Flow-induced vibration type micro-channel reactor and application thereof

Abstract

The application discloses a flow-induced vibration type micro-flow channel reactor and application thereof, and relates to the technical field of micro-mixers. In the reactor, a lower bottom plate and an upper cover plate covering the lower bottom plate jointly form a micro-flow channel structure. The lower bottom plate is internally provided with a first liquid inlet, a second liquid inlet, a first liquid inlet flow channel and a second liquid inlet flow channel which are respectively communicated, a mixed flow channel, a liquid outlet flow channel and a liquid outlet. The first liquid inlet flow channel and the second liquid inlet flow channel are communicated with the mixed flow channel after converging at the terminal ends. The mixed flow channel is internally provided with a cantilever flexible thin plate which is fixed to the upper cover plate and extends along the downstream direction of fluid. After two streams of fluid converge into the mixed flow channel, the cantilever flexible thin plate only occurs fluid-structure coupling self-excitation vibration under the action of liquid flow without external excitation. Through the technical scheme, the micro-scale fluid mixing can be strengthened without introducing external energy field and complex flow channel structure, and the liquid mixing uniformity and continuous preparation stability are improved.

Description

Technical Field

[0001] This invention relates to the field of micromixer technology, and more particularly to a flow-induced vibration microfluidic reactor and its application in the preparation of lipid nanoparticles. Background Technology

[0002] Lipid nanoparticles (LNPs) are important delivery carriers for nucleic acid and gene drugs. Their particle size, particle size distribution uniformity, encapsulation efficiency, and structural stability are closely related to the mixing efficiency and mixing temperature of the two-phase feed solutions during preparation. Among existing LNP preparation methods, microchannel continuous preparation has gradually become an important technical route to replace traditional batch methods because it can achieve stable confluence and continuous reaction of two liquids within microscale channels.

[0003] However, in microfluidic reactors, the two liquid streams are typically in a low Reynolds number laminar flow state, and the mixing process mainly relies on molecular diffusion, which is slow and difficult to meet the requirements for rapid and uniform mixing in the formation of LNPs. To improve mixing efficiency, one type of existing technology uses external energy such as electric fields, acoustic fields, temperature fields, or mechanical vibrations to drive the vibration of movable components to disturb the flow field and promote mixing; however, this type of active approach has a complex structure, is difficult to integrate, and the external physical field or external excitation conditions may affect the stability of the nucleic acid active components.

[0004] Another approach employs a passive microfluidic reactor, which enhances local turbulence by incorporating fixed geometric disturbance structures within the mixing channels or by constructing complex two-dimensional or three-dimensional channel topologies. While this approach avoids external excitation, its mixing efficiency is often still quite sensitive to flow rate, with a significant decrease in efficiency at lower flow rates. Furthermore, complex channels or fixed mixing chip structures can lead to challenges such as difficult fabrication, inconvenient cleaning, susceptibility to clogging, and difficulties in scale-up engineering.

[0005] Therefore, there is an urgent need to provide a new passive microfluidic reactor that can effectively enhance local flow field disturbance and improve mixing efficiency after two liquids converge in the mixing channel without the need for external excitation, while avoiding the adverse effects of existing complex fixed turbulence structures on processing, cleaning and stable operation. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a flow-induced vibration microfluidic reactor and its application. By placing a cantilevered flexible plate fixed to the reactor's top cover within the mixed-flow channel after two liquids converge, the cantilevered flexible plate undergoes self-excited vibration due to fluid-structure interaction solely through liquid flow without external excitation. This continuously generates dynamic disturbance within the mixed-flow channel, enhancing interfacial renewal and mass transfer between the two liquids under laminar flow conditions, and improving liquid mixing uniformity. Furthermore, this approach eliminates the need for additional excitation devices, resulting in a simpler structure and higher system integration, which helps reduce device complexity and operating energy consumption. It also improves the process stability and application feasibility of the microfluidic reactor for lipid nanoparticle preparation.

[0007] To achieve the above objectives, the present invention provides a flow-induced vibration microchannel reactor, comprising a reactor bottom plate and a reactor top cover plate covering the reactor bottom plate; The reactor bottom plate is provided with a first liquid inlet, a first liquid inlet channel communicating with the first liquid inlet, a second liquid inlet, a second liquid inlet channel communicating with the second liquid inlet, a mixed flow channel, an outlet channel communicating with the mixed flow channel, and an outlet. The first liquid inlet channel and the second liquid inlet channel merge at the end and then communicate with the mixed flow channel. The mixed flow channel is provided with a cantilever flexible plate, which has a fixed end and a free end. The fixed end is fixed to the upper cover plate of the reactor, and the free end extends out of the mixed flow channel and extends in the downstream direction of the fluid. After the two fluids converge into the mixed flow channel through the first and second inlet channels, the cantilever flexible sheet undergoes fluid-structure interaction self-excited vibration under the action of liquid flow without external excitation.

[0008] In the above technical solution, preferably, the upper cover plate of the reactor is provided with a first liquid inlet adapter, a second liquid inlet adapter, and a liquid outlet adapter that are respectively connected to the first liquid inlet, the second liquid inlet, and the liquid outlet. The first liquid inlet adapter is perpendicular to the extension direction of the first liquid inlet channel, the second liquid inlet adapter is perpendicular to the extension direction of the second liquid inlet channel, and the liquid outlet adapter is perpendicular to the extension direction of the liquid outlet channel. The first liquid inlet, the second liquid inlet, and the liquid outlet have the same geometric interface.

[0009] In the above technical solution, preferably, the fixed end of the cantilever flexible thin plate is fixed to the upper cover plate of the reactor by embedding.

[0010] In the above technical solution, preferably, the characteristic length of the cantilever flexible thin plate in a static state accounts for 20% to 60% of the length of the mixed flow channel.

[0011] In the above technical solution, preferably, the characteristic width of the cantilever flexible thin plate in a static state accounts for 20% to 80% of the width of the mixed flow channel.

[0012] In the above technical solution, preferably, the characteristic height of the cantilever flexible thin plate in a static state accounts for 40% to 60% of the height of the mixed flow channel.

[0013] In the above technical solution, preferably, the plate body of the cantilever flexible thin plate is provided with a turbulence microstructure, which is at least one of fish scale protrusions, wave-like undulations or through holes.

[0014] In the above technical solution, preferably, the cantilever flexible sheet is detachably connected to the reactor top cover plate via a cantilever column; The upper part of the cantilever column is mechanically fitted with the upper cover plate of the reactor, and the connection part is sealed. The middle part of the cantilever column is provided with a through structure for the cantilever flexible thin plate to pass through and be fixed. The characteristic height of the cantilever column accounts for 40% to 80% of the width of the mixed flow channel.

[0015] In the above technical solution, preferably, the material of the cantilever flexible sheet is a polydimethylsiloxane (PDMS) film or a polyether ether ketone (PEEK) film. The portions of the reactor bottom plate and the reactor top cover plate that come into contact with the feed liquid are made of polypropylene, stainless steel, or polyetheretherketone.

[0016] The present invention also proposes the application of the fluid-induced vibration microfluidic reactor according to any one of the above technical solutions in the preparation of lipid nanoparticles, comprising: using a lipid ethanol phase solution and an aqueous buffer solution containing active ingredients as the first liquid and the second liquid, respectively, pumping them into the microfluidic reactor through the first liquid inlet and the second liquid inlet, and achieving mixing of the two phase solutions in the mixed flow channel by means of the fluid-structure coupling self-excited vibration of the cantilever flexible thin plate, for continuous preparation of lipid nanoparticles.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) By setting a cantilever flexible thin plate with one end fixed and the other end extending in the downstream direction of the fluid in the mixed flow channel, and making the cantilever flexible thin plate generate fluid-structure coupling self-excited vibration by relying only on the liquid flow under the condition of no external excitation, it can continuously disturb the flow field in the mixed flow channel without introducing additional sound field, electric field or mechanical drive mechanism, thereby strengthening the mixing process of the liquid entering the first liquid inlet channel and the second liquid inlet channel. While keeping the overall structure of the reactor relatively simple, the mixing uniformity in the channel is improved.

[0018] (2) By setting the cantilever flexible plate in the mixed flow channel after the two liquids converge, and combining the proportional relationship between the length, width and height of the cantilever flexible plate and the corresponding size of the mixed flow channel, the cantilever flexible plate can obtain a vibration response suitable for mixing enhancement under the target flow conditions, and take into account both flow capacity and disturbance capacity. This is conducive to forming more effective interface renewal and fluid exchange in the micro-scale flow channel, and improves mixing efficiency.

[0019] (3) By setting at least one of the fish scale structure, wave structure and perforation structure on the surface of the cantilever flexible thin plate, the local flow state of the surrounding fluid when the cantilever flexible thin plate vibrates can be further changed, the liquid contact and exchange opportunities can be increased, which is beneficial to improving the mixing adaptability under different working conditions and enhancing the reactor's ability to control the mixing process.

[0020] (4) By using cantilever columns to achieve a detachable connection between the cantilever flexible thin plate and the reactor cover plate, and by limiting the material of the liquid part and the material of the cantilever flexible thin plate, it is possible to ensure the structural stability and sealing of the reactor while facilitating the replacement of the vibrating thin plate or related components according to different liquid systems. This is beneficial to improving the reactor's maintenance convenience, reusability and adaptability to different lipid nanoparticle preparation conditions.

[0021] (5) By using this fluidized vibration microfluidic reactor for continuous mixing of lipid ethanol phase solution and aqueous buffer solution containing active ingredients, a continuous and stable mixing environment can be provided for the formation of lipid nanoparticles, which is beneficial to improving the consistency and continuity of the lipid nanoparticle preparation process. Attached Figure Description

[0022] Figure 1 This is a three-dimensional structural schematic diagram of a flow-induced vibration microchannel reactor disclosed in one embodiment of the present invention; Figure 2 This is a schematic diagram of the exploded structure of a flow-induced vibration microchannel reactor disclosed in one embodiment of the present invention; Figure 3 This is a schematic diagram of the structure of the bottom plate of a microfluidic reactor disclosed in one embodiment of the present invention; Figure 4 This is a schematic diagram of the structure of the reactor top cover plate disclosed in one embodiment of the present invention; Figure 5 This is a schematic diagram of the structure of the first liquid inlet adapter disclosed in one embodiment of the present invention; Figure 6 This is a schematic diagram of the assembly structure of the first liquid inlet adapter and the reactor top cover plate disclosed in one embodiment of the present invention; Figure 7 This is a schematic diagram of the structure of the first liquid inlet adapter disclosed in another embodiment of the present invention; Figure 8 This is a schematic diagram of the assembly structure of the first liquid inlet adapter and the reactor top cover plate disclosed in one embodiment of the present invention; Figure 9 This is a schematic diagram of the structure of a cantilever flexible thin plate disclosed in one embodiment of the present invention; Figure 10 This is a schematic diagram of an embodiment of the cantilever flexible thin plate disclosed in one embodiment of the present invention; Figure 11 This is a schematic diagram of the cantilever flexible thin plate according to another embodiment of the present invention; Figure 12 This is a schematic diagram of the cantilever flexible thin plate according to another embodiment of the present invention; Figure 13 This is a schematic diagram of the installation structure of a cantilever flexible thin plate and a cantilever column disclosed in one embodiment of the present invention; Figure 14 This is a schematic diagram of the disassembly and assembly structure of the cantilever flexible thin plate and cantilever column disclosed in another embodiment of the present invention; Figure 15 This is a schematic diagram of the installation structure of the cantilever flexible thin plate and cantilever column disclosed in another embodiment of the present invention; Figure 16 This is a schematic diagram of the disassembly and assembly structure of the cantilever flexible thin plate and cantilever column disclosed in yet another embodiment of the present invention. Figure 17 This is a schematic diagram of the disassembly and assembly structure of a cantilever flexible thin plate and a cantilever column disclosed in another embodiment of the present invention.

[0023] In the diagram, the correspondence between the components and the reference numerals is as follows: 1. Reactor bottom plate; 2. Reactor top cover plate; 3. Cantilever flexible thin plate; 4. First liquid inlet adapter; 5. Second liquid inlet adapter; 6. Liquid outlet adapter; 11. First liquid inlet; 12. First liquid inlet channel; 13. Mixed flow channel; 14. Liquid outlet channel; 15. Liquid outlet; 16. Second liquid inlet channel; 17. Second liquid inlet; 21. Cantilever column. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] The present invention will now be described in further detail with reference to the accompanying drawings: like Figure 1 and Figure 2 As shown, the fluidized vibrating microfluidic reactor provided by the present invention consists of a reactor bottom plate 1 and a reactor top cover plate 2 covering it, forming a closed microscale flow channel system. The microscopic cavity formed between the two is the functional space for liquid mixing. The reactor bottom plate 1 is etched with all the flow channel structures on the bottom plate substrate by precision machining methods (such as milling, injection molding, or photolithography), so that the entire reactor has a flat structure, which takes into account both the convenience of processing and manufacturing and the precision of flow channel size control.

[0026] like Figure 3 As shown, the reactor's lower bottom plate 1 is machined to form a first liquid inlet 11, a first liquid inlet channel 12 connected to the first liquid inlet 11, a second liquid inlet 17, a second liquid inlet channel 16 connected to the second liquid inlet 17, a mixing channel 13, an outlet channel 14 connected to the mixing channel 13, and an outlet 15. The first liquid inlet 11 and the second liquid inlet 17 are located at opposite ends of the reactor's lower bottom plate 1, converging towards the center via the first liquid inlet channel 12 and the second liquid inlet channel 16, respectively. The two streams of liquid to be mixed are transported via the first liquid inlet channel 12 and the second liquid inlet channel 16, respectively, and converge at a certain angle at their ends. The resulting mixture enters the mixing channel 13, and the end of the mixing channel 13 is sequentially connected to the outlet channel 14 and the outlet 15, thus forming a complete flow path on the bottom plate from dual-path liquid inlet, confluence and mixing, to single-path liquid outlet. This confluence-type flow channel design ensures that the two liquids generate opposing impacts and shears upon entering the mixing section, creating favorable initial turbulent conditions for subsequent flow-induced vibration mixing.

[0027] A cantilevered flexible plate 3 is installed within the mixed-flow channel 13. The cantilevered flexible plate 3 has a fixed end and a free end. The fixed end is fixed to the reactor cover plate 2, and the free end extends outward from the mixed-flow channel 13 and along the downstream direction of the fluid. The cantilevered flexible plate 3 is located in the main mixing region after the two liquid flows converge, and is used to form a fluid-structure interaction interface when the fluid passes through it. The fixed end is rigidly connected to the reactor cover plate 2, which constrains and supports the vibration of the plate. The free end extends freely along the downstream direction of the fluid in the mixed-flow channel 13, forming a typical cantilever beam boundary condition. The design of this boundary state has key mechanical significance: the stiffness gradient between the cantilever end and the constrained end makes it easy for the plate to form an initial deflection driven by pressure difference on one side when subjected to fluid impact. Then, under the positive feedback mechanism of fluid-structure interaction, the amplitude is continuously amplified. Finally, without any external excitation, the plate can maintain a continuous self-excited vibration state solely by the kinetic energy of the liquid flow itself.

[0028] In use, two liquids to be mixed (e.g., lipid ethanol phase and nucleic acid aqueous phase buffer) are pumped in through the first inlet 11 and the second inlet 17, respectively. After converging through their respective channels, they impact the frontal surface of the cantilever flexible plate 3 at a certain speed. After the two fluids converge through the first inlet channel 12 and the second inlet channel 16 and enter the mixing channel 13, they are subjected to continuous fluid dynamic impact. Under the condition of no external excitation, the cantilever flexible plate 3 undergoes flutter instability under the action of fluid-structure interaction, entering a state of large-amplitude periodic flapping. It undergoes fluid-structure interaction self-excited vibration only under the action of liquid flow, thereby inducing micro-eddies and secondary flows in the mixing channel 13, continuously stretching, folding and reconstructing the laminar interface, thus efficiently stretching and folding the contact interface of the two liquid phases, significantly shortening the effective distance of molecular diffusion, and achieving efficient and uniform mixing of the two liquids within a short channel length. The mixed liquid is then stably output to the downstream process through the outlet channel 14 and the outlet 15.

[0029] This technical solution does not rely on complex three-dimensional tortuous flow channels, nor on acoustic, electric, or magnetic field inputs. Instead, it directly converts the fluid's own kinetic energy into hybrid power, thereby achieving passive dynamic mixing. Compared to traditional passive mixers that rely on fixed geometric structures (such as spiral chips, interlaced patterns, etc.), the flow-induced vibration mechanism can maintain effective dynamic mixing over a wide flow velocity range, overcoming the inherent defect of traditional static passive mixers where mixing efficiency drops sharply at low flow velocities.

[0030] In this embodiment, by introducing a self-excited vibrating cantilevered flexible thin plate 3 into the mixing channel 13, the laminar mixing process, which is mainly based on molecular diffusion, is transformed into a dynamic mixing process accompanied by continuous disturbance. This can significantly improve the contact efficiency and mixing uniformity of the two-phase liquids in the microscale space, while retaining the engineering advantages of the microchannel device, such as simple structure and stable continuous operation.

[0031] like Figures 4 to 8 As shown, in the above embodiment, preferably, the reactor cover plate 2 is provided with a first liquid inlet adapter 4, a second liquid inlet adapter 5 and a liquid outlet adapter 6 respectively connected to the first liquid inlet 11, the second liquid inlet 17 and the liquid outlet 15. The first liquid inlet adapter 4 is perpendicular to the extension direction of the first liquid inlet channel 12, the second liquid inlet adapter 5 is perpendicular to the extension direction of the second liquid inlet channel 16, and the liquid outlet adapter 6 is perpendicular to the extension direction of the liquid outlet channel 14, so that the external pipeline is connected to the device along the normal direction of the cover plate. The first liquid inlet adapter 4 is vertically connected to the first liquid inlet 11, and the second liquid inlet adapter 5 is vertically connected to the second liquid inlet 17, forming a complete liquid inlet flow path. This allows the liquid to be mixed to smoothly enter the mixing channel 13. The liquid outlet adapter 6 is vertically connected to the liquid outlet 15, forming a complete liquid outlet flow path. This ensures that the uniformly mixed liquid can be stably transported to the downstream process. All three adapters are installed perpendicular to the extension direction of their corresponding channels, meaning the liquid flow direction of the adapter is orthogonal to the direction of the horizontally extending channel within the bottom plate. This design is based on the physical limitations of the actual device: the reactor is relatively thin. If the adapters are arranged parallel to the channels, it is unavoidable to set large-angle bends inside the bottom plate, increasing the difficulty of channel processing. Vertical arrangement allows external pipes to be inserted vertically from the top surface of the cover plate, resulting in the most compact structure and ensuring that the liquid can smoothly enter the horizontal channel without stagnation and flow out after mixing.

[0032] The first liquid inlet 11, the second liquid inlet 17, and the liquid outlet 15 have the same geometric interface, and their geometric shapes are completely consistent to unify the external connection standard. This ensures that they can be matched with standard Luer connectors or straight-through connectors and other common interface forms, avoiding the procurement and adaptation costs caused by dedicated interfaces. At the same time, it is convenient to directly connect with standard drive equipment such as syringe pumps and peristaltic pumps, which significantly reduces the difficulty of system integration and improves the flexibility of industrial applications.

[0033] During implementation, each adapter can be integrally machined with the cover plate, or it can be machined separately and then assembled with the cover plate and sealed at the connection to prevent liquid leakage under high pressure and ensure operational safety. The unified geometric interface can be adapted to standard Luer connectors, straight connectors or pagoda connectors for connection with syringes, pump lines or continuous liquid supply systems.

[0034] In this embodiment, by placing all three adapters on the upper cover and vertically connecting them to the corresponding flow channels, the inlet and outlet liquid paths can be made more regular, facilitating the arrangement of the external pumping system. By designing the three interfaces to be of the same geometric shape, the assembly complexity and changeover cost can be reduced, and the compatibility and maintenance convenience between the reactor and conventional fluid transport components can be improved.

[0035] like Figure 9 As shown, in the above embodiment, preferably, the fixed end of the cantilever flexible plate 3 is fixed to the upper cover plate 2 of the reactor by embedding, and the free end extends out of the mixing channel 13 and extends in the downstream direction of the fluid.

[0036] During implementation, a groove matching the cross-sectional profile of the fixed end of the cantilever flexible plate 3 can be pre-cut on the lower surface of the reactor cover plate 2 at the position corresponding to the mixing channel 13. After the fixed end of the cantilever flexible plate 3 is inserted into the groove, a stable constraint boundary is formed by mechanical fitting constraint and / or interference fit to achieve spatial clamping of the fixed end. If necessary, UV-curable adhesive can be used for sealing reinforcement to prevent liquid leakage or plate loosening during operation. With this installation method, the fixed end of the cantilever flexible plate 3 can provide reliable support when subjected to continuous impact from the converging liquid, while the free end can periodically flap in the downstream direction.

[0037] Specifically, compared to irreversible fixing methods such as riveting and bonding, the embedded connection method also offers excellent disassembly and assembly capabilities. When it is necessary to replace thin plates of different specifications, simply separate the cover plate from the base plate to easily remove and replace the corresponding embedded component at the fixing end.

[0038] In this embodiment, the structure of the fixed end embedded in the upper cover plate can form a clear and stable cantilever boundary condition, which is conducive to the repeated and stable generation of self-excited vibration of the cantilever flexible thin plate 3 under the action of liquid flow; at the same time, the free end is arranged to face downstream, which is conducive to the vibration direction coordinating with the mainstream flow direction and improving the coverage of the disturbance on the subsequent mixing area.

[0039] In the above embodiments, preferably, the characteristic length of the cantilever flexible plate 3 in a static state (i.e., the extension length of the plate along the axial direction of the mixing channel 13, which is equal to the axial distance from the free end to the fixed end of the cantilever) accounts for 20% to 60% of the length of the mixing channel 13.

[0040] During implementation, the length of the cantilever flexible thin plate 3 does not exceed the effective length of the mixing channel 13. Instead, it is arranged in an appropriate proportion within the front to middle section of the mixing channel 13, ensuring that it can fully enter the main mixing zone without excessively extending to the outlet side and affecting the stable discharge of the mixture. For operating conditions with lower flow rates or longer mixing times, a relatively larger length proportion can be selected within the above range to expand the disturbed area; for operating conditions with higher pressure drop control requirements, a relatively smaller length proportion can be selected to balance dynamic response and flow smoothness.

[0041] Specifically, the determination of this ratio range is based on the following two engineering considerations: First, the lower limit of the characteristic length of the thin plate must meet the self-excitation condition of flow-induced vibration, that is, the thin plate must have sufficient exposed area in the mixed flow channel 13 so that the fluid can form a stable Karman vortex street or flutter boundary layer separation at the free end of the thin plate, thereby providing continuous vibration excitation for the thin plate. Engineering experience and fluid dynamics analysis show that when the characteristic length is less than 20% of the effective length of the mixed flow channel 13, the fluid excitation force on the thin plate is insufficient to overcome the bending stiffness of the material, making it difficult to establish continuous self-excited vibration. Second, the upper limit of the characteristic length of the thin plate is constrained by the steady flow requirement in the mixed flow channel 13. A sufficiently long undisturbed flow section must be reserved behind the thin plate so that the liquid after mixing can gradually return to a stable laminar flow before entering the outlet flow channel 14, avoiding the local pulsating flow caused by vibration from being carried into subsequent processes. When the characteristic length exceeds 60% of the effective length of the mixed flow channel 13, the eddy currents caused by the vibration of the thin plate will extend to the inlet of the liquid outlet channel 14, resulting in fluctuations in the liquid outlet pressure, which is not conducive to continuous and stable preparation.

[0042] In this embodiment, the length of the cantilever flexible plate 3 is limited to 20% to 60% of the length of the mixing channel 13, which is beneficial to establish stable flow-induced vibration in the effective mixing zone, while taking into account the flow resistance and the stability of the mixed liquid output, thereby achieving a balance between the mixing enhancement effect and the process controllability.

[0043] In the above embodiments, preferably, the characteristic width of the cantilever flexible thin plate 3 in a static state accounts for 20% to 80% of the width of the mixing channel 13. The characteristic width refers to the unfolded size of the thin plate in the direction perpendicular to the axis of the mixing channel 13 (i.e., the transverse direction of the channel), and this parameter directly determines the coverage ratio of the thin plate on the cross-sectional flow of the mixing channel 13.

[0044] During implementation, the central axis of the cantilever flexible thin plate 3 coincides with the central axis of the mixed flow channel 13, placing the thin plate in the core region of the mainstream on the cross-section of the mixed flow channel 13. By controlling the ratio of the thin plate width to the channel width, the local flow area, the mainstream flow pattern, and the shear distribution on both sides of the thin plate can be changed: when the width ratio is small (close to 20%), the thin plate has a small obstruction area and a weak excitation force, but the bending mode frequency of the thin plate is relatively high in this state, and the liquid can form a more obvious bypass flow on both sides of the thin plate, which is suitable for high flow rate and low viscosity systems; when the width ratio increases (close to 80%), the coupling effect between the mainstream and the thin plate is enhanced, the thin plate almost covers the entire channel cross-section, the excitation force increases significantly, and the amplitude also increases, which is more conducive to forming large-amplitude disturbances, suitable for maintaining effective turbulent mixing in low flow rate or high viscosity solutions.

[0045] It is important to note that the upper limit of the characteristic width must be controlled within 80%. This is because sufficient liquid flow clearance needs to be maintained on both sides of the thin plate during vibration to maintain continuous liquid flow without local blockage. If the characteristic width exceeds 80%, the liquid channels on both sides of the thin plate become too narrow, and the flow resistance increases sharply. This not only leads to an uncontrollable increase in operating pressure drop, but may also disrupt the stability of self-excited vibration, resulting in vibration interruption or irregular jumps.

[0046] In this embodiment, by proportionally designing the width of the cantilever flexible thin plate 3, the vibration response can be adjusted for different flow velocities and different viscosity systems, so that the device can maintain effective mixing capacity in a wide range of operating conditions; at the same time, the thin plate is located in the central region of the flow channel, which is conducive to making the disturbance effect cover the entire mixing cross section.

[0047] In the above embodiments, preferably, the characteristic height of the cantilever flexible plate 3 in a static state accounts for 40% to 60% of the height of the mixed flow channel 13. This characteristic height refers to the dimension of the plate in the depth direction (i.e., the direction perpendicular to the bottom surface of the flow channel) of the mixed flow channel 13, and can be used as one of the adjustment parameters for the stiffness and fluid coupling characteristics of the cantilever flexible plate 3. Together with its length and width, it determines the vibration frequency, amplitude, and instability threshold of the plate under the impact of the liquid flow. By selecting a suitable characteristic height within the above-mentioned proportion range, the plate can have both sufficient flexibility to respond to the liquid flow and sufficient structural stability to avoid excessive adhesion to the wall, permanent deformation, or vibration attenuation during operation.

[0048] Specifically, when the plate height is approximately 50% of the channel height, the plate forms a significant asymmetric flow obstruction region on the channel cross-section. One side of the plate is a low-velocity region shielded by the plate, while the other side (and below the plate) is a free-flowing high-velocity region. This cross-sectional asymmetry is crucial for triggering flow-induced vibration. When the plate initially deflects slightly, the pressure difference across the plate further drives the deflection, creating positive feedback and ultimately triggering flutter instability and continuous self-excited vibration. If the plate height is too small (below 40%), the obstruction effect on the cross-section is insufficient, and the flow field around it remains approximately axisymmetric, making it difficult to generate an effective deflection driving force. If the plate height is too large (above 60%), the plate's blockage of the channel cross-section is excessive. Although the amplitude of the plate vibration is large, the channel resistance increases dramatically. Furthermore, when the plate vibrates to its limit, it may collide with the bottom plate or sidewall, damaging the plate and generating uncontrollable pressure pulses that cause shear damage to the downstream LNP particle structure.

[0049] In this embodiment, by controlling the characteristic height of the cantilever flexible plate 3 within the range of 40% to 60%, the dynamic characteristics of the cantilever structure can be further optimized, making it easier to form continuous and controllable flow-induced vibrations in the mixing channel 13, thereby improving the stability and repeatability of the mixing process.

[0050] like Figures 10 to 12 As shown, in the above embodiment, preferably, the cantilever flexible thin plate 3 is provided with a turbulence microstructure. The turbulence microstructure is at least one of fish scale protrusions, wave-like undulations or through holes. Due to their unique geometric shape, each type of microstructure can generate an additional secondary turbulence effect when the thin plate vibrates, further enhancing the mixing process.

[0051] Among them, such as Figure 10 As shown, the fish-scale protrusion structure refers to the micro-arc protrusions arranged on the surface of the thin plate in a manner resembling fish scales, with a periodic scale distribution. When the cantilever flexible thin plate 3 adopts the fish-scale protrusion structure, during the plate's flapping process, the protrusions generate alternating shedding of local separation vortices and attachment vortices, which can form a stronger local boundary layer disruption effect near the plate surface, significantly increasing the three-dimensional complexity of the flow field. This generates a large number of smaller vortex structures in the near-wall region of the thin plate, which helps to further break up the interface between the two phases of the liquid and accelerate the microscale mixing of the components.

[0052] like Figure 11 As shown, the wavy undulation structure refers to a thin plate surface with a periodic sinusoidal curved profile along its width or length, giving the thin plate an overall spatial curved surface shape. When a wavy undulation structure is used, the thin plate can generate more complex disturbance forms during vibration, including coupled modes of bending and torsion, which can induce more complex three-dimensional flow separation and backflow. This generates disturbances simultaneously in all directions of the mixing channel 13, significantly enhancing the three-dimensional mixing degree of the flow field, thereby more effectively promoting the contact and mixing between solutions and further improving the overall mixing efficiency.

[0053] like Figure 12 As shown, a through-hole structure refers to the creation of several adjustable-shape and-size perforated holes in the thin plate body as required. When using a through-hole structure, in addition to the vibration and disturbance of the liquid on both sides of the thin plate, local penetration and exchange can also occur through the through-holes, forming an additional microjets effect. This enhances mass transfer between different flow layers and significantly increases the contact probability between the two phases of the liquid. The number, size, shape, and arrangement of the through-holes can be adjusted according to the viscosity of the liquid being processed, the target particle size, and the allowable pressure drop.

[0054] In this embodiment, after further introducing turbulent microstructures on the surface or inside the cantilever flexible thin plate 3, the dimension of flow field disturbance is expanded from simple overall flapping to a composite mixing mechanism of overall vibration, local micro-disturbance and local commutation, which can further enhance the renewal speed of the liquid interface and improve the solution mixing efficiency, especially beneficial for rapid and uniform mixing under low Reynolds number conditions.

[0055] like Figure 13As shown, in the above embodiment, preferably, the cantilever flexible thin plate 3 is detachably connected to the reactor upper cover plate 2 via the cantilever column 21. The upper part of the cantilever column 21 is mechanically fitted with the reactor cover plate 2 (such as an interference fit or threaded connection), and the connection is sealed to prevent liquid from leaking to the outside of the reactor along the fit gap. The middle part of the cantilever column 21 is provided with a through structure for the cantilever flexible thin plate 3 to pass through and be fixed. In specific implementation, a through rectangular flow channel structure can be formed on the cantilever column 21. After the cantilever flexible thin plate 3 passes through the through structure, it is held by the limiting part at the bottom of the cantilever column 21. Thus, the rigid frame of the column maintains the stable assembly and fixation of the fixed end during vibration, avoiding the thin plate from drifting at the fixed end in a strong flow field.

[0056] The characteristic height of the cantilever column 21 accounts for 40% to 80% of the width of the mixed flow channel 13. This ensures that it provides sufficient installation support without excessively encroaching on the main flow section, achieving a balance between ensuring mechanical reliability and preserving sufficient vibration space. When the column height is less than 40%, the constraint section of the column at the fixed end is too short, and the bending moment reaction force at the fixed end of the thin plate under strong flow field may cause loosening of the fit. When the column height exceeds 80%, the column itself will occupy too much of the cross-sectional space of the mixed flow channel 13, reducing the effective flow area and increasing the flow resistance.

[0057] like Figure 14 As shown, in one embodiment, the reactor bottom plate 1 consists of two parts: a cantilever column 21 and a flexible sheet. A "door" shape is cut out on one side of the flexible sheet to connect with the cantilever column 21. The upper part of the cantilever column 21 is mechanically fitted to the reactor top cover plate 2, and the connection is sealed. A through rectangular flow channel is provided in the upper part of the cantilever column 21 for the flexible sheet to pass through, and part of the lower part is removed to hold the flexible sheet in place. When the two are connected, the upper parts of the cantilever column 21 and the upper part of the flexible sheet are inserted into the reactor top cover plate 2, preventing the flexible sheet from falling off. Specific dimensions can be changed according to actual needs. The cantilever column 21 is made of a rigid material such as acrylic, and the flexible sheet is made of a material resistant to organic solvents and acids / alkalis, such as PDMS or PEEK.

[0058] like Figure 15 As shown, in another embodiment, the cantilever flexible plate 3 is a one-piece molded structure, made of materials resistant to organic solvents and acids / alkalis, such as PDMS or PEEK. The upper part of the cantilever flexible plate 3 is mechanically fitted with the reactor upper cover plate 2, and the lower part is interference-fitted with the reactor lower bottom plate 1. The connection can be sealed with UV-cured adhesive. The flexible plate is located in the mixing channel 13. The specific dimensions can be changed according to actual needs.

[0059] like Figure 16As shown, in another embodiment, the reactor bottom plate 1 is composed of two parts: a cantilever column 21 and a flexible sheet. The cantilever column 21 is made of a rigid material such as acrylic, while the flexible sheet is made of a material resistant to organic solvents and acids / alkalis, such as PDMS or PEEK. The two parts are mechanically fitted together, and the connection is secured by bonding and reinforcing structures. The upper part of the cantilever flexible sheet 3 has a clearance fit with the reactor top cover plate 2, and the lower part has a clearance fit with the reactor bottom plate 1; the connection is sealed. Specific dimensions can be modified according to actual needs.

[0060] like Figure 17 As shown, in another embodiment, the reactor bottom plate 1 is composed of two parts: a cantilever column 21 and a flexible sheet. The cantilever column 21 is made of a rigid material such as acrylic, while the flexible sheet is made of a material resistant to organic solvents and acids / alkalis, such as PDMS or PEEK. The flexible sheet is sleeve-shaped and connected to the cantilever column 21. The connection between the flexible sheet and the cantilever column 21 is mechanical. The upper part of the cantilever flexible sheet 3 is mechanically connected to the reactor top cover plate 2, and the lower part is mechanically connected to the reactor bottom plate 1, with the connection sealed. Specific dimensions can be modified according to actual needs.

[0061] In this embodiment, by setting a detachable cantilever column 21 and a through-fixed structure, the core mixing unit is transformed from a non-detachable fixed structure into a modular structure, which is beneficial for the replacement, maintenance and parameter tuning of the cantilever flexible thin plate 3. At the same time, the column height is controlled within a limited proportional range, which can take into account the assembly reliability, sealing performance and flow capacity of the mixing channel 13, providing a clearer implementation path for parallel amplification and engineering applications.

[0062] In the above embodiments, preferably, the material of the cantilever flexible sheet 3 is a polydimethylsiloxane PDMS film or a polyether ether ketone (PEEK) film. The portions of the reactor bottom plate 1 and reactor top cover plate 2 that come into contact with the feed liquid are made of polypropylene, stainless steel or polyetheretherketone (PEEK).

[0063] PDMS is an organosilicon material with excellent elasticity and biocompatibility. Its Young's modulus can be in the MPa range, exhibiting excellent flexibility at the micrometer to millimeter scale. It readily vibrates at low flow rates, making it suitable for nucleic acid-lipid systems highly sensitive to shear forces. PDMS also shows good tolerance to ethanol solutions and aqueous buffer solutions, meeting the solvent environment requirements of LNP synthesis processes. PEEK films, on the other hand, possess higher stiffness (its Young's modulus can be in the GPa range), making them more suitable for high-flow-rate or high-viscosity solution systems, or applications requiring high vibration frequencies for thin plates. PEEK also exhibits excellent chemical resistance, withstanding long-term immersion in acidic and alkaline solutions and organic solvents, and can be reused after cleaning.

[0064] When PDMS or PEEK is used as the material for the cantilever flexible sheet 3, it can meet the requirements of elastic vibration of the sheet under the action of liquid flow, and can also take into account the tolerance to ethanol phase, buffer solution and cleaning medium. When polypropylene, stainless steel or PEEK is used as the material for the liquid-wetting parts, the material can be selected by combining processing accuracy, cost control and chemical stability. Among them, PEEK has good acid and alkali resistance, organic solvent resistance and cleaning adaptability.

[0065] In this embodiment, by using a combination of materials resistant to organic solvents and acids and alkalis for the cantilever flexible thin plate 3 and the liquid-contacting structure, the long-term operational stability of the device under the combined action of lipid ethanol phase and aqueous buffer can be improved, the risk of material swelling, corrosion or precipitation can be reduced, and it is conducive to the implementation of clean, reusable or disposable application schemes for the device.

[0066] The present invention also proposes the application of the flow-induced vibration microfluidic reactor according to any of the above embodiments in the preparation of lipid nanoparticles, comprising: using a lipid ethanol phase solution and an aqueous buffer solution containing active ingredients as the first liquid and the second liquid, respectively, and pumping them into the microfluidic reactor through the first inlet 11 and the second inlet 17, respectively.

[0067] The lipid ethanol phase solution is used as the first liquid, which typically contains ionizable lipids (such as SM-10), auxiliary lipids (such as DSPC), cholesterol, and PEGylated lipids (such as DMG-PEG-k) dissolved in ethanol at a specified molar ratio. The aqueous buffer containing active ingredients (such as messenger RNA (mRNA), small interfering RNA (siRNA), plasmid DNA (pDNA), and other nucleic acid molecules) is used as the second liquid. By controlling the flow rates of the two phases and the cantilever vibration state inside the device, the formation process of lipid nanoparticles can be continuously regulated.

[0068] Two liquid streams are stably transported in their respective inlet channels and enter the mixed-flow channel 13 at a certain relative velocity. They converge at the inlet of the mixed-flow channel 13 and jointly impact the cantilevered flexible thin plate 3. Under the action of the fluid, the cantilevered flexible thin plate 3 generates fluid-structure interaction self-excited vibration. The continuous pulsation of the plate continuously disturbs the local flow field, allowing the lipid components to quickly contact the active ingredients and form a uniform mixing environment. This enables rapid and uniform contact between the lipid ethanol phase and the nucleic acid aqueous phase at the microscale, driving the lipid molecules to rapidly self-assemble and form a lipid bilayer membrane structure around the nucleic acid molecules. Under highly controllable nucleation and growth conditions, LNP particles with uniform particle size and high nucleic acid encapsulation efficiency are formed. The resulting particle dispersion is output through the outlet channel 14 and enters subsequent collection, purification, or filling stages.

[0069] In this embodiment, when the fluidized vibrating microfluidic reactor is applied to the preparation of lipid nanoparticles, a rapid and mild dynamic mixing environment can be formed in the mixed flow channel 13 without an external energy field. This better matches the dual requirements of LNP for rapid nucleation and low-damage mixing, which is conducive to obtaining lipid nanoparticle products with more uniform particle size, higher encapsulation efficiency, and better stability. In addition, the process has good continuity and has the basis for parallel scale-up.

[0070] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A fluid-induced vibration microchannel reactor, characterized in that, Includes a reactor bottom plate and a reactor top cover plate covering the reactor bottom plate; The reactor bottom plate is provided with a first liquid inlet, a first liquid inlet channel communicating with the first liquid inlet, a second liquid inlet, a second liquid inlet channel communicating with the second liquid inlet, a mixed flow channel, an outlet channel communicating with the mixed flow channel, and an outlet. The first liquid inlet channel and the second liquid inlet channel merge at the end and then communicate with the mixed flow channel. The mixed flow channel is provided with a cantilever flexible plate, which has a fixed end and a free end. The fixed end is fixed to the upper cover plate of the reactor, and the free end extends out of the mixed flow channel and extends in the downstream direction of the fluid. After the two fluids converge into the mixed flow channel through the first and second inlet channels, the cantilever flexible sheet undergoes fluid-structure interaction self-excited vibration under the action of liquid flow without external excitation.

2. The flow-induced vibration microchannel reactor according to claim 1, characterized in that, The reactor cover plate is provided with a first liquid inlet adapter, a second liquid inlet adapter, and a liquid outlet adapter, which are respectively connected to the first liquid inlet, the second liquid inlet, and the liquid outlet. The first liquid inlet adapter is perpendicular to the extension direction of the first liquid inlet channel, the second liquid inlet adapter is perpendicular to the extension direction of the second liquid inlet channel, and the liquid outlet adapter is perpendicular to the extension direction of the liquid outlet channel. The first liquid inlet, the second liquid inlet, and the liquid outlet have the same geometric interface.

3. The flow-induced vibration microchannel reactor according to claim 1, characterized in that, The fixed end of the cantilever flexible thin plate is fixed to the upper cover plate of the reactor by embedding.

4. The flow-induced vibration microchannel reactor according to claim 3, characterized in that, The characteristic length of the cantilever flexible thin plate in a static state accounts for 20% to 60% of the length of the mixed flow channel.

5. The fluid-induced vibration microchannel reactor according to claim 4, characterized in that, The characteristic width of the cantilever flexible thin plate in a static state accounts for 20% to 80% of the width of the mixed flow channel.

6. The flow-induced vibration microchannel reactor according to claim 5, characterized in that, The characteristic height of the cantilever flexible sheet in a static state accounts for 40% to 60% of the height of the mixed flow channel.

7. The flow-induced vibration microchannel reactor according to claim 1, characterized in that, The cantilever flexible sheet has a flow-disrupting microstructure, which is at least one of fish-scale protrusions, wave-like undulations, or through holes.

8. The flow-induced vibration microchannel reactor according to claim 1, characterized in that, The cantilever flexible sheet is detachably connected to the reactor top cover via a cantilever column. The upper part of the cantilever column is mechanically engaged with the upper cover plate of the reactor, and the connection part is sealed. The middle part of the cantilever column is provided with a through structure for the cantilever flexible thin plate to pass through and be fixed. The characteristic height of the cantilever column accounts for 40% to 80% of the width of the mixed flow channel.

9. The flow-induced vibration microchannel reactor according to claim 1, characterized in that, The cantilever flexible sheet is made of polydimethylsiloxane film or polyetheretherketone film. The portions of the reactor bottom plate and the reactor top cover plate that come into contact with the feed liquid are made of polypropylene, stainless steel, or polyetheretherketone.

10. The application of the fluidized vibration microchannel reactor according to any one of claims 1 to 9 in the preparation of lipid nanoparticles, characterized in that, include: A lipid ethanol phase solution and an aqueous buffer solution containing active ingredients are used as the first liquid and the second liquid, respectively. They are pumped into a microfluidic reactor through the first inlet and the second inlet, respectively. The two-phase solutions are mixed in the mixed flow channel by the self-excited vibration of the cantilever flexible thin plate through fluid-structure coupling, which is used for the continuous preparation of lipid nanoparticles.

Images