Device for automatically synthesizing nanoparticles

Abstract

The present application provides a device for automatically synthesizing nanoparticles, comprising: a pressure supply module, one or more air outlets corresponding to microfluidic chip inlets being formed at the pressure supply module, so as to supply or stop supplying air to the microfluidic chip inlets through the air outlets; a pipetting module, the pipetting module being able to pipet a liquid to the microfluidic chip inlets; and a movement module, the movement module being able to drive the pressure supply module and the pipetting module to move in a horizontal direction and in a vertical direction. By means of the device provided in the present application, nanoparticles can be automatically synthesized by means of microfluidic chips, and especially when each microfluidic chip is provided with a plurality of reaction combinations and / or a device bottom plate is provided with a plurality of microfluidic chips, the same or different liquid nanoparticles can be prepared more efficiently.

Description

An apparatus for automated synthesis of nanoparticles TECHNICAL FIELD

[0001] The present application relates to the technical field of analysis systems, and in particular to an apparatus for automated synthesis of nanoparticles. BACKGROUND

[0002] Nanoparticle synthesis technology is a technology frontier in the field of rapidly developing nanotechnology. Its unique size-dependent characteristics enable these materials to exhibit great advantages in many fields and occupy an irreplaceable position. This technology has been widely applied in many industries, such as drug delivery, energy, and electronics. Nanoparticle synthesis technology is one of the key steps to realize the application of nanoparticles. Microreactors based on microfluidic technology can achieve rapid mixing of reagents, temperature control, and precise spatiotemporal manipulation during reactions. Using microfluidic technology for nanoparticle synthesis, the mixing is controlled and uniform, which can produce nanoparticles with uniform size. At the same time, the repeatability of the physical and chemical properties of nanoparticles can also be precisely controlled. In addition, by regulating the microenvironment of nanoparticle synthesis, the size uniformity and repeatability of nanoparticles can be further improved, thereby improving the process yield of nanoparticle preparation.

[0003] The formulation of nanoparticles plays a very important role in the encapsulation efficiency, particle size, particle size uniformity, surface charge, and transfection efficiency of drugs. Therefore, when developing nanoparticle drugs, a large number of screening of the nanoparticle formulation library is needed according to the type of drug and the transfection target. In addition to the formulation of nanoparticles, the type of drug and the modification of the drug also have a great impact on the actual effect of the drug (such as the protein expression level of mRNA drugs). Therefore, in addition to screening the formulation of nanoparticles, screening of the drug library is also needed. In summary, during the development of drugs, large-scale screening of nanoparticle formulation libraries and drug libraries is often required.

[0004] Existing nanoparticle synthesis equipment based on microfluidic technology is based on single-operation synthesis of a single or small batch of samples. When screening large-scale nanoparticle formulations and drug formulations, a large amount of manpower and time is required. SUMMARY

[0005] To solve the problems in the prior art, the present application provides an apparatus for automated synthesis of nanoparticles. The technical solution of the present application is as follows:

[0006] 1. An apparatus for automated synthesis of nanoparticles, comprising:

[0007] a pressure supply module, wherein one or more gas outlets corresponding to the inlets of the microfluidic chip are arranged on the pressure supply module, so that the pressure supply module can supply or stop supplying gas to the inlets of the microfluidic chip through the gas outlets;

[0008] a pipetting module, wherein the pipetting module can pipette to the inlets of the microfluidic chip;

[0009] a movement module, wherein the movement module can drive the pressure supply module and the pipetting module to move in horizontal direction and vertical direction.

[0010] 2. The device of item 1, wherein the pressure supply module comprises: a pressure plate assembly; and a gas supply assembly, wherein the gas supply assembly can supply gas to the gas outlets.

[0011] 3. The device of item 2, wherein the pressure plate assembly comprises: a pressure plate body; a gas inlet and the gas outlets, which are arranged on the pressure plate body; and a gas flow channel, which is arranged in the pressure plate body to connect the gas inlet and the gas outlets.

[0012] 4. The device of item 3, wherein,

[0013] the gas inlet comprises at least a first gas inlet and a second gas inlet;

[0014] the gas outlets comprise at least a first gas outlet and a second gas outlet;

[0015] the gas flow channel comprises at least a first flow channel and a second flow channel;

[0016] wherein,

[0017] the first gas outlet is used to supply or stop supplying gas to the first phase inlet of the microfluidic chip;

[0018] the second gas outlet is used to supply or stop supplying gas to the second phase inlet of the microfluidic chip;

[0019] the first flow channel is used to connect the first gas inlet and the first gas outlet;

[0020] the second flow channel is used to connect the second gas inlet and the second gas outlet.

[0021] 5. The device of item 4, wherein,

[0022] the pressure plate assembly further comprises:

[0023] a first control valve and a second control valve, wherein each of the first control valve and the second control valve comprises at least a first interface, a second interface and a third interface, and can switch between the first interface communicating with the second interface and the first interface communicating with the third interface;

[0024] The first connection port group and the second connection port group are arranged on the pressing plate body and each comprises at least a first connection port, a second connection port and a third connection port;

[0025] Wherein,

[0026] The first interface of the first control valve is connected to the first gas outlet through the first connection port of the first connection port group and a gas flow channel, the second interface of the first control valve is connected to the first gas inlet through the second connection port of the first connection port group and a gas flow channel, and the third interface of the first control valve is connected to the atmosphere.

[0027] The first interface of the second control valve is connected to the second gas outlet through the first connection port of the second connection port group and a gas flow channel, the second interface of the second control valve is connected to the second gas inlet through the second connection port of the second connection port group and a gas flow channel, and the third interface of the second control valve is connected to the atmosphere.

[0028] 6. The device of item 5, wherein the gas supply assembly comprises at least a first gas tank and a second gas tank, the inlet of the first gas tank and the inlet of the second gas tank are each independently connected to a gas source, the outlet of the first gas tank is connected to the first gas inlet, and the outlet of the second gas tank is connected to the second gas inlet.

[0029] 7. The device of item 6, wherein the pressure supply module further comprises a control assembly, the control assembly independently controls the gas source to supply gas to the first gas tank and the second gas tank.

[0030] 8. The device of item 3, wherein the pressure supply module further comprises a sealing gasket, the sealing gasket is provided with a through hole corresponding to the gas outlet, and the sealing gasket is arranged on the side of the pressing plate body where the gas outlet is arranged to seal when the gas outlet supplies gas or stops supplying gas to the inlet of the microfluidic chip.

[0031] 9. The device of item 8, wherein a filter element is arranged on the through hole of at least one sealing gasket corresponding to the gas outlet.

[0032] 10. The device of item 8, wherein the pressure supply module further comprises a sealing gasket fixing assembly, the sealing gasket assembly can fix the sealing gasket on the side of the pressing plate body where the gas outlet is arranged and can also detach the sealing gasket from the pressing plate body.

[0033] 11. The apparatus of claim 10, wherein the platen body is provided with a magnetic passage; a gasket fixing assembly is located on the opposite side of the platen body where the air outlet is provided; the gasket fixing assembly comprises: a magnetic unit; a first moving unit, which can drive the magnetic unit to pass through the magnetic passage to magnetically attract the gasket, and can drive the magnetic unit to move away from the gasket to make the gasket separate from the platen body.

[0034] 12. The apparatus of claim 11, wherein the first moving unit comprises: a magnetic unit fixing plate, which fixes the magnetic unit; a first motor, which can drive the magnetic unit fixing plate to move close to or away from the platen body.

[0035] 13. The apparatus of claim 1, wherein the pipetting module comprises: a pipetting unit, which can suck and discharge liquid.

[0036] 14. The apparatus of claim 13, wherein the pipetting unit is a pipetting gun, which is a single-channel pipetting gun or a multi-channel pipetting gun; the pipetting module further comprises: a second moving unit, which can drive the control button of the pipetting gun to perform pipetting; and a third moving unit, which can drive the tip eject button of the pipetting gun to eject the tip.

[0037] 15. The apparatus of claim 14, wherein the moving module comprises: a fixing assembly; a horizontal moving assembly, which can drive the fixing assembly to move in a horizontal direction; and a vertical moving assembly, which, together with the pressure supply module and the pipetting module, is arranged on the fixing assembly, and can independently drive the pressure supply module and the pipetting module to move in a vertical direction.

[0038] 16. The apparatus of claim 15, wherein the horizontal moving assembly comprises: a first horizontal moving unit, which can drive the fixing assembly to move in a first horizontal direction; and a second horizontal moving unit, which can drive the first horizontal moving unit to move in a second horizontal direction.

[0039] 17. The apparatus of claim 16, wherein the first horizontal moving unit comprises: a first guide rail, which is arranged along a first horizontal direction; and a fourth moving unit, which can drive the fixing assembly to slide along the first guide rail; and / or,

[0040] The second horizontal movement unit comprises a second guide rail arranged along a second horizontal direction, and a fifth movement unit capable of driving the first horizontal movement unit to slide along the second guide rail.

[0041] 18. The apparatus of item 15, wherein the vertical movement assembly comprises a first vertical movement unit capable of driving the pressure supply module to move in a vertical direction, and a second vertical movement unit capable of driving the pipette module to move in a vertical direction.

[0042] 19. The apparatus of item 1, further comprising a cabinet module accommodating the pressure supply module, the pipette module and the movement module, and an air filter module arranged on the cabinet module.

[0043] 20. The apparatus of item 1, further comprising a plurality of accommodating portions.

[0044] 21. The apparatus of item 20, wherein,

[0045] one or more of the accommodating portions is prearranged with a raw material;

[0046] one or more of the accommodating portions is an empty accommodating portion;

[0047] one or more of the accommodating portions is prearranged with an ultrafiltration membrane;

[0048] one or more of the accommodating portions is prearranged with a dialysis membrane;

[0049] an upper portion of one or more of the accommodating portions is arranged with an exchange column; and / or,

[0050] one or more of the accommodating portions is prearranged with a filtration membrane.

[0051] 22. The apparatus of item 20, wherein,

[0052] one or more of the accommodating portions is an empty accommodating portion;

[0053] the apparatus further comprises an ultrafiltration membrane, a dialysis membrane, an exchange column and / or a filtration membrane.

[0054] The apparatus for automated synthesis of nanoparticles provided in the present application can realize automatic synthesis of nanoparticles by microfluidic chips. When a plurality of the above reaction combinations are arranged on each microfluidic chip, and a corresponding number of gas outlets to the inlets of the microfluidic chips are arranged on the pressure supply module, a plurality of reactions can be carried out simultaneously to prepare the same or different liquid nanoparticles. Especially when a plurality of such microfluidic chips are arranged on the base plate, the same or different liquid nanoparticles can be prepared with higher efficiency.

[0055] The above description is only a summary of the technical solutions of the present application. In order to make the technical means of the present application more clear and understandable, to the extent that a person skilled in the art can implement the content of the description, and in order to make the above and other purposes, features and advantages of the present application more obvious and easy to understand, the following will be illustrated by the specific embodiments of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1: a schematic diagram of the structure of the device for automated synthesis of nanoparticles in one embodiment;

[0057] Figure 2: a schematic diagram of the relative positions of the fixing assembly, pressure supply module, pipetting module and control assembly in one embodiment;

[0058] Figure 3: a schematic diagram of the relative positions of the fixing assembly, pressure supply module and pipetting module in one embodiment;

[0059] Figure 4: a schematic diagram of the structure of the microfluidic chip in one embodiment;

[0060] Figure 5: a schematic diagram of the relative positions of the pressure plate assembly and microfluidic chip when performing liquid nanoparticle synthesis in one embodiment;

[0061] Figure 6: a schematic diagram of the structure of the pressure plate assembly in one embodiment, without showing the magnetic attraction channel;

[0062] Figure 7: a schematic diagram of the relative positions of the pressure plate body and gas supply assembly in one embodiment;

[0063] Figure 8: a schematic diagram of the structure of the sealing gasket fixing assembly and pressure plate assembly in one embodiment;

[0064] Figure 9: a schematic diagram of the structure of the sealing gasket in one embodiment;

[0065] Figure 10: a schematic diagram of the structure of the ultrafiltration unit in one embodiment;

[0066] Figure 11: a schematic diagram of the structure of the ultrafiltration unit in another embodiment;

[0067] Figure 12: a schematic diagram of the structure of the dialysis unit in one embodiment;

[0068] Figure 13: a schematic diagram of the structure of the exchange unit in one embodiment;

[0069] Figure 14: a schematic diagram of the structure of the filtration unit in one embodiment;

[0070] Figure 15: a schematic diagram of the structure of the filtration unit in another embodiment;

[0071] Figure 16: a flowchart of the synthesis of the device of the present application in one embodiment.

[0072] Explanation of reference signs: 1000, pressure supply module; 1100, pressure plate assembly; 1110, pressure plate body; 1120, air inlet; 1121, first air inlet; 1122, second air inlet; 1130, air outlet; 1131, first air outlet; 1132, second air outlet; 1150, first control valve; 1160, second control valve; 1171, first connection port group; 1172, second connection port group; 1180, air outlet channel; 1190, magnetic attraction channel; 1200, sealing gasket; 1210, iron sheet; 1300, sealing gasket fixing assembly; 1310, magnetic attraction unit; 1321, magnetic attraction unit fixing plate; 1322, first motor; 1323, screw rod; 1410, first gas storage tank; 1411, inlet of first gas storage tank; 1420, second gas storage tank; 1421, inlet of second gas storage tank; 1500, control assembly; 1600, pressure pump; 2000, pipetting module; 3100, fixing assembly; 3211, first guide rail; 3221, second guide rail; 4000, box module; 4100, bottom plate; 5000, microfluidic chip; 5100, microfluidic chip inlet; 5110, first phase inlet; 5120, second phase inlet; 5200, microfluidic chip outlet; 6000, chip tray; 7110, ultrafiltration containing part; 7120, ultrafiltration membrane; 7210, dialysis containing part; 7220, dialysis membrane; 7310, exchange containing part; 7320, exchange column body; 7410, filtration containing part; 7420, filtration membrane; 8000, vacuum container. DETAILED DESCRIPTION

[0073] The following embodiments of the present application are only used to illustrate the specific embodiments of the present application, and these embodiments cannot be understood as limiting the present application. Any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods, which fall within the protection scope of the present application.

[0074] Those skilled in the art should understand that in the disclosure of the present application, the terms "first", "second", "third", "fourth", "fifth" and the like are only used to distinguish different structures, without limiting the number, connection relationship, etc. of specific structures; in addition, the orientation or positional relationship indicated by "longitudinal", "transverse", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer" and the like is based on the orientation or positional relationship shown in the drawings, which is only for the convenience of describing the present application and simplifying the description, and does not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, therefore the above terms cannot be understood as limiting the present application.

[0075] The embodiment provides a device for automatically synthesizing nanoparticles, as shown in Figures 1-9, which comprises:

[0076] a pressure supply module 1000, wherein one or more gas outlets 1130 corresponding to the inlet of the microfluidic chip (microfluidic chip inlet 5100) of the microfluidic chip 5000 are arranged on the pressure supply module 1000, so that the gas can be supplied to the inlet of the microfluidic chip through the gas outlets 1130 or stopped;

[0077] a pipetting module 2000, wherein the pipetting module 2000 can pipette liquid to the inlet of the microfluidic chip 5000 (microfluidic chip inlet 5100); preferably, the pipetting module 2000 can also pipette liquid from the outlet of the microfluidic chip 5000 (microfluidic chip outlet 5200);

[0078] a movement module, wherein the movement module can drive the pressure supply module 1000 and the pipetting module 2000 to move in the horizontal direction and the vertical direction.

[0079] Regarding the microfluidic chip 5000 for synthesizing nanoparticles, as shown in Figure 4, generally, it comprises a microfluidic chip inlet 5100 and a microfluidic chip outlet 5200, which are generally arranged in the form of a liquid storage pool (in the embodiment, the volume is 1 μl-10 ml). The microfluidic chip inlet 5100 is divided into a first phase inlet 5110 and a second phase inlet 5120 (the first phase inlet 5110 and the second phase inlet 5120 can independently store aqueous phase liquid and organic phase liquid according to needs, and in the embodiment, they are respectively used for storing aqueous phase liquid and organic phase liquid), one first phase inlet 5110, one second phase inlet 5120, one microfluidic chip outlet 5200 and flow channels connecting them form a reaction combination (a plurality of reaction combinations can be arranged on the same microfluidic chip 5000, as shown in Figure 4, which exemplarily shows a microfluidic chip 5000 comprising four reaction combinations). When the microfluidic chip 5000 is used, the first phase inlet 5110 and the second phase inlet 5120 can independently store aqueous phase liquid and organic phase liquid (which can be the same phase liquid or different phase liquid) according to needs, and then pressurize the first phase inlet 5110 and the second phase inlet 5120, so that the liquid stored therein is mixed in the flow channel to form nanoparticles (for example, drugs) entering the microfluidic chip outlet 5200 and being stored for subsequent analysis to control the drug packaging effect and the like.

[0080] The skilled person knows that the spatial movement of an object includes six degrees of freedom, including translational movement in three directions and rotational movement in three directions. In the present application, movement in the horizontal direction and movement in the vertical direction refer to translational movement in at least one direction (such as the x direction or the y direction) in the horizontal direction (such as the horizontal plane direction formed by the x direction and the y direction) and translational movement in the vertical direction (such as the z direction perpendicular to the horizontal plane direction formed by the x direction and the y direction), and preferably translational movement in three directions (such as the x direction, the y direction, and the z direction). In addition, the skilled person knows that movement in the horizontal direction and movement in the vertical direction can be translational movement in one direction at a time to achieve movement in multiple directions (such as two directions or three directions), or translational movement in multiple directions (such as two directions or three directions) at the same time. Regarding movement in the vertical direction, the present application preferably allows the pressure supply module 1000 and the pipetting module 2000 to move independently in the vertical direction.

[0081] The device for automatically synthesizing nanoparticles provided by the present application is used to realize the automatic synthesis of nanoparticles by the above-mentioned microfluidic chip 5000. When the above-mentioned microfluidic chip 5000 is placed on the base plate, the container (or the storage containing part such as the storage well plate, the liquid storage pool, the centrifugal tube, etc.) storing the liquid phase liquid (such as the aqueous phase and the organic phase), and the collection container (or the collection containing part such as the collection well plate, the centrifugal tube, etc.), first, the movement module drives the pipetting module 2000 to move to the upper part of the container (storage containing part) storing the liquid phase liquid (such as the aqueous phase and the organic phase), and the pipetting module 2000 absorbs the liquid; then, the movement module drives the pipetting module 2000 to move to the upper part of the inlet (such as the first phase inlet 5110 and the second phase inlet 5120) of the microfluidic chip 5000 to add liquid to the inlet (such as the first phase inlet 5110 and the second phase inlet 5120) of the microfluidic chip 5000; then, the movement module drives the pressure supply module 1000 to move to the upper part of the inlet (such as the first phase inlet 5110 and the second phase inlet 5120) of the microfluidic chip 5000 to supply gas to the inlet of the microfluidic chip 5000, so that the liquid stored in the inlet of the microfluidic chip 5000 is mixed through the flow channel to form liquid nanoparticles, which enter the microfluidic chip outlet 5200 and are stored; then, the movement module drives the pipetting module 2000 to move to the upper part of the outlet (microfluidic chip outlet 5200) of the microfluidic chip 5000, and the pipetting module 2000 absorbs the liquid (absorbs the reaction generated liquid nanoparticles); finally, the movement module drives the pipetting module 2000 to move to the upper part of the collection container (collection containing part), and the pipetting module 2000 stores the absorbed liquid nanoparticles into the collection container (collection containing part) for subsequent use (such as purification, cell transfection, etc.).

[0082] When a plurality of the above-mentioned reaction combinations (including one first phase inlet 5110, one second phase inlet 5120, one microfluidic chip outlet 5200, and a flow channel connecting them) are arranged on each microfluidic chip 5000, the pressure supply module 1000 is provided with a corresponding number of gas outlets 1130 corresponding to the inlets of the microfluidic chip 5000, so that multiple reactions can be carried out simultaneously to prepare the same or different liquid nanoparticles. Especially when a plurality of such microfluidic chips 5000 are arranged on the base plate, the same or different liquid nanoparticles can be prepared more efficiently. When a plurality of microfluidic chips 5000 are arranged, a plurality of microfluidic chips 5000 can be placed on a chip tray 6000 to facilitate the whole of the plurality of microfluidic chips 5000 to be put into or taken out of the device.

[0083] In addition, the device of the present application can further comprise a box module 4000, which accommodates the pressure supply module 1000, the pipetting module 2000 and the movement module, so that the entire device can be realized as a closed environment to ensure the cleanliness inside the device. In addition, an air filtration module (such as a filter screen / filter element, not shown in the figure) can be provided on the box module 4000 to further ensure the cleanliness inside the device.

[0084] The device of the present application can further comprise a temperature control module to control the temperature of the reagents in the containers (storage containing parts such as well plates, liquid reservoirs, etc.) storing liquid phase liquids (such as aqueous phase and organic phase), and / or to control the temperature of the liquid nanoparticle synthesis process of the microfluidic chip 5000 for heating or cooling or temperature preservation. Specifically, the temperature control module can comprise a heating assembly and / or a cooling assembly, wherein the heating assembly can be an electric heating assembly and the cooling assembly can be an air cooling assembly. The temperature control module can be provided on the bottom plate of the device and / or on the chip tray 6000.

[0085] In one embodiment, as shown in Figures 1-9, and particularly as shown in Figures 6 and 7, the pressure supply module 1000 comprises a pressure plate assembly 1100 and a gas supply assembly 1400 capable of supplying gas to the gas outlet 1130.

[0086] Specifically, the pressure plate assembly 1100 comprises:

[0087] a pressure plate body 1110;

[0088] a gas inlet 1120 and the gas outlet 1130, both provided on the pressure plate body 1110;

[0089] a gas flow channel provided in the pressure plate body 1110 for connecting the gas inlet 1120 and the gas outlet 1130.

[0090] Thus, the gas outlet 1130 corresponding to the number and position of the inlets (first phase inlet 5110 and second phase inlet 5120) of the microfluidic chip 5000 can be provided on the pressure plate body 1110 to supply gas to the inlets of the microfluidic chip 5000, and the pressure plate body 1110 is further provided with a gas inlet 1120 and a gas flow channel for connecting the gas inlet 1120 and the gas outlet 1130, so that gas can be supplied from the gas inlet 1120 to the gas outlet 1130, thereby realizing the pressing of the upper part of the microfluidic chip 5000 by the pressure plate body 1110, so that the gas outlet 1130 corresponds to and connects with the inlets of the microfluidic chip 5000 to supply gas to the inlets of the microfluidic chip 5000, to prepare liquid nanoparticles by the microfluidic chip 5000.

[0091] In addition, as shown in FIG. 6, the pressing plate assembly 1100 can further comprise an air outlet channel 1180, which is arranged in the pressing plate body 1110 and corresponds to the microfluidic chip outlet 5200 of the microfluidic chip, so that when the upper part of the microfluidic chip is pressed by the pressing plate assembly 1100, the microfluidic chip outlet 5200 is in communication with the atmosphere, facilitating the synthesis of liquid nanoparticles by the microfluidic chip 5000.

[0092] Further, as shown in FIG. 6, the air inlet 1120 comprises at least a first air inlet 1121 and a second air inlet 1122, and in the present embodiment, both the first air inlet 1121 and the second air inlet 1122 are arranged as one;

[0093] The air outlet 1130 comprises at least a first air outlet 1131 and a second air outlet 1132, and in the present embodiment, both the first air outlet 1131 and the second air outlet 1132 are arranged as a plurality, specifically four;

[0094] The gas flow channel comprises at least a first flow channel and a second flow channel;

[0095] Among them,

[0096] The first air outlet 1131 is used to supply or stop supplying gas to the first phase inlet 5110 of the microfluidic chip 5000;

[0097] The second air outlet 1132 is used to supply or stop supplying gas to the second phase inlet 5120 of the microfluidic chip 5000;

[0098] The first flow channel is used to connect the first air inlet 1121 and the first air outlet 1131;

[0099] The second flow channel is used to connect the second air inlet 1122 and the second air outlet 1132.

[0100] That is, in the pressing plate assembly 1100 shown in FIG. 6, the first air inlet 1121 is in communication with the first air outlet 1131 through a gas flow channel (first flow channel); the second air inlet 1122 is in communication with the second air outlet 1132 through a gas flow channel (second flow channel). Thus, gas can be transported from the first air inlet 1121 to the first air outlet 1131, and from the second air inlet 1122 to the second air outlet 1132; to achieve independent gas supply to the first phase inlet 5110 and the second phase inlet 5120 of the microfluidic chip 5000, so as to control the flow rate ratio and the total flow rate of different phase liquids by supplying gas to different inlets (first phase inlet 5110 and second phase inlet 5120) at different pressures, thereby adjusting the nanoparticle synthesis process and the physical properties of nanoparticles (including size, surface charge, particle size uniformity, etc.).

[0101] The platen assembly 1100 shown in FIG. 6 adopts a tubeless connection mode. When the platen assembly 1100 presses down the microfluidic chip 5000, the gas path that needs to be inflated is limited to the gas path in the platen structure, thereby minimizing the dead volume of the gas path, increasing the pressure speed of the control valve (first control valve 1150; second control valve 1160) switching to make the gas inlet 1120 (first gas inlet 1121, second gas inlet 1122) to the inlet (first phase inlet 5110, second phase inlet 5120) of the microfluidic chip 5000, so that the pressure in the inlet of the microfluidic chip 5000 reaches the set pressure faster, that is, the driven liquid can quickly reach the set flow rate, and increase the uniformity of the synthesized nanoparticles (lower flow rate in the initial stage will cause larger nanoparticles to be produced).

[0102] In one embodiment, as shown in FIG. 6, FIG. 7, the platen assembly 1100 further comprises:

[0103] The first control valve 1150 and the second control valve 1160 each at least include a first interface, a second interface, and a third interface, and can be switched between the first interface and the second interface in communication, and the first interface and the third interface in communication;

[0104] The first connection port group 1171 and the second connection port group 1172 are each provided on the platen body 1110, and each at least includes a first connection port, a second connection port, and a third connection port (as shown in FIG. 6, in the first connection port group 1171 and the second connection port group 1172, the second connection port, the first connection port, and the third connection port are sequentially arranged from top to bottom);

[0105] Wherein,

[0106] The first interface of the first control valve 1150 can be connected to the first gas outlet 1131 through the first connection port of the first connection port group 1171 and the gas flow channel, the second interface of the first control valve 1150 can be connected to the first gas inlet 1121 through the second connection port of the first connection port group and the gas flow channel, and the third interface of the first control valve 1150 is in communication with the atmosphere;

[0107] The first interface of the second control valve 1160 can be connected to the second gas outlet 1132 through the first connection port of the second connection port group 1172 and the gas flow channel, the second interface of the second control valve 1160 can be connected to the second gas inlet through the second connection port of the second connection port group 1172 and the gas flow channel, and the third interface of the second control valve 1160 is in communication with the atmosphere.

[0108] The platen assembly 1100 shown in FIG. 6, FIG. 7 is further provided with a first control valve 1150 and a second control valve 1160.

[0109] For the first control valve 1150, when it is in communication between the first interface and the second interface, it realizes the communication between the first gas inlet 1121 and the first gas outlet 1131, so that the gas can be supplied to the first phase inlet 5110 through the first gas inlet 1121, the gas flow channel and the first gas outlet 1131; when it is in communication between the first interface and the third interface, the first gas outlet 1131 is in communication with the atmosphere, so that the supply of gas to the first phase inlet 5110 is stopped, and the first phase inlet 5110 is in communication with the atmosphere.

[0110] For the second control valve 1160, when it is in communication between the first interface and the second interface, it realizes the communication between the second gas inlet 1122 and the second gas outlet 1132, so that the gas can be supplied to the second phase inlet 5120 through the second gas inlet 1122, the gas flow channel and the second gas outlet 1132; when it is in communication between the first interface and the third interface, the supply of gas to the second phase inlet 5120 is stopped, and the second phase inlet 5120 is in communication with the atmosphere.

[0111] That is, by setting the first control valve 1150 and the second control valve 1160, the independent supply or stop of the gas to the first phase inlet 5110 and the second phase inlet 5120 is realized.

[0112] Regarding the control of the first control valve 1150 and the second control valve 1160, the control can be realized by a PLC or a single-chip microcomputer, for example, the control can be performed by the control assembly 1500 set below.

[0113] In one embodiment, as shown in FIG. 7,

[0114] The gas supply assembly 1400 at least includes:

[0115] The first gas tank 1410 and the second gas tank 1420, the inlet 1411 of the first gas tank and the inlet 1421 of the second gas tank are each independently connected with a gas source;

[0116] Among them,

[0117] The outlet of the first gas tank is connected with the first gas inlet 1121;

[0118] The outlet of the second gas tank is connected with the second gas inlet 1122.

[0119] Regarding the gas source, the present application has no specific limitation, as long as it can realize stable gas supply, which can be specifically listed as a gas tank, a pressure pump, etc. In the present embodiment, a pressure pump 1600 (gas pump) is adopted.

[0120] In this embodiment, instead of directly supplying gas to the gas inlet 1120 (the first gas inlet 1121 and the second gas inlet 1122) from the gas source, a first gas storage tank 1410 and a second gas storage tank 1420 are arranged between the gas source and the gas inlet 1120 (the first gas inlet 1121 and the second gas inlet 1122). When the gas supply pressure is unstable, or when the control valve (the first control valve 1150 and the second control valve 1160) controls the gas supply to the microfluidic chip inlet, the gas storage tank can buffer the gas supplied by the gas source, and can ensure the stability of the pressure of the entire gas path when pressurizing the microfluidic chip inlet, so as to ensure the stable synthesis of liquid nanoparticles.

[0121] In one embodiment, as shown in FIG. 1, FIG. 2, etc.,

[0122] The pressure supply module 1000 further comprises:

[0123] The control assembly 1500 independently controls the gas source to supply gas to the first gas storage tank 1410 and the second gas storage tank 1420, for example, can control whether to supply gas and control the size of the supplied gas pressure, that is, the control assembly independently controls the gas source to supply gas to the first gas storage tank and the second gas storage tank, including: the control assembly independently controls whether the gas source supplies gas to the first gas storage tank and the second gas storage tank and the pressure of the supplied gas.

[0124] Specifically, the control assembly 1500 can be in the form of a PLC or a single-chip microcomputer, etc. When the gas source is a pressure pump, the pressure of the supplied gas can be controlled by electrically connecting the control assembly 1500 with the pressure pump; when the gas source is a constant pressure gas source, a proportional valve, etc. can be arranged on the gas source gas supply pipeline, and a pressure sensor, etc. can be arranged on the gas source gas supply pipeline or in the first gas storage tank 1410 and the second gas storage tank 1420, and the output gas pressure can be controlled by electrically connecting the control assembly 1500 with the proportional valve and the pressure sensor, etc., so as to realize the control of the output pressure of the gas source.

[0125] In addition, the control assembly 1500 can also be electrically connected with the control valve (such as the first control valve 1150, the second control valve 1160, etc.) in this specification; the motor in the lead screw / electric push rod involved in the first to fifth motion units, the first vertical motion unit, the second vertical motion unit, etc. and the control valve of the involved air cylinder; the heating assembly and the cooling assembly involved in the temperature control module, so as to further realize the automatic control of the device of the present application.

[0126] In one embodiment, as shown in FIG. 5, FIG. 8, FIG. 9, etc., the pressure supply module 1000 further comprises:

[0127] A sealing gasket 1200 is arranged on the side of the pressing plate body 1110 where the air outlet 1130 is arranged (in this embodiment, the lower side of the pressing plate body 1110), and has a through hole corresponding to the air outlet 1130 and the air outlet channel 1180, so as to seal the air outlet 1130 when the air outlet 1130 supplies or stops supplying air to the inlet of the microfluidic chip 5000.

[0128] Preferably, a filter element is arranged in the through hole of at least one (e.g. one, part or all, preferably all) of the sealing gaskets. The filter element arranged on the sealing gasket can prevent liquid in the inlet 5100 of the microfluidic chip from splashing into the air channel, and can also prevent dust and particles in the air used to provide pressure from entering the liquid pool, so as to ensure that the microfluidic chip 5000 can stably synthesize liquid nanoparticles.

[0129] The material of the sealing gasket can be common rubber.

[0130] In one embodiment, as shown in FIGS. 5, 8 and 9, the pressure supply module 1000 further comprises:

[0131] A sealing gasket fixing assembly 1300 is arranged on the side of the pressing plate body 1110 where the air outlet is arranged (in this embodiment, the lower side of the pressing plate body 1110), and can fix the sealing gasket 1200 to the pressing plate body 1110 and detach the sealing gasket 1200 from the pressing plate body 1110.

[0132] The sealing gasket fixing assembly 1300 can fix the sealing gasket 1200 in various ways, such as by magnetic attraction, clamping jaws, etc.

[0133] That is, the device provided in this embodiment is provided with a sealing gasket fixing assembly 1300, so that the sealing gasket 1200 can be fixed and replaced by the sealing gasket fixing assembly 1300.

[0134] In one embodiment, as shown in FIGS. 8 and 9, a magnetic attraction channel 1190 is arranged on the pressing plate body 1110;

[0135] The sealing gasket fixing assembly is arranged on the side of the pressing plate body 1110 where the air outlet is arranged (in this embodiment, the upper side of the pressing plate body 1110);

[0136] The sealing gasket fixing assembly 1300 comprises:

[0137] A magnetic attraction unit 1310;

[0138] The first movement unit can drive the magnetic attraction unit to pass through the magnetic attraction channel 1190 to magnetically attract the sealing gasket 1200, and can drive the magnetic attraction unit 1310 to move away from the sealing gasket 1200 to make the sealing gasket 1200 separate from the pressing plate body 1110.

[0139] That is, in the embodiment, a scheme is given in which the sealing gasket fixing assembly 1300 fixes the sealing gasket 1200 by magnetic attraction.

[0140] Regarding the magnetic attraction, the magnetic attraction unit 1310 and the part of the sealing gasket 1200 to be magnetically attracted can be a combination of a magnet and an iron material, or can be a magnet that attracts each other. Specifically, in the embodiment, the magnetic attraction unit 1310 is a magnetic rod, and the sealing gasket 1200 is provided with an iron sheet 1210 corresponding to the magnetic attraction unit 1310.

[0141] The first movement unit is not specifically limited in the application, and in the embodiment, a lead screw is used to drive the magnetic attraction unit 1310 to move up and down. Specifically, the first movement unit includes a magnetic attraction unit fixing plate 1321 that fixes the magnetic attraction unit 1310, and a first motor 1322 that can drive the magnetic attraction unit fixing plate to move closer to or away from the pressing plate body 1110 through a screw rod 1323. Of course, those skilled in the art can know that the first movement unit can also include a cylinder and a magnetic attraction unit fixing plate 1321, and the cylinder drives the magnetic attraction unit 1310 to move up and down through the magnetic attraction unit fixing plate 1321.

[0142] When the device is used, a plurality of sealing gaskets 1200 can be further placed on the bottom plate, and a recycling area is provided. When the movement module drives the pressure supply module 1000 to move to the upper part of the sealing gasket 1200, the first movement unit drives the magnetic attraction unit 1310 to move downward, and the magnetic attraction unit 1310 can magnetically attract the iron sheet on the sealing gasket 1200 to fix the sealing gasket 1200 on the bottom of the pressing plate body 1110. When a reaction for preparing liquid nanoparticles is completed, the movement module drives the pressure supply module 1000 to move to the recycling area, the first movement unit drives the magnetic attraction unit 1310 to move upward, and the magnetic attraction unit 1310 moves away from the sealing gasket 1200 to make the sealing gasket 1200 separate from the pressing plate body 1110, thereby achieving the purpose of replacing the sealing gasket 1200, so that the sealing gasket 1200 can be automatically replaced after a single preparation and synthesis.

[0143] In one embodiment, as shown in FIG. 2, FIG. 3, the pipetting module 2000 comprises a pipetting unit capable of aspirating and dispensing liquid. Thus, the pipetting unit can pipette liquid from the containers (storage containing parts) storing liquid phase liquid (such as aqueous phase and organic phase) to the inlets of the microfluidic chip 5000 (such as the first phase inlet 5110 and the second phase inlet 5120), and pipette liquid from the outlets of the microfluidic chip 5000 (such as the microfluidic chip outlet 5200) to the collection containers (collection containing parts, such as well plates / centrifuge tubes).

[0144] Specifically, in the present embodiment, the pipetting unit is a pipetting gun. The pipetting gun can be a single-channel pipetting gun or a multi-channel pipetting gun. In order to be able to add liquid to all inlets of the microfluidic chip 5000 at the same time to improve the operation efficiency of the device, the number of channels of the pipetting gun is preferably consistent with the number of inlets of the microfluidic chip 5000, i.e., in the present application, the pipetting gun is preferably a multi-channel pipetting gun. Specifically, as shown in FIG. 3, an 8-channel pipetting gun is used in the present embodiment.

[0145] As for the structure of the pipetting gun, it generally comprises a control button for pipetting and a tip eject button for replacing the gun tip. As for other specific structures of the pipetting gun, since the pipetting gun is a mature commercial product, they will not be described herein.

[0146] Further, the pipetting module 2000 further comprises a second movement unit capable of driving the control button of the pipetting gun to perform pipetting, and / or a third movement unit capable of driving the tip eject button of the pipetting gun to remove the gun tip.

[0147] Thus, the pipetting module 2000 can realize automatic pipetting through the second movement unit and automatic replacement of the gun tip through the third movement unit.

[0148] As for pipetting, when the pipetting gun needs to aspirate liquid, the second movement unit pushes the control button of the pipetting gun, and then the pipetting gun aspirates liquid through automatic rebound or rear pull of the second movement unit; when the pipetting gun needs to dispense liquid, the second movement unit pushes the control button of the pipetting gun to dispense liquid.

[0149] As for replacing the gun tip, the gun tip and the recycling area can be pre-installed on the bottom plate. When the pipetting gun needs to install the gun tip, the movement module drives the pipetting gun to move to the upper part of the gun tip and press down to install the gun tip; when the pipetting is completed and the gun tip needs to be replaced, the movement module drives the pipetting gun to move to the recycling area, and the third movement unit pushes the tip eject button of the pipetting gun to remove the gun tip. Thus, the gun tip can be automatically replaced to prevent the residual liquid in the gun tip from affecting the accuracy of the reaction.

[0150] As to the second movement unit and the third movement unit, the present application is not specifically limited as long as it can realize pushing and pulling, for example, a lead screw, an electric push rod, an air cylinder, etc. In the present embodiment, a lead screw is used.

[0151] In one embodiment, as shown in FIGS. 1-3, the movement module comprises:

[0152] a fixed assembly 3100 (in the present embodiment, a mechanical arm);

[0153] a horizontal movement assembly capable of moving the fixed assembly in a horizontal direction;

[0154] a vertical movement assembly, the pressure supply module and the pipetting module are arranged on the fixed assembly, and the vertical movement assembly is capable of independently moving the pressure supply module and the pipetting module in a vertical direction (z direction as mentioned above).

[0155] Thus, the pressure supply module 1000 and the pipetting module 2000 arranged on the fixed assembly can be moved in a horizontal direction by the horizontal movement assembly, and the pressure supply module 1000 and the pipetting module 2000 can be moved in a vertical direction by the vertical movement assembly.

[0156] In one embodiment, as shown in FIG. 1, the horizontal movement assembly comprises: a first horizontal movement unit capable of moving the fixed assembly in a first horizontal direction (x direction as mentioned above); and a second horizontal movement unit capable of moving the first horizontal movement unit in a second horizontal direction (y direction as mentioned above).

[0157] That is, the horizontal movement assembly in the present embodiment can move the pressure supply module 1000 and the pipetting module 2000 arranged on the fixed assembly in the entire horizontal plane direction (the horizontal plane direction formed by the first horizontal direction and the second horizontal direction) through the first horizontal movement unit and the second horizontal movement unit, in combination with the above-mentioned vertical movement assembly, so that the movement module can move the pressure supply module 1000 and the pipetting module in three directions in space.

[0158] As shown in FIG. 1, as to the first horizontal movement unit, it comprises: a first guide rail 3211 arranged along a first horizontal direction; and a fourth movement unit capable of driving the fixed assembly to slide along the first guide rail. As to the second horizontal movement unit, it comprises: a second guide rail 3221 (two parallel second guide rails 3221 in the embodiment) arranged along a second horizontal direction; and a fifth movement unit capable of driving the first horizontal movement unit to slide along the second guide rail. Thus, the horizontal movement assembly drives the pressure supply module 1000 and the pipetting module 2000 arranged on the vertical movement assembly to move in the whole horizontal plane direction (the horizontal plane direction formed by the first horizontal direction and the second horizontal direction).

[0159] As to the fourth movement unit and the fifth movement unit, the present application is not specifically limited, and for example, a lead screw, an electric push rod, etc. can be listed. In the embodiment, a lead screw is used.

[0160] In one embodiment, the vertical movement assembly comprises: a first vertical movement unit capable of driving the pressure supply module to move in a vertical direction; and a second vertical movement unit capable of driving the pipetting module to move in a vertical direction. Thus, the vertical movement assembly can independently drive the pressure supply module and the pipetting module to move in a vertical direction by the first vertical movement unit and the second vertical movement unit respectively, so as to independently press the upper part of the microfluidic chip 5000 by the pressure supply module to facilitate the synthesis of liquid nanoparticles, and independently move the pipetting module up and down to facilitate pipetting and replacement of the gun head, etc.

[0161] As to the first vertical movement unit and the second vertical movement unit, the present application is not specifically limited, and for example, a lead screw, an electric push rod, a pneumatic cylinder, etc. can be listed. In the embodiment, a lead screw is used.

[0162] It should be noted that, on the bottom plate 4100, in addition to the above-mentioned components (such as the storage containing part, the collection containing part, the microfluidic chip 5000, the sealing gasket, the gun head), etc., a mixing containing part can also be arranged.

[0163] In the organic phase liquid required for the preparation of common nanoparticles (such as liposome nanoparticles), it is usually mixed by different lipids in different proportions with organic solvents. Different lipids have different functions, and the difference in formula and the difference in proportion can affect the drug loading efficiency, the nanoparticle size, the drug delivery efficiency to cells, the drug targeting, etc.

[0164] In the scheme of setting the mixing container, the material stored in the storage container does not need to be a specific liquid phase mixed by hand, but only needs to be the original material itself stored independently. Therefore, when synthesizing the required nanoparticles under the preset conditions, the pipetting module can move different raw materials in the storage container into the mixing container according to the required type and amount / proportion, respectively, to mix the required organic phase solution or the like directly used for nanoparticle synthesis. Then, the pipetting module moves the mixed liquid in the mixing container into the inlet of the microfluidic chip to synthesize nanoparticles. Therefore, the function of the device for automatically synthesizing nanoparticles according to the present application can be further expanded, and the automation of nanoparticle synthesis is further realized.

[0165] In addition, on the bottom plate 4100, a buffer replacement unit capable of performing buffer replacement and / or concentrating nanoparticles on the liquid nanoparticles can also be provided, and / or a filtering unit capable of making the nanoparticles more uniform or filtering impurities and / or bacteria from the liquid nanoparticles.

[0166] In the synthesis of liposome nanoparticles, it is necessary to remove alcohol in the solution, or / and perform buffer replacement, so that the solution in which the nanoparticles are dissolved can meet the requirements of cell culture and animal experiments. At the same time, methods such as ultrafiltration can realize the concentration of nanoparticle concentration, so as to meet the concentration requirements of subsequent experiments. In the present application, the buffer replacement unit can be selected from one or more of an ultrafiltration unit, a dialysis unit, an exchange unit, and a filtration unit.

[0167] Regarding the ultrafiltration unit, as shown in FIGS. 10 and 11, it can include an ultrafiltration container 7110 and an ultrafiltration membrane 7120 arranged in the ultrafiltration container. Therefore, the liquid nanoparticles can be moved to one side 7120 (in the present application, the upper side) of the ultrafiltration membrane by the pipetting module, and further ultrafiltration is performed by positive pressure (such as a pressure supply module 1000) or negative pressure (another vacuum extraction device needs to be arranged). Regarding the pore size of the ultrafiltration membrane, it can be selected according to the components to be removed, and the pore size is larger than the components to be removed (such as alcohol, free drugs, etc.), but smaller than the size of the nanoparticles. The nanoparticles cannot pass through the ultrafiltration membrane because the diameter is larger than the pore size of the ultrafiltration membrane. After the above ultrafiltration is performed once, the required buffer can be moved into one side 7120 (in the present application, the upper side) of the ultrafiltration membrane by the pipetting module, and after mixing, the nanoparticles mixed with the buffer are moved out by the pipetting module. Of course, the ultrafiltration can also be repeated multiple times to achieve the purpose of multiple washing, and then the nanoparticles finally mixed with the buffer are moved out by the pipetting module.

[0168] As to the dialysis unit, as shown in FIG. 12, it can include a dialysis accommodating part 7210 and a dialysis membrane 7220 arranged in the dialysis accommodating part. Thus, the liquid nanoparticles can be pipetted by the pipetting module to one side (in this application, the inner side) of the dialysis membrane 7220, and the buffer solution can be arranged on the other side of the dialysis membrane 7220 by the pipetting / presetting mode, so as to perform dialysis. The pore size of the dialysis membrane can be selected according to the components to be removed, which is larger than the components (such as alcohol, free drugs, etc.) to be removed, but smaller than the size of the nanoparticles. As to the arrangement / removal mode of the dialysis membrane 7220 in the dialysis accommodating part 7210, it can be preset, manually arranged / removed or arranged / removed by another mechanical arm. Of course, the buffer solution can be replaced by the pipetting module for multiple times, so as to perform multiple dialysis. The liquid nanoparticles after dialysis can be removed by the pipetting module.

[0169] As to the exchange unit, as shown in FIG. 13, it can include an exchange column body 7320 and an exchange accommodating part 7310 arranged at the lower part of the exchange column body. Thus, the liquid nanoparticles can be pipetted by the pipetting module into the exchange column body 7320, and the liquid nanoparticles can pass through the exchange column body 7320 into the exchange accommodating part 7320 at the lower part thereof by gravity, so as to remove the components to be removed which are adsorbed in the exchange column body 7320, thereby achieving the purpose of removing the unnecessary solution components. As to the mode of arranging the exchange column body 7320 at the upper part of the exchange accommodating part 7310, the exchange column body 7320 can be moved to the upper part of the exchange accommodating part 7310 by another mechanical arm, and the exchange column body 7320 can be removed by the mechanical arm after the buffer solution replacement is completed; or a support can be arranged on the exchange accommodating part 7310, and the exchange column body 7320 can be manually placed on the support, and the exchange column body 7320 can be manually removed after the buffer solution replacement is completed. In addition, the pressure supply module 1000 can be used to apply air pressure to the exchange column body with the liquid nanoparticles, so as to accelerate the exchange speed.

[0170] In addition, as shown in FIG. 14 and FIG. 15, the filtration unit can include a filtration accommodating portion 7410 and a filtration membrane 7420 arranged in the filtration accommodating portion 7410. Thus, the liquid nanoparticles (freshly synthesized liquid nanoparticles or liquid nanoparticles after any of the above buffer replacement units) can be pipetted by the pipetting module to one side (the upper side in this application) of the filtration membrane 7420, and further filtered by positive pressure (such as the pressure supply module 1000) or negative pressure (another vacuum device needs to be arranged) to further obtain nanoparticles with more uniform particle size, or remove impurities in the nanoparticle solution, or sterilize by removing bacteria in the solution. The pore size of the filtration membrane is selected according to the size of the nanoparticles and the impurities to be removed. The pore size needs to be larger than the size of the nanoparticles and smaller than the size of the impurities. The desired nanoparticles are smaller than the filtration membrane and can pass through the filtration membrane, while the impurities, bacteria, etc. to be removed are larger than the pore size of the filtration membrane and cannot pass through the filtration membrane. Of course, as described above, the above filtration membrane 7420 can be arranged or removed by manual / mechanical arm.

[0171] Regarding the above accommodating portions (such as the storage accommodating portion, the collection accommodating portion, the mixing accommodating portion, the ultrafiltration accommodating portion 7110, the dialysis accommodating portion 7210, the exchange accommodating portion 7310, the filtration accommodating portion 7410, etc.), each of the accommodating portions can be provided by a separate container (such as a liquid storage tube, specifically a centrifuge tube, etc.), or some or all of them can be provided by a container with multiple accommodating portions (such as a microwell plate, specifically a 96-well, 48-well, 24-well, etc.).

[0172] Thus, the device of the present application can further include a plurality of accommodating portions, wherein, preferably, two or more of the accommodating portions are pre-provided with raw materials (such as the above storage accommodating portion); preferably, one or more of the accommodating portions are empty (such as the above mixing accommodating portion and the collection accommodating portion); preferably, one or more of the accommodating portions are pre-provided with an ultrafiltration membrane 7120 (such as the above ultrafiltration unit); preferably, one or more of the accommodating portions are pre-provided with a dialysis membrane 7220 (such as the above dialysis unit); preferably, the upper part of one or more of the accommodating portions is provided with an exchange column 7320 (such as the above exchange unit); and preferably, one or more of the accommodating portions are pre-provided with a filtration membrane 7420 (such as the above filtration unit). Of course, the above ultrafiltration membrane 7120, dialysis membrane 7220, exchange column 7320 and / or filtration membrane 7420 are only arranged on the bottom plate, and when synthesizing nanoparticles, they are placed in the corresponding position of the corresponding accommodating portion by manual / mechanical arm.

[0173] At present, the above-mentioned device (see FIGS. 1-9, etc.) developed by the applicant has been experimentally verified for automatic nanoparticle formula screening based on microfluidic technology. Only by placing the raw materials (such as aqueous phase, organic phase liquid) and consumables (such as gun head, sealing gasket) required for nanoparticle synthesis, and collecting containers (such as well plate / centrifuge tube), and configuring the reagents in the control system (such as the software of the above-mentioned control assembly) of the device and setting the synthesis parameters (such as total flow rate and flow rate ratio of each phase reagent, synthesis volume), the device can automatically screen up to 96 formulas within 1 hour, greatly shortening the time and manpower required for formula / drug screening. At the same time, the volume of each sample synthesis can be as low as 20 μl, greatly reducing the consumption of samples, thereby saving a large amount of material cost.

[0174] The nanoparticle synthesis using the device provided in the present application (see FIGS. 1-9) specifically includes the following procedures:

[0175] 1. Consumable / reagent preparation

[0176] 1) Place the containers (storage 96-well plate and liquid pool) storing the liquid phase liquid (such as aqueous phase and organic phase), collecting containers (collecting 96-well plate) on the corresponding base and then on the bottom plate; place the microfluidic chip on the chip tray and then on the bottom plate; place other consumables (pipette gun head, sealing gasket) on the base and then on the equipment bottom plate;

[0177] 4) Set the reagent library preparation, reagent library configuration, and nanoparticle synthesis parameters (including total flow rate, flow rate ratio of different reagents, and synthesis volume) through software.

[0178] 2. Reagent library preparation (optional)

[0179] Mix and dilute the reagents in the wells of different storage 96-well plates or in the liquid pool using a pipette to obtain nanoparticle synthesis reagents mixed with different raw materials or different concentrations.

[0180] If reagent library preparation is not required, the pre-prepared nanoparticle synthesis reagents can be placed in the corresponding storage 96-well plate and liquid pool and directly configured in the software.

[0181] 3. Nanoparticle synthesis

[0182] The microfluidic chip contains four reaction combinations as described above. Once, four reaction combinations on the chip can be pressurized at the same time to realize the synthesis of four samples.

[0183] 1) Multi-channel pipette picks up the gun head and moves above the online dilution liquid storage pool, and sucks 100 μl x 4 online dilution liquid (as an example of 1:1 dilution);

[0184] 2) The pipette moves above the microfluidic chip outlet, and the online diluent is released into the 4 outlets;

[0185] 3) The pipette changes the gun head;

[0186] 4) The pipette moves above the storage 96-well plate, and 75 μl x 4 of the aqueous phase reagent (nucleic acid solution) is sucked up;

[0187] 5) The pipette moves above the microfluidic chip aqueous phase reagent inlet, and the aqueous phase reagent is released into the 4 aqueous phase reagent inlets;

[0188] 6) The pipette changes the gun head;

[0189] 7) The pipette moves above the storage 96-well plate, and 25 μl x 4 of the organic phase reagent (lipid solution) is sucked up;

[0190] 8) The pipette moves above the microfluidic chip organic phase reagent inlet, and the organic phase reagent is released into the 4 organic phase reagent inlets;

[0191] 9) The pipette gun head is removed;

[0192] 10) The platen assembly moves above the gasket storage base, and the gasket fixing assembly picks up a new gasket;

[0193] 11) The platen assembly moves above the microfluidic chip containing the reagent, and the platen assembly is lowered, the platen body contacts and seals the microfluidic chip through the gasket;

[0194] 12) After the pressure module is pressurized to a certain pressure, the first control valve and the second control valve are switched at the same time to supply gas to the microfluidic chip, and the aqueous phase and the organic phase reagent in the microfluidic chip inlet are driven at the same time to enter the flow channel in the microfluidic chip at a certain flow rate to mix, synthesize 100 μl of nanoparticle solution, and drive the nanoparticle solution into the microfluidic chip outlet;

[0195] 13) The first control valve and the second control valve are switched to connect the microfluidic chip inlet to the atmosphere, and the liquid storage tank is depressurized, so that the reagent no longer flows, and the nanoparticle synthesis is completed;

[0196] 14) The platen assembly rises together with the gasket and leaves the microfluidic chip;

[0197] 15) The platen assembly moves away and removes the gasket to the consumable recovery chamber;

[0198] 16) The pipette picks up the gun head, moves above the microfluidic chip outlet, and sucks up 200 μl x 4 of the synthesized nanoparticle solution;

[0199] 17) The pipette moves above the collection 96-well plate, and 200 μl x 4 of the nanoparticle solution is released into the corresponding hole;

[0200] 18) Pipette tip is removed to the consumable recycling chamber (i.e. the recycling zone described above);

[0201] 19) Steps 1-18 are repeated for the synthesis of the next set (4 samples) of samples;

[0202] 20) When all the microfluidic chips on one microfluidic chip base are synthesized, the platen module is moved to the top of the next microfluidic chip base with microfluidic chips and steps 1-18 are repeated for the synthesis of samples

[0203] 21) Synthesis is complete.

[0204] Although the foregoing application has been described in some detail to provide a clear understanding of the application presented, various embodiments described above are merely illustrative of certain specific embodiments thereof and are indicative of the present application as defined by the appended claims. Numerous and various modifications as well as substitutions of equivalents therefore are permissible without departing from the scope of the present application as defined in the claims.

Claims

1. An apparatus for automated synthesis of nanoparticles, wherein, The device comprises: a pressure supply module, which is provided with one or more gas outlets corresponding to the inlets of the microfluidic chip, so as to supply or stop supplying gas to the inlets of the microfluidic chip through the gas outlets; a pipetting module, which is capable of pipetting into the inlets of the microfluidic chip; a movement module, which is capable of moving the pressure supply module and the pipetting module in the horizontal direction and in the vertical direction.

2. The device of claim 1, wherein the pressure supply module comprises: a pressure plate assembly; a gas supply assembly, which is capable of supplying gas to the gas outlets.

3. The device of claim 2, wherein the pressure plate assembly comprises: a pressure plate body; the gas inlets and the gas outlets are arranged on the pressure plate body; a gas flow channel is arranged in the pressure plate body for connecting the gas inlets and the gas outlets.

4. The device of claim 3, wherein the gas inlets comprise at least a first gas inlet and a second gas inlet; the gas outlets comprise at least a first gas outlet and a second gas outlet; the gas flow channel comprises at least a first flow channel and a second flow channel; wherein the first gas outlet is used to supply or stop supplying gas to the first phase inlet of the microfluidic chip; the second gas outlet is used to supply or stop supplying gas to the second phase inlet of the microfluidic chip; the first flow channel is used to connect the first gas inlet and the first gas outlet; the second flow channel is used to connect the second gas inlet and the second gas outlet.

5. The device of claim 4, wherein the pressure plate assembly further comprises: a first control valve and a second control valve, each of which comprises at least a first interface, a second interface, and a third interface, and is capable of switching between the communication between the first interface and the second interface and the communication between the first interface and the third interface; a first connection port group and a second connection port group, each of which is arranged on the pressure plate body and comprises at least a first connection port, a second connection port, and a third connection port; wherein the first interface of the first control valve is connected to the first gas outlet through the first connection port of the first connection port group and the gas flow channel, the second interface of the first control valve is connected to the first gas inlet through the second connection port of the first connection port group and the gas flow channel, and the third interface of the first control valve is in communication with the atmosphere; the first interface of the second control valve is connected to the second gas outlet through the first connection port of the second connection port group and the gas flow channel, the second interface of the second control valve is connected to the second gas inlet through the second connection port of the second connection port group and the gas flow channel, and the third interface of the second control valve is in communication with the atmosphere.

6. The device of claim 5, wherein the gas supply assembly comprises at least: a first gas tank and a second gas tank, the inlets of the first gas tank and the second gas tank are each independently connected to a gas source; wherein the outlet of the first gas tank is connected to the first gas inlet; the outlet of the second gas tank is connected to the second gas inlet.

7. The device of claim 6, wherein the pressure supply module further comprises: A control assembly independently controls the gas source to supply gas to the first and second gas tanks.

8. The device of claim 3, wherein, The pressure supply module further comprises: A sealing gasket having a through hole corresponding to the gas outlet, the sealing gasket being disposed on the side of the pressure plate body where the gas outlet is disposed to seal when the gas outlet supplies or stops supplying gas to the inlet of the microfluidic chip.

9. The device of claim 8, wherein, A filter is disposed on the through hole of the sealing gasket corresponding to the gas outlet.

10. The device of claim 8, wherein, The pressure supply module further comprises: A sealing gasket fixing assembly, the sealing gasket assembly being capable of fixing the sealing gasket on the side of the pressure plate body where the gas outlet is disposed and disengaging the sealing gasket from the pressure plate body.

11. The device of claim 10, wherein, The pressure plate body is provided with a magnetic passage; The sealing gasket fixing assembly is located on the opposite side of the pressure plate body where the gas outlet is disposed; The sealing gasket fixing assembly comprises: A magnetic unit; A first movement unit capable of driving the magnetic unit through the magnetic passage to magnetically attract the sealing gasket and disengage the sealing gasket from the pressure plate body.

12. The device of claim 11, wherein, The first movement unit comprises: A magnetic unit fixing plate fixing the magnetic unit; A first motor capable of driving the magnetic unit fixing plate to approach or move away from the pressure plate body.

13. The device of claim 1, wherein, The pipetting module comprises: A pipetting unit capable of sucking and discharging liquid.

14. The device of claim 13, wherein, The pipetting unit is a pipetting gun, which is a single-channel pipetting gun or a multi-channel pipetting gun; The pipetting module further comprises: A second movement unit capable of driving the control button of the pipetting gun to perform pipetting; A third movement unit capable of driving the tip eject button of the pipetting gun to eject the tip.

15. The device of claim 14, wherein, The movement module comprises: A fixing assembly; A horizontal movement assembly capable of driving the fixing assembly to move in the horizontal direction; A vertical movement assembly, the pressure supply module and the pipetting module being disposed on the fixing assembly, the vertical movement assembly being capable of independently driving the pressure supply module and the pipetting module to move in the vertical direction.

16. The device of claim 15, wherein, The horizontal movement assembly comprises: A first horizontal movement unit capable of driving the fixing assembly to move in a first horizontal direction; A second horizontal movement unit capable of driving the first horizontal movement unit to move in a second horizontal direction.

17. The device of claim 16, wherein, The first horizontal movement unit comprises: A first horizontal movement unit capable of driving the fixing assembly to move in a first horizontal direction; A second horizontal movement unit capable of driving the first horizontal movement unit to move in a second horizontal direction. a first guide rail, disposed along a first horizontal direction, a fourth movement unit capable of driving the fixed assembly to slide along the first guide rail; and / or, the second horizontal movement unit comprises: a second guide rail, disposed along a second horizontal direction, a fifth movement unit capable of driving the first horizontal movement unit to slide along the second guide rail.

18. The device of claim 15, wherein, the vertical movement assembly comprises: a first vertical movement unit capable of driving the pressure supply module to move in a vertical direction; a second vertical movement unit capable of driving the pipette module to move in a vertical direction.

19. The apparatus of claim 1, wherein, Further comprising: a box module containing the pressure supply module, the pipette module, and the movement module; and, an air filtration module disposed on the box module.

20. The device of claim 1, wherein, further comprising a plurality of containing portions.

21. The device of claim 20, wherein, two or more of the containing portions are pre-provisioned with raw materials; one or more of the containing portions are empty containing portions; one or more of the containing portions are pre-provisioned with ultrafiltration membranes; one or more of the containing portions are pre-provisioned with dialysis membranes; an upper portion of one or more of the containing portions is provided with an exchange column; and / or, one or more of the containing portions are pre-provisioned with filtration membranes.

22. The device of claim 20, wherein, one or more of the containing portions are empty containing portions; the device further comprises ultrafiltration membranes, dialysis membranes, exchange columns, and / or filtration membranes.

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