyor 3553, and the conveyor 3553 transports the container 3551 and the holder 3552 upward to the feeding device 351, so that the biochip 20 in the container is transferred to the feeding device 351. Further, the conveying unit 3553 also transports the accommodating unit 3551 and the clamping unit 3552 downward to the position of the feeding unit 354, so as to continuously receive the biochips 20 transferred from the feeding unit 354.

The feeding device 351 comprises a feeding device 3510, a vibrating disk 3511, a straight vibrating track 3512, a sorting device 3513 and a feeding assembly 3514. Feed arrangement 3510 leads biochip 20 to on the vibration dish 3511, vibration dish 3511 carries out the orderly arrangement back output to straight rail 3512 that shakes with biochip 20 of placing on it, straight rail 3512 one end that shakes links to each other with vibration dish 3511, and the other end links to each other with sorting unit 3513, straight rail 3512 that shakes drives biochip 20 and queues up and move from being close to vibration dish 3511 one end toward being close to sorting unit 3513 one end, straight rail 3512 that shakes sets up a material pushing component 3515 near the end of sorting unit 3513, through material pushing component 3515 shifts the biochip 20 of rearmost end to on the sorting unit 3513.

In this embodiment, the feeding device 3510 is an inclined guiding groove 3510a, which includes a lower end 3510b and a higher end 3510c, wherein the lower end 3510b is overlapped on the vibrating tray 3511, and the higher end 3510c is disposed near the transmitting portion 3553 of the transferring device 355 to engage with the receiving portion 3551 transmitted thereto by the transmitting portion 3553, so as to guide the biochip 20 in the receiving portion 3551 to the vibrating tray 3511 for the next reaction (for the biochips 20 that do not complete all reaction processes) or chip collection (for the abnormal biochips 20 or the biochips 20 that have completed all reaction processes). On the other hand, the feeding device 3510 is also located close to the channel 36, so that a user or other feeding device can feed the material from the outside of the synthesizer 30 to the synthesizer 35.

In the present embodiment, the vibration plate 3511 and the straight vibration rail 3512 are made of the prior art and will not be described in detail herein.

Referring to fig. 6, in the present embodiment, the sorting device 3513 is a disk-shaped rotating device, and a plurality of loading positions 3513a are disposed along an edge region of the disk-shaped rotating device, and each loading position 3513a can be abutted to the pushing assembly 3515 during the rotation of the sorting device 3513, so that the biochips 20 at the extreme end of the straight vibrating track 3512 are transferred to the loading position 3513a by the pushing assembly 3515.

Referring to fig. 7, in the present embodiment, a material pushing assembly 3515 is disposed at the end of the straight vibrating track 3512 and perpendicular to the straight vibrating track 3512, the material pushing assembly 3515 includes a material pushing member 3515a and a power member 3515b for pushing the material pushing member 3515a to extend out of the material pushing member and retract back, in the present embodiment, the power member 3515b is a cylinder, the power member 3515b is controlled by the control device 34, in the present embodiment, a sensor (not shown) for sensing a chip is disposed at the end of the straight vibrating track 3512, the sensor sends a sensing signal to the control device 34 after sensing the biochip 20, the control device 34 starts the power member 3515b to push the material pushing member 3515a to extend out of the material pushing member, and the material pushing member 3515a is retracted back after the material pushing member 3515a is completed.

Referring to fig. 6, in the present embodiment, a plurality of feeding assemblies 3514 are provided, and the plurality of feeding assemblies 3514 are disposed along the periphery of the sorting device 3513, wherein at least some of the feeding assemblies 3514 respectively correspond to a combination component position, each combination component position respectively corresponds to a reaction vessel 3531, and the other two feeding assemblies 3514 correspond to an abnormal chip collecting point and a completed chip collecting point. In this embodiment, the number of synthetic component positions is four, including an adenine (A) synthetic position, a thymine (T) synthetic position, a cytosine (C) synthetic position, and a guanine (G) synthetic position. In this embodiment, the reaction vessel group 353 includes at least four reaction vessels 3531, i.e., a first reaction vessel 3531a, a second reaction vessel 3531b, a third reaction vessel 3531c and a fourth reaction vessel 3531d (see fig. 9), wherein the lower portion of the feeding module 3514 corresponding to the adenine synthesis site is connected to the inlet of the first reaction vessel 3531a through a first conduit 3516a, the lower portion of the feeding module 3514 corresponding to the thymine synthesis site is connected to the inlet of the second reaction vessel 3531b through a second conduit 3516b, the lower portion of the feeding module 3514 corresponding to the cytosine synthesis site is connected to the third reaction vessel 3531c through a third conduit 3516c, and the lower portion of the feeding module 3514 corresponding to the guanine synthesis site is connected to the fourth reaction vessel 3531d through a fourth conduit 3516 d. Containers are respectively arranged below the two feeding assemblies 3514 corresponding to the abnormal chip collecting point and the completed chip collecting point, and are used for accommodating the dropped abnormal biochips 20 or the biochips 20 completing all reaction processes.

Under the control of the control device 34, the sorting device 3513 is sequentially driven to rotate, such that each loading position 3513a first docks the pusher assembly 3515 to load a biochip 20 at the loading position 3513 a. Thereafter, the sorting device 3513 is driven to rotate such that one of the loading levels 3513a is in a position that can be sensed by the recognition device 352, and the recognition device 352 recognizes the identity 21 of the biochip 20 at the loading level 3513 a. A plurality of loading positions 3513a are arranged on the sorting device 3513, and the sorting device 3513 rotates for a certain angle each time. In this embodiment, 12 feeding positions 3513a are provided on the sorting device 3513, and the sorting device 3513 rotates 30 ° every time (360 °/12 °), so that the next feeding position 3513a rotates to the position of the previous feeding position 3513a every time the sorting device 3513 rotates. Correspondingly, the pushing assemblies 3515, the recognition device 352 and the feeding assemblies 3514 are arranged in a circumferential array at a certain angle (30 °). For each rotation of the sorting device 3513, the control device 34 determines whether the biochip 20 at each loading position 3513a needs to be dropped at the current position, and if the biochip needs to be dropped, the corresponding loading assembly 3514 causes the biochip 20 to be dropped below the current position. The control device 34 can control the sorting device 3513 to rotate continuously according to the reaction or other treatment (such as abnormality or completion of all reaction processes) required by the biochip 20, so that the corresponding loading position 3513a is connected with a corresponding loading assembly 3514, specifically, for example, when the biochip 20 at the loading position 3513a needs to synthesize an adenine component, the control device 34 controls the sorting device 3513 to rotate, and when the loading position 3513a is connected with the loading assembly 3514 at the corresponding adenine synthesis position, the biochip 20 is dropped at the current position; when the biochip 20 at the loading position 3513a needs to synthesize a thymine component, the control device 34 controls the sorting device 3513 to rotate, and when the loading position 3513a is butted with the loading assembly 3514 corresponding to the thymine synthesizing position, the biochip 20 falls down at the current position; when the biochip 20 at the loading position 3513a needs to synthesize a cytosine component, the control device 34 controls the sorting device 3513 to rotate, and when the loading position 3513a is abutted to the loading assembly 3514 corresponding to the cytosine synthesis position, the biochip 20 is dropped at the current position; when the biochip 20 at the loading position 3513a needs to synthesize a guanine component, the control device 34 controls the sorting device 3513 to rotate, and when the loading position 3513a is abutted to the loading assembly 3514 corresponding to the guanine synthesis position, the biochip 20 falls at the current position; when the biochip 20 at the loading position 3513a is recognized as an abnormal biochip 20 by the control device 34, the control device 34 controls the sorting device 3513 to rotate, and when the loading position 3513a abuts against the loading module 3514 corresponding to an abnormal chip collecting point, the biochip 20 is dropped at the current position; when the biochip 20 at the loading position 3513a is recognized by the control unit 34 as a biochip 20 having completed all the reaction processes, the control unit 34 controls the sorting unit 3513 to rotate, and when the loading position 3513a abuts against the loading unit 3514 corresponding to the completed chip collecting point, the biochip 20 is dropped at the current position. In summary, the sorting apparatus 3513 is rotated all the time, and each time it is rotated by a certain angle, when the biochip 20 needs to be dropped at the current position, the loading assembly 3514 drops it, otherwise it will be transported to the next position. As to which biochip 20 the biochip 20 is placed at each loading position 3513a, whether the biochip needs to be dropped or not are recorded and judged by the control device 34.

It is understood that in other embodiments, the number of the loading levels 3513a can be set according to the requirement, for example, the loading levels 3513a can be one, when the loading levels 3513a are one, the identification device 352 only needs to identify the identifier 21 of the biochip 20 placed on the loading level 3513a, and the control device 34 only needs to control the loading level 3513a to be connected to the corresponding loading assembly 3514 according to the identifier 21 of the biochip.

Fig. 8 is a schematic perspective view of a material loading assembly 3514 abutting against a material loading position 3513 a. The loading position 3513a is provided with an accommodating space 3513b for accommodating the biochip, and specifically, in the present embodiment, the accommodating space 3513b is formed by the loading position 3513a being recessed downward and is a through hole. A movable support member 3513c is arranged below the accommodating space 3513b, the movable support member 3513c forms the bottom of the accommodating space 3513b and supports the biochip 20 placed in the accommodating space 3513b, and the movable support member 3513c can be pushed away from the accommodating space 3513b, so that the bottom of the accommodating space 3513b is hollowed out, and the biochip 20 falls into a corresponding conduit from the hollowed-out position and enters the corresponding reaction vessel 3531 through the conduit. The movable supporting member 3513c can be pushed to be repositioned to be placed under the accommodating space 3513b again, so as to hold the biochip 20 placed in the accommodating space 3513 b.

The feeding assembly 3514 includes a matching portion 3514a and a pushing portion 3514b, the matching portion 3514a and the movable support 3513c are matched to push the movable support 3513c back and forth, so that the movable support 3513c leaves from below the accommodating space 3513b or returns to below the accommodating space 3513 b. The pushing part 3514b pushes the fitting part 3514a to and fro under the driving of a power source 3514c to realize the reciprocating motion of the movable supporting part 3513 c. In the present embodiment, the power source is a cylinder that reciprocally pushes the push portion 3514b under the control of the control device 34.

Referring to fig. 9, the reaction container group 353 is disposed on the lower supporting structure 3561, and specifically, in the present embodiment, the reaction container group 353 includes a first layer of reaction containers 353a, a second layer of reaction containers 353b and a third layer of reaction containers 353 c. The first reaction vessel 353a includes a first reaction vessel 3531a, a second reaction vessel 3531b, a third reaction vessel 3531c and a fourth reaction vessel 3531 d. The second and

third reaction vessels

353b and 353c each comprise only one reaction vessel 3531. The second layer of reaction vessels 353b is located at a position higher than the third layer of reaction vessels 353c, and the first layer of reaction vessels 353a is located at a position higher than the second layer of reaction vessels 353 b. Each reaction vessel 3531 is provided with a port 3532 (see fig. 10) for introducing and discharging a reaction reagent, and the reaction reagent is introduced and discharged through the port 3532 in each reaction. Specifically, in this embodiment, the inlet/outlet 3532 is located at the bottom of the reaction vessel 3531, and the introduction and discharge of reagents for each reaction in each reaction vessel 3531 are controlled by the control device 34, so that the full-automatic control of the synthesis reaction is realized. After the reaction in any one of the reaction vessels 3531 of the first layer of reaction vessels 353a is completed, the reaction reagent in the reaction vessel 3531 is discharged, and the biochip 20 in the reaction vessel 3531 is discharged to a first collection device 357a and introduced into the second layer of reaction vessels 353b via the first collection device 357 a. After the reaction in the second layer of reaction vessels 353b is completed, the reagents in the second layer of reaction vessels 353b are discharged, and the biochips 20 in the second layer of reaction vessels 353b are discharged to a second collection device 357b and introduced into the third layer of reaction vessels 353c via the second collection device 357 b. After the reaction in the third reaction vessel 353c is completed, the reagent in the third reaction vessel 353c is discharged, and the biochip 20 in the third reaction vessel 353c is discharged to the loading unit 354 and introduced into the accommodating unit 3551 by the loading unit 354. In order to prevent the biochip 20 from entering a conduit for introducing or removing reagents, a filter is provided on the port 3532, or the diameter of the port 3532 is set to be smaller than the size of the biochip 20.

Fig. 10 is a perspective view of a tilting mechanism 358 connected to a reaction vessel. The dumping mechanism 358 includes a push-pull power source 3581, and the push-pull power source 3581 is a push-pull cylinder in this embodiment. One end of the push-pull power source 3581 is rotatably connected to the support bracket 356, and the other end is rotatably connected to a rotating member 3582 for holding the reaction vessel 3531. The rotating member 3582 is mounted on a fixed shaft 3583 and can rotate around the fixed shaft 3583. The fixed axle 3583 is then secured to the support bracket 356. The rotating member 3582 rotates around the fixed shaft 3583 during the process of being pushed and pulled by the push-pull power source 3581, so as to drive the reaction vessel 3531 to tilt or reset. The push-pull power source 3581 is also controlled by the control device 34, and the corresponding reaction vessel 3531 is tilted and reset under the control of the control device 34.

The feeding device 354 is an inclined guiding groove 3541, and includes a lower end 3542 and a higher end 3543, wherein the higher end 3543 is disposed corresponding to the position of the inlet of the third layer of reaction container 353c when the third layer of reaction container 353c is poured, so that the biochips in the third layer of reaction container 353c are poured into the feeding device 354 through the inlet, and the lower end 3542 is disposed near the transmission portion 3553 of the transfer device 355 to engage with the receiving portion 3551 transmitted thereto by the transmission portion 3553, so as to guide the biochips 20 into the receiving portion 3551.

Referring to FIG. 11, after the biochip 20 is received in the receiving portion 3551, the transporting portion 3553 transports the receiving portion 3551 to a position close to the feeding device 3510 under the control of the control device 34. In this embodiment, the conveying part 3553 includes a linear rail 3553a, and the accommodating part 3551 runs along the linear rail 3553a to a position close to the feeding device 3510. The clamping portion 3552 clamps the receiving portion 3551 to the conveying portion 3553 in a movable manner, which means that the receiving portion 3551 can be moved up and down along the conveying portion 3553 by the clamping portion 3552 and the receiving portion 3551 can be driven to tilt and reset in the present embodiment. The clamping unit 3552 includes a rotating unit 3552a for clamping the housing 3551, the rotating unit 3552a is fixedly mounted on a rotating shaft 3552b, the rotating shaft 3552b can be driven by a power device (not shown) to rotate, so that the power device can drive the housing 3551 to tilt and return under the control of the control unit 34, so as to pour the biochip 20 in the housing 3551 to the feeding unit 3510, and guide the biochip to the vibrating tray 3511 through the feeding unit 3510 for the next reaction or chip collection. It is understood that in the above embodiment, the receiving portion 3551 can move up and down along the transmission portion 3553, so that the clamping portion 3552 is slidably or rollably connected to the transmission portion 3553, and a power device (not shown) drives the clamping portion 3552 to move up and down along the transmission portion 3553. In another embodiment, the clamping portion 3552 and the transmitting portion 3553 are fixedly connected, that is, the clamping portion 3552 cannot slide or roll along the transmitting portion 3553, at this time, the transmitting portion 3553 drives the clamping portion 3552 to ascend and descend, and a power device (not shown) drives the transmitting portion 3553 to ascend and descend.

The working principle and the working flow of the synthesizer 30 and the synthesizer 35 thereof are described below with reference to the above embodiments. The following description will be made by taking the synthesis of DNA as an example, and the synthesizing apparatus 35 is provided with an adenine synthesis site, a thymine synthesis site, a cytosine synthesis site, a guanine synthesis site, and an abnormal chip collection point and a completed chip collection point. The adenine synthesis site is correspondingly connected with a first reaction vessel 3531a for synthesizing A base, the thymine synthesis site is correspondingly connected with a second reaction vessel 3531b for synthesizing T base, the cytosine synthesis site is correspondingly connected with a third reaction vessel 3531C for synthesizing C base, the guanine synthesis site is correspondingly connected with a fourth reaction vessel 3531d for synthesizing G base, the abnormal chip collection point is connected with a vessel for collecting abnormal biochip 20, and the chip collection point is connected with a vessel for collecting biochip 20 for completing all reaction processes.

It is assumed that a single DNA strand with the sequence TAGC … … is synthesized on the first biochip 20 and a single DNA strand with the sequence ATCG … … is synthesized on the second biochip 20.

A plurality of biochips 20 including a first biochip 20 and a second biochip 20 are guided onto a vibrating disk 3511 by a feeding device 3510, the first biochip 20 is fed to a feeding position 3513a by a pushing assembly 3515 through the integrated arrangement of the vibrating disk 3511 and a straight vibrating track 3512, a sorting device 3513 rotates to enable the first biochip 20 to be located at a position which can be identified by an identification device 352, and the identification device 352 identifies the identification of the first biochip 20. Meanwhile, the second biochip 20 is also fed to another loading position 3513a by the pusher assembly 3515, the sorting device 3513 continues to rotate, so that the identifier of the second biochip 20 is identified by the identification device 352, and the sorting device 3513 continues to rotate, loads the next biochip 20, and sequentially proceeds. Of course, the present invention does not require that all of the loading levels 3513a on the sorting apparatus 3513 be loaded with biochips 20. In fact, depending on the speed of the vibrating plate 3511 and the vibrating track 3512, it is possible to empty the individual feed positions 3513a, but this does not affect the operation of the synthesizer 35 and the synthesizer 30 of the present invention.

Since the first biochip 20 needs to synthesize T-base components in the first reaction, the loading position 3513a loaded with the first biochip 20 is switched to the thymine synthesis position, and the loading assembly 3514 corresponding to the thymine synthesis position is actuated to drop the first biochip 20 into the second reaction vessel 3531 b. At the same time, the second reaction vessel 3531b has been filled with a T base reagent.

Since the second biochip 20 needs to synthesize the A base component in the first reaction, the loading position 3513a loaded with the second biochip 20 is switched to the adenine synthesis position, and the loading assembly 3514 corresponding to the adenine synthesis position is started to move, so that the second biochip 20 falls into the first reaction vessel 3531 a. At the same time, the first reaction vessel 3531a has been filled with an A base reagent.

The base components to be synthesized in this round of the biochip 20 loaded by the sorting unit 3513 at the other loading position 3513a are transferred to the corresponding synthesis component position, and the biochip 20 is dropped into the corresponding reaction vessel 3531 of the first layer of reaction vessel 353 a.

After the biochip 20 is immersed in the corresponding reaction vessel 3531 for a period of time, the reaction vessel 3531 is replaced with other reagents as needed until the reaction preset in the reaction vessel 3531 is completed.

After the reaction is completed, the biochips 20 in the first layer of reaction container 353a are poured into the second layer of reaction container 353b in batches, the second layer of reaction container 353b is filled with/drained of the reagent, the biochips 20 are allowed to react in the second layer of reaction container 353b sufficiently, and then the biochips 20 are poured into the third layer of reaction container 353c in batches.

The third reaction container 353c is filled with/drained of reagents, and after the biochip 20 is allowed to react in the third reaction container 353c, the biochip 20 is poured into the holding part 3551 in batch.

The enclosure part 3551 is transferred to a position near the feeding device 3510 after collecting the biochips 20 of a predetermined number range/a predetermined weight range/a predetermined height range. The biochips 20 in the container 3551 are poured into the feeding device 3510 and enter a next reaction cycle in which a first biochip 20 synthesizes an a base component and a second biochip 20 synthesizes a T base component, so that the first biochip 20 is introduced into the first reaction vessel 3531a and the second biochip 20 is introduced into the second reaction vessel 3531 b.

This sequence of cycles is repeated, one base component being synthesized in each cycle, until each biochip 20 synthesizes the desired DNA sequence. After the final reaction, the synthesized biochip 20 is loaded into the loading unit 351 again from the container unit 3551, and is introduced into a container below the collection point of the completed biochip on the loading unit 351. The biochip 20 having an abnormality itself or having an abnormality during the reaction is introduced into the container below the abnormal chip collecting point on the loading device 351 after the biochip 20 identified as abnormal.

It should be noted that a plurality of biochips 20 can be simultaneously present in each reaction vessel 3531, and the plurality of biochips 20 are individually subjected to synthesis reactions in the same reaction vessel 3531. Since each biochip 20 has a label that is respectively distinguished from other biochips 20, each biochip 20 can be controlled by the control device 34 to be put into the corresponding reaction vessel 3531 according to the synthesis reaction to be performed in each round, and the corresponding reaction vessel 3531 is also controlled by the control device 34 to perform the injection and removal of the reaction reagent according to the synthesis reaction to be performed in each round. Of course, if the reagents are available in the reaction vessel 3531, there is no need to replace the reagents before each reaction. In the present application, a "synthesis reaction" refers to a series of reactions required to produce a product, should be understood to include pre-and post-steps, and should not be understood to include only a single step at the moment of synthesis.

In general, DNA single strand synthesis is carried out, and the following steps are required in each round: deprotection- > cleaning- > coupling- > cleaning- > capping- > cleaning- > oxidizing- > cleaning, in the above embodiment, the above steps of each round are performed in three layers of reaction vessels, such as deprotection, cleaning, coupling and cleaning in the first layer of reaction vessel 353a, capping and cleaning in the second layer of reaction vessel 353b, and oxidizing and cleaning in the third layer of reaction vessel 353 c. In other embodiments, the above steps can be distributed in other ways in the three-layer reaction vessel, such as performing deprotection and washing in the first layer reaction vessel 353a, performing coupling, washing, capping and washing in the second layer reaction vessel 353b, and performing oxidation and washing in the third layer reaction vessel; alternatively, deprotection and washing are performed in the first layer reaction vessel 353a, coupling and washing are performed in the second layer reaction vessel 353b, and oxidation, washing, capping, and washing are performed in the third layer reaction vessel 353 c. Of course, the above steps can also be divided into multiple reaction rounds. In other embodiments, the number of each layer of reaction vessels 3531 can be set according to the needs, for example, the number of the first layer of reaction vessels 353a can be more than four or less than four, and the number of the second layer of reaction vessels 353b and the third layer of reaction vessels 353c can be more than one. In addition, the number of reaction vessels 3531 may be set as needed, and the number of reaction vessels 3531 may be smaller than three or more than three, for example, only two reaction vessels 3531, only one reaction vessel 3531, or four reaction vessels 3531 may be provided.

As an extreme example, only one reaction vessel 3531 is provided in a layer, i.e., all reactions of all biochips 20 are performed in the reaction vessel 3531. Since each biochip 20 has the label 21, under the control of the control device 34, for example, the control device 34 controls the injection of reagents into the reaction vessel 3531 according to the synthesis reaction to be performed by the biochip 20 loaded into the loading position 3513a, for example, the control device controls the synthesis reaction to be performed according to the first biochip 20 loaded at the loading position 3513a, injecting corresponding reagents into the reaction vessel 3531 and simultaneously identifying the biochips 20 subsequently loaded at the loading position 3513a, if one or more of the biochips 20 are the same as the synthesis reaction to be performed by the first loaded biochip 20, the first biochip 20 and the other biochips 20 to be subjected to the same synthesis reaction are put into the reaction vessel 3531, all reactions required for this round are completed in the reaction vessel 3531, and the biochip 20 is introduced into the housing 3551 after all the reactions are completed. Then, the controller 34 puts a second batch of biochips 20 to be subjected to the same synthesis reaction into the reaction vessel 3531 according to the loading sequence of other biochips 20 loaded on the loading position 3513a, and the controller 34 controls the injection of the corresponding reagents into the reaction vessel 3531 according to the synthesis reaction to be performed in the second batch, so that the reactions of the third batch, the fourth batch, the nth (n is a natural number) batch … … and the subsequent second, third and nth (n is a natural number) batches … … are performed through one reaction vessel 3531 until all reaction processes of all the biochips 20 are completed.

It can be understood that when the number of layers of the reaction vessel 3531 is changed, the structure of the supporting frame 356 may be changed correspondingly, in addition, the structure of the supporting frame 356 may be set to be a transverse structure or other arrangement structure, the feeding device 351, the identifying device 352, the reaction vessel group 353, and the discharging device 354 are arranged appropriately according to the structure of the supporting frame 356, and the direction of the transferring device 355 may be set correspondingly according to the relative position relationship between the feeding device 351 and the discharging device 354.

It should be understood that although the above embodiments of the present invention only disclose the sorting device 3513 as a disk-shaped rotating device, the control device 34 controls the sorting device 3513 to rotate so that the loading position 3513a abuts against the pushing assembly 3515 and the loading assembly 3514. However, in other embodiments, the sorting device 3513 may have other shapes, and the control device 34 controls the sorting device 3513 to move along a straight line or a curve to enable the loading position 3513a to butt against the pushing assembly 3515 and the loading assembly 3514.

It should be understood that although the above embodiments of the present invention disclose a method of guiding the biochip 20 from the loading device 351 to the reaction vessel 3531, the loading assembly 3514 pushes the movable supporting member 3513c supporting the biochip 20, so that the biochip 20 falls from the hollow portion after the movable supporting member 3513c leaves, and is guided into the reaction vessel 3531 by the guide tube, in other embodiments, the method of guiding the biochip 20 from the loading device 351 to the reaction vessel 3531 may have many other methods, such as directly pushing the biochip 20 into the channel leading to the reaction vessel 3531 by the loading assembly 3514, for example, the guide tube.

It is understood that the above embodiments of the present invention disclose that the biochip 20 after the reaction is discharged out of the reaction vessel 3531 by pouring the reaction vessel 3531, but in other embodiments, the biochip 20 may be discharged out of the reaction vessel 3531 in many other ways, for example, by arranging a valve at the bottom of the reaction vessel 3531 and controlling the valve to open or close by the control device 34 to discharge the biochip 20 or to accommodate the biochip 20 in the reaction vessel 3531 for the reaction.

It is understood that the above embodiments of the present invention disclose two ways of pouring the reaction vessel 3531/containing part 3551 to extract the biochip 20, one way is to push and pull the rotating member 3582 holding the reaction vessel 3531 by the push-pull power source 3581, so that the rotating member 3582 drives the reaction vessel 3531 to rotate around the fixed shaft 3583 to pour the reaction vessel 3531; in another embodiment, the rotating shaft 3552b is rotated by a power device, the rotating member 3552a holding the accommodating portion 3551 is fixedly mounted on the rotating shaft 3552b, and the rotating shaft 3552b rotates to drive the rotating member 3552a to rotate so as to tilt the accommodating portion 3551. However, in other embodiments, the reaction vessel 3531/enclosure 3551 may be dumped in many other ways, such as by rotating the reaction vessel 3531/enclosure 3551 directly by a power plant without the use of an intermediate element such as a rotor.

It is understood that the sensing member may be provided to sense the amount of the biochip 20 within the housing 3551, such as sensing the weight, accumulated height, etc. of the biochip 20 within the housing 3551. In another embodiment, the sensing member may not be provided, and the control unit 34 may control the receiving unit 3551 to transfer to the feeding unit 3510 to reintroduce the biochip 20 into the feeding unit 351 after unloading the biochip 20 from the discharging unit 354 to the receiving unit 3551 is completed.

It is to be understood that the power unit, power device, power source and other power outputting units referred to in this specification may be a cylinder, a motor or other suitable power device. The power unit, the power device and the power source can all be controlled by the control device 34 to drive, stop or reversely drive the driven object, so as to realize the functions required by the synthesizer 30 and the synthesizer 35 of the present invention.

It can be understood that the main purpose of the present invention is to perform a synthesis of bio-macromolecules by using the biochip 20 with the identification mark 21, the identification mark 21 of the biochip 20 can be identified by the identification device 352 and controlled by the control device 34 to perform a series of synthesis reactions, each biochip 20 can synthesize a different macromolecule sequence from other biochips 20 because each biochip 20 has the identification mark 21 different from other biochips 20, and each biochip 20 can share the same reaction vessel 3531 with other biochips 20 that need to synthesize the same component when synthesizing each component constituting the macromolecule sequence, and each synthesis reaction is performed in the reaction vessel 3531, so that the synthesizer 30 and the synthesis device 35 provided in the embodiment of the present invention can realize various desired synthesis processes with high flexibility; the biomacromolecule with different structures can be synthesized in batches, the synthesis flux is high, and in addition, the synthetic reaction is carried out in a batch soaking mode, so that the reagent dosage is greatly saved.

FIG. 12 is a flow chart of a method for synthesizing a biological macromolecule, which includes the following steps. Step S1: an identifier 21 for identifying each biochip 20; step S2: identifying the biochip 20 to be subjected to the synthesis reaction process according to the identifier 21 of each biochip 20, and putting the biochip 20 to be subjected to the synthesis reaction process into the corresponding reaction vessel 3531 for synthesis reaction; step S3: identifying the biochips 20 which have completed all the synthetic reaction processes according to the identification 21 of each biochip 20, and putting the biochips 20 which have completed all the synthetic reaction processes into the completed chip collection points; step S4: identifying abnormal biochips 20 according to the identifier 21 of each biochip 20, and putting the abnormal biochips 20 into abnormal chip collection points; step S5: the biochips 20, for which the synthesis reaction is completed, are unloaded from the reaction vessel 3531, and the aforementioned steps S1-S5 are repeatedly performed until all the abnormal biochips 20 are put into the abnormal chip collecting point and all the normal biochips 20 complete all the reaction processes and are put into the completed chip collecting point. The sequence of the above steps S2-S4 can be changed, for example, S2- > S3- > S4, or S2- > S4- > S3, or S3- > S4- > S2, or S3- > S2- > S4, or S4- > S2- > S3, or S4- > S3- > S2.

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

1. A synthesis device is used for synthesizing biomacromolecules and is characterized by comprising a feeding device, a recognition device, a reaction container group, a discharging device and a transfer device, wherein the recognition device is used for recognizing the identification of biochips and feeding the identification back to a control device, the feeding device is used for throwing each biochip into a reaction container matched with the biochip in the reaction container group under the control of the control device to carry out synthesis reaction, the discharging device is used for transferring the biochips completing the synthesis reaction to the transfer device, and the transfer device is used for returning the biochips to the feeding device again.

2. The synthesizer according to claim 1, wherein the loading device is further adapted to put an abnormal biochip into an abnormal biochip collecting point where an abnormal biochip is collected and put a biochip having completed all synthesis reaction processes into a completed biochip collecting point where a biochip having completed all synthesis reaction processes is collected under the control of the controller.

3. The synthesizer according to claim 1, wherein each reaction vessel of the set of reaction vessels contains a plurality of biochips simultaneously for performing the synthesis reaction, and the feeding device feeds a plurality of biochips to be subjected to the same synthesis reaction into the same reaction vessel of the set of reaction vessels under the control of the control device.

4. The synthesizer according to claim 1, wherein the loading device comprises a sorting device and a loading assembly, the sorting device is provided with a loading position, and the sorting device moves or rotates under the control of the control device, so that the loading position loads the biochip to the pushing assembly and unloads the biochip to the reaction vessel matched with the biochip in the reaction vessel group.

5. The synthesis apparatus according to claim 2, wherein the feeding apparatus comprises a plurality of feeding units, at least some of the feeding units correspond to synthesis component positions, each synthesis component position corresponds to one of the reaction vessels in the reaction vessel group, at least one of the feeding units corresponds to the abnormal chip collecting point, and at least another one of the feeding units corresponds to the completed chip collecting point.

6. A synthesizer comprising the synthesizer according to any one of claims 1 to 5, 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 the content input from the input unit to control the synthesizer and displays the related information on the output unit.

7. The synthesizer according to claim 6, wherein the input means is for setting a synthesis reaction to be performed for each biochip.

8. A method of synthesis for synthesizing a biological macromolecule, comprising:

s1: identifying the identity of each biochip;

9. The method of synthesis of claim 8, further comprising: s3: identifying the biochips which have completed all synthesis reaction processes according to the identification of each biochip, and putting the biochips which have completed all synthesis reaction processes into the completed chip collection points; s4: and identifying abnormal biochips according to the identification of each biochip and putting the abnormal biochips into abnormal chip collection points.

10. The method of synthesis of claim 9, further comprising: s5: the biochip on which the synthesis reaction has been completed is unloaded from the reaction vessel, and the aforementioned steps are repeatedly performed.