Micro / nano-liter droplet quality control device for high-throughput gene synthesis

Abstract

The utility model relates to a micro / nano-liter droplet quality control device for high-throughput gene synthesis. The micro / nano-liter droplet quality control device comprises a base station; the base is arranged on the base table, and a combined clamp assembly can be installed on the base; the vertical frame is vertically arranged on the base table, an array spray head assembly can be installed on the vertical frame, and the array spray head assembly is located above the combined clamp assembly; and the first camera unit is arranged on the base table, the shooting direction of the first camera unit is perpendicular to the height direction of the vertical frame, and the first camera unit can shoot a nozzle of the array spray head assembly. According to the quality control device, the liquid separation state of the spray head and the liquid drop form can be horizontally shot through the camera, whether the liquid separation operation is qualified or not is accurately monitored, and closed-loop monitoring of the liquid drop generation process is formed.

Description

Technical Field

[0001] The utility model relates to the field of synthetic biology technology, in particular to a micro- and nanoliter droplet quality control device for high-throughput gene synthesis. Background Art

[0002] The traditional commercial oligonucleotide synthesis method is based on the principle of in situ chemical solid-phase synthesis, and usually uses standard SBS synthesis microplates (96-well plates, 384-well plates) on the market for low-throughput synthesis. In this method, the liquid separation nozzle used is usually a structure of a solenoid valve and a steel needle, in which the steel needles are arranged and separated into the synthesis microplate in a point-to-point mode, that is, after each movement of a certain distance, it pauses, separates the liquid, and then moves a certain distance again, and so on. However, this method has a low synthesis efficiency because the installation accuracy of the steel needle structure is not high, and it cannot meet the liquid injection requirements of high-throughput synthesis plates. In addition, the solenoid valve has a long response time and a large separation volume, resulting in high cost, and crystal blockage is easily generated inside the steel needle, affecting the flow of the liquid, and droplets are easily hung on the end of the steel needle. At present, there is no corresponding quality control method to monitor and adjust the working status of the nozzle.

[0003] High-throughput gene synthesis targets higher-throughput microplate array printing, which means greater print volume and higher printing frequency. Consequently, this requires more precise nozzle volumetric dispensing, more reliable droplet generation, and higher precision in dot printing. Low or no nozzle output can lead to base omissions, while deviations in dot printing can introduce base errors. This significantly increases the error rate in DNA synthesis, leading to failure in oligonucleotide synthesis of the corresponding sequence. Utility Model Content

[0004] Based on this, it is necessary to provide a micro- and nanoliter droplet quality control device for high-throughput gene synthesis that can use a camera to horizontally capture the liquid separation status and droplet morphology of the nozzle, accurately monitor whether the liquid separation operation is qualified, and form a closed-loop monitoring of the droplet generation process to address the problem of being unable to accurately judge the liquid separation status of the nozzle, monitor whether the nozzle is discharging liquid, hanging droplets, and whether the droplet shape is qualified.

[0005] A micro- and nanoliter droplet quality control device for high-throughput gene synthesis, comprising:

[0006] abutment;

[0007] A base, disposed on the base, and capable of mounting a composite fixture assembly on the base;

[0008] A stand is vertically arranged on the base, and a movable array nozzle assembly can be installed on the stand, and the array nozzle assembly is located above the composite fixture assembly;

[0009] a liquid collecting tank, provided on the stand; and

[0010] The first camera unit is arranged on the base. The shooting direction of the first camera unit is perpendicular to the height direction of the stand and opposite to the liquid collecting tank. The first camera unit can capture the nozzle of the array nozzle assembly located above the liquid collecting tank.

[0011] The above-mentioned micro- and nanoliter droplet quality control device for high-throughput gene synthesis can be equipped with a fixture assembly on the base, the synthesis microplate can be positioned and installed on the fixture assembly, and the array nozzle assembly is arranged on the upper part of the stand. When the array nozzle assembly moves to above the liquid collection tank, the first camera unit can horizontally capture the liquid separation state and droplet morphology of the nozzle, accurately monitor whether the liquid separation operation is qualified, and form a closed-loop monitoring of the droplet generation process.

[0012] In one embodiment, the first camera unit includes a first camera, a first lens, and a first light source. The first camera is mounted on the base, the first lens is coaxially mounted on the first camera, and the first light source is spaced apart from the first lens, with the nozzle positioned between the first light source and the first lens. The first camera, the first lens, and the first light source can more clearly and accurately capture the horizontal state of the printhead.

[0013] In one embodiment, the first camera unit further includes an angle rotating base, the angle rotating base is disposed on the base, and the first camera is disposed on the angle rotating base, so as to be able to rotate and adjust the angle of the first camera unit to horizontally photograph the nozzle.

[0014] In one embodiment, the first camera unit further includes a first driving member, which is disposed on the base, and a driving end of the first driving member is connected to the angle rotating seat, and the first driving member can drive the first camera to move closer to or away from the first light source.

[0015] In one embodiment, a second driving member is further included, which is arranged on the base, and a driving end of the second driving member is connected to the base. The second driving member can drive the base to move closer to or away from the stand along a first direction, and the first direction is perpendicular to the height direction of the stand.

[0016] In one embodiment, the stand is a gantry structure, the second driving member is located in the stand, and an array nozzle assembly is provided on the upper portion of the stand.

[0017] In one embodiment, the stand includes a crossbeam, a first column and a second column, the first column and the second column are arranged on the base at intervals along a second direction, the second direction is horizontal and perpendicular to the first direction, the crossbeam is connected to the top of the first column and the second column, the second driving member is arranged under the crossbeam and between the first column and the second column, and the array nozzle assembly is arranged on the crossbeam.

[0018] In one embodiment, a second camera unit is further included. The second camera unit is located on the upper portion of the stand and above the base. The second camera unit is capable of capturing the injection point of the array nozzle assembly. This allows for precise monitoring of the injection point of the nozzle, enabling closed-loop control of the nozzle printing accuracy.

[0019] In one embodiment, the second camera unit includes a second camera, a second lens and a second light source. The second camera is arranged on the upper part of the stand, and the shooting direction is vertically downward. The second lens is coaxially arranged on the second camera, and the second light source is coaxial with the second lens.

[0020] In one embodiment, a third driving member and a fourth driving member are further included, wherein the third driving member is arranged on the upper part of the stand, the driving end of the third driving member is connected to the fourth driving member, and the third driving member can drive the fourth driving member to move horizontally along the stand, and the driving end of the fourth driving member is connected to the second camera, and the fourth driving member can drive the second camera to move vertically along the stand toward or away from the base. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a structural diagram of a first embodiment of the quality control device of the present utility model;

[0022] Figure 2 This is a structural diagram of a second embodiment of the quality control device of the present utility model;

[0023] Figure 3 This is a schematic diagram of the first camera in use. Figure 1 ;

[0024] Figure 4 This is a schematic diagram of the second camera in use. Figure 1 ;

[0025] Figure 5 This is a schematic diagram of the second camera in use. Figure 2 ;

[0026] Figure 6 This is a schematic diagram of the second camera in use. Figure 3 .

[0027] In the accompanying drawings, the components represented by the reference numerals are as follows:

[0028] 100. Quality control device; 1. Base; 2. Base; 3. Stand; 31. Beam; 32. First column; 33. Second column; 4. First camera unit; 41. First camera; 42. First lens; 43. First light source; 44. Angle rotation seat; 51. First driving member; 52. Second driving member; 53. Third driving member; 54. Fourth driving member; 6. Second camera unit; 61. Second camera; 62. Second lens; 63. Second light source; 631. Ring light source; 632. Point light source; 200. Synthetic fixture assembly; 300. Array nozzle assembly; 400. Synthetic microplate; 401. Mark; 500. Calibration slide; 600. Liquid collection tank. DETAILED DESCRIPTION

[0029] To make the above-mentioned purposes, features, and advantages of the present invention more clearly understood, the following provides a clear and complete description of the specific embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the specific details described below are only a portion of the embodiments of the present invention, and the present invention can also be implemented in many other embodiments different from those described herein. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are also within the scope of protection of the present invention.

[0030] It should be noted that when an element is referred to as being "fixed to" another element, it may be directly attached to the other element or there may be an intermediate element. When an element is referred to as being "connected to" another element, it may be directly connected to the other element or there may be an intermediate element. The terms "vertical," "horizontal," "left," "right," and similar expressions used herein are for illustrative purposes only and do not represent the only implementation methods.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0032] See also Figure 1In one embodiment, a micro- and nanoliter droplet quality control device 100 for high-throughput gene synthesis includes: a base 1, a pedestal 2, a stand 3, and a first camera unit 4. The base 2 is mounted on the base 1 and can be mounted with a synthesis fixture assembly 200. The stand 3 is vertically mounted on the base 1 and can be mounted with an array nozzle assembly 300, which is located above the synthesis fixture assembly 200. The first camera unit 4 is mounted on the base 1, with the shooting direction of the first camera unit 4 being horizontal and longitudinal, and the first camera unit 4 can capture the nozzle of the array nozzle assembly 300.

[0033] The micro- and nanoliter droplet quality control device 100 for high-throughput gene synthesis has a synthesis fixture assembly 200 that can be installed on the base 2, and a synthesis microplate 400 that can be positioned and installed on the synthesis fixture assembly 200. The array nozzle assembly 300 is arranged on the upper part of the stand 3. When the array nozzle assembly 300 moves above the liquid collection tank 600, the first camera unit 4 can horizontally capture the liquid separation state and droplet morphology of the nozzle, accurately monitor whether the liquid separation operation is qualified, and form a closed-loop monitoring of the droplet generation process.

[0034] See also Figure 2 and Figure 3 In one embodiment of the first camera unit 4, the first camera unit 4 includes a first camera 41, a first lens 42, and a first light source 43. The first camera 41 is disposed on the base 1, and the first lens 42 is coaxially disposed on the first camera 41. The first light source 43 is spaced apart from the first lens 42, and the nozzle is positioned between the first light source 43 and the first lens 42. The arrangement of the first camera 41, the first lens 42, and the first light source 43 allows for clearer and more accurate horizontal capture of the printhead state.

[0035] It should be noted that the first light source 43 can be a brightness-adjustable light source, which can achieve infinite adjustment of the light brightness (value) through bus communication to be compatible with droplet quality control of each nozzle on different forms and numbers of array nozzle assemblies 300. The first lens 42 can be a telecentric lens.

[0036] The first camera unit 4 also includes an angle rotating seat 44, which is arranged on the base 1. The first camera 41 is arranged on the angle rotating seat 44, which can rotate and adjust the angle of the first camera unit 4 to horizontally shoot the nozzle to avoid interference from adjacent nozzles during shooting.

[0037] Furthermore, the first camera unit 4 also includes a first driving member 51, which is arranged on the base 1. The driving end of the first driving member 51 is connected to the angle rotating seat 44. The first driving member 51 can drive the first camera 41 to move horizontally and longitudinally toward or away from the first light source 43, and can adjust the horizontal and longitudinal displacement of the first camera 41 to meet the alignment of different nozzles.

[0038] See also Figure 1 In another embodiment, the quality control device 100 also includes a second driving member 52, which is arranged on the base 1, and the driving end of the second driving member 52 is connected to the base 2. The second driving member 52 can drive the base 2 to move toward or away from the stand 3 in the horizontal longitudinal direction, and can adjust the longitudinal displacement of the synthetic microplate 400 according to the needs of liquid separation.

[0039] In one embodiment of the stand 3 , the stand 3 is a gantry structure, the second driving member 52 is located in the stand 3 , and an array nozzle assembly 300 is provided on the upper portion of the stand 3 .

[0040] Furthermore, the stand 3 includes a crossbeam 31, a first column 32, and a second column 33. The first column 32 and the second column 33 are arranged on the base 1 in a horizontal and transverse manner. The crossbeam 31 is connected to the tops of the first column 32 and the second column 33. The second drive member 52 extends longitudinally below the crossbeam 31 and is located between the first column 32 and the second column 33. The array nozzle assembly 300 is movably arranged on the crossbeam 31, and the liquid collection tank 600 is arranged on the second column 33.

[0041] See also Figure 1 In order to accurately monitor the landing point of the liquid dispensed by the nozzle and realize closed-loop control of the printing accuracy of the nozzle, the quality control device 100 also includes a second camera unit 6. The second camera unit 6 is arranged on the beam 31. The second camera unit 6 can capture the liquid injection landing point of the array nozzle assembly 300.

[0042] See also Figure 2 and Figure 4 In one embodiment of the second camera unit 6, the second camera unit 6 includes a second camera 61, a second lens 62 and a second light source 63. The second camera 61 is arranged on the beam 31, and the shooting direction is vertically downward. The second lens 62 is coaxially arranged on the second camera 61, and the second light source 63 is coaxial with the second lens 62. The second camera 61 is equipped with the second lens 62 and the second light source 63, which can capture the landing position of the nozzle more clearly and accurately. The second light source 63 may include a ring light source 631 and a point light source 632. The second lens 62 may be a telecentric lens. The ring light source 631 is coaxially installed with the second lens 62, and the point light source 632 is arranged on the outside of the second lens 62. The second light source 63 may also include only the ring light source 631, and the landing accuracy of the second camera 61 only requires the ring light source 631.

[0043] See also Figure 1In other embodiments, the quality control device 100 also includes a third driving member 53 and a fourth driving member 54. The third driving member 53 extends laterally and is arranged on the beam 31. The driving end of the third driving member 53 is connected to the fourth driving member 54. The third driving member 53 can drive the fourth driving member 54 to move laterally. The driving end of the fourth driving member 54 is connected to the second camera 61. The fourth driving member 54 can drive the second camera 61 to move vertically along the stand 3 toward or away from the base 2.

[0044] In a specific implementation, the second camera 61 and the array nozzle assembly 300 can be installed together on the driving end of the fourth driving member 54, and the shooting height of the second camera 61 is driven by the fourth driving member 54, and the quality control height (relative to the liquid collection tank 600) and the liquid injection height (relative to the synthetic microplate 400) of the array nozzle assembly 300 are driven by the fourth driving member 54.

[0045] A calibration glass slide 500 can also be provided on the composite fixture assembly 200. Before the liquid dispensing operation, the array nozzle assembly 300 prints droplets on the calibration glass slide 500 at intervals, and then combined with the driving system: the third driving member 53 drives the second camera 61 to move horizontally, and the second driving member 52 drives the composite fixture assembly 200 to drive the calibration glass slide 500 to move vertically. The second camera 61 takes pictures of a droplet matrix on the calibration glass slide 500 in sequence according to the blocks, and then splices and analyzes the images of each block, thereby realizing the verification of the printing accuracy of the array nozzle assembly 300.

[0046] It is understandable that the first driving member 51 , the second driving member 52 , the third driving member 53 and the fourth driving member 54 may be servo control systems, which may be in the form of a ball screw module, a synchronous belt module, or a linear motor.

[0047] See also Figure 5 In the application of the second camera 61, the third driving member 53 can be used to drive the second camera 61 to move horizontally, and the second driving member 52 can drive the synthetic fixture assembly 200 to drive the synthetic microporous plate 400 to move longitudinally. The second camera 61 can sequentially measure the x and y direction offsets of each mark on the synthetic microporous plate 400, and feed them back to the servo control system for compensation and elimination, so as to realize the positioning function of the synthetic microporous plate 400 before printing.

[0048] See also Figure 6 After the synthetic microporous plate 400 is dispensed, the second camera 61 can be driven by the third driving member 53 to move horizontally, and the second driving member 52 can drive the synthetic clamp assembly 200 to move the synthetic microporous plate 400 longitudinally. A microporous matrix on the synthetic microporous plate 400 is photographed in sequence according to the blocks, and then the images of each block are spliced ​​and analyzed, thereby realizing the quality control of the printing status or color inspection of the synthetic microporous plate 400.

[0049] The state of droplet generation is a prerequisite for printing accuracy, state and color quality control. Only after each valve of the array nozzle assembly 300 passes the droplet morphology quality control can the droplet quality control landing accuracy and the synthetic microplate 400 base printing state quality control or color inspection be further performed.

[0050] After coupled printing, a second camera 61 takes photos of each well of the synthesis microplate 400 to perform quality control of the base printing results. After auxiliary liquid dispensing during capping, oxidation, and washing, photos are taken to verify even distribution of the auxiliary liquid. After auxiliary liquid aspiration, photos are taken to verify complete dryness of the synthesis support. After deprotection reagent dispensing, reaction, and aspiration, the synthesis support appears red, and this can also be photographed by the second camera 61 for color detection. This combined process allows for full, closed-loop monitoring of the critical steps of liquid dispensing, reaction, and aspiration during synthesis production.

[0051] It should be noted that process files support online programming and distribution, and the above-mentioned camera quality control functions can be added between specified steps as needed.

[0052] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0053] The above-described embodiments merely represent several implementation methods of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the utility model patent. It should be noted that a person skilled in the art would be able to make various modifications, substitutions, and improvements without departing from the concept of the present invention, all of which are intended to fall within the scope of protection of the present invention. Therefore, the scope of protection of the present utility model patent should be determined by the claims.

Claims

1. A micro- and nanoliter droplet quality control device for high-throughput gene synthesis, characterized in that: include: abutment; A base, disposed on the base, and capable of mounting a composite fixture assembly on the base; A stand is vertically arranged on the base, and a movable array nozzle assembly can be installed on the stand, and the array nozzle assembly is located above the composite fixture assembly; A liquid collecting tank is provided on the stand; and The first camera unit is arranged on the base. The shooting direction of the first camera unit is perpendicular to the height direction of the stand and opposite to the liquid collecting tank. The first camera unit can capture the nozzle of the array nozzle assembly located above the liquid collecting tank.

2. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 1, characterized in that: The first camera unit includes a first camera, a first lens and a first light source. The first camera is arranged on the base. The first lens is coaxially arranged on the first camera. The first light source is spaced from the first lens, and the nozzle is located between the first light source and the first lens.

3. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 2, characterized in that: The first camera unit further includes an angle rotating seat, the angle rotating seat is arranged on the base, and the first camera is arranged on the angle rotating seat.

4. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 3, characterized in that: The first camera unit further includes a first driving member, which is disposed on the base. A driving end of the first driving member is connected to the angle rotating seat. The first driving member can drive the first camera to move closer to or away from the first light source.

5. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 1, characterized in that: It also includes a second driving member, which is arranged on the base and has a driving end connected to the base. The second driving member can drive the base to move closer to or away from the stand along a first direction, and the first direction is perpendicular to the height direction of the stand.

6. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 5, characterized in that: The stand is a gantry structure, the second driving member is located in the stand, and an array nozzle assembly is provided on the upper portion of the stand.

7. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 6, characterized in that: The stand includes a crossbeam, a first column and a second column. The first column and the second column are arranged on the base at intervals along a second direction. The second direction is horizontal and perpendicular to the first direction. The crossbeam is connected to the top of the first column and the second column. The second driving member is arranged below the crossbeam and between the first column and the second column. The array nozzle assembly is arranged on the crossbeam.

8. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 1, characterized in that: It also includes a second camera unit, which is arranged on the upper part of the stand and above the base. The second camera unit can capture the injection landing point of the array nozzle assembly.

9. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 8, characterized in that: The second camera unit includes a second camera, a second lens and a second light source. The second camera is arranged on the upper part of the stand, and the shooting direction is vertically downward. The second lens is coaxially arranged on the second camera, and the second light source is coaxial with the second lens.

10. The micro- and nanoliter droplet quality control device for high-throughput gene synthesis according to claim 9, characterized in that: It also includes a third driving member and a fourth driving member. The third driving member is arranged on the upper part of the stand. The driving end of the third driving member is connected to the fourth driving member. The third driving member can drive the fourth driving member to move horizontally along the stand. The driving end of the fourth driving member is connected to the second camera. The fourth driving member can drive the second camera to move vertically along the stand towards or away from the base.

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