Integrated chip and droplet sorting and printing method

Abstract

The invention discloses an integrated chip and a liquid drop sorting and printing method, the integrated chip comprises a chip main body, the chip main body is provided with a positive channel, a negative channel and a sorting channel, the sorting channel extends along a first direction, the inlet end of the positive channel and the inlet end of the negative channel are respectively communicated with the outlet end of the sorting channel, and the outlet end of the sorting channel is communicated with a second direction; the positive channel and the negative channel are located on the two sides of the sorting channel in the second direction correspondingly. The activating assembly is used for forming a laser detection line, and the laser detection line penetrates through the sorting channel in the second direction; the electrode assembly comprises a first grounding electrode and multiple input electrodes, the first grounding electrode and the input electrodes are located on the two sides of the sorting channel in the second direction correspondingly, and the multiple input electrodes are arranged in the first direction; the printing assembly comprises a positive pipeline and a negative pipeline, the positive pipeline is connected with the outlet end of the positive channel and extends to the outer side of the chip main body, and the negative pipeline is connected with the outlet end of the negative channel and extends to the outer side of the chip main body.

Description

Technical Field

[0001] This invention relates to the field of droplet sorting technology, and in particular to an integrated chip and a droplet sorting printing method. Background Technology

[0002] The core principle of droplet electrosort is based on real-time detection and sorting of droplets using biochemical fluorescent labeling. As a droplet flows through the detection area, a high-speed optical sensor (PMT) collects data and rapidly identifies the target droplet using machine learning classification or threshold judgment algorithms. The sorting actuator applies a controllable Coulomb force or dielectric force to the target droplet using a high-frequency electric field, causing it to deviate from the default flow path and enter the designated collection channel. This technology offers advantages such as non-contact operation, low shear force, high throughput, and programmable control. Its throughput is 2-3 orders of magnitude higher than traditional multi-well plate methods, and it is widely used in single-cell sequencing, rare cell sorting, droplet digital PCR (ddPCR), and high-throughput drug screening.

[0003] However, in related technologies, the throughput of the sorting chip still needs to be improved, the equipment operates for a long time, and cell activity is low. If the sorting voltage is increased, the degree of electrical damage to the cells is high. Furthermore, it is necessary to add a flow-through fluid to achieve discharge in order to print droplets, which is difficult to operate. Summary of the Invention

[0004] This invention aims to address at least one of the technical problems existing in the prior art. To this end, this invention proposes an integrated chip and droplet sorting printing method, which can improve sorting throughput, shorten working time, reduce cell droplet damage, and reduce the difficulty of printing operation.

[0005] The solution to the technical problem of this invention is: Firstly, an integrated chip is proposed, comprising: The chip body has a positive channel, a negative channel and a sorting channel. The sorting channel extends along a first direction. The entrance end of the positive channel and the entrance end of the negative channel are respectively connected to the exit end of the sorting channel. The positive channel and the negative channel are respectively located on both sides of the sorting channel along a second direction. An activation component is used to form a laser detection line that passes through the sorting channel in a second direction; The electrode assembly includes a first ground electrode and an input electrode, the first ground electrode and the input electrode being located on both sides of the sorting channel along a second direction, and multiple input electrodes being arranged along a first direction. The printing assembly includes a positive conduit and a negative conduit, the positive conduit being connected to the outlet end of the positive channel and extending to the outside of the chip body, and the negative conduit being connected to the outlet end of the negative channel and extending to the outside of the chip body.

[0006] The present invention has at least the following beneficial effects: After the droplets enter the sorting channel, the positive droplets are activated by the laser detection line and flow to the positive channel under the action of the input electrode, and finally flow out of the positive pipe for printing; while the negative droplets can be activated, and after flowing along the sorting channel to the negative channel, they flow out of the negative pipe for printing, making printing easier; throughout the process, since there are multiple input electrodes, the positive droplets are acted on by the input electrodes multiple times before flowing to the positive channel. Therefore, compared with conventional single-electrode chips, the action time is longer, the throughput is higher, and the sorting voltage is lower, which can shorten the overall working time of sorting and printing and reduce cell droplet damage.

[0007] As a further improvement to the above technical solution, the integrated chip also includes a circuit board, which has a circuit structure. The circuit structure has a ground terminal and multiple input interface terminals. The first ground electrode is electrically connected to the ground terminal, and the input electrodes correspond one-to-one with the input interface terminals and are electrically connected.

[0008] As a further improvement to the above technical solution, the circuit board is provided with contact pins, which are electrically connected to the circuit structure.

[0009] As a further improvement to the above technical solution, the circuit board is provided with a mounting groove in the middle, the chip body is located in the mounting groove, and the grounding terminal and the input interface terminal are both located on the outside of the mounting groove.

[0010] As a further improvement to the above technical solution, the electrode assembly further includes a second ground electrode. The second ground electrode and the input electrode are located on the same side of the sorting channel. The second ground electrode has a connecting portion, a first extension portion and a second extension portion. One end of the first extension portion is connected to the connecting portion. The number of the first extension portions is equal to the number of the input electrodes and is arranged at intervals from the input electrodes. One end of the second extension portion is connected to the connecting portion. The second extension portion is located at the entrance end of the sorting channel and extends along a first direction.

[0011] As a further improvement to the above technical solution, the width of the input electrode along the first direction is greater than the width of the first extension along the first direction.

[0012] As a further improvement to the above technical solution, the input electrode is a three-dimensional liquid metal electrode.

[0013] As a further improvement to the above technical solution, the aspect ratio of the input electrode is 3:1.

[0014] As a further improvement to the above technical solution, the chip body is also provided with a sample inlet channel and multiple sample inlets, the sample inlets being connected to the inlet end of the sample inlet channel, and the outlet end of the sample inlet channel being connected to the inlet end of the sorting channel.

[0015] Secondly, a droplet sorting and printing method is proposed, which uses an integrated chip as described in any of the above technical solutions to sort and print droplets. The droplet sorting and printing method includes the following steps: A droplet is added to the chip body, allowing it to enter the sorting channel and pass through the laser detection line, whereby a positive droplet is activated. The input electrodes are controlled to be energized sequentially, so that the positive droplets in the sorting channel are acted on by the input electrodes multiple times and flow into the positive channel, while the negative droplets in the sorting channel flow into the negative channel. The integrated chip is placed vertically, allowing droplets to flow along the positive or negative channel and then drip vertically, thus achieving the printing of a single droplet.

[0016] As a further improvement to the above technical solution, the total energizing time of the input electrode is equal to the time it takes for the droplet to flow through the sorting channel.

[0017] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly explained below. Obviously, the described drawings are only a part of the embodiments of the present invention, and not all of them. Those skilled in the art can obtain other design schemes and drawings based on these drawings without creative effort.

[0019] Figure 1 This is a schematic diagram of the chip body and electrode assembly of the integrated chip according to an embodiment of the present invention; Figure 2 yes Figure 1 A magnified structural diagram of part A in the middle; Figure 3 This is a schematic diagram of the upper circuit board structure according to an embodiment of the present invention; Figure 4 This is a schematic diagram of the lower circuit board structure according to an embodiment of the present invention; Figure 5 This is a schematic diagram of the printing component according to an embodiment of the present invention; Figure 6 This is a flowchart of the droplet sorting and printing method according to an embodiment of the present invention; Figure 7 This is a schematic diagram of the sorted droplets; Figure 8 This is a schematic diagram of the printed droplet.

[0020] Reference numerals: 100, Chip body; 110, Upper circuit board; 111, Input interface terminal; 112, Ground terminal; 113, Mounting slot; 120, Lower circuit board; 121, Contact pin; 200, Input electrode; 300, First ground electrode; 400, Positive channel; 410, Positive conduit; 411, Positive outlet; 500, Negative channel; 510, Negative conduit; 511, Negative outlet; 600, Sorting channel; 700, Sample inlet; 710, Sample inlet channel; 720, Chip inlet; 800, Second ground electrode; 810, First extension; 820, Second extension; 900, Laser detection line. Detailed Implementation

[0021] Embodiments of the present invention are described in detail below. Examples of these embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0022] In the description of this invention, the orientation descriptions, such as up, down, front, back, left, right, etc., are based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limiting this invention.

[0023] In the description of this invention, "several" means one or more, "more than" means two or more, "greater than," "less than," and "exceeding" are understood to exclude the stated number, while "above," "below," and "within" are understood to include the stated number. The use of "first" and "second" in the description is merely for distinguishing technical features and should not be construed as indicating or implying relative importance, or implicitly indicating the number of indicated technical features, or implicitly indicating the order of the indicated technical features.

[0024] In the description of this invention, unless otherwise explicitly defined, terms such as "set up," "install," and "connect" should be interpreted broadly, and those skilled in the art can reasonably determine the specific meaning of the above terms in this invention in conjunction with the specific content of the technical solution.

[0025] Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention. The various technical features of the present invention can be combined interactively without contradicting each other.

[0026] Reference Figures 1 to 4 In a first aspect, embodiments of the present invention propose an integrated chip, including a chip body 100, an activation component, an electrode component, and a printing component, which achieves high throughput and low voltage sorting, enables integrated sorting and printing functions, and simplifies the droplet printing process.

[0027] Reference Figure 1 and Figure 2 In this embodiment, the chip body 100 is provided with a positive channel 400, a negative channel 500 and a sorting channel 600. The sorting channel 600 extends along a first direction. The entrance end of the positive channel 400 and the entrance end of the negative channel 500 are respectively connected to the exit end of the sorting channel 600. Moreover, the positive channel 400 and the negative channel 500 are respectively located on both sides of the sorting channel 600 along a second direction.

[0028] It is understood that the length direction of the sorting channel 600 is the first direction, and the width direction of the sorting channel 600 is the second direction. For ease of description, when the integrated chip is laid flat, the left-right direction is taken as the first direction, and the front-back direction is taken as the second direction. In this embodiment, the positive channel 400 is located on the rear side of the sorting channel 600, and the negative channel 500 is located on the front side of the sorting channel 600.

[0029] The activation component forms a laser detection line 900, which passes through the sorting channel 600 in the front-to-back direction and can activate droplets within the sorting channel 600. Understandably, as droplets flow along the sorting channel 600, negative droplets cannot be excited by the laser detection line 900 to produce a fluorescence signal, while positive droplets can be excited to produce a fluorescence signal. Understandably, through fluorescent dye droplets and fluorescent cells, the integrated chip can achieve a maximum sorting performance of over 3000 Hz and a sorting rate of up to 99%.

[0030] The electrode assembly includes a first ground electrode 300 and an input electrode 200. The first ground electrode 300 is disposed on the front side of the sorting channel 600, while the input electrode 200 is disposed on the rear side of the sorting channel 600. Multiple input electrodes 200 are provided and arranged along the left-right direction on the edge of the sorting channel 600.

[0031] Understandably, when an alternating current is applied to the input electrode 200, the positive droplet flows into the positive channel 400 under the action of the input electrode 200.

[0032] Understandably, because the positive droplets are acted upon multiple times by the input electrode 200 before flowing into the positive channel 400, the action time is longer, the throughput is higher, and the sorting voltage is lower compared to conventional single-electrode chips. The sorted droplets are referenced... Figure 7 .

[0033] Reference Figure 5 In this embodiment, the printing assembly includes a positive channel 410 and a negative channel 510. The outlet end of the positive channel 400 is a positive outlet 411. The positive channel 410 is connected to the positive outlet 411 and extends to the outside of the chip body 100. The outlet end of the negative channel 500 is a negative outlet 511. The negative channel 510 is connected to the negative outlet 511 and extends to the outside of the chip body 100. Droplets pass through the chip inlet 720 into the chip body 100. After being sorted within the chip body 100, the chip body 100 is placed vertically. Negative droplets can flow along the negative channel 510 to the outside of the chip body 100 and drip vertically, while positive droplets can flow along the positive channel 410 to the outside of the chip body 100 and drip vertically. This enables the printing function of a single droplet.

[0034] Understandably, by setting up negative and positive channels 510, the buoyancy effect can be avoided, enabling the export of sorted negative and positive droplets, resulting in faster printing speeds and a simpler process. A schematic diagram of the printed droplets is shown below. Figure 8 .

[0035] In some embodiments, the lengths of the negative conduit 510 and the positive conduit 410 range from greater than or equal to 1 cm to less than or equal to 50 cm, and the inner diameters of the negative conduit 510 and the positive conduit 410 are less than or equal to 200 micrometers and greater than or equal to 100 micrometers.

[0036] In some embodiments, the integrated chip further includes a circuit board, which has a circuit structure, a ground terminal 112 and a plurality of input interface terminals 111, a first ground electrode 300 electrically connected to the ground terminal 112, and an input electrode 200 corresponding to and electrically connected to the input interface terminals 111.

[0037] In some embodiments, the first ground electrode 300 is electrically connected to the ground terminal 112 by a wire, and the input electrode 200 is electrically connected to the input interface terminal 111 by a wire. It is understood that by providing a circuit board, all connection lines can be grouped onto the circuit board, reducing mutual inductance between electrodes and effectively improving situations where multiple input electrodes 200 operate simultaneously or non-operating input electrodes 200 are energized due to high frequency and high voltage on adjacent wires.

[0038] In some embodiments, the circuit board is provided with contact pins 121, which are electrically connected to the circuit structure. This configuration simplifies the overall structure of the integrated chip and makes it easier to use. In use, simply contact the contact pins 121 on the circuit board with the power supply point of the power supply device.

[0039] In some embodiments, the circuit board includes an upper circuit board 110 and a lower circuit board 120. In use, the upper circuit board 110 is located above the lower circuit board 120, and the contact pins 121 are disposed on the lower circuit board 120.

[0040] In some embodiments, a mounting groove 113 is provided in the middle of the circuit board, the chip body 100 is disposed in the mounting groove 113, and the ground terminal 112 and the input interface terminal 111 are both disposed on the outside of the mounting groove 113, which can avoid interference between the circuit structure and the chip body 100.

[0041] In some embodiments, the electrode assembly further includes a second ground electrode 800, which is disposed on the side of the sorting channel 600 where the input electrode 200 is disposed. The second ground electrode 800 is provided with a connecting portion, a first extension portion 810 and a second extension portion 820. One end of the first extension portion 810 is connected to the connecting portion. The number of first extension portions 810 is equal to the number of input electrodes 200 and they are arranged at intervals from the input electrodes 200. One end of the second extension portion 820 is connected to the connecting portion. The second extension portion 820 is disposed at the entrance end of the sorting channel 600 and extends in the left-right direction.

[0042] It is understood that in this embodiment, three input electrodes 200 and three first extensions 810 are provided. On the rear side of the sorting channel 600, they are arranged from the inlet end to the outlet end of the sorting channel in the following order: second extension 820, first input electrode 200, first first extension 810, second input electrode 200, second first extension 810, third input electrode 200 and third first extension 810.

[0043] Understandably, this setup can further avoid mutual inductance between two adjacent input electrodes 200 and effectively achieve sequential power supply to the droplet.

[0044] In some embodiments, the width of the input electrode 200 in the left-right direction is greater than the width of the first extension 810 in the left-right direction. This configuration effectively enables the ground electrode to flow into the positive channel 400, ensuring the reliability of the sorting process.

[0045] In some embodiments, the input electrode 200 is a three-dimensional liquid metal electrode. Using a liquid metal-infused electrode, a force is applied to the droplets in three-dimensional space. Compared to nanometer-thick metal-coated electrodes, the three-dimensional liquid metal electrode exerts a stronger force, meaning that droplet sorting can be achieved with lower voltage and in a shorter experimental time, avoiding electrical damage to cell droplets and ensuring cell viability.

[0046] In some embodiments, the aspect ratio of the input electrode 200 is 3:1. It is understood that the input electrode 200 has an energizing end facing the sorting channel 600, and the aspect ratio here specifically refers to the ratio of the height of the energizing end in the vertical direction to its width in the horizontal direction. With this aspect ratio, the input electrode 200 can effectively sort droplets, apply force to the droplets in three-dimensional space, and improve throughput.

[0047] In some embodiments, two-photon printing technology is used to fabricate electrode molds with a 3:1 aspect ratio, achieving a precision of up to hundreds of nanometers. This demonstrates the significant advantages of two-photon printing in mold fabrication. Compared to conventional photolithography, where mold length, width, and height errors can reach up to 5 micrometers and batch-to-batch variations are difficult to control, this is particularly problematic for chips requiring identical parameters for one-click startup in commercialization. In contrast, the integrated chip fabricated using two-photon printing technology in this solution achieves a precision at the hundreds of nanometer level with significantly reduced batch-to-batch variations.

[0048] In some embodiments, the chip body 100 further includes a sample inlet channel 710 and a plurality of sample inlet holes 700. The sample inlet holes 700 are connected to the inlet end of the sample inlet channel 710, and the outlet end of the sample inlet channel 710 is connected to the inlet end of the sorting channel 600. A specific sized perforation sampling method can effectively reduce droplet inlet fusion. In some embodiments, the pore size of the sample inlet holes 700 is greater than or equal to 100 μm and less than or equal to 1000 μm. Sample inlet through small holes within this range is beneficial for droplet dispersion.

[0049] Secondly, the present invention provides a droplet sorting and printing method, which uses an integrated chip as proposed in any of the embodiments of the first aspect to sort and print droplets. This method can improve sorting throughput, reduce equipment working time, ensure that the activity of cells meets the requirements during the sorting and printing process, avoid cell electrical damage, and reduce the difficulty of printing operation.

[0050] The droplet sorting and printing method includes steps S101, S102, and S103, as described above. Figure 6 .

[0051] In step S101, a droplet is added to the chip body 100, allowing it to enter the sorting channel 600 and pass through the laser detection line 900, activating positive droplets. Specifically, the droplet enters the sample inlet channel 710 through the sample inlet 700 and flows along the sample inlet channel 710 to the sorting channel 600 for sorting. When the droplet passes through the laser detection line 900, negative droplets cannot be excited by the laser detection line 900 to emit a fluorescence signal. However, positive droplets emit a fluorescence signal after passing through the laser detection line 900. By exciting fluorescent dye droplets and fluorescent cells, the sorting performance and sorting rate can be improved.

[0052] In step S102, the input electrodes 200 are sequentially energized, causing positive droplets in the sorting channel 600 to be acted upon multiple times by the input electrodes 200 and flow to the positive channel 400, while negative droplets in the sorting channel 600 flow to the negative channel 500. It can be understood that after being acted upon by the electrode assembly multiple times, the droplets flow towards the target channel, thereby achieving the droplet sorting effect.

[0053] Furthermore, the total energizing time of all input electrodes 200 is equal to the time it takes for the droplet to flow through the sorting channel 600. With this setting, the positive droplet will be acted on by the input electrodes 200 multiple times before flowing into the positive channel 400. Compared with conventional single-electrode chips, the action time is longer, the throughput is higher, and the sorting voltage is lower.

[0054] In step S103, the chip is placed vertically, allowing the droplet to flow along the positive channel 410 or the negative channel 510 and then drip vertically, thus achieving the printing of a single droplet. It is understood that, due to the use of the integrated chip of the first aspect embodiment and the droplet sorting printing method of this embodiment, the discharge of droplet fluid within 2 μL can be achieved within 3 seconds, resulting in high printing efficiency.

[0055] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.

Claims

1. An integrated chip, characterized in that, include: The chip body has a positive channel, a negative channel and a sorting channel. The sorting channel extends along a first direction. The entrance end of the positive channel and the entrance end of the negative channel are respectively connected to the exit end of the sorting channel. The positive channel and the negative channel are respectively located on both sides of the sorting channel along a second direction. An activation component is used to form a laser detection line that passes through the sorting channel in a second direction; The electrode assembly includes a first ground electrode and an input electrode, the first ground electrode and the input electrode being located on both sides of the sorting channel along a second direction, and multiple input electrodes being arranged along a first direction. The printing assembly includes a positive conduit and a negative conduit, the positive conduit being connected to the outlet end of the positive channel and extending to the outside of the chip body, and the negative conduit being connected to the outlet end of the negative channel and extending to the outside of the chip body.

2. The integrated chip according to claim 1, characterized in that, The integrated chip also includes a circuit board, which contains a circuit structure. The circuit structure has a ground terminal and multiple input interface terminals. The first ground electrode is electrically connected to the ground terminal, and the input electrodes correspond one-to-one with the input interface terminals and are electrically connected.

3. The integrated chip according to claim 2, characterized in that, The circuit board is provided with contact pins, which are electrically connected to the circuit structure.

4. The integrated chip according to claim 2, characterized in that, The circuit board has a mounting slot in the middle, the chip body is located in the mounting slot, and the ground terminal and the input interface terminal are both located on the outside of the mounting slot.

5. The integrated chip according to claim 1, characterized in that, The electrode assembly further includes a second ground electrode, which is located on the same side of the sorting channel as the input electrode. The second ground electrode has a connecting portion, a first extension portion, and a second extension portion. One end of the first extension portion is connected to the connecting portion. The number of the first extension portions is equal to the number of the input electrodes and they are arranged at intervals from the input electrodes. One end of the second extension portion is connected to the connecting portion. The second extension portion is located at the entrance end of the sorting channel and extends along a first direction.

6. The integrated chip according to claim 5, characterized in that, The width of the input electrode along the first direction is greater than the width of the first extension along the first direction.

7. The integrated chip according to claim 1, characterized in that, The input electrode is a three-dimensional liquid metal electrode.

8. The integrated chip according to claim 1, characterized in that, The aspect ratio of the input electrode is 3:

1.

9. The integrated chip according to claim 1, characterized in that, The chip body is also provided with a sample inlet channel and multiple sample inlets. The sample inlets are connected to the inlet end of the sample inlet channel, and the outlet end of the sample inlet channel is connected to the inlet end of the sorting channel.

10. A method for droplet sorting and printing, characterized in that, The droplet sorting and printing method uses an integrated chip as described in any one of claims 1 to 9 to perform droplet sorting and printing, the droplet sorting and printing method comprising the following steps: A droplet is added to the chip body, allowing it to enter the sorting channel and pass through the laser detection line, whereby a positive droplet is activated. The input electrodes are controlled to be energized sequentially, so that the positive droplets in the sorting channel are acted on by the input electrodes multiple times and flow into the positive channel, while the negative droplets in the sorting channel flow into the negative channel. The integrated chip is placed vertically, allowing droplets to flow along the positive or negative channel and then drip vertically, thus achieving the printing of a single droplet.

11. The droplet sorting and printing method according to claim 10, characterized in that, The total energizing time of the input electrode is equal to the time it takes for the droplet to flow through the sorting channel.

Images