CN110914403A

CN110914403A - DNA sample loading apparatus, gene sequencing system, and DNA sample loading method

Info

Publication number: CN110914403A
Application number: CN201780093168.3A
Authority: CN
Inventors: 倪鸣; 徐讯; 魏栋; 伍家波; 马炜; 唐建生
Original assignee: MGI Tech Co Ltd
Current assignee: MGI Tech Co Ltd
Priority date: 2017-08-01
Filing date: 2017-08-01
Publication date: 2020-03-24
Anticipated expiration: 2037-08-01
Also published as: WO2019023947A1; CN110914403B

Abstract

A DNA sample loading apparatus, a gene sequencing system and a DNA sample loading method. The DNA sample loading apparatus comprises: the loading device comprises a soaking module, the soaking module comprises a soaking container, and the soaking container is used for containing a chemical reagent for loading the DNA sample and soaking the biochip with the DNA sample loading structure on the surface in the chemical reagent; the temperature control device is used for controlling the temperature of the chemical reagent in the soaking container; the moving device is used for inserting or extracting the biochip into or from the soaking container. The DNA sample loading apparatus may load a DNA sample onto a biochip by immersing the biochip in a chemical reagent.

Description

DNA sample loading apparatus, gene sequencing system, and DNA sample loading method

Technical Field

The invention relates to the technical field of gene sequencing, in particular to DNA sample loading equipment, a gene sequencing system and a DNA sample loading method.

Background

In the prior art, DNA samples are loaded onto biochips (sequencing chips) prior to gene sequencing reactions. The DNA sample loading process is actually a process in which DNA molecules adhere to the surface of the biochip.

Chinese utility model patent CN205133580U provides a sequencing chip of current general use, and the chip is equipped with internal flow channel, and different chemical reagents pour into the runner from the entry, flow through behind the runner by the export discharge, no matter be the loading of DNA sample or sequence, all need implement above-mentioned process. The DNA sample is loaded (adhered) to the inner wall of the flow channel.

In the process of implementing the invention, the inventor finds that the sequencing chip and the DNA sample loading technology in the prior art have the following defects:

the chemical agent can only be used once, resulting in high operating costs.

The uneven flow velocity of the chemical reagent in the flow channel is easy to have corners where the chemical reagent can not flow, which causes uneven and insufficient chemical reaction, thereby causing uneven and unstable loading of the DNA sample.

And the flowing chemical reagent easily washes off the DNA molecules loaded on the chip surface.

The pressure generated by the chemical reagent in the flow channel is easy to cause the phenomenon of chip surface collapse, and the chip surface deformation will increase the error rate of DNA sequencing.

The available area of the chip is only the part in the flow channel, and other parts cannot be effectively utilized, so that the chip cannot be utilized to the maximum extent.

Disclosure of Invention

The invention aims to provide a DNA sample loading device, a gene sequencing system and a DNA sample loading method for loading a DNA sample by using a soaking mode.

The present invention provides in a first aspect a DNA sample loading apparatus comprising: the loading device comprises a soaking module, wherein the soaking module comprises a soaking container, and the soaking container is used for containing a chemical reagent for loading a DNA sample and soaking a biochip with a DNA sample loading structure on the surface in the chemical reagent; the temperature control device is used for controlling the temperature of the chemical reagent in the soaking container; a moving means for inserting or withdrawing the biochip into or from the soaking container.

Further, the steeping module comprises a plurality of the steeping containers; and/or the steeping container comprises a plurality of steeping spaces isolated from each other.

Further, the DNA sample loading device further comprises a supporting platform, the temperature control device is arranged on the supporting platform, and the loading device is arranged on the supporting platform through the temperature control device.

Further, temperature control device includes loading temperature control module, loading temperature control module includes loading temperature control portion and loading water bath, loading water bath is used for holding the liquid that can transfer heat, soak the container set up in the loading water bath, loading temperature control portion control the temperature of liquid in the loading water bath is in order to control soak the temperature of the interior chemical reagent of container.

Further, the loading device further comprises: the loading module is used for placing a biochip to be loaded with a DNA sample; and/or a blanking module, wherein the blanking module is used for placing the biochip loaded with the DNA sample.

Further, the loading module comprises a loading container for placing the biochip to be loaded with the DNA sample; and/or the blanking module comprises a blanking container for placing the biochip loaded with the DNA sample.

Further, the steeping container comprises an overflow port; and/or the feeding container comprises an overflow port; and/or the blanking container comprises an overflow opening.

Further, the mobile device is further configured to: inserting or withdrawing the biochip into or from the loading container; inserting or extracting the biochip into or from the baiting container.

Further, the temperature control device is also used for controlling the temperature of the feeding module; and/or the temperature control device is also used for controlling the temperature of the blanking module.

Further, the loading module comprises a loading container for placing a biochip to be loaded with a DNA sample, the temperature control device further comprises a loading temperature control module, the loading temperature control module comprises a loading temperature control part and a loading water bath, the loading water bath is used for containing liquid capable of transferring heat, the loading container is arranged in the loading water bath, and the loading temperature control part is used for controlling the temperature of the liquid in the loading water bath; and/or, the unloading module is including the unloading container that is used for placing the biochip of loading the DNA sample, temperature control device still includes unloading temperature control module, unloading temperature control module includes unloading temperature control portion and unloading water bath, unloading water bath is used for holding the liquid that can transfer the heat, the unloading container set up in the unloading water bath, unloading temperature control portion is used for control the temperature of the liquid in the unloading water bath.

Further, the moving device is used for moving the biochip and comprises a connecting part and a moving mechanism, wherein the connecting part is connected with the biochip, and the moving mechanism is in driving connection with the connecting part so as to change the working position of the connecting part.

Further, a plurality of the soaking containers are arranged along the transverse direction; the motion mechanism comprises a transverse moving shaft and a vertical moving shaft, the transverse moving shaft is arranged on the supporting platform, the vertical moving shaft is arranged on the transverse moving shaft, the connecting portion is arranged on the vertical moving shaft, the transverse moving shaft drives the vertical moving shaft to move transversely, and the vertical moving shaft drives the connecting portion to move vertically.

Further, the DNA sample loading apparatus further comprises a chip holding device including one or more chip mounting sites at which the biochip is mounted to move the biochip by moving the chip holding device.

Further, the double-sided surface of the biochip has the DNA sample loading structure; the chip mounting position comprises a chip mounting opening, the biological chip is mounted in the chip mounting opening, and the chip mounting opening is an opening with two open sides.

Further, chip fixing device includes the chip frame, be provided with on the chip frame the chip installation position, the surface of chip frame is hydrophobic surface and/or the lower extreme of chip frame is from last to tapering down gradually.

Further, the chip holding device comprises a frame clamp and one or more chip frames connected to the frame clamp, one or more chip mounting positions are arranged on the chip frames, and the moving device is connected with the frame clamp.

Further, the frame anchor clamps include fixed plate, clamp splice and locating pin, one or more the clamp splice set up in on the fixed plate, the clamp splice is equipped with at least one slot, chip frame one end insert in the slot, the clamp splice is in the cotter way has been seted up at the both ends of slot, chip frame be equipped with the opening that the cotter way corresponds, the locating pin insert locate in the cotter way with in the opening will chip frame fixed mounting in on the clamp splice, mobile device with the fixed plate is connected.

Further, the locating pin is provided with an inserting shaft, the chip frame is provided with a jack in the opening, and the inserting shaft is inserted into the jack.

Further, the frame fixture further comprises a bolt, the clamping block is arranged on two sides of the pin groove and provided with screw holes penetrating through the clamping block, the bolt is matched with the screw holes, the positioning pin is provided with through holes corresponding to the screw holes, the bolt penetrates through the fixing plate and is locked in the screw holes, and the bolt further penetrates through the through holes of the positioning pin.

Further, the DNA sample loading apparatus further comprises a control device, wherein the control device is coupled with the temperature control device to control the temperature of the chemical reagent; and/or, the control device is coupled with the moving device to control the soaking time and/or the soaking sequence of the biochips in the soaking container.

Further, the DNA sample loading apparatus includes the biochip, and a surface of the biochip has a loading structure for loading a DNA sample.

Further, the DNA sample loading apparatus further comprises a cover plate disposed above the loading device and having an orifice corresponding to the container orifice of the soaking container.

Further, the DNA sample loading device comprises a protection cover, and the loading device is covered in the protection cover.

In a second aspect, the present invention provides a gene sequencing system, comprising a DNA sample loading device and a gene sequencing reaction device, wherein the DNA sample loading device is the DNA sample loading device according to any one of the first aspect of the present invention.

The third aspect of the present invention provides a DNA sample loading method, comprising: adding a chemical reagent for loading the DNA sample into the soaking container; controlling the temperature of the chemical agent within the soak vessel; and soaking the biochip with the DNA sample loading structure on the surface in the chemical reagent for a period of time, and then taking out.

Further, the DNA sample loading method comprises: filling different chemical reagents for loading DNA samples into a plurality of soaking containers or a plurality of soaking spaces, and soaking the biochips in the plurality of soaking containers or the plurality of soaking spaces for preset time in sequence according to a preset sequence.

The loading device of the DNA sample loading equipment comprises a soaking module, wherein the soaking module comprises a soaking container, and the soaking container is used for containing a chemical reagent for loading a DNA sample and soaking a biochip with a DNA sample loading structure on the surface in the chemical reagent; the temperature control device is used for controlling the temperature of the chemical reagent in the soaking container; the moving device is used for inserting the biochip into the soaking container or extracting the biochip from the soaking container. The DNA sample loading apparatus may load a DNA sample onto a biochip by immersing the biochip in a chemical reagent.

Further, the DNA sample loading device of the invention can also realize at least one of the following technical effects: different chemical reagents are filled into different soaking containers or different soaking spaces of the soaking containers, and the biochip is soaked in different soaking containers or different soaking spaces, so that each link of loading the DNA sample can be completed. The chemical reagent can be reused, and the reagent cost is saved. The problem of uneven liquid flow rate does not exist in the process of chemical reaction, bubbles are not easily generated on the surface of the biochip, and the chemical reaction can be ensured to be more even and sufficient, so that a DNA sample can be more evenly and more stably loaded on the biochip. DNA molecules that have adhered to the biochip during the chemical reaction do not fall off by the chemical reagent. The biochip is uniformly heated by the liquid pressure in the soaking container, so that the phenomenon of surface collapse and deformation can not occur. The surface utilization rate of the biochip is maximized, and the throughput of loading the DNA sample can be improved.

The gene sequencing system and the DNA sample loading method of the present invention have similar technical effects to those of the DNA sample loading apparatus of the present invention.

Other features of the present invention and advantages thereof will become apparent from the following detailed description of exemplary embodiments thereof, which proceeds with reference to the accompanying drawings.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the invention without limiting the invention. In the drawings:

FIG. 1 is a schematic perspective view of a DNA sample loading apparatus according to an embodiment of the present invention;

FIG. 2 is a schematic perspective view of the DNA sample loading apparatus of FIG. 1 with the cover plate removed;

FIG. 3 is a schematic perspective view of another angle of the DNA sample loading apparatus shown in FIG. 1;

FIG. 4 is a schematic structural view of a chip holding device of the DNA sample loading apparatus shown in FIG. 1.

FIG. 5 is an exploded view of FIG. 4;

FIG. 6 is an exploded view of a frame clamp of the DNA sample loading apparatus shown in FIG. 1;

FIG. 7 is a schematic view of an exploded view of another angle of a frame clamp of the DNA sample loading apparatus shown in FIG. 1;

FIG. 8 is a schematic perspective view of a chip frame of the DNA sample loading apparatus shown in FIG. 1;

FIG. 9 is a schematic view of the structure of a chip frame of the DNA sample loading apparatus shown in FIG. 1, to which a biochip is not mounted, and the biochip;

FIG. 10 is a schematic perspective view of the dipping container of the DNA sample loading apparatus shown in FIG. 1.

In fig. 1 to 10, each reference numeral represents:

1. DNA sample loading equipment, 2, a biochip, 3, a loading device, 4, a temperature control device, 5, a moving device, 6, a clamping jaw, 7, a supporting platform, 8, a chip frame, 9, a frame clamp, 10, a clamping block, 11, a fixing plate, 12, a positioning pin, 13, a slot, 14, a pin slot, 15, an opening, 16, an inserting shaft, 17, an inserting hole, 18, a bolt, 19, a screw hole, 20, a through hole and 21, the device comprises a transverse moving shaft, 22, a vertical moving shaft, 23, a feeding module, 24, a soaking module, 25, a discharging module, 26, a control device, 27, notches, 28, grooves, 29, trundles, 30, a cover plate, 31, signal lamps, 32, round holes, 33, a chip mounting port, 301, a soaking container, 302, a feeding container, 303, a discharging container, 304, an overflow port, 401, a loading temperature control module, 402, a feeding temperature control module, 403 and a discharging temperature control module.

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. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. 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.

The relative arrangement of the components and steps, the numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless specifically stated otherwise. Meanwhile, it should be understood that the sizes of the respective portions shown in the drawings are not drawn in an actual proportional relationship for the convenience of description. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate. In all examples shown and discussed herein, any particular value should be construed as merely illustrative, and not limiting. Thus, other examples of the exemplary embodiments may have different values. It should be noted that: like reference numbers and letters refer to like items in the following figures, and thus, once an item is defined in one figure, further discussion thereof is not required in subsequent figures.

In the description of the present invention, it should be understood that the terms "first", "second", etc. are used to define the components, and are used only for the convenience of distinguishing the corresponding components, and if not otherwise stated, the terms have no special meaning, and thus, should not be construed as limiting the scope of the present invention.

In the description of the present invention, it is to be understood that the orientation or positional relationship indicated by the orientation words such as "front, rear, upper, lower, left, right", "lateral, vertical, horizontal" and "top, bottom", etc. are usually based on the orientation or positional relationship shown in the drawings, and are only for convenience of description and simplicity of description, and in the case of not making a reverse description, these orientation words do not indicate and imply that the device or element being referred to must have a specific orientation or be constructed and operated in a specific orientation, and therefore, should not be considered as limiting the scope of the present invention; the terms "inner and outer" refer to the inner and outer relative to the profile of the respective component itself.

The embodiment of the invention discloses a DNA sample loading device 1.

As shown in fig. 1 to 10, the DNA sample loading apparatus 1 mainly includes a loading device 3, a temperature control device 4, and a moving device 5. The loading device 3 comprises a soaking module 24, the soaking module 24 comprises a soaking container 301, and the soaking container 301 is used for containing a chemical reagent for loading a DNA sample and soaking the biochip 2 with a DNA loading structure on the surface in the chemical reagent; the temperature control device 4 is used for controlling the temperature of the chemical reagent in the soaking container 301; the moving means 5 is used to insert the biochip 2 into the soaking vessel 301 or to withdraw it from the soaking vessel 301.

The DNA sample loading apparatus 1 can load a DNA sample on the biochip 2 by immersing the biochip 2 in a chemical reagent.

The DNA sample loading device 1 can also achieve at least one of the following technical effects:

by filling different chemical reagents in different soaking containers 301 or different soaking spaces of the soaking containers and soaking the biochip 2 in different soaking containers 301 or soaking spaces, various links of DNA sample loading can be performed. The chemical reagent can be reused, and the reagent cost is saved. The problem of uneven liquid flow rate does not exist in the process of chemical reaction, bubbles are not easily generated on the surface of the biochip 2, and the chemical reaction can be ensured to be more even and sufficient, so that a DNA sample can be more evenly and more stably loaded on the biochip 2. DNA molecules that have adhered to the biochip 2 during the chemical reaction do not fall off by the chemical reagent. The biochip 2 is uniformly heated by the liquid pressure in the soaking container 301, so that the phenomenon of surface collapse and deformation can not occur. The surface utilization of the biochip 2 is maximized, and the throughput of loading the DNA sample can be improved.

The following describes an embodiment of the present invention in detail with reference to fig. 1 to 10.

As shown in fig. 1 to 3, the DNA sample loading apparatus 1 of the present embodiment includes a biochip 2, a loading device 3, a temperature control device 4, a moving device 5, a chip holding device, a support platform 7, and a control device 26.

Wherein, the biochip 2 is used for loading DNA samples and gene sequencing. The surface of the biochip 2 has a DNA sample loading structure. In this embodiment, the biochip 2 is a silicon wafer, and linkers capable of capturing DNA molecules are preset on both surfaces of the silicon wafer. DNA molecules can be captured by the joints after a series of chemical reactions, and finally adhere to the surface of the silicon wafer. The linker may be formed by modifying the surface of a silicon wafer with an amino group, for example.

The DNA sample referred to in this example may be a nanosphere molecule (nanoball) disclosed in US8445197B2, also referred to as DNB. The genome DNA is firstly subjected to fragmentation treatment, then an adaptor sequence is added, and the genome DNA is cyclized to form single-chain circular DNA, and then the single-chain circular DNA is amplified by 2-3 orders of magnitude by using a rolling circle amplification technology to form DNB.

As shown in fig. 1 to 3, the loading device 3 in this embodiment includes a soaking module 24, a feeding module 23, and a discharging module 25. The soaking module 24 is used to load a DNA sample on the biochip 2. The loading module 23 is used for placing the biochip 2 to be loaded with the DNA sample. The discharging module 25 is used for placing the biochip 2 loaded with the DNA sample.

As shown in fig. 1-3, the steeping module 24 comprises a plurality of steeping vessels 301. The soaking container 301 is used for containing chemical reagents for loading the DNA sample and soaking the biochip 2 in the chemical reagents, and the corresponding links for loading the DNA sample can be realized through a soaking mode. In this embodiment, steeping module 24 comprises a plurality of steeping vessels 301. The plurality of dipping containers 301 are used for holding different chemical reagents for loading the DNA samples, and the plurality of dipping containers 301 are arranged on the support platform 7.

The loading module 23 includes one or more loading containers 302 for placing the biochips 2 to be loaded with DNA samples. The loading container 302 contains chemical reagents for maintaining the activity of the biochemical substances of the biochip 2. The loading container 302 may be provided for temporarily placing a biochip to be subjected to DNA sample loading.

The blanking module 25 includes one or more blanking containers 303 for placing the biochips 2 loaded with DNA samples. The feeding container 303 contains chemical reagents for maintaining the biochemical activity of the biochip. The placement of the feeding container 303 can be used to temporarily place the biochip loaded with the DNA sample.

In this embodiment, the soaking vessel 301, the feeding vessel 302 and the discharging vessel 303 are all soaking cylinders with the same structure.

See fig. 1-3. The feeding module 23 includes 10 soaking cylinders, the 10 soaking cylinders are divided into 5 groups according to two groups, and the 5 groups of soaking cylinders are transversely arranged on the left section of the loading device 3. The soaking module 24 includes 16 soaking cylinders, the 16 soaking cylinders are divided into 8 groups according to two groups, and the 8 groups of soaking cylinders are transversely arranged on the right side of the loading module 23 and located in the middle section of the loading device 3. The blanking module 25 includes 10 soaking cylinders, the 10 soaking cylinders are divided into 5 groups according to two groups, and the 5 groups of soaking cylinders are transversely arranged on the right section of the loading device 3.

In this embodiment, in the soaking module 24, each set of soaking containers 301 is respectively filled with various reagents required for each step of loading DNA samples, so as to complete different DNA loading steps by soaking the biochips 2 in each set of soaking cylinders.

In other embodiments, not shown, the steeping container may also comprise a plurality of steeping spaces which may be arranged to place different chemical agents in groups. Of course, the steeping module 24 may also comprise a plurality of steeping containers, each of which comprises a plurality of steeping spaces. The chemical agents in the plurality of immersion spaces may be arranged the same (as a group) or different as desired.

The temperature control device 4 is arranged on the supporting platform 7, and the loading device 3 is arranged on the supporting platform 7 through the temperature control device 4.

In this embodiment, the temperature control device 4 includes a loading temperature control module 401, a loading temperature control module 402, and a discharging temperature control module 403. The load temperature control module 401 is used to control the temperature of the chemical agent in the infusion vessel 301. The loading temperature control module 402 is used to control the temperature of the chemical agent in the loading container 302 of the loading module 23. The blanking temperature control module 403 is used for controlling the temperature of the chemical reagent in the blanking module 25.

As shown in fig. 1 to 3, the loading temperature control module 401 includes a loading temperature control unit and a loading water bath, the loading water bath is used for containing liquid capable of transferring heat, the soaking container 301 is disposed in the loading water bath, and the loading temperature control unit controls the temperature of the liquid in the loading water bath, so as to control the temperature of the chemical reagent in the soaking container 301.

The feeding temperature control module 402 comprises a feeding temperature control part and a feeding water bath, the feeding water bath is used for containing liquid capable of transferring heat, the feeding container 302 is arranged in the feeding water bath, and the feeding temperature control part controls the temperature of the liquid in the feeding water bath so as to control the temperature of the chemical reagent in the feeding container 302.

The blanking temperature control module 403 includes a blanking temperature control portion and a blanking water bath, the blanking water bath is used for containing liquid capable of transferring heat, the blanking container 303 is disposed in the blanking water bath, and the blanking temperature control portion controls the temperature of the liquid in the blanking water bath, so as to control the temperature of the chemical reagent in the blanking container 303.

In the embodiment of the invention, a water bath is selected to carry out indirect temperature control on the soaking cylinder and the chemical reagent in the soaking cylinder, the water bath contains liquid capable of transferring heat, and the soaking cylinder is arranged in the corresponding water bath. Through inputting or outputting heat to the wall of the water bath kettle or to the liquid in the water bath kettle, the heat-conducting liquid in the water bath kettle can be heated or cooled along with the heat-conducting liquid, and the soaking cylinder is soaked in the heat-conducting liquid, so that the temperature of the chemical reagent in the soaking cylinder can be controlled. The liquid is used as a heat-conducting medium, so that the temperature of the chemical reagent in each soaking cylinder can be controlled more uniformly.

In other embodiments not shown, a temperature controller may be used to directly control the temperature of the soaking tank or the liquid therein, but the direct temperature control method is more likely to cause uneven cooling and heating than the indirect temperature control method using a water bath.

In this embodiment, the temperature control device 4 includes a loading temperature control module 401, a loading temperature control module 402, and a discharging temperature control module 403, and each temperature control module includes a temperature control unit and a water bath, so that the temperature of the loading module 23, the temperature of the soaking module 24, and the temperature of the discharging module 25 can be controlled respectively. Of course, if the three modules are not required to be controlled at different temperatures, the temperature control device 4 can uniformly control the temperature of the loading device 3, for example, each soaking tank in the three modules is disposed in the same water bath. Or even in the same module, different temperature control can be carried out on the soaking cylinders aiming at different loading links. For example, the loading temperature control module 401 may include more than two loading temperature control sections and corresponding more than two loading water bathtubs, and the infusion containers 301 with different temperature requirements may be placed in different bathtubs.

Preferably, at least one of the soaking container 301, the feeding container 302 and the discharging container 303 may include an overflow port. Taking the steeping vessel 301 as an example, as shown in fig. 10, the steeping cylinder as the steeping vessel 301 includes an overflow port 304. When the liquid in the soaking cylinder exceeds a certain water level, the liquid overflows from the overflow port 304, so that the liquid level in the soaking cylinder can be prevented from being ultrahigh.

It should be noted that although the feeding module 23 includes the feeding container 302 and the discharging module 25 includes the discharging container 302 in this embodiment, the specific modes of the feeding module 23 and the discharging module 25 may be different in other embodiments not shown in the drawings. Even the feeding module 23 and the discharging module 25 are not necessary. For example, after the biochip 2 is mounted on the chip holder, it can be directly placed in the soaking container 301 corresponding to the first step of loading DNA without passing through the loading module 23. For another example, after the biochip is loaded with the DNA sample, it can be directly sent to a gene sequencing device for gene sequencing reaction without passing through the blanking module 25.

In this embodiment, the moving device 5 is used for moving the biochip 2 to insert the biochip 2 into the soaking container 301 or to withdraw the biochip 2 from the soaking container 301; the moving device 5 may also be used to move the biochip 2 to insert the biochip 2 into the loading container 302 or to withdraw the biochip 2 from the loading container 302; the moving device 5 may also be used to move the biochip 2 to insert the biochip 2 into the baiting container 303 or to withdraw the biochip 2 from the baiting container 303. Therefore, the moving device 5 of the present embodiment can move the biochips 2 in one soaking cylinder of any one of the loading module 23, the soaking module 24, and the unloading module 25 of the loading device 3 to another soaking cylinder of the same module or a different module.

In this embodiment, the biochip 2 to be loaded with the DNA sample may be placed in the loading container 302 of the loading module 23 by another external moving device, or the biochip 2 may be manually placed in the loading container 302. Likewise, the biochips 2 loaded with DNA samples can be removed by another moving means from the outside, or the biochips 2 can be removed manually.

The arrangement of the moving device 5 can improve the automation degree of the DNA loading device 1, reduce the error rate caused by manual operation, and accurately control the soaking sequence and the soaking time by matching with the control device 26, thereby being beneficial to realizing the loading work of the DNA sample with high quality.

In the present embodiment, the moving device 5 includes a connection portion for connecting with the biochip 2 and a moving mechanism drivingly connected with the connection portion to change the working position of the connection portion. The moving means 5 may be mounted on the supporting platform 7, or may be mounted on other supports, as long as the function of connecting and moving the biochip 2 is achieved.

The connecting portion in this embodiment includes a holding jaw 6 for holding the biochip 2.

As shown in fig. 1 to 3, in the present embodiment, a plurality of feeding containers 302, a plurality of soaking containers 301, and a plurality of discharging containers 303 are arranged in the lateral direction. The moving mechanism of the moving device 5 comprises a transverse moving shaft 21 and a vertical moving shaft 22, the transverse moving shaft 21 is arranged on the supporting platform 7, the vertical moving shaft 22 is arranged on the transverse moving shaft 21, and the connecting part is arranged on the vertical moving shaft 22. The transverse moving shaft 21 drives the vertical moving shaft 22 to move transversely, and the vertical moving shaft 22 drives the connecting part to move vertically.

Since the plurality of dipping cylinders of each module of the loading unit 3 are arranged along the transverse moving axis 21 and the holding jaw 6 is suspended above the dipping cylinders, it is possible to put the biochip 2 into any one of the dipping cylinders or to extract the biochip 2 from any one of the dipping cylinders.

In other illustrated embodiments, the movement mechanism may take other forms, for example, the movement mechanism may also cause the connecting portion to perform a three-dimensional movement. In addition, the soaking cylinders can be arranged in a ring shape, and in this case, the moving mechanism can comprise a rotating function. The connection portion may also be in other forms, such as a vacuum chuck, an electromagnetic chuck, etc. that cooperate with a chip holding device for holding the biochip 2.

In addition, although the movement of the biochip 2 between different soaking cylinders is realized by moving the biochip 2 through the moving mechanism and the connecting portion in the present embodiment, in other embodiments not shown, the change of the positional relationship between the biochip and the loading device may be realized by moving the loading device alone or by moving the loading device and the biochip at the same time.

The chip holding device is used for fixing the biochip 2, so that the biochip 2 moves along with the chip holding device. The chip holding means includes one or more chip mounting sites for mounting the biochip 2, and the moving means 5 moves the biochip 2 mounted on the chip mounting sites by controlling the position of the chip holding means.

The provision of the chip holding means can reduce contamination caused by direct handling of the biochips on the one hand, and can simultaneously move the plurality of biochips 2 by the chip holding means as needed and maintain the plurality of biochips 2 at predetermined intervals on the other hand, thereby improving the throughput of the biochips 2.

In this embodiment, the clamping jaws 6 of the moving device 5 indirectly clamp the biochip 2 by the chip holding device to achieve the connection between the moving device and the biochip 2. The indirect clamping of the biochip 2 prevents the clamping jaw 6 from clamping different biochips 2 and then causing cross contamination.

Of course, in other embodiments not shown, the moving device and the biochip may be connected in such a way that the clamping jaws directly clamp the biochip.

As shown in fig. 4 and 5, the chip holding apparatus includes a frame jig 9 and four chip frames 8 connected to the frame jig 9. Each chip frame 8 is provided with a chip mounting location. The frame jig 9 is used in connection with the moving device 5 to move the biochip 2. In this embodiment, in other embodiments not shown, more or fewer chip frames 8 may be connected to each frame clamp 9, and two or more chip mounting positions may be provided on each chip frame 8.

In this embodiment, the double-sided surface of the biochip 2 has a DNA sample loading structure. As shown in FIGS. 4, 5 and 8, the chip mounting site includes a chip mounting opening 33, the biochip 2 is mounted in the chip mounting opening 33, and the chip mounting opening 33 is a through opening with both sides opened. This arrangement can increase the number of DNA sample molecules loaded on the single biochip 2.

As shown in fig. 4 to 7, the frame jig 9 includes a fixing plate 11, a clamp block 10, and a positioning pin 12. Two clamping blocks 10 are arranged on the fixing plate 11 side by side. The clamping block 10 is provided with two slots 13, one end of the chip frame 8 is inserted into one slot 13, the clamping block 10 is provided with pin grooves 14 at two ends of the slot 13, the chip frame 8 is provided with openings 15 corresponding to the pin grooves 14, the positioning pins 12 are inserted into the pin grooves 14 and the openings 15 to fixedly mount the chip frame 8 on the clamping block 10, and the moving device 5 is used for being connected with the fixing plate 11 to move the biochip 2.

When the positioning pins 12 are inserted into the pin grooves 14, since the openings 15 of the chip frame 8 are aligned with the pin grooves 14, the positioning pins 12 are also inserted into the openings 15, and the chip frame 8 is fixedly mounted on the clamping block 10.

To facilitate removal of the locating pin 12, a notch 27 may be formed at one end of the pin slot 14 to facilitate prying off of the locating pin 12.

As shown in fig. 4 to 7, in the present embodiment, two sides of each clamping block 10 are respectively provided with a pin slot 14 and a corresponding positioning pin 12. In other embodiments, not shown, the pin groove 14 may be formed only on one side of the clamp block 10, and the slot 13 may be formed to be engaged with the other side opening 15 of the chip frame 8, so that the chip frame 8 can be fixed by inserting the positioning pin 12 only on one side. This structure makes it very convenient to load and unload the chip frame 8.

In addition, in order to facilitate the positioning of the positioning pins 12 relative to the clamping blocks 10 and to more firmly connect the chip frame 8 and the clamping blocks 10, as shown in fig. 6 and 7, the positioning pins 12 are provided with insertion shafts 16, the chip frame 8 is provided with insertion holes 17 in the openings 15, and the insertion shafts 16 are inserted into the insertion holes 17.

In order to securely connect the chip frame 8 with the clamping blocks 10, the positioning pins 12 and the fixing plate 11, the frame clamp 9 further comprises bolts 18. Screw holes 19 penetrating through the clamping block 10 are formed in the clamping block 10 on two sides of the pin groove 14, and the bolts 18 are matched with the screw holes 19. The positioning pin 12 is provided with a through hole 20 corresponding to the screw hole 19. The bolt 18 is locked in the screw hole 19 through the fixing plate 11. The bolt 18 also passes through a through hole 20 of the locating pin 12. Therefore, the positioning pin 12 is fixed in the pin groove 14 by the bolt 18 and does not fall off due to vibration.

In addition, the fixing plate 11 may be provided with a groove 28 for the clamping jaw 6 to be clamped into, so as to clamp the fixing plate 11 more firmly.

In addition, the chip frame 8 is transferred between different soaking cylinders, and in order to reduce cross contamination between different chemical reagents as much as possible, the chip frame 8 is generally transferred to the next soaking cylinder after residual liquid on the surface of the chip frame 8 is dripped out. In order to increase the liquid dripping speed on the surface of the chip frame 8, as shown in fig. 8 and 9, in the present embodiment, the lower end of the chip frame 8 is tapered from top to bottom. In an alternative embodiment, the surface of the chip frame 8 may be provided as a hydrophobic surface. It is of course also possible to make the surface of the chip frame 8 a hydrophobic surface while the chip frame 8 has a lower end which tapers from top to bottom, so that a more rapid dripping of the chemical agent is achieved.

The frame jig 9 in this embodiment includes two clamping blocks 10, each clamping block 10 is provided with two insertion grooves 13, each insertion groove 13 can be inserted into one chip frame 8, and thus 4 chip frames 8 can be mounted on one frame jig 9. In other words, the moving device 5 is connected to one frame jig 9, and four biochips 2 can be moved simultaneously by moving the frame jig 9. Of course, more or less clamping blocks 10 can be arranged on the frame clamp 9 according to actual needs, more or less slots 13 are arranged on each clamping block 10, and the more clamping blocks 10 and slots 13, the more biochips 2 can be clamped and transferred at one time.

A control device 26 is provided on the support platform 7 for controlling and monitoring the operation of the DNA sample loading apparatus 1. In this embodiment, the control device 26 is coupled to the temperature control device 4 to control the temperature of each module of the loading device 3, such as the temperature of the chemical reagent in the soaking container 301. The control means 26 are also coupled with the moving means 5 to control the soaking sequence and/or the soaking time of the biochips 2 inside the soaking vessel 301.

The process of loading the DNA sample can be completely open if environmental conditions permit, for example, operation in a sterile environment. However, in many cases, the process of loading the DNA sample needs to be performed in a closed environment in order to avoid external interference, and therefore, the DNA sample loading apparatus 1 preferably includes a protective cover in which the loading device 3 is located. This provides a closed environment for the DNA sample loading process. The moving device 5 may be optionally disposed in the protective cover or not disposed therein as required.

The support platform 7 may be a support plate or a cabinet. As shown in fig. 1 to 3, the support platform 7 in this embodiment is a cabinet. The cabinet can store and contain reagents, tools and the like required by gene sequencing. In order to facilitate the movement of the DNA sample loading apparatus 1, casters 29 are installed under the cabinet.

As shown in FIGS. 1 to 3, in this embodiment, a signal lamp 31 may be added to the DNA sample loading apparatus 1 for alarming when an abnormality occurs in the DNA sample loading apparatus 1.

In order to reinforce the mounting of the soaking cylinder, facilitate the placement of the chip holding device, and prevent foreign matters from falling into the water bath, the loading device 3 is further provided with a cover plate 30. The cover 30 is provided with openings corresponding to the container openings of the soaking container 301, the feeding container 302 and the discharging container 303.

In this embodiment, each set of soaking containers 301 is filled with a chemical reagent for loading a DNA sample, the mobile device 5 holds the biochip 2 and soaks the biochip 2 in one soaking container 301 for a period of time, and then transfers the biochip 2 to the next set of soaking containers 301 and soaks for a period of time, and the process is repeated. The biochip 2 can be loaded with DNA sample molecules on the biochip 2 after being soaked in the plurality of soaking containers 301. The process of immersing the biochip 2 in the chemical reagent is actually a process of generating a chemical reaction. The temperature control device 4 is capable of producing a suitable temperature for the chemical reaction.

The embodiment also provides a gene sequencing system, which comprises a DNA sample loading device and a gene sequencing reaction device, wherein the DNA sample loading device is the DNA sample loading device 1.

The present embodiment also provides a DNA sample loading method, including: adding a chemical reagent for loading the DNA sample into the soaking container 301; controlling the temperature of the chemical reagent within the soak vessel 301; the biochip 2 having the DNA sample loading structure on the surface is immersed in a chemical reagent for a certain period of time and then taken out.

Wherein, different chemical reagents for loading DNA samples are filled in the plurality of soaking containers 301, and the biochips 2 are sequentially soaked in the plurality of soaking containers 301 for a predetermined time in a predetermined order.

The operation of the DNA sample loading apparatus 1 of the present embodiment will be briefly described below with reference to FIGS. 1 to 3:

1. in an initial state, required chemical reagents are contained in soaking cylinders of modules of the loading device 3, water baths of the temperature control device 4 are adjusted to proper temperatures, all the biochips 2 to be loaded with DNA samples are mounted on the chip frames 8, and all the chip frames 8 are mounted on the frame clamps 9; the frame jig 9 with the chip frames 8 mounted thereon is placed on the cover plate 30 above the loading module 23, and the chip frames 8 are each inserted into each of the loading containers 302 of the loading module 23 through the opening in the cover plate.

2. The gripper 6 grips the frame gripper 9 closest to the soaking module 24, i.e. the last frame gripper 9 in the loading module 23, transfers and inserts its chip frame 8 into the closest soaking container 301, i.e. the first soaking container 301 in the soaking module 24, and allows the biochip 2 to soak in the corresponding soaking container 301 for a certain time.

3. The gripper fingers 6 displace the penultimate frame gripper 9 of the loading module 23 so that its chip frame 8 is inserted into the last loading receptacle 302 of the loading module 23, in which way the frame grippers 9 of the loading module 23 are displaced one position to the right in succession.

4. After the first group of biochips 2 in the soaking module 24 is soaked, the frame holder 9 is moved to the second soaking container 301 of the soaking module 24, and the previous frame holder 9 is moved to the right side by one position according to the above manner.

5. And (3) continuously circulating the steps 2-4, and after the group of biochips 2 mounted on the same chip holding device are respectively soaked in all the soaking containers 301 of the soaking module 24, transferring the chip holding device and the group of biochips 2 thereon to a discharging container 303 of a discharging module 25.

6. And continuously circulating the steps 2-5.

Thus, the biochips 2 can be soaked in each soaking container 301 by transferring them from left to right one by one.

It should be understood that the above steps are only one of the working processes that the DNA sample loading device 1 can perform, and do not represent that it can only perform these steps, nor do it limit the scope of the present invention.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.

Claims

A DNA sample loading device (1), characterized by comprising:

the loading device (3) comprises a soaking module (24), the soaking module (24) comprises a soaking container (301), and the soaking container (301) is used for containing a chemical reagent for loading the DNA sample and soaking the biochip (2) with a DNA sample loading structure on the surface in the chemical reagent;

-temperature control means (4) for controlling the temperature of said chemical agent inside said infusion container (301);

-moving means for inserting the biochip (2) into the soaking vessel (301) or for extracting it from the soaking vessel (301).
The DNA sample loading apparatus (1) according to claim 1, wherein said soaking module (24) comprises a plurality of said soaking containers (301); and/or the steeping container comprises a plurality of steeping spaces isolated from each other.
The DNA sample loading device (1) according to claim 2, characterized in that the DNA sample loading device (1) further comprises a support platform (7), the temperature control means (4) being arranged on the support platform (7), the loading means (3) being arranged on the support platform (7) by means of the temperature control means (4).
The DNA sample loading apparatus (1) according to claim 1, wherein the temperature control device (4) comprises a loading temperature control module (401), the loading temperature control module (401) comprises a loading temperature control part and a loading water bath, the loading water bath is used for containing liquid capable of transferring heat, the soaking container (301) is disposed in the loading water bath, and the loading temperature control part controls the temperature of the liquid in the loading water bath to control the temperature of the chemical reagent in the soaking container (301).
The DNA sample loading device (1) according to claim 1, characterized in that said loading means (3) further comprises:

a loading module (23), wherein the loading module (23) is used for placing a biochip (2) to be loaded with a DNA sample; and/or the presence of a gas in the gas,

a blanking module (25), wherein the blanking module (25) is used for placing the biochip (2) loaded with the DNA sample.
The DNA sample loading device (1) according to claim 5,

the loading module (23) comprises a loading container (302) for placing a biochip (2) to be loaded with a DNA sample; and/or the presence of a gas in the gas,

the blanking module (25) comprises a blanking container (303) for placing the biochip (2) loaded with the DNA sample.
The DNA sample loading device (1) according to claim 6, characterized in that said soaking vessel (301) comprises an overflow (304); and/or the feed vessel (302) comprises an overflow; and/or the blanking container (303) comprises an overflow opening.
The DNA sample loading device (1) according to claim 6, characterized in that said moving means are also adapted to:

inserting the biochip (2) into the loading container (302) or extracting the biochip from the loading container (302);

inserting the biochip (2) into the baiting container (303) or extracting the biochip from the baiting container (303).
The DNA sample loading device (1) according to claim 5, wherein the temperature control means (4) is further configured to control the temperature of the loading module (23); and/or the temperature control device (4) is also used for controlling the temperature of the blanking module (25).
The DNA sample loading device (1) according to claim 9,

the feeding module (23) comprises a feeding container (302) for placing a biochip (2) to be loaded with a DNA sample, the temperature control device (4) further comprises a feeding temperature control module (402), the feeding temperature control module (402) comprises a feeding temperature control part and a feeding water bath, the feeding water bath is used for containing liquid capable of transferring heat, the feeding container (302) is arranged in the feeding water bath, and the feeding temperature control part is used for controlling the temperature of the liquid in the feeding water bath; and/or the presence of a gas in the gas,

unloading module (25) is including unloading container (303) that is used for placing biochip (2) of loading DNA sample, temperature control device (4) still includes unloading temperature control module (403), unloading temperature control module (403) are including unloading temperature control portion and unloading water bath, unloading water bath is used for holding the liquid that can transfer heat, unloading container (303) set up in the unloading water bath, unloading temperature control portion is used for control the temperature of the liquid in the unloading water bath.
The DNA sample loading device (1) according to any one of claims 1 to 10, wherein the moving means (5) is for moving the biochip (2), comprising a connection portion for connecting with the biochip (2) and a movement mechanism drivingly connected with the connection portion to change the working position of the connection portion.
The DNA sample loading device (1) according to claim 11, characterized in that a plurality of said soaking containers (301) are arranged in a transverse direction; the motion mechanism comprises a transverse moving shaft (21) and a vertical moving shaft (22), the transverse moving shaft (21) is arranged on the supporting platform (7), the vertical moving shaft (22) is arranged on the transverse moving shaft (21), the connecting part is arranged on the vertical moving shaft (22), the transverse moving shaft (21) drives the vertical moving shaft (22) to move transversely, and the vertical moving shaft (22) drives the connecting part to move vertically.
The DNA sample loading device (1) according to any one of claims 1 to 10, characterized in that the DNA sample loading device (1) further comprises a chip holding means comprising one or more chip mounting sites at which the biochip (2) is mounted to move the biochip (2) by moving the chip holding means.
The DNA sample loading device (1) according to claim 13, characterized in that the double-sided surface of the biochip (2) has the DNA sample loading structure; the chip mounting position comprises a chip mounting opening (33), the biological chip (2) is mounted in the chip mounting opening (33), and the chip mounting opening (33) is an opening with two open sides.
The DNA sample loading apparatus (1) according to claim 13, wherein the chip holding device comprises a chip frame (8), the chip mounting site is disposed on the chip frame (8), the surface of the chip frame (8) is a hydrophobic surface and/or the lower end of the chip frame (8) is tapered from top to bottom.
The DNA sample loading apparatus (1) according to claim 13, wherein said chip holding means comprises a frame clamp (9) and one or more chip frames (8) connected to said frame clamp (9), said chip frames (8) having one or more chip mounting sites provided thereon, and said moving means (5) is connected to said frame clamp (9).
The DNA sample loading apparatus (1) according to claim 16, wherein the frame fixture (9) comprises a fixing plate (11), clamping blocks (10) and positioning pins (12), one or more clamping blocks (10) are disposed on the fixing plate (11), the clamping blocks (10) are provided with at least one slot (13), one end of the chip frame (8) is inserted into the slot (13), the clamping blocks (10) are provided with pin grooves (14) at two ends of the slot (13), the chip frame (8) is provided with openings (15) corresponding to the pin grooves (14), the positioning pins (12) are inserted into the pin grooves (14) and the openings (15) to fixedly mount the chip frame (8) on the clamping blocks (10), and the moving device (5) is connected to the fixing plate (11).
The DNA sample loading device (1) according to claim 17, characterized in that the positioning pin (12) is provided with an insertion shaft (16), the chip frame (8) is provided with a receptacle (17) in the opening (15), and the insertion shaft (16) is inserted in the receptacle (17).
The DNA sample loading device (1) according to claim 17, wherein the frame clamp (9) further comprises a bolt (18), the clamping block (10) is provided with a screw hole (19) penetrating through the clamping block (10) at both sides of the pin slot (14), the bolt (18) is adapted to the screw hole (19), the positioning pin (12) is provided with a through hole (20) corresponding to the screw hole (19), the bolt (18) is locked in the screw hole (19) through the fixing plate (11), and the bolt (18) further penetrates through the through hole (20) of the positioning pin (12).
The DNA sample loading device (1) according to any one of claims 1 to 10, wherein said DNA sample loading device (1) further comprises a control means (26), wherein,

the control device (26) is coupled with the temperature control device (4) to control the temperature of the chemical reagent; and/or the presence of a gas in the gas,

the control means (26) are coupled with the moving means (5) to control the soaking time and/or the soaking sequence of the biochips (2) within the soaking vessel (301).
The DNA sample loading device (1) according to any one of claims 1 to 10, characterized in that the DNA sample loading device (1) comprises the biochip (2), the surface of the biochip (2) having loading structures for loading DNA samples.
The DNA sample loading device (1) according to any one of claims 1 to 10, characterized in that the DNA sample loading device (1) further comprises a cover plate (30), the cover plate (30) being disposed above the loading means (3) and having an aperture corresponding to the receptacle aperture of the soaking receptacle (301).
The DNA sample loading device (1) according to any one of claims 1 to 10, characterized in that the DNA sample loading device (1) comprises a protective cover, inside which the loading means (3) is housed.
A gene sequencing system comprising a DNA sample loading device and a gene sequencing reaction device, characterized in that the DNA sample loading device is a DNA sample loading device (1) according to any one of claims 1 to 23.
A DNA sample loading method, characterized in that it comprises:

adding a chemical reagent for loading the DNA sample into the soaking container (301);

controlling the temperature of the chemical agent within the infusion container (301);

and (3) soaking the biochip (2) with the DNA sample loading structure on the surface in the chemical reagent for a period of time and then taking out.
The DNA sample loading method of claim 25, wherein the DNA sample loading method comprises: filling different chemical reagents for loading DNA samples into a plurality of soaking containers (301) or a plurality of soaking spaces, and soaking the biochips (2) in the plurality of soaking containers (301) or the plurality of soaking spaces for a preset time in sequence according to a preset sequence.