WO2020034143A1 - Handle device, positioning device, loading device and gene sequencer - Google Patents

Abstract

Provided is a handle device (100) for assisting a bare chip to perform a biochemical reaction, wherein a chip slot (110) is provided at a middle section of the device for the mounting of a bare chip (300), a sealed slot (120) is provided in the chip slot (110) for fixed connection of the bare chip (300), a vacuum slot (130) is provided on an inner side of the sealed slot (120), the vacuum slot (130) is in communication with the outside for suctioning the bare chip (300) under negative pressure, and a positioning slot is provided at a side of the chip slot (110) for positioning during delivery. The handle device (100) and the bare chip (300) can be applied, as a set, to a gene sequencing system, achieving a large reaction flux, a high re-utilization rate, improved utilization of a sequencing area, reduced material and manufacturing costs, convenient operation, a high degree of automation, and a good testing efficiency.

Description

Handle device, positioning device, loading device and gene sequencer Technical field

The invention relates to the technical field of gene sequencing equipment, in particular to a handle device for a sequencing chip and a positioning device thereof, and a gene sequencer.

Background technique

This section is intended to provide a background or context to the embodiments of the invention that are set forth in the claims. The description herein is not admitted to be prior art by inclusion in this section.

The second-generation sequencing technology is based on the development of the first-generation Sanger sequencing technology and has the characteristics of low cost, high throughput, and automation. It is applied to whole genome sequencing, transcriptome sequencing, and metagenomic sequencing. The low cost and high throughput are An important direction for its future development. The current sequencing chip is usually used after the entire 8-inch chip is subjected to secondary cutting and special process packaging. The raw materials are wasted, and the sequencing area of the chip cannot be maximized. The chip needs to be cut and packaged. Increasing the production process of the chip, and at the same time each package requires auxiliary materials such as cover glass, which is costly, and the gap between the cover glass and the chip is usually controlled at the micron or even nanometer level. The consistency of the thickness of the sealed cavity formed is difficult to control and affects Efficiency and effect of fluid loading; not only that, the chip can only be positioned by the chip itself during chip transportation and information collection, which is easy to damage the chip. Therefore, there is a need to develop a sequencing system and auxiliary equipment that indirectly carry bare chips for gene molecule loading, reagent synthesis, and information collection.

Summary of the Invention

In view of the above, it is necessary to provide an improved handle device that can carry a bare chip for biochemical reactions and improve the utilization of sequencing area; and can indirectly transport the chip to ensure the security of the chip; secondly, provide a supporting positioning device, It is used for positioning of the chip and the handle device during assembly, ensuring the relative position of the two, and improving the efficiency and accuracy of assembly and transportation. Finally, a genetic sequencer using bare chip testing is provided.

The technical solution provided by the present invention is: a handle device for assisting a bare chip to perform a biochemical reaction, a chip slot is provided in the middle of the device to install the bare chip, and a sealing slot is provided inside the chip slot to fixedly connect the chip slot For a bare chip, a vacuum groove is provided on the inner side of the sealing groove, and the vacuum groove is communicated with the outside to adsorb the bare chip with a negative pressure. A positioning groove is provided on the side of the chip groove for positioning during the transportation process.

Further, the reaction surface and edge of the bare chip do not touch the reagent tank.

Further, the outside of the chip slot is a clamping portion and a limiting portion, and a middle portion of the limiting portion extends out of the positioning portion toward the chip slot. The clamping portion, the limiting portion, and the positioning The part is engaged with the bare chip.

Further, a plurality of conductive internal channels are opened between the clamping portion and the vacuum tank.

Further, a plurality of conductive internal channels are opened between the limiting portion and the vacuum tank.

Further, the handle device opens a plurality of conductive internal channels between an outer side wall between the limiting portion and the vacuum tank and the vacuum tank.

Further, the sealing groove is adhesively connected to the bare chip.

Further, the clamping portion is provided with a plurality of mounting holes for mounting to other equipment.

The invention also provides a positioning device for assembling and positioning the handle device and a bare chip, including a base, and a plurality of convex portions, sliders and fastening portions provided on the base, wherein the slider is located Above the side of the clamping portion, the convex portion and the fastening portion are enclosed outside the chip groove and the stopper portion, and the convex portion and the slider that are in contact with the stopper portion An end protrusion surrounds the outside of the bare chip.

Further, the fastening portions are provided outside the same side wall of the handle device, and each of the fastening portions includes a fastener and penetrates from the inside of the fastener and abuts the side wall of the handle device The pin is threadedly assembled with the pin.

Further, the sliders are respectively provided with limiting blocks on both sides of the moving direction to restrain the displacement of the slider, and a slide groove is provided on the base for installing a slide rail that cooperates with the slider.

The present invention also provides a loading device for loading gene molecules on the surface of a bare chip. The device includes a bottom plate and a cover plate, and a groove is provided on the bottom plate to fix the handle device with a negative pressure on the bare chip. The bottom surface of the cover plate facing the bare chip is provided with a second sealing groove and a flow channel groove, the second sealing groove is bonded to the bare chip to form a cavity, and the flow channel groove or the second sealing groove is opened for liquid inlet. And outlet.

Further, each of the second sealing grooves is fan-shaped and encloses a circle; the flow channel groove is located inside the edge of the second sealing groove.

Further, an adhesive is fixed on the edge of the second sealing groove, and the adhesive is adhered to the bare chip.

The invention further provides a gene sequencer, comprising a manipulator, a liquid exchange system, a bare chip, and the handle device carrying the bare chip. The manipulator is connected to the clamping portion for transporting the bare chip into Biochemical reactions are performed in several reagent tanks of the liquid exchange system. The top of each reagent tank is open, and the side wall is provided with an extension that cooperates with the positioning tank for the handle device, the bare Chip limit.

Further, the bottom of the reagent tank and a side wall remote from the handle device are not in contact with the bare chip.

Compared with the prior art, the present invention provides a handle device for assisting a bare chip to perform a biochemical reaction. A chip slot is provided in the middle of the device to install the bare chip, and a sealing slot is provided inside the chip slot to fix Connect the bare chip, a vacuum groove is opened inside the sealed groove, the vacuum groove is communicated with the outside to suck the bare chip with negative pressure, and a positioning groove is provided at the side of the chip groove for positioning during the transportation process. The handle device can be used in a gene sequencing system with a bare chip, which has a high repetition rate, improves the utilization rate of the sequencing area, and reduces material and manufacturing costs. In combination with the positioning device of the present invention, the assembly relationship between each bare chip and the handle device is highly repeatable and reproducible, and the coordination relationship is good. In combination with the loading device of the present invention, gene molecules can be directly loaded on each bare chip. Applied to the gene sequencer, on the one hand, the sequencing throughput is large and the sequencing accuracy is high; on the other hand, the operation is convenient, the degree of automation is high, and the test efficiency is good.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

FIG. 1 is a schematic structural diagram of a part of a gene sequencer of the present invention.

FIG. 2 is a schematic diagram of the handle device shown in FIG. 1.

Fig. 3 is a sectional view of the handle device shown in Fig. 2 at the IV-IV position.

FIG. 4 is a combined view of a positioning device, a handle device, and a bare chip according to the present invention.

FIG. 5 is an exploded view of the overall structure shown in FIG. 4.

FIG. 6 is an assembly diagram of a loading device, a handle device, and a bare chip according to an embodiment of the present invention.

FIG. 7 is a schematic view of the structure shown in FIG. 6 from another angle.

FIG. 8 is a schematic structural diagram of a reagent tank shown in FIG. 1.

Reference sign description:

Handle device	100
Chip slot	110
the seal groove	120
Vacuum tank	130
Positioning slot	170
Clamping section	150
Limiting Department	140
aisle	160
Mounting holes	151
Positioning Department	141
Positioning means	200
Base	220
Convex	221
Slider	210
Fastening section	225
Raised	211
fastener	2252

Pin	2251
Limit block	222, 223
Slide rail	224
Bare chip	300
Gene sequencer	500
Manipulator	510
Reagent tank	520
Protrusion	521
Loading device	400
Cover	410
Floor	420
Runner groove	412
Second seal slot	411
Inlet	461
Outlet	462, 463, 464

The following specific implementations will further explain the embodiments of the present invention with reference to the foregoing drawings.

detailed description

In order to more clearly understand the foregoing objectives, features, and advantages of the embodiments of the present invention, the following describes the present invention in detail with reference to the accompanying drawings and specific implementations. It should be noted that, in the case of no conflict, the features in the embodiments of the present application may be combined with each other.

In the following description, many specific details are set forth in order to fully understand the embodiments of the present invention. The described implementations are only part of the implementations of the present invention, but not all of the implementations. Based on the embodiments of the present invention, all other implementations obtained by a person of ordinary skill in the art without making creative efforts fall within the protection scope of the embodiments of the present invention.

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 belonging to the embodiments of the present invention. The terms used herein in the description of the present invention are only for the purpose of describing specific implementations, and are not intended to limit the embodiments of the present invention.

The second-generation sequencing technology is currently a powerful tool for analyzing the evolution and classification of organisms, studying cancer-related autism and other disease-related genes, and conducting in vitro diagnostics, which has promoted a better understanding of life sciences and also promoted the development of the health industry . After ten years of development, the second-generation sequencing technology has become relatively mature, and new sequencing platforms and products have also changed from generation to generation, and are rapidly developing towards the trend of low cost and high throughput. Therefore, the present invention designs an 8-inch sequencing chip (hereinafter referred to as a bare chip 300) loaded with gene molecules (such as DNA nanospheres) on a handle for sequencing, which greatly reduces the sequencing cost and greatly improves the sequencing throughput.

The composition and structure of the gene sequencer 500 of the present invention will be described in detail below with reference to FIG. 1.

FIG. 1 shows a part of a gene sequencer 500, which is an immersion sequencing system, including a robotic hand 510, a liquid exchange system, a bare chip 300, and a handle device 100, wherein the bare chip 300 is carried by the handle device 100, In addition, the manipulator 510 grips the upper end of the handle device 100, and the manipulator 510 can move up, down, left, and right to transport the bare chip 300 into the reagent tanks 520 of different liquid exchange systems for biochemical reactions.

among them,

The sequencing chip is an indispensable element in the test. Throughout the test process, the second-generation sequencing technology includes the process of loading genetic molecules on the sequencing chip, and then pairing, labeling, and collecting information on the bases of the molecules one by one. Complete genetic sequence information. Therefore, the main use process of the bare chip 300 in this article includes:

1) Assembly with the handle device 100;

2) loading of gene molecules;

3) base pairing reaction;

4) Acquire a fluorescent image.

The handle device 100 of the present invention will be described in detail below with reference to FIGS. 2 and 3.

The handle device 100, as shown in FIG. 2 (omitting the middle length section), has a long shape, and the bare chip 300 to be carried is circular, of which:

The chip slot 110 is opened in the middle section of the handle device 100 and is used to install the bare chip 300;

The sealing groove 120 is opened inside the chip groove 110 and is used to fixedly connect the bare chip 300, such as an adhesive connection;

A vacuum tank 130 is opened inside the sealing tank 120, and the vacuum tank 130 is electrically connected to the outside, and is used to adsorb the bare chip 300 by negative pressure;

The positioning groove 170 is provided on the side of the chip groove 110 in the longitudinal direction, so as to prevent the bare chip 300 and the reagent groove 520 from touching.

In this embodiment, the chip groove 110 matches the contour of the bare chip 300 and has the same thickness. After assembly, the surface to be loaded of the bare chip 300 is flush with the end surface of the handle device 100; and The outline of the sealing groove 120 and the vacuum groove 130 is a rectangular frame, and the distance between corresponding sides is the same. The depth and width of the sealing groove 120 are smaller than the depth and width of the vacuum groove 130. The positioning groove 170 is a strip-shaped groove on the side of the chip slot 110, and the strip-shaped groove extends to the rear end of the handle device 100 to form a planar slide groove communicating with the outside. The depth of the positioning groove 170 is greater than The depth of the vacuum groove 130 and the width of the positioning groove 170 are greater than the width of the vacuum groove 130. It can be understood that the shapes and sizes of the sealing grooves 120 and the vacuum grooves 130 are not limited to this embodiment, and the shapes and sizes of the positioning grooves 170 are designed according to actual needs, and details are not described herein.

The handle device 100 can be gripped by auxiliary equipment (such as a robot hand 510) and has a partial positioning function. As shown in FIG. 2, the chip slot 110 has a clamping portion 150 and a limiting portion 140 on the outer side, respectively. A positioning portion 141 extends from a middle portion of the bit portion 140 toward the chip slot 110. The clamping portion 150, the limiting portion 140, and the positioning portion 141 are engaged with the bare chip 300. In a specific embodiment, a plurality of conductive internal channels 160 are defined between the clamping portion 150 and the vacuum tank 130. The clamping portion 150 is provided with a plurality of mounting holes 151 for mounting to other equipment. The sealing groove 120 is adhesively connected to the bare chip 300; the glue may not be adhered to the silicon chip, and acts as a flexible or elastic sealing material and is squeezed on the back of the bare chip 300 to facilitate the bare chip. Reuse of 300 helps reduce material costs.

In this embodiment, the positioning portion 141 is an arcuate shape (refers to a long arc segment including a circle center, where the arc angle is greater than 180 °), and protrudes from the middle portion of the limiting portion 140 toward the chip slot 110. The end of the junction is recessed toward the inside of the limiting portion 140 for holding the bare chip 300. The surface of the chip groove 110 is a cross-sectional direction, and the channel 160 approaches the vacuum groove 130 The corner region of the clamping portion 150 opens vertically downward, and then is laterally conducted to the side of the clamping portion 150 (as shown in FIG. 3), and the channel 160 has a circular cross section (as shown in FIG. 2). It can be understood that the relative relationship between the positioning portion 141 and the limiting portion 140 is not limited to this embodiment, and the shape and size of the positioning portion are designed according to actual needs, and may be a square or a triangle. In other embodiments, the channel 160 may be formed between the vacuum groove 130 and the limiting portion 140, or from any position on an outer side wall between the limiting portion 140 and the clamping portion 150. When the handle device 100 is placed on top of the chip slot 110 and placed horizontally, the external side wall includes a bottom wall and two vertical side walls. When the handle device 100 is held vertically, the external side wall includes a distance from The back wall of the chip slot 110 and the two vertical side walls, so that the position of the channel 160 is not limited to this embodiment.

The connection principle of the handle device 100 and the bare chip 300 is: dispensing is performed in the sealing groove 120, the bare chip 300 is correctly assembled, and fixed for a period of time in a negative pressure adsorption manner, so that the handle device 100 It is attached to the bare chip 300, sealed, and does not fall, which is enough to complete the subsequent reactions and the transportation of the operation process. Of course, the bonding can be adhesion or compaction, and the transportation process can always be performed in the form of negative pressure adsorption.

In order to achieve correct assembly of the handle device 100 and the bare chip 300, the positioning device 200 of the present invention will be described in detail below with reference to FIGS. 4 and 5.

The positioning device 200 includes a base 220 and a plurality of convex portions 221, a slider 210 and a fastening portion 225 provided on the base 220.

among them:

The slider 210 is located above the side of the clamping portion 150, and the convex portion 221 and the fastening portion 225 are enclosed outside the chip groove 110 and the limiting portion 140, and the limiting portion The convex portion 221 contacted by the portion 140 and the protrusion 211 at the end of the slider 210 are surrounded by the outside of the bare chip 300.

The fastening portions 225 are disposed outside the same side wall of the handle device 100, and each of the fastening portions 225 includes a fastener 2252 and penetrates from the inside of the fastener 2252 and abuts the handle device 100ach side pin 2251. In this embodiment, the fastener 2252 is fixedly installed on the base 220, the pin 2251 is threaded, and is screwed in the threaded hole of the fastener 2252. After the handle device 100 is placed, the pin 2251 is locked so that one end thereof squeezes the handle device 100 , The handle device 100 can be fixed.

Limit blocks (222, 223) are respectively provided on both sides of the slider 210 in the moving direction to restrict the displacement of the slider 210, and a slide groove is provided on the base 220 for installation and connection with the slider. 210 cooperates with the slide rail 224.

In this embodiment, as shown in FIG. 5, the convex portion 221 is a cylinder and is provided with three, two of which are provided at the end of the same side of the handle device 100, especially one side of the chip slot 110. At the end, the height of the two protrusions 221 is not greater than the thickness of the handle device 100 (the vertical distance between the surface of the chip slot 110 and the bottom surface of the handle device 100). Another one of the convex portions 221 is provided outside the midpoint of the limiting portion 140. In this embodiment, the height of the convex portion 221 is higher than the thickness of the handle device 100, and three of the convex portions 221 are formed. Three positioning points that are not in a straight line can position the handle device 100. It can be understood that the number and shape of the convex portions 221 are not limited to this embodiment, and details are not described herein.

In this embodiment, as shown in FIG. 5, the fastening portion 225 is provided on the opposite side of the convex portion 221, that is, the other side of the chip groove 110. Two fastening portions are provided, each of which is fastened. The portion 225 is provided with a fastener 2252 and a pin 2251. The fastener 2252 is provided with two holes perpendicular to the direction of the chip slot 110, and the interior of the fastener 2252 is opened parallel to the direction of the chip slot 110. 1 through hole, the 1 horizontal through hole is provided between 2 vertical holes, and the horizontal through hole is provided with a thread for inserting a pin 2251 to abut the side wall of the handle device 100, and the vertical hole is used for The fastener 2252 is locked with the base 220 (correspondingly, the base 220 is provided with a threaded hole, which can be locked with each other with screws), so as to fix the position of the fastener 2252, and thus the handle device 100 fix. It can be understood that the number, shape, and structure of the fastening portions 225 are not limited to this embodiment. It only needs to be combined with the convex portion 221 to fix the handle device 100. For example, if the pin 2251 is inserted to a certain depth, it will interfere with The side wall of the handle device 100 is then tightened with screws on both sides of the fastener 2252, so that the position of the pin 2251 is fixed, so that the pin 2251 and the convex portion 221 surround the side wall of the handle device 100.

In this embodiment, as shown in FIG. 5, the slider 210 is provided at an end of the base 220, above the side of the clamping portion 150, and a protrusion 211 is provided on the slider 210 for Abutting the bare chip 300, the protrusion 211 in this embodiment is a cylinder and is provided with two symmetrically distributed on both sides of the horizontal center axis of the slider 210 (the plane of the bare chip 300 is regarded as a horizontal plane), and At the same time, a convex portion 221 is located on the extension line of the horizontal central axis of the slider 210, and is provided outside the limiting portion 140. The protrusion 211 (positioning portion 141), the convex portion 221 are formed, etc. Waist triangle, the three points are used to locate the bare chip 300. The slider 210 shown in FIG. 4 can slide along the horizontal central axis. FIGS. 4 and 5 also show two parts of the slider 210 in the moving direction. Limit blocks (222, 223) are provided on the side for restraining the displacement of the slider 210. In this embodiment, the limit blocks (222, 223) are divided into an internal limit block 222 and an external limit block 223, and the internal limit block 222 is close to the bare chip 300 and is provided with one, corresponding to the The outer limit block 223 is provided on a side of the slider 210 facing outward and perpendicular to the surface of the bare chip 300. There are two outer limit blocks 223, which are respectively located at the ends of the slider 210, and the inner limit block 222 The outer limit block 223 is fixed on the base 220. In addition, in this embodiment, a slide groove is provided on the base 220 for installing slide rails 224 that cooperate with the slider 210. Correspondingly, there are two slide grooves, and the slide rail 224 is also provided. 2; In addition, as shown in FIGS. 4 and 5, the base 220 is provided with an opening in a region corresponding to an end portion of the clamping portion 150, and the slider 210 is located above the clamping portion 150, corresponding to An opening is also provided in the region, and the clamping portion 150 is not in contact with the slider 210, and only the protrusion 211 contacts the bare chip 300. It can be understood that the shape and number of the slider 210 and the protrusion 211 are not limited to this embodiment.

The assembly sequence of the positioning device 200, the handle device 100, and the bare chip 300:

The base 220 is placed on a platform, the sealing groove 120 is dispensed to be solidified, and then the handle device 100 is placed on the base 220 against the convex portion 221 in a correct manner;

The pins 2251 of the adjusting portion 225 and the convex portion 221 are jointly enclosed by the outside of the handle device 100 and fixed;

Moving the slider 210 to be in contact with the outer limit block 223, and placing the bare chip 300, the gap on the bare chip 300 corresponds to the positioning portion 141;

Moving the slider 210 toward the bare chip 300 until it interferes;

The channel 160 of the clamping part 150 is connected to an air pump, and the air pump is turned on. The bare chip 300 is correctly and negatively attached to the handle device 100, and the positioning device 200 is removed.

It can be understood that the glue can also be adhered to the back of the bare chip 300, so that the air pump and the positioning device 200 can be removed at the same time after the glue is solidified.

Since the bare chip 300 and the handle device 100 are connected together, the surface of the untouched bare chip 300 can make full use of its area to load gene molecules, and the reaction flux can be greatly improved. The loading process of gene molecules will be described below with reference to FIGS. 6 and 7.

First, the loading of gene molecules on the bare chip 300 requires a certain period of time and harsh reaction conditions, including that the bare chip 300 must not be in contact with air during the reaction, that is to say, the reaction surface of the bare chip 300 needs to be sealed. A loading device 400 for sealing and loading a bare chip 300.

FIG. 6 shows that the loading device 400 is provided with a cover plate 410 and a bottom plate 420. A groove is formed on the bottom plate 420 to match the handle device 100, and can be directly embedded. The depth of the insertion is the thickness of the handle device 100 (here is the support Distance between the top surface and the bottom surface of the portion 150 or the limiting portion 140); as shown in FIG. 7, the bottom surface of the cover plate 410 is provided with a fan-shaped second sealing groove 411, the arc edge of the second sealing groove 411 and On the inside of the right-angle side (two vertical radii), there are flow channel grooves 412, the midpoint of the arc-side flow channel groove 412, and the right-angle side flow channel groove 412 are provided with liquid outlets (463, 462, 464) near the arc edge. The right-angle side flow channel groove 412 is provided with a liquid inlet 461 near the center of the circle, and the outline of the second sealing groove 411 is closed by glue, and is adhered to the bare chip 300 to form a fan-shaped cavity. In this embodiment, four second sealing grooves 411 are provided, each of which is a quarter circle, which is enclosed to form a complete circle. The corresponding glue is a circle with an internal cross, which is attached to the bare chip 300 to form 4 Independent fan-shaped cavities.

Loading process: first locate the assembled bare chip 300 and the handle device 100, and then insert the handle device 100 into the base plate 420 correctly, cover the cover plate 410 (the second sealing groove 411 has been glued and solidified), and lock the cover plate 410 and the bottom plate 420 form a cavity; connect the inlet and outlet (461, 462, 463, 464) and the liquid pump, drain the pipe gas, open the inlet 461 and the corresponding outlet (462, 464) correspondingly The liquid pump fills the flow channel groove 412 with liquid reagents; close the previous liquid outlets (462, 464), and simultaneously open the liquid pump corresponding to the liquid outlet 463, and the liquid flows to the midpoint of the arc; when it reaches the liquid outlet At port 463, the liquid fills the entire cavity. The fluid change process is similar to the above steps.

In another embodiment, after opening the liquid inlet 461, the liquid outlet 462 is first opened to generate a negative pressure to suck the liquid reagent, so that the liquid reagent fills the corresponding right-angle side flow channel groove; and then the liquid outlet 462 is closed to open the liquid outlet. 464 generates a negative pressure to suck the liquid reagent, so that the liquid reagent fills the corresponding right-angle side flow channel groove; finally, the liquid outlet 464 is closed, and the liquid outlet 463 is opened to generate a negative pressure to suck the liquid reagent, so that the liquid reagent fills the corresponding arc-side flow channel groove. , So the liquid fills the entire cavity.

It can be understood that the shape and structure of the loading device 400 are not limited to this embodiment, as long as the bare chip 300 does not come into contact with air during the reagent loading process on the reaction surface of the bare chip 300 and is easy to handle after completion (such as setting nesting with the handle device 100) Structure). The number, shape, connection relationship, and the like of each group of the corresponding loading device 400 are also determined according to the actual situation, and are not repeated here.

In the previous stage, the bare chip 300 completed the loading of the gene molecules. Next, the base molecules in the bare chip 300 need to be subjected to a base pairing reaction one by one in order to obtain the information of each synthetic base indirectly to obtain the gene. Complete molecular information for diagnosis, prevention, etc. of diseases. The process is briefly explained below with reference to FIGS. 1 and 8.

First, as with the gene molecule loading process, the pairing reaction process also needs to be isolated from the air. The gene sequencer 500 has designed and developed a liquid exchange system with an open reagent tank 520 that automatically completes the liquid addition and exchange operations to control the reaction of the bare chip 300. It is completely immersed (immersed) in the reagent tank 520 and is automatically transported between different reagent tanks 520 of a series of reactions, and the reaction time is automatically controlled.

In this embodiment, the liquid exchange system includes a plurality of reagent tanks 520, which are used to load various reagents that react with gene molecules; an opening is provided on the top of each reagent tank 520 for the entry of the bare chip 300, At the same time, the leakage of reagents and the fluctuation of the reagent liquid level (mainly a drop phenomenon will cause the bare chip 300 to be completely immersed and the reaction will be insufficient); a side wall of each reagent tank 520 is provided with a positioning tank 170 The protruding portion 521 is used for accurately inserting and moving the handle device 100 up and down. In this embodiment, after positioning grooves 170 are provided on both sides of the handle device 100, it can be understood that the two sides are thin walls (also referred to as "wings" or "wings" or "flange"), and the corresponding reagent grooves 520 A groove is formed on the inner wall of the groove. The cross-section of the groove is “convex” when viewed from the inner surface to the outer surface. The inner wall forms a two-arm embracing shape. Here, it is referred to as the protruding portion 521. Move up and down to enter the groove, it will be stuck, it can only move up and down without tilting, avoiding the bare chip 300 and the inner wall of the reagent tank 520 from being damaged by collision; at the same time, the clamping portion 150 is assembled with the robot 510 (the robot 510 is surrounded by The clamping part 150 is around and clamped and fixed), the thickness of the assembly part is greater than the thickness of the handle device 100, and the equipment part is adjustable, on the one hand, it limits the depth of the bare chip 300 to be submerged in the reagent; on the other hand, it can greatly improve the test efficiency in combination with automated control In addition, the reaction surface and edge of the bare chip 300 do not touch the reagent tank 520, which can maximize the utilization of the reaction area of the bare chip 300 and improve the utilization rate. It can be understood that the positioning groove 170 and the protruding portion 521 only need to satisfy the positioning and sliding relationship, and are not limited to this embodiment. For example, the back of the handle device 100 may be provided with an extended structure, and the inner side of the positioning groove 170 is provided with a sliding groove. Coordination can also achieve this function, which needs to be considered comprehensively according to actual needs and manufacturing costs.

The liquid exchange system also includes a water bath (heating component), a liquid adding component, a draining component, a refrigerator and other parts. The water bath is used to heat the reagent tank 520 to ensure the temperature required for the biochemical reaction. Here, the reagent tank is set at the top. The opening also avoids changing the liquid with water, which affects the reaction; the liquid adding component and the liquid discharging component complete the loading and control of the reagent through the control system; the refrigerator is used to ensure the activity of the reagent.

In summary, the above-mentioned immersed gene sequencer 500 can directly perform gene molecule loading reaction and sequencing reaction on the bare chip 300 by means of the handle device 100, greatly improving the utilization rate of the sequencing area, saving the consumption of auxiliary materials and saving costs; and using positioning The device 200 can uniformly install the bare chip 300 to the same correct position, with high assembly accuracy and efficiency; the combined robot 510 can automate the program to control the transportation and the reaction process, which improves the sequencing efficiency and has a high degree of automation.

The above implementations are only used to describe the technical solutions of the embodiments of the present invention and are not restrictive. Although the embodiments of the present invention have been described in detail with reference to the above preferred embodiments, those skilled in the art should understand that the techniques of the embodiments of the present invention can be Modifications or equivalent replacements of the solutions should not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (15)

1. A handle device for assisting a bare chip to perform a biochemical reaction is characterized in that: a chip slot is provided in the middle of the device to install the bare chip, and a sealed slot is provided inside the chip slot to fixedly connect the bare chip. A vacuum groove is provided on the inner side of the sealing groove, and the vacuum groove is communicated with the outside to adsorb the bare chip with a negative pressure. A positioning groove is provided on the side of the chip groove for positioning during the transportation process.
2. The handle device according to claim 1, wherein the outside of the chip slot is a clamping portion and a limiting portion, and a middle portion of the limiting portion extends out of the positioning portion toward the chip slot, and the clamping Part, the limiting part, and the positioning part are engaged with the bare chip.
3. The handle device according to claim 1, wherein the sealing groove is adhesively connected to the bare chip.
4. The handle device according to claim 2, wherein a plurality of conductive internal channels are provided between the clamping portion and the vacuum groove.
5. The handle device according to claim 2, wherein a plurality of conductive internal channels are provided between the limiting portion and the vacuum groove.
6. The handle device according to claim 2, wherein the handle device is provided with a plurality of conductive internal channels between an outer side wall between the limiting portion and the vacuum tank and the vacuum tank.
7. The handle device according to claim 2, wherein the clamping portion is provided with a plurality of mounting holes for mounting to other equipment.
8. A positioning device, characterized in that it is used for assembling and positioning a handle device and a bare chip according to any one of claims 1 to 7, comprising a base, and a plurality of projections, sliders and The fastening portion, wherein the slider is located above the side of the clamping portion, the convex portion and the fastening portion are enclosed outside the chip groove and the stopper portion, and the stopper portion The protrusions in contact with the protrusions at the end of the slider surround the outside of the bare chip.
9. The positioning device according to claim 8, wherein the fastening portions are provided outside the same side wall of the handle device, and each of the fastening portions includes a fastener and an inner portion from the fastener. The pin is penetrated and abutted against the side wall of the handle device, and the fastener is threadedly assembled with the pin.
10. The positioning device according to claim 8, characterized in that: the sliders are respectively provided with limit blocks on both sides of the moving direction to restrain the displacement of the slider, and a sliding groove is provided on the base for: A slide rail fitted with the slider is installed.
11. A loading device for loading gene molecules on the surface of a bare chip, characterized in that the device comprises a bottom plate and a cover plate, and a groove is provided on the bottom plate to fix the negative chip adsorbed on the bare chip as claimed in claims 1 to 7. The handle device according to any one of the preceding claims, wherein a second sealing groove and a flow channel groove are provided on a bottom surface of the cover plate facing the bare chip, and the second sealing groove is bonded to the bare chip to form a cavity, and the flow channel The tank or the second sealed tank is provided with a liquid inlet and a liquid outlet.
12. The loading device according to claim 11, wherein each of the second sealing grooves is fan-shaped, and the surrounding is circular; and the flow channel groove is located inside the edge of the second sealing groove.
13. The loading device according to claim 11, wherein an adhesive is fixed to an edge of the second sealing groove, and the adhesive is adhered to the bare chip.
14. A gene sequencer, comprising: a manipulator, a liquid exchange system, a bare chip, and the handle device according to any one of claims 1 to 7 carrying the bare chip, wherein the manipulator is connected to the clamp A holding part for carrying the bare chip into several reagent tanks of the liquid exchange system for biochemical reaction, the top of each of the reagent tanks is an opening, and the side wall is provided with an extension that cooperates with the positioning tank For limiting the handle device and the bare chip.
15. The gene sequencer according to claim 14, wherein a bottom of the reagent tank and a side wall remote from the handle device are not in contact with the bare chip.

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