Rotary microfluidic circulation microsphere preparation system and preparation method thereof

Abstract

The invention discloses a rotary microfluidic circulation microsphere preparation system and a preparation method thereof.The rotary microfluidic circulation microsphere preparation system comprises a microsphere preparation device and a microsphere circulation device, the microsphere preparation device comprises a multi-channel microfluidic liquid drop generation part and a rotary microsphere preparation part, and the multi-channel microfluidic liquid drop generation part comprises a plurality of independent liquid drop variable-diameter distribution pressure control channels; the liquid drop variable-diameter distribution pressure control channel is used for distributing and controlling the pressure for generating liquid drops step by step; the rotating microsphere preparation part comprises a rotating disc and a fixed disc, the inlet end of the rotating disc corresponds to the liquid drop variable-diameter distribution pressure control channel, the outlet end of the rotating disc is communicated to the fixed disc through a micropore array, the outlet end of the fixed disc is connected with a microsphere circulating device, and the microsphere circulating device is used for separating microspheres from preparation liquid. The preparation liquid is circularly returned to the inlet end of the fixed disc so as to control the liquid level height of the preparation liquid; the device can efficiently, continuously and circularly prepare the microspheres, and meanwhile, can ensure the high consistency of the particle sizes of the microspheres.

Description

Technical Field

[0001] The present invention belongs to the technical field of microfluidic microsphere preparation, and relates to a rotary microfluidic circulation microsphere preparation system and a preparation method thereof. Background Art

[0002] Microfluidic technology realizes microsphere preparation by precisely controlling the flow and dispersion of multiphase fluids in the channels of a microfluidic chip. For example, in the patent application with the patent number "CN114534590A", a rotary sleeve microfluidic device and method for controllably preparing monodisperse double emulsions are disclosed. By setting a rotating platform to drive a collection container to rotate, and through the cooperation of a constant pressure pump and a nested injection tube, droplets are injected into the preparation liquid in the collection container to form microspheres. However, the microsphere preparation device in the above patent application has the following defects:

[0003] 1. For high-viscosity liquids, such as when injecting HA fluid, it is easy to cause blockage of the flow channels on the microfluidic chip and the nested injection tube, and it is difficult to control the pressure of the fluid in the channels of the microfluidic chip only by a constant pressure pump, thereby affecting the uniformity of the particle size and the preparation efficiency of the finally prepared microspheres;

[0004] 2. The generated microspheres deposit inside the collection container, causing the liquid level inside the collection container to rise. At the same time, the presence of microspheres also disturbs the rotational flow field of the preparation liquid, making it difficult to keep the distance between the nested injection tube and the liquid surface constant, further affecting the uniformity of the particle size of the generated microspheres;

[0005] 3. After a large amount of microspheres accumulate in the collection container, coupled with the rotational disturbance of the preparation liquid, the microspheres fuse with each other, affecting the quality of the prepared microspheres.

[0006] Therefore, aiming at the defects of difficult control of the particle size uniformity of microspheres and insufficient microsphere production efficiency in the existing microfluidic microsphere preparation technology, the present invention discloses a rotary microfluidic circulation microsphere preparation system and a preparation method thereof. Summary of the Invention

[0007] The purpose of the present invention is to provide a rotary microfluidic circulation microsphere preparation system and a preparation method thereof, which can efficiently and continuously circulate to prepare microspheres, and at the same time can ensure a high degree of consistency in the particle size of the microspheres.

[0008] The present invention is achieved by the following technical solutions:

[0009] A rotary microfluidic circulation system for preparing microspheres, comprising a microsphere preparation device and a microsphere circulation device. The microsphere preparation device includes a multi-channel microfluidic droplet generation part and a rotary microsphere preparation part. The multi-channel microfluidic droplet generation part includes a number of independent droplet diameter-variable distribution and pressure control channels, which are used to gradually distribute and control the pressure of the generated droplets. The rotary microsphere preparation part includes a rotating disk and a fixed disk with preparation liquid inside. The inlet end of the rotating disk is arranged corresponding to a number of droplet diameter-variable distribution and pressure control channels. The outlet end of the rotating disk is connected to the fixed disk through a microporous array. The outlet end of the fixed disk is connected to the microsphere circulation device. The microsphere circulation device is used to separate the microspheres from the preparation liquid and recycle the preparation liquid back to the inlet end of the fixed disk to control the relative distance between the liquid levels of the preparation liquid in the rotating disk and the fixed disk with respect to the outlet end of the droplet diameter-variable distribution and pressure control channels.

[0010] A constant pressure pump is used to supply high-viscosity liquid to the multi-channel microfluidic droplet generation part. After the high-viscosity liquid enters the interior of the multi-channel microfluidic droplet generation part, due to the poor fluidity of the high-viscosity liquid, a high-pressure initial power needs to be provided by the constant pressure pump to ensure the normal pumping of the high-viscosity liquid. During the process of the high-viscosity liquid passing through a number of droplet diameter-variable distribution and pressure control channels, the initial high-pressure high-viscosity liquid is evenly distributed and gradually decompressed through the droplet diameter-variable distribution and pressure control channels, ensuring that the high-viscosity liquid forms uniform droplets with a consistent height at a suitable low pressure and flow rate and then drips into the preparation liquid inside the rotating disk, thereby realizing the high-efficiency multi-channel preparation of microspheres from high-viscosity liquid and improving the efficiency of microsphere production. Moreover, when the liquid passes through the droplet diameter-variable distribution and pressure control channels, the pressure of the liquid finally injected into the inside of the rotating disk is regulated by the gradual diameter variation of the droplet diameter-variable distribution and pressure control channels, thereby ensuring the consistency of the particle diameters of the formed droplets. The rotating disk rotates at a constant speed relative to the fixed disk. The droplets formed after passing through the droplet diameter-variable distribution and pressure control channels enter the preparation liquid to form microspheres, and the centrifugal force generated by the rotation of the rotating disk causes the microspheres to settle into the inside of the fixed disk through the microporous array, preventing the microspheres from accumulating in the rotating disk and affecting the liquid level height in the rotating disk. The microspheres settled in the fixed disk are further transported to the microsphere circulation device. The microsphere circulation device is used to separate the microspheres and the preparation liquid, retain the microspheres in the microsphere circulation device, and at the same time recycle the separated preparation liquid back to the fixed disk. By controlling the flow rate of the preparation liquid recycled back to the fixed disk, the liquid level heights in the fixed disk and the rotating disk are maintained constant, further ensuring the consistency of the formation of microspheres after the droplets enter the preparation liquid.

[0011] To better implement the present invention, further, the multi-channel microfluidic droplet generation part includes a liquid distribution disk, a dropper module, and a liquid distribution tube. Inside the liquid distribution disk, a number of mutually independent droplet diameter-changing distribution and pressure control channels are evenly arranged along the circumferential direction. The end with the largest diameter of the droplet diameter-changing distribution and pressure control channel is connected to the outlet end of the liquid distribution tube, and the end with the smallest diameter of the droplet diameter-changing distribution and pressure control channel is detachably connected to the dropper module. The outlet end of the dropper module extends downward above the liquid level inside the rotating disk.

[0012] To better implement the present invention, further, the droplet diameter-changing distribution and pressure control channel includes a first channel, a second channel, and a third channel that are coaxially connected in sequence. The diameters of the first channel, the second channel, and the third channel decrease in sequence.

[0013] To better implement the present invention, further, it further includes a lifting and rotating device. The lifting and rotating device includes a lifting part and a rotating part. The lifting part is used to drive the liquid distribution disk to lift to adjust the height of the liquid distribution disk, and the rotating part is used to drive the liquid distribution disk to flip.

[0014] To better implement the present invention, further, a fixed disk is coaxially arranged outside the rotating disk. A microporous array is arranged at the edge of the bottom plate of the rotating disk. The internal environment of the rotating disk is communicated with the internal environment of the fixed disk through the microporous array. The bottom of the fixed disk is connected to the inlet end of the microsphere circulation device.

[0015] To better implement the present invention, further, it further includes a distance detection device and a rotation speed detection device. The distance detection device is used to detect in real time the distance between the outlet end of the dropper module and the liquid level inside the rotating disk, and the rotation speed detection device is used to detect in real time the rotation speed of the rotating disk.

[0016] To better implement the present invention, further, the microsphere circulation device includes a collection cylinder. An osmotic membrane is arranged inside the collection cylinder. A feed pipe and a microsphere output pipe are arranged at the bottom of the collection cylinder. A return pipe is arranged at the top of the collection cylinder. The feed pipe is connected to the outlet end of the fixed disk, the outlet end of the return pipe is connected to one side of the top of the fixed disk, and a peristaltic pump is arranged on the return pipe.

[0017] To better implement the present invention, further, solenoid valves are arranged on the feed pipe, the microsphere output pipe, and the return pipe.

[0018] A preparation method for rotating microfluidic circulation to prepare microspheres, which is implemented based on the above-mentioned rotating microfluidic circulation to prepare microsphere system, includes the following steps:

[0019] Step 1: Prepare a high-viscosity HA aqueous solution. The high-viscosity HA aqueous solution contains 1-3 wt% of HA and 0.1-1 wt% of NaOH. The viscosity of the high-viscosity HA aqueous solution is 100-160 mPas. Introduce the high-viscosity HA aqueous solution as the inner phase into the multi-channel microfluidic droplet generation part.

[0020] Step 2: Prepare a paraffin oil solution added with a surfactant. The content of the surfactant is 1-9 wt%. The viscosity of the paraffin oil solution is 50-60 mPas. Introduce the paraffin oil solution as the outer phase into the rotating microsphere preparation part.

[0021] Step 3: Use a constant-pressure pump to provide pressure for the inner-phase injection of the high-viscosity HA aqueous solution. After the high-viscosity HA aqueous solution passes through the pressure regulation of the droplet diameter-varying distribution pressure control channels in the multi-channel microfluidic droplet generation part, it flows out from the dropper module at a pressure of 500-2000 mBar.

[0022] Step 4: Drive the flow of the paraffin oil solution through the rotation of the rotating disk in the rotating microsphere preparation part to provide shear force to cut off the high-viscosity HA aqueous solution flowing out from the dropper module to form uniform microspheres. The rotation speed of the rotating disk is 20-80 r / min.

[0023] Step 5: Start the microsphere circulation device. Introduce the microspheres prepared in Step 4 into the collection cylinder in the microsphere circulation device through the bottom connecting pipe, and separate the microspheres from the paraffin oil solution in the collection cylinder. Return the separated paraffin oil solution to the inside of the fixed disk.

[0024] Step 6: After the separation and return of the paraffin oil solution in the collection cylinder are completed, release the microspheres prepared in the collection cylinder.

[0025] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0026] (1) By setting a number of droplet diameter-varying distribution pressure control channels in the multi-channel microfluidic droplet generation part, the present invention performs step-by-step distribution and pressure control on the liquid through the multi-stage diameter-varying structure of the droplet diameter-varying distribution pressure control channels, ensuring that the liquid finally flows out through the droplet diameter-varying distribution pressure control channels at an appropriate pressure to form uniform droplets with high consistency. Furthermore, it ensures that highly consistent microspheres are formed after the droplets enter the preparation liquid of the rotating disk, guaranteeing the preparation quality of the microspheres. At the same time, by setting a number of droplet diameter-varying distribution pressure control channels, synchronous preparation of multi-channel microspheres is achieved, significantly improving the preparation efficiency of the microspheres.

[0027] (2) The present invention forms a rotating microsphere preparation part with an inner and outer layer structure. By arranging a fixed disk outside the rotating disk to form the inner and outer layer structure, droplets enter the preparation liquid inside the rotating disk to form microspheres. The centrifugal force generated by the rotation of the rotating disk drives the microspheres to move to the bottom edge of the rotating disk, and the microspheres slowly fall into the fixed disk through the micropore array for temporary storage, avoiding the accumulation of microspheres in the rotating disk, which affects the liquid level height of the preparation liquid in the rotating disk, and at the same time avoiding the rotation of the preparation liquid in the rotating disk from causing the microspheres to fuse with each other;

[0028] (3) The present invention sets up a microsphere circulation device. Through the microsphere circulation device, the microspheres and the preparation liquid in the fixed disk are separated, so that the microspheres are retained in the rotating microsphere preparation part, and the separated preparation liquid circulates back to the fixed disk. By regulating the flow rate of the recycled preparation liquid, the liquid level heights of the preparation liquids in the fixed disk and the rotating disk are accurately regulated, ensuring that the distance between the liquid level of the preparation liquid and the droplets remains constant, and thus ensuring that the droplets slowly fall into the preparation liquid at a constant height to form microspheres with high consistency;

[0029] (4) The present invention sets up a droplet variable-diameter distribution and pressure control channel to gradually distribute and regulate the injection pressure of the liquid, replacing the structure of a single microchannel chip for regulating the liquid flow state in the prior art, enabling the high-viscosity liquid to finally form uniform droplets with high consistency at a suitable low pressure and flow rate after gradually reducing the pressure, and thus ensuring the high consistency of the finally prepared microspheres. Description of the Drawings

[0030] Figure 1 is a schematic structural diagram of a rotary microfluidic circulation microsphere preparation system;

[0031] Figure 2 is a schematic structural diagram of a multi-channel microfluidic droplet generation part;

[0032] Figure 3 is a schematic diagram of a droplet variable-diameter distribution and pressure control channel;

[0033] Figure 4 is a schematic structural diagram of a rotating microsphere preparation part;

[0034] Figure 5 is a schematic connection diagram of a fixed disk and a microsphere circulation device;

[0035] Figure 6 is a schematic diagram of a lifting and rotating device;

[0036] Figure 7 is a schematic internal structure diagram of a microsphere circulation device.

[0037] Wherein: A1 - microsphere preparation device; A2 - microsphere circulation device; A11 - multi-channel microfluidic droplet generation section; A12 - rotating microsphere preparation section; 1 - liquid distribution tray; 2 - dropper module; 3 - liquid distribution pipe; 4 - lifting and rotating device; 5 - collection cylinder; 6 - permeable membrane; 7 - droplet diameter-changing distribution and pressure control channel; 8 - rotating disk; 9 - fixed disk; 01 - first channel; 02 - second channel; 03 - third channel; 100 - microporous array; 41 - lifting section; 42 - rotating section. Detailed implementation mode

[0038] The following detailed descriptions are all illustrative and are intended to provide further explanations of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0039] It should be noted that the terms used herein are only for describing specific implementation modes and are not intended to limit the exemplary implementation modes of the present invention. As used herein, unless the present invention clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0040] For the convenience of description, if the words "upper", "lower", "left", and "right" appear in the present invention, they only represent the same directions as the upper, lower, left, and right of the attached drawings themselves, and do not limit the structure. They are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation of the present invention.

[0041] Term explanation part: The terms "installation", "connection", "connection", "fixation", etc. in the present invention should be understood in a broad sense. For example, it can be a fixed connection, a detachable connection, or an integral body; it can be a mechanical connection, an electrical connection, a direct connection, or an indirect connection through an intermediate medium. It can be an internal connection between two elements, or the interaction relationship between two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0042] Example 1:

[0043] A rotary microfluidic circulation microsphere preparation system according to this embodiment is as Figure 1As shown in the figure, it includes a microsphere preparation device A1 and a microsphere circulation device A2. The microsphere preparation device A1 includes a multi-channel microfluidic droplet generation part A11 and a rotating microsphere preparation part A12. The multi-channel microfluidic droplet generation part A11 includes a number of independent droplet diameter-variable distribution and pressure control channels 7, and the droplet diameter-variable distribution and pressure control channels 7 are used to gradually distribute and control the pressure for generating droplets; the rotating microsphere preparation part A12 includes a rotating disk 8 with a preparation liquid therein and a fixed disk 9. The inlet end of the rotating disk 8 is correspondingly arranged for a number of droplet diameter-variable distribution and pressure control channels 7. The outlet end of the rotating disk 8 is connected to the fixed disk 9 through a microporous array 100. The outlet end of the fixed disk 9 is connected to the microsphere circulation device A2. The microsphere circulation device A2 is used to separate microspheres from the preparation liquid and recycle the preparation liquid back to the inlet end of the fixed disk 9 to control the relative distance between the liquid levels of the preparation liquid in the rotating disk 8 and the fixed disk 9 relative to the outlet end of the droplet diameter-variable distribution and pressure control channels 7.

[0044] Inside the multi-channel microfluidic droplet generation part A11, a number of independent droplet diameter-variable distribution and pressure control channels 7 are provided to perform the consistent preparation of multi-channel droplets. When the liquid passes through the droplet diameter-variable distribution and pressure control channels 7, the pressure for generating droplets of the liquid is gradually distributed and regulated by the continuous change of the path diameter of the droplet diameter-variable distribution and pressure control channels 7, ensuring the consistency and uniformity of the multi-channel droplet diameters.

[0045] The rotating microsphere preparation part A12 is used to receive droplets. When the droplets fall into the preparation liquid inside the rotating disk 8, microspheres are formed. At the same time, the formed microspheres enter the fixed disk 9 through the microporous array 100 at the bottom of the rotating disk 8 under the action of the centrifugal force generated by the rotation of the rotating disk 8, avoiding the deposition of microspheres in the rotating disk 8, thus avoiding the disturbance of the liquid level height inside the rotating disk 8 by the microspheres and also avoiding the situation of a large amount of deposition and fusion of microspheres.

[0046] The microspheres inside the fixed disk 9 further enter the microsphere circulation device A2. The microsphere circulation device A2 separates the microspheres from the preparation liquid. The separated microspheres are intercepted and collected inside the microsphere circulation device A2, and the separated preparation liquid is recycled back to the inside of the fixed disk 9 under the action of the microsphere circulation device A2. And by controlling the flow rate of the recycled preparation liquid, the liquid levels inside the rotating disk 8 and the fixed disk 9 are controlled at a constant level, thereby ensuring the constancy of the distance between the droplets and the liquid level inside the rotating disk 8, ensuring that multiple droplets enter the preparation liquid at a consistent height, and realizing continuous cyclic preparation to obtain microspheres with high consistency.

[0047] Example 2:

[0048] A rotary microfluidic circulation microsphere preparation system in this example is improved on the basis of Example 1, such as Figure 2 and Figure 3As shown in the figure, the multi-channel microfluidic droplet generation unit A11 includes a liquid distribution disc 1, a dropper module 2, and a liquid distribution pipe 3. Inside the liquid distribution disc 1, a number of mutually independent droplet diameter-changing distribution and pressure control channels 7 are evenly arranged along the circumference. The end with the largest diameter of the droplet diameter-changing distribution and pressure control channel 7 is connected to the outlet end of the liquid distribution pipe 3, and the end with the smallest diameter of the droplet diameter-changing distribution and pressure control channel 7 is detachably connected to the dropper module 2. The outlet end of the dropper module 2 extends downward above the liquid level inside the rotating disc 8.

[0049] The liquid distribution disc 1 includes an upper disc body and a lower disc body that are joined together. At the center of the top of the upper disc body, there is a connection port, which is detachably connected to the outlet end of the liquid distribution pipe 3. At the center of the top of the lower disc body, corresponding to the outlet end of the liquid distribution pipe 3, there is a central cavity. Around the central cavity, a number of mutually independent droplet diameter-changing distribution and pressure control channels 7 are evenly spaced along the circumference. The end with the largest diameter of the droplet diameter-changing distribution and pressure control channel 7 communicates with the edge of the central cavity. On the bottom end face of the lower disc body, corresponding to the ends with the smallest diameter of a number of circumferentially evenly arranged droplet diameter-changing distribution and pressure control channels 7, there are installation ports, and the dropper module 2 is detachably installed in the installation ports. The inlet end of the dropper module 2 is docked with the end with the smallest diameter of the droplet diameter-changing distribution and pressure control channel 7, and the outlet end of the dropper module 2 extends downward above the liquid level of the preparation liquid inside the rotating disc 8.

[0050] The inlet end of the liquid distribution pipe 3 is connected to a constant pressure pump. The liquid is injected into the central cavity through the constant pressure pump, so that the liquid flows through the droplet diameter-changing distribution and pressure control channels 7 evenly distributed along the circumference around the central cavity. The extrusion pressure of the liquid is distributed and regulated through the multi-stage diameter-changing structure of the droplet diameter-changing distribution and pressure control channels 7, so that the liquid enters the dropper module 2 at a stable and appropriate pressure, and uniform droplets with high consistency are formed at the outlet end of the dropper module 2 and then drop into the preparation liquid in the rotating disc 8 to form microspheres.

[0051] Further, a circumferential sealing ring is provided between the upper disc body and the lower disc body for sealing to prevent liquid leakage.

[0052] Further, the droplet diameter-changing distribution and pressure control channel 7 includes a first channel 01, a second channel 02, and a third channel 03 that are coaxially connected in sequence. The diameters of the first channel 01, the second channel 02, and the third channel 03 decrease in sequence. Specifically, the diameter of the first channel 01 is 3 mm, the diameter of the second channel 02 is 2 mm, and the diameter of the third channel 03 is 1 mm. The depths of the first channel 01, the second channel 02, and the third channel 03 are all 1 mm.

[0053] Moreover, the connections between the first channel 01, the second channel 02, and the third channel 03 are connected by smooth transition arc surfaces to avoid sudden pressure changes at the connections between the channels.

[0054] Further, a rotating shaft for driving the rotating disk 8 to rotate is provided at the center of the rotating disk 8. The bottom end of the rotating shaft is connected to the output end of the speed reducer, and the input end of the speed reducer is connected to the output end of the motor through a belt transmission mechanism, thereby realizing driving the rotating disk 8 to rotate at a constant speed.

[0055] Embodiment 3:

[0056] A rotary microfluidic circulation microsphere preparation system according to this embodiment is improved on the basis of Embodiment 1 or 2, as Figure 1 and Figure 6 shown, and further includes a lifting and rotating device 4. The lifting and rotating device 4 includes a lifting part 41 and a rotating part 42. The lifting part 41 is used to drive the liquid distribution disk 1 to lift to adjust the height of the liquid distribution disk 1, and the rotating part 42 is used to drive the liquid distribution disk 1 to flip.

[0057] The lifting part 41 includes a lifting platform, a lifting screw rod, and a guiding rod. The rotating part 42 is arranged at the middle position of the lifting platform. Guiding sleeves slidably sleeved on the guiding rod are arranged at both ends of the lifting platform. At the same time, a lifting screw rod is rotatably arranged in parallel on one side of the guiding rod. The lifting screw rod is in threaded fit connection with the lifting platform. By rotating the lifting screw rod, the lifting platform is driven to lift in the vertical direction to adjust the height of the lifting platform. At the same time, the sliding fit between the guiding sleeve and the guiding rod is used to ensure that the lifting platform strictly lifts in the plumb direction.

[0058] The rotating part 42 includes a bearing seat, a rotating shaft, and a connecting seat. The bearing seat is arranged at the middle position of the lifting platform. A rotating shaft extending to the top of the liquid distribution disk 1 is rotatably arranged inside the bearing seat. A connecting seat is sleeved at one end of the rotating shaft close to the liquid distribution disk 1. The bottom of the connecting seat is connected to the top of the liquid distribution disk 1. By rotating the rotating shaft, the liquid distribution disk 1 can be driven to flip, so that the dropper module 2 at the bottom of the liquid distribution disk 1 can be flipped to the upward position, which is convenient for the replacement and maintenance of the dropper module 2.

[0059] Embodiment 4:

[0060] A rotary microfluidic circulation microsphere preparation system according to this embodiment is improved on the basis of any one of Embodiments 1-3, as Figure 4 and Figure 5 shown. A fixed disk 9 is coaxially arranged outside the rotating disk 8. A microporous array 100 is arranged at the edge of the bottom plate of the rotating disk 8. The internal environment of the rotating disk 8 is communicated with the internal environment of the fixed disk 9 through the microporous array 100. The bottom of the fixed disk 9 is connected to the inlet end of the microsphere circulation device A2.

[0061] At the edge of the bottom plate of the rotating disk 8, a number of micropores are evenly spaced circumferentially to form a micropore array 100. The diameter of the micropores is equal to or slightly larger than the diameter of the microspheres, ensuring that the microspheres can move to the edge of the bottom plate under the centrifugal force generated by the rotation of the rotating disk 8 and slowly fall into the interior of the fixed disk 9 through the micropore array 100.

[0062] Furthermore, the fixed disk 9 includes a cylindrical barrel and a funnel-shaped conical barrel provided at the bottom of the cylindrical barrel. The microspheres passing through the micropore array 100 enter the interior of the cylindrical barrel and slowly fall into the interior of the funnel-shaped conical barrel for collection. At the same time, there is a sufficient distance between the funnel-shaped conical barrel and the micropore array 100, reducing the influence of the rotating fluid inside the rotating disk 8 on the microspheres inside the funnel-shaped conical barrel.

[0063] Example 5:

[0064] A rotary microfluidic circulation microsphere preparation system according to this example is improved on the basis of any one of Examples 1-4, and further includes a distance detection device and a rotation speed detection device. The distance detection device is used to detect the distance between the outlet end of the dropper module 2 and the liquid level height inside the rotating disk 8 in real time, and the rotation speed detection device is used to detect the rotation speed of the rotating disk 8 in real time.

[0065] The distance detection device includes an infrared distance sensor provided at the outlet end of the dropper module 2 and a liquid level sensor provided inside the rotating disk 8. The liquid level height of the preparation liquid in the rotating disk 8 is detected in real time by the liquid level sensor. At the same time, the distance between the outlet end of the dropper module 2 and the liquid level of the preparation liquid in the rotating disk 8 is detected in real time by the infrared distance sensor, and the liquid level height and distance data are sent to an external computer. The rotation speed detection device includes a rotation speed sensor provided on the rotating shaft at the bottom of the rotating disk 8. The rotation speed of the rotating disk 8 is detected in real time by the rotation speed sensor, and the rotation speed data is sent to the external computer in real time. The external computer calculates and predicts the change of the distance between the outlet end of the dropper module 2 and the liquid level of the preparation liquid in real time according to the received liquid level height, distance parameter, and rotation speed parameter, and adjusts the rotation speed of the rotating disk 8 and the flow rate of the preparation liquid returned by the microsphere circulation device A2 to the interior of the fixed disk 9 in real time according to the change situation, so as to control the distance between the outlet end of the dropper module 2 and the liquid level at a constant level to ensure the consistency of the particle size of the finally formed microspheres.

[0066] Example 6:

[0067] A rotary microfluidic circulation microsphere preparation system according to this example is improved on the basis of any one of Examples 1-5, such as Figure 7As shown, the microsphere circulation device A2 includes a collection cylinder 5. An osmotic membrane 6 is provided inside the collection cylinder 5. A feed pipe and a microsphere output pipe are provided at the bottom of the collection cylinder 5. A reflux pipe is provided at the top of the collection cylinder 5. The feed pipe is connected to the outlet end of a fixed disk 9, and the outlet end of the reflux pipe is connected to one side of the top of the fixed disk 9. A peristaltic pump is provided on the reflux pipe.

[0068] Power is provided by the peristaltic pump to transport the microspheres and the preparation liquid accumulated inside the fixed disk 9 to the inside of the collection cylinder 5 through the feed pipe. The osmotic membrane 6 inside the collection cylinder 5 allows the preparation liquid to pass through but does not allow the microspheres to pass through. By setting the osmotic membrane 6, the microspheres are intercepted inside the collection cylinder 5. The preparation liquid passing through the osmotic membrane 6 is circulated back to the inside of the fixed disk 9 through the reflux pipe. By controlling the flow rate of the circulated preparation liquid, the liquid level height of the preparation liquid inside the fixed disk 9 and the rotating disk 8 is regulated to ensure that the distance between the outlet end of the dropper module 2 and the liquid level of the preparation liquid remains constant.

[0069] Furthermore, solenoid valves are provided on the feed pipe, the microsphere output pipe, and the reflux pipe. The opening and closing of the solenoid valves and the opening degree of the solenoid valves are controlled by an external computer, thereby realizing the on-off control of the feed pipe, the microsphere output pipe, and the reflux pipe and controlling the flow rate of the fluid in the feed pipe, the microsphere output pipe, and the reflux pipe.

[0070] Example 7:

[0071] A preparation method for rotating microfluidic circulation to prepare microspheres in this embodiment is realized based on the rotating microfluidic circulation microsphere preparation system described in any one of Examples 1-6, and specifically includes the following steps:

[0072] Step 1: Prepare a high-viscosity HA aqueous solution. The high-viscosity HA aqueous solution contains 1-3 wt% of HA by mass and 0.1-1 wt% of NaOH by mass. The viscosity of the high-viscosity HA aqueous solution is 100-160 mPas. The high-viscosity HA aqueous solution is introduced as the inner phase into the multi-channel microfluidic droplet generation part A11.

[0073] Step 2: Prepare a paraffin oil solution added with a surfactant. The content of the surfactant is 1-9 wt%. The viscosity of the paraffin oil solution is 50-60 mPas. The paraffin oil solution is introduced as the outer phase into the rotating microsphere preparation part A12.

[0074] Step 3: Provide pressure to the high-viscosity HA aqueous solution through a constant pressure pump for inner phase injection. After the high-viscosity HA aqueous solution passes through the pressure regulation of the droplet diameter variable distribution pressure control channel 7 in the multi-channel microfluidic droplet generation part A11, it flows out from the dropper module 2 at a pressure of 500-2000 mBar.

[0075] Step 4: Rotate the rotating disk 8 in the microsphere preparation part A12 to drive the flow of the paraffin oil solution to provide a shear force to cut off the high-viscosity HA aqueous solution flowing out of the dropper module 2 to form uniform microspheres. The rotation speed of the rotating disk 8 is 20 - 80 r / min;

[0076] Step 5: Start the microsphere circulation device A2, introduce the microspheres prepared in Step 4 into the collection cylinder 5 in the microsphere circulation device A2 through the bottom connecting pipe, and separate the microspheres from the paraffin oil solution in the collection cylinder 5, and send the separated paraffin oil solution back to the inside of the fixed disk 9;

[0077] Step 6: After the separation and return of the paraffin oil solution in the collection cylinder 5 are completed, release the microspheres prepared in the collection cylinder 5.

[0078] The above method for preparing microspheres by rotary microfluidic circulation can shear the high-viscosity internal phase liquid to form microspheres, solving the problem that the existing microfluidic chips usually have too small flow channels and too large internal resistance, resulting in too slow flow rates of the high-viscosity internal and external phases in the chip channels, and the external phase liquid cannot provide enough shear force required to cut the internal phase fluid, thus unable to cut the internal phase to form microspheres. This method adopts the method of storing the internal and external phase liquids separately in the fixed part and the rotating part, and forms a high-speed shear flow by rotating the external phase liquid to provide a large enough shear force to smoothly cut the high-viscosity internal phase liquid, overcoming the problem that when other microfluidic chips prepare high-viscosity internal phase microspheres, the flow rates of the internal and external phases are too slow and the shear force is too small to cut out microspheres.

[0079] The above is only a preferred embodiment of the present invention, and does not impose any form of limitation on the present invention. Any simple modification or equivalent change made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A rotary microfluidic circulation system for preparing microspheres, characterized in that, It includes a microsphere preparation device (A1) and a microsphere circulation device (A2). The microsphere preparation device (A1) includes a multi-channel microfluidic droplet generation part (A11) and a rotating microsphere preparation part (A12). The multi-channel microfluidic droplet generation part (A11) includes a number of independent droplet diameter-changing distribution and pressure control channels (7), and the droplet diameter-changing distribution and pressure control channels (7) are used to gradually distribute and control the pressure for generating droplets. The rotating microsphere preparation part (A12) includes a rotating disk (8) with a preparation liquid therein and a fixed disk (9). The inlet end of the rotating disk (8) is arranged corresponding to a number of droplet diameter-changing distribution and pressure control channels (7). The outlet end of the rotating disk (8) is connected to the fixed disk (9) through a microporous array (100). The outlet end of the fixed disk (9) is connected to the microsphere circulation device (A2), and the microsphere circulation device (A2) is used to separate microspheres from the preparation liquid and recycle the preparation liquid back to the inlet end of the fixed disk (9) to control the relative distance between the liquid levels of the preparation liquid in the rotating disk (8) and the fixed disk (9) relative to the outlet end of the droplet diameter-changing distribution and pressure control channels (7).

2. The rotary microfluidic circulation microsphere preparation system according to claim 1, wherein The multi-channel microfluidic droplet generation part (A11) includes a liquid separation disk (1), a dropper module (2), and a liquid separation tube (3). Inside the liquid separation disk (1), a number of independent droplet diameter-changing distribution and pressure control channels (7) are evenly arranged along the circumference. The end with the largest diameter of the droplet diameter-changing distribution and pressure control channel (7) is connected to the outlet end of the liquid separation tube (3). The end with the smallest diameter of the droplet diameter-changing distribution and pressure control channel (7) is detachably connected to the dropper module (2), and the outlet end of the dropper module (2) extends downward above the liquid level inside the rotating disk (8).

3. A rotary microfluidic circulation system for preparing microspheres according to claim 2, wherein The droplet diameter-changing distribution and pressure control channel (7) includes a first channel (01), a second channel (02), and a third channel (03) that are coaxially connected in sequence. The diameters of the first channel (01), the second channel (02), and the third channel (03) decrease in sequence.

4. A rotary microfluidic circulation system for preparing microspheres according to claim 3, characterized in that, A fixed disk (9) is coaxially arranged outside the rotating disk (8). A microporous array (100) is arranged at the edge of the bottom plate of the rotating disk (8). The internal environment of the rotating disk (8) is communicated with the internal environment of the fixed disk (9) through the microporous array (100). The bottom of the fixed disk (9) is connected to the inlet end of the microsphere circulation device (A2).

5. A rotary microfluidic circulation system for preparing microspheres according to claim 4, characterized in that, It also includes a distance detection device and a rotation speed detection device. The distance detection device is used to detect in real time the distance between the outlet end of the dropper module (2) and the liquid level height inside the rotating disk (8). The rotation speed detection device is used to detect in real time the rotation speed of the rotating disk (8).

6. The rotary microfluidic circulation microsphere preparation system according to claim 5, characterized in that, It also includes a lifting and rotating device (4). The lifting and rotating device (4) includes a lifting part (41) and a rotating part (42). The lifting part (41) is used to drive the liquid separation disk (1) to lift to adjust the height of the liquid separation disk (1). The rotating part (42) is used to drive the liquid separation disk (1) to flip.

7. A rotary microfluidic circulation system for preparing microspheres according to any one of claims 1-6, characterized in that The microsphere circulation device (A2) includes a collection cylinder (5). An osmotic membrane (6) is arranged inside the collection cylinder (5). A feed pipe and a microsphere output pipe are arranged at the bottom of the collection cylinder (5). A reflux pipe is arranged at the top of the collection cylinder (5). The feed pipe is connected to the outlet end of a fixed disk (9). The outlet end of the reflux pipe is connected to one side of the top of the fixed disk (9). A peristaltic pump is arranged on the reflux pipe.

8. A rotary microfluidic circulation system for preparing microspheres according to claim 7, characterized in that, Electromagnetic valves are arranged on the feed pipe, the microsphere output pipe, and the reflux pipe.

9. A preparation method for preparing microspheres by rotary microfluidic circulation, characterized in that, It includes the following steps: Step 1: Prepare a high-viscosity HA aqueous solution. The high-viscosity HA aqueous solution contains 1-3 wt% of HA and 0.1-1 wt% of NaOH. The viscosity of the high-viscosity HA aqueous solution is 100-160 mPas. The high-viscosity HA aqueous solution is introduced as the inner phase into the multi-channel microfluidic droplet generation part (A11). Step 2: Prepare a paraffin oil solution added with a surfactant. The content of the surfactant is 1-9 wt%. The viscosity of the paraffin oil solution is 50-60 mPas. The paraffin oil solution is introduced as the outer phase into the rotating microsphere preparation part (A12). Step 3: Use a constant pressure pump to provide pressure for the high-viscosity HA aqueous solution for inner phase injection. After the high-viscosity HA aqueous solution passes through the pressure regulation of the droplet diameter variable distribution and pressure control channel (7) in the multi-channel microfluidic droplet generation part (A11), it flows out from the dropper module (2) at a pressure of 500-2000 mBar. Step 4: The rotation of the rotating disk (8) in the rotating microsphere preparation part (A12) drives the flow of the paraffin oil solution to provide a shear force to cut off the high-viscosity HA aqueous solution flowing out from the dropper module (2) to form uniform microspheres. The rotation speed of the rotating disk (8) is 20-80 r / min. Step 5: Start the microsphere circulation device (A2). Introduce the microspheres prepared in Step 4 into the collection cylinder (5) in the microsphere circulation device (A2) through the bottom connecting pipe, and separate the microspheres from the paraffin oil solution in the collection cylinder (5). The separated paraffin oil solution is sent back to the inside of the fixed disk (9). Step 6: After the separation and return of the paraffin oil solution in the collection cylinder (5) are completed, release the microspheres prepared in the collection cylinder (5).

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